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Understanding the genetics of neuropsychiatric disorders requires an understanding of the genetics of brain structure and function. The Vietnam Era Twin Study of Aging (VETSA) is a longitudinal behavioral genetic study focused on cognitive and brain aging. Here, we describe basic science work carried out within the VETSA MRI study that provides meaningful contributions toward the study of neuropsychiatric disorders. VETSA produced the first comprehensive assessment of the heritability of cortical and subcortical brain structure sizes, all within the same individuals. We showed that neocortical thickness and surface area are largely genetically distinct. With continuous neocortical thickness maps, we demonstrated regional specificity of genetic influences, and that genetic factors did not conform to traditional regions of interest (ROIs). However, there was some evidence for different genetic factors accounting for different types of cortex, and for genetic relationships across cortical regions corresponding to anatomical and functional connectivity and brain maturation patterns. With continuous neocortical surface area maps, we confirmed the anterior–posterior gradient of genetic influences on cortical area patterning demonstrated in animal models. Finally, we used twin methods to create the first map of cortical ROIs based entirely on genetically informative data. We conclude that these genetically based cortical phenotypes may be more appropriate for genetic studies than traditional ROIs based on structure or function. Our results also suggest that cortical volume—the product of thickness and surface area is a problematic phenotype for genetic studies because two independent sets of genes may be obscured. Examples supporting the validity of these conclusions are provided.

This study aimed to validate the Computerized UCSD Performance-Based Skills Assessment (C-UPSA), a newly developed scale for assessing functional capacity in patients with schizophrenia.The C-UPSA was administered to 21 middle-aged and older adults with schizophrenia and 20 healthy comparison (HC) subjects. Schizophrenia participants also completed the original UPSA and a symptom inventory (during a separate visit), and cognitive functioning was assessed in both groups using a brief neuropsychological screening battery.The C-UPSA total score was significantly correlated with UPSA total scores, and the magnitude of the correlation was comparable to the test-retest reliability of the original UPSA. The C-UPSA was also significantly correlated with UPSA-Brief scores and neuropsychological status among schizophrenia participants. Furthermore, the schizophrenia group scored significantly lower than the HCs on the C-UPSA. ROC curves were generated to determine the optimal C-UPSA value for discriminating between the two groups, with results indicating an optimal cutoff of 75, which is consistent with the derived cutoff from the original UPSA. The C-UPSA identified persons with schizophrenia with 95% accuracy.The C-UPSA appears to be highly related to the original UPSA. It has several advantages over the standard version, including increased portability, decreased administration time, and minimized examiner impact on participant performance. Future research would benefit from establishing this test as a clinical and research tool to effectively assess functional capacity.

Objective Sleep disturbances are prevalent, persistent, and impairing features of bipolar disorder. However, the near-term and cumulative impact of the severity and variability of sleep disturbances on symptoms and functioning remains unclear. We examined self-reported daily sleep duration and variability in relation to mood symptoms, medication adherence, cognitive functioning, and concurrent daily affect. Methods Forty-one outpatients diagnosed with bipolar disorder were asked to provide daily reports of sleep duration and affect collected via ecological momentary assessment with smartphones over eleven weeks. Measures of depressive and manic symptoms, medication adherence, and cognitive function were collected at baseline and concurrent assessment of affect were collected daily. Analyses examined whether sleep duration or variability were associated with baseline measures and changes in same-day or next-day affect. Results Greater sleep duration variability (but not average sleep duration) was associated with greater depressive and manic symptom severity, and lower medication adherence at baseline, and with lower and more variable ratings of positive affect and higher ratings of negative affect. Sleep durations shorter than 7–8 h were associated with lower same-day ratings of positive and higher same-day ratings of negative affect, however this did not extend to next-day affect. Conclusions Greater cumulative day-to-day sleep duration variability, but not average sleep duration, was related to more severe mood symptoms, lower self-reported medication adherence and higher levels of negative affect. Bouts of short- or long-duration sleep had transient impact on affect. Day-to-day sleep variability may be important to incorporate into clinical assessment of sleep disturbances in bipolar disorder.

Author(s): Moore, Raeanne C; Marquine, Maria J; Straus, Elizabeth; Depp, Colin A; Moore, David J; Schiehser, Dawn M; Richtand, Neil M; Jeste, Dilip V; Eyler, Lisa T | Abstract: ObjectiveTo identify key mood, social, and functional correlates of current participation in mental health treatment and barriers to participation in mental health treatment among older HIV infected (HIV+) veterans.MethodsHIV+ veterans (N = 150) aged ≥ 50 years receiving HIV-related medical care at the VA San Diego Healthcare System, San Diego, California, anonymously completed a survey assessing current self-reported mood, social support, daily functioning problems, mental health service utilization, and barriers to participating in mental health services. Veterans also completed the 2-item Patient Health Questionnaire (PHQ-2), a validated depression screening instrument frequently used in primary care settings. Data were collected from February 2014 to May 2014.ResultsOverall, 44% of participants screened positive for depressive symptomatology on the PHQ-2; 55% of those who screened positive were participating in mental health treatment. Of the 45% of veterans who screened positive on the PHQ-2 and were not in treatment, two-thirds (66%) stated they had been offered services; however, they were not engaging in or accepting the services. Regardless of PHQ-2 status, current self-reported depressive symptoms emerged as an independent, significant positive predictor of participation in mental health treatment (odds ratio = 5.98; 95% CI, 1.16-30.72; P = .03), whereas anxiety, HIV-related stigma, sufficiency of social support, and daily functioning problems were not associated with mental health treatment utilization. Primary reported barriers to mental health treatment included scheduling/availability, travel time and transportation, and discomfort with group settings.ConclusionsResults of this study suggest there may be a need to better engage older HIV+ veterans in depression-related treatment. The use of telehealth technology, such as teletherapy, electronic devices, and cell phone-based programs, may be beneficial in helping older HIV+ veterans overcome many barriers that restrict their participation in mental health treatment.

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc.

Background Schizophrenia is one of the most disabling psychiatric disorders with increased morbidity and mortality. Both schizophrenia and oxidative stress have been associated with accelerated aging. Previous studies found increased oxidative stress in individuals with schizophrenia, though only one study measured F2-isoprostanes and did so in urine. To our knowledge, the present study is the first to assess plasma F2-isoprostane levels, the putative gold standard measure of systemic oxidative stress in vivo, in schizophrenia. Methods We compared plasma F2-isoprostane levels in 134 stable outpatients with schizophrenia and 120 age- and gender-matched healthy comparison (HC) subjects. Sociodemographic and clinical data were collected in both groups. Results Plasma F2-isoprostane levels were significantly higher in the schizophrenia group than in the HC group. Women had higher F2-isoprostane levels compared to men, and those with higher body mass index (BMI) had higher levels, within each group. F2-isoprostane levels correlated with BMI, physical functioning, and medical comorbidity but not with severity of psychopathology or executive function. Linear models showed significant effects of diagnosis, gender, and BMI on F2-isoprostane levels, but no interactions. Discussion Our finding of increased oxidative stress in schizophrenia is consistent with reports of increased morbidity and mortality as well as accelerated aging in schizophrenia. The significant associations between F2-isoprostane levels and both gender and BMI warrant further study.

Objective This study aimed to examine the feasibility, acceptability, and initial validity of using smartphone-based ecological momentary assessment (EMA) to assess daily functioning and other behavioral factors among older HIV+ adults. Methods Twenty older HIV+ adults (mean age: 59 years) completed laboratory-based neurobehavioral and functional assessments then completed EMA surveys via smartphones five times per day for one week. Results Excellent EMA adherence (86.4%) was found, and participants rated their experience with EMA methods positively. Time-use data indicated participants were spending 74% of their waking-sampled time at home, 63% of their time alone, and 32% of their time engaged in passive leisure activities (e.g., watching TV). Better neurocognitive and functional capacity abilities were correlated with less time spent in passive leisure activities. Lastly, mood and cognitive symptom data collected via EMA were significantly associated with scores from laboratory-based assessments of these same constructs. Conclusions EMA via smartphones is a feasible and acceptable data collection method among older HIV+ adults and appears to be a promising mobile tool to assess daily functioning behaviors in HIV. These preliminary findings indicate older HIV+ adults are spending a considerable amount of time at home, alone, and engaged in passive leisure activities, primarily watching TV. EMA may contribute to future research examining functional disability among the growing population of older HIV+ adults.

© 2016 Elsevier Inc. General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical "bigger is better" view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions.

Little is known about the brain systems that contribute to vulnerability to post-traumatic stress disorder (PTSD). Comparison of the resting-state patterns of intrinsic functional synchronization, as measured by functional magnetic resonance imaging (fMRI), between groups with and without PTSD following a traumatic event can help identify the neural mechanisms of the disorder and targets for intervention. Fifty-four PTSD patients and 72 matched traumatized subjects who experienced the 2008 Sichuan earthquake were imaged with blood oxygen level-dependent (BOLD) fMRI and analyzed using the measure of regional homogeneity (ReHo) during the resting state. PTSD patients presented enhanced ReHo in the left inferior parietal lobule and right superior frontal gyrus, and reduced ReHo in the right middle temporal gyrus and lingual gyrus, relative to traumatized individuals without PTSD. Our findings showed that abnormal brain activity exists under resting conditions in PTSD patients who had been exposed to a major earthquake. Alterations in the local functional connectivity of cortical regions are likely to contribute to the neural mechanisms underlying PTSD.

Many neuroimaging studies interpret the commonly reported findings of age-related increases in frontal response and/or increased bilateral activation as suggestive of compensatory neural recruitment. However, it is often unclear whether differences are due to compensation or reflective of other cognitive or physiological processes. This study aimed to determine whether there are compensatory age-related changes in brain systems supporting successful associative encoding while taking into account potentially confounding factors including age-related differences in task performance, atrophy, and resting perfusion. Brain response during encoding of face-name pairs was measured using functional magnetic resonance imaging in 10 older and nine young adults and was correlated with memory performance. During successful encoding, older adults demonstrated increased frontal and decreased occipital activity as well as greater bilateral involvement relative to the young. Findings remained significant after controlling for age-related cortical atrophy and hypoperfusion. Among the older adults, greater response was associated with better memory performance. Cognitive aging may involve recruitment of compensatory mechanisms to improve performance or prevent impairment. Results extend previous findings by suggesting that age-related alterations in activation cannot be attributed to the commonly observed findings of poorer task performance, reduced resting perfusion, or cortical atrophy among older adults.

Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small sample ( n = 12) of sleeping 2–3 year olds with autism in contrast to typically developing children, a finding also reported in autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample, and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was used in which brain activity was measured in a large sample of toddlers ( n = 80) during the presentation of a bedtime story during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between 12–48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to language; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of language in autism across two separate samples, including a large sample of young infants who later are diagnosed with autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism. * Abbreviation : ADOS : autism diagnostic observation schedule ASD : austism spectrum disorder

Twin studies generally show great consistency for the heritability of brain structures. Ironically, the lateral ventricles-perhaps the most reliably measured brain regions of interest-are the most inconsistent when it comes to estimating genetic influences on their volume. Heritability estimates in twin studies have ranged from zero to almost 0.80. Here we aggregate heritability estimates from extant twin studies, and we review and reinterpret some of the findings. Based on our revised estimates, we conclude that lateral ventricular volume is indeed heritable. The weighted average heritability of the revised estimates was 0.54. Although accumulated environmental insults might seem most logical as the predominant cause of age-related ventricular expansion, the data strongly suggest that genetic influences on lateral ventricular volume are increasing with age. Genetic influences accounted for 32-35% of the variance in lateral ventricular volume in childhood, but about 75% of the variance in late middle and older age. These conclusions have implications for the basic understanding of the genetic and environmental underpinnings of normative and pathological brain aging. © 2012 Elsevier Inc.

Author(s): Dev, Sheena Isha | Advisor(s): Eyler, Lisa T | Abstract: Rationale: Bipolar disorder (BD) is associated with deficits in executive functions and processing speed, yet little is known about risk factors that contribute to the development and sustainment of these deficits. Studies have demonstrated chronic inflammation, characterized by high levels of pro-inflammatory interleukin-6 (IL-6) and C-reactive protein (CRP), and reduced physical activity in BD. Both chronic inflammation and low physical activity are linked to cognitive deficits in other clinical populations, though less is known about these associations in BD. The current dissertation project proposed to a) explore associations between cognition, inflammation and physical activity in BD; and b) examine potential lagged influences between variable mood symptoms, a primary clinical feature of BD, and the amount of daily physical activity exhibited.Design: Thirty-eight BD and 68 healthy comparison participants underwent psychiatric interview, neuropsychological assessment of executive functioning and processing speed, and a 15ml blood draw analyzed for blood serum concentration of IL-6 and CRP. For the following two weeks, participants submitted thrice-daily mood ratings on a smartphone device and wore an actigraphy watch designed to measure physical activity. Linear regression analyses determined associations between inflammation, cognition, and physical activity. Mixed effects linear regression determined the impact of mood on subsequent levels of physical activity. Results: BD patients exhibited worse executive functioning and processing speed, less physical activity, and greater levels of IL-6 and CRP; higher BMI in the BD group appeared to explain group differences in inflammation and physical activity. There were no significant associations between inflammation, physical activity, and cognition in BD. Further, mood ratings did not predict subsequent levels of physical activity exhibited by BD individuals. Conclusion: This study is among the first to examine relationships between inflammation, physical activity, and cognition in BD. Results suggest that inflammation and physical activity are not significant correlates of cognition in middle-aged BD individuals, and daily mood ratings do not predict next-day physical activity. Future studies are needed to better understand individual differences in cognitive performance in BD, as well as associations between inflammation and physical activity, in order to develop targeted treatment strategies aimed to reduce functional disability in this population.

Preserved cognitive performance is a key feature of successful aging. Several theoretical models (compensation, hemispheric asymmetry reduction, and posterior-anterior shift) have been proposed to explain the putative underlying relationship between brain function and performance. We aimed to review imaging studies of the association between brain functional response and cognitive performance among healthy younger and older adults in order to understand the neural correlates of successful cognitive aging. MEDLINE-indexed articles published between January 1989 and May 2008, and bibliographies of these articles and related reviews were searched. Studies that measured brain function using fMRI or PET, evaluated cognitive performance, analyzed how cognitive performance related to brain response, and studied healthy older individuals were included. Forty-seven of 276 articles met these criteria. Eighty-one percent of the studies reported some brain regions in which greater activation related to better cognitive performance among older participants. This association was not universal, however, and was seen mainly in frontal cortex brain response and seemed to be more common among older compared to younger individuals. This review supports the notion of compensatory increases in brain activity in old age resulting in better cognitive performance, as suggested by hemispheric asymmetry reduction and posterior-anterior shift models of functional brain aging. However, a simple model of bigger structure → greater brain response → better cognitive performance may not be accurate. Suggestions for future research are discussed.

Aims Alcohol and marijuana are the most widely used intoxicants among adolescents, yet their potential unique and interactive influences on the developing brain are not well established. Brain regions subserving learning and memory undergo continued maturation during adolescence, and may be particularly susceptible to substance-related neurotoxic damage. Here, we characterize brain response during verbal learning among adolescent users of alcohol and marijuana.

Little is known about genetic influences on the volume of subcortical brain structures in adult humans, particularly whether there is regional specificity of genetic effects. Understanding patterns of genetic covariation among volumes of subcortical structures may provide insight into the development of individual differences that have consequences for cognitive and emotional behavior and neuropsychiatric disease liability. We measured the volume of 19 subcortical structures (including brain and ventricular regions) in 404 twins (110 monozygotic and 92 dizygotic pairs) from the Vietnam Era Twin Study of Aging and calculated the degree of genetic correlation among these volumes. We then examined the patterns of genetic correlation through hierarchical cluster analysis and by principal components analysis. We found that a model with four genetic factors best fit the data: a Basal Ganglia/Thalamus factor; a Ventricular factor; a Limbic factor; and a Nucleus Accumbens factor. Homologous regions from each hemisphere loaded on the same factors. The observed patterns of genetic correlation suggest the influence of multiple genetic influences. There is a genetic organization among structures which distinguishes between brain and cerebrospinal fluid spaces and between different subcortical regions. Further study is needed to understand this genetic patterning and whether it reflects influences on early development, functionally dependent patterns of growth or pruning, or regionally specific losses due to genes involved in aging, stress response, or disease.

Background Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally specific sets of genes. Methods We mapped the heritability of cortical thickness throughout the brain using three-dimensional structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface. Results There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions. Conclusions These results provide strong evidence of regionally specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders and normal and pathological cognitive aging.

Corrigendum to “Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study” [NeuroImage 49 (2010) 1213–1223] William S. Kremen ⁎, Elizabeth Prom-Wormley , Matthew S. Panizzon , Lisa T. Eyler , Bruce Fischl , Michael C. Neale , Carol E. Franz , Michael J. Lyons , Jennifer Pacheco , Michele E. Perry , Allison Stevens , J. Eric Schmitt , Michael D. Grant , Larry J. Seidman , Heidi W. Thermenos , Ming T. Tsuang , Seth A. Eisen , Anders M. Dale , Christine Fennema-Notestine a,j

Binge alcohol use is common among teenagers with 28% of 12th graders reporting getting drunk in the past month. Chronic heavy drinking has been associated with verbal learning and memory deficits in adolescents and adults, yet verbal encoding in less frequently drinking teens has not yet been studied. Here, we examined functional magnetic resonance imaging (fMRI) response during verbal encoding among adolescent binge drinkers. Participants recruited from local high schools were of ages 16–18 and consisted of 12 binge drinkers and 12 demographically similar nondrinkers. Participants were all nonsmokers, and drinkers were abstinent from alcohol for an average of 33 days at the time of scanning. Participants performed a verbal paired associates learning task during fMRI acquisition. Drinkers recalled marginally fewer words than nondrinkers (P = .07). Compared with nondrinkers, bingers showed more response in right superior frontal and bilateral posterior parietal cortices but less response in occipital cortex during novel encoding (Ps < .05, clusters > 1,512 µL). In addition, controls showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. Adolescent binge drinkers demonstrated (1) more response than nondrinkers in frontal and parietal regions, which could suggest greater engagement of working memory systems during encoding; (2) no hippocampal activation to novel word pairs; and (3) slightly poorer word pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope. Longitudinal studies will be needed to ascertain the degree to which emergence of binge drinking is linked temporally to these brain response patterns.

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

Performance-based measures may be useful in quantifying functional impairment associated with bipolar disorder, particularly among older adults. Among 30 outpatients with bipolar disorder and 31 normal comparison subjects (NCs), we administered the UCSD Performance-Based Skills Assessment (UPSA) and 2 subjective measures of functioning. The UPSA simulates real-world everyday tasks, such as financial management. We compared UPSA scores between groups and, within the bipolar group, examined associations between UPSA scores and subjective functioning, cognitive functioning, and depressive, and manic symptoms. By large effect sizes, the bipolar disorder group had lower scores on the UPSA and its subscales compared with NCs. Within the bipolar group, UPSA scores correlated strongly with Quality of Well-Being Scale but not SF-36 scores, and the UPSA was not related to depressive or manic symptoms, but was associated with cognitive functioning. Given its relative independence from symptoms, the UPSA may be useful in gauging the effectiveness of rehabilitation for bipolar disorder.

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51–59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

In a web-based survey asking adults diagnosed with bipolar disorder about illness management, we obtain frequency of self-reported usage and perceived helpfulness of 27 self-management strategies. We correlated the strategy use and perceived helpfulness with demographic and clinical characteristics, along with the Illness Intrusiveness Scale total score. Completed surveys were obtained from 1,024 individuals. Perceived helpfulness of 18 of 27 strategies was correlated negatively with illness intrusiveness at the P < 0.001 level. Given limitations of web-based surveys, our study underscores the substantial negative impact of bipolar disorder, along with the potential of the Internet to enhance the use of self-management strategies.

Medication nonadherence is a key clinical concern in bipolar disorder (BD) across the life span. Cognitive deficits in older adults with BD may hinder medication management ability, which, in turn, may lead to nonadherence. Using an innovative performance-based measure of medication management ability, the Medication Management Ability Assessment (MMAA), we compared performance of 29 middle-aged older community-dwelling outpatients with BD who were clinically stable (mean age, 61 years; SD, 11 years; range, 45-86 years) with those of 59 normal control subjects (NCs) and 219 outpatients with schizophrenia. The MMAA is a role-play task that simulates a medication regimen likely to be encountered by older adults. Within the BD group, we examined the relationships of MMAA scores to demographic, psychiatric symptoms severity, and the Mattis Dementia Rating Scale (DRS) scores. The BD group made 2.8 times the errors on the MMAA than NCs (BD group, 6.2; SD, 5.5 vs NCs, 2.2; SD, 2.5) and did not significantly differ from the Schizophrenia group in errors on the MMAA. Errors in the BD group were more likely to be taking in too few medications as taking in too many. Within the BD group, a significant correlation was seen between MMAA scores and the DRS Total score, but not with age, education, Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, number of psychiatric medications, or medical conditions. Among DRS subscales, the Memory Subscale correlated most strongly with MMAA errors. This small cross-sectional study suggests that deficits in medication management ability may be present in later-life BD. Neurocognitive deficits may be important in understanding problems with unintentional nonadherence.

Working memory (WM) was studied in 82 healthy volunteers, 43 schizophrenia patients, and 81 bipolar patients. Schizophrenia patients were impaired on verbal and figural WM tasks that possessed similar test discriminating power. Bipolar patients performed similarly to healthy volunteers. A mathematical model of WM performance revealed a primary role for reduced WM span in accounting for the impaired verbal WM of schizophrenia patients and a primary role for diminished attention in accounting for impaired figural WM. Although WM impairment in schizophrenia is due neither to the general effects of severe mental illness nor to the specific type of material studied, the microarchitecture of abnormal WM in schizophrenia may depend on the stimulus material presented.

This article reviews the extant twin studies employing magnetic resonance imaging data (MRI), with an emphasis on studies of populationbased samples. There have been approximately 75 twin reports using MRI, with somewhat under half focusing on typical brain structure. Of these, most are samples of adults. For large brain regions such as lobar volumes, the heritabilities of large brain volumes are consistently high, with genetic factors accounting for at least half of the phenotypic variance. The role of genetics in generating individual differences in the volumes of small brain regions is less clear, mostly due to a dearth of information, but rarely because of disagreement between studies. Multivariate analyses show strong genetic relationships between brain regions. Cortical regions involved in language, executive function, and emotional regulation appear to be more heritable than other areas. Studies of brain shape also show significant, albeit lower, genetic effects on population variance. Finally, there is evidence of significant genetically mediated relationships between intelligence and brain structure. At present, the majority of twin imaging studies are limited by sample sizes small by the standards of behavioral genetics; nevertheless the literature at present represents a pioneering effort in the pursuit of answers to many challenging neurobiological questions.

Objective: Although clinical trials are needed to advance treatments for bipolar disorder, there has been little empirical research on the capacity of bipolar patients to consent to research. The aim of the present study was to evaluate levels of decisional capacity of bipolar patients compared with those of schizophrenia patients and healthy comparison subjects, as well as to examine whether symptom and neurocognitive deficits correlate with patients' decisional abilities. Method: Participants were 31 outpatients with bipolar disorder, 31 outpatients with schizophrenia, and 28 healthy comparison subjects; each participant's decisional capacity was evaluated with the MacArthur Competence Assessment Tool for Clinical Research. Patient participants were also evaluated with standardized clinical rating scales and neurocognitive tests. Data were collected from April 2002 through November 2005. Results: Bipolar patients had worse understanding than healthy comparison subjects, and their level of decisional capacity did not differ from that of schizophrenia patients. Within the combined patient sample, neurocognitive deficits and negative symptoms were significantly correlated (p

The capacity of schizophrenia patients to make decisions regarding research consent relates to neurocognition, but the exact nature of the relationship is unclear. The authors examined the correlation of scores on the MacArthur Competence Assessment Tool for Clinical Research with functional magnetic resonance imaging brain response during a verbal learning task. Understanding of a consent form correlated with activation of the right hippocampus during verbal learning and with brain response in a large area that included the bilateral parahippocampus, cerebellum, and thalamus. Reasoning scores were not significantly related to brain activation. Understanding deficits during informed consent relates to particular brain abnormalities among schizophrenia patients.

Aim: To use the superior spatial resolution of magnetic resonance imaging (MRI) to examine differences in cerebral perfusion between young alcohol dependent and normal women. Methods: Eight alcohol dependent women and 8 controls (all ages 18–25) received single-slice resting perfusion-weighted MRI (directly proportional to brain blood flow), with slices located above the corpus callosum. Results: Alcohol-dependent women had decreased perfusion in prefrontal and left parietal regions. Conclusions: Reduced perfusion has not previously been reported in young, physically healthy alcohol dependent females, yet is consistent with previously reported decreased cerebral activity in alcohol dependence.

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques-biometrical genetic modeling, cluster analysis, and graph theory-to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several of the genetic parcellations. Cluster analysis suggested small distinct groupings of genetic covariance; networks highlighted several significant negative and positive genetic correlations between bilateral parcellations. Graph theoretical analysis suggested that small world, but not rich club, network properties may characterize the genetic relationships between these regional size measures. These findings suggest that cortical genetic parcellations exhibit short characteristic path lengths across a broad network of connections. This property may be protective against network failure. In contrast, previous research with structural data has observed strong rich club properties with tightly interconnected hub networks. Future studies of these genetic networks might provide powerful phenotypes for genetic studies of normal and pathological brain development, aging, and function.

Objectives Affective dysregulation is a core feature of bipolar disorder (BD). Abnormalities in neural circuits underlying affect regulation have been observed in BD, specifically in the structure and function of the amygdala and orbital frontal cortex (OFC). Fear extinction is an automatic affect regulatory process relying on neural circuits that are abnormal in BD. Thus, fear extinction might be useful in probing automatic affect regulation deficits in BD. We tested the hypothesis that BD is associated with reduced ability to extinguish fear responses. Methods We examined fear conditioning, extinction, and extinction memory recall in a sample of stable, euthymic participants with BD ( n =19) vs. healthy comparison participants ( n =32). A limited number of subjects (BD: n =12; healthy comparison: n =11) underwent structural MRI scanning to examine cortical size associations with extinction recall. Results Both healthy comparison and BD participants were successful in acquiring a fear response, but BD participants responded with greater startle to both threat and safety cues. Both groups showed significant extinction. The BD group showed superior extinction recall. Extinction recall was associated with right rostral middle frontal cortex thickness across groups, whereas right OFC surface area was associated with recall only in healthy comparisons. Limitations Limitations include use of a stable, highly screened sample and a relatively small number of participants available for MRI analysis. Conclusions Increased fear reactivity may be related to a “trait” disruption in BD patients similar to that previously described in anxiety disorders. This task may be useful for probing automatic affect regulatory processes in BD, and understanding treatment response.

© 2015, Springer Science+Business Media New York. Chronic cigarette use has been consistently associated with differences in the neuroanatomy of smokers relative to nonsmokers in case–control studies. However, the etiology underlying the relationships between brain structure and cigarette use is unclear. A community-based sample of male twin pairs ages 51–59 (110 monozygotic pairs, 92 dizygotic pairs) was used to determine the extent to which there are common genetic and environmental influences between brain structure and average lifetime cigarette use. Brain structure was measured by high-resolution structural magnetic resonance imaging, from which subcortical volume and cortical volume, thickness and surface area were derived. Bivariate genetic models were fitted between these measures and average lifetime cigarette use measured as cigarette pack-years. Widespread, negative phenotypic correlations were detected between cigarette pack-years and several cortical as well as subcortical structures. Shared genetic and unique environmental factors contributed to the phenotypic correlations shared between cigarette pack-years and subcortical volume as well as cortical volume and surface area. Brain structures involved in many of the correlations were previously reported to play a role in specific aspects of networks of smoking-related behaviors. These results provide evidence for conducting future research on the etiology of smoking-related behaviors using measures of brain morphology.

© 2015 American Heart Association, Inc. Most studies examining associations between hypertension and brain white matter microstructure have focused on older adults or on cohorts with a large age range. Because hypertension effects on the brain may vary with age, it is important to focus on middle age, when hypertension becomes more prevalent. We used linear mixed-effect models to examine differences in white matter diffusion metrics as a function of hypertension in a well-characterized cohort of middle-aged men (n=316; mean, 61.8 years; range, 56.7-65.6). Diffusion metrics were examined in 9 tracts reported to be sensitive to hypertension in older adults. Relative to normotensive individuals, individuals with long-standing hypertension (>5.6 years) showed reduced fractional anisotropy or increased diffusivity in most tracts. Effects were stronger among carriers than among noncarriers of the apolipoprotein E ε4 allele for 2 tracts connecting frontal regions with other brain areas. Significant differences were observed even after adjustment for potentially related lifestyle and cardiovascular risk factors. Shorter duration of hypertension or better blood pressure control among hypertensive individuals did not lessen the adverse effects. These findings suggest that microstructural white matter alterations appear early in the course of hypertension and may persist despite adequate treatment. Although longitudinal studies are needed to confirm these findings, the results suggest that prevention - rather than management - of hypertension may be vital to preserving brain health in aging.

© 2014 Elsevier Inc. The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N. = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA.

Functional magnetic resonance imaging (fMRI) provides a means of identifying neural circuitry associated with startle and its modulation in humans. Twelve subjects who demonstrated eyeblink startle in the laboratory were recruited for an fMRI study in which they were scanned while presented with two identical runs consisting of alternating blocks of no stimuli and startling tactile stimuli. Together, behavioral and imaging data are consistent with a pattern of general cortical and thalamic activation induced by startling stimuli that shows habituation both across and within runs. From Run 1 to Run 2, both the eyeblink amplitude and the fMRI signal decreased. Within Run 1, there was a graded decrease in eyeblink amplitude and whole-brain fMRI signal across blocks of startling stimuli. A similar graded decrease was observed in the thalamus signal, as well. Thus, startling tactile stimuli initially induce widespread cortical and thalamic activity, perhaps mediated by the reticular activating system. The activity then habituates in a graded fashion with repeated presentations of the stimuli.

Functional magnetic resonance imaging (MRI) is a noninvasive, highly repeatable, and increasingly available method to study disordered brain activity among patients with psychological or neurological disorders. In this chapter the biophysical principles underlying functional MRI are presented, and methodological limitations of the method are discussed. Artifacts related to the biophysical basis of the functional MRI signal or associated with image acquisition methods are presented, as are artifacts related to baseline effects—especially those associated with medication, caffeine, and nicotine use. The difficulties associated with the comparison of groups of subjects differing in performance receive special attention. The limitations of cognitive subtraction designs for functional MRI are also discussed. Functional MRI studies of schizophrenia patients are used to illustrate these points.

While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55 years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (r(p)) and genetic (r(g)) correlations were observed between left amygdala volume and positive emotionality (r(p)=.16, p

Cortical surface area (CSA) has particular relevance for understanding development, behavior, and the connection between brain structure and function. Little is known about genetic and environmental determinants of CSA during development. We utilized bivariate twin methods to identify global and regionally specific genetic factors which influence CSA in a preliminary sample of typically-developing adolescents, with hypotheses based on findings in middle-aged adults. Similar to previous findings, we observed high heritability for total CSA. There was also significant evidence for genetic influences on regional CSA, particularly when these were not adjusted for total CSA, with highest heritability in frontal cortex and relatively fewer genetic contributions to medial temporal cortical structures. Adjustment for total CSA reduced regional CSA heritability dramatically, but a moderate influence of genetic factors remained in some regions. Both global and regionally-specific genetic factors influence regional CSA during adolescence.

Individuals with bipolar disorder (BPD) exhibit motor, perceptual, and cognitive disturbances involving predominantly right hemisphere dysfunction. This asymmetry has been used to advance the hypothesis that the pathogenesis of bipolar disorder may be related to disturbances of the right cerebral hemisphere. We employed functional magnetic resonance imaging to examine hemispheric asymmetries in manic and depressed BPD. A secondary goal of the study was to examine effects of psychotropic medications on blood volume changes in the motor cortices.We studied 18 right-handed BPD and 13 right-handed normal healthy comparison subjects. Blood oxygen level dependent (BOLD) responses in the primary motor area (M1) and supplementary motor area (SMA) of both hemispheres were elicited during reaction time (RT) tasks.Healthy subjects activated the SMA in a reciprocal fashion with significantly greater activity in the left SMA for right hand trials and the right SMA for left hand trials. Depressed BPD subjects failed to show this normal reciprocity indicating a failure to suppress unwanted activity in the ipsilateral right SMA, whereas manic BPD subjects failed to suppress unwanted ipsilateral SMA activity in both hemispheres. Manic and depressed BPD subjects exhibited greater activity in the left primary motor area suggesting increased cortical excitability. BPD subjects treated with antipsychotics or mood-stabilizing medications exhibited longer RTs, lower BOLD responses in M1 and SMA, and a loss of normal hemispheric asymmetry in the SMA than untreated subjects.The presence of a right hemisphere disturbance in BPD is consistent with the hypothesis that the right hemisphere may be dominant in mood regulation. The presence of both left and right hemisphere disturbances in mania may explain the coexisting psychotic and affective symptoms observed in this condition.

Backround: Learning deficits are prominent among patients with chronic schizophrenia and are associated with poor everyday functioning. Little is known, however, about the brain physiology underlying these difficulties with encoding new information. Purpose: The purpose of the current study was to compare the brain response during novel picture encoding between patients with chronic schizophrenia and healthy individuals using functional magnetic resonance imaging (fMRI). Methods: Nine middle-aged patients with DSM-III-R or DSM-IV schizophrenia and 10 age- and education-comparable healthy individuals were studied. Using fMRI, the blood oxygenation level dependent (BOLD) signal was measured during novel picture encoding (experimental condition) and during presentation of a repeated picture (control condition). Encoding-related brain response was examined in both groups and compared between the patient and comparison groups in each voxel within four bilateral search regions (fusiform gyrus, parahippocampal gyrus, hippocampus, and inferior frontal gyrus). Results: Despite comparable subsequent ability to recognize the presented pictures, patients with schizophrenia showed abnormal encoding-related brain response in regions of the hippocampus and parahippocampal and fusiform gyrii compared to healthy individuals. In medial temporal regions, patients showed greater BOLD response during the control condition (repeated picture) than during the experimental condition (novel pictures). Conclusion: Abnormalities of the medial temporal brain systems examined in this study may underlie learning deficits in schizophrenia. Further research is needed to illuminate the role of these brain dysfunctions in poor everyday functioning and their amenability to treatment.

The relationship between disordered brain function and learning deficits in chronic schizophrenia is unclear. The authors compared correlations of brain response to picture encoding with subsequent recognition memory between samples of clinically stable patients over age 45 with schizophrenia and demographically similar healthy individuals. Subjects were studied with functional magnetic resonance imaging during novel picture encoding and a control condition. Comparison subjects showed an inverse relationship between subsequent recognition memory and brain response in medial temporal areas. Among schizophrenia patients, brain response in these regions was positively correlated with recognition memory. Brain–behavior relationships during learning were thus found to be qualitatively different between schizophrenic patients and healthy subjects.