[F31] Investigating the role of ketamine in modulating intrinsic neural timescales in treatment resistant depression
Ente: National Institute of Mental Health
Scadenza: 2029-06-30
Importo max: 50.114 EUR
Paese: US
Descrizione
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
Istituzione: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
PI: Elizabeth Alcantara
Progetto: 1F31MH144832-01
Settori: National Institute of Mental Health
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