Investigating the role of ketamine in modulating intrinsic neural timescales in treatment resistant depression

About This Grant

Major depressive disorder is one of the leading causes of disability worldwide and approximately a third of patients develop treatment resistant depression (TRD). Cognitive impairments are a hallmark feature of depression and greatly impact severity of disability and quality of life. Current treatment options for TRD do not, however, specifically target cognitive impairments. Ketamine has recently been shown to be an effective treatment of TRD and improves cognition. Ketamine is known to work through the antagonism of N-methyl-D- aspartate (NMDA) receptors specifically on inhibitory interneurons. This suggests ketamine modulates the excitation/inhibition balance (E/I) and potentially indicates that alterations in E/I could underlie TRD. Intrinsic neural timescales (INT) are a resting state functional magnetic resonance imaging (rs-fMRI) measure can be acquired from the human brain and are theorized to be sensitive to the strength of recurrent excitation and therefore reflective of E/I function. Additionally, recurrent excitation (and E/I more broadly) is a property of canonical microcircuits responsible for the representation and processing of information, linking it as a possible mechanism underlying cognition. The main hypothesis of this proposal is that disruptions of E/I in canonical microcircuits are responsible for cognitive deficits and contribute to symptom severity in TRD. Further, we hypothesize that ketamine normalizes this disruption to improve cognitive deficits in TRD. Although preclinical work has highlighted E/I dysfunction as the potential mechanism of ketamine’s antidepressant effects, clinical work measuring E/I function has been limited specifically as a theoretically informed assessment of E/I in individuals with depression before and after ketamine treatment has not been conducted. This project will leverage a pre-existing large-scale neuroimaging dataset (HCP-PDC and HCP-A) including data from 180 TRD and 180 matched controls, with 58 TRD imaged at 3 timepoints (baseline; 24hr post 1st ketamine dose; 24hr post final ketamine dose). I will test for alterations in INT (measured using 3 Tesla rs-fMRI) in TRD (Aim 1a), relationships with depression severity (Aim 1b) and cognitive function, specifically the domains relating to working memory and processing speed (Aim 1c), as well as the impact of ketamine treatment on these measures and their relationships (Aim 2). Further, this project will investigate the potential of INT as a biomarker for identifying individuals who respond to ketamine (Aim 2c). The results from this project will provide mechanistic understanding for cognitive deficits in TRD and will identify individuals with impaired microcircuit function who would benefit from ketamine or other glutamatergic therapies, both for depression and cognitive deficits. The Icahn School of Medicine is an excellent training environment for novel research focused on using neuroimaging techniques to probe biological mechanisms that can be translated to improve clinical outcomes. Additionally, this project will facilitate professional development, mentorship, and technical skill expansion for a smooth transition into an independent academic research scientist.