TY - JOUR
T1 - Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex
AU - Nabulsi, Leila
AU - Farrell, Jennifer
AU - McPhilemy, Genevieve
AU - Kilmartin, Liam
AU - Dauvermann, Maria R.
AU - Akudjedu, Theophilus N.
AU - Najt, Pablo
AU - Ambati, Srinath
AU - Martyn, Fiona M.
AU - McLoughlin, James
AU - Gill, Michael
AU - Meaney, James
AU - Morris, Derek
AU - Frodl, Thomas
AU - McDonald, Colm
AU - Hallahan, Brian
AU - Cannon, Dara M.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85123244355&partnerID=8YFLogxK
U2 - 10.1038/s41386-022-01268-7
DO - 10.1038/s41386-022-01268-7
M3 - Article
C2 - 35046509
AN - SCOPUS:85123244355
SN - 0893-133X
VL - 47
SP - 1643
EP - 1651
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 9
ER -