lederr

Saw this today and found it positively fascinating!

In ADHD on Thursday, 6 September 2012 at 20:55

Adult ADHD: New Findings in Neurobiology and Genetics 

Scott H. Kollins, PhD

http://www.medscape.org/viewarticle/765528

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders, affecting approximately 8% to 9% of school-aged children and 2.5% to 4.4% of adults in the United States.[1-4] Variants of the disorder have been recognized in pediatric populations for more than 100 years (and according to some sources, more than 200 years).[5] Recognition of ADHD as a persistent condition that affects a substantial minority of adult patients has increased substantially in the past 20 years. For example, the search term “adult ADHD” identified a total of 39 articles in the National Library of Medicine database in 1991, compared with 558 articles in 2011.

In recent years, much work on adult ADHD has focused on characterizing the neurobiology of the adult condition. This overview of the current state of knowledge of adult ADHD includes findings from genetics and pharmacogenetics studies, and from neuroimaging studies, and describes the potential clinical implications of these neurobiological discoveries for ADHD diagnosis and treatment in adults.

Adult ADHD is the form of ADHD that results in symptomatic and functional impairment in individuals above the age of 18. Wide variation exists in estimates of the prevalence and persistence of ADHD from childhood through adolescence; this is related to how such persistence is defined (eg, by strict diagnostic criteria vs high levels of symptoms).[6,7] A meta-analysis of long-term follow-up studies reported that approximately 65% of individuals experiencing ADHD as children continued to exhibit impairment into adulthood.[7] This article focuses on understanding the genetic, neurobiological, and treatment outcome studies for this group of individuals.

Genetics of Adult ADHD

ADHD has consistently been shown to be among the most heritable of all psychiatric conditions. A range of methodological approaches exists for assessing the genetic contributions to ADHD, including family studies, adoption studies, twin studies, and molecular genetic studies. We will consider evidence from each of these approaches with respect to the genetics of adult ADHD.

Family, Adoption, and Twin Studies

Family studies evaluate the extent to which disorders “run” in families across and within generations. If the risk of having a disorder is higher in relatives of an identified “case” than in the general population, the likelihood of genetic influences contributing to the development of the disorder is higher. ADHD tends to cluster in families; risk for the disorder is higher in siblings and parents of diagnosed children and in children of diagnosed parents.[8,9] Moreover, siblings of adults diagnosed with variants of ADHD also have been shown to be at significantly greater risk.[10] Familial risk of ADHD is increased in relatives of individuals whose ADHD persists from childhood into adolescence and adulthood, suggesting that adult ADHD may be a particularly heritable variant of the disorder.[11,12]

Family studies cannot fully evaluate the relative genetic contributions to the development of ADHD since members of the same family are also likely to share environments that can give rise to the condition. Adoption and twin studies can help to control for such shared environmental influences. In general, the risk for ADHD and related difficulties is higher among the biological relatives of identified cases compared with adoptive relatives, suggesting a stronger role for genetic factors in the expression of the condition.[13,14]

Twin studies compare the concordance rates of ADHD in identical/monozygotic twins vs fraternal/dizygotic twin pairs. The extent to which concordance rates are higher among monozygotic twins reflects the relative genetic contributions to the disorder. Across several dozen studies of child twin pairs, ADHD is consistently one of the most highly heritable of all child psychiatric disorders, with most studies reporting heritability estimates of between 0.60 and 0.95, indicating that 60% to 95% of the variance in the presentation of the disorder can be accounted for by genetic factors.[15,16] In adult studies, however, heritability estimates are substantially lower: 30% to 41%.[17-19] The lower heritability estimates in adult studies of ADHD are likely associated with increased measurement error of the phenotype (eg, self-report ratings in adults may be less reliable and valid than parent/teacher ratings of symptoms in children). Nonetheless, the pattern of heritability findings in adult twin studies of ADHD are remarkably consistent with those observed in children, including no gender differences in heritability estimates, stability of heritability estimates across the age span, and similar correlations between the heritability of inattention vs hyperactivity-impulsivity symptoms.[20]

Molecular Genetic Studies

A number of techniques have been developed to isolate the specific gene(s) that confer risk for ADHD as shown by family, adoption, and twin studies. Two such methods include genome-wide association studies (GWAS) and candidate gene studies.

Genome-Wide Association Studies of ADHD

GWAS studies of ADHD and other psychiatric disorders have become increasingly common, due in part to the development of sophisticated analytical methods that are able to examine hundreds of thousands or even millions of single nucleotide polymorphisms (SNPs) across the entire genome. GWAS studies generally involve recruitment of hundreds or thousands of clinical case patients diagnosed with a well-characterized phenotype/disorder and a group of nondiagnosed comparison subjects. The statistical power for these so-called “case-control” designs to identify significant genetic markers for a particular disorder depends on a number of factors, including the total sample size, the relative genetic risk of the disorder, and the population frequency of the minor allele under study. An important component of GWAS studies is that they are atheoretical, with no a priori predictions about specific genes that may or may not be involved. Rather, the entire genome is probed to identify regions that are consistently associated with a disorder. As a result of this approach, however, rigorous statistical corrections are used to control for chance findings that might arise from a large number of tests. Studies therefore often refer to findings reaching “genome-wide” significance for a particular region being associated with a condition. Several good reviews of GWAS approaches in psychiatric genetics broadly[21] and ADHD specifically[22,23] have recently been published.

To date, only 2 studies have been published employing GWAS methods in samples of adults with ADHD, although a number of other GWAS studies have been reported with child samples. Lesch and colleagues[24] did not report any risk genes that met genome-wide significance for ADHD, but did report several candidates with considerable overlap with genes implicated in GWAS studies of substance use disorders, including genes coding for cell adhesion molecules and regulators of synaptic plasticity.[24] A more recent study reported that SNPs located in the diacylglycerol kinase eta (DGKH) gene were associated not only with adult ADHD but also bipolar disorder and unipolar major depression at levels that withstood stringent statistical corrections for multiple testing.[25] These data were interpreted to suggest that the mood dysregulation observed in all 3 of these conditions may be related to variation in the DGKH gene, which modulates the activity of protein kinase C, which has in turn been implicated in a range of psychiatric conditions, including ADHD, bipolar disorder, and substance use disorders.[26-28]

Although more limited in number, results from GWAS studies of adult ADHD have generally been more fruitful than similar approaches in studies of pediatric populations, which have failed to report findings reaching genome-wide significance.[29] If additional GWAS studies of adult samples demonstrate similar patterns of effects, it would suggest that relatively common genetic variants may exert stronger effects for persistent forms of ADHD (ie, the adult form of the disorder) than in child samples. In any case, it is increasingly recognized that GWAS studies for ADHD and other psychiatric conditions will require ever-growing, large, multi-institution, and multinational collaborations to assemble sample sizes large enough to detect relevant effects. It has been estimated that sample sizes exceeding 12,000 individuals (cases plus controls) will be required to detect genome-wide significant findings for ADHD.[20]

Candidate Gene Studies of Adult ADHD

In addition to GWAS studies, a second approach for identifying the genetic substrates of ADHD (or any complex disorder) is to identify specific genes that are hypothesized to be involved with the disorder and then examine whether variations in these genes are associated with aspects of the disorder. The genes are usually selected on the basis of a priori hypotheses about the causes of the disorder. Also, results from GWAS studies can suggest specific chromosomal regions or genes or both that may confer risk for ADHD. To date, hundreds of studies reporting on associations of dozens of candidate genes have emerged, though the majority of these studies have been conducted in pediatric populations. Meta-analyses of candidate gene studies of pediatric ADHD have reported replicable evidence for associations between variants of several candidate genes and risk for the disorder, including the dopamine transporter gene (DAT1) and the dopamine D4 receptor gene (DRD4), although even in meta-analytic studies, these results are not always consistent.[15,30-32]

Gene variants consistently found to confer risk for ADHD in pediatric populations have been the most widely studied candidates in genetic studies of adult ADHD. A recent review summarized studies of adult ADHD that examined the effects of variants in DAT1 and DRD4.[20] In general this review found that studies with adult samples did not follow the same pattern of findings as studies with pediatric samples with respect to these specific risk genes, suggesting that the relationship between DAT1 and DRD4 risk variants are different in pediatric ADHD compared with persistent adult ADHD. Other genes involved in dopamine neurotransmission have also been examined in samples of adults with ADHD. Several studies of adult ADHD and variants of the dopamine D5 (DRD5) receptor have reported similar results as pediatric ADHD studies, whereas studies of catecholamine-O-methyltransferase (COMT) have reported results in adult studies that conflict with results in children.[20]

Studies examining genes associated with serotonergic neurotransmission, noradrenergic neurotransmission, and neurotrophic factors have generally been inconsistent or negative, although some nominal associations have been reported. For example, 1 large study of adult ADHD with more than 3500 cases and controls reported some evidence of an association between a variant of the tryptophan hydroxylase 1 gene (TPH1) and risk for the disorder.[33] A handful of additional candidate genes have been identified but are in need of replication. Variants of the latrophilin 3 (LPHN3) gene,[34,35] the brain-specific angiogenesis inhibitor-1 associated protein (BAIAP2) gene,[36] and the nitric oxide synthase 1 (NOS1) gene[37] have all been found to be associated with adult ADHD in single studies and make theoretical sense in terms of how they may confer risk for the disorder. As such, independent replication of these findings will be critical in future studies.

Pharmacogenetic Studies of Adult ADHD

The use of molecular genetic approaches to predict drug treatment response in individuals with ADHD has considerable clinical implications.[38] A number of studies have examined both efficacy and adverse events with stimulant and nonstimulant treatment in children with ADHD. For example, variants of all of the following genes have been reported to be associated with differential treatment response in pediatric samples: adrenergic α 2-A receptor (ADRA2), DRD4, SNAP-25, DAT1, COMT, and the serotonin transporter genes.[39-44]

However, very few studies have examined the pharmacogenetics of adult ADHD. Three studies have examined variants of the DAT1 gene in relation to treatment response in adults with ADHD. One study reported a positive association between the DAT1 genotype and positive treatment response in 42 adults with ADHD.[45] However, 2 other studies failed to report an association between DAT1 and methylphenidate treatment response in considerably larger samples (N=106 and 142, respectively).[46,47] One additional study of the ADRA2 gene and treatment response to methylphenidate in adults with ADHD failed to report significant findings.[48]

Overall, research on the pharmacogenetics of adult ADHD is in its infancy. Given that a larger proportion of adults vs children with the disorder respond optimally to medication, and because a wide range of compounds affecting multiple brain systems has been evaluated or is currently being evaluated, pharmacogenetic studies of adult ADHD hold promise for truly individualizing treatment.

Neuroimaging in Adult ADHD

The field of neuroimaging has dramatically advanced our understanding of the neuroscience of all psychiatric disorders, including ADHD. As with studies in the genetics of ADHD, there are generally fewer neuroimaging studies in adults than in children. Nevertheless, the number of imaging studies in adults with ADHD has steadily increased in each of the last 5 years.

A wide range of imaging modalities can be used to probe different aspects of brain structure and function. Structural brain imaging techniques can examine brain volume and composition, whereas functional brain imaging studies can elucidate activity of the brain during certain tasks. In the following sections, we examine the evidence for altered brain structure and function in adults with ADHD, including a discussion of how these findings are similar to or different from neuroimaging studies in children.

Structural Neuroimaging Studies of Adult ADHD

Structural or morphometric magnetic resonance imaging (MRI) studies allow for the comparison of size, volume, or organization of the whole brain or specific brain regions in individuals with and without ADHD. Inferences can therefore be made about the functional significance of any differences that are identified. A number of studies in children with ADHD have reported reduced volume across a number of brain regions, including the basal ganglia, frontal lobes, and cerebellum.[49] Moreover, several longitudinal studies have shown that brain volume and cortical thickness and structure are maturationally delayed in children with ADHD.[50-53]

Structural imaging studies in adults have generally replicated findings reported in pediatric populations. Compared with studies of nondiagnosed peers, structural MRI studies in adults with ADHD have found overall reductions in cortical gray matter, and reductions in volume and cortical thickness in the superior frontal and orbitofrontal cortex, anterior cingulate cortex, inferior frontal cortex, dorsolateral prefrontal cortex, and temporoparietal, cerebellar, and occipital regions.[54-58] Moreover, volumetric reductions in subcortical areas — including the amygdala, caudate, and nucleus accumbens — have been reported in adults with ADHD compared with nondiagnosed controls.[58-60]

A relatively new approach for characterizing brain structure in individuals with ADHD is diffusion tensor imaging (DTI), which allows for examination of white matter integrity across brain regions. At least 3 studies have used DTI to examine white matter abnormalities in samples of individuals with ADHD. An early study using this approach reported that white matter fiber tracts in adults with ADHD were smaller in size in an area connecting the anterior cingulate cortex to the dorsolateral prefrontal cortex. This region is also reported to be critically involved in executive functioning and attention.[61] In another study of adults with ADHD and healthy control subjects, Konrad and colleagues found significant differences in white matter integrity in frontostriatal regions, and the abnormalities were significantly correlated with measures of both attention and impulsivity.[62] Finally, a recent DTI study of adults with ADHD and a matched group of controls found that white matter integrity was compromised in frontostriatal and left temporal regions in the ADHD group, and that the degree of white matter deficits was negatively correlated with attentional performance on a neuropsychological task.[63]

Although some findings from structural MRI studies in adults with ADHD have conflicted with findings in children and adolescents,[64] the relatively few published reports have shown patterns of deficits similar to those observed in children. A wide range of gray and white matter abnormalities has been found, and the degree of structural abnormalities has often been associated with behavioral or cognitive/neuropsychological outcomes. Continued work to determine the causal factors of structural (eg, genetic) differences as well as the functional and clinical implications is needed.

Functional Neuroimaging Studies of Adult ADHD

Critical companions to methods that precisely characterize brain structure are those techniques that capture brain activation both during task performance and at rest. A range of techniques allows for observing brain activity, including traditional task-based functional MRI (fMRI), positron emission tomography (PET), and, more recently, functional connectivity analyses, which have examined circuit-based connectivity both during tasks and at rest.

fMRI and Adult ADHD. Although fMRI studies of adult ADHD are still fewer in number than studies in children, considerable progress has been made in this area. Two recent review papers summarized the findings from adult ADHD imaging studies.[65,66] A number of different cognitive processes known to be disrupted in adult ADHD have been examined with brain imaging studies. Table 1 lists 5 of these processes, summarizes the imaging findings, and notes whether the results are consistent with studies in pediatric samples.

Table 1. Summary of fMRI Studies in Adults with ADHD

Task/Process Imaging findings Consistent with Child Studies? Comments
Motor inhibition (eg, stop-signal task; go/no-go task) Reduced frontostriatal activation; increased activation in medial frontal and parietal regions (but not observed in medication-naïve adults)[67,68] Yes Overactivation of certain regions during task completion may be associated with effects of medication
Interference inhibition (eg, the Stroop effect) Underactivation of anterior cingulate and inferior prefrontal cortex[69-71] Yes Some differences across studies with respect to laterality of underactivation
Attention (eg, vigilance task; attentional switch task) Underactivation of left inferior and dorsolateral prefrontal cortex[67,71] Yes Findings more lateralized in adults vs children
Working memory (eg, paced serial addition task) Underactivation in inferior ventrolateral, prefrontal, parietal, temporo-occipital, and cerebellar regions[67,71] Insufficient child studies to determine One study with large number of women found that activation deficits are only present in men and not women[72]
Reward processing and motivation (eg, gambling tasks) Consistent evidence for differential functioning in a range of regions, including the limbic/paralimbic, ventral striatum, amygdala, and ventromedial and orbital prefrontal cortex[67,71] Yes Some variation across studies with respect to over- vs underactivation of certain regions; likely related to characteristics of task and sample[73,74]

Adapted from Cubillo A, et al. Expert Rev Neurother. 2010;10:603-620.[65]

Several conclusions can be drawn from the fMRI literature in adults with ADHD. First, there is consistent evidence for disrupted brain function in several regions known to be involved in specific neuropsychological processes implicated in ADHD.Although not consistently reported across studies, some evidence also exists for so-called “compensatory activation,” in which adults with ADHD exhibit increases in brain activation in regions not typically associated with task performance. This finding may be associated with a general level of inefficient neural processing in adults with ADHD.[75] Moreover, the patterns of functional abnormalities are remarkably consistent across pediatric and adult studies. This further validates the conceptualization of ADHD as a disorder with a clinical presentation that is strongly mediated by neurobiological processes. Finally, the collective literature on fMRI in adults with ADHD suggests that additional work needs to be done, especially with respect to samples that are representative of true clinical populations, such as those with a high proportion of women and individuals with comorbid conditions.

PET Studies of Adult ADHD. PET studies have been used for a number of years to measure brain activity in real time. PET imaging methods involve the injection or inhalation of radioactive materials that are distributed in the brain and can then be measured using specialized equipment. PET studies of patients with ADHD conducted in the United States have almost exclusively involved adult populations because of concerns over radiation exposure in pediatric populations. Some of the earliest studies were conducted more than 20 years ago,[76] and most studies since that time have focused on characterizing the activity of the dopamine system. There have been discrepancies across studies, though. For example, some studies have reported higher levels of dopamine transporters in adults with ADHD compared with control participants, whereas others have reported lower levels of dopamine transporters.[77] Despite these differences, PET studies have generally reported that individuals with ADHD differ from non-ADHD comparison subjects with respect to frontostriatal functioning, that the disorder can also be characterized by deficits in dopamine release in the caudate and limbic regions, and that these differences provide a rationale for the therapeutic action of commonly used stimulant drugs.[78,79]

One of the largest and arguably most definitive PET studies of ADHD to date compared 53 medication-naïve adults with ADHD with 44 matched controls. The adults with ADHD exhibited significantly diminished dopamine activity in areas of the brain that are known to be involved in reward processing and motivation, including the nucleus accumbens and the caudate nucleus. Moreover, ratings of attention were associated with dopamine activity in a number of regions, indicating that the degree of dopamine hypoactivity was correlated with the degree of problems with attention. This study also found evidence for decreased dopamine activity in the hypothalamic regions, which was interpreted to be a potential underpinning of comorbidities seen commonly with ADHD, such as sleep problems, obesity, and abnormal reactions to stress.[80]

Several follow-up studies of this same sample have also been published.[81,82] In the first follow-up analysis, deficits in motivation were significantly correlated with dopamine activity in the reward pathway in the cohort with ADHD, but not in controls.[81] More recently, a subset (n=20) of the original 53 adults with ADHD were examined after 12 months of carefully controlled treatment with methylphenidate. Findings showed that subjects experienced significant improvement in self- and clinician ratings of ADHD symptoms and that the magnitude of clinical response was associated with the level of methylphenidate-induced increases in dopamine in ventral striatum. Combined with previous studies of this sample, results were interpreted to suggest that one possible mechanism of long-term stimulant treatment in ADHD is to augment dopamine neurotransmission, which is deficient prior to treatment.[82]

Another potentially significant recent advance using PET imaging has been the characterization of the norepinephrine transporter (NET) in human subjects. A recent study measured the extent to which oral methylphenidate occupied NET in healthy participants without ADHD and reported that clinically relevant doses of the drug significantly occupied this receptor to a degree that was comparable with or greater than the dopamine transporter.[83] This study has implications for better understanding the therapeutic effects of methylphenidate and other drugs used to treat ADHD, such as the selective norepinephrine reuptake inhibitor atomoxetine. Further PET studies of the NET will be important to conduct in patients with ADHD.

Functional Connectivity Studies in Adult ADHD. While traditional functional imaging approaches have focused on brain activation (or lack thereof) in specific regions, functional connectivity approaches focus on “the temporal correlation or coherence of spatially remote neurophysiological events.”[84] As such, functional connectivity analyses allow for examination of much broader systems of neural functioning and how these systems relate to different psychopathological conditions. In general, functional connectivity analyses have examined brain circuits both at rest (ie, not engaged in a specific task) or during some set of demands designed to engage some kind of process (ie, working memory, inhibitory control). Although this is a relatively recent area of research, the number of functional connectivity studies has increased rapidly, including studies in adults. Some of the earliest work on functional connectivity in ADHD focused on a specific set of interrelated brain regions known as the “default mode network” (DMN). This network, comprising nodes in the precuneus/posterior cingulate cortex, the medial prefrontal cortex, and the medial, lateral, and inferior parietal cortex, is associated with task-irrelevant mental processes and exhibits strongest connectivity during rest.[85] Connectivity in the DMN is also reduced during task performance and the degree of deactivation is associated with more complex task demands.[86] Conversely, unsuccessful suppression of DMN connectivity during task demands is associated with greater lapses in attention.[87] These cognitive neuroscientific findings have led to the hypothesis that individuals with ADHD have dysfunctional deactivation of DMN during task demands, which leads to poorer performance.[88] One of the earliest studies to evaluate the integrity of the DMN was conducted in adults with ADHD and found that, compared with nondiagnosed controls, those with ADHD demonstrated less connectivity of the DMN. [89]

Several studies have also examined task-related functional connectivity in adults with ADHD. In 1 study, adults with and without ADHD performed a working memory task; connectivity among several different brain regions was examined. Similar to traditional fMRI findings, this study reported that, compared with adults without ADHD, adults with ADHD demonstrated lower functional connectivity of a network involving the inferior prefrontal cortex, left anterior cingulate cortex, superior medial frontal cortex, superior parietal regions, and cerebellum. However, adults with ADHD also showed increased connectivity in a different network involving the left dorsal anterior cingulate, right superior frontal gyrus, and left occipital lobe.[90] Using a task of motor inhibitory control, another study reported that adults with ADHD demonstrated less functional connectivity in a network known to subserve this process, including the right inferior prefrontal cortex, caudate/thalamus, anterior and posterior cingulate, and bilateral temporoparietal regions.[67]

Overall, functional connectivity studies of adults with ADHD are consistent with studies conducted in children and also complement research using other modalities of brain imaging. Increasingly, neuroimaging studies have been able to isolate the brain regions and networks associated with ADHD in both children and adults.

Neurobiological Next Steps: Combining Brain Imaging and Molecular Genetics

The pace of discovery is rapid in both molecular genetics and the neuroimaging of ADHD, with several hundred papers published each year. One emerging field that holds promise for integrating these areas in the service of more fully elucidating the etiology and pathophysiology of ADHD is imaging genetics.[91] In this approach, brain markers (either structural or functional) can be used as endophenotypes for ADHD and linked to genetic variance. Several recent studies highlight the potential of this area for advancing our understanding of the genetics and neurobiology of ADHD. For example, variants of the ADRA2 gene have been shown to be associated with differences in blood flow in relevant brain regions (eg, the orbitofrontal cortex) in children with and without ADHD.[92] Functional connectivity in brain regions associated with cognitive control has been found to be related to familial risk for ADHD, indicating the potential heritability of brain functioning.[93]

Imaging genetics studies have also been conducted in adults with ADHD. For example, in a relatively large sample of 91 adult individuals (n=53 with ADHD, n=38 non-ADHD controls), variants of the DAT1 gene were associated with the presence of adult ADHD, as well as task-related suppression of portions of the DMN. Moreover, a small statistical interaction between genotype and diagnosis was observed for activity in the anterior cingulate cortex, suggesting that DAT1 genotype effects on brain function were particularly pronounced among individuals with ADHD.[94]

Clinical Implications of Neurobiological Findings in Adult ADHD

This review has summarized 2 active and key areas relevant to the neurobiology of adult ADHD: genetics/molecular genetics and neuroimaging. In addition, the emerging field of imaging genetics, which combines these areas, was also discussed. Methodological advances in these areas provide for an array of complex findings. But the relevant clinical questions of how these advances will influence and improve the prevention, identification, and treatment of persistent adult ADHD remain unanswered. The myriad findings from genetic and neuroimaging studies likely vary with respect to how close they are to influencing clinical practice. What are the possible clinical implications of the main findings?

ADHD Is Highly Heritable and Runs in Families

Long before the advent of molecular genetic techniques, it was well established that ADHD tended to run in families and was more common in identical vs fraternal twins. This pattern of heritability likely provides more clinical utility than findings from molecular studies of specific genes or genome scans. Since it is well established that the risk for ADHD is significantly higher in biological parents of children diagnosed with ADHD and vice versa, careful history gathering during an assessment can help a clinician determine whether family members of a patient have been affected and use this information to inform decision making about a diagnosis. If the child of an adult patient has been diagnosed with ADHD, it is not a foregone conclusion that the parent will have the disorder, but it does help the clinician weigh the rest of the clinical evidence in drawing diagnostic conclusions.

Limited GWAS Findings in Adults Have Been Somewhat More Promising Than Findings in Pediatric Samples

Across a number of GWAS studies in children, no consistently replicated regions have been identified that are associated with the disorder and withstand rigorous statistical correction. In adults, 2 GWAS studies have been conducted, with 1 reporting significant findings for association between ADHD and a gene that has also been implicated in mood disorders and substance abuse. This suggests that common genetic variants identified in such studies may be more strongly associated with persistent (ie, adult) forms of the disorder and associated with features of the disorder (ie, mood problems, risk for drug use) that are not part of the core diagnostic criteria. Such findings underscore the common clinical observation that mood dysregulation and other impairments are common in adults with ADHD, but otherwise GWAS studies are not yet advanced enough to directly inform clinical practice.

A Number of Relatively Common Candidate Gene Variants Have Been Associated With Adult ADHD

Findings from candidate gene studies in adults with ADHD have varied somewhat from studies in pediatric populations. This suggests that the molecular genetic basis for persistent ADHD may be somewhat different than the basis for pediatric ADHD. In any case, a number of gene variants have been shown to confer risk for the disorder. Moreover, the functions of identified genes make theoretical sense in terms of how they might affect neural processes to give rise to the clinical condition. Nevertheless, the effect sizes for any individual candidate gene are quite small. Stated differently, even for the risk genes with the largest effects, the majority of patients with a true diagnosis of ADHD will not carry the risk variant, and a considerable minority of the population without a true diagnosis may also carry the risk gene. As such, the immediate clinical utility of such findings is, at present, limited.

Genetic Variation Has Been Associated With Response to Treatment, Although the Effects Are Not Consistent Across Studies of Adults With ADHD

The possibility of stratifying patients with respect to their likely response (or nonresponse) to various pharmacological treatments is a promising application of molecular genetics. Although some consistency has been seen in pediatric pharmacogenetic studies, far fewer studies have been conducted with adult samples and the findings are more mixed. Several aspects of the current state of pharmacotherapy of adults with ADHD suggest that continued pharmacogenetic studies could yield considerable clinical utility. First, as awareness of adult ADHD has increased, use of pharmacotherapy in this population has also increased. Second, a number of drugs are available or in development for use in adults that target a range of neurotransmitter systems in the brain. To the extent that the functioning of these different systems is partially regulated by genetic factors, a large number of genetic targets may be explored with respect to predicting treatment response. For example, using genetic data to determine whether an individual is more likely to respond to a stimulant (eg, methylphenidate or amphetamine), a norepinephrine reuptake inhibitor (eg, atomoxetine), some other agent (eg, α-2 adrenergic agonists), or a combination of these could be useful from a clinical perspective. Such studies have not yet been conducted, but their potential benefits are sizeable.

Size and Structure of the Brains of Adults With ADHD Differ From Adults Without ADHD

This finding, which is similar to findings reported in pediatric populations, does not provide much in the way of direct clinical implications on its own. It is not much use to clinicians to know that, on average, an adult with ADHD might have a brain volume or cortical thickness that is 8% to 10% less than that of an average adult without ADHD. Still, these consistent findings do provide information about the etiology of ADHD, which could eventually lead to better diagnostic tools. At present, however, these findings have not been translated into clinical utility.

Brain Activation Tends to Be Different in Adults With ADHD

This finding is consistent with studies conducted in pediatric populations. Differential activation across a range of brain regions has been demonstrated with tasks measuring inhibitory control, interference, and working memory, among others. Importantly, many of these studies have also shown that adults with ADHD (like children with the disorder) may also exhibit increased or compensatory activity in other brain regions. This finding has led to speculation about inefficiencies of neural processing as a core feature of ADHD. Although, on average, adults with ADHD exhibit altered patterns of brain activation, the effect sizes across these studies are not enough to discriminate a priori individuals with the disorder from normal individuals. Similar to genetic risk variants, many adults with ADHD will exhibit normal brain activation in relevant regions, and many adults without ADHD will exhibit altered activation patterns. Enhancing the signal of differential brain activation via task refinements or more sophisticated approaches to measuring activation may increase the potential diagnostic utility of brain imaging techniques for identifying ADHD.

Dopamine Activity Is Disrupted in Adults With ADHD

It has long been speculated that ADHD is related to altered dopamine function. The mechanism of action of stimulant drugs known to be effective to treat ADHD, early findings of genetic risk variants in dopamine-related genes, and findings from fMRI studies provide convergent evidence for the involvement of the dopamine system. More recently, studies of real-time dopamine activity have more strongly supported the role of the dopamine system, particularly in motivation and reward pathways. These findings are not ready for direct clinical application but have important implications for the development of new pharmacological compounds to treat the disorder, the measurement of how treatment (pharmacological or other modalities) influences dopamine activity, and the understanding of common conditions that are comorbid with ADHD.

Interconnectivity of Different Brain Regions Is Altered in Adults With ADHD

Technological and analytical advances in recent years have allowed for the measurement of correlated activity across spatially distinct brain regions. These techniques have demonstrated that adults with ADHD differ not only in activation patterns in specific brain regions but also in the activity across brain regions. These differences have been demonstrated for both task-related activity as well as activity at rest. Although not currently of clinical use, functional connectivity analyses, similar to studies of brain activation, hold some promise as objective diagnostic tools if patterns of connectivity can be identified that reliably discriminate individuals with ADHD from those without the disorder.

Conclusion

At present, the direct clinical implications of genetic and neuroimaging findings are limited. However, the volume of information generated from these studies and the pace at which data are generated hold promise for continuing to better understand the genetic and neurobiological basis of this common and highly impairing disorder.

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