Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex

Abstract

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.

Multi-Site Statistical Mapping of Along-Tract Microstructural Abnormalities in Bipolar Disorder with Diffusion MRI Tractometry

“…Furthermore, adding more samples to this analysis improved effect size estimates for each tract. Abnormal FA in anterior portions within the cingulum is consistent with the regions where activations are detected in emotion-related fMRI studies in BD [33]. Morphological and network-based connectivity studies have reported deficits in FA in the limbic right anterior and subgenual cingulate cortex [34].…”

Along-Tract Statistical Mapping of Microstructural Abnormalities in Bipolar Disorder: A Pilot Study

“…Our regional findings implicate fronto-limbic and interhemispheric connections in BD. FA alterations, in anterior sections within the cingulum, are in regions where activations are detected in emotion-related fMR studies in BD [39], among other morphological and connectivity studies [16]. Additionally, alterations in the corpus callosum have been consistently found in structural, diffusion and functional MR studies of BD, particularly within the anterior horn (connecting bilateral prefrontal and limbic regions) [16].…”

Neural Basis of Pain Empathy Dysregulations in Mental Disorders – A Pre-registered Neuroimaging Meta-Analysis

“…Hyperactivity in this region may thus reflect a stronger distress-related pain-empathic reactivity or a stronger need to regulate the negative affective experience. 22,68 Increasing number of reports indicated that individuals with mental disorders experience greater levels of empathic distress 69,70 and the role of this region in the experience of pain-related emotional distress findings may reflect higher pain empathic reactivity. The vACC subregion of the ACC has moreover been found to play an important role in other related functions such as social cognitive decision-making, behavior encoding, and outcome prediction 71,72 and can mediate the saliency of the external stimuli thus triggering pain empathic experiences.…”

“…Etkin et al, 2011a; Xiang et al, 2018). Hyperactivity in this region may thus reflect a stronger distress-related pain-empathic reactivity or a stronger need to regulate the negative affective experience (Betti and Aglioti, 2016; Nabulsi et al, 2022). The increasing number of reports indicated that individuals with mental disorders experience greater levels of empathic distress (Allman et al, 2001; Apps et al, 2016) and the role of this region in the experience of pain-related emotional distress findings may reflect higher pain empathic reactivity.…”