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Archive for the ‘Neuroscience’ Category

the brain is so very awesome…

In Brain imaging, Brain studies, Neurogenesis, Neuropsychology, Neuroscience on Thursday, 17 April 2014 at 15:39

http://www.nature.com/ncomms/2014/140411/ncomms4687/full/ncomms4687.html

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Phillip Seymour Hoffman did not have choice or free will and neither do you.

In ADHD, Anxiety, Brain imaging, Brain studies, Child/Adolescent Psychology, General Psychology, Medicine, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry on Tuesday, 11 March 2014 at 12:37

one of the best things about this subject that i’ve read in a long time.  give it a read. it makes you think.

Phillip Seymour Hoffman did not have choice or free will and neither do you..

Insomnia and Heart Failure Risk: Something to Lose Sleep Over?

In Neuropsychology, Neuroscience, Psychiatry on Tuesday, 21 May 2013 at 06:55

Insomnia and Heart Failure Risk: Something to Lose Sleep Over?

By: Shelley Wood

Clinical Context

Insomnia can lead to activation of the neuroendocrine system, which in turn may promote a higher risk for cardiovascular disease. The authors of the current study previously used the same study cohort to evaluate the risk for acute myocardial infarction (AMI) associated with insomnia. Their results, which were published in the November 8, 2011, issue of Circulation, demonstrated that mild, intermittent sleep problems were not associated with a higher risk for AMI. However, insomnia almost every night and nonrestorative sleep experienced more than once per week were associated with increases in the risk for AMI of more than 40%.

The current study by Laugsand and colleagues examines whether insomnia can affect the risk for incident heart failure.

Study Synopsis and Perspective

Insomnia symptoms in middle age are strongly associated with the subsequent development of heart failure, a large Norwegian cohort study has found[1]. The analysis, which considered over 54 000 men and women, linked insomnia symptoms and heart failure, even in subjects who had never experienced a coronary event.

While the study does not demonstrate causation, researchers led by Dr Lars E Laugsand (Norwegian University of Science and Technology, Trondheim) say their findings have important implications for patient management and, potentially, reducing progression to heart failure.

“If subsequent studies confirm our findings and if causality is better established, the observed prospective association between insomnia and HF [heart failure] risk could have implications for cardiovascular prevention, since insomnia is an easily recognizable and potentially manageable condition,” the authors write.

Speaking with heartwire , Laugsand stressed that the findings do not have immediate implications for physicians, beyond the fact that sleep is important to good health generally.

“I think cardiologists should talk to their patients about sleep problems, but I think it’s a little too early to say that anything should be implemented in the CV [cardiovascular] risk assessment,” he said. “More research is clearly needed to evaluate the possible underlying mechanisms.”

For example, he continued, the chronic activation of stress responses seen in insomnia could be expected to have an impact on the heart. “Patients who are stressed both at night and during the day have increased BP [blood pressure], increased release of stress hormones, increased heart rate, etc, and all of these factors are related to HF, so that’s a potential link between the neuroendocrine system and the sympathetic nervous system. We cannot say this is the case from our study,” but it’s a plausible link, he said.

Community-Based Analysis

Laugsand et al reviewed baseline data relating to insomnia symptoms from the Nord-Trøndelag Health Study on the 54 279 patients enrolled between 1995 and 1997, none of whom had HF at the study outset. By 2008, 1412 patients had developed heart failure.

In a range of analyses that took into account different factors, such as age, cardiovascular disease risk factors, or psychological factors, insomnia symptoms remained strongly correlated with new-onset heart failure, with more symptoms linked with higher risk. For example, subjects who reported having “difficulty initiating sleep” on “almost every night” had a 27% to 66% risk of developing heart failure (depending on the model used), compared with subjects with no insomnia symptoms. By contrast, patients who reported “difficulty initiating sleep” on a frequent basis, in addition to “difficulty maintaining sleep” and feeling that their sleep was “nonrestorative,” had a risk of heart failure that ranged from two to five times higher than in subjects with no insomnia symptoms.

Women were at an increased risk of having heart failure in relation to certain insomnia risk factors and for cumulative measures of insomnia, compared with men, but Laugsand was reluctant to make much of this observation. “You cannot say from these numbers that insomnia is more dangerous for women than men when it comes to having heart failure,” he said. They have a higher relative risk, but that might be due to their lower baseline risk of HF.”

The next step, said Laugsand, would be a trial treating patients for insomnia to see whether such a strategy could mitigate the development of heart failure.

“That would be the ultimate goal, to do a randomized controlled trial. This study is an observational study and saying anything too firm about causality is difficult,” he cautioned. “But from the studies done in insomnia and other sleep problems, we know that sleep problems affect the physiology of the heart.”

References

  1. Laugsand LE, Strand LB, Platou, et al. Insomnia and the risk of incident heart failure: A population study. Eur Heart J 2013; DOI: 10.1093/eurheartj/eht019. Available at: http://eurheartj.oxfordjournals.org.

Study Highlights

  • Study data were derived from the Nord-Trøndelag cohort, which reflects the general population of Norway. Study recruitment began in 1995. The current study focused on individuals between 20 and 89 years old without a history of heart failure.
  • Participants completed a thorough examination at the outset of the study, including questions regarding insomnia and the use of hypnotic medications. The insomnia history focused on difficulty falling asleep (early insomnia), waking during sleep (middle insomnia), and nonrestorative sleep. A laboratory assessment was also part of the initial examination.
  • The main study outcome was incident heart failure, which was identified from hospital diagnoses and national death registers.
  • The study analyzed the risk for heart failure associated with insomnia, and researchers adjusted their analyses to account for demographic data and traditional cardiovascular risk factors. Researchers also performed an analysis that accounted for patients’ other chronic diseases.
  • 54,279 participants provided study data. The rates of severe insomnia in the study cohort varied between 2.5% and 8.1%, depending on which domain of insomnia was being queried.
  • Older adults and women were more likely to have insomnia. Insomnia was closely related to depression, anxiety, and the presence of cardiovascular risk factors.
  • During a mean evaluation period of 11.3 years, there were 1412 incident cases of heart failure. 408 of these cases were reported from the death registry.
  • In fully adjusted analyses, including psychiatric diagnoses, the presence of early insomnia, middle insomnia, or nonrestorative sleep individually did not significantly increase the risk for heart failure, even when these symptoms were severe.
  • However, there was a dose-dependent positive effect on the risk for heart failure with a greater number of insomnia symptoms. The presence of 1 insomnia symptom was associated with a hazard ratio (HR) for heart failure of 0.96 (95% [confidence interval] CI, 0.57 – 1.61). Having 2 or 3 of these symptoms was associated with respective HRs of 1.35 (95% CI, 0.72 – 2.50) and 4.53 (95% CI, 1.99 – 10.31).
  • The presence of nonrestorative sleep was associated with a higher risk for incident heart failure among women vs men.
  • Exclusion of cases of heart failure diagnosed early during follow-up failed to significantly alter the main study outcome.

Clinical Implications

  • A previous study of the current cohort of adults found that severe, but not mild, insomnia was independently associated with a higher risk for AMI.
  • In the current study by Laugsand and colleagues, only the presence of multiple insomnia symptoms was significantly associated with a higher risk for incident heart failure.

Retrieved from: http://www.medscape.org/viewarticle/781692

increase in adhd diagnoses…

In ADHD, ADHD Adult, ADHD child/adolescent, Neuropsychology, Neuroscience, School Psychology, Special Education on Tuesday, 12 March 2013 at 11:59

is this because of increased awareness, greater recognition of adhd, better diagnostics and screening, etc. or is it because of the heightened demands put upon all of us in today’s society?  i do believe adhd is a very real diagnosis and can have deleterious effects on the brain if left untreated.  what i can tell you i do see in my work as a school psychologist is some children with a true disability and some very savvy parents (or kids, in some instances) who know that a stimulant will help them meet any increased demands and are able to “get” an adhd diagnosis by going to certain doctors or knowing what to say and what “symptoms” to report.  a comprehensive adhd diagnosis is not an easy one to make and takes way more than a ten-minute session with a pediatrician.  this is one of the reasons i am such a proponent of  the advancements in genome wide association studies, neuroanatomy, neurobiology, etc. that can effectively show differences between a brain with adhd and a brain without adhd, thus, one day hopefully being able to diagnose with more than parent and self-report and some testing.  and, with the large population of untreated adhd or late-diagnosed adhd (so, no treatment until adulthood), we are able to see the effects of no treatment, then getting proper treatment.  

i am a fan of a new book on adhd by cecil reynolds, et al.  it is a comprehensive look at adhd by one of the foremost neuropsychologists today.  http://www.amazon.com/Energetic-Brain-Understanding-Managing-ADHD/dp/0470615168 

there’s my two-cents.  here is the article:

Study Suggests Increased Rate of Diagnosis of Attention-Deficit/Hyperactivity Disorder at Health Plan

EMBARGOED FOR RELEASE: 3 P.M. (CT), MONDAY, JANUARY 21, 2013

Media Advisory: To contact study author Darios Getahun, M.D., Ph.D., call Sandra Hernandez-Millett at 626-405-5384 or email sandra.d.hernandez-millett@kp.org or call Vincent Staupe at 415-318-4386 or email vstaupe@golinharris.com.


CHICAGO – A study of medical records at the Kaiser Permanente Southern California health plan suggests the rate of attention-deficit/hyperactivity disorder (ADHD) diagnosis increased from 2001 to 2010, according to a report published Online First by JAMA Pediatrics, a JAMA Network publication.

ADHD is one of the most common chronic childhood psychiatric disorders, affecting 4 percent to 12 percent of all school-aged children and persisting into adolescence and adulthood in about 66 percent to 85 percent of affected children. The origin of ADHD is not fully understood, but some emerging evidence suggests that both genetic and environmental factors play important roles, the authors write in the study background.

Darios Getahun, M.D., Ph.D., of the Kaiser Permanente Southern California Medical Group, Pasadena, Calif., and colleagues used patient medical records to examine trends in the diagnosis of ADHD in all children who received care at Kaiser Permanente Southern California (KPSC) from January 2001 through December 2010. Of the 842,830 children cared for during that time, 39,200 (4.9 percent) had a diagnosis of ADHD.

“The findings suggest that the rate of ADHD diagnosis among children in the health plan notably has increased over time. We observed disproportionately high ADHD diagnosis rates among white children and notable increases among black girls,” according to the study.

The rates of ADHD diagnosis were 2.5 percent in 2001 and 3.1 percent in 2010, a relative increase of 24 percent. From 2001 to 2010, the rate increased among whites (4.7 percent to 5.6 percent); blacks (2.6 percent to 4.1 percent); and Hispanics (1.7 percent to 2.5 percent). Rates for Asian/Pacific Islanders remained unchanged over time, according to study results.

Boys also were more likely to be diagnosed with ADHD than girls, but the study results suggest that the sex gap for black children may be closing over time. Children who live in high-income households ($70,000 or more) also were at an increased risk of diagnosis, according to the results.

(JAMA Intern Med. Published online January 21, 2013. doi:10.1001/2013.jamapediatrics.401. Available pre-embargo to the media at http://media.jamanetwork.com.)

Retrieved from: http://media.jamanetwork.com/news-item/study-suggests-increased-rate-of-diagnosis-of-attention-deficithyperactivity-disorder-at-health-plan/

genes, genes…

In ADHD, ADHD Adult, ADHD child/adolescent, Autism Spectrum Disorders, General Psychology, Genes, Neuropsychology, Neuroscience, Personality Disorders, Psychiatry on Friday, 1 March 2013 at 06:15

i love gwas and really feel it will continue to broaden our understanding of psychiatric illnesses and, hopefully, lead to better treatment options.

Five Major Psychiatric Disorders Genetically Linked

By: Caroline Cassels

In the largest genetic study of psychiatric illness to date, scientists have discovered genetic links between 5 major psychiatric disorders.

Investigators from the Cross-Disorder Group of the Psychiatric Genomics Consortium have found that autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share common genetic risk factors.

Specifically, the results of the genome-wide association study (GWAS) reveal single-nucleotide polymorphisms (SNPs) in 2 genes —CACNA1C and CACNB2 — both of which are involved in the balance of calcium in brain cells, are implicated in several of these disorders, and could provide a potential target for new treatments.

“This analysis provides the first genome-wide evidence that individual and aggregate molecular genetic risk factors are shared between 5 childhood-onset or adult-onset psychiatric disorders that are treated as distinct categories in clinical practice,” study investigator Jordan Smoller, MD, Massachusetts General Hospital, Boston, said in a release.

The study was published online February 28 in the Lancet.

Potential Therapeutic Target

The researchers note that findings from family and twin studies suggest that genetic risks for psychiatric disorders do not always map to current diagnostic categories and that “doubt remains about the boundaries between the syndromes and the disorders that have overlapping foundations or different variants of one underlying disease.”

“The pathogenic mechanisms of psychiatric disorders are largely unknown, so diagnostic boundaries are difficult to define. Genetic risk factors are important in the causation of all major psychiatric disorders, and genetic strategies are widely used to assess potential overlaps,” the investigators write.

The aim of the study was to identify specific variants underlying genetic effects shared between 5 major psychiatric disorders: ASD, ADHD, BD, MDD, and schizophrenia.

The researchers analyzed genome-wide SNP data for the 5 disorders in 33,332 cases and 27,888 control participants of European ancestry. They identified 4 risk loci that have significant and overlapping links with all 5 diseases. These included regions on chromosomes 3p21 and 10q24, and SNPs in the gene CACNA1C,which has previously been linked to bipolar disorder and schizophrenia, and in theCACNB2 gene.

Polygenic risk scores confirmed cross-disorder effects, most strongly between adult-onset disorders BD and MDD and schizophrenia. Further pathway analysis corroborated that calcium channel activity could play an important role in the development of all 5 disorders.

“Significant progress has been made in understanding the genetic risk factors underlying psychiatric disorders. Our results provide new evidence that may inform a move beyond descriptive syndromes in psychiatry and towards classification based on underlying causes.

“These findings are particularly relevant in view of the imminent revision of classifications in the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases,” said Dr. Smoller.

The investigators add that the study results “implicate a specific biological pathway — voltage-gated calcium-channel signalling — as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease.”

In an accompanying editorial, Alessandro Serretti, MD, PhD, and Chiara Fabbri, MD, from the University of Bologna, Italy, assert that “the main innovative contribution of the present study is the combination of qualitative and quantitative analyses of the shared genetic features associated with vulnerability of these 5 disorders.”

They add, “the present study might contribute to future nosographic systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments.”

The authors and editorialists have reported no relevant financial relationships.

Retrieved from: http://www.medscape.com/viewarticle/779979?src=nl_topic

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

Background

Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

Methods

We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.

Findings

SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.

Interpretation

Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

Funding-National Institute of Mental Health.

Retrieved from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62129-1/abstract

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Cross-Disorder Group of the Psychiatric Genomics Consortium
The Lancet – 28 February 2013
DOI: 10.1016/S0140-6736(12)62129-1

what causes depression? a possible answer.

In Genes, Genomic Medicine, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Thursday, 21 February 2013 at 06:54

Potential Cause of Depression Identified

By: Meagan Brooks

A protein involved in synaptic structure has been identified as a potential cause of depression, a finding that according to researchers has “enormous therapeutic potential for the development of biomarkers and novel therapeutic agents.”

Investigators at the Mount Sinai School of Medicine in New York City found decreased expression of Rac1 in the postmortem brains of people with major depressive disorder (MDD) and in mice subjected to chronic stress. They were able to control the depressive response in mice by manipulating the expression of Rac1.

“Our study is among only a few in depression research in which 2 independent human cohorts and animal models validate each other. Rac1 has enormous therapeutic potential, and I look forward to investigating it further,” study investigator Scott

Looking for Drug Targets

Rac1 is a small Rho GTPase protein involved in modulating synaptic structure.

“There is a hypothesis that depression and stress disorders are caused by a restructuring of brain circuitry,” Dr. Russo explained in an interview with Medscape Medical News.

The scientists subjected mice to repeated bouts of social stress and then evaluated the animals for changes in gene expression in the nucleus accumbens (NAc), the brain’s reward center.

The researchers found that expression of Rac1 was significantly downregulated in the brains of mice for at least 35 days following the end of the chronic social stressor. Rac1 was not affected by only a single episode of stress, indicating that only prolonged stressors that induce depression are capable of downregulating Rac1.

The scientists note that chronic stress in the mice caused epigenetic changes in chromatin that led to Rac1 downregulation.

They were able to control the depressive response to chronic stress to some extent by chronic antidepressant treatment. Histone deacetylase (HDAC) inhibitors were “extremely effective in both normalizing the reduction in Rac1 and also promoting antidepressant responses,” Dr. Russo told Medscape Medical News.

“What we think is happening is that chronic stress leads to a lasting change in the ability of our genes to transcribe this RAC1 gene, and if you target the epigenome, you can reverse that loss of Rac1 and promote synapses and more normal healthy responses,” he said.

As in the mice, Rac1 expression was also strongly downregulated in the NAc in postmortem brains of patients with MDD, who displayed similar epigenetic changes. In most of the individuals with MDD who were taking antidepressants at the time of death, Rac1 expression was not restored to the levels seen in control participants, “suggesting a need for more direct RAC1-targeting strategies to achieve therapeutic effects,” the authors write.

“Currently, there aren’t any approved drugs or even experimental drugs that target Rac1 that are safe and effective,” Dr. Russo said. “It would be nice if we could team up with some chemists or pharma and figure out if there are some safe and effective Rac activators.”

However, there are caveats to that, he said.

“It might be difficult to target Rac specifically, because it is involved in cell proliferation and restructuring so it may be difficult to get a compound that doesn’t cause cancer. It might be better to screen for targets that more generally regulate synaptic plasticity. Ketamine is a drug that does this, and there is huge interest in ketamine” in depression, Dr. Russo said.

Experts Weigh In

Commenting on the findings for Medscape Medical News, David Dietz, PhD, assistant professor of pharmacology and toxicology, State University of New York at Buffalo, who was not involved in the research, said the study “is exquisitely well done. The researchers did an excellent job of translating their findings in the rodent model to the human condition.”

Maria V. Tejada-Simon, PhD, who also was not involved in this research but who has studied Rac1, noted that her group has been “highlighting the importance of Rac1 in the brain in general, and in psychiatric diseases in particular, for a while now. Therefore, I am not surprised that Rac1 has been found to be also associated to stress disorders and depression.”

“Mood disorders have been linked to changes in synaptic structure, and it is certain that small GTPases such as Rac1 have a tremendous role as modulators of these processes. However, we need to understand that alterations in Rac1 signaling are not likely to be the primary defect in mood disorders.

“Thus, targeting Rac1 to moderate clinical symptoms (while there is potential for a translational approach there) has to be done very carefully, given the broad role of Rac1 in many cellular functions involving the actin cytoskeleton,” said Dr. Tejada-Simon, assistant professor of pharmacology and adjunct assistant professor of biology and psychology at University of Houston College of Pharmacy in Texas.

“The highlight of this research is in identifying a possible mechanism by which we can study pathways that are involved in remodeling of the brain; we might be able to find something a little bit more specific down the line,” Dr. Dietz said.

He noted that Rac1 has also been linked to addiction.

“It’s well known that there is comorbidity between depression and addiction, that one may lead to the other, so there seems to be something fundamentally related between Rac1 and these 2 psychiatric disease states.”

The research was supported by the National Institute of Mental Health and the Johnson and Johnson International Mental Health Research Organization Rising Star Award (presented to Dr. Russo). The other authors, Dr. Tejada-Simon, and Dr. Dietz have disclosed no relevant financial relationships.

Nat Med. Published online February 17, 2013. Abstract

Retrieved from: http://www.medscape.com/viewarticle/779544?src=nl_topic

Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression

Sam A Golden, Daniel J Christoffel, Mitra Heshmati, Georgia E Hodes, Jane Magida,Keithara Davis, Michael E Cahill, Caroline Dias, Efrain Ribeiro, Jessica L Ables, Pamela J Kennedy, Alfred J Robison, Javier Gonzalez-Maeso, Rachael L Neve, Gustavo Turecki, Subroto Ghose, Carol A TammingaScott J Russo

Nature Medicine(2013) doi:10.1038/nm.3090; Received 11 October 2012.  Accepted 14 January 2013.  Published online 17 February 2013.

Abstract:

Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase–related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat–induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.

Retrieved from: http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3090.html

the future of neuropsychology…

In Neuropsychology, Neuroscience on Saturday, 26 January 2013 at 07:14

to read or not to read…

In Education, Neuropsychology, Neuroscience, School Psychology on Saturday, 19 January 2013 at 09:25

reading is fundamental!

http://www.telegraph.co.uk/science/science-news/9797617/Shakespeare-and-Wordsworth-boost-the-brain-new-research-reveals.html

things that dumb you down…

In Brain studies, Neuroscience on Saturday, 24 November 2012 at 06:21

http://health.yahoo.net/articles/mens-health/photos/5-things-make-you-dumb#0

and another one:

http://www.popsci.com/science/article/2012-11/are-people-getting-dumber-one-geneticist-thinks-so

computerized neuropsychological assessment…

In Brain imaging, Brain studies, Neuropsychology, Neuroscience on Friday, 23 November 2012 at 16:45

this has to be coming soon.  and i will be thrilled.  can you imagine how many opportunities for further research there will be???  yay!

 

http://www.tandfonline.com/doi/full/10.1080/13854046.2012.663001

The Mind of Oliver Sacks

In Brain studies, Neuropsychology, Neuroscience on Monday, 19 November 2012 at 12:41

The Mind of Oliver Sacks.

Optogenetics illuminates pathways of motivation through brain

In Brain imaging, Brain studies, Neuroscience on Monday, 19 November 2012 at 12:40

Optogenetics illuminates pathways of motivation through brain.

Mending the Brain Through Music

In Brain imaging, Brain studies, Neuropsychology, Neuroscience on Wednesday, 7 November 2012 at 07:45

Mending the Brain Through Music

Bret S. Stetka, MD, Concetta M. Tomaino, MA, DA, LCAT

Editor’s Note: 
From a Darwinian perspective, music is a mystery. It’s unclearwhether the human ability to appreciate a catchy melody conferred some specific evolutionary advantage or was a by-product of more general adaptations involving sound and pattern processing. But what is known is that evidence of music has been found in every documented human culture[1,2] — and that nearly all of us have at least some innate capacity to recognize and process song. The human brain houses a staggeringly complex neuronal network that can integrate rhythm, pitch, and melody into something far greater with, it turns out, significant therapeutic potential.

Research and clinical experience increasingly support music as medicine. Accessing and manipulating our musical minds can benefit numerous psychiatric, developmental, and neurologic conditions, often more effectively than traditional therapies. Dr. Concetta M. Tomaino, along with noted neurologist and author Dr. Oliver Sacks, cofounded the Institute for Music and Neurologic Function to study the effects of music on the brain and neurologic illness in particular. In light of increasing interest in music therapy and accumulating data supporting the approach, Medscape spoke with Dr. Tomaino about how the brain perceives music and the role of the Beatles in treating neurologic disease.

Introduction

Medscape: Thanks for speaking with us today, Dr. Tomaino. The Institute for Music and Neurologic Function has been integral to our understanding of how the brain processes music, and how music can be used as therapy in certain neurologic conditions. Can you give us some background on the Institute and discuss your role and work there?

Dr. Tomaino: The Institute was incorporated in 1995 to bridge the worlds of neuroscience and clinical music therapy. It grew out of the work of both myself and Dr. Oliver Sacks, with support from CenterLight Health System (formerly Beth Abraham Family of Health Services).

I’m a music therapist by training, with a master’s degree and doctorate in music therapy but also with a strong neuroscience background. Back in the 1970s, I was working in a nursing home and was amazed at how people with end-stage dementia, with little to no cognitive ability or awareness of their surroundings, could still process familiar music. I started wondering whether music could be used as a specific therapy to arouse cognition in patients with severe dementia.

When I came to Beth Abraham in 1980, Oliver Sacks was the attending neurologist and had been asking similar questions about the postencephalitic patients he wrote about in Awakenings, wondering how music and arts affected people who’d lost brain function through disease or trauma. And so we sought each other out and became good friends.

We worked together, him using music to test patients and me clinically applying music to help people recover or improve function. Both of us realized that there was something important going on here, and in the mid-1980s, we began seeking out scientists who could help us study the effects of music on brain function. In 1985, Oliver’s book The Man Who Mistook His Wife for a Hat became popular, and I was president of the American Association for Music Therapy. Our administration took notice of the attention both Oliver and I were receiving from the media and asked whether there was something they could help us do to expand upon our ideas. And so the Institute was formed as a center dedicated to studying music and brain and bridging the clinical and neuroscience communities.

Medscape: Can you speak about the origins of music therapy and how it’s been used over the years?

Dr. Tomaino: The therapeutic aspects of music have been noted in societies for thousands of years; however, interest really grew around the time of World War II, in part because the Works Progress Administration (WPA) program started bringing musicians into veterans hospitals. Doctors and nurses observed that people who seemed to be totally unresponsive would come to life when music was played. The hospital staff wanted to bring more musicians in, but training was needed to prepare them to better understand the conditions and needs of the patients. The approach gained attention, and eventually music therapy came together as a profession in the late 1940s. We now have a certification board, and the American Association for Music Therapy oversees academic and clinical training approaches.

The scope of music therapy has become very broad. It’s been studied and shown effective in psychiatric illness; developmental issues; and medical conditions, including pre- and postoperative settings. However, Dr. Sacks’ and my interests and contributions to the field have been in the area of neurologic function.

Medscape: In which neurologic conditions has music therapy shown the greatest effectiveness?

Dr. Tomaino: There are so many, but one of the most recognized areas is motor initiation in patients with neuromuscular and movement disorders, such as Parkinson disease (PD). Patients with PD often have a slowness of movement and a shuffling gait. Music, specifically highly rhythmic music, has been shown — and there’s quite a bit of supporting data here — to help them in training and coordinating their movements and gait. Music also enhances the length of their stride and improves balance.

Later in the course of PD, cognitive and short-term memory decline are common; in this case, music has been shown to be an effective mnemonic tool, a memory enhancer for remembering basic information — phone numbers, people, addresses, things like that (I’ll get to other forms of dementia in a second). My work and that of some colleagues has also shown that singing and using music to enhance voice and communication is also beneficial for people with PD.

Medscape: Is music therapy used preventatively or symptomatically to address the cognitive component of PD?

Dr. Tomaino: Ideally, it’s started early to help prevent memory decline and create new associative memories early in the disease — linking acquaintances, places, and events, for example, in order to prevent or slow future memory problems and enhance recall. Recent research is really enhancing our knowledge of neuroplasticity. Forming these associations — these new neuronal connections — appears to be neuroprotective.

Recalling Words and Memories

Medscape: Another area researched at the Institute is using music therapy to help patients with nonfluent aphasias recover speech — patients who comprehend language and know what they want to say, but just can’t find the words. How successful has this approach been?

Dr. Tomaino: These are patients who have had damage, such as a stroke, to the Broca region of the brain, in the left frontal lobe. Some do have mild cognitive impairment, but mostly they fully understand what’s being said to them — at least, that’s the case in the patients we work with.

We apply several techniques depending on the patient’s residual skills: for example, can they sing a simple song and tap their finger along with the rhythm. We cue them to sing along with familiar lyrics from memory and help prompt word retrieval by leaving pauses within the lyrics — you leave out a few lyrics in a familiar Beatles song and have the patient try to find the words without losing the beat. This helps a great deal. As the person improves, we move toward a more traditional form of melodic intonation therapy (MIT), focusing on the tone and rhythm or normal speech phrases rather than singing lyrics to songs.

Traditional MIT, developed by a team at the Boston Veterans Affairs Hospital in 1973, is being studying by such neuroscientists as Gottfried Schlaug at Harvard Medical School. A simple, 2-tone sequence — a high and a low pitch — is used to pattern the inflection of speech. It has 4 levels, beginning with humming and tapping short phrases and gradually moving toward a Sprechstimme, or a more normal rhythmic speech with little melodic change.

Patients are asked to repeat single words with the beat and tones, gradually increasing to more complex phrases, such as “Good morning, how are you today?” [Editor’s Note: Imagine each syllable alternating between 2 tones.] The repetition overlaid on the music helps reinforce the patterns of normal speech and helps patients recover words and fluency. Neuroimaging studies indicate compensatory changes in the right frontal lobe areas.

Music therapy is also used to as a psychotherapeutic application in mental illness and can help alleviate stress and anxiety. This has an impact on neurologic function as well; for example, multiple sclerosis symptoms can be exacerbated by stress. Preliminary research shows that music can be an excellent tool for self-relaxation and stress management in these patients. And one of the most fascinating areas in which music is used is dementia and amnesia.

Medscape: Dr. Sacks has written about a number of patients who, despite exhibiting severe amnesia, can remember song lyrics perfectly. What does this say about the neuronal pathways involved in musical memory vs say, declarative memory, our ability to consciously recall information? And what is the therapeutic potential here?

Dr. Tomaino: They are most likely primarily processed by separate brain systems. So a person with dementia or amnesia may not consciously recognize a familiar song, but something in their subconscious knows it’s familiar. There are feelings, emotions, or moments of history in there somewhere. And if they listen to those songs, we’re realizing that sometimes these feelings or the emotions are so strong that they trigger fleeting glimpses of pieces of memory. If we can work with those fleeting moments and build upon them, maybe stronger connections can be made and more memories experienced.

Medscape: Do the memories and recollections last once the music has stopped?

Dr. Tomaino: It depends on the patient. I’ve had a few patients with short-term memory problems in whom using music, and progressing from older memories forward, have then been able to recall recent events. In people with Alzheimer-type dementia, who have seemingly lost the ability to recall past events, music with strong emotional ties and meaning can lead to enduring remembrances and recall.

Medscape: Several case reports — including a recent documentary clip that went viral on YouTube — have demonstrated how effective music can be in helping patients with dementia open up and engage with their environment. How much of this is an actual heightened sense of awareness vs reflexive neurologic activity in response to the music?

Dr. Tomaino: It’s both, depending on the individual. Initially, it’s more reflexive and reactive. But if the musical interventions are provided on a regular basis and for longer periods — 15 minutes, 20 minutes, an hour — we find that their short-term memory and attention improve over time.

We did some studies years ago that were funded by the New York State Department of Health and engaged people with mid- to late-stage Alzheimer disease in music therapy sessions for 1 hour, 3 times a week for 10 months. We found that over time, their awareness of other people improved significantly. Some even recognized those people by name, increased their group interactions, and demonstrated improvement in memory and awareness — they once again knew when it was lunch time.

So yes, in patients with dementia, things that you think are lost forever are retrievable over time with this kind of stimulation. I believe there is now scientific evidence showing this — that when somebody’s engaged in an activity that’s meaningful, it involves regions of their frontal cortex that stimulate short term memory and attention. Then if you can hold somebody’s attention with something that’s meaningful for a long period, the very mechanisms that are breaking down in somebody with dementia are actually being enhanced and activated.

Medscape: Interesting. So, music-based therapies work via a variety of musical qualities, with aspects like rhythm, melody, and emotional familiarity having much different effects, respectively?

Dr. Tomaino: Right. There are totally different mechanisms at work here. The emotional and personal connection is important in dementia, whereas in PD, we’re looking at the person’s ability to perceive and feel the beat. In patients with PD, rhythm is so important and unique to the patient. Instead of just picking a beat and using a metronome, we experiment with different rhythms and rhythmic styles to see what the person responds best to. They have to feel the pulse in order for that pulse to drive their motor function. So when we talk about “music therapy,” we’re talking about components of music, such as rhythm, tone, melody, harmony, song — all of these qualities can be used together or individually to affect the patients with certain conditions.

Who Benefits Most?

Medscape: I’m curious about how an individual’s degree of engagement with music before therapy affects the outcome. Does a person’s musical skill or appreciation come into play? Does a classical violinist benefit most from music therapy? A music critic? A Deadhead?

Dr. Tomaino: Anybody can benefit from music therapy, but their background in music can help or hurt them. Most humans have an affinity for sound and can process it in highly complex ways. However, in certain diseases people may lose this ability, and in fact sound may get so distorted that they have a negative response to it, even if they’d loved music before their injury. This is especially evident in people with damage to the right temporal lobe: These patients often lose their perception of pitch. In fact, I think in Musicophilia, Dr. Sacks writes about a classically trained, professional musician who, after localized brain damage, is a quarter tone off in his perception of pitch.

Medscape: That’s right. And he ended up just tuning his piano up a quarter step!

Dr. Tomaino: Yes! So that’s where the music therapist really has to look at what a person is able to perceive. This patient’s perceptive problem probably wouldn’t have bothered someone who couldn’t tell the difference. With a professional musician, you can imagine that their neural connections to sound and perception are greatly enhanced.

For example, we treated a percussionist who’d had a stroke. The traditional therapy would be to work with the nonaffected side to encourage the intact side of the brain to take over function. For example, a right-handed person would be taught to perform tasks with the left hand. But because percussionists and musicians, by nature of their craft, presumably have stronger bilateral neural representation, we convinced the physical therapist to try working with the affected side of the brain and body. The person was able to regain function. By encouraging the patient to use the affected limb, we try to restore as much function as possible to this limb rather than compensate with the other side.

Medscape: We know that certain areas of the brain are highly dedicated to certain aspects of perception and information processing. The left frontal and temporal lobes are highly involved in speech recognition and production. The occipital cortex processes visual information. But music and sound perception and processing seems to involve numerous regions all over the brain. Can you speak about how the brain perceives and processes music, and how this lends itself to therapeutic applications?

Dr. Tomaino: There are some areas of the brain that are known to be involved in specific aspects of sound processing, mainly through looking at people who have lost certain abilities through certain brain lesions. As I mentioned earlier, patients with a lesion in the right temporal lobe often experience loss of pitch perception. We know that singing is dominant in the right temporal lobe; however, syntax of both speech and music is left dominant. And there are areas on both sides of the brain that inform and coordinate with each other when it comes to music, because music isn’t just one specific skill. That said, music processing is incredibly complex, and as far as I know, a complete map of the areas responsible for music and sound processing doesn’t yet exist.

This complexity is probably why music is so beneficial as a therapeutic tool. It’s processed bilaterally: in the cortex and subcortically, where it stimulates evolutionarily primitive areas of brain function, such as the cerebellum and the basal ganglia. So when a person does have a deficit, there is still some part of the brain functioning properly that is involved in music processing and can be stimulated through sound.

Another interesting aspect here is that in patients with damage to higher cortical regions — those with frontal temporal dementia (FTD) — their appreciation for music may change. Oliver wrote about a classically trained musician who didn’t care for any other types of music; after developing FTD, he starting liking rock and roll.

Functional imaging studies, such as those by Dr. Schlaug that I mentioned earlier, are really helping us understand neural plasticity as well as which areas of the brain are involved in what. You can first isolate the components of music, studying where pitch is processed, and beat, and melody. Then you can put them all together, and it becomes very complex. With functional imaging, it became possible to literally watch the brain work in real time while it listens to music.

Acting, Painting, Listening

Medscape: In reading Musicophilia, one of the things that really fascinated me was the idea that our memory for music is far more high-fidelity than it is for nonmusical creative sensory stimuli. Our recollections of visual art and narrative are often distorted or approximated; however, musical memories and dreams have been proven highly accurate in pitch, melody, mood, and rhythm. How does this distinguish music therapy from other forms of creative arts-based interventions, such as art and drama therapy?

Dr. Tomaino: I should admit that I used to be biased when I sat on the board for the creative arts therapy coalition, because I knew that music — especially the components of music, such as rhythm — could directly affect brain function rather than requiring the interpretation by the arts therapist. I think the big difference is the other arts therapies tend to work psychotherapeutically. And in fact, many music therapists work psychotherapeutically, which can be very effective.

But myself, Dr. Sacks, and a few of our colleagues became interested in the neurologic underpinnings of music and how sound itself could arouse and stimulate basic brain functioning. Whereas art and drama tend toward the emotions and personal associations — a sense of self and ego, and all those areas of psychotherapy — the specific components of music can actually affect brain function in a very measurable, functional way.

Because of this, music therapy is one of the therapies still available to people with devastating diseases, such as Alzheimer disease and neuromuscular conditions, in whom the other creative arts therapies would no longer have a therapeutic benefit. Music can bypass upper-brain processes and higher cognition, as well as stimulate some of the fundamental lower and midbrain areas.

I should say that although we don’t treat psychiatric patients at our facility, so often neurologic and psychiatric illnesses — as well as medical illnesses — are intertwined. So the psychotherapeutic component of our music-based interventions are very important to our patients too.

Medscape: How widely accessible is music therapy, and how many therapists are there in the United States?

Dr. Tomaino: There are close to 6000 music therapists in the United States. It’s not that many, when you think about how many people could benefit from it.

Medscape: Short of having access to a music therapy resource for referral, how can clinicians incorporate music therapy techniques into their practice?

Dr. Tomaino: It’s really great that something so effective is available to everyone. Although it is always important to seek out a professional music therapist first, there are therapeutic applications of music that others can make use of: for example, using personalized music to help someone with Alzheimer disease feel connected, or using rhythmic cues to help increase stride and gait in someone with PD.

And we haven’t even touched on children. Professionals who are working with children with autism-spectrum disorders should really seek out music therapy because it’s been very, very successful with this population. It can be so important in developing early language and motor skills, as well as self-identity and social skills.

I could also see a psychiatrist or social worker who’s having a hard time having a patient open up asking them to bring their favorite piece of music in; it could be an effective entry point into forming a relationship. Speech therapists who have a patient with aphasia can ask the persons to sing.

Likewise, a physical or occupational therapist can use rhythmic cues to help with motor problems. It’s amazing how little rhythm is used in rehabilitation especially in helping people with PD move more effectively. Just remember that each patient responds to different musical cues and rhythms, which requires time to navigate. I’ve talked to a few neurologists who will put on a Sousa march and expect a patient to immediately get up and walk!

Editor’s Note: The American Music Therapy Association’s Website maintains a list of music therapists in the United States, many of whom provide Skype services for remote patients.

Retrieved from: http://www.medscape.com/viewarticle/773401?src=mp

NIMH · In-sync Brain Waves Hold Memory of Objects Just Seen

In Brain imaging, Brain studies, Neuroscience, Uncategorized on Monday, 5 November 2012 at 12:47

NIMH · In-sync Brain Waves Hold Memory of Objects Just Seen.

How Your Eyes Deceive You

In Brain studies, Neuroscience on Thursday, 1 November 2012 at 07:09

How Your Eyes Deceive You

Neuroscience News

Researchers at the University of Sydney have thrown new light on the tricks the brain plays as it struggles to make sense of the visual and other sensory signals it constantly receives.

The research has implications for understanding how the brain interprets the world visually and how the brain itself works.

People rely on their eyes for most tasks – yet the information provided by our visual sensing system is often distorted, unreliable and subject to illusion.

In a just published article in Proceedings of the National Academy of Science, Dr Isabelle Mareschal and Professor Colin Clifford, from the University’s School of Psychology and The Vision Centre, report a series of groundbreaking experiments tracing the origins of the tilt illusion to the cells of the primary visual cortex. This is where the first stage of vision processing takes place before the conscious mind takes over.

“We tend to regard what we see as the real world,” said Dr Mareschal.

“In fact a lot of it is distortion, and it is occurring in the early processing of the brain, before consciousness takes over. Our work shows that the cells of the primary visual cortex create small distortions, which then pass on to the higher levels of the brain, to interpret as best it can.”

A common example of this that is often exploited by artists and designers is known as the tilt illusion where perfectly vertical lines appear tilted because they are placed on an oriented background.

“We wanted to test at what level the illusion occurs in the brain, unconscious or conscious – and also to see if the higher brain is aware of the illusions it is receiving and how it tries to correct for them,” she explains.

“The answer is that the brain seeks more contextual information from the background to try to work out the alignment of the object it is seeing.”

The team subjected volunteers to a complex test in which they indicated the orientation of a vertical line, perceived as constantly tilting from side to side, against a fuzzy background that was also changing.

“These illusions happen very fast, perhaps in milliseconds,” Dr Mareschal says. “And we found that even the higher brain cannot always correct for them, as it doesn’t in fact know they are illusions.”

This is one reason why people’s eyes sometimes mislead them when looking at objects in their visual landscape.

Normally, Dr Mareschal explains, it doesn’t matter all that much – but in the case of a person driving a car fast in traffic, an athlete performing complex acrobatic feats, a pilot landing an aircraft or other high-speed uses of sight, the illusion may be of vital importance by causing them to misinterpret the objects they ‘see’.

The brain uses context, or background, to interpret a host of other visual signals besides the orientation of objects. For example, it uses context to tell colour, motion, texture and contrast. The research will help study how the brain understands these visual cues adding to our overall understanding of brain function.

In this tilt illusion, the lines in the centre of the image appear tilted counterclockwise, but they are actually vertical. Image adapted from University of Sydney image.

The Vision Centre is funded by the Australian Research Council as the ARC Centre of Excellence in Vision Science.

Contact: Verity Leatherdale – The University of Sydney

Source: The University of Sydney press release

Image Source: Neuroscience News image adapted from press release image

Original Research: Abstract for “Dynamics of unconscious contextual effects in orientation processing” by Isabelle Mareschal and Colin W. G. Clifford in Proceedings of the National Academy of Science Published online before print April 23, 2012, doi: 10.1073/pnas.1200952109

Retrieved from: http://neurosciencenews.com/how-your-eyes-deceive-you-neuroscience-optical-illusion/

The Serotonin Hypothesis, Informed Consent and SSRI Antidepressants

In Medication, Mood Disorders, Neuropsychology, Neuroscience, Psychiatry on Wednesday, 31 October 2012 at 15:36

The Serotonin Hypothesis, Informed Consent and SSRI Antidepressants.

happy birthday, glutamate.

In Medication, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology, Uncategorized on Wednesday, 31 October 2012 at 15:20

Twenty Five Years of Glutamate in Schizophrenia

Daniel C. Javitt

Schizophr Bull. 2012;38(5):911-913. © 2012 Oxford University Press

Abstract and Introduction

Abstract

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.

Introduction

The mid-20th century was an exciting period for drug development in psychiatry. Antipsychotics were developed based on the seminal observations of Delay and Deniker and linked to D2 blockade shortly thereafter. By 1971, clozapine, the current “gold standard” treatment for schizophrenia, had already been marketed. Antidepressants were developed based on clinical observations with isoniazid (INH) in the 1950s; benzodiazepines were developed based upon GABA receptor-binding assays in the 1960s; and definitive studies demonstrating efficacy of lithium were performed by the early 1970s. Decades later, these classes of compounds continue to form the core of today’s psychopharmacological armamentarium.

In the midst of this transformational period, initial reports appeared as well for a class of novel sedative agent termed “dissociative anesthetics” exemplified by the molecules phencyclidine (PCP, “angel dust”) and ketamine. In monkeys, these compounds produced behavioral symptoms closely resembling those of schizophrenia, including behavioral withdrawal at low dose and catalepsy at high dose (figure 1). Domino and Luby[1] describe the critical steps by which he and his contemporaries verified the unique clinical effects of these compounds in man. The initial characterizations of PCP as causing a centrally mediated sensory deprivation syndrome and producing electroencephalography changes similar to those in schizophrenia were, in retrospect, particularly critical.

Figure 1.

Effect of phencyclidine (PCP) on behavior in monkey, showing dissociation at low dose (A) and catatonia at high dose (B). From Chen and Weston.12

Although the clinical effects of PCP were well documented by the early 1960s, it took another 20 years to characterize these effects at the molecular level. As described by Coyle,[2] key milestones along the way included the pharmacological identification of the PCP receptor in 1979; demonstration of electrophysiological interactions between PCP and N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the early 1980s followed shortly thereafter by pharmacological confirmation; identification of the glycine modulatory site of the NMDAR in 1987; and confirmation of the psychotomimetic effects of ketamine in the mid-1990s. Although researchers still disagree to the paths leading from NMDAR blockade to psychosis, few currently dispute the concept that NMDAR serve as the molecular target of PCP, ketamine, dizocilpine (MK-801), and a host of other clinical psychotomimetic agents.[2–4]

At their simplest, glutamatergic models predict that compounds stimulating NMDAR function should be therapeutically beneficial in schizophrenia.[2,4] Potential sites for intervention include the glycine/D-serine and redox sites of the NMDAR, as well as pathways regulating glutamate, glycine/D-serine, and glutathione synthesis/release.[4] D-Cycloserine, a partial NMDAR glycine-site agonist, may enhance learning and neural plasticity across a range of disorders, including schizophrenia.[5] In addition to providing new drug targets, glutamatergic models provide effective explanation for the hippocampal activation deficits,[6] positive and negative symptoms, distributed neurocognitive deficits, and sensory processing abnormalities[4] that are critical components of the pathophysiology of schizophrenia.

Since the original description, several variations have been developed with somewhat different treatment predictions. The term “NMDA receptor hypofunction” was originally developed to describe the vacuolization and neurodegeneration seen within specific brain regions following high-dose NMDAR antagonist administration.[7] In animal models, neurotoxic effects of PCP were reversed by numerous compounds, including benzodiazepines and α2 adrenergic agonists that ultimately proved ineffective in clinical studies. Nevertheless, this model may explain the pattern of persistent frontotemporal neurocognitive deficits observed in some ketamine abusers.[8] Subsequent hyperglutamatergic models focused on the excess glutamate release induced by NMDAR antagonists, particularly in prefrontal cortex, and prompted studies with compounds, such as lamotrigine or metabotropic glutamate receptor (mGluR) 2/3 agonists, that inhibit presynaptic glutamate release.[9] GABAergic models focus on NMDAR antagonist-induced downregulation of parvalbumin (PV) expression in interneurons and resultant local circuit level (gamma) dysfunction, and suggest use of subunit selective GABAA receptor modulators.[10]

More than 50 years after the initial characterization of PCP, and 25 years after the identification of NMDARs as the molecular target of PCP, we still do not know whether the novel pharmacology of dissociative anesthetics can be translated into effective clinical treatments. Encouraging small-scale single site studies have been published with NMDAR agonists, but have not yet been replicated in academic multicenter trials. Encouraging phase 2 results have also recently been reported by Roche with glycine transport inhibitors.[4] Nevertheless, phase 3 studies remain ongoing and results cannot be predicted. Additional beneficial effects may be observed in obsessive-compulsive disorder, substance abuse and Parkinsons disease.[4] Conversely, NMDAR antagonists, such as ketamine, may be therapeutically beneficial in treatment-resistant depression or autism, suggesting complementary pathology across a range of disorders.[11] More than anything else, 50 years of research shows that treatment development in neuropsychiatric disorders is a journey and not a destination, although fortunately one where the end now finally seems in sight.

Retrieved from: http://www.medscape.com/viewarticle/771599?src=nl_topic

References

  1. Domino EF, Luby ED. Phencyclidine/schizophrenia: one view toward the past, the other to the future Schizophr Bull. 2012.In press.
  2. Coyle JT. The NMDA receptor and schizophrenia: a brief history Schizophr Bull. 2012.In press
  3. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia Am J Psychiatry 1991 148 1301–1308
  4. Javitt DC. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull In press.
  5. Goff D. D-cycloserine: an evolving role in learning and neuroplasticity in schizophrenia.Schizophr Bull In press.
  6. Tamminga CA, Southcott S, Sacco C, Gao XM, Ghose S. Glutamate dysfunction in hippocampus: relevance of dentate gyrus and ca3 signaling.Schizophr Bull. 2012. In press
  7. Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia J Psychiatr Res.1999 33 523–533
  8. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study Addiction 2010 105 121–133
  9. Moghaddam B, Krystal JH. Capturing the angel in angel dust: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans Schizophr Bull. In press.
  10. Lewis DA, Gonzalez-Burgos G. NMDA receptor hypofunction, parvalbumin-positive neurons and cortical gamma oscillations in schizophrenia. Schizophr Bull In press.
  11. Javitt DC, Schoepp D, Kalivas PW, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011;3:102mr102.
  12. Chen GM, Weston JK. The analgesic and anesthetic effects of 1-(1-phenylcyclohexyl)-piperidine HCl in the monkey Anesth Analg. 1960 39 132–137

if you want to make lasting memories, get moving!

In Fitness/Health, Neuroscience on Tuesday, 30 October 2012 at 08:04

How Exercise Can Help You Master New Skills

By: Dr. Mercola

Just as your mind forms intellectual memories, it also forms what are known as muscle or “motor” memories.

Have you ever marveled at how well you can still ride a bike, even if you haven’t been on one in 20 years?

This is an example of motor memory at its best; while your muscles don’t actually “remember” how to ride a bike, your brain does, and sends a complex, though seemingly effortless, array of signals to your muscles instructing them how to perform the proper movements to keep you upright and pedaling.

Motor memory is obviously extremely important for everyday tasks like walking and climbing stairs, but it’s also crucial for more specialized skills – like mastering your golf swing or tennis serve.

If you’re in the process of mastering a new skill, research has revealed a novel way to “cement” that knowledge into your brain for later recollection – so you can remember how to get that “hole-in-one” the same way you remember how to ride a bike…

Exercising Right After Learning Makes Long-Term Memories Stronger

Researchers at the University of Copenhagen asked men to learn a tracking skill on a computer, which required them to use a joystick to trace a red line as it squiggled across the screen. A portion of the men exercised before learning the new task, some of the men did not exercise at all, and another group exercised just after learning the new skill.

At follow-up testing an hour later, the men performed basically the same, but as time went on, those who exercised gained a clear advantage. Those who fared the best belonged to the group who exercised just after learning the task. At testing sessions one day, and then one week, later, they traced the line more accurately and with greater agility. The group that exercised before learning the new skill also performed better than those who didn’t exercise (though not as well as the group that exercised after).

It appears, then, that if you want to help strengthen your memories, and be sure new information you’re receiving is successfully imprinted into your brain for later use and recall, a workout just after the learning may be very beneficial. The researchers concluded:1

“These findings indicate that one bout of intense exercise performed immediately before or after practicing a motor task is sufficient to improve the long-term retention of a motor skill. The positive effects of acute exercise on motor memory are maximized when exercise is performed immediately after practice, during the early stages of memory consolidation.”

Exercise Even Builds New Brain Cells

The hippocampus is a major component of your brain. It belongs to the more ancient part of your brain known as the limbic system and plays an important role in the consolidation of information from your short-term memory to long-term memory and spatial navigation. An animal study found that not only does mild exercise activate hippocampal neurons, it actually promotes their growth. In the brain, this also, in turn, helps with the creation of new brain cells.2

Another study, for instance, revealed that when mice exercised, they grew an average of 6,000 new brain cells in every cubic millimeter of tissue sampled.3 The growth occurred in the hippocampus, which, as mentioned, is considered the memory center of your brain, and the mice showed significant improvements in the ability to recall memories without any confusion.

During exercise, nerve cells in your brain also release proteins known as neurotrophic factors. One in particular, called brain-derived neurotrophic factor (BDNF), triggers numerous other chemicals that promote neural health, and has a direct benefit on cognitive functions, including memory consolidation and enhanced learning.

So while the featured study focused on exercise to benefit motor memory, research also supports its benefit for intellectual memories as well. If you want to have a memory like an elephant’s… it’s time to hit the gym. Some of the research highlights include:4

  • Among elementary school students, 40 minutes of daily exercise increased IQ by an average of nearly 4 points
  • Among 6th graders, the fittest students scored 30 percent higher than average students, and the less fit students scored 20 percent lower
  • Among older students, those who play vigorous sports have a 20 percent improvement in Math, Science, English and Social Studies
  • Fit 18-year-olds are more likely to go on to higher education and get full-time jobs
  • Students who exercise before class improved test scores 17 percent, and those who worked out for 40 minutes improved an entire letter grade

Even once you’re in the workforce, exercise can be an invaluable tool to increase your performance and productivity. Research shows an employee who exercises regularly is 15 percent more efficient than those who do not, which means a fit employee only needs to work 42.5 hours in a week to do the same work as an average employee does in 50.5

Think You Don’t Have Enough Time to Exercise?

I understand that you are busy, but if you take time out of your day to eat and sleep, it is equally important in the long term to make time to exercise (and not in lieu of sleeping, either!). If you neglect to exercise, you are literally passing up dozens of benefits to your health, the value of which simply cannot be measured. Do you want to slow down your aging process? Lower your risk of heart disease, diabetes and cancer? Relieve pain? Fight depression? Cure insomnia?

Exercise may be the answer you’ve been searching for.

As for the time element, it does take some practice to make exercise part of your routine. It’s generally said that it takes 3-4 weeks to turn an action into a habit, but some estimates put it at closer to 66 days, or just over two months. I find that it’s easiest to schedule exercise into my day the way I would any other important event or meeting. Write it down on your calendar, add it to your smartphone reminders… do whatever you need to do to set aside the time, and then stick with it.

The time you need to devote may actually be far less than you think, too, as short periods of intense exercise, such as Peak Fitness, are proving to be even better for you than longer sessions of traditional cardio. Here’s a summary of what a typical high-intensity Peak Fitness routine might look like:

  • Warm up for three minutes
  • Exercise as hard and fast as you can for 30 seconds. You should feel like you couldn’t possibly go on another few seconds
  • Recover at a slow to moderate pace for 90 seconds
  • Repeat the high intensity exercise and recovery 7 more times

As you can see, the entire workout is only 20 minutes. That really is a beautiful thing. And within those 20 minutes, 75 percent of that time is warming up, recovering or cooling down. You’re really only working out intensely for four minutes. If you have never done this, it’s hard to believe that you can actually get that much benefit from only four minutes of intense exercise, but that’s all it is. You can see a demonstration in the video below.

Since it’s so intense, you only need to do Peak Fitness two or three times a week. Then, round out your exercise program with strength training, core exercises and stretching to give your brain, and body, a wonderful, healthy boost.

Retrieved from: http://fitness.mercola.com/sites/fitness/archive/2012/10/12/exercise-improves-memory.aspx

Area of the Brain that Processes Empathy Identified

In Brain imaging, Brain studies, Neuropsychology, Neuroscience on Sunday, 28 October 2012 at 08:49

Area of the Brain that Processes Empathy Identified

ScienceDaily (Oct. 24, 2012)

An international team led by researchers at Mount Sinai School of Medicine in New York has for the first time shown that one area of the brain, called the anterior insular cortex, is the activity center of human empathy, whereas other areas of the brain are not. The study is published in the September 2012 issue of the journal Brain.

Empathy, the ability to perceive and share another person’s emotional state, has been described by philosophers and psychologists for centuries. In the past decade, however, scientists have used powerful functional MRI imaging to identify several regions in the brain that are associated with empathy for pain. This most recent study, however, firmly establishes that the anterior insular cortex is where the feeling of empathy originates.

“Now that we know the specific brain mechanisms associated with empathy, we can translate these findings into disease categories and learn why these empathic responses are deficient in neuropsychiatric illnesses, such as autism,” said Patrick R. Hof, MD, Regenstreif Professor and Vice-Chair, Department of Neuroscience at Mount Sinai, a co-author of the study. “This will help direct neuropathologic investigations aiming to define the specific abnormalities in identifiable neuronal circuits in these conditions, bringing us one step closer to developing better models and eventually preventive or protective strategies.”

Xiaosi Gu, PhD, who conducted the research in the Department of Psychiatry at Mount Sinai, worked with researchers from the United States and China, to evaluate Chinese patients, at Beijing Tiantan Hospital, who were shown color photographs of people in pain. Three patients had lesions caused by removing brain tumors in the anterior insular cortex; nine patients had lesions in other parts of the brain and 14 patients (the controls) had neurologically intact brains. The research team found that patients with damage restricted to the anterior insular cortex had deficits in explicit and implicit empathetic pain processing.

“In other words, patients with anterior insular lesions had a hard time evaluating the emotional state of people in pain and feeling empathy for them, compared to the controls and the patients with anterior cingulate cortex lesions.” said Dr. Jin Fan, corresponding author of this study and an assistant professor at the Department of Psychiatry at Mount Sinai.

According to Dr. Gu, this study provides the first evidence suggesting that the empathy deficits in patients with brain damage to the anterior insular cortex are surprisingly similar to the empathy deficits found in several psychiatric diseases, including autism spectrum disorders, borderline personality disorder, schizophrenia, and conduct disorders, suggesting potentially common neural deficits in those psychiatric populations.

“Our findings provide strong evidence that empathy is mediated in a specific area of the brain,” said Dr. Gu, who now works at University College London. “The findings have implications for a wide range of neuropsychiatric illnesses, such as autism and some forms of dementia, which are characterized by prominent deficits in higher-level social functioning.”

This study suggests that behavioral and cognitive therapies can be developed to compensate for deficits in the anterior insular cortex and its related functions such as empathy in patients. These findings can also inform future research evaluating the cellular and molecular mechanisms underlying complex social functions in the anterior insular cortex and develop possible pharmacological treatments for patients.

The study was funded by the National Institute of Health, the James S. McDonnell Foundation and a Brain and Behavior Research Foundation NARSAD young investigator award.

Retrieved from: http://www.sciencedaily.com/releases/2012/10/121024175240.htm?utm_source=twitterfeed&utm_medium=linkedin&utm_campaign=Feed%3A+sciencedaily%2Fmind_brain%2Fdisorders_and_syndromes+%28ScienceDaily%3A+Mind+%26+Brain+News+–+Disorders+and+Syndromes%29

***

 

Anterior insular cortex is necessary for empathetic pain perception

Xiaosi Gu,  Zhixian Gao, Xingchao Wang, Xun Liu,  Robert T. Knight,  Patrick R. Hof, and

Jin Fan

Summary

Empathy refers to the ability to perceive and share another person’s affective state. Much neuroimaging evidence suggests that observing others’ suffering and pain elicits activations of the anterior insular and the anterior cingulate cortices associated with subjective empathetic responses in the observer. However, these observations do not provide causal evidence for the respective roles of anterior insular and anterior cingulate cortices in empathetic pain. Therefore, whether these regions are ‘necessary’ for empathetic pain remains unknown. Herein, we examined the perception of others’ pain in patients with anterior insular cortex or anterior cingulate cortex lesions whose locations matched with the anterior insular cortex or anterior cingulate cortex clusters identified by a meta-analysis on neuroimaging studies of empathetic pain perception. Patients with focal anterior insular cortex lesions displayed decreased discrimination accuracy and prolonged reaction time when processing others’ pain explicitly and lacked a typical interference effect of empathetic pain on the performance of a pain-irrelevant task. In contrast, these deficits were not observed in patients with anterior cingulate cortex lesions. These findings reveal that only discrete anterior insular cortex lesions, but not anterior cingulate cortex lesions, result in deficits in explicit and implicit pain perception, supporting a critical role of anterior insular cortex in empathetic pain processing. Our findings have implications for a wide range of neuropsychiatric illnesses characterized by prominent deficits in higher-level social functioning.

Retrieved from: http://brain.oxfordjournals.org/content/135/9/2726

autism and schizophrenia…kissing cousins.

In Autism Spectrum Disorders, Genes, Genomic Medicine, Neuroscience on Thursday, 25 October 2012 at 16:29

http://www.eurekalert.org/pub_releases/2012-10/afot-asa102312.php

Are autism and schizophrenia related?

Posted on October 23, 2012 by Stone Hearth News

Autism Spectrum Disorders (ASD), a category that includes autism, Asperger Syndrome, and Pervasive Developmental Disorder, are characterized by difficulty with social interaction and communication, or repetitive behaviors. The U.S. Centers for Disease Control and Management says that one in 88 children in the US is somewhere on the Autism spectrum — an alarming ten-fold increase in the last four decades.

New research by Dr. Mark Weiser of Tel Aviv University’s Sackler Faculty of Medicine and the Sheba Medical Center has revealed that ASD appears share a root cause with other mental illnesses, including schizophrenia and bipolar disorder. At first glance, schizophrenia and autism may look like completely different illnesses, he says. But closer inspection reveals many common traits, including social and cognitive dysfunction and a decreased ability to lead normal lives and function in the real world.

Studying extensive databases in Israel and Sweden, the researchers discovered that the two illnesses had a genetic link, representing a heightened risk within families. They found that people who have a schizophrenic sibling are 12 times more likely to have autism than those with no schizophrenia in the family. The presence of bipolar disorder in a sibling showed a similar pattern of association, but to a lesser degree.

A scientific leap forward, this study sheds new light on the genetics of these disorders. The results will help scientists better understand the genetics of mental illness, says Dr. Weiser, and may prove to be a fruitful direction for future research. The findings have been published in the Archives of General Psychiatry.

All in the family

Researchers used three data sets, one in Israel and two in Sweden, to determine the familial connection between schizophrenia and autism. The Israeli database alone, used under the auspices of the ethics committees of both the Sheba Medical Center and the Israeli Defense Forces, included anonymous information about more than a million soldiers, including patients with schizophrenia and ASD.

“We found the same results in all three data sets,” he says, noting that the ability to replicate the findings across these extensive databases is what makes this study so significant.

Understanding this genetic connection could be a missing link, Dr. Weiser says, and provides a fresh direction for study. The researchers are now taking this research in a clinical direction. For now, though, the findings shouldn’t influence the way that doctors treat patients with either illness, he adds.

Retrieved from: http://www.stonehearthnewsletters.com/are-autism-and-schizophrenia-related/autism/

genes, genes, genes…more awesomeness in genomic medicine!

In Autism Spectrum Disorders, Genes, Genomic Medicine, Neuroscience on Thursday, 25 October 2012 at 14:26

http://boards.medscape.com/forums?128@410.Oln9aayNn1L@.2a35a68e!comment=1

Multiple papers recently published have documented links between de novo mutations and autism, schizophrenia, and intellectual disability. Here, I review the topic and raise some of the key questions on this issue going forward.

References:
– Kong A, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471-475.
– Wang J, et al. Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell. 2012;150:402-412.
– Rauch A, et al. Range of genetic mutations associated with severe non-syndromic intellectual disability: an exome sequencing study. Lancet. 2012 Sept 26. [Epub ahead of print]
– de Ligt J, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Oct 3. [Epub ahead of print]

______________________

Below is a transcript of Dr. Topol’s post “De Novo Mutations and the Implications for the Father’s Biological Clock.” We look forward to your feedback.
Our topic is de novo mutations and the implication of these new mutations for expectant fathers. This is a really important topic that was highlighted by the cover article in August 2012 in Nature. It was also in recent multiple papers in Cell, where sperm was sequenced for the first time, as well as in multiple papers on de novo mutations in Nature and Nature Genetics.

While we have known about the possibility for new mutations to occur that are not heritable, the quantification of this has become possible now that we can do sequencing of sperm and compare that to the germline DNA of the father. What is fascinating is that there have been now multiple papers that have come out in recent weeks to demonstrate the link between de novo mutations and intellectual disability, schizophrenia, and autism — and especially the paper coming from the Icelandic group DECODE, which linked the father’s age with the incidence of de novo mutations.

These new mutations are not frequent, of course, but if there’s just one per exome, that is, throughout the coding elements of the genome, that can be quite damaging. In fact, it is characteristic of de novo mutations that they tend to be bad and have adverse consequences.

While there are many more in a typical genome, somewhere around 70 or more of various types of mutations, whether they’re single nucleotide polymorphisms or insertions/deletions, most of them do not fall in protein coding elements. But when they do, the data we have so far from this collective work suggest that they can be damaging.

The big issue going forward is — what can we do about this? Is this de novo mutation related to our environment? Can we try to reduce the age of fathers and set up the “male biological clock,” which, for all of the years, has been largely restricted to the mother’s story? Can we someday screen sperm for de novo mutations, screen them out or at least get a sense of the frequency? It seems unlikely that we would sequence and then use the sperm for in vitro fertilization, but perhaps we can leverage this knowledge. Of course, the age relationship is tricky because, so far, we don’t have much data to suggest an age range, but clearly there is a relationship with age of the father as it extends to 40 and beyond with a higher rate of de novo mutations.

We also know that, concurrently, the rate of diagnosis of autism is increasing. Could this have something to do with this de novo mutation increase and the overall trend of a higher paternal age?

There is a lot here to consider on a theme that is showing up in multiple papers: the way to quantify de novo mutations, understand their increased frequency as fathers age, and this very interesting link to multiple neurologic, neurocognitive, and neuropsychiatric conditions.

Over time, it’s likely that these de novo mutations will exert a phenotype that is beyond the neurology world. It will also be interesting to see how de novo mutations could potentially have a beneficial role. But one thing for sure is that this is part of the story about missing heritability: we couldn’t account for things that were happening in a new generation that were not present from the parents, and de novo mutations are certainly a part of that story.

Thanks for your attention. I look forward to your comments about de novo mutations and especially the father’s biological clock phenomenon.

Retrieved from: http://boards.medscape.com/forums?128@410.Oln9aayNn1L@.2a35a68e!comment=1

dream a little dream of me…

In Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Tuesday, 23 October 2012 at 09:51

What Physicians Need to Know about Dreams and Dreaming

James F. Pagel

Abstract

Purpose of review: An overview of the current status of dream science is given, designed to provide a basic background of this field for the sleep-interested physician.

Recent findings: No cognitive state has been more extensively studied and is yet more misunderstood than dreaming. Much older work is methodologically limited by lack of definitions, small sample size, and constraints of theoretical perspective, with evidence equivocal as to whether any special relationship exists between rapid eye movement (REM) sleep and dreaming. As the relationship between dreams and REM sleep is so poorly defined, evidence-based studies of dreaming require a dream report. The different aspects of dreaming that can be studied include dream and nightmare recall frequency, dream content, dreaming effect on waking behaviors, dream/nightmare associated medications, and pathophysiology affecting dreaming.

Summary: Whether studied from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives, dreaming reveals itself to be a complex cognitive state affected by a wide variety of medical, psychological, sleep and social variables.

Introduction

As most individuals experience the cognitive mentation that we call dreams during sleep, any physician treating sleep needs to have at least a basic understanding of dreaming. It was just 50 years ago that polysomnography allowed for sleep to be electrophysiologically staged. Although sleep had yet to be examined, a huge literature existed on dreaming and, through psychoanalysis, the use of dreams in the treatment of the spectrum of mental illness. Today, the scientific study of dreams has come full circle. We now know a huge amount about sleep, its associated pathophysiology, and treatment, yet what we know scientifically about the dream state is far less than what we thought we knew a generation ago. Much older work was not evidence based, and was methodologically limited by lack of definitions, small sample size, and the constraints of theoretical perspective. After 50 years of dogmatic insistence that rapid eye movement (REM) sleep is dreaming, most researchers in the field now accept that the evidence is overwhelming that REM sleep occurs without dreaming and dreaming without REM sleep.[1] Evidence remains equivocal as to whether any special relationship exists between REM sleep and dreaming.[2•] It is unclear as to what part, if any, of the highly developed neuroanatomical and neurochemical model for REM sleep is applicable to the cognitive state of dreaming.

Definitions: What is a Dream?

Early in the 20th century, Sigmund Freud and his adherents developed the psychoanalytic techniques of free association and dream analysis for use in diagnosing and treating individuals with psychiatric illnesses. Freud focused on the psychopathologic associations of bizarre and unusual dreams, eventually giving us a definition of dreaming as ‘wish fulfillment.’ Psychoanalysts stretched the definition of dreaming to include parasomnias and the REM sleep-associated states of narcolepsy, defining dreams as bizarre, hallucinatory mental activity that can occur in either sleep or wake.[3] This psychoanalytic definition of dreaming became the generally accepted definition for this phenomenon among many psychiatrists and neuroscientists.

From its initial discovery, REM sleep = dreaming was proof of the correlate between psychoanalysis and brain structure, a postulate at the basis of grand theories of dreaming including Activation, Input, Modulation (AIM), now termed protoconsciousness theory and the most developed and widely accepted theory of central nervous system (CNS) functioning.[4] It is a primary postulate of AIM that the neurons and neurochemicals that modulate REM sleep alter dreaming and other conscious states in a similar manner. The AIM model has been adopted and extended into proposals that REM sleep dreaming is the process that organizes neural nets in higher cortical regions.[5] These theories postulate that the cognitive activity of dreaming is based on the CNS activation associated with REM sleep, with dreaming an upper cerebral cognitive process utilizing the CNS activation associated with a primitive electrophysiological state of activation that we call REM sleep. If REM sleep is dreaming, animal models and scanning studies of REM sleep as reported in the popular and scientific press can be construed to be studies of the cognitive state of dreaming. Such studies must be considered suspect, however, as dreaming occurs throughout sleep in forms (except for nightmares) indistinguishable from REM sleep dreaming.[6]

Most sleep medicine physicians consider dreaming to be mentation reported as occurring in sleep by a human participant. This definition contradicts the psychoanalytic definition for dreaming, restricting dreaming to sleep irrespective of content. This definition also differs from the REM sleep = dreaming model in requiring a dream report. Because of this conflation of contradicting definitions, it is important for anyone interested in perusing either scientific or popular literature to note what the author may be referring to in any discussion of dreams and dreaming.[7]

Evidence-based Research Into Dreaming

Characteristics of the dream state amenable to scientific study include recall, content, dream incorporation into waking, and associated pathophysiology.

Dream Recall

Collection methodology including time since waking, process, and defined state characteristics affect reported dream recall frequency. Sleep stage of origin is a primary variable known to affect dream recall frequency. Multiple studies indicate that dream recall reported from REM sleep and sleep onset is in the range of 80%. Although recall from stage 2 varies through the night, recall approximates the 40% recall from stage 3.[8] Recall is generally higher for women and in the young.[9] Increased dream salience and intensity, typical of nightmares, also results in an increase in recall. Significant subjective and objective insomnia is associated with diminished dream recall.[10] Bi-basilar frontal CNS damage can be associated with a loss of dreaming.[11] Although some individuals report that they do not dream, most have experienced dreams at some point in their lives. The much smaller percentage of sleep laboratory patients that have never experienced dreaming (0.038%) do not report dreams in the laboratory when awakened from either REM sleep or non-REM sleep.[12] Despite their lack of dream recall, these individuals have no obvious memory impairment and function normally in our society.

Dream Content

Guttenberg’s first printed book was the Bible, but his second was the Oneirocritica, an interpretation of the meaning of dream symbols.[13] Mankind’s focus on dream content likely predates the development of either printing or writing.[2•] Dream content has been incorporated into the worlds’ major religions, philosophies, literature, and science. The argument can cogently be made that the structure and narrative form of language itself is derived from our attempts to organize and share our dreams. Most dreams are narratives occurring, and often presented without applied organization, grammar, or expectation of critique. In the dream, we can literally observe the ‘thinking of the body,’ and with it, the birth of the literary process. Our dreams can be considered an exercise in pure storytelling whose end is nothing more (or less) than the organization of experience into set patterns that help to maintain order for the thinking system.[14]

Freud postulated that an individual’s psychic structure could be inferred from information derived from the associative interpretation of dreams, and then could be utilized in developing a therapeutic plan for the treatment of psychiatric symptoms.[15] He stated, ‘Psychoanalysis is related to psychiatry approximately as histology is related to anatomy’.[16] For more than a generation, psychiatrists were trained in the method, with the data derived from psychoanalytic techniques used to make diagnoses and form treatment plans. Although psychoanalysis was utilized with occasional success in treating psychiatric illness, most of the evidence attesting to its therapeutic efficacy was anecdotal and subjective.[3]

More recent studies of dream content have attempted to address the significant methodological problems of transference, collection and interpretation that led to the nonreplicable characteristics of dream content studies. Methodologically sound studies have been developed that utilize computerized analysis of the validated Hall and Van de Castle content system.[17] Such studies have shown few, if any, significant differences in dream content between personality types, psychopathologic diagnoses, or socio-ethnic groups.[18] The primary significant correlate for dream content has proven to be waking experience, supporting the so-called continuity hypothesis – dream content reflects our waking experience.[18] Dream researchers have persisted in developing alternative content scales in order to support theoretical perspectives.[19] Although few of these scales have been validated or subjected to independent analysis, the best data is for Hartmann’s analysis of personality correlates (boundaries) that affect both dream recall frequency and content.[20]

Studies have also started to address other aspects of dream content. Visual imagery, the primary characteristic of most reported dreams, follows an operative pattern in dreaming that can be studied and applied externally to filmmaking methodology.[6] Memories follow characteristic patterns in both dream-associated sleep and varied waking states.[21•] Emotions, particularly negative emotions, are routinely incorporated into dreaming.[22]

Dream Incorporation Into Waking Behavior

Many individuals use their dreams. As in recall, dream-use tends to be sex-based and age-based (higher in women and the young).[23] Although ethnic and cultural differences in dream-use exist, such variations do not tend to be present in general population samples.[24] Dream use is significantly higher among individuals reporting creative interests.[25] Among successfully creative individuals, dream and nightmare recall, as well as dream incorporation into work and waking behavior is much higher than in the general population, suggesting that one function of dreaming may be in the creative process.[6,26]

Medications Inducing Disturbed Dreaming and Nightmares

Until recently, neurochemists interested in dreaming focused their studies on the effects of various neurochemicals on REM sleep based on the belief that medications affecting dreaming would be the same ones known to affect REM sleep. Acetylcholine is the primary neuromodulator affecting REM sleep.[27] A wide variety of pharmaceutical agents have anticholinergic activity, and the reported side effects of some of these agents include nightmares, disordered dreaming and hallucinations. This has led some authors to postulate that cholinergic effects of medications induce nightmares, hallucinations, and psychosis.[28] Based on this theoretical construct, the anticholinesterase agents in widespread use for the treatment of the cognitive effects of Alzheimer’s disease should alter dreaming. These agents, however, are reported to induce the side effect of disturbed dreaming or nightmares in only 0.4% of clinical trial participants.[29]

Agents that suppress REM sleep such as ethanol and benzodiazepines induce episodes of REM sleep rebound on withdrawal. These REM sleep rebound episodes have been associated with reports of nightmares and disturbed dreaming, and were considered the primary mechanism for drug-induced disordered dreaming and nightmares. However, nightmares and disordered dreaming are often reported as part of the withdrawal syndrome from addictive medications such as cannabis, cocaine and opiates that, which are not known to affect REM sleep. This suggests that during withdrawal from addictive agents, disturbed dreaming and nightmares may be an intrinsic part of that process rather than occurring secondary to REM sleep rebound.[29,30]

Data based on clinical trials and case reports of effects and side effects of clinically utilized pharmaceutical agents indicate that a much different pattern of medications induce disordered dreaming and nightmares than those known to affect REM sleep.[29] The spectrum of medications affecting dreaming indicates that the state is neurochemically complex with medications influencing the neurotransmitters/neuromodulators dopamine, nicotine, histamine, GABA, serotonin, nicotine, and norepinephrine altering dreaming and reported nightmare frequency in 1–5% of patients using these medications.[29] Medications with clinical cognitive effects and/or side-effects of arousal (insomnia) and/or sedation are those that most commonly alter the reported frequency of disordered dreaming and nightmares ( ).

Among drug classes of prescription medications in clinical use, β-blockers affecting norepinephrine neuroreceptors are most likely to result in patient complaints of disturbed dreaming. The strongest clinical evidence for a specific drug to induce disordered dreaming or nightmares is for the selective serotonin reuptake inhibitor paroxetine – a medication known to suppress REM sleep. Because of the high frequency of use of over-the-counter preparations containing type-1 antihistamines for sleep induction and the treatment of allergies, such preparations are likely responsible for most reports of drug-induced disordered dreaming and nightmares.[29]

Table 1.  Cognitive effects and side effects of medications: neurotransmitter/neuromodulator-associated central nervous system effects

Basis for central nervous system activity Sleepiness Insomnia Alterations in dreaming
Neuromodulator and/or neurotransmitter mediated effects
   Serotonin +++ ++ +++
   Norepinephrine ++ ++ +++
   Dopamine +++ +++ +++
   Histamine +++ + ++
   GABA +++ + ++
   Acetylcholine ++
   Adenosine + +++
   Nicotine +++ +++
Other medication effects
   Effects on inflammation ++ ++ ++
   Addictive drug withdrawal + +++ +++
   Altered conscious interaction with environment +++ + ++
   Alterations in sleep associated disease +++ +++ +

+++, majority of drugs with this activity cause this effect in more than 5% of patients; ++, some drugs with this activity induce this effect in 1–5% of patients; +, an idiosyncratic effect for some agents in this group or withdrawal effect; −reported in less than 1% of patients using agents affecting this neurotransmitter/neuromodulator [29]

Pathophysiology of Dreaming And Nightmares

Although changes in dreaming are sometimes reported, most reports of pathophysiological correlates for dreaming are reports of nightmares – coherent dream sequences usually occurring in REM sleep that become increasingly more disturbing as they unfold and usually resulting in awakening.[31]

Dream-like Parasomnias

Dreaming (cognitive narrative, feeling, or awareness of dreaming on awakening) occurs in association with many parasomnias – unwanted behaviors occurring during sleep.

Parasomnias are in general classified based on sleep stage of origin.

Disorders of Arousal

The disorders of arousal occurring out of deep sleep are associated with dream mentation up to 40% of the time. Somambulism is characterized by autonomic and inappropriate behaviors, frantic attempts to escape a perceived threat, and fragmentary recall. Sleep terrors and confusional arousals are associated with incoherent vocalizations, intense autonomic discharge, confusion and disorientation, and fragmentary dream recall.[32]

Hypnogognic Phenomena

The sleep onset nightmares typical of posttraumatic stress disorder (PTSD) and sleep onset sleep paralysis can occur without the classic REM sleep association. Sleep onset PTSD nightmares often induce distress that interferes with the initiation of sleep. Hypnogogic hallucinations are primarily visual and have coherent dream storylines that are perceived as potentially real. Although commonly experienced (prevalence rates vary from 25 to 37%), such experiences are also a part of the classic tetrad of narcolepsy.[33] The regularly experienced hypnogogic hallucinations reported by 40–60% of individuals carrying the diagnosis of narcolepsy with cataplexy may have more complex storylines than those reported in the general population.[3,34] Sleep starts, most commonly experienced at sleep onset, can be associated with the impression of falling.

Rapid Eye Movement Sleep-associated Parasomnias 

REM sleep is classically associated with dream-like parasomnias. Some of these parasomnias can also occur outside REM sleep. PTSD nightmares and sleep paralysis can occur at sleep onset. REM sleep behavior disorder (RBD) phenomena can also occur in association with arousal disorders.

Nightmare Disorder

Nightmare disorder is characterized by recurrent nontrauma-related REM sleep dreams that result in intense anxiety, fear or terror, and a coherent dream story usually involving imminent physical danger for the dreamer. Associated insomnia and difficulty returning to sleep are usually present. As in most parasomnias, arousals associated with obstructive sleep apnea (OSA) or periodic limb movement disorder can result in increased symptomatology; however, in patients with the disordered sleep associated with moderate to severe OSA, normal dreaming is maintained while reported nightmares actually decline in frequency.[35] Personality patterns typically present in individuals with frequent nightmares include fantasy proneness, psychological absorption, dysphoric daydreaming and ‘thin’ boundaries.[20] Such individuals are more likely to have a creative or artistic focus in their daily lives. Some of these individuals may utilize their dreams and nightmares in highly successful creative careers in writing, acting and film.[36 

Posttraumatic Stress Disorder-associated Nightmares

Frequent nightmares are the most common symptom of PTSD, affecting approximately 25% of individuals who have experienced severe emotional or physical trauma.[37] The nightmares that characterize PTSD are frightening and sometimes stereotypic dreams that can include re-experiencing of the individual’s trauma. Nightmares may be a failure of emotional processing systems that are active during sleep, particularly REM sleep.[22,38] Significant improvement in both sleep onset and maintenance insomnia has been achieved in PTSD patients with the use of both cognitive/behavioral and medication approaches that demonstrably reduce the frequency and distress associated with these disturbing dreams.[39]

Rapid Eye Movement Sleep Behavior Disorder (RBD) and Sleep Paralysis

In patients with RBD, vivid dreams are often ‘acted out.’ Such dream-related behavior can be violent and can result in injury to the victim or bedpartner. In contrast to those who experience sleep terrors, the victim will often recall coherent dream stories that, in a minority of cases, correlate with observed RBD behaviors.[40] RBD events can occur outside the sleep stage for which it is named.[41] During REM sleep associated with sleep paralysis, the inability to perform voluntary movements on waking, with full recall of dreaming, can lead to intense anxiety.

Other Dream-like Parasomnias

Sleep talking (somniloquy), which usually occurs in stage-2 non-REM sleep but which can accompany any stage of sleep, may include embarrassing waking content. Anxiety and panic attacks, also predominately occurring in stage-2, may also include coherent dream content. Sleep related dissociative disorder occurring in individuals with waking dissociative disorders is characterized by re-experiencing of trauma that presents during nighttime awakenings. Nocturnal partial epileptic seizures can include thoughts and hallucinations.[42]

Conclusion 

The recent progress that researchers have made in understanding dreams has been incremental, and is not nearly as exciting as the simplified insights, at the time regarded as breakthroughs into the process of consciousness, that were once attributed to dreaming. This recent work indicates that dreaming is a complex cognitive state whether viewed from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives. Our dreams are what we remember in the morning of the cognition taking place in our CNS during sleep. It is recommended that physicians treating sleep and its disorders be familiar with current knowledge of the science of dreaming. 

Sidebar

Key Points

  • Dreaming is not limited to rapid eye movement (REM) sleep, but rather occurs throughout sleep.
  • Dreaming defined as cognitive narrative, feeling, or awareness of dreaming on awakening occurs in association with many parasomnias.
  • Dreaming is a complex cognitive state whether viewed from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives.
  • Medications affecting the neurotransmitters/neuromodulators dopamine, nicotine, histamine, gamma-aminobutyric acid (GABA), serotonin, nicotine, and norepinephrine alter dreaming and reported nightmare frequency.

References

  1. Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. In: Pace-Schott E, Solms M, Blagtove M, Harnad S, editors. Sleep and dreaming: scientific advances and reconsiderations. Cambridge, UK: Cambridge University Press; 2003. pp. 51–58.
  2. Pagel JF. REMS and dreaming – historical perspectives. In: Mallick BN, Pandi Perumal SR, McCarley RW, Morrison AR, editors. Rapid eye movement sleep – regulation and function. Cambridge, UK: Cambridge University Press; 2011. pp. 1–14.
    • This book providesa state of the art analysis of the highly developed neuroanatomic and neurochemical model for REM sleep.
  3. Pagel JF, Scrima L. Psychoanalysis and narcolepsy. In: Goswami M, Pandi-Perumal SR, Thorpy M, editors. Narcolepsy – a clinical guide. New York, NY: Springer/Humana Press; 2010. pp. 129–134.
  4. Hobson J. Dream life: an experimental memoir. Cambridge, MA: MIT Press; 2011.
  5. Crick F, Mitchenson G. The function of dream sleep. Nature 1983; 304:111– 114.
  6. Pagel JF. The limits of dream – a scientific exploration of the mind/brain interface. Oxford, UK: Academic Press (Elsiever); 2008.
  7. Pagel JF, Blagrove M, Levin R, et al. Defining dreaming – a paradigm for comparing disciplinary specific definitions of dream, Dreaming 2001; 11:195–202.
  8. Foulks D. Data constraints on theorizing about dream function, In: Moffitt A, Kramer M, Hoffmann R, Albany, editors. The functions of dreaming. New York: SUNY Press; 1993. pp. 11–20.
  9. Schredl M, Lahl O. Gender, sex role orientation, and dream recall frequency. Dreaming 2010; 20:19–24.
  10. Pagel JF, Shocknasse S. Dreaming and insomnia: polysomnographic correlates of reported dream recall frequency. Dreaming 2007; 17:140–151.
  11. Kaplan-Solmes K, Solmes M. Clinical studies in neuro-psychoanalysis: introduction to depth neuropsychology. New York & London: Karnac Books; 2000.
  12. Pagel JF. Nondreamers. Sleep Med 2003; 4:235–241.
  13. Hunt H. Dreams as literature/science: an essay. Dreaming 1991; 1:235–242.
  14. States BO. Dreaming and Storytelling. Ithaca NY: Cornell University Press; 1993. p. 53.
  15. Freud S. New Introductory lectures on psychoanalysis. Harmondsworth, UK; Penguin: 1933/1973. p.83.
  16. Freud S. Psychoanalysis and psychiatry general theory of the neuroses, In: Ed. J. Strachey, editor. Introductory lectures on psychoanalysis trans, New York, NY; W. W. Norton: 1917/1966. p. 255.
  17. Hall C, Van de Castle R. The content analysis of dreams. New York, NY: Appleton-Century-Crofts; 1966.
  18. Domhoff GW. The scientific study of dreams; neural networks, cognitive development and content analysis. Washington DC: American Psychological Association; 2003.
  19. Kramer M. The dream experience: a systemic exploration. New York & London: Routledge; 2007:; pp. 51–53.
  20. Hartmann E, Kunzendorf R. The central image (CI) in recent dreams, dreams that stand out, and earliest dreams: relationship to boundaries. Imagination, Cogn Pers 2006; 25:383–392.
  21. Kozmova M. Dreamers as agents making strategizing efforts exemplify core aggregate of executive function in nonlucid dreaming. Int J Dream Res 2012; 5:47–67.
    An in-depth study into the incorporation of forms of thinking into dreaming.
  22. Levin R, Fireman G, Nielsen T. Disturbed dreaming, and emotional dysregulation. In: Pagel JF, editor. Dreaming and nightmares – sleep medicine clinics, vol. 5. Philadelphia, PA: Saunders; 2010. pp. 229–240.
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Curr Opin Pulm Med. 2012;18(6):574-579

Retrieved from: http://www.medscape.com/viewarticle/772192_2

 

crazily creative…

In Brain imaging, Brain studies, Neuropsychology, Neuroscience on Sunday, 21 October 2012 at 09:38

Link Between Creativity and Mental Illness Confirmed in Large-Scale Swedish Study

ScienceDaily (Oct. 16, 2012)

People in creative professions are treated more often for mental illness than the general population, there being a particularly salient connection between writing and schizophrenia. This according to researchers at Karolinska Institutet, whose large-scale Swedish registry study is the most comprehensive ever in its field.

Last year, the team showed that artists and scientists were more common amongst families where bipolar disorder and schizophrenia is present, compared to the population at large. They subsequently expanded their study to many more psychiatric diagnoses — such as schizoaffective disorder, depression, anxiety syndrome, alcohol abuse, drug abuse, autism, ADHD, anorexia nervosa and suicide — and to include people in outpatient care rather than exclusively hospital patients.

The present study tracked almost 1.2 million patients and their relatives, identified down to second-cousin level. Since all were matched with healthy controls, the study incorporated much of the Swedish population from the most recent decades. All data was anonymized and cannot be linked to any individuals.

The results confirmed those of their previous study, that certain mental illness — bipolar disorder — is more prevalent in the entire group of people with artistic or scientific professions, such as dancers, researchers, photographers and authors. Authors also specifically were more common among most of the other psychiatric diseases (including schizophrenia, depression, anxiety syndrome and substance abuse) and were almost 50 per cent more likely to commit suicide than the general population.

Further, the researchers observed that creative professions were more common in the relatives of patients with schizophrenia, bipolar disorder, anorexia nervosa and, to some extent, autism. According to Simon Kyaga, Consultant in psychiatry and Doctoral Student at the Department of Medical Epidemiology and Biostatistics, the results give cause to reconsider approaches to mental illness.

“If one takes the view that certain phenomena associated with the patient’s illness are beneficial, it opens the way for a new approach to treatment,” he says. “In that case, the doctor and patient must come to an agreement on what is to be treated, and at what cost. In psychiatry and medicine generally there has been a tradition to see the disease in black-and-white terms and to endeavour to treat the patient by removing everything regarded as morbid.”

Simon Kyaga, Mikael Landén, Marcus Boman, Christina M. Hultman, Niklas Långström, Paul Lichtenstein. Mental illness, suicide and creativity: 40-Year prospective total population studyJournal of Psychiatric Research, 2012; DOI: 10.1016/j.jpsychires.2012.09.010

Retrieved from: http://www.sciencedaily.com/releases/2012/10/121016084934.htm

adhd…a longitudinal follow-up

In ADHD, ADHD Adult, ADHD child/adolescent, ADHD stimulant treatment, Brain imaging, Brain studies, Neuropsychology, Neuroscience, Psychiatry, School Psychology on Tuesday, 16 October 2012 at 07:34

Men Diagnosed with ADHD as Children had Worse Outcomes as Adults, Study Says

ScienceDaily (Oct. 15, 2012) — Men who were diagnosed as children with attention-deficit/hyperactivity disorder (ADHD) appeared to have significantly worse educational, occupational, economic and social outcomes in a 33-year, follow-up study that compared them with men without childhood ADHD, according to a report published Online First by Archives of General Psychiatry, a JAMA Network publication.

ADHD has an estimated worldwide prevalence of 5 percent, so the long-term outcome of children with ADHD is a major concern, according to the study background.

Rachel G. Klein, Ph.D., of the Child Study Center at NYU Langone Medical Center in New York, and colleagues report the adult outcome (follow-up at average age of 41 years) of boys who were diagnosed as having ADHD at an average age of 8 years. The study included 135 white men with ADHD in childhood, free of conduct disorder (probands), and a comparison group of 136 men without childhood ADHD.

“On average, probands had 2½ fewer years of schooling than comparison participants … 31.1 percent did not complete high school (vs. 4.4 percent of comparison participants) and hardly any (3.7 percent) had higher degrees (whereas 29.4 percent of comparison participants did). Similarly, probands had significantly lower occupational attainment levels,” the authors note. “Given the probands’ worse educational and occupational attainment, their relatively poorer socioeconomic status at [follow-up at average age of 41 years] is to be expected. Although significantly fewer probands than comparison participants were employed, most were holding jobs (83.7 percent). However, the disparity of $40,000 between the median annual salary of employed probands and comparisons is striking.”

In further comparisons of the two groups, the men who were diagnosed with ADHD in childhood also had more divorces (currently divorced, 9.6 percent vs. 2.9 percent, and ever been divorced 31.1 percent vs. 11.8 percent); and higher rates of ongoing ADHD (22.2 percent vs. 5.1 percent, the authors suspect the comparison participants’ ADHD symptoms might have emerged during adulthood), antisocial personality disorder (ASPD, 16.3 percent vs. 0 percent) and substance use disorders (SUDs, 14.1 percent vs. 5.1 percent), according to the results.

During their lifetime, the men who were diagnosed with ADHD in childhood (the so-called probands) also had significantly more ASPD and SUDs but not mood or anxiety disorders and more psychiatric hospitalizations and incarcerations than comparison participants. And relative to the comparison group, psychiatric disorders with onsets at 21 years of age or older were not significantly elevated in the probands, the study results indicate.

The authors note the design of their study precludes generalizing the results to women and all ethnic and social groups because the probands were white men of average intelligence who were referred to a clinic because of combined-type ADHD.

“The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD,” the study concludes.

Retrieved from: http://www.sciencedaily.com/releases/2012/10/121015162407.htm

 

                                                                                             

Brain Gray Matter Deficits at 33-Year Follow-up in Adults With Attention-Deficit/Hyperactivity Disorder Established in Childhood

Erika Proal, PhD; Philip T. Reiss, PhD; Rachel G. Klein, PhD; Salvatore Mannuzza, PhD; Kristin Gotimer, MPH; Maria A. Ramos-Olazagasti, PhD; Jason P. Lerch, PhD; Yong He, PhD; Alex Zijdenbos, PhD; Clare Kelly, PhD; Michael P. Milham, MD, PhD; F. Xavier Castellanos, MD

Arch Gen Psychiatry. 2011;68(11):1122-1134. doi:10.1001/archgenpsychiatry.2011.117.

 

Context  Volumetric studies have reported relatively decreased cortical thickness and gray matter volumes in adults with attention-deficit/hyperactivity disorder (ADHD) whose childhood status was retrospectively recalled. We present, to our knowledge, the first prospective study combining cortical thickness and voxel-based morphometry in adults diagnosed as having ADHD in childhood.

Objectives  To test whether adults with combined-type childhood ADHD exhibit cortical thinning and decreased gray matter in regions hypothesized to be related to ADHD and to test whether anatomic differences are associated with a current ADHD diagnosis, including persistent vs remitting ADHD.

Design  Cross-sectional analysis embedded in a 33-year prospective follow-up at a mean age of 41.2 years.

Setting  Research outpatient center.

Participants  We recruited probands with ADHD from a cohort of 207 white boys aged 6 to 12 years. Male comparison participants (n = 178) were free of ADHD in childhood. We obtained magnetic resonance images in 59 probands and 80 comparison participants (28.5% and 44.9% of the original samples, respectively).

Main Outcome Measures  Whole-brain voxel-based morphometry and vertexwise cortical thickness analyses.

Results  The cortex was significantly thinner in ADHD probands than in comparison participants in the dorsal attentional network and limbic areas (false discovery rate < 0.05, corrected). In addition, gray matter was significantly decreased in probands in the right caudate, right thalamus, and bilateral cerebellar hemispheres. Probands with persistent ADHD (n = 17) did not differ significantly from those with remitting ADHD (n = 26) (false discovery rate < 0.05). At uncorrected P < .05, individuals with remitting ADHD had thicker cortex relative to those with persistent ADHD in the medial occipital cortex, insula, parahippocampus, and prefrontal regions.

Conclusions  Anatomic gray matter reductions are observable in adults with childhood ADHD, regardless of the current diagnosis. The most affected regions underpin top-down control of attention and regulation of emotion and motivation. Exploratory analyses suggest that diagnostic remission may result from compensatory maturation of prefrontal, cerebellar, and thalamic circuitry.

Retrieved from: http://archpsyc.jamanetwork.com/article.aspx?articleid=1107429

The Unfulfilled Promises of Psychotropics

In Brain studies, Medication, Neuropsychology, Neuroscience, Psychiatry, Psychopharmacology on Sunday, 14 October 2012 at 11:33

The Unfulfilled Promises of Psychotropics

By Richard Kensinger, MSW

I remember thinking over 40 years ago when I began my clinical career, that with the rapid advances made in psychotropic agents, psychotherapy would become a venture of the past. A recent editorial published in Schizophrenia Bulletindispels my myth of becoming unemployed.

Psychopharmacology is in crisis. The data are in, and it is clear that a massive experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years. Indeed, despite enormous effort, the field has not been able to escape the “me too/me (questionably) better” straightjacket. In recent years, the appreciation of this reality has had profound consequences for innovation in psychopharmacology because nearly every major pharmaceutical company has either reduced greatly or abandoned research and development of mechanistically novel psychiatric drugs. This decision is understandable because pharmaceutical and biotechnology executives see less risky opportunities in other therapeutic areas, cancer and immunology being the current pipeline favorites. Indeed, in retrospect, one can wonder why it took so long for industry to abandon psychiatry therapeutics. So how did we get here and more importantly, what do we need to do to find a way forward?

The discovery of all three major classes of psychiatric drugs, antidepressants, antipsychotics, and anxiolytics, came about on the basis of serendipitous clinical observation. At the time of their discoveries, the mechanisms by which these molecules produce their effects were unknown, and it was only later that antipsychotics were shown to be D2 receptor antagonists, antidepressants monoamine reuptake inhibitors, and anxiolytics GABA receptor modulators. It is interesting and perhaps instructive to consider whether any of these classes of drugs could have been discovered by current drug discovery strategies. For example, what genetic or preclinical data exist that point to the D2 dopamine receptor as a likely target for antipsychotic activity? Presently there are no genetic data that suggest that this receptor is expressed or functions abnormally in psychotic disorders (emphasis added). And without the benefit of the prior clinical validation, it is difficult to see how preclinical data alone would point to the D2 receptor as an interesting potential target for the treatment of psychotic disorders. The same can be said for monoamine transporters with respect to depression where, like psychosis, there are no animal models based on disease pathophysiology and no compelling preclinical data pointing to these as potential targets for antidepressant drugs. This raises a troubling question: if in retrospect the three major classes of currently prescribed psychiatric drugs would likely never have been discovered using current drug discovery strategies, why should we believe that such strategies are likely to bear fruit now or in the future?

Given that there cannot be a coherent biology for syndromes as heterogeneous as schizophrenia, it is not surprising that the field has failed to validate distinct molecular targets for the purpose of developing mechanistically novel therapeutics. Although it has taken our field too long to gain this insight, we seem to be getting there. For example, at the 2011 meeting of the American College of Neuropsychopharmacology, the need for change and the need for new strategies were predominant themes.

In summation the excitement in the past two decades about the “Decades of the Brain” are fading to realism. Our human genome is much more complex than we can imagine. Half of our genes are devoted to brain form and function. The interaction between geneotype and phenotype is also more complex that we realize. Thus, we are approaching this science with more skepticism and realism.

Reference

Fibiger HC (2012). Psychiatry, the pharmaceutical industry, and the road to better therapeutics. Schizophrenia bulletin, 38 (4), 649-50 PMID: 22837348

Retrieved from: http://brainblogger.com/2012/10/08/the-unfulfilled-promises-of-psychotropics/

 

Cannabis and the Adolescent Brain

In Brain studies, Fitness/Health, Neuropsychology, Neuroscience on Sunday, 14 October 2012 at 11:23

Cannabis and the Adolescent Brain

By India Bohanna, PhD

For some time, people have known that using cannabis during adolescence increases the risk of developing cognitive impairment and mental illness (e.g. depression, anxiety or schizophrenia) later in life. Importantly however, the mechanisms responsible for this vulnerability are not well understood. A new study, published in Brain, shows that long-term cannabis use that starts during adolescence damages the neural pathways connecting brain regions, and that this may cause the later development of cognitive and emotional problems.

The authors used diffusion tensor imaging (DTI), a MRI technique that measures water diffusion, to examine the microstructure of white matter in 59 heavy cannabis users, who used cannabis at least twice a month for three years or longer, as well as 33 non-users. In the human brain, white matter pathways are formed by bundles of axons, which carry the neural signals, and myelin, which coat the axons and speeds up signal transfer. These white matter pathways are crucial for normal brain function as they enable disparate regions of the brain to communicate, and act together.

When the authors investigated white matter microstructure in the cannabis users, they found damage in the white matter pathways of the hippocampus, crucial for memory, and the corpus callosum, which connects the brain’s two hemispheres. Both pathways are critical for normal brain function. The authors suggest that impaired connectivity due to damage in these pathways may be the cause of the cognitive impairment and vulnerability to schizophrenia, depression and anxiety seen in long-term users.

The authors also show an inverse relationship between the amount of white matter damage and the age of first use. That is, participants who started using cannabis younger had more white matter damage and showed poorer brain connectivity. Adolescence is a critical period in the development of white matter in the brain, when the neural connections we rely on in adulthood are being finally formed. The authors point out that white matter cells have cannabinoid receptors (those susceptible to cannabis) during adolescence, which disappear as the brain matures. This new study demonstrates a mechanism that may help explain how cannabis use in adolescence causes long-term changes in brain function. The cannabis users in the study had significantly higher levels of depression and anxiety compared to the non-users.

This important new study suggests that young people’s brains are at risk of white matter injury due to cannabis, and that cannabis exposure during adolescence may permanently damage white matter development. Future research must address the question; can white matter pathways and connectivity recover when a person quits using cannabis?

References

Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, Lorenzetti V, Wang R, Searle K, Pantelis C, & Seal M (2012). Effect of long-term cannabis use on axonal fibre connectivity. Brain : a journal of neurology, 135 (Pt 7), 2245-55 PMID: 22669080

Retrieved from: http://brainblogger.com/2012/08/18/cannabis-and-the-adolescent-brain/

Smoking and the Adolescent Brain

In Fitness/Health, Neuropsychology, Neuroscience on Sunday, 14 October 2012 at 11:18

Smoking and Adolescent Brain Development

By Shefali Sabharanjak, PhD

When it comes to substance abuse like smoking or abuse of intoxicating drugs, it is very difficult to determine what a “safe” limit of exposure is.  Quite often, the initial exposure to mood altering substances like nicotine occurs during the teenage years. The period ofadolescence is marked by a tendency towards risk-taking behavior which often results in ‘experimental’ exposure to psychedelic substances. Adolescents who tend to flirt with danger in this fashion are often convinced that a small trial will not actually have lasting damaging effects. However, research on the development of prefrontal cortex in similarly age-matched animals says otherwise.

The prefrontal cortex in teenagers is in a state of growth and development. Contrary to established notions, brain development continues well into the teenage years and changes in synapses (connections between brain cells that facilitate the transmission of chemical messengers between cells) occur well into adolescence.  Research on adolescent mice and rats shows that exposure to nicotine during this period has long-lasting effects. For starters, nicotine is known to be able to excite neurons bearing nicotinic acetylcholine receptors. In the prefrontal cortex, nicotine has been shown to induce greater expression of a specific subset of nicotinic acetylcholine receptors, by 34%.  In the normal course of development, the number of acetylcholine receptors declines in these cells. This phenomenon is specific to the period of adolescence since a similar increase in the number of receptors is not seen when the initial exposure to nicotine occurs in adulthood, in these animals. Research has also shown that exposure to nicotine in early adolescence enhances the nicotinic ‘reward’ feeling during adulthood. It is therefore surmised that early exposure to smoking is likely to set the stage for long-term addiction and perhaps it also explains why addiction to nicotine is so prevalent, worldwide.

One might argue that since the teenage years are a short period in the life-span of a person, occasional exposure to nicotine is not likely to leave lasting damage. Here’s the catch. Exposure to nicotine also changes the pattern of synaptic connectivity between neurons in the prefrontal cortex.  The ability of neurons to establish new synaptic connections and develop new firing patterns in response to different stimuli is also known as “synaptic plasticity”. Neuroscientists have shown that all “learning” as well as  information analysis and assimilation in the brain is a net result of the pattern of exchange of neurotransmitter molecules (also referred to as pattern of ‘firing’) between neurons which respond to training stimuli. So, the more you learn, the better you get at learning by stimulating your neurons to make new synaptic connections. However, exposure to nicotine in early adolescence, changes the pattern of firing of neurons in the prefrontal cortex. Now this change reduces the capability of neurons in the prefrontal cortex to make new synaptic connections. Therefore exposure to psychedelic and addictive substances like nicotine results in reduced synaptic plasticity and has a negative impact on cognitive processes in adult life.

All these significant changes take place in early adolescence and perhaps parental guidance may play a huge role in preventing nicotine addiction and associated cognitive deficits.

References

Adriani W, Macrì S, Pacifici R, & Laviola G (2002). Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 27 (2), 212-24 PMID: 12093595

Counotte DS, Goriounova NA, Moretti M, Smoluch MT, Irth H, Clementi F, Schoffelmeer AN, Mansvelder HD, Smit AB, Gotti C, & Spijker S (2012). Adolescent nicotine exposure transiently increases high-affinity nicotinic receptors and modulates inhibitory synaptic transmission in rat medial prefrontal cortex. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 26 (5), 1810-20 PMID: 22308197

Goriounova NA, & Mansvelder HD (2012). Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood. Frontiers in synaptic neuroscience, 4 PMID: 22876231

Goriounova NA, & Mansvelder HD (2012). Nicotine exposure during adolescence leads to short- and long-term changes in spike timing-dependent plasticity in rat prefrontal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (31), 10484-93 PMID: 22855798

Kawai HD, Kang HA, & Metherate R (2011). Heightened nicotinic regulation of auditory cortex during adolescence. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (40), 14367-77 PMID: 21976522

Kota D, Robinson SE, & Imad Damaj M (2009). Enhanced nicotine reward in adulthood after exposure to nicotine during early adolescence in mice. Biochemical pharmacology, 78 (7), 873-9 PMID: 19576867

Retrieved from: http://brainblogger.com/2012/10/14/smoking-and-adolescent-brain-development/?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+GNIFBrainBlogger+%28Brain+Blogger%29

 

more awesomeness in neuroscience…

In Education, Neurogenesis, Neuropsychology, Neuroscience, School Psychology on Saturday, 13 October 2012 at 09:30

Brain Scans Can Detect Children’s Reading Ability

BY AMBER MOORE

Stanford researchers say that brain scans can help detect whether or not a child will develop reading-related problems in the future, a discovery that opens up possibility of intervention programs for helping children improve their reading ability.  In a study, conducted over a period of three years, researchers at Stanford University assessed children’s reading skills with the help of standardized tests. They observed and analyzed the participants’ brain scans taken during the study.

Researchers found that in each of the 39 children, the rate of development in the white matter region accurately predicted the child’s score on a reading test. The white matter regions of the brain are associated with reading; the rate of development in the brain region is measured by fractional anisotropy, or FA.

Further, children who displayed above-average reading skills had FA in two regions, the left hemisphere arcuate fasciculus and the left hemisphere inferior longitudinal fasciculus. Interestingly, in children who develop good reading skills, the initial FA was lower but increased over time. In children that had lower reading abilities, the FA was higher initially but declined afterwards.

According to researchers, a child’s ability to read at seven years of age can predict hisor her reading ability at 17 years of age. But, detecting if the child has problems with reading can be a challenge. “By the time kids reach elementary school, we’re not great at finding ways of helping them catch up,” said Jason D. Yeatman, a doctoral candidate in psychology at Stanford and the lead author on the study.

The great news is the study could one day lead to an early warning system for struggling students and this could help children improve their reading ability as the brain is young and is still developing.

“Once we have an accurate model relating the maturation of the brain’s reading circuitry to children’s acquisition of reading skills, and once we understand which factors are beneficial, I really think it will be possible to develop early intervention protocols for children who are poor readers, and tailor individualized lesson plans to emphasize good development. Over the next five to 10 years, that’s what we’re really hoping to do,” Yeatman said.

The study was published in the Proceedings of the National Academy of Sciences.

Retrieved from: http://www.medicaldaily.com/articles/12666/20121012/brain-scans-detect-childrens-reading-ability.htm#go5H3ZzSAe1jtK0g.99

Development of white matter and reading skills

PNAS Plus – Biological Sciences – Psychological and Cognitive Sciences

Jason D. Yeatman, Robert F. Dougherty, Michal Ben-Shachar, and Brian A. Wandell

White matter tissue properties are highly correlated with reading proficiency; we would like to have a model that relates the dynamics of an individual’s white matter development to their acquisition of skilled reading. The development of cerebral white matter involves multiple biological processes, and the balance between these processes differs between individuals. Cross-sectional measures of white matter mask the interplay between these processes and their connection to an individual’s cognitive development. Hence, we performed a longitudinal study to measure white-matter development (diffusion-weighted imaging) and reading development (behavioral testing) in individual children (age 7–15 y). The pattern of white-matter development differed significantly among children. In the left arcuate and left inferior longitudinal fasciculus, children with above-average reading skills initially had low fractional anisotropy (FA) that increased over the 3-y period, whereas children with below-average reading skills had higher initial FA that declined over time. We describe a dual-process model of white matter development comprising biological processes with opposing effects on FA, such as axonal myelination and pruning, to explain the pattern of results.

PNAS Plus: Development of white matter and reading skillsPNAS 2012 ; published ahead of print October 8, 2012,doi:10.1073/pnas.1206792109

Retrieved from: http://www.pnas.org/search?fulltext=reading&go.x=0&go.y=0&go=GO&submit=yes

 

 

ketamine isn’t just for kitties anymore…

In Medication, Mood Disorders, Neuroscience, Psychiatry, Psychopharmacology on Thursday, 11 October 2012 at 14:43

Ketamine a Viable Option for Severe Depression?

Megan Brooks

October 11, 2012 — The discovery that ketamine produces rapid antidepressant effects in patients with severe treatment-resistant depression is fueling basic neuroscience research, leading to a greater understanding of the neurobiology of depression and maybe more effective treatments, a new review suggests.

Ketamine, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, is best known in medicine as an anesthetic but also has some notoriety as a street drug, sometimes dubbed “Special K,” and is taken illicitly for its psychedelic effects.

However, recently ketamine has gained interest among researchers for its potential as a unique, rapid-acting antidepressant.

Typical antidepressants such as the serotonin selective reuptake inhibitors (SSRIs) take weeks to months to have an effect and are only moderately effective, leaving more than one third of depressed patients resistant to drug therapy.

“The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research in half a century,” review author Ronald Duman, PhD, professor of psychiatry and neurobiology at Yale University in New Haven, Connecticut, said in a statement.

However, Dr. Dunham told Medscape Medical News, although clearly promising for depression, ketamine does have some roadblocks.

“It produces transient side effects [for about 1 hour], including mild hallucinations and dissociative effects in some patients, subsequent to the antidepressant response. Ketamine is also a drug of abuse, so caution is needed when considering widespread use of this agent.”

“Nevertheless, there are millions of depressed patients who do not respond to conventional antidepressants and are in dire need of a drug like ketamine,” Dr. Duman added.

With Dr. Duman and coauthor George Aghajanian, MD, professor emeritus of psychiatry at Yale University, the review was published October 5 in Science.

Timely, Authoritative

Commenting for Medscape Medical News, James W. Murrough, MD, from Mount Sinai School of Medicine’s Mood and Anxiety Disorders Program in New York City, described the article as a “timely, well written, and authoritative review by 2 neuroscience researchers who have really done the bulk of the work looking at the biological basis for how ketamine might bring about a rapid antidepressant effect.”

The original link between ketamine and relief of depression was made by John Krystal, MD, chair of the Department of Psychiatry at Yale, and Dennis Charney, MD, formerly of Yale, now professor of psychiatry, neuroscience, and pharmacology and dean at Mount Sinai School of Medicine.

In 2000, they published results of a small, double-blinded, placebo-controlled study showing that intravenous infusions of ketamine produced significant and rapid antidepressant effects (Berman et al; Biol Psychiatry, 2000;47:351-354).

“That was the first controlled study that showed that ketamine had sort of an unexpected rapid antidepressant effect in patients,” said Dr. Murrough. “We knew it was a glutamate antagonist, but at this time (in 2000), the role of glutamate in depression was not at all on the radar.”

That study was followed by an article published in 2006 that also showed rapid (within 2 hours) and significant antidepressant effects after a single infusion of ketamine in 18 patients with treatment-resistant depression (Zarate Jr et al; Arch Gen Psychiatry, 2006;63:856-864).

Since then, a number of studies replicated and extended the findings — including a study by Carlos Zarate Jr, MD, and colleagues published in 2010 in Archives of General Psychiatry and reported by Medscape Medical News at the time.

These studies sent neuroscientists on a quest to figure out at a cellular level, using animal models, how ketamine worked and what it could reveal about depression.

Jury Still Out

The literature suggests that depression is caused by disruption of homeostatic mechanisms that control synaptic plasticity, resulting in destabilization and loss of synaptic connections in mood and emotion circuitry, the authors note. Ketamine appears to target synaptic dysfunction in depression.

The findings highlight the “central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response,” the review authors write.

Is ketamine currently used to treat refractory depression?

“A year ago, I would have said no, it’s not being used clinically. But in the last year, I’ve run into patients who’ve said they had been treated with low-dose ketamine by their psychiatrist, and doctors at national meetings who’ve said they’ve used it in their practice, but it’s very sparse, it’s far from widespread,” said Dr. Murrough.

It is important to note, he added, that to date, most of the research has been limited to the effects of a single dose.

At a medical conference in June, as reported by Medscape Medical News, Dr. Murrough and colleagues demonstrated that administration of 6 low-dose infusions of ketamine over 2 weeks improved symptoms in a small study of patients with treatment-resistant depression.

It helped “at least while they were getting the ketamine, then there was a relapse that came in as few as a couple days to several months or longer in a few cases,” he said.

Dr. Murrough said he and his colleagues are now “closing out” another study of ketamine that should be published in a couple of months. Other trials are ongoing.

“The jury is still out on whether ketamine itself could be developed into a bona fide treatment. We happen to believe that it can be. We advocate a cautious approach, but we are cautiously optimistic that ketamine could be a treatment option for severe refractory depression,” he said.

“The benchmark treatment right now for severe refractory depression is electroconvulsive therapy [ECT],” Dr. Murrough pointed out, “so you’d have to believe that ketamine has a worse risk-benefit profile than ECT, and so far, we don’t see that; it appears to be very well tolerated.”

Dr. Duman and Dr. Aghajanian have disclosed no relevant financial relationships. In the past 2 years, Dr. Murrough has received research support from Evotec Neurosciences and Janssen Research & Development. Dr. Charney has been named as an inventor on a use patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the US Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially.

Science. 2012;338:68-72. Abstract

Retrieved from: http://www.medscape.com/viewarticle/772467?src=nl_topic

Noninvasive Prenatal Diagnosis: Can Ethics and Science Meet?

In Genes, Genomic Medicine, Neuropsychology, Neuroscience on Wednesday, 26 September 2012 at 07:30

posting as an addition to my recent post on genomic medicine.  the growing field and research in genomic medicine raises some interesting ethical issues.

Noninvasive Prenatal Diagnosis: Can Ethics and Science Meet?

Elizabeth H. Dorfman; Mildred Cho, PhD

Editor’s Note:
Technological advances have enabled researchers to sequence an entire fetal genome noninvasively by extracting cell-free fetal DNA from maternal plasma.[1,2] This use of noninvasive prenatal diagnosis (NIPD) shifts the focus away from screening for known or suspected anomalies and inherited conditions to potentially discovering a wide array of information about the fetus that patients and clinicians might not be prepared to address.

On behalf of Medscape, Elizabeth H. Dorfman, a graduate student at the University of Washington Institute for Public Health Genetics, Seattle, Washington, interviewed Mildred Cho, PhD, Professor at the Stanford Center for Biomedical Ethics, Stanford, California, about the ethical and social implications of NIPD and how advances in these techniques might affect clinical practice.

Ms. Dorfman: Let’s start with a few background questions to set the stage. Can you briefly describe the technique behind NIPD using cell-free fetal DNA?

Dr. Cho: NIPD allows prenatal testing to be done from a sample of maternal blood instead of having to take a sample through invasive techniques, such as amniocentesis or chorionic villus sampling. There are a lot of different ways of analyzing fetal DNA in maternal serum; this technology, which is more recently developed, enables one to look at fragments of cell-free fetal DNA as opposed to fetal cells in maternal blood.

Ms. Dorfman: In regard to the timing of testing, risk to the fetus or the pregnancy, or potential for incidental findings — are they substantively different for NIPD compared with existing tests, or are they similar?

Dr. Cho: NIPD could potentially be used earlier in gestation, so that would give people more time to think about what to do with the results. Right now, I don’t think it’s being used very early because the ability to get enough DNA in the sample hasn’t been worked out fully, but that is the hope. Obviously, because it’s noninvasive, that makes a big difference to the person who is giving the sample: Not only is it not uncomfortable or painful, but there is virtually no risk to the fetus from taking the sample.

Ms. Dorfman: A team at the University of Washington recently announced that they had used noninvasive cell-free fetal DNA methods to sequence the entire genome of a developing fetus.[1] Could you go into a little bit of detail about how this changes the scope of NIPD?

Dr. Cho: Currently, fetal testing is done either to screen for one of a small number of conditions, or as follow-up to a prior screening, such as a genetic screening or fetal ultrasonography. In these cases, the fetal diagnostic test will be used to focus on any conditions or anomalies that turned up positive in the prior screen, or to detect a condition that is of particular concern that may have been identified through a family history. So, diagnostic testing will be just that: diagnostic, trying to come up with a genetic cause for an observed or suspected anomaly.

When or if it becomes possible to do whole-genome analysis in a clinical setting routinely, it will open up the possibility that people can get information about the fetus that is well beyond a handful of known fetal conditions, such as a trisomy. This raises the concern that people will be faced with a huge amount of information about which there might be a lot of uncertainty and will have very little time to consider what to do with the information.

Thinking even further into the future, one of the concerns is that it could potentially change the way people think about pregnancy because it might be perceived that they have a lot of choices to make about what kind of children they want to have. Moving from a limited set of conditions to potentially any kind of human trait that has a major genetic component could really change the way people think about pregnancy and prenatal testing.

Ms. Dorfman: How does this potentially expanded capability reconcile with current practice guidelines and policy statements related to genetic testing in children? For example, the American Academy of Pediatrics Committee on Genetics’ recommendations on ethical issues with genetic testing in pediatrics,[3] or the National Society of Genetic Counselors’ position statements on prenatal and childhood testing for adult-onset disorders.[4]

Dr. Cho: There is going to have to be some further thought about how this kind of fetal testing might be used by clinicians. The current guidelines don’t really speak to whether there are professional limits on what clinicians will and will not use genetic testing for, so the clinical communities will have to ask themselves whether there are any genetic traits for which they won’t offer testing, or whether there are any limits on information that they will provide to patients.

Ms. Dorfman: As a follow-up to that, the editor’s summary of the University of Washington study that was published in Science Translational Medicine [1] stated, “An ideal prenatal genetic diagnostic would noninvasively screen for all Mendelian disorders early in pregnancy.” I was wondering whether you agreed with or had any comments about that statement.

Dr. Cho: We have to think about what “ideal” means to different people. We can currently test for a lot of mendelian conditions, and yet a lot of people don’t opt to get those tests. For a lot of people, that kind of information might be unwanted; some of it may be the kind of information that won’t have any bearing on how people treat their pregnancies, or it may not be relevant until after the child is born. I think that’s something that can be debated, whether that’s an ideal situation or not.

Ms. Dorfman: NIPD requires a blood sample from the pregnant woman, and as you have described, carries no risk for miscarriage or direct fetal harm. Of note, this has raised concerns about inadequate informed consent, and I was hoping that you can comment on where this concern came from.

Dr. Cho: People who are already familiar with prenatal screening tests that analyze maternal serum already know that sometimes, women may not realize that one of the blood samples taken during pregnancy was not used to check their blood glucose, but was actually a prenatal screening test. So I think the concern is that if there isn’t a specific and unique procedure that is part of the prenatal testing process, it could go almost unnoticed until the results come back — and then be a shock to people who get the results. They might not understand the implications of this type of testing.

Ms. Dorfman: Is there consensus about the information and risks that should be disclosed in the informed consent process before NIPD?

Dr. Cho: I don’t think there is consensus on how to deal with information that should be disclosed in almost any clinical situation, and no, I don’t think that there is consensus for how to deal with genomic results and NIPD.

Ms. Dorfman: What risks do you think should be disclosed before testing?

Dr. Cho: People should understand that a prenatal test is being done and that the information they might receive from that test could be very broad and potentially have a major impact on decision-making. And if they have a choice to not get all that information, they should understand that as well.

The consent process should note the risk for getting information that the person might not want, and also that the information might affect family members as well, who may not be interested in getting genomic information.

Ms. Dorfman: Noninvasive testing using cell-free fetal DNA can be used to determine fetal gender as early as 7 weeks’ gestation. Is there any reason to think that this will promote prenatal sex selection in regions where this has not been a problem or exacerbate the practice in regions where this is already a concern?

Ms. Cho: There might be reason to be concerned about the use of cell-free fetal DNA testing for sex selection, especially in areas where gender imbalance is already widespread. Even if there are laws against sex selection, it would be relatively easy to get a blood sample and also relatively easy to send it out of the country, and to get a result back.

It’s something to be aware of and keep tabs on. Companies that offer testing will have to think about how they’re going to determine whether the samples are being used for things that are actually illegal in other countries; it may be their obligation to ensure that they’re not contributing to illegal behavior.

Ms. Dorfman: The American College of Obstetrics and Gynecology has published a position statement that this new technology should not be used for the purposes of sex selection.[5] Do you have any recommendations on what, if anything, should be done proactively to prevent that from becoming an issue in such countries as the United States, where we don’t see this as an issue but where we also don’t have laws banning it?

Dr. Cho: There is a professional stance against sex testing in the United States. But in places where sex testing is not necessarily against professional guidelines or is illegal, there needs to be more thought about what responsibility the testing companies have and what practical measures laboratories can take to ensure that they’re not potentially violating the law.

Ms. Dorfman: There is significant interest in whether and when to return genetic results to patients. How does this take shape in NIPD?

Dr. Cho: This question of returning results of genomic findings may be even more important in prenatal testing than in other clinical situations. In prenatal settings, patients typically have very broad autonomy to make decisions about what kind of information they seek and about what kind of information they have access to. It’s a little different from returning results in, say, adult medicine where you could argue that genomic results shouldn’t be treated any differently from other kinds of medical testing. But in the prenatal setting, there is usually such a premium put on autonomy of the patient to make decisions about her pregnancy that it puts the issue of returning results in a bit of a different light.

Ms. Dorfman: Noninvasive methods that require both a maternal and a paternal sample to determine which of the DNA segments are from the fetus could introduce additional opportunities for incidental findings. Could you comment on that?

Dr. Cho: I agree; when you’re getting samples from the mother and the father, you definitely have a much greater potential for incidental findings. It should be part of the consent process and their understanding of what kind of results they may potentially get back.

Ms. Dorfman: What efforts are currently under way to characterize how NIPD is affecting clinical practice and reproductive decision-making, if any?

Dr. Cho: Some people are studying the clinical implementation of NIPD, which is currently limited to aneuploidy detection. I don’t know that it’s being studied broadly for applications other than aneuploidy at this point, but I imagine that will happen in the near future.

A side issue that might become influential in the application of cell-free fetal DNA research to clinical practice is the question of intellectual property and whether patents for cell-free fetal DNA testing might affect how clinicians can or cannot use the test. The ethical side of this is how or whether intellectual property policy should be allowed to dictate how clinical tests are or are not available to clinicians and patients.

Ms. Dorfman: Looking ahead, how do you think can we best maximize the benefits of cell-free fetal DNA testing capabilities while minimizing the potential harm? Are there regulations or policies that can be implemented that you think would yield a favorable balance of risks and benefits?

Dr. Cho: That’s a good question, but I don’t have a very good answer. Some of the concerns about potentially eugenic uses of cell-free fetal DNA in a prenatal setting are very difficult to address at the policy level, and we haven’t done a very good job of that so far with other kinds of prenatal testing. A lot will depend on such things as informed consent, which has not proven very effective right now for other types of prenatal testing, so it is likely going to be a difficult problem to tackle.

The US Food and Drug Administration might be more willing to regulate this kind of genetic testing than other kinds of genetic testing simply because the nature of the decisions made in the prenatal setting are so much more ethically fraught and important. More specific scrutiny of prenatal genetic testing, putting into play some kind of mechanism for quality control, quality assessment, and accuracy at an analytic level would at least help to minimize some of the risks from having inaccurate results.

But the large social and ethical issues are going to be very difficult to address through policy, and clinicians are going to have a hard time dealing with them. Up to this point, we’ve been very reluctant to interfere with prenatal decision-making. Much of this will probably end up being left to public education efforts, which may be of limited effectiveness.

References

  1. Kitzman JO, Snyder MW, Ventura M, et al. Noninvasive whole-genome sequencing of a human fetus. Sci Transl Med. 2012;4:137ra76.
  2. Fan HC, Gu W, Wang J, Blumenfeld YJ, El-Sayed YY, Quake SR. Non-invasive prenatal measurement of the fetal genome. Nature. 2012;487:320-324. Abstract
  3. Committee on Bioethics. Ethical issues with genetic testing in pediatrics. Pediatrics. 2001;107:1451-1455. Abstract
  4. National Society of Genetic Counselors. Position Statement: Prenatal and Childhood Testing for Adult-onset Disorders. 1995. http://www.nsgc.org/Advocacy/PositionStatements/tabid/107/Default.aspx#PrenatalChildTestingAdultOnsetAccessed July 12, 2012.
  5. American College of Obstetrics and Gynecology. ACOG Committee Opinion: Sex Selection; February 2007 (reaffirmed 2011). http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Ethics/Sex_SelectionAccessed July 12, 2012.

Medscape Genomic Medicine © 2012 WebMD, LLC

Retrieved from: http://www.medscape.com/viewarticle/771190?src=nl_topic

 

Your brain on books…

In Brain imaging, Brain studies, Education, Neuroscience on Friday, 21 September 2012 at 04:30

today’s technology has led to SO many amazing breakthroughs and allows for new and more precise understanding of so many things.  possible genetic markers for autism (and a possible vaccine), neurogenesis, new understandings of ADHD and treatment implications, just to name a few i have posted about.  following is an article on reading and our brains.  while fMRI’s have been around a while, it is through such instruments that we are really changing our understanding of the brain and its related functions.  i remember when i first read yvette sheline’s article* on hippocampal volume in 2003 that i realized we were at a turning point in brain research and understanding how the brain works.  from that point on, my interest in all things ‘neuro’ became much stronger.  the following is an article on reading and the brain.  while i can’t conceptualize what i would do if i didn’t have reading as an outlet.  i know, for some, reading is a “necessary evil” and while those people might read all day at work (work-related) are unlikely to read for pleasure.  maybe this research will help to convince people that reading has SO many benefits besides being able to get completely lost in a book.  happy reading, everyone!

*Sheline’s article: http://www.ncbi.nlm.nih.gov/pubmed/12900317 (the one that hooked me)

MRI reveals brain’s response to reading

Posted By Stanford On September 10, 2012 @ 4:13 pm In Science & Technology

STANFORD (US) — Researchers asked people to read Jane Austen in an MRI machine, and say the surprising results suggest reading closely could be “training” for our brains.

Neurobiological experts, radiologists, and humanities scholars are working together to explore the relationship between reading, attention, and distraction—by reading Jane Austen.

Surprising preliminary results reveal a dramatic and unexpected increase in blood flow to regions of the brain beyond those responsible for “executive function,” areas which would normally be associated with paying close attention to a task, such as reading, says Natalie Phillips, the literary scholar leading the project.

During a series of ongoing experiments, functional magnetic resonance images track blood flow in the brains of subjects as they read excerpts of a Jane Austen novel. Experiment participants are first asked to skim a passage leisurely as they might do in a bookstore, and then to read more closely, as they would while studying for an exam.

Phillips says the global increase in blood flow during close reading suggests that “paying attention to literary texts requires the coordination of multiple complex cognitive functions.” Blood flow also increased during pleasure reading, but in different areas of the brain. Phillips suggests that each style of reading may create distinct patterns in the brain that are “far more complex than just work and play.”

The experiment focuses on literary attention, or more specifically, the cognitive dynamics of the different kinds of focus we bring to reading. This experiment grew out of Phillips’ ongoing research about Enlightenment writers who were concerned about issues of attention span, or what they called “wandering attention.”

Phillips, who received her PhD in English literature at Stanford in 2010, is now an assistant professor of English at Michigan State University. She says one of the primary goals of the research is to investigate the value of studying literature.

Beyond producing good writers and thinkers, she is interested in “how this training engages the brain.”

The research is “one of the first fMRI experiments to study how our brains respond to literature,” Phillips says, as well as the first to consider “how cognition is shaped not just by what we read, but how we read it.”

Print overload

Critical reading of humanities-oriented texts are recognized for fostering analytical thought, but if such results hold across subjects, Phillips says it would suggest “it’s not only what we read—but thinking rigorously about it that’s of value, and that literary study provides a truly valuable exercise of people’s brains.”

Though modern life’s cascade of beeps and buzzes certainly prompts a new kind of distraction, Phillips warns against “adopting a kind of historical nostalgia, or assuming those of the 18th century were less distracted than we are today.”

Many Enlightenment writers, Phillips notes, were concerned about how distracted readers were becoming “amidst the print-overload of 18th-century England.”

Rather than seeing the change from the 18th century to today as a historical progression toward increasing distraction, Phillips likes to think of attention in terms of “changing environmental, cultural, and cognitive contexts: what someone’s used to, what they’re trying to pay attention to, where, how, when, for how long, etc.”

Ironically, the project was born out of a moment of distraction. While sitting on a discussion panel (which happened to be one of the first on cognitive approaches to literature), Phillips found herself distracted from the talk by the audience’s varieties of inattention: “One man was chatting to his neighbor; another person was editing their talk; one guy was looking vaguely out the window; a final had fallen asleep.”

The talk inspired Phillips to consider connections between her traditional study of 18th-century literature and a neuroscientific approach to literary analysis.

Phillips was especially intrigued by the concept of cognitive flexibility, which she defines as “the ability to focus deeply on one’s disciplinary specialty, while also having the capacity to pay attention to many things at once,” such as connections between literature, history of mind, philosophy, neuroscience, and so on.

Samantha Holdsworth, a research scientist specializing in MRI techniques, recalls an early conversation about the project when two scientists were trying to communicate with three literary scholars: “We were all interested, but working at the edge of our capacity just to understand even 10 percent of what each other were saying.”

Heightened attention

After working through the challenges of disciplinary lingo, the team devised a truly interdisciplinary experiment. Participants read a full chapter from Mansfield Park, which is projected onto a mirror inside an MRI scanner. Together with a verbal cue, color-coding on the text signals participants to move between two styles of attention: reading for pleasure or reading with a heightened attention to literary form.

The use of the fMRI allows for a dynamic picture of blood flow in the brain, “basically, where neurons are firing, and when,” says Phillips. Eye-tracking compatible with fMRI shows how people’s eyes move as they read. As Phillips explains, the micro-jumps of the eyes “can be aligned with the temporal blood flow to different regions in the brain.”

When participants are done with a chapter, they leave the scanner and write a short literary essay on the sections they analyzed closely. The test subjects, all literary PhD candidates from the Bay Area, were chosen because Phillips felt they could easily alternate between close reading and pleasure reading.

After reviewing early scans, neuroscientist Bob Doherty, director of the Stanford Center for Cognitive and Neurobiological Imaging (CNI), says he was impressed by “how the right patterns of ink on a page can create vivid mental imagery and instill powerful emotions.”

Doherty was also surprised to see how “a simple request to the participants to change their literary attention can have such a big impact on the pattern of activity during reading.”

The researchers expected to see pleasure centers activating for the relaxed reading and hypothesized that close reading, as a form of heightened attention, would create more neural activity than pleasure reading.

If the ongoing analysis continues to support the initial theory, Phillips says, teaching close reading (i.e., attention to literary form) “could serve—quite literally—as a kind of cognitive training, teaching us to modulate our concentration and use new brain regions as we move flexibly between modes of focus.”

With the field of literary neuroscience in its infancy, Phillips says this project is helping to demonstrate the potential that neuroscientific tools have to “give us a bigger, richer picture of how our minds engage with art—or, in our case, of the complex experience we know as literary reading.”

Source: Stanford University

Article printed from Futurity.org: http://www.futurity.org

URL to article: http://www.futurity.org/science-technology/mri-reveals-brain%e2%80%99s-response-to-reading/

For more information on Dr. Sheline and her work: http://wuphysicians.wustl.edu/physician2.aspx?PhysNum=1319http://wuphysicians.wustl.edu/physician2.aspx?PhysNum=1319

New autism research (with promising findings…)

In Autism Spectrum Disorders, Neuroscience, Psychiatry on Tuesday, 18 September 2012 at 16:24

some promising new studies on autism.  the first discusses the development of a genetic test that may be able to predict the risk of developing an asd.  while gene studies bring up both ethical and moral concerns for some, the findings and possible implications can not be dismissed.  the next study discusses the possibility of a drug involving glutamate receptor antagonists as a treatment for asd.  good stuff…ENJOY!

Genetic Test Predicts Risk for Autism Spectrum Disorder

Australian researchers have developed a genetic test that is able to predict the risk of developing autism spectrum disorder (ASD). (Credit: © Lucian Milasan / Fotolia)

ScienceDaily (Sep. 11, 2012) — A team of Australian researchers, led by University of Melbourne has developed a genetic test that is able to predict the risk of developing autism spectrum disorder (ASD).

Lead researcher Professor Stan Skafidas, Director of the Centre for Neural Engineering at the University of Melbourne said the test could be used to assess the risk for developing the disorder. “This test could assist in the early detection of the condition in babies and children and help in the early management of those who become diagnosed,” he said. “It would be particularly relevant for families who have a history of autism or related conditions such as Asperger’s syndrome,” he said.

Autism affects around one in 150 births and is characterized by abnormal social interaction, impaired communication and repetitive behaviours. The test correctly predicted ASD with more than 70 per cent accuracy in people of central European descent. Ongoing validation tests are continuing including the development of accurate testing for other ethnic groups.

Clinical neuropsychologist, Dr Renee Testa from the University of Melbourne and Monash University, said the test would allow clinicians to provide early interventions that may reduce behavioural and cognitive difficulties that children and adults with ASD experience. “Early identification of risk means we can provide interventions to improve overall functioning for those affected, including families,” she said.

A genetic cause has been long sought with many genes implicated in the condition, but no single gene has been adequate for determining risk. Using US data from 3,346 individuals with ASD and 4,165 of their relatives from Autism Genetic Resource Exchange (AGRE) and Simons Foundation Autism Research Initiative (SFARI), the researchers identified 237 genetic markers (SNPs) in 146 genes and related cellular pathways that either contribute to or protect an individual from developing ASD.

Senior author Professor Christos Pantelis of the Melbourne Neuropsychiatry Centre at the University of Melbourne and Melbourne Health said the discovery of the combination of contributing and protective gene markers and their interaction had helped to develop a very promising predictive ASD test.

The test is based on measuring both genetic markers of risk and protection for ASD. The risk markers increase the score on the genetic test, while the protective markers decrease the score. The higher the overall score, the higher the individual risk.

“This has been a multidisciplinary team effort with expertise across fields providing new ways of investigating this complex condition,” Professor Pantelis said.

The study was undertaken in collaboration with Professor Ian Everall, Cato Chair in Psychiatry and Dr Gursharan Chana from the University of Melbourne and Melbourne Health, and Dr Daniela Zantomio from Austin Health.

The next step is to further assess the accuracy of the test by monitoring children who are not yet diagnosed over an extended study. The study has been published today in the journal Molecular Psychiatry.


Story Source:

The above story is reprinted from materials provided by University of Melbourne.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

University of Melbourne (2012, September 11). Genetic test predicts risk for autism spectrum disorder. ScienceDaily. Retrieved September 18, 2012, from http://www.sciencedaily.com­ /releases/2012/09/120912093827.htm?goback=.gde_2514160_member_163245605

Retrieved from: http://www.sciencedaily.com/releases/2012/09/120912093827.htm?goback=.gde_2514160_member_163245605

***

Disorder of Neuronal Circuits in Autism is Reversible

14 September 2012 08:43 Universität Basel

People with autism suffer from a pervasive developmental disorder of the brain that becomes evident in early childhood. Peter Scheiffele and Kaspar Vogt, Professors at the Biozentrum of the University of Basel, have identified a specific dysfunction in neuronal circuits that is caused by autism. In the respected journal „Science“, the scientists also report about their success in reversing these neuronal changes. These findings are an important step in drug development for the treatment for autism.

According to current estimates, about one percent of all children develop an autistic spectrum disorder. Individuals with autism may exhibit impaired social behavior, rigid patterns of behavior and limited speech development. Autism is a hereditary developmental disorder of the brain. A central risk factor for the development of autism are numerous mutations in over 300 genes that have been identified, including the gene neuroligin-3, which is involved in the formation of synapses, the contact junction between nerve cells.

Loss of neuroligin-3 interferes with neuronal signal transmission

The consequences of neuroligin-3 loss can be studied in animal models. Mice lacking the gene for neuroligin-3 develop behavioral patterns reflecting important aspects observed in autism. In collaboration with Roche the research groups from the Biozentrum at the University of Basel have now identified a defect in synaptic signal transmission that interferes with the function and plasticity of the neuronal circuits. These negative effects are associated with increased production of a specific neuronal glutamate receptor, which modulates the signal transmission between neurons. An excess of these receptors inhibits the adaptation of the synaptic signal transmission during the learning process, thus disrupting the development and function of the brain in the long term.

Of major importance is the finding that the impaired development of the neuronal circuit in the brain is reversible.  When the scientists reactivated the production of neuroligin-3 in the mice, the nerve cells scaled down the production of the glutamate receptors to a normal level and the structural defects in the brain typical for autism disappeared. Hence, these glutamate receptors could be a suitable pharmacological target in order to stop the developmental disorder autism or even reverse it.

Vision for the future: Medication for autism

Autism currently cannot be cured.  At present, only the symptoms of the disorder can be alleviated through behavioral therapy and other treatment. A new approach to its treatment, however, has been uncovered through the results of this study. In one of the European Union supported projects, EU-AIMS, the research groups from the Biozentrum are working in collaboration with Roche and other partners in industry on applying glutamate receptor antagonists for the treatment of autism and hope, that in the future, this disorder can be treated successfully in both children and adults.

http://www.unibas.ch/index.cfm?uuid=BF9F46B0ADFE4138B2556373D7286FD5&type=search&show_long=1

  • Full bibliographic information: Baudouin S. J., Gaudias J., Gerharz S., Hatstatt L., Zhou K., Punnakkal P., Tanaka K. F., Spooren W., Hen R., De Zeeuw C.I., Vogt K., Scheiffele K.
    Shared Synaptic Pathophysiology in Syndromic and Non-syndromic Rodent Models of Autism
    Science; Published online September 13 (2012) | doi: 10.1126/science.1224159

 

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis

In Neuroscience, Psychiatry, School Psychology on Thursday, 13 September 2012 at 13:03

Molecular Psychiatry advance online publication 11 September 2012; doi: 10.1038/mp.2012.126

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2012126a.html

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis
E Skafidas1, R Testa2,3, D Zantomio4, G Chana5, I P Everall5 and C Pantelis2,5

  1. 1Centre for Neural Engineering, The University of Melbourne, Parkville, VIC, Australia
  2. 2Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, VIC, Australia
  3. 3Department of Psychology, Monash University, Clayton, VIC, Australia
  4. 4Department of Haematology, Austin Health, Heidelberg, VIC, Australia
  5. 5Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia

Correspondence: Professor C Pantelis, National Neuroscience Facility (NNF), Level 3, 161 Barry Street, Carlton South, VIC 3053, Australia. E-mail: cpant@unimelb.edu.au

Received 6 July 2012; Accepted 9 July 2012
Advance online publication 11 September 2012

Abstract

Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.

Introduction

Autism spectrum disorders (ASDs) are a complex group of sporadic and familial developmental disorders affecting 1 in 150 births1 and characterized by: abnormal social interaction, impaired communication and stereotypic behaviors.2 The etiology of ASD is poorly understood, however, a genetic basis is evidenced by the greater than 70% concordance in monozygotic twins and elevated risk in siblings compared with the population.3, 4, 5 The search for genetic loci in ASD, including linkage and genome-wide association screens (GWAS), has identified a number of candidate genes and loci on almost every chromosome,6, 7, 8, 9, 10, 11 with multiple hotspots on several chromosomes (for example, CNTNAP2, NGLNX4, NRXN1, IMMP2L, DOCK4, SEMA5A, SYNGAP1, DLGAP2, SHANK2 and SHANK3),7, 12, 13, 14, 15 and copy number variations.9, 13, 16, 17, 18, 19, 20, 21 However, none of these have provided adequate specificity or accuracy to be used in ASD diagnosis. Novel approaches are required22 to examine multiple genetic variants and their additive contribution19, 23, 24 taking into account genetic differences between ethnicities and consideration of protective versus vulnerability single-nucleotide polymorphisms (SNPs).

The present study interrogated the Autism Genetics Resource Exchange (AGRE)25 SNP data with two aims: (1) to identify groups of SNPs that populate known cellular pathways that may be pathogenic or protective for ASD, and (2) to apply machine learning to identified SNPs to generate a predictive classifier for ASD diagnosis.26 The results were validated in two independent samples: the US Simons Foundation Autism Research Initiative (SFARI) and UK Wellcome Trust 1958 normal birth cohort (WTBC). This novel and strategic approach assessed the contribution of various SNPs within an additive SNP-based predictive test for ASD.

Materials and methods

The University of Melbourne Human Research Ethics Committee approved the study (Approval Numbers 0932503.1, 0932503.2).

Subjects

(i) Index sample: subject data from 2609 probands with ASD (including Autism, Asperger’s or Pervasive Developmental Disorder-not otherwise specified, but excluding RETT syndrome and Fragile X), and 4165 relatives of probands, was available from AGRE (http://www.agre.org); 1862 probands and 2587 first-degree relatives had SNP data from the Illumina 550 platform relevant to analyses (Figure 1a). Diagnosis of ASD was made by a specialist clinician and confirmed using the Autism Diagnostic Interview Revised (ADI-R27). Control training data was obtained from HapMap28 instead of relatives, as the latter may possess SNPs that predispose to ASD and skew analysis (Figures 1a and b).

Figure 1.

(a and b) Flow charts show the subjects used in the analyses. Key: AGRE, Autism Genetic Research Exchange; SFARI, Simons Foundation Autism Research Initiative; WTBC, Wellcome Trust 1958 normal birth cohort; CEU, of Central (Western and Northern) European origin; HAN, of Han Chinese origin; TSI, of Tuscan Italian origin; For panels 1a and b: ‘red boxes’—samples used in developing the predictive algorithm; ‘blue boxes’—samples used to investigate different ethnic groups; ‘green boxes’—validation sets; ‘light green boxes’—relatives assessed, including parents and unaffected siblings. Numbers in brackets represent numbers of males/females.

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(ii) Independent validation samples: 737 probands with ASD (ADI-R diagnosed) derived from SFARI; 2930 control subjects from WTBC (Figure 1b).

As SNP incidence rates vary according to ancestral heritage, HapMap data (Phase 3 NCBI build 36) was utilized to allocate individuals to their closest ethnicity. Individuals of mixed ethnicity were excluded; HapMap data has 1 403 896 SNPs available from 11 ethnicities. Any SNPs not included in the AGRE data measured on the Illumina 550 platform were discarded, resulting in 407 420 SNPs. Mitochondrial SNPs reported in AGRE, but not available in HapMap were excluded. The 30 most prevalent (>95%) SNPs within each ethnicity were identified and each ASD individual assigned to the group for which they shared the highest number of ethnically specific SNPs. HapMap groups were determined to be appropriate for analysis, as prevalence rates of the 30 SNPs relevant to each ethnicity were similar for each AGRE group assigned to that ethnicity, P<0.05.

Gene set enrichment analysis (GSEA)

Pathway analysis was selected because it depicts how groups of genes may contribute to ASD etiology (Supplementary S1) and mitigates the statistical problem of conducting a large number of multiple comparisons required in GWAS studies. The current pathway analysis differs from previous ASD analyses in three unique ways: (1) we divided the cohort into ethnically homogeneous samples with similar SNP rates; (2) both protective and contributory SNPs were accounted for in the analysis and (3) the pathway test statistic was calculated using permutation analysis. Although this is computationally expensive, benefits include taking account of rare alleles, small sample sizes and familial effects. It also relaxes the Hardy–Weinberg equilibrium assumption, that allele and genotype frequencies remain constant within a population over generations. Pathways were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and SNP-to-gene data obtained from the National Center for Biotechnology Information (NCBI). Intronic and exonic SNPs were included. AGRE individuals most closely matching the genetics of Utah residents of Western and Northern European (CEU), Tuscan Italian (TSI) and Han Chinese origin were used in the analysis. CEU individuals (975 affected individuals and 165 controls) were chosen as the index sample, representing the largest group affected in AGRE (Figure 1a). The CEU and Han Chinese had 116 753 SNPs that differed, whereas the CEU and TSI had 627 SNPs, differing in allelic prevalence at P<1 × 10−5. The pathway test statistic was calculated for CEU and Han individuals using a ‘set-based test’ in the PLINK29 software package, with P=0.05, r2=0.5 and permutations set to at least 2 000 000. Significance threshold was set conservatively at P<1 × 10−5, calculated from the number of pathways being examined (200). Therefore, significance was <0.05/200, set at <1 × 10−5 (see Supplementary S1).

Predicting ASD phenotype based upon candidate SNPs

For each individual, a 775-dimensional vector was constructed, corresponding to 775 unique SNPs identified as part of the GSEA. To examine whether SNPs could predict an individual’s clinical status (ASD versus non-ASD), two-tail unpaired t-tests were used to identify which of the 775 SNPs had statistically significant differences in mean SNP value (P<0.005). This significance level provided low classification error while maintaining acceptable variance in estimation of regression coefficients for each SNP’s contribution status, and provided the set of SNPs that maximized the classifier output between the populations (Figure 2 and Supplementary S2). This resulted in 237 SNPs selected for regression analysis. Each dimension of the vector was assigned a value of 0, 1 or 3, dependent on a SNP having two copies of the dominant allele, heterozygous or two copies of the minor allele. The ‘0, 1, 3’ weighting provided greater classification accuracy over ‘0, 1, 2’. Such approaches using superadditive models have been used previously to understand genetic interactions.30 The formula for the classifier and classifier performance are presented in Supplementary S3.

Figure 2.

Cumulative coefficient estimation error and percentage classification error as a function of P-value; P=0.005 provides good trade-off between classification performance and cumulative regression coefficient error.

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The CEU sample was divided into a training set (732 ASD individuals and 123 controls) and the remainder comprised the validation set. An affected individual was given a value of 10 and an unaffected individual a value of −10, providing a sufficiently large separation to maximize the distance between means (see Supplementary S3). Least squares regression analysis of the training set determined coefficients whose sum over product by SNP value mapped SNPs to clinical status. Kolmogorov–Smirnov goodness of fit test assessed the nature of distribution of SNPs by classification. At P=0.05, the distributions were accepted as being normally distributed, allowing determination of positive and negative predictive values (see ROC, Supplementary S4). The Durbin–Watson test was used to investigate the residual errors of the training set to determine if further correlations existed. At P=0.05, the residuals were uncorrelated. Regression coefficients were used to assess individual SNP contribution to clinical status.

AGRE validation

After analyzing the CEU training cohort, three cohorts were used for validation: 285 (243 probands, 42 controls) CEUs; a genetically similar TSI sample (65 patients, 88 controls); and a genetically dissimilar Han Chinese population (33 patients, 169 controls). To illustrate overlap in SNPs in first-degree relatives of individuals with ASD (n=1512), we mapped the SNPs of parents (n=1219; 581 male) and unaffected siblings (n=293; 98 male) of CEU origin who did not meet criteria for ASD. Finally, the accuracy of the predictive model was modified to test predictive ability using 10, 30 and 60 SNPs having the greatest weightings.

Independent validation

Samples included 507 CEU and 18 TSI subjects with ASD from SFARI, and 2557 CEU and 63 TSI from WTBC (Figure 1b).

Results

Identification of affected pathways

Analyses focused on 975 CEU ASD individuals, in which 13 KEGG pathways were significantly affected (P<1 × 10−5). The pathway analysis identified 775 significant SNPs perturbed in ASD. A number of the pathways were populated by the same genes and had inter-related functions (Table 1).

Table 1 – Statistically significant pathways for the CEU and Han Chinese.

Full table

The most significant pathways were: calcium signaling, gap junction, long-term depression (LTD), long-term potentiation (LTP), olfactory transduction and mitogen-activated kinase-like protein signaling. GSEA on the genetically distinct Han Chinese identified six pathways that overlapped with 13 pathways in the CEU cohort (estimate of this occurring by chance, P=0.05), including: purine metabolism, calcium signaling, phosphatidylinositol signaling, gap junction, long-term potentiation and long-term depression. Related to these pathways, the statistically significant SNPs in both populations were rs3790095 within GNAO1, rs1869901 within PLCB2, rs6806529 within ADCY5 and rs9313203 in ADCY2.

Diagnostic prediction of ASD

From the 775 SNPs identified within the CEU cohort, accurate genetic classification of ASD versus non-ASD was possible using 237 SNPs determined to be highly significant (P<0.005). Figure 3a shows the distribution of ASD and non-ASD individuals based on genetic classification. An individual’s clinical status was set to ASD if their score exceeded the threshold of 3.93. This threshold corresponds to the intersection points of the two normal curves. The theoretical classification error was 8.55%, and positive (ASD) and negative predictive values (controls) were 96.72% and 94.74%, respectively. Classification accuracy for the 285 CEU AGRE validation individuals was 85.6% and 84.3% for the TSI, while accuracy for the Han Chinese population was only 56.4%. Using the same classifier with the identical set of SNPs, accuracy of prediction of ASD in the independent data sets was 71.6%; positive and negative predictive accuracies were 70.8% and 71.8%, respectively.

Figure 3.

(a) Genetic-based classification of CEU population (AGRE and Controls) for ASD and non-ASD individuals, showing Gaussian approximation of distribution of individuals. As both the mapped ASD and control populations were well approximated by normal distributions, the asymptotic Test Positive Predictive Value (PPV) and Negative Predictive Value (NPV) was determined. For individuals with CEU ancestry, the PPV and NPV were 96.72% and 94.74%, respectively. (Note the test was substantially less predictive on individuals with different ancestry, that is, Han Chinese). (b) Genetic-based classification of CEU population, including first-degree relatives (parents and siblings of ASD children). Note that the distribution of relatives of ASD children maps between the ASD and the control groups, with no difference found between mothers and fathers (see Supplementary material S5). Key: ASD, autism spectrum disorder; relatives, first-degree relatives (parents and siblings); Siblings, siblings of ASD cases not meeting criteria for ASD; Autism Classifier Score, scores for each individual derived from the predictive algorithm, with greater values representing greater risk for autism.

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SNPs were compared with the affected and unaffected individuals. Figure 3b shows that relatives (parents and unaffected siblings combined) fall between the two distributions, with a mean score of 2.68 (s.d.=2.27). The percentage overlap of the relatives and affected individuals was 30.4%. The mean scores of the mothers and fathers did not differ (at P=0.05) with scores of 2.83 (s.d.=2.17) and 2.93 (s.d.=2.34), respectively (see Supplementary S5), whereas unaffected siblings (not meeting diagnostic criteria for ASD) fell between parents and cases (mean=4.74, s.d.=3.80). In testing the robustness of the predictive model, using fewer SNPs monotonically decreased accuracy in the AGRE-CEU analyses to 72% for 60 SNPs, 58% for 30 SNPs and 53.5% for 10 SNPs, with the distribution of parents being indistinguishable from controls.

Of the 237 SNPs within our classifier, presence of some contributed to vulnerability to ASD (Table 2a), whereas others were protective (Table 2b). Eight SNPs in three genes, GRM5, GNAO1 and KCNMB4, were highly discriminatory in determining an individual’s classification as ASD or non-ASD. For KCNMB4, rs968122 highly contributed to a clinical diagnosis of ASD, whereas rs12317962 was protective; for GNAO1, SNP rs876619 contributed, whereas rs8053370 was protective; for GRM5, SNPs rs11020772 was contributory, whereas rs905646 and rs6483362 were protective.

Table 2 – List of 15 most contributory (Table 2a) and 15 most protective (Table 2b) SNPs for ASD diagnosis in the CEU Cohort.

Full table

Discussion

Using pathway analysis, we have generated a genetic diagnostic classifier based on a linear function of 237 SNPs that accurately distinguished ASD from controls within a CEU cohort. This same diagnostic classifier was able to correctly predict and identify ASD individuals with accuracy exceeding 85.6% and 84.3% in the unseen CEU and TSI cohorts, respectively. Our classifier was then able to predict ASD group membership in subjects derived from two independent data sets with an accuracy of 71.6%, thus greatly adding strength to our original finding. However, the classifier was sub-optimal at predicting ASD in the genetically distinct Han Chinese cohort, which may be explained by differences in allelic prevalence. Although only 627 SNPs significantly differed between the TSI and CEU cohorts, this figure increased to 116 753 SNPs between the CEU and Han Chinese. It is likely that an additional set of SNPs may be predictive of ASD diagnosis in Han Chinese and that methods used for our classifier could be applicable to other ethnicities. Interestingly, parents and siblings of ASD-CEU individuals fell as distinct groups between the ASD and controls, reinforcing a genetic basis for ASD with neurobehavioral abnormalities reported in parents of ASD individuals also supporting our findings.31 When we altered the classifier by reducing the number of SNPs, not only did the predictive accuracy suffer but also the relatives merged into the control group. This suggests that use of relatives as controls in SNP GWAS studies is only valid when examining small numbers of SNPs and may not be appropriate when assessing genetic interactions.

There was considerable overlap in the pathways implicated in both the CEU and Han Chinese populations. The analysis demonstrated that SNPs in the Wnt signaling pathway contributed to a diagnosis of ASD in the CEU cohort, but not in the Han Chinese population. Although of interest, a firm conclusion regarding these differences and similarities will require replication in a larger Han Chinese population. Completion of diagnostic classification studies for other ethnic groups will invariably aid in identification of common pathological mechanisms for ASD.

The SNPs contributing most to diagnosis in our classifier corresponded to genes for KCNMB4, GNAO1, GRM5, INPP5D and ADCY8. The three SNPs that markedly skewed an individual towards ASD were related to the genes coding for KCNMB4, GNAO1 and GRM5. Homozygosity for KCNMB4 SNP carries a higher risk of ASD than SNPs related to GNAO1 and GRM5. By contrast, a number of SNPs protected against ASD, including rs8053370 (GNAO1), rs12317962 (KCNMB4), rs6483362 and rs905646 (GRM5). KCNMB4 is a potassium channel that is important in neuronal excitability and has been implicated in epilepsy and dyskinesia.32, 33 It is highly expressed within the fusiform gyrus, as well as in superior temporal, cingulate and orbitofrontal regions (Allen Human Brain Atlas, http://human.brain-map.org/), which are areas implicated in face identification and emotion face processing deficits seen in ASD.34 GNAO1 protein is a subgroup of Ga(o), a G-protein that couples with many neurotransmitter receptors. Ga(o) knockout mice exhibit ‘autism-like’ features, including impaired social interaction, poor motor skills, anxiety and stereotypic turning behavior.35 GNAO1 has also been shown to have a role in nervous development co-localizing with GRIN1 at neuronal dendrites and synapses,36 and interacting with GAP-43 at neuronal growth cones,37 with increased levels of GAP-43 demonstrated in the white matter adjacent to the anterior cingulate cortex in brains from ASD patients.38

In our findings, GRM5 SNPs have both a contributory (rs11020772) and protective (rs905646, rs6483362) effect on ASD. GRM5 is highly expressed in hippocampus, inferior temporal gyrus, inferior frontal gyrus and putamen (Allen Human Brain Atlas), regions implicated in ASD brain MRI studies.39 GRM5 has a role in synaptic plasticity, modulation of synaptic excitation, innate immune function and microglial activation.40, 41, 42, 43 GRM5-positive allosteric modulators can reverse the negative behavioral effects of NMDA receptor antagonists, including stereotypies, sensory motor gating deficits and deficits in working, spatial and recognition memory,44 features described in ASD.45, 46 With regard to GRM5’s involvement with neuroimmune function, this receptor is expressed on microglia,40, 47 with microglial activation demonstrated by us and others in frontal cortex in ASD.48, 49

Further, as GRM5 signaling is mediated via signaling through Gene Protein Couple Receptors, a possible interaction between GNAO1 and GRM5 is plausible. Genes such as PLCB2, ADCY2, ADCY5 and ADCY8 encode for proteins involved in G-protein signaling. Given this association, GRM5 may represent a pivotal etiological target for ASD; however, further work is needed in demonstrating these potential interactions and contribution to glutamatergic dysregulation in ASD.

In conclusion, within genetically homogeneous populations, our predictive genetic classifier obtained a high level of diagnostic accuracy. This demonstrates that genetic biomarkers can correctly classify ASD from non-ASD individuals. Further, our approach of identifying groups of SNPs that populate known KEGG pathways has identified potential cellular processes that are perturbed in ASD, which are common across ethnic groups. Finally, we identified a small number of genes with various SNPs of influential weighting that strongly determined whether a subject fell within the control or ASD group. Overall these findings indicate that a SNP-based test may allow for early identification of ASD. Further studies to validate the specificity and sensitivity of this model within other ethnic groups are required. A predictive classifier as described here may provide a tool for screening at birth or during infancy to provide an index of ‘at-risk status’, including probability estimates of ASD-likelihood. Identifying clinical and brain-based developmental trajectories within such a group would provide the opportunity to investigate potential psychological, social and/or pharmacological interventions to prevent or ameliorate the disorder. A similar approach has been adopted in psychosis research, which has improved our understanding of the disorder and prognosis for affected individuals.50

Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

Professor Christos Pantelis was supported by a NHMRC Senior Principal Research Fellowship (ID 628386). AGRE: We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. The Autism Genetic Resource Exchange is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M Lajonchere (PI). SFARI: We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A Beaudet, R Bernier, J Constantino, E Cook, E Fombonne, D Geschwind, R Goin-Kochel, E Hanson, D Grice, A Klin, D Ledbetter, C Lord, C Martin, D Martin, R Maxim, J Miles, O Ousley, K Pelphrey, B Peterson, J Piggot, C Saulnier, M State, W Stone, J Sutcliffe, C Walsh, Z Warren, E Wijsman). WTBC: We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G1234567 and the Wellcome Trust grant 012345.

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