Aberrant intrinsic functional connectivity within and between corticostriatal and temporal-parietal networks in adults and youth with bipolar disorder.

BACKGROUND: Major questions remain regarding the dysfunctional neural circuitry underlying the pathophysiology of bipolar disorder (BD) in both youths and adults. In both age groups, studies implicate abnormal intrinsic functional connectivity among prefrontal, limbic and striatal areas. METHOD: We collected resting-state functional magnetic resonance imaging (fMRI) data from youths and adults (ages 10-50 years) with BD (n = 39) and healthy volunteers (HV; n = 78). We identified brain regions with aberrant intrinsic functional connectivity in BD by first comparing voxel-wise mean global connectivity and then conducting correlation analyses. We used k-means clustering and multidimensional scaling to organize all detected regions into networks. RESULTS: Across the brain, we detected areas of dysconnectivity in both youths and adults with BD relative to HV. There were no significant age-group × diagnosis interactions. When organized by interregional connectivity, the areas of dysconnectivity in patients with BD comprised two networks: one of temporal and parietal areas involved in late stages of visual processing, and one of corticostriatal areas involved in attention, cognitive control and response generation. CONCLUSIONS: These data suggest that two networks show abnormal intrinsic functional connectivity in BD. Regions in these networks have been implicated previously in BD. We observed similar dysconnectivity in youths and adults with BD. These findings provide guidance for refining models of network-based dysfunction in BD.

An fMRI study of emotional face encoding in youth at risk for bipolar disorder.

Face memory deficits may be a bipolar disorder (BD) endophenotype. BD (n=27) and unaffected youth at risk (n=13) exhibited middle frontal gyrus hypoactivation during successful vs. unsuccessful encoding. Parahippocampal gyrus dysfunction was found in BD and at-risk youth (vs. low-risk, n=37). Middle occipital gyrus hypoactivation was only present in BD.

Fronto-limbic-striatal dysfunction in pediatric and adult patients with bipolar disorder: impact of face emotion and attentional demands.

BACKGROUND: Research in bipolar disorder (BD) implicates fronto-limbic-striatal dysfunction during face emotion processing but it is unknown how such dysfunction varies by task demands, face emotion and patient age. METHOD: During functional magnetic resonance imaging (fMRI), 181 participants, including 62 BD (36 children and 26 adults) and 119 healthy comparison (HC) subjects (57 children and 62 adults), engaged in constrained and unconstrained processing of emotional (angry, fearful, happy) and non-emotional (neutral) faces. During constrained processing, subjects answered questions focusing their attention on the face; this was processed either implicitly (nose width rating) or explicitly (hostility; subjective fear ratings). Unconstrained processing consisted of passive viewing. RESULTS: Pediatric BD rated neutral faces as more hostile than did other groups. In BD patients, family-wise error (FWE)-corrected region of interest (ROI) analyses revealed dysfunction in the amygdala, inferior frontal gyrus (IFG), anterior cingulate cortex (ACC) and putamen. Patients with BD showed amygdala hyperactivation during explicit processing (hostility ratings) of fearful faces and passive viewing of angry and neutral faces but IFG hypoactivation during implicit processing of neutral and happy faces. In the ACC and striatum, the direction of dysfunction varied by task demand: BD demonstrated hyperactivation during unconstrained processing of angry or neutral faces but hypoactivation during constrained processing (implicit or explicit) of angry, neutral or happy faces. CONCLUSIONS: Findings suggest amygdala hyperactivation in BD while processing negatively valenced and neutral faces, regardless of attentional condition, and BD IFG hypoactivation during implicit processing. In the cognitive control circuit involving the ACC and putamen, BD neural dysfunction was sensitive to task demands.

Impaired probabilistic reversal learning in youths with mood and anxiety disorders.

BACKGROUND: From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. METHOD: We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. RESULTS: Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07). CONCLUSIONS: Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.

Validation of the prospective NIMH-Life-Chart Method (NIMH-LCM-p) for longitudinal assessment of bipolar illness.

BACKGROUND: Systematic and accurate depiction of a patient's course of illness is crucial for assessing the efficacy of maintenance treatments for bipolar disorder. This need to rate the long-term prospective course of illness led to the development of the National Institute of Mental Health prospective Life Chart Methodology (NIMH-LCM-p or LCM). The NIMH-LCM-p allows for the daily assessment of mood and episode severity based on the degree of mood associated functional impairment. We have previously presented preliminary evidence of the reliability and validity of the LCM, and its utility in clinical trials. This study is a further and more extensive validation of the clinician rated NIMH-LCM-p. METHODS: Subjects included 270 bipolar patients from the five sites participating in the Stanley Foundation Bipolar Network. Daily prospective LCM ratings on the clinician form were initiated upon entry, in addition to at least monthly ratings with the Inventory of Depressive Symptomatology-clinician rated (IDS-C), the Young Mania Rating Scale (YMRS) and the Global Assessment of Functioning (GAF). We correlated appropriate measures and time domains of the LCM with the IDS-C, YMRS and GAF. RESULTS: Severity of depression on the LCM and on the IDS-C were highly correlated in 270 patients (r = -0.785, P < 0.001). Similarly, a strong correlation was found between LCM mania and the YMRS (r = 0.656, P < 0.001) and between the LCM average severity of illness and the GAF (r = -0.732, P < 0.001). CONCLUSIONS: These data further demonstrate the validity and potential utility of the NIMH-LCM-p for the detailed daily longitudinal assessment of manic and depressive severity and course, and response to treatment.

High exposure to neuroleptics in bipolar patients: a retrospective review.

BACKGROUND: Acute and long-term use of neuroleptics to treat bipolar disorder remains prevalent despite safety concerns. Neuroleptic-treated patients with bipolar disorder have been reported to have rates of tardive dyskinesia, akathisia, and acute dystonia as high as or higher than patients with schizophrenia. Moreover, the pattern of repeated, intermittent use of neuroleptics in bipolar disorder may increase rather than decrease the risk of tardive dyskinesia. METHOD: Retrospective life charts of 133 treatment-refractory patients with bipolar disorder (diagnosed according to Research Diagnostic Criteria or a clinical interview with the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or the Structured Clinical Interview for DSM-IV Axis I Disorders) admitted to the National Institute of Mental Health (NIMH) were reviewed for prior neuroleptic use, medication exposure, and course of illness variables. Patients' medication response and degree of improvement while at NIMH were also assessed. RESULTS: A total of 72.2% (N = 96) of the bipolar patients examined had exposure to neuroleptics prior to referral to NIMH. Neuroleptic-treated patients had a mean of 5.6 neuroleptic trials with a mean duration of 166.4 days for each trial and a dose range of 25 to 960 mg in chlorpromazine equivalents. Life chart data showed that the neuroleptic-exposed and nonexposed bipolar patients were distinguished by 1 course-of-illness variable: increased suicidality in the neuroleptic-treated group. Patients with and without prior neuroleptic exposure experienced the same high degree of improvement at discharge from NIMH. Only 12.5% (N = 12) of the group previously treated with typical neuroleptics (N = 96) required neuroleptics at discharge. CONCLUSION: Our data suggest that the majority of even treatment-refractory bipolar patients can be stabilized without neuroleptics. Given the high risk of tardive dyskinesia and the availability of other novel agents, the routine intermittent use of typical neuroleptics to treat patients with bipolar disorder should be minimized.