# A Circuit Approach to Mechanisms and Predictors of Topiramate Response

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $439,571

## Abstract

SUMMARY
Post-traumatic stress disorder (PTSD) is a chronic and disabling disorder with currently limited effective
treatments. Its severity and functional impairment is compounded by frequently comorbid alcohol use disorder
(AUD), which also has limited effective treatments in isolation or in combination with PTSD. Alcohol use can
be considered within the broader framework of emotion dysregulation in PTSD, as it is often pursued initially as
an (often maladaptive) way to cope with distressing emotions. When alcohol use is prolonged and excessive,
alcohol dependence can ensue, manifesting in substantially greater functional impairment and deficiency of
prefrontal function and emotion regulation. Together, these lines of evidence suggest that: a) reduced ability to
regulate excessive negative affect presents a primary vulnerability factor for alcohol use in PTSD+AUD; and b)
individual differences in prefrontal-amygdala neural circuit interactions may be important predictors and/or
mechanistic determinants of outcomes for PTSD + AUD treatments. As such, there is a pressing clinical need
to advance the treatment of PTSD+AUD, which is most efficiently accomplished by understanding who
responds best to a given treatment and what are the mechanisms by which that treatment works. Here we
propose to answer these questions using a sophisticated moderation/mediation framework and multi-modal
human brain circuit functional assessments in the context of a randomized clinical trial comparing the treatment
of PTSD+AUD with topiramate versus placebo. Evidence exists for the utility of topiramate, which facilitates
inhibitory γ-amino-butyric acid (GABA) signaling and antagonizes excitatory glutamatergric signaling, in the
treatment of AUD, with initial evidence of utility for PTSD+AUD, making it a promising target for
neuromechanistic study. Therefore, at the heart of our approach is a thorough cognitive neuroscience
assessment of emotional reactivity and regulation to general negative stimuli and reactivity to alcohol cues
more specifically (using functional magnetic resonance imaging (fMRI)). This is complemented by a cutting-
edge mapping of the same brain circuits at the neurophysiological level using concurrent transcranial magnetic
stimulation and EEG (TMS/EEG). Given the pharmacological action of topiramate, concurrent TMS/EEG is an
ideal tool for direct interrogation of its neurophysiological actions. This is because TMS/EEG indexes distinct
excitation-related and inhibition-related neurophysiological responses to brain circuit-targeted targeted
neurostimulation, with EEG responses source-localized to the specific cortical structures investigated by the
fMRI tasks above and investigated at a neuronal temporal scale.

## Key facts

- **NIH application ID:** 10237286
- **Project number:** 5P01AA027057-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Amit Etkin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $439,571
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237286

## Citation

> US National Institutes of Health, RePORTER application 10237286, A Circuit Approach to Mechanisms and Predictors of Topiramate Response (5P01AA027057-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10237286. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*