Emotional regulation neural circuitry abnormalities in adult bipolar disorder: dissociating effects of long-term depression history from relationships with present symptoms

Abstract

Bipolar disorder (BD) is common and debilitating and confounding effects of depression history on neural activity in BD are unknown. We aimed to dissociate neural activity reflecting past depression-load vs. present symptom severity using the Course and Outcome of Bipolar Youth (COBY), a prospective longitudinal cohort study of pediatric-onset BD. In n = 54 COBY (18–32 years), we modeled depression scores over time (up to 17.5 years) using a standardized autoregressive moving average (ARMA) model, followed by k-means cluster analysis. N = 36 healthy participants (HC, 20–36 years) were included. Using two factorial analyses, we parsed the impact of ARMA-defined past depression-load on neural activity from the impact of current symptoms on neural activity (p < 0.001, k > 30) and examined relationships with past and present symptoms (ps FDR-corrected). ARMA identified three COBY groups based on past depression-load. ARMA-defined COBY participants with the greatest past depression-load vs. other groups showed greater activity in right temporoparietal junction, thalamus, insula, premotor cortex, left fusiform gyrus, bilateral precuneus and cerebellum. In contrast, BD-COBY participants vs. HC showed greater activity in left hippocampus, dorsolateral prefrontal cortex, and right somatosensory cortex, plus the above thalamus, premotor cortex and cerebellum; activity positively correlated with present symptom severity in most regions. Past depression-load was related to social cognition and salience perception network activity, potentially reflecting heightened attention to socially relevant distracters, while present symptoms were associated with emotion processing and reappraisal network activity, potentially reflecting abnormal emotional experience and regulation. Differentiating aberrant neural activity related to long-term depression vs. present affective symptoms can help target interventions to networks associated with pathophysiological processes, rather than long-term illness effects.

Inflammation and emotional regulation: a narrative review of evidence and mechanisms in emotional dysregulation disorders

“…Meanwhile, an fMRI study examining euthymic patients with BD I compared to HC showed similar results, with patients demonstrating ED via impaired control of amygdala reactivity to emotional stimuli and dysfunctional amygdala connectivity (184). In a recent study investigating ER circuitry, researchers found patterns of elevated neural activity in BD patients as compared to HC during ER task performance in the left dlPFC, left hippocampus, and right somatosensory cortex (177). The potential involvement of the somatomotor network (SMN) in ED displayed in BD is discussed in Section 3.3.…”

“…However, findings across studies do not always correspond on the directionality of these changes (174), and the frequent presence of lithium medication, which has been tied to volumetric brain alterations, complicates the interpretation of results (176). Moreover, although the topic is still underexplored, brain alterations may differ between BD subtypes (177,178) and mood states (175).…”

Predicting depressed and elevated mood symptomatology in bipolar disorder using brain functional connectomes

“…Depressed episodes of BD, the most common and studied of the acute BD episode types, were associated with dysfunction in the left PFC and dorsolateral PFC (dlPFC) areas (Altshuler et al, 2008 ; Goldman et al, 2022 ). Dysfunctions in the dlPFC have also been associated with depressed symptom severity (Bertocci et al, 2020 ; Brooks et al, 2009 ; Fernández-Corcuera et al, 2013 ; Ketter et al, 2001 ; Koenigs & Grafman, 2009 ). Studies of elevated mood episodes, albeit fewer, suggest dysfunction particularly in the right hemisphere and in ventral PFC (vPFC) areas (Blond & Blumberg, 2010 ; Blumberg et al, 1999 , 2003 ; Elliott et al, 2004 ; Liu et al, 2012 ; Strakowski et al, 2011 ).…”

Aluminium oxide nanoparticles compromise spatial memory performance and proBDNF-mediated neuronal function in the hippocampus of rats

“…Other findings also indicate that memory consolidation rather than memory acquisition requires the NMDAR-LTD mechanism to modify the hippocampal circuit to store memory [ 22 – 24 ]. Furthermore, it has been well known that abnormal hippocampal LTD in depression, schizophrenia and bipolar disorder leads to deficits in attention, cognition and working memory [ 25 – 27 ]. Therefore, impairments of hippocampal LTD are not only necessary but sufficient to mediate spatial learning and memory.…”