Altered frontal cortex functioning in emotion regulation and hopelessness in bipolar disorder.

OBJECTIVES: Emotion regulation difficulties precipitate and exacerbate acute mood symptoms in individuals with bipolar disorder (BD), and contribute to suicidal behavior. However, few studies have examined regional brain responses in explicit emotion regulation during acute BD mood states, or hopelessness, a major suicide risk factor. We assessed brain responses during explicit emotion regulation, and their relationship with hopelessness, in acutely symptomatic and euthymic individuals with BD. METHODS: Functional MRI data were obtained from individuals with BD who were either in acute negative (BD-A; n = 24) or euthymic (BD-E; n = 24) mood states, and from healthy volunteers (HV; n = 55), while participants performed a paradigm that instructed them to downregulate their responses to fearful (EmReg-Fear) and happy (EmReg-Happy) facial stimuli. Emotion regulation-related differences in brain responses during negative and euthymic BD states, as well as their associations with negative affective symptoms (hopelessness and depression), were examined. RESULTS: Decreased responses were observed in ventral and dorsal frontal regions, including medial orbitofrontal (mOFC) and dorsal anterior cingulate cortices, during EmReg-Fear across symptomatic and euthymic states in participants with BD relative to HVs. The lowest responses were observed in the BD-A group. Across BD participants, negative associations were observed between mOFC responses and hopelessness, particularly due to loss of motivation. Differences were not significant during EmReg-Happy. CONCLUSIONS: Lesser emotion regulation-related ventral and dorsal frontal engagement in BD could represent a trait abnormality that worsens during acute negative states. The reduced mOFC engagement in BD during explicit regulation of negative emotions may contribute to hopelessness particularly in the context of diminished motivation.

Multimodal Neuroimaging of Frontolimbic Structure and Function Associated With Suicide Attempts in Adolescents and Young Adults With Bipolar Disorder.

OBJECTIVE: Bipolar disorder is associated with high risk for suicidal behavior that often develops in adolescence and young adulthood. Elucidation of involved neural systems is critical for prevention. This study of adolescents and young adults with bipolar disorder with and without a history of suicide attempts combines structural, diffusion tensor, and functional MR imaging methods to investigate implicated abnormalities in the morphology and structural and functional connectivity within frontolimbic systems. METHOD: The study had 26 participants with bipolar disorder who had a prior suicide attempt (the attempter group) and 42 participants with bipolar disorder without a suicide attempt (the nonattempter group). Regional gray matter volume, white matter integrity, and functional connectivity during processing of emotional stimuli were compared between groups, and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors. RESULTS: Compared with the nonattempter group, the attempter group showed significant reductions in gray matter volume in the orbitofrontal cortex, hippocampus, and cerebellum; white matter integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions; and amygdala functional connectivity to the left ventral and right rostral prefrontal cortex. In exploratory analyses, among attempters, there was a significant negative correlation between right rostral prefrontal connectivity and suicidal ideation and between left ventral prefrontal connectivity and attempt lethality. CONCLUSIONS: Adolescent and young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral frontolimbic neural system subserving emotion regulation. Among attempters, reductions in amygdala-prefrontal functional connectivity may be associated with severity of suicidal ideation and attempt lethality.

Anterior Cortical Development During Adolescence in Bipolar Disorder.

BACKGROUND: Increasing evidence supports a neurodevelopmental model for bipolar disorder (BD), with adolescence as a critical period in its development. Developmental abnormalities of anterior paralimbic and heteromodal frontal cortices, key structures in emotional regulation processes and central in BD, are implicated. However, few longitudinal studies have been conducted, limiting understanding of trajectory alterations in BD. In this study, we performed longitudinal neuroimaging of adolescents with and without BD and assessed volume changes over time, including changes in tissue overall and within gray and white matter. Larger decreases over time in anterior cortical volumes in the adolescents with BD were hypothesized. Gray matter decreases and white matter increases are typically observed during adolescence in anterior cortices. It was hypothesized that volume decreases over time in BD would reflect alterations in those processes, showing larger gray matter contraction and decreased white matter expansion. METHODS: Two high-resolution magnetic resonance imaging scans were obtained approximately 2 years apart for 35 adolescents with bipolar I disorder (BDI) and 37 healthy adolescents. Differences over time between groups were investigated for volume overall and specifically for gray and white matter. RESULTS: Relative to healthy adolescents, adolescents with BDI showed greater volume contraction over time in a region including insula and orbitofrontal, rostral, and dorsolateral prefrontal cortices (p < .05, corrected), including greater gray matter contraction and decreased white matter expansion over time, in the BD compared with the healthy group. CONCLUSIONS: The findings support neurodevelopmental abnormalities during adolescence in BDI in anterior cortices, including altered developmental trajectories of anterior gray and white matter.

Translational analysis of effects of prenatal cocaine exposure on human infant cries and rat pup ultrasonic vocalizations.

Spectral and temporal features of human infant crying may detect neurobehavioral effects of prenatal cocaine exposure (PCE). Finding comparable measures of rodent ultrasonic vocalizations (USVs) would promote translational analyses by controlling the effects of correlated variables that confound human studies. To this end, two studies examined the sensitivity of similar acoustic structures in human infant and rat pup vocalizations to effects of PCE. In Study 1, cry sounds of 107 one month-old infants were spectrum analyzed to create a novel set of measures and to detect the presence of hyperphonation - a qualitative shift to an atypically high fundamental frequency (basic pitch) associated with neurobehavioral insult. Infants with PCE were compared to infants with prenatal polydrug-exposure (PPE) without cocaine and with infants in a standard comparison (SC) group with no prenatal drug exposure. In Study 2, USVs of 118 five day-old rat pups with either PCE, prenatal saline exposure or no prenatal exposures were spectrum analyzed to detect the presence of frequency shifts - acoustic features that have a frequency waveform similar to that of hyperphonation. Results of study 1 showed PCE had two sets of sex-dependent effects on human infants: PCE males had higher pitched cries with more dysphonation (turbulence); PCE females had longer pauses between fewer cry sounds that were of lower amplitude than comparison groups. PCE and PPE infants had more cries with hyperphonation than SC infants. In study 2, PCE pups had a greater percentage of USVs with shift in the acoustic structure than pups in the two control groups. As such, the novel measures of human infant crying and rat pup USVs were sensitive to effects of PCE. These studies provide the first known translational analysis of similar acoustic structures of vocalizations in two species to detect adverse effects of prenatal drug exposure.

Neurobiological risk factors for suicide: insights from brain imaging.

CONTEXT: This article reviews neuroimaging studies on neural circuitry associated with suicide-related thoughts and behaviors to identify areas of convergence in findings. Gaps in the literature for which additional research is needed are identified. EVIDENCE ACQUISITION: A PubMed search was conducted and articles published before March 2014 were reviewed that compared individuals who made suicide attempts to those with similar diagnoses who had not made attempts or to healthy comparison subjects. Articles on adults with suicidal ideation and adolescents who had made attempts, or with suicidal ideation, were also included. Reviewed imaging modalities included structural magnetic resonance imaging, diffusion tensor imaging, single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging. EVIDENCE SYNTHESIS: Although many studies include small samples, and subject characteristics and imaging methods vary across studies, there were convergent findings involving the structure and function of frontal neural systems and the serotonergic system. CONCLUSIONS: These initial neuroimaging studies of suicide behavior have provided promising results. Future neuroimaging efforts could be strengthened by more strategic use of common data elements and a focus on suicide risk trajectories. At-risk subgroups defined by biopsychosocial risk factors and multidimensional assessment of suicidal thoughts and behaviors may provide a clearer picture of the neural circuitry associated with risk status-both current and lifetime. Also needed are studies investigating neural changes associated with interventions that are effective in risk reduction.

Frontotemporal White Matter in Adolescents with, and at-Risk for, Bipolar Disorder.

Frontotemporal neural systems are highly implicated in the emotional dysregulation characteristic of bipolar disorder (BD). Convergent genetic, postmortem, behavioral and neuroimaging evidence suggests abnormalities in the development of frontotemporal white matter (WM) in the pathophysiology of BD. This review discusses evidence for the involvement of abnormal WM development in BD during adolescence, with a focus on frontotemporal WM. Findings from diffusion tensor imaging (DTI) studies in adults and adolescents are reviewed to explore possible progressive WM abnormalities in the disorder. Intra- and interhemispheric frontotemporal abnormalities were reported in adults with BD. Although evidence in children and adolescents with BD to date has been limited, similar intrahemispheric and interhemispheric findings have also been reported. The findings in youths suggest that these abnormalities may represent a trait marker present early in the course of BD. Functional connectivity studies, demonstrating a relationship between WM abnormalities and frontotemporal dysfunction in BD, and DTI studies of vulnerability in first-degree relatives of individuals with BD, are discussed. Together, findings suggest the involvement of abnormal frontotemporal WM development in the pathophysiology of BD and that these abnormalities may be early trait markers of vulnerability; however, more studies are critically needed.