Attachments: My Journey Into Research and Why I Opted for a Different Road.

My hope was that through research I could improve earlier detection, prevention, and treatment. Perhaps I also hoped it would help me find an explanation for why my father suffered for so many years.

Preliminary examination of gray and white matter structure and longitudinal structural changes in frontal systems associated with future suicide attempts in adolescents and young adults with mood disorders.

BACKGROUND: Mood disorders are major risk factors for suicidal behavior. While cross-sectional studies implicate frontal systems, data to aid prediction of suicide-related behavior in mood disorders are limited. Longitudinal research on neuroanatomical mechanisms underlying suicide risk may assist in developing targeted interventions. Therefore, we conducted a preliminary study investigating baseline gray and white matter structure and longitudinal structural changes associated with future suicide attempts. METHODS: High-resolution structural magnetic resonance imaging, diffusion tensor imaging, and suicide-related behavioral assessment data for 46 adolescents and young adults with mood disorders [baseline agemean = 18 years; 61% female] were collected at baseline and at follow-up (intervalmean = 3 years). Differences in baseline and longitudinal changes in gray matter volume and white matter fractional anisotropy in frontal systems that distinguished the participants who made future attempts from those who did not were investigated. RESULTS: Seventeen (37%) of participants attempted suicide within the follow-up period. Future attempters (those attempting suicide between their baseline and follow-up assessment), compared to those who did not, showed lower baseline ventral and rostral prefrontal gray matter volume and dorsomedial frontal, anterior limb of the internal capsule, and dorsal cingulum fractional anisotropy, as well as greater decreases over time in ventral and dorsal frontal fractional anisotropy (p < 0.005, uncorrected). LIMITATIONS: Sample size was modest. CONCLUSIONS: Results suggest abnormalities of gray and white matter in frontal systems and differences in developmental changes of frontal white matter may increase risk of suicide-related behavior in youths with mood disorders. Findings provide potential new leads for early intervention and prevention strategies.

Longitudinal Diffusion Tensor Imaging Study of Adolescents and Young Adults With Bipolar Disorder.

OBJECTIVE: Longitudinal neuroimaging during adolescence/young adulthood, when bipolar disorder (BD) commonly emerges, can help elucidate the neurodevelopmental pathophysiology of BD. Adults with BD have shown reduced structural integrity in the uncinate fasciculus (UF), a white matter (WM) tract providing major connections between the amygdala and ventral prefrontal cortex (vPFC), important in emotion regulation. In this longitudinal diffusion tensor imaging (DTI) study of adolescents/young adults, we hypothesized differences in age- and time-related changes in UF integrity in BD compared to healthy controls (HC). METHOD: Two DTI scans were obtained in 27 adolescents/young adults with BD and 37 HC adolescents/young adults, on average approximately 2.5 years apart. Interactions between diagnosis with age and with time for UF fractional anisotropy (FA) were assessed. Exploratory analyses were performed including euthymic-only participants with BD, and for potential influences of demographic and clinical factors. Whole-brain analyses were performed to explore for interactions in other regions. RESULTS: There were significant interactions between diagnosis with age and with time for UF FA (p < .05). Healthy control adolescents/young adults showed significant UF FA increases with age and over time (p < .05), whereas no significant changes with age or over time were observed in the adolescents/young adults with BD. Significant interactions with age and time were also observed in analyses including euthymic-only participants with BD (p < .05). CONCLUSION: These findings provide neuroimaging evidence supporting differences in UF WM structural development during adolescence/young adulthood, suggesting that differences in the development of an amygdala-vPFC system subserving emotion regulation may be a trait feature of BD neurodevelopment.

Brain circuitry associated with the development of substance use in bipolar disorder and preliminary evidence for sexual dimorphism in adolescents.

Substance use disorders and mood disorders are highly comorbid and confer a high risk for adverse outcomes. However, data are limited on the neurodevelopmental basis of this comorbidity. Substance use initiation typically occurs during adolescence, and sex-specific developmental mechanisms are implicated. In this preliminary study, we review the literature and investigate regional gray matter volume (GMV) associated with subsequent substance use problems in adolescents with bipolar disorder (BD) and explore these associations for females and males. Thirty adolescents with DSM-IV-diagnosed BD and minimal alcohol/substance exposure completed baseline structural magnetic resonance imaging scans. At follow-up (on average 6 years post baseline), subjects were administered the CRAFFT interview and categorized into those scoring at high ( ≥ 2: CRAFFTHIGH ) vs. low ( < 2: CRAFFTLOW ) risk for alcohol/substance problems. Lower GMV in prefrontal, insular, and temporopolar cortices were observed at baseline among adolescents with BD reporting subsequent alcohol and cannabis use compared to adolescents with BD who did not (P < 0.005, clusters ≥ 20 voxels). Lower dorsolateral prefrontal GMV was associated with future substance use in both females and males. In females, lower orbitofrontal and insula GMV was associated with future substance use, while in males, lower rostral prefrontal GMV was associated with future use. Lower orbitofrontal, insular, and temporopolar GMV was observed in those who transitioned to smoking tobacco. Findings indicate that GMV development is associated with risk for future substance use problems in adolescents with BD, with results implicating GMV development in regions subserving emotional regulation in females and regions subserving executive processes and attention in males. © 2016 Wiley Periodicals, Inc.

A developmental study on the neural circuitry mediating response flexibility in bipolar disorder.

Cross-sectional neuroimaging studies are an important first step in examining developmental differences in brain function between adults and youth with bipolar disorder (BD). Impaired response flexibility may contribute to reduced ability to modify goal-directed behavior in BD appropriately. We compared neural circuitry mediating this process in child (CBD) vs. adult BD (ABD) and age-matched healthy subjects. fMRI data from 15 CBD, 23 ABD, 20 healthy children, and 27 healthy adults were acquired during a response flexibility paradigm, a task where subjects inhibit a prepotent response and execute an alternative response. When successfully executing an alternate response, CBD showed frontal, parietal, and temporal hyperactivation relative to healthy children and ABD, while ABD hypoactivated these regions relative to healthy adults. Previous studies of response flexibility in healthy volunteers revealed frontal, temporal, and parietal cortex hyperactivation in children and hypoactivation in adults. Relative to age-matched healthy subjects, we found hyperactivation in these regions in CBD and hypoactivation in ABD. This suggests that our findings in patients may represent the extreme extension of the age-related response flexibility activation differences found in healthy subjects. Future studies should use longitudinal fMRI to examine the developmental trajectory of the neural circuitry mediating response flexibility in BD.

A developmental study of the neural circuitry mediating motor inhibition in bipolar disorder.

OBJECTIVE: Despite increased interest in the developmental trajectory of the pathophysiology mediating bipolar disorder, few studies have compared adults and youths with bipolar disorder. Deficits in motor inhibition are thought to play an important role in the pathophysiology of the illness across the age spectrum. The authors compared the neural circuitry mediating this process in bipolar youths relative to bipolar adults and in healthy volunteers. METHOD: Participants were pediatric (N=16) and adult (N=23) patients with bipolar disorder and healthy child (N=21) and adult (N=29) volunteers. Functional MRI (fMRI) data were acquired while participants performed the stop-signal task. RESULTS: During failed inhibition, an age group-by-diagnosis interaction manifested in the anterior cingulate cortex, with bipolar youths exhibiting hypoactivation relative to both healthy youths and bipolar adults, and bipolar adults exhibiting hyperactivation relative to healthy adults. During successful inhibition, a main effect of diagnosis emerged in the right nucleus accumbens and the left ventral prefrontal cortex, with bipolar patients in both age groups showing less activation than healthy subjects. CONCLUSIONS: Anterior cingulate cortex dysfunction during failed motor inhibition was observed in both bipolar youths and adults, although the nature of this dysfunction differed between the two groups. Adults and youths with bipolar disorder exhibited similar deficits in activation of the nucleus accumbens and the ventral prefrontal cortex during successful inhibition. Therefore, while subcortical and ventral prefrontal cortex hypoactivation was present in bipolar patients across the lifespan, anterior cingulate cortex dysfunction varied developmentally, with reduced activation in youths and increased activation in adults during failed inhibition. Longitudinal fMRI studies of the developmental trajectory of the neural circuitry mediating motor inhibition in bipolar disorder are warranted.