Diverse pathophysiological processes converge on network disruption in mania

Abstract

Background: Neuroimaging of psychiatric disease is challenged by the difficulty of establishing the causal role of neuroimaging abnormalities. Lesions that cause mania present a unique opportunity to understand how brain network disruption may cause mania in both lesions and in bipolar disorder. Methods: A literature search revealed 23 case reports with imaged lesions that caused mania in patients without history of bipolar disorder. We traced these lesions and examined resting-state functional Magnetic Resonance Imaging (rsfMRI) connectivity to these lesions and control lesions to find networks that would be disrupted specifically by mania-causing lesions. The results were then used as regions-of-interest to examine rsfMRI connectivity in patients with bipolar disorder (n=16) who underwent imaging longitudinally across states of both mania and euthymia alongside a cohort of healthy participants scanned longitudinally. We then sought to replicate these results in independent cohorts of manic (n=26) and euthymic (n=21) participants with bipolar disorder. Results: Mania-inducing lesions overlap significantly in network connectivity. Mania-causing lesions selectively disrupt networks that include orbitofrontal cortex, dorsolateral prefrontal cortex, and temporal lobes. In bipolar disorder, the manic state was reflected in strong, significant, and specific disruption in network communication between these regions and regions implicated in bipolar pathophysiology: the amygdala and ventro-lateral prefrontal cortex. Limitations: There was heterogeneity in the clinical characterization of mania causing lesions. Conclusions: Lesions causing mania demonstrate shared and specific network disruptions. These disruptions are also observed in bipolar mania and suggest a convergence of multiple disorders on shared circuit dysfunction to cause mania.

Mapping mania symptoms based on focal brain damage

“…Our findings are based on lesion network mapping, a technique that has been successfully applied to hallucinations (20,51), delusions (25), criminality (26), depression (4), and many other neuropsychiatric symptoms (3). In fact, our study is not the first to apply lesion network mapping to mania, with a prior study also concluding that mania lesions show a distinct pattern of brain connectivity (52). However, which connections are most important differ between the 2 studies, including the description of right-sided lateralization here.…”

“…The alignment of our lesion results with therapeutic effects of brain stimulation in primary mania suggests some overlap, but further work comparing the 2 is needed (for an example see ref. 52). Furthermore, this study focuses only on lesion location, while ignoring potential contributions from genetic loading (16,86), environmental or treatment exposures (87)(88)(89), and the use of pharmacologic agents (103-106), with known impact in primary bipolar disorder.…”

Functional neuroanatomy of mania

“…Lesion network mapping is a recently developed neuroimaging methodology, developed to address this phenomenon [ 107 ], that takes advantageous of normative connectomes [ 108 , 109 ] to highlight regions that are functionally connected to each lesion location, thus resulting in brain network maps. Two studies have applied this approach to lesional mania [ 110 , 111 ]. Lee and colleagues showed that the temporal lobe and OFC, on both sides of the brain, were more functionally connected to lesion locations associated with mania than control lesions, with the possibility of negative connectivity with the DLPFC, also bilaterally, suggested.…”

A case report of mania with abnormal cerebral blood flow and cognitive impairment 24 years after head trauma

“…Both decreased orbitofrontal cortex (OFC) activity during rest [1] and an underactive inferior frontal cortex [2] have been reported to be associated with manic states in bipolar disorder. Furthermore, networks that include the OFC, the dorsolateral prefrontal cortex, and the temporal lobe are selectively disrupted in mania-inducing lesions [3], further confirming the importance of the OFC in manic pathophysiology.…”

“…Although no visual morphological abnormalities were observed by CT at the onset of mania, head trauma in early childhood may have conferred vulnerability on the OFC, which may in turn have led to the tendency toward disinhibited behaviors during adolescence. Under stress, vulnerability of the OFC might have led to lowered cerebral blood flow and subsequent mania [3]. OFC dysfunction could also explain the patient's apathic behavior when he was referred to our hospital.…”