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Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Bipolar disorder co-occurs with alcohol use disorder at a rate 3-5 times higher than the general population. We recently reported that individuals with bipolar disorder differ in the positive stimulating and anxiolytic effects of alcohol compared with healthy peers. This study used a randomized, placebo-controlled, cross-over, within-subject alcohol administration design to investigate neurobiological mechanisms within ventral prefrontal cortical (vPFC) systems that may underlie altered sensitivity to alcohol in bipolar disorder (NCT04063384). Forty-seven young adults (n = 23 with bipolar disorder, 64% women) completed clinical assessment and two beverage administration sessions (alcohol and placebo, counter-balanced). Participants were dosed to 0.08 g% breath alcohol concentration during the alcohol condition and completed measures of subjective response to alcohol and an emotional processing fMRI task during the ascending limb. Timing during the placebo condition mirrored the alcohol session. Acute alcohol was associated with reduced functional connectivity between the insula - subcallosal cingulate cortex, and increased connectivity between the left nucleus accumbens - ventromedial PFC in bipolar disorder, but with no change in functional connectivity between these regions in healthy peers. Alcohol-related increases in nucleus accumbens - ventromedial PFC functional connectivity was associated with greater positive stimulating effects of alcohol in bipolar disorder and heavier recent alcohol use. Results suggest vPFC brain systems respond differently to acute alcohol during emotional processing in young adults with bipolar disorder compared with healthy peers, and that vPFC system responses relate to the subjective experience of intoxication and recent alcohol use., (© 2023. American College of Neuropsychopharmacology.)

Background: When assessing the value of an intervention in bipolar disorder, researchers and clinicians often focus on metrics that quantify improvements to core diagnostic symptoms (e.g., mania). Providers often overlook or misunderstand the impact of treatment on life quality and function. We wanted to better characterize the shared experiences and obstacles of bipolar disorder within the United States from the patient's perspective., Methods: We recruited 24 individuals diagnosed with bipolar disorder and six caretakers supporting someone with the condition. Participants were involved in treatment or support services for bipolar disorder in central Texas. As part of this qualitative study, participants discussed their everyday successes and obstacles related to living with bipolar disorder during personalized, open-ended interviews. Audio files were transcribed, and Nvivo software processed an initial thematic analysis. We then categorized themes into bipolar disorder-related obstacles that limit the patient's capability (i.e., function), comfort (i.e., relief from suffering) and calm (i.e., life disruption) (Liu et al., FebClin Orthop 475:315-317, 2017; Teisberg et al., MayAcad Med 95:682-685, 2020). We then discuss themes and suggest practical strategies that might improve the value of care for patients and their families., Results: Issues regarding capability included the struggle to maintain identity, disruptions to meaningful employment, relationship loss and the unpredictable nature of bipolar disorder. Comfort related themes included the personal perception of diagnosis, social stigma and medication issues. Calm themes included managing dismissive doctors, finding the right psychotherapist and navigating financial burdens., Conclusions: Qualitative data from patients with bipolar disorder helps identify gaps in care or practical limitations to treatment. When we listen to these individuals, it is clear that treatments must also address the unmet psychosocial impacts of the condition to improve patient care, capability and calm., (© 2023. The Author(s).)

Limited data exists on mechanisms contributing to elevated risk for alcohol use disorder (AUD) in bipolar disorder. Variation in subjective response to alcohol may relate to alcohol use and risk for AUD. This study used a randomized, placebo-controlled, cross-over, within-subjects design to investigate differences in subjective response to alcohol in 50 euthymic young adults (n = 24 with and n = 26 without bipolar disorder type I). Eighty-three percent of participants with bipolar disorder were medicated. Participants completed assessments of clinical history, alcohol expectancies, and recent alcohol use. Participants were dosed to a .08 g% breath alcohol concentration. The placebo condition occurred on a separate counter-balanced day. Subjective response to alcohol was investigated at similar time points during both conditions. Group, condition, and group-by-condition interactions were modeled, with condition and time of subjective response assessment as repeated within-subject variables, and subjective response to alcohol as the dependent variable. Greater stimulating effects and liking of alcohol were reported in people with bipolar disorder (group-by-condition interactions, p < .05) than healthy young adults. While young adults with bipolar disorder reported anticipating feeling less "mellow/relaxed" when drinking (p = .02), during both beverage conditions they reported feeling more "mellow/relaxed" (main effect of group, p = .006). Feeling more "mellow/relaxed" during the alcohol condition related to greater recent alcohol use in bipolar disorder (p = .001). Exploratory analyses suggested anticonvulsants and sedatives/antihistamines may relate to differences in subjective response to alcohol in bipolar disorder. Results suggest young adults with bipolar disorder may differ in alcohol expectancies and experience alcohol intoxication differently-with distinct relations between subjective response to alcohol and alcohol use-compared to healthy young adults., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Functional Assessment Short Test (FAST) is a clinician-administered assessment scale of psychosocial dysfunction across various domains typically impacted in individuals with bipolar disorder. The FAST is formally validated as a clinician-administered measure, but support for self-administration would allow its wider use. Therefore, this study aimed to determine whether the FAST could reliably serve as a self-report measure in individuals seeking mental health treatment. Participants completed both the self-report and clinician-administered versions of the FAST as part of their routine outpatient clinical care at the Bipolar Disorders Clinic at The University of Texas Health Austin (UTHA). We investigated correlations between self-report and clinician-administered FAST scores. There were significant positive correlations between self-report and clinician-administered scores in a diverse group of 84 individuals undergoing outpatient mental health treatment (Total FAST scores r S  = 0.75; p < .001). These findings support using the FAST as a self-report scale, further increasing its utility to measure functional disability in mental health conditions such as bipolar disorder. Self-report application will increase the utility of the FAST in busy clinical workflows and, therefore, contribute to a more comprehensive clinical assessment of recovery and spur interventions that improve psychosocial functioning and quality of life., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Magnetic resonance imaging (MRI) studies comparing bipolar and unipolar depression characterize pathophysiological differences between these conditions. However, it is difficult to interpret the current literature due to differences in MRI modalities, analysis methods, and study designs., Methods: We conducted a systematic review of publications using MRI to compare individuals with bipolar and unipolar depression. We grouped studies according to MRI modality and task design. Within the discussion, we critically evaluated and summarized the functional MRI research and then further complemented these findings by reviewing the structural MRI literature., Results: We identified 88 MRI publications comparing participants with bipolar depression and unipolar depressive disorder. Compared to individuals with unipolar depression, participants with bipolar disorder exhibited heightened function, increased within network connectivity, and reduced grey matter volume in salience and central executive network brain regions. Group differences in default mode network function were less consistent but more closely associated with depressive symptoms in participants with unipolar depression but distractibility in bipolar depression., Conclusions: When comparing mood disorder groups, the neuroimaging evidence suggests that individuals with bipolar disorder are more influenced by emotional and sensory processing when responding to their environment. In contrast, depressive symptoms and neurofunctional response to emotional stimuli were more closely associated with reduced central executive function and less adaptive cognitive control of emotionally oriented brain regions in unipolar depression. Researchers now need to replicate and refine network-level trends in these heterogeneous mood disorders and further characterize MRI markers associated with early disease onset, progression, and recovery., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Burkholderia cepacia complex (BCC) is group of widespread gram-negative bacillus organized in over 20 phylogenetically distinct bacterial species. According to previous studies, BCC species pathogens are widely reported in patients with cystic fibrosis (CF), but not in individuals with diabetes mellitus (DM). In this case report, a 42-year-old male patient with DM and a foot infection caused by BCC is presented. The patient was hospitalized after antibiotic treatment failure and improved after two surgical debridement procedures and a high-dose extended infusion (EI) of meropenem. The team of vascular surgeons and the infectious disease specialists worked fervently to solve the case. Finally, a scoping review was conducted to map BCC infections in patients with DM.

Objective: Bipolar disorder (BD) is a chronic illness with recurrent exacerbations. The objective was to evaluate longitudinal costs related to BD in an employer-sponsored medical plan., Methods: This analysis utilized 5 years of administrative claims data. Claimants with a diagnosis of BD were matched to plan members (1:5) based on age, sex, and years of follow-up., Results: Medical costs for hospitalized BD members were 3.5 times more expensive than the general population (BDhosp = $92.2K vs General population = $26.8K). Average 5-year paid costs among hospitalized members with BD was $107K, $105.4K with cancer, and $103.3K with myocardial infarction (MI)., Conclusions: Hospitalized BD plan members consumed more than 3.5 times the medical resources and were similar in longitudinal costs when compared with members with other costly conditions. These findings highlight the need for novel employer-sponsored programs to help manage BD., Competing Interests: The listed authors do not have any conflicts of interest to disclose., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Background: Individuals with bipolar disorder (BD) show aberrant brain activation patterns during reward and loss anticipation. We examined for the first time longitudinal changes in brain activation during win and loss anticipation to identify trait markers of aberrant anticipatory processing in BD., Methods: Thirty-four euthymic and depressed individuals with BD-I and 17 healthy controls (HC) were scanned using functional magnetic resonance imaging twice 6 months apart during a reward task., Results: HC, but not individuals with BD, showed longitudinal reductions in the right lateral occipital cortex (RLOC) activation during processing of cues predicting possible money loss (p-corrected <0.05). This result was not affected by psychotropic medication, mood state or the changes in depression/mania severity between the two scans in BD. Elevated symptoms of subthreshold hypo/mania at baseline predicted more aberrant longitudinal patterns of RLOC activation explaining 12.5% of variance in individuals with BD., Conclusions: Increased activation in occipital cortex during negative outcome anticipation may be related to elevated negative emotional arousal during anticipatory cue processing. One interpretation is that, unlike HC, individuals with BD were not able to learn at baseline that monetary losses were smaller than monetary gains and were not able to reduce emotional arousal for negative cues 6 months later. Future research in BD should examine how modulating occipital cortical activation affects learning from experience in individuals with BD.

Background: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could "accurately" identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labelling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD., Methods: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomised, placebo-controlled trial investigating clinical, behavioural, and biological predictors of antidepressant response. Participants received sertraline (n = 114) or placebo (n = 117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the "preferred" treatment. Remission rates were calculated for participants "accurately" treated based on the composite moderator ( lucky ) versus "inaccurately" treated ( unlucky )., Findings: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment., Interpretation: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favouring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates., Funding: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O'Donnell Brain Institute at UT Southwestern Medical Center.Trial Registration.Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMARC) Registration Number: NCT01407094 (https://clinicaltrials.gov/ct2/show/NCT01407094).

Background: Transcranial Magnetic Stimulation (TMS) is not currently FDA approved for depressed patients with bipolar disorder (BD), but many unipolar depressed patients presenting for TMS have soft signs of bipolarity. It is not known whether or not these soft signs portend differential outcomes., Objective: To investigate the relationship between BD soft signs and TMS treatment outcomes in a naturalistic treatment setting., Methods: We conducted a retrospective chart review of MDD patients (n = 105) treated with TMS. BD diathesis was defined by responses to a modified version of the Mood Disorder Questionnaire and family history., Results: TMS response rates for the group with BD diathesis and the group without were equivalent using two self-report depression severity scales. Remission rate was significantly lower for the bipolar soft signs group (13.5% versus 30.2%; p = 0.04) on one scale. This result does not hold when corrected for multiple comparisons. We did not observe switch to mania., Limitations: These data are limited to patients diagnosed with unipolar depression with "soft" bipolar features defined by subthreshold symptoms. The results cannot be extrapolated to patients with a full bipolar diagnosis., Conclusion: Bipolar diathesis in MDD is not a safety concern but may lead to somewhat lower remission rates when considering TMS treatment., (Copyright © 2018. Published by Elsevier B.V.)

Background: The DSM-5 separates the diagnostic criteria for mood and behavioral disorders. Both types of disorders share neurocognitive deficits of executive function and reading difficulties in childhood. Children with dyslexia also have executive function deficits, revealing a role of executive function circuitry in reading. The aim of the current study is to determine whether there is a significant relationship of functional connectivity within the fronto-parietal and cingulo-opercular cognitive control networks to reading measures for children with mood disorders, behavioral disorders, dyslexia, and healthy controls (HC)., Method: Behavioral reading measures of phonological awareness, decoding, and orthography were collected. Resting state fMRI data were collected, preprocessed, and then analyzed for functional connectivity. Differences in the reading measures were tested for significance among the groups. Global efficiency (GE) measures were also tested for correlation with reading measures in 40 children with various disorders and 17 HCs., Results: Significant differences were found between the four groups on all reading measures. Relative to HCs and children with mood disorders or behavior disorders, children with dyslexia as a primary diagnosis scored significantly lower on all three reading measures. Children with mood disorders scored significantly lower than controls on a test of phonological awareness. Phonological awareness deficits correlated with reduced resting state functional connectivity MRI (rsfcMRI) in the cingulo-opercular network for children with dyslexia. A significant difference was also found in fronto-parietal global efficiency in children with mood disorders relative to the other three groups. We also found a significant difference in cingulo-opercular global efficiency in children with mood disorders relative to the Dyslexia and Control groups. However, none of these differences correlate significantly with reading measures., Conclusions/significance: Reading difficulties involve abnormalities in different cognitive control networks in children with dyslexia compared to children with mood disorders. Findings of the current study suggest increased functional connectivity of one cognitive control network may compensate for reduced functional connectivity in the other network in children with mood disorders. These findings provide guidance to clinical professionals for design of interventions tailored for children suffering from reading difficulties originating from different pathologies.

Introduction: Previous investigations of test-retest reliability of cerebral blood flow (CBF) at rest measured with pseudo-continuous Arterial Spin Labeling (pCASL) demonstrated good reliability, but are limited by the use of similar scanner platforms. In the present study we examined test-retest reliability of CBF in regions implicated in emotion and the default mode network., Material and Methods: We measured absolute and relative CBF at rest in thirty-one healthy subjects in two scan sessions, one week apart, at four different sites and three different scan platforms. We derived CBF from pCASL images with an automated algorithm and calculated intra-class correlation coefficients (ICCs) across sessions for regions of interest. In addition, we investigated site effects., Results: For both absolute and relative CBF measures, ICCs were good to excellent (i.e. >0.6) in most brain regions, with highest values observed for the subgenual anterior cingulate cortex and ventral striatum. A leave-one-site-out cross validation analysis did not show a significant effect for site on whole brain CBF and there was no proportional bias across sites. However, a significant site effect was present in the repeated measures ANOVA., Conclusions: The high test-retest reliability of CBF measured with pCASL in a range of brain regions implicated in emotion and salience processing, emotion regulation, and the default mode network, which have been previously linked to depression symptomatology supports its use in studies that aim to identify neuroimaging biomarkers of treatment response., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mood disorders and behavioral are broad psychiatric diagnostic categories that have different symptoms and neurobiological mechanisms, but share some neurocognitive similarities, one of which is an elevated risk for reading deficit. Our aim was to determine the influence of mood versus behavioral dysregulation on reading ability and neural correlates supporting these skills in youth, using diffusion tensor imaging in 11- to 17-year-old children and youths with mood disorders or behavioral disorders and age-matched healthy controls. The three groups differed only in phonological processing and passage comprehension. Youth with mood disorders scored higher on the phonological test but had lower comprehension scores than children with behavioral disorders and controls; control participants scored the highest. Correlations between fractional anisotropy and phonological processing in the left Arcuate Fasciculus showed a significant difference between groups and were strongest in behavioral disorders, intermediate in mood disorders, and lowest in controls. Correlations between these measures in the left Inferior Longitudinal Fasciculus were significantly greater than in controls for mood but not for behavioral disorders. Youth with mood disorders share a deficit in the executive-limbic pathway (Arcuate Fasciculus) with behavioral-disordered youth, suggesting reduced capacity for engaging frontal regions for phonological processing or passage comprehension tasks and increased reliance on the ventral tract (e.g., the Inferior Longitudinal Fasciculus). The low passage comprehension scores in mood disorder may result from engaging the left hemisphere. Neural pathways for reading differ mainly in executive-limbic circuitry. This new insight may aid clinicians in providing appropriate intervention for each disorder.

Background: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth., Method: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables., Results: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%., Conclusions: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Background: Changes in neural circuitry function may be associated with longitudinal changes in psychiatric symptom severity. Identification of these relationships may aid in elucidating the neural basis of psychiatric symptom evolution over time. We aimed to distinguish these relationships using data from the Longitudinal Assessment of Manic Symptoms (LAMS) cohort., Methods: Forty-one youth completed two study visits (mean=21.3 months). Elastic-net regression (Multiple response Gaussian family) identified emotional regulation neural circuitry that changed in association with changes in depression, mania, anxiety, affect lability, and positive mood and energy dysregulation, accounting for clinical and demographic variables., Results: Non-zero coefficients between change in the above symptom measures and change in activity over the inter-scan interval were identified in right amygdala and left ventrolateral prefrontal cortex. Differing patterns of neural activity change were associated with changes in each of the above symptoms over time. Specifically, from Scan1 to Scan2, worsening affective lability and depression severity were associated with increased right amygdala and left ventrolateral prefrontal cortical activity. Worsening anxiety and positive mood and energy dysregulation were associated with decreased right amygdala and increased left ventrolateral prefrontal cortical activity. Worsening mania was associated with increased right amygdala and decreased left ventrolateral prefrontal cortical activity. These changes in neural activity between scans accounted for 13.6% of the variance; that is 25% of the total explained variance (39.6%) in these measures., Conclusions: Distinct neural mechanisms underlie changes in different mood and anxiety symptoms overtime.

Objective: Neuroimaging studies have identified distinct neural correlates of obsessive-compulsive disorder (OCD) symptom dimensions in adult subjects and may be related to functional abnormalities in different cortico-striatal-thalamic neural systems underlying cognition and affective processing. Similar symptom dimensions are apparent in childhood and adolescence, but their functional neural correlates remain to be elucidated., Method: Pediatric subjects with OCD (n = 18) and matched controls (n = 18), ages 10 to 17 years, were recruited for two functional magnetic resonance imaging experiments. They were scanned while viewing alternating blocks of symptom provocation (contamination-related or symmetry-related) and neutral pictures and imagining scenarios related to the content of each picture type., Results: The subjects with OCD demonstrated reduced activity in the right insula, putamen, thalamus, dorsolateral prefrontal cortex, and left orbitofrontal cortex (contamination experiment) and in the right thalamus and right insula (symmetry experiment). Higher scores on OCD symptom-related measures (contamination and total severity) were significantly predictive of reduced neural activity in the right dorsolateral prefrontal cortex during the contamination experiment., Conclusions: Our findings indicate reduced activity in neural regions underlying emotional processing, cognitive processing, and motor performance in pediatric subjects with OCD compared with the controls. These between-group differences are present during both contamination and symmetry provocation experiments and during symptom provocation as well as viewing neutral pictures. The direction of activity is in contrast to adult findings in the insula and in components of cortico-striatal-thalamic neural systems. Our findings suggest developmental effects on neural systems underlying symptom dimensions in pediatric OCD.

Objective: A growing number of structural neuroimaging studies have shown that bipolar disorder (BD) is associated with gray matter (GM) volume abnormalities in brain regions known to support affect regulation. The goal of this study was to examine whole-brain regional GM volume in healthy bipolar offspring (HBO) relative to age-matched controls to identify possible structural abnormalities that may be associated with risk for BD., Method: Participants were 20 youths (8-17 years old) with at least one parent diagnosed with BD, and 22 age-matched healthy individuals. All of them were free of Axis I diagnoses. High-resolution magnetic resonance imaging structural images were acquired using a 3-T Siemens scanner. Voxel-based morphometric analyses were conducted using SPM5., Results: Relative to controls, HBO had significantly increased GM volume in left parahippocampal/hippocampal gyrus (p <.05 corrected), following whole-brain analyses. This increase was correlated with puberty but not age in HBO. Region-of-interest analyses on the amygdala and orbitomedial prefrontal cortex did not yield any significant group differences after conducting small volume correction., Conclusions: The pattern of increased GM volume in parahippocampal/hippocampal gyrus in HBO suggests a potential marker for risk for BD. It can also be considered as a potential neuroprotective marker for the disorder because HBO were free of current psychopathology. Prospective studies examining the relationship between changes in GM volume in these regions and subsequent development of BD in HBO will allow us to elucidate further the role of this region in either conferring risk for or protecting against the development of BD.