TY - JOUR
T1 - Ketamine's modulation of cerebro-cerebellar circuitry during response inhibition in major depression
AU - Loureiro, Joana R.A.
AU - Sahib, Ashish K.
AU - Vasavada, Megha
AU - Leaver, Amber
AU - Kubicki, Antoni
AU - Wade, Benjamin
AU - Joshi, Shantanu
AU - Hellemann, Gerhard
AU - Congdon, Eliza
AU - Woods, Roger P.
AU - Espinoza, Randall
AU - Narr, Katherine L.
N1 - Funding Information:
This work was supported by the National Institute of Mental Health of the National Institutes of Health (Grant Nos. MH110008 [to KLN and RE], and MH102743 [to KLN]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021
PY - 2021/1
Y1 - 2021/1
N2 - Patients with major depressive disorder (MDD) exhibit impaired control of cognitive and emotional systems, including deficient response selection and inhibition. Though these deficits are typically attributed to abnormal communication between macro-scale cortical networks, altered communication with the cerebellum also plays an important role. Yet, how the circuitry between the cerebellum and large-scale functional networks impact treatment outcome in MDD is not understood. We thus examined how ketamine, which elicits rapid therapeutic effects in MDD, modulates cerebro-cerebellar circuitry during response-inhibition using a functional imaging NoGo/Go task in MDD patients (N = 46, mean age: 39.2, 38.1% female) receiving four ketamine infusions, and healthy controls (N = 32, mean age:35.2, 71.4% female). We fitted psychophysiological-interaction (PPI) models for a functionally-derived cerebellar-seed and extracted average PPI in three target functional networks, frontoparietal (FPN), sensory-motor (SMN) and salience (SN) networks. Time and remission status were then evaluated for each of the networks and their network-nodes. Follow-up tests examined whether PPI-connectivity differed between patient remitter/non-remitters and controls. Results showed significant decreases in PPI-connectivity after ketamine between the cerebellum and FPN (p < 0.001) and SMN networks (p = 0.008) in remitters only (N = 20). However, ketamine-related changes in PPI-connectivity between the cerebellum and the SN (p = 0.003) did not vary with remitter status. Cerebellar-FPN, -SN PPI values at baseline were also associated with treatment outcome. Using novel methodology to quantify the functional coupling of cerebro-cerebellar circuitry during response-inhibition, our findings highlight that these loops play distinct roles in treatment response and could potentially serve as novel biomarkers for fast-acting antidepressant therapies in MDD.
AB - Patients with major depressive disorder (MDD) exhibit impaired control of cognitive and emotional systems, including deficient response selection and inhibition. Though these deficits are typically attributed to abnormal communication between macro-scale cortical networks, altered communication with the cerebellum also plays an important role. Yet, how the circuitry between the cerebellum and large-scale functional networks impact treatment outcome in MDD is not understood. We thus examined how ketamine, which elicits rapid therapeutic effects in MDD, modulates cerebro-cerebellar circuitry during response-inhibition using a functional imaging NoGo/Go task in MDD patients (N = 46, mean age: 39.2, 38.1% female) receiving four ketamine infusions, and healthy controls (N = 32, mean age:35.2, 71.4% female). We fitted psychophysiological-interaction (PPI) models for a functionally-derived cerebellar-seed and extracted average PPI in three target functional networks, frontoparietal (FPN), sensory-motor (SMN) and salience (SN) networks. Time and remission status were then evaluated for each of the networks and their network-nodes. Follow-up tests examined whether PPI-connectivity differed between patient remitter/non-remitters and controls. Results showed significant decreases in PPI-connectivity after ketamine between the cerebellum and FPN (p < 0.001) and SMN networks (p = 0.008) in remitters only (N = 20). However, ketamine-related changes in PPI-connectivity between the cerebellum and the SN (p = 0.003) did not vary with remitter status. Cerebellar-FPN, -SN PPI values at baseline were also associated with treatment outcome. Using novel methodology to quantify the functional coupling of cerebro-cerebellar circuitry during response-inhibition, our findings highlight that these loops play distinct roles in treatment response and could potentially serve as novel biomarkers for fast-acting antidepressant therapies in MDD.
KW - Cerebellum
KW - Ketamine
KW - Large-scale networks
KW - PPI
KW - Response-inhibition
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U2 - 10.1016/j.nicl.2021.102792
DO - 10.1016/j.nicl.2021.102792
M3 - Article
C2 - 34571429
AN - SCOPUS:85115608615
SN - 2213-1582
VL - 32
JO - NeuroImage: Clinical
JF - NeuroImage: Clinical
M1 - 102792
ER -