# Neural Circuit-Specific Mechanisms of Ketamine's Effect on Anhedonia and Anxiety in Depression Using Ultra-High Field 7-Tesla MRI

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $765,927

## Abstract

Depression is a devastating public health problem, yet the pathophysiological mechanisms underlying distinct
aspects of the disorder remain largely unknown. Convergent evidence from animal and human studies have
strongly implicated functional perturbations in the subgenual anterior cingulate cortex (sgACC) in depression.
However, it is not known how dysfunction within specific sub-circuits of this heterogenous structure map to
specific depression-related symptom domains. This gap in knowledge concerning the pathophysiology of
depression is a major impediment to the advancement of diagnostic and therapeutic approaches to this disabling
disorder. To address this gap, we propose a rigorous translational neuroscience study to define the distinct
circuit-specific mechanisms of anhedonia and anxiety in humans with depression, building upon work in non-
human primates, and converging human evidence from our laboratories. In marmosets, selective over-activation
of Brodmann Area 25 (BA25) within the sgACC via glutamate re-uptake inhibition causally leads to deficits in
anticipatory arousal – an established analogue of anhedonia in humans. Critically, these behavioral deficits are
selectively reversed by peripheral administration of the glutamate NMDA receptor antagonist ketamine. Pilot
work from our laboratory show a remarkable degree of inter-species convergence, pointing towards conservation
of a glutamate-sensitive sub-circuit within the sgACC/BA25 that controls hedonic responses to environmental
stimuli. We show that the sgACC/BA25 is specifically overactive in response to positive (but not negative)
incentives in individuals with major depressive disorder (MDD) compared to unaffected health control (HC)
individuals. We also show that the magnitude of activation specifically within BA25 (but not more rostral prelimbic
area 32 [PL32]) is positively associated with degree of self-reported anhedonia, as predicted by primate work.
Finally, we show that a single intravenous infusion of ketamine specifically reverses overactivation of the BA25
to positive stimuli; the degree of reduction in BA25 following ketamine correlated with improved in self-reported
anhedonia (but not anxiety), as predicted by primate work. The overall goal of the proposed work is to define the
distinct circuit-specific mechanisms of anhedonia and anxiety in humans with depression. To complete Aim 1,
we will enroll N=60 medication-free adults with MDD and N=60 HC adults. All individuals will undergo clinical
and behavioral assessment of anhedonia, anxiety, and other depression-relevant domains and both resting-state
and task-based acquisitions with a validated reward task using ultra-high-field 7-Tesla (7T) MRI. To complete
Aim 2, the N=60 medication-free adults with MDD from Aim 1 will be randomized to either a single IV infusion of
0.5 mg/kg racemic ketamine (KET) or placebo (PBO, saline) and undergo repeated clinical and behavioral
assessments and 7T MRI at 24 hours post treatment....

## Key facts

- **NIH application ID:** 10890096
- **Project number:** 5R01MH134045-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** James Warren Murrough
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $765,927
- **Award type:** 5
- **Project period:** 2023-07-21 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890096

## Citation

> US National Institutes of Health, RePORTER application 10890096, Neural Circuit-Specific Mechanisms of Ketamine's Effect on Anhedonia and Anxiety in Depression Using Ultra-High Field 7-Tesla MRI (5R01MH134045-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890096. Licensed CC0.

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