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

Nabulsi, L., Farrell, J., McPhilemy, G., Kilmartin, L., Dauvermann, M., Akudjedu, T.. N., Najt, P., Ambati, S., Martyn, F.M., McLoughlin, J., Gill, M., Meaney, J., Morris, D., Frodl, T., McDonald, C., Hallahan, B. and Cannon, D.M., 2022. Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex. Neuropsychopharmacology, 47, 1643-1651.

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s41386-022-01268-7 (1).pdf - Published Version
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DOI: 10.1038/s41386-022-01268-7


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.

Item Type:Article
Additional Information:FUNDING This research is supported by the Irish Research Council (IRC) Postgraduate Scholarship, Ireland awarded to Leila Nabulsi, PhD, and by the Health Research Board (HRA-POR-324) awarded to Dr Dara M. Cannon, PhD. We gratefully acknowledge the participants and the support of the Wellcome-Trust HRB Clinical Research Facility and the Centre for Advanced Medical Imaging, St. James Hospital, Dublin, Ireland. Open Access funding provided by the IReL Consortium.
Group:Faculty of Health & Social Sciences
ID Code:36537
Deposited By: Symplectic RT2
Deposited On:24 Jan 2022 14:45
Last Modified:20 Jul 2022 10:19


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