Neuroprogression in bipolar disorder.
ABSTRACT Recent theories regarding the neuropathology of bipolar disorder suggest that both neurodevelopmental and neurodegenerative processes may play a role. While magnetic resonance imaging has provided significant insight into the structural, functional, and connectivity abnormalities associated with bipolar disorder, research assessing longitudinal changes has been more limited. However, such research is essential to elucidate the pathophysiology of the disorder. The aim of our review is to examine the extant literature for developmental and progressive structural and functional changes in individuals with and at risk for bipolar disorder.
We conducted a literature review using MEDLINE and the following search terms: bipolar disorder, risk, child, adolescent, bipolar offspring, MRI, fMRI, DTI, PET, SPECT, cross-sectional, longitudinal, progressive, and developmental. Further relevant articles were identified by cross-referencing with identified manuscripts.
There is some evidence for developmental and progressive neurophysiological alterations in bipolar disorder, but the interpretation of correlations between neuroimaging findings and measures of illness exposure or age in cross-sectional studies must be performed with care. Prospective longitudinal studies placed in the context of normative developmental and atrophic changes in neural structures and pathways thought to be involved in bipolar disorder are needed to improve our understanding of the neurodevelopmental underpinnings and progressive changes associated with bipolar disorder.
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ABSTRACT: Objectives Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood.Methods Twenty-two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight-week scans.ResultsAt baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003).Conclusions These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex—restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non-specific marker of affective change.Bipolar Disorders 10/2014; 17(4). DOI:10.1111/bdi.12274 · 4.89 Impact Factor
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ABSTRACT: Clinical evidence shows that bipolar disorder (BD) is characterized by white matter (WM) microstructural abnormalities. However, little is known about the biological mechanisms associated with these abnormalities and their relationship with cognitive functioning. 49 adult BD patients ((M±SD): 29.27 ± 7.92 years; 17 males, 32 females; 34 BD-I, 10 BD-II, and 5 BD-NOS) and 28 age-matched normal subjects ((M±SD): 29.19 ± 7.35 years; 10 males and 18 females) underwent diffusion tensor imaging (DTI) imaging. DTI metrics were computed using whole-brain tract-based spatial statistics (TBSS) as part of the FMRIB Software Library. Measures of WM coherence (fractional anisotropy - FA) and axonal structure (mean, axial and radial diffusivity - MD, AD and RD) were employed to characterize the microstructural alterations in the limbic, commissural, association and projection fiber tracts. All participants performed the Brief Assessment of Cognition for Affective disorders (BAC-A). BD patients performed poorly on verbal fluency tasks and exhibited large clusters of altered FA, RD and MD values within the retrolenticular part of the internal capsule, the superior and anterior corona radiata, and the corpus callosum. Increased FA values in the left IFOF and the forceps minor correlated positively with verbal fluency scores. Altered RD parameters in the corticospinal tract and the forceps minor were associated with reduced visuomotor abilities. The reported verbal fluency deficits and FA, RD and MD alterations in WM structures are potential cognitive and neural markers of BD. Abnormal RD values may be associated with progressive demyelination. Copyright © 2015 Elsevier Ltd. All rights reserved.Journal of Psychiatric Research 02/2015; 62. DOI:10.1016/j.jpsychires.2015.01.008 · 4.09 Impact Factor
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ABSTRACT: Psychiatric disorders in youth characterized by behavioral and emotional dysregulation are often comorbid and difficult to distinguish. An alternative approach to conceptualizing these disorders is to move toward a diagnostic system based on underlying pathophysiologic processes that may cut across conventionally defined diagnoses. Neuroimaging techniques have potentials for the identification of these processes. To determine whether diffusion imaging, a neuroimaging technique examining white matter (WM) structure, can identify neural correlates of emotional dysregulation in a sample of youth with different psychiatric disorders characterized by behavioral and emotional dysregulation. Using global probabilistic tractography, we examined relationships between WM structure in key tracts in emotional regulation circuitry (ie, cingulum, uncinate fasciculus, and forceps minor) and (1) broader diagnostic categories of behavioral and emotional dysregulation disorders (DDs) and (2) symptom dimensions cutting across conventional diagnoses in 120 youth with behavioral and/or emotional DDs, a referred sample of the Longitudinal Assessment of Manic Symptoms (LAM) study. Thirty age- and sex-matched typically developing youth (control participants) were included. Multivariate multiple regression models were used. The study was conducted from July 1, 2010, to February 28, 2014. Fractional anisotropy as well as axial and radial diffusivity were estimated and imported into a well-established statistical package. We hypothesized that (1) youth with emotional DDs and those with both behavioral and emotional DDs would show significantly lower fractional anisotropy compared with youth with behavioral DDs in these WM tracts and (2) that there would be significant inverse relationships between dimensional measures of affective symptom severity and fractional anisotropy in these tracts across all participants. Multivariate multiple regression analyses revealed decreased fractional anisotropy and decreased axial diffusivity within the uncinate fasciculus in youth with emotional DDs vs those with behavioral DDs, those with both DDs, and the controls (F6,160 = 2.4; P = .032; all pairwise comparisons, P < .002). In the same model, greater severity of manic symptoms was positively associated with higher fractional anisotropy across all affected youth (F3,85 = 2.8; P = .044). These findings suggest that abnormal uncinate fasciculus and cingulum WM structure may underlie emotional, but not behavioral, dysregulation in pediatric psychiatric disorders and that a different neural mechanism may exist for comorbid emotional and behavioral DDs.JAMA Psychiatry 02/2015; 72(4). DOI:10.1001/jamapsychiatry.2014.2170 · 12.01 Impact Factor