L. Cinnamon Bidwell

Testing for Neuropsychological Endophenotypes in Siblings Discordant for Attention-Deficit/ Hyperactivity Disorder

BACKGROUND Neurocognitive deficits associated with attention-deficit/hyperactivity disorder (ADHD) might be useful intermediate endophenotypes for determining specific genetic pathways that contribute to ADHD. METHODS This study administered 17 measures from prominent neuropsychological theories of ADHD (executive function, processing speed, arousal regulation and, motivation/delay aversion) in dizygotic (DZ) twin pairs discordant for ADHD and control twin pairs (ages 8-18 years) to compare performance between twins affected with ADHD (n = 266), their unaffected co-twins (n = 228), and control children from twin pairs without ADHD or learning difficulties (n = 332). RESULTS The ADHD subjects show significant impairment on executive function, processing speed, and response variability measures compared with control subjects. Unaffected co-twins of ADHD subjects are significantly impaired on nearly all the same measures as their ADHD siblings, even when subclinical symptoms of ADHD are controlled. CONCLUSIONS Executive function, processing speed, and response variability deficits might be useful endophenotypes for genetic studies of ADHD.

The neural basis of sustained and transient attentional control in young adults with ADHD.

Differences in neural activation during performance on an attentionally demanding Stroop task were examined between 23 young adults with ADHD carefully selected to not be co-morbid for other psychiatric disorders and 23 matched controls. A hybrid blocked/single-trial design allowed for examination of more sustained vs. more transient aspects of attentional control. Our results indicated neural dysregulation across a wide range of brain regions including those involved in overall arousal, top-down attentional control, response selection, and inhibition. Furthermore, this dysregulation was most notable in lateral regions of DLPFC for sustained attentional control and in medial areas for transient aspects of attentional control. Because of the careful selection and matching of our two groups, these results provide strong evidence that the neural systems of attentional control are dysregulated in young adults with ADHD and are similar to dysregulations seen in children and adolescents with ADHD.

Cognitive enhancers for the treatment of ADHD.

Attention-deficit hyperactivity disorder (ADHD) is associated with multiple cognition-related phenotypic features in both children and adults. This review aims to clarify the role of cognition in ADHD and how prevailing treatments, which are often highly effective at reducing the clinical symptoms of the disorder, fare in modulating ADHD-related cognitive processes. First, we consider how the broad construct of cognition can be conceptualized in the context of ADHD. Second, we review the available evidence for how a range of both pharmacological and non-pharmacological interventions have fared with respect to enhancing cognition in individuals affected by this pervasive disorder. Findings from the literature suggest that the effects across a broad range of pharmacological and non-pharmacological interventions on the characteristic symptoms of ADHD can be distinguished from their effects on cognitive impairments. As such the direct clinical relevance of cognition enhancing effects of different interventions is somewhat limited. Recommendations for future research are discussed, including the identification of cognition-related endophenotypes, the refinement of the ADHD clinical phenotype, and studying the difference between acute and chronic treatment regimens.

Behavioral performance predicts grey matter reductions in the right inferior frontal gyrus in young adults with combined type ADHD

Optimized voxel-based morphometry (VBM) was used in the present study to investigate morphometric differences between young adults with combined type Attention Deficit/Hyperactivity Disorder (ADHD) and a well-matched control group. Investigations examined differences on a between-group whole brain level, as well as how individual differences in behavioral performance predicted grey matter differences. Although a whole brain analysis revealed no significant differences between ADHD and control individuals, ADHD but not control individuals exhibited reduced grey matter volume in the right inferior frontal gyrus (rIFG), predicted by poorer behavioral performance on all three measures. A subsequent region-of-interest approach revealed lower grey matter volume in the rIFG in ADHD compared to control individuals. These results suggest that young adults with ADHD show morphometric differences in inferior prefrontal regions, as compared to controls. These morphometric differences are related to disruptions in performance on behavioral tasks that frequently have been reported to be affected in individuals with ADHD.

A family based association study of DRD4, DAT1, and 5HTT and continuous traits of attention-deficit hyperactivity disorder.

Despite its high heritability, genetic association studies of attention deficit-hyperactivity disorder (ADHD) have often resulted in somewhat small, inconsistent effects. Refining the ADHD phenotype beyond a dichotomous diagnosis and testing associations with continuous information from the underlying symptom dimensions may result in more consistent genetic findings. This study further examined the association between ADHD and the DRD4, DAT1, and 5HTT genes by testing their association with multivariate phenotypes derived from continuous measures of ADHD symptom severity. DNA was collected in 202 families consisting of at least one ADHD proband and at least one parent or sibling. VNTR polymorphisms of the DRD4 and DAT1 genes were significantly associated with the continuous ADHD phenotype. The association with DRD4 was driven by both inattentive and hyperactive symptoms, while the association with DAT1 was driven primarily by inattentive symptoms. These results use novel methods to build upon important connections between dopamine genes and their final behavioral manifestation as symptoms of ADHD.

Differential activation patterns of occipital and prefrontal cortices during motion processing: Evidence from normal and schizophrenic brains

Visual motion perception is normally mediated by neural processing in the posterior cortex. Focal damage to the middle temporal area (MT), a posterior extrastriate region, induces motion perception impairment. It is unclear, however, how more broadly distributed cortical dysfunction affects this visual behavior and its neural substrates. Schizophrenia manifests itself in a variety of behavioral and perceptual abnormalities that have proved difficult to understand through a dysfunction of any single brain system. One of these perceptual abnormalities involves impaired motion perception. Motion processing provides an opportunity to clarify the roles of multiple cortical networks in both healthy and schizophrenic brains. Using fMRI, we measured cortical activation while participants performed two visual motion tasks (direction discrimination and speed discrimination) and one nonmotion task (contrast discrimination). Normal controls showed robust cortical activation (BOLD signal changes) in MT during the direction and speed discrimination tasks, documenting primary processing of sensory input in this posterior region. In patients with schizophrenia, cortical activation was significantly reduced in MT and significantly increased in the inferior convexity of the prefrontal cortex, an area that is normally involved in higher level cognitive processing. This shift in cortical responses from posterior to prefrontal regions suggests that motion perception in schizophrenia is associated with both deficient sensory processing and compensatory cognitive processing. Furthermore, this result provides evidence that in the context of broadly distributed cortical dysfunction, the usual functional specificity of the cortex becomes modified, even across the domains of sensory and cognitive processing.

Trait vs. State Markers for Schizophrenia: Identification and Characterization through Visual Processes

One central issue in schizophrenia research is to identify and characterize behavioral and biological markers that are intrinsic to the complex psychiatric disorder and that can serve as targets for detection, treatment, and prevention. A trait marker represents the properties of the behavioral and biological processes that play an antecedent, possibly causal, role in the pathophysiology of the psychiatric disorder, whereas a state marker reflects the status of clinical manifestations in patients. Certain visual functions, while deficient in schizophrenia, may be independent of psychosis. The question of what types of visual functions can serve as trait or state markers is beginning to be understood. Examining clinically unaffected relatives of schizophrenia patients and patients with bipolar disorder can provide information about the relationship between a schizophrenic disposition and visual response traits. In this effort, researchers found that motion integration is dysfunctional in schizophrenia patients but not in their relatives or bipolar patients, whereas motion discrimination is dysfunctional in schizophrenia patients and their relatives, but not in bipolar patients. By synthesizing these findings, this review suggests that distinguishing enduring trait markers from transient state markers for schizophrenia through visual processes is helpful for developing neurobiologically and psychologically based intervention strategies.

Symptom-correlated brain regions in young adults with combined-type ADHD: Their organization, variability, and relation to behavioral performance

Attention Deficit Hyperactivity Disorder (ADHD) is a widely diagnosed psychiatric disorder of childhood that may continue to manifest itself during adulthood. Across adults and children, inattention appears to be the most developmentally stable symptomatology of ADHD. To determine the neural systems that may be linked to such symptoms, the association between brain activation in a group of young adults in the face of an attentional challenge (the Stroop task) and inattentive symptoms was examined with functional magnetic resonance imaging. The results implicated a broad array of brain regions that are linked to behaviors compromised in ADHD, including executive function/cognitive control (prefrontal cortex, dorsal striatum), reward and motivational circuitry (ventral striatum), and stimulus representation and timing (posterior cortex and cerebellum). Also implicating these regions as being important for the manifestation of ADHD symptoms, the variability in the size of the BOLD signal across individuals was significantly higher for the ADHD group than for the control group, and variability across the time series in individuals with ADHD was linked to symptom severity and behavioral performance. The results suggest that a diverse set of brain structures is linked to ADHD symptoms and that the variability of activation within these regions may contribute to compromised attentional control.

Examining the role of common genetic variants on alcohol, tobacco, cannabis and illicit drug dependence: genetics of vulnerability to drug dependence

BACKGROUND AND AIMS Twin and family studies suggest that genetic influences are shared across substances of abuse. However, despite evidence of heritability, genome-wide association and candidate gene studies have indicated numerous markers of limited effects, suggesting that much of the heritability remains missing. We estimated (1) the aggregate effect of common single nucleotide polymorphisms (SNPs) on multiple indicators of comorbid drug problems that are typically employed across community and population-based samples, and (2) the genetic covariance across these measures. PARTICIPANTS A total of 2596 unrelated subjects from the Study of Addiction: Genetics and Environment provided information on alcohol, tobacco, cocaine, cannabis and other illicit substance dependence. Phenotypic measures included: (1) a factor score based on DSM-IV drug dependence diagnoses (DD), (2) a factor score based on problem use (PU; i.e. 1+ DSM-IV symptoms) and (3) dependence vulnerability (DV; a ratio of DSM-IV symptoms to the number of substances used). FINDINGS Univariate and bivariate genome-wide complex trait analyses of this selected sample indicated that common SNPs explained 25-36% of the variance across measures, with DD and DV having the largest effects [h(2) SNP (standard error) = 0.36 (0.13) and 0.33 (0.13), respectively; PU = 0.25 (0.13)]. Genetic effects were shared across the three phenotypic measures of comorbid drug problems [rDD-PU = 0.92 (0.08), rDD-DV = 0.97 (0.08) and rPU-DV = 0.96 (0.07)]. CONCLUSION At least 20% of the variance in the generalized vulnerability to substance dependence is attributable to common single nucleotide polymorphisms. The additive effect of common single nucleotide polymorphisms is shared across important indicators of comorbid drug problems.

Aging and visual motion discrimination in normal adults and schizophrenia patients

Motion perception is impaired in many neuropathological conditions, including schizophrenia. Motion perception also declines in the course of normal aging. In this study, we ask whether aging is an additive factor in the motion-discrimination deficits of schizophrenia patients. We examined motion perception in schizophrenia patients (n=44) and non-psychiatric controls (n=40) whose ages ranged from 18 to 55. The tasks included velocity discrimination and contrast detection. Thresholds for each of the two tasks were determined for each subject using psychophysical methods. Schizophrenia patients showed significantly increased thresholds (degraded performance) for velocity discrimination compared with the controls. Degraded performance in patients was not related to age. In controls, however, velocity discrimination thresholds were significantly increased beginning by age 45. Performance on a contrast-detection task, which does not require precise discrimination of motion signals, was not significantly affected by age in either group. Aging, even in its early stages, degrades motion discrimination in normal adults. Aging, however, does not adversely affect motion-discrimination deficits in schizophrenia patients through age 55. A similar motion-discrimination deficit in schizophrenia patients and aging normal adults suggests that the mechanisms underlying motion processing in schizophrenia and normal aging may be associated.