Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression

Abstract

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systemslevel to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.

A Resting-state Functional Magnetic Resonance Imaging Study of Whole-brain Functional Connectivity of Voxel Levels in Patients With Irritable Bowel Syndrome With Depressive Symptoms

“… 36 Numerous studies have found that functional changes in SMA networks can be used as predictors of antidepressant treatment outcomes, and may serve as a biomarker of treatment response. 37 - 39 Our previous study found that DEP-IBS patients had decreased gray matter volume in the insula and sensorimotor cortex. 19 Therefore, we speculate that the insula and SMA may be the key pathogenesis of DEP-IBS patients, and may provide a certain guiding value for the formulation of clinical treatment strategies.…”

Biomarkers of ketamine’s antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology

“…Sahib et al used an inhibitory control task to reveal changes in brain regions responsible for inhibitory and executive functioning in response to four ketamine infusions, and these findings correlated with treatment response. 36 More specifically, in the precentral gyrus, remitters had lower baseline BOLD signal that normalized to healthy control levels, whereas non-remitters had baseline BOLD signals that resembled healthy controls but decreased after the ketamine series. Supplemental motor area changes in BOLD signal corresponded to reductions in depressive symptoms.…”

Ketamine’s modulation of cerebro-cerebellar circuitry during response inhibition in major depression

“…Ketamine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist known to elicit fast-acting antidepressant effects in patients with MDD unresponsive to standard treatments (i.e., defined as having treatment resistant depression - TRD) ( Iadarola et al, 2015 , Zanos and Gould, 2018 ). Recently, ketamine therapy in MDD is also demonstrated to affect the brain at the systems level by disrupting the interaction between multiple networks during rest ( Evans et al, 2018 , Fleming et al, 2019 ) and task fMRI ( Anticevic et al, 2012 , Reed et al, 2018 , Scheidegger et al, 2016 , Sahib et al, 2020 , Loureiro et al, 2020 ). For example, we have shown significant decreases in activation in the inhibitory control network and right cerebellum during a Go/NoGo task following ketamine treatment where regional changes in activation associated with clinical remission ( Sahib et al, 2020 ).…”

“…Recently, ketamine therapy in MDD is also demonstrated to affect the brain at the systems level by disrupting the interaction between multiple networks during rest ( Evans et al, 2018 , Fleming et al, 2019 ) and task fMRI ( Anticevic et al, 2012 , Reed et al, 2018 , Scheidegger et al, 2016 , Sahib et al, 2020 , Loureiro et al, 2020 ). For example, we have shown significant decreases in activation in the inhibitory control network and right cerebellum during a Go/NoGo task following ketamine treatment where regional changes in activation associated with clinical remission ( Sahib et al, 2020 ). Notably, other imaging studies using ketamine in MDD have also reported blood-oxygenation-level-dependent (BOLD) changes in the cerebellum, as well as connectivity changes between the cerebellum and cortical networks ( Barch et al, 2013 , Downey et al, 2016 ).…”

“…However, there are no studies specifically targeting ketamine’s modulation of cerebro-cerebellar systems. In the current investigation we thus sought to target the perturbation of cerebro-cerebellar circuitry using the Go/NoGo task previously shown to elicit treatment-related effects in response-inhibition networks in patients with TRD receiving serial ketamine ( Sahib et al, 2020 ). Specifically, changes in target cortico-cerebellar networks were achieved by computing psychophysiological interaction (PPI) scores between a cerebellum-seed located in lobuleVIIb, involved in response-inhibition processes, and three main LSNs of the brain (FPN, SN and SMN) with respective nodes.…”