Sex differences in alcohol's effects on fronto-amygdalar functional connectivity during processing of emotional stimuli.

BACKGROUND: Amygdala function underlying emotion processing has been shown to vary with an individuals' biological sex. Expanding upon functional magnetic resonance imaging (fMRI) findings reported previously where a low level of response was the focus, we examined alcohol and sex effects on functional connectivity between the amygdala and other brain regions. The central hypothesis predicted that sex would influence alcohol's effects on frontal-limbic functional circuits underlying the processing of negative and positive facial emotions. METHODS: Secondary analyses were conducted on data from a double-blind, placebo controlled, within-subjects, cross-over study in 54 sex-matched pairs (N = 108) of 18- to 25-year-old individuals without an alcohol use disorder at baseline. Participants performed an emotional faces fMRI processing task after placebo or approximately 0.7 mL/kg of ethanol. Psychophysiological interaction analyses examined functional connectivity between the amygdala with other brain regions. RESULTS: There were significant alcohol-by-sex interactions when processing negatively valenced faces. Whereas intoxicated men exhibited decreased functional connectivity between the amygdala and ventral and dorsal anterior cingulate, angular gyrus, and middle frontal gyrus connectivity was increased in intoxicated women. There was also a main sex effect where women exhibited less functional connectivity in the middle insula than men regardless of whether they received alcohol or placebo. For happy faces, main effects of both sex and alcohol were observed. Women exhibited less amygdala functional connectivity in the right inferior frontal gyrus than men. Both men and women exhibited greater functional connectivity in the superior frontal gyrus in response to alcohol than placebo. CONCLUSIONS: Alcohol's effects on amygdala functional circuits that underlying emotional processing vary by sex. Women had higher functional connectivity than men following exposure to a moderate dose of alcohol which could indicate that women are better than men at processing affectively laden stimuli when intoxicated.

Combining varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with serious mental illness who smoke: The randomized ACTSLow pilot feasibility trial.

BACKGROUND: People with serious mental illness (SMI; bipolar [BD] or schizophrenia spectrum disorders [SSD]) who smoke have 30-60% lower odds of quitting and are more prone to experience neuropsychiatric adverse events (NPSAEs) when quitting than smokers without SMI. We pilot-tested the feasibility of combining two different dosing strategies of varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with SMI in an attempt to bolster quit rates without increasing NPSAEs. METHODS: Twelve-week, single center, randomized, double-blind, pilot feasibility trial of low (0.5mg twice daily, slower titration) versus standard dose (1.0mg twice daily, standard titration) varenicline in persons with BD or SSD with a 12-week follow-up. All participants received up to 10 sessions of ACT for smoking cessation. Participants were asked to preload with varenicline while still smoking and set a flexible target quit day (TQD) by day 35. RESULTS: Recruitment was hampered by shutdowns related to COVID-19 and the worldwide varenicline recall, respectively. Retention goals were met. Treatment satisfaction was high across both dosing and diagnostic groups. Most participants (92.9%) adhered to preloading instructions and the flexible TQD. Seven-day point prevalence abstinence at week 12 was highest in BD participants (37.5%) but lowest in SSD participants (16.7%) who received the standard dose. Medication was well tolerated. CONCLUSIONS: Although recruitment was hindered by unanticipated world events, feasibility was demonstrated. Participants adhered to and were highly satisfied with the combination of pre-cessation varenicline plus ACT. Findings support testing this combined treatment approach in a fully powered trial of persons with BD who smoke.

NIH Toolbox Emotion Battery Findings Among People with HIV: Normative Comparisons and Clinical Associations.

Purpose: Depression and other aspects of emotional health in people with HIV (PWH) can affect functional independence, disease progression, and overall life quality. This study used the NIH Toolbox Emotion Battery (NIHTB-EB), which assesses many features of emotional health, to more comprehensively investigate differences among adults living with and without HIV, and to identify factors associated with emotional health for PWH. Patients and Methods: Participants (n=1451; age: M=50.19, SD=16.84; 47.90% women) included 433 PWH living in southern California seen from 2003 to 2021 (64.72% AIDS, 92.25% on antiretroviral therapy) and 1018 healthy participants from NIHTB-EB national normative cohort. Participants completed the NIHTB-EB and PWH underwent comprehensive HIV disease and psychiatric evaluations. We investigated differences in emotional health by HIV status via independent samples t-tests (continuous scores) and Chi2 tests ("problematic" emotional health scores). Multivariable linear regression models examined correlates of emotional health among PWH. Results: PWH had significantly worse emotional health than people without HIV across Social Satisfaction (Cohen's d=0.71, p<0.001), Psychological Well-Being (Cohen's d=0.49, p<0.001) and Negative Affect (Cohen's d=0.19, p<0.01) summary T-scores, and most component scales. PWH also had higher rates of "problematic" emotional health, particularly in Social Satisfaction (45% vs 17%, p<0.0001). Poor emotional health among PWH was associated with lifetime Major Depressive and Substance Use Disorders, relationship status (lost relationship versus in relationship), unemployment, and cognitive difficulties and loss of functional independence. Conclusion: The NIHTB-EB identified that difficulties with multiple aspects of emotional health are common among PWH, and appear to be relatively independent of cognitive impairment as well as HIV disease and treatment history, but are strongly associated with everyday functioning. Given the cross-sectional nature of this study, longitudinal studies should be employed to evaluate causality pertaining to predictors of emotional health in PWH. These findings may inform interventions to promote emotional wellbeing in PWH.

Low versus high level of response to alcohol affects amygdala functional connectivity during processing of emotional stimuli.

BACKGROUND: Low levels of response (low LR) to alcohol predict heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies of emotion processing have shown that low LR individuals exhibit lower activation in task-related brain regions following both placebo and alcohol administration, but these studies did not examine functional brain networks that might contribute to the phenomena. The current study expands upon the earlier results by evaluating whether functional connectivity differences between the amygdala and other brain regions modulated by emotional face processing are associated with LR. Based on prior findings, we hypothesized that low LR is related to lower functional connectivity in fronto-amygdalar functional circuits, which underlie the processing of emotional stimuli. METHODS: Secondary analyses were conducted on data from a double-blind, placebo-controlled, within-subjects, cross-over study in 108 18-to-25-year-old low and high LR sex-matched pairs without alcohol use disorder at baseline. Participants performed modified emotional faces processing tasks after receiving placebo or approximately 0.7 ml/kg of ethanol. Psychophysiological interaction analyses examined functional connectivity between left and right amygdalae and related brain circuits using LR-by-alcohol general linear models. The data included 54 sex-matched pairs with 216 fMRI scans comprising alcohol and placebo conditions. RESULTS: Compared with individuals with high LR, low LR subjects demonstrated lower functional connectivity between the amygdala and the frontal lobes, insula, and parietal regions, while processing angry and happy faces. Interactions showed lower connectivity following alcohol in low LR and higher connectivity in high LR groups. CONCLUSIONS: Low LR individuals demonstrated lower functional connectivity in response both to placebo and a modest dose of ethanol. Attenuated connectivity among low LR individuals when processing emotional faces may contribute to an impaired ability to recognize alcohol intoxication in social situations and to appraise angry and happy emotions irrespective of whether alcohol is consumed.

Relationship between level of response to alcohol and acute tolerance.

BACKGROUND: A low level of response (low LR) to alcohol correlates with the later development of alcohol-related problems. Although some of the underpinnings of LR are understood, little is known about the potential relationship between LR and acute tolerance. The current analyses tested the hypothesis that a low LR will be explained in part by more intense acute tolerance to alcohol during a drinking session. METHODS: Data were generated through a reanalysis of data from 120 individuals who were 18- to 25-year-old, sex-matched pairs of low and high LR drinkers who at baseline did not meet criteria for an alcohol use disorder. Each subject participated in an oral alcohol challenge in which they consumed about 0.7 ml ethanol per kg and acute tolerance was measured as the differences in alcohol's effects at similar breath alcohol levels (BrACs) during the rising and falling breath alcohol concentration (BrAC) curve. Measures included aspects of the Subjective High Assessment Scale (SHAS) and body sway. RESULTS: Contrary to our hypothesis, but similar to results with other alcohol measures, acute tolerance was significantly attenuated in low LR compared with high LR individuals on most SHAS scores. Neither LR group demonstrated acute tolerance to alcohol for sleepiness or body sway. Men and women did not differ on any of these measures. CONCLUSION: These data do not support a role of acute tolerance in the low LR to alcohol as measured by subjective feelings of intoxication or body sway in these subjects, findings that were similar across males and females. In addition, consistent with the literature, the analyses demonstrated differences across measures such that acute tolerance was observed for most measures of subjective effects but not for body sway. Among the subjective effects, acute tolerance was observed for alcohol's intoxicating effect but not for feeling sleepy.

Psychiatric Comorbidity and Multimorbidity in the EAGLES Trial: Descriptive Correlates and Associations With Neuropsychiatric Adverse Events, Treatment Adherence, and Smoking Cessation.

INTRODUCTION: Psychiatric and substance use disorders represent barriers to smoking cessation. We sought to identify correlates of psychiatric comorbidity (CM; 2 diagnoses) and multimorbidity (MM; 3+ diagnoses) among smokers attempting to quit and to evaluate whether these conditions predicted neuropsychiatric adverse events (NPSAEs), treatment adherence, or cessation efficacy (CE). AIMS AND METHODS: Data were collected from November 2011 to January 2015 across sixteen countries and reflect the psychiatric cohort of the EAGLES trial. Participants were randomly assigned to receive varenicline, bupropion, nicotine replacement therapy, or placebo for 12 weeks and were followed for an additional 12 weeks posttreatment. NPSAE outcomes reflected 16 moderate-to-severe neuropsychiatric symptom categories, and CE outcomes included continuous abstinence at weeks 9-12 and 9-24. RESULTS: Of the 4103 participants included, 36.2% were diagnosed with multiple psychiatric conditions (20.9% CM, 15.3% MM). Psychiatric CM and MM were associated with several baseline factors, including male gender, nonwhite race or ethnicity, more previous quit attempts, and more severe mental health symptoms. The incidence of moderate-to-severe NPSAEs was significantly higher (p < .01) in participants with MM (11.9%) than those with CM (5.1%) or primary diagnosis only (4.6%). There were no significant (ps > .05) main effects or interactions with treatment condition for diagnostic grouping on treatment adherence or CE outcomes. CONCLUSIONS: While having multiple psychiatric diagnoses increased risk of developing moderate-to-severe NPSAEs during a quit attempt, neither CM nor MM were associated with treatment adherence or odds of quitting. These findings reassure providers to advise smokers with multiple stable psychiatric conditions to consider using Food and Drug Administration (FDA)-approved medications when trying to quit. IMPLICATIONS: Psychiatric MM may be associated with development of NPSAEs when smokers make a medication-assisted quit attempt, but it does not appear to be differentially associated with medication compliance or efficacy. Prescribing healthcare professionals are encouraged to not only promote use of FDA-approved pharmacotherapies by smokers with complex psychiatric presentations, but also to closely monitor such smokers for neuropsychiatric side effects that may be related to their mental health conditions. NCT #: NCT01456936.

Abstinence from ethanol dependence produces concomitant cortical gray matter abnormalities, microstructural deficits and cognitive dysfunction.

Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence (CIE-PA) produces significant alterations in oligodendrogenesis in the rodent medial prefrontal cortex (mPFC). Specifically, CIE-PA produced an unprecedented increase in premyelinating oligodendroglial progenitor cells and myelin, which have been associated with persistent elevated drinking behaviors during abstinence. The current study used neuroimaging and electron microscopy to evaluate the integrity of enhanced myelin and microstructural deficits underlying enhanced myelination in the mPFC in male rats experiencing forced abstinence for 1 day (D), 7D, 21D and 42D following seven weeks of CIE. In vivo diffusion tensor imaging (DTI) detected altered microstructural integrity in the mPFC and corpus callosum (CC). Altered integrity was characterized as reduced fractional anisotropy (FA) in the CC, and enhanced mean diffusivity (MD) in the mPFC in 7D abstinent rats. Increased MD occurred concomitantly with increases in myelin associated proteins, flayed myelin and enhanced mitochondrial stress in the mPFC in 7D abstinent rats, suggesting that the increases in myelination during abstinence was aberrant. Evaluation of cognitive performance via Pavlovian conditioning in 7D abstinent rats revealed reduced retrieval and recall of fear memories dependent on the mPFC. These findings indicate that forced abstinence from moderate to severe alcohol use disorder produces gray matter damage via myelin dysfunction in the mPFC and that these microstructural changes were associated with deficits in PFC dependent behaviors.

DTI-identified microstructural changes in the gray matter of mice overexpressing CRF in the forebrain.

Increased corticotroping releasing factor (CRF) contributes to brain circuit abnormalities associated with stress-related disorders including posttraumatic stress disorder. However, the causal relationship between CRF hypersignaling and circuit abnormalities associated with stress disorders is unclear. We hypothesized that increased CRF exposure induces changes in limbic circuit morphology and functions. An inducible, forebrain-specific overexpression of CRF (CRFOE) transgenic mouse line was used to longitudinally investigate its chronic effects on behaviors and microstructural integrity of several brain regions. Behavioral and diffusion tensor imaging studies were performed before treatment, after 3-4 wks of treatment, and again 3 mo after treatment ended to assess recovery. CRFOE was associated with increased perseverative movements only after 3 wks of treatment, as well as reduced fractional anisotropy at 3 wks in the medial prefrontal cortex and increased fractional anisotropy in the ventral hippocampus at 3 mo compared to the control group. In the dorsal hippocampus, mean diffusivity was lower in CRFOE mice both during and after treatment ended. Our data suggest differential response and recovery patterns of cortical and hippocampal subregions in response to CRFOE. Overall these findings support a causal relationship between CRF hypersignaling and microstructural changes in brain regions relevant to stress disorders.

NIH Toolbox® Emotion Batteries for Children: Factor-Based Composites and Norms.

The recently released National Institutes of Health Toolbox (NIHTB) batteries for neurological and behavioral function were designed to serve as standardized, common measures in clinical and epidemiological research. The current study aimed to examine constructs assessed by the self-report and parental proxy-report scales in the NIHTB Emotion Battery (NIHTB-EB) for Children by using factor analyses on data from the U.S. national normative sample of 2,916 English-speaking children. This battery contains 31 scales designed to assess both positive and negative aspects of social and emotional functioning that are considered developmentally relevant at each of three age ranges (3-7, 8-12, and 13-17 years). Results revealed four similar self-report factors for ages 8 to 12 years and 13 to 17 years. Proxy reports for ages 3 to 7 years revealed three factors, and for ages 8 to 12 years two factors. Based on the standardization sample data, age- and gender-corrected norms are presented for all NIHTB-EB individual scales and factor-based composites.

National Institutes of Health Toolbox Emotion Battery: Application of Summary Scores to Adults With Spinal Cord Injury, Traumatic Brain Injury, and Stroke.

OBJECTIVE: To examine the validity of factor analytically based summary scores that were developed using the National Institutes of Health Toolbox Emotion Battery (NIHTB-EB); (ie, psychological well-being, social satisfaction, negative affect) normative sample in individuals with neurologic conditions. DESIGN: Cross-sectional, observational cohort. SETTING: Community. PARTICIPANTS: A total of 1036 English-speaking adults from the National Institutes of Health Toolbox (NIHTB) normative project and 604 community-dwelling adults with neurologic conditions including spinal cord injury (SCI n=209), traumatic brain injury (TBI n=184), and stroke (cerebrovascular accident [CVA] n=211) (N=1640). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The NIHTB-EB. RESULTS: A series of univariate analyses comparing summary scores across the 4 groups (SCI, TBI, CVA, normative group) were conducted to identify group differences. Base rates (defined as >1 SD toward the problematic direction) were also identified. The normative group demonstrated better emotional functioning characterized by greater social satisfaction and psychological well-being (normative group > SCI, TBI, CVA; P's <.0001), and less negative affect (normative group < SCI, P=.016; normative group < TBI, P<.001; normative group < CVA; P=.034) compared with each neurologic group. Using base rates to identify problematic emotions for the 3 summary scores, there were higher rates of problematic emotions on all 3 summary scores for the neurologic groups compared with the normative group. CONCLUSIONS: The NIHTB-EB summary scores demonstrate an increased prevalence of problematic emotions among individuals with 3 neurologic conditions, and might be useful for identifying individuals with similar conditions and potentially in need of psychological support.

Effects of HIV Infection, methamphetamine dependence and age on cortical thickness, area and volume.

OBJECTIVE: This study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age. METHOD: T1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels. RESULTS: Following correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers. CONCLUSIONS: Methamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.

Sex differences in the ACTH and cortisol response to pharmacological probes are stressor-specific and occur regardless of alcohol dependence history.

Women and men differ in their risk for developing stress-related conditions such as alcohol use and anxiety disorders and there are gender differences in the typical sequence in which these disorders co-occur. However, the neural systems underlying these gender-biased psychopathologies and clinical course modifiers in humans are poorly understood and may involve both central and peripheral mechanisms regulating the limbic-hypothalamic-pituitary-adrenal axis. In the present randomized, double blind, placebo-controlled, triple-dummy crossover study, we juxtaposed a centrally-acting, citalopram (2 mg/unit BMI) neuroendocrine stimulation test with a peripherally-acting, dexamethasone (Dex) (1.5 mg)/corticotropin-releasing factor (CRF) (1 µg/kg) test in euthymic women (N = 38) and men (N = 44) with (54%) and without histories of alcohol dependence to determine whether sex, alcohol dependence or both influenced the adrenocorticotropic hormone (ACTH) and cortisol responses to the pharmacological challenges and to identify the loci of these effects. We found that central serotonergic mechanisms, along with differences in pituitary and adrenal sensitivity, mediated sexually-diergic ACTH and cortisol responses in a stressor-specific manner regardless of a personal history of alcohol dependence. Specifically, women exhibited a greater response to the Dex/CRF test than they did the citalopram test while men exhibited the opposite pattern of results. Women also had more robust ACTH, cortisol and body temperature responses to Dex/CRF than men, and exhibited a shift in their adrenal glands' sensitivity to ACTH as measured by the cortisol/log (ACTH) ratio during that session in contrast to the other test days. Our findings indicate that central serotonergic and peripheral mechanisms both play roles in mediating sexually dimorphic, stressor-specific endocrine responses in humans regardless of alcohol dependence history.

National Institutes of Health Toolbox Emotion Battery for English- and Spanish-speaking adults: normative data and factor-based summary scores.

BACKGROUND: The National Institutes of Health Toolbox Emotion Battery (NIHTB-EB) is a "common currency", computerized assessment developed to measure the full spectrum of emotional health. Though comprehensive, the NIHTB-EB's 17 scales may be unwieldy for users aiming to capture more global indices of emotional functioning. METHODS: NIHTB-EB was administered to 1,036 English-speaking and 408 Spanish-speaking adults as a part of the NIH Toolbox norming project. We examined the factor structure of the NIHTB-EB in English- and Spanish-speaking adults and developed factor analysis-based summary scores. Census-weighted norms were presented for English speakers, and sample-weighted norms were presented for Spanish speakers. RESULTS: Exploratory factor analysis for both English- and Spanish-speaking cohorts resulted in the same 3-factor solution: 1) negative affect, 2) social satisfaction, and 3) psychological well-being. Confirmatory factor analysis supported similar factor structures for English- and Spanish-speaking cohorts. Model fit indices fell within the acceptable/good range, and our final solution was optimal compared to other solutions. CONCLUSION: Summary scores based upon the normative samples appear to be psychometrically supported and should be applied to clinical samples to further validate the factor structures and investigate rates of problematic emotions in medical and psychiatric populations.

Effects of sleep deprivation on component processes of working memory in younger and older adults.

Study Objectives: Working memory (WM) has been described as a multicomponent process, comprised of the following: attention-driven encoding, maintenance and rehearsal of information, and encoding to and retrieval from episodic memory. Impairments can affect higher-order cognitive processes and many everyday functions. The impact of sleep changes on these cognitive processes across the life span needs to be investigated. The aim of the current study is to examine the effects of sleep deprivation on component processes of WM, comparing younger and older adults across verbal and visuospatial modalities. Methods: Thirty-one younger adults (19-38 years) and 33 older adults (59-82 years) attended two counterbalanced sleep protocols: a regular night of sleep followed by testing the next day (normally rested condition), and 36 hr of total sleep deprivation (TSD), followed by testing (TSD condition). Participants completed matched versions of verbal and visuospatial WM tasks across conditions. Results: Younger adults significantly outperformed older adults on encoding and displacement component processes, for both verbal and visuospatial WM. Following TSD, younger adults showed a significantly larger drop compared with older adults in verbal encoding and in visuospatial displacement. A main effect of condition was observed for verbal displacement. Conclusions: Differences were observed in the performance of younger and older adults on component processes of WM following TSD. This suggests that TSD can have differential effects on each component process when younger and older adults are compared, in both verbal and visuospatial tasks. Understanding this profile of changes is important for the development of possible compensatory strategies or interventions and the differentiation of clinical and healthy populations.

Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. DESIGN: Cross-sectional study. SETTING: University of California San Diego and the Veterans Administration San Diego Healthcare System. PARTICIPANTS: 33 euthymic BD and 38 HC participants. MEASUREMENTS: Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. RESULTS: BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. CONCLUSIONS: Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

Neural Predictors of Initiating Alcohol Use During Adolescence.

OBJECTIVE: Underage drinking is widely recognized as a leading public health and social problem for adolescents in the United States. Being able to identify at-risk adolescents before they initiate heavy alcohol use could have important clinical and public health implications; however, few investigations have explored individual-level precursors of adolescent substance use. This prospective investigation used machine learning with demographic, neurocognitive, and neuroimaging data in substance-naive adolescents to identify predictors of alcohol use initiation by age 18. METHOD: Participants (N=137) were healthy substance-naive adolescents (ages 12-14) who underwent neuropsychological testing and structural and functional magnetic resonance imaging (sMRI and fMRI), and then were followed annually. By age 18, 70 youths (51%) initiated moderate to heavy alcohol use, and 67 remained nonusers. Random forest classification models identified the most important predictors of alcohol use from a large set of demographic, neuropsychological, sMRI, and fMRI variables. RESULTS: Random forest models identified 34 predictors contributing to alcohol use by age 18, including several demographic and behavioral factors (being male, higher socioeconomic status, early dating, more externalizing behaviors, positive alcohol expectancies), worse executive functioning, and thinner cortices and less brain activation in diffusely distributed regions of the brain. CONCLUSIONS: Incorporating a mix of demographic, behavioral, neuropsychological, and neuroimaging data may be the best strategy for identifying youths at risk for initiating alcohol use during adolescence. The identified risk factors will be useful for alcohol prevention efforts and in research to address brain mechanisms that may contribute to early drinking.

Microstructural changes to the brain of mice after methamphetamine exposure as identified with diffusion tensor imaging.

Methamphetamine (METH) is an addictive psychostimulant inducing neurotoxicity. Human magnetic resonance imaging and diffusion tensor imaging (DTI) of METH-dependent participants find various structural abnormities. Animal studies demonstrate immunohistochemical changes in multiple cellular pathways after METH exposure. Here, we characterized the long-term effects of METH on brain microstructure in mice exposed to an escalating METH binge regimen using in vivo DTI, a methodology directly translatable across species. Results revealed four patterns of differential fractional anisotropy (FA) and mean diffusivity (MD) response when comparing METH-exposed (n=14) to saline-treated mice (n=13). Compared to the saline group, METH-exposed mice demonstrated: 1) decreased FA with no change in MD [corpus callosum (posterior forceps), internal capsule (left), thalamus (medial aspects), midbrain], 2) increased MD with no change in FA [posterior isocortical regions, caudate-putamen, hypothalamus, cerebral peduncle, internal capsule (right)], 3) increased FA with decreased MD [frontal isocortex, corpus callosum (genu)], and 4) increased FA with no change or increased MD [hippocampi, amygdala, lateral thalamus]. MD was negatively associated with calbindin-1 in hippocampi and positively with dopamine transporter in caudate-putamen. These findings highlight distributed and differential METH effects within the brain suggesting several distinct mechanisms. Such mechanisms likely change brain tissue differentially dependent upon neural location.

Fusing Functional MRI and Diffusion Tensor Imaging Measures of Brain Function and Structure to Predict Working Memory and Processing Speed Performance among Inter-episode Bipolar Patients.

Evidence for abnormal brain function as measured with diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) and cognitive dysfunction have been observed in inter-episode bipolar disorder (BD) patients. We aimed to create a joint statistical model of white matter integrity and functional response measures in explaining differences in working memory and processing speed among BD patients. Medicated inter-episode BD (n=26; age=45.2±10.1 years) and healthy comparison (HC; n=36; age=46.3±11.5 years) participants completed 51-direction DTI and fMRI while performing a working memory task. Participants also completed a processing speed test. Tract-based spatial statistics identified common white matter tracts where fractional anisotropy was calculated from atlas-defined regions of interest. Brain responses within regions of interest activation clusters were also calculated. Least angle regression was used to fuse fMRI and DTI data to select the best joint neuroimaging predictors of cognitive performance for each group. While there was overlap between groups in which regions were most related to cognitive performance, some relationships differed between groups. For working memory accuracy, BD-specific predictors included bilateral dorsolateral prefrontal cortex from fMRI, splenium of the corpus callosum, left uncinate fasciculus, and bilateral superior longitudinal fasciculi from DTI. For processing speed, the genu and splenium of the corpus callosum and right superior longitudinal fasciculus from DTI were significant predictors of cognitive performance selectively for BD patients. BD patients demonstrated unique brain-cognition relationships compared to HC. These findings are a first step in discovering how interactions of structural and functional brain abnormalities contribute to cognitive impairments in BD.

Increased cerebral blood flow associated with better response inhibition in bipolar disorder.

Impairment on inhibitory tasks has been well documented in bipolar disorder (BD). Differences in cerebral blood flow (CBF) between BD patients and healthy comparison (HC) participants have also been reported. Few studies have examined the relationship between cognitive performance and regional CBF in this patient population. We hypothesized that group differences on an inhibitory task (the Delis-Kaplan Executive Function Scale's Color-Word Inhibition task) would be associated with differential CBF in bilateral anterior cingulate cortex (ACC), inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) regions. Whole brain resting CBF was measured using Multiphase Pseudocontinuous Arterial Spin Labeling MR imaging for 28 euthymic BD and 36 HC participants. Total gray matter (GM) CBF was measured, and regional CBF values were extracted for each region of interest (ROI) using Freesurfer-based individual parcellations. Group, CBF, and group-by-CBF interaction were examined as predictors of inhibition performance. Groups did not differ in age, gender or education. BD patients performed significantly worse on Color-Word inhibition. There were no significant group differences in CBF in either total GM or in any ROI. There was a group by CBF interaction in the bilateral ACC, right IPL and right DLPFC such that better inhibitory performance was generally associated with higher resting state CBF in BD subjects, but not HC participants. Although CBF was not abnormal in this euthymic BD sample, results confirm previous reports of inter-episode inhibitory deficits and indicate that the perfusion-cognition relationship is different in BD compared to HC individuals.

Associations between circadian activity rhythms and functional brain abnormalities among euthymic bipolar patients: a preliminary study.

BACKGROUND: Working memory and underlying functional brain deficits have been observed in euthymic bipolar disorder (BD) patients, though there is heterogeneity in the degree of deficits. Sleep/circadian rhythm abnormalities are thought to be a core component of BD and may explain some of the heterogeneity in functional abnormalities. This preliminary study examined associations between sleep/circadian rhythm abnormalities and functional magnetic resonance imaging (fMRI) brain response on a working memory task among BD patients. METHODS: Fourteen euthymic medicated BD patients wore an actigraph for 7 days before undergoing fMRI with a working memory task. Two matched healthy comparison (HC) groups were used (14 in each sample). One group completed the actigraphy portion and the other completed the fMRI portion of the study. Circadian activity rhythm and sleep variables were calculated and compared between BD and HC participants. Variables that significantly differed were used to examine the association between activity rhythms/sleep abnormalities and fMRI working memory brain response in anatomically defined regions. RESULTS: Sleep efficiency and the rhythm robustness, mesor, and amplitude-to-width ratio were significantly abnormal in BD patients. Individual variability in all the sleep/circadian variables was significantly associated with the degree of abnormality of brain response in the dorsolateral prefrontal cortex and supramarginal gyri. LIMITATIONS: Small sample size and multiple comparison groups limit the interpretability of these findings. CONCLUSIONS: BD patients have abnormal activity rhythms and sleep efficiency, which are associated with abnormal working memory brain response. These preliminary findings support the notion that the sleep/circadian system is important in the functional brain deficits among BD patients.