# Using human brain connectivity to identify the causal neuroanatomical substrate of depression symptoms

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $661,868

## Abstract

PROJECT SUMMARY: Using human brain connectivity to identify the causal neuroanatomical
substrate of depression symptoms
Depression is the leading cause of disability worldwide and new treatments are needed. Identifying the brain
regions causing depression symptoms can lead to treatment targets and better therapies. However, identifying
these regions has been difficult. Neuroimaging of patients identifies brain areas where activity correlates with
depression symptoms, but can’t determine whether these regions actual cause symptoms. Animal models
allow for causal manipulations, but only approximate human symptoms. The goal of this grant is to link
depression symptoms to human neuroanatomy in a causal way. Here I focus on two sources of information
that can provide theses causal neuroanatomical links. The first is patients with focal brain lesions causing
depression symptoms. The second is patients with depression who have received focal brain stimulation for
symptomatic relief. In both cases, there is a causal link between symptoms and the site of the lesion or
stimulation. However, this causal link can be indirect. Lesion-induced symptoms can come from brain regions
connected to the lesion location rather than the lesion location itself. Similarly, benefits of brain stimulation can
come from modulation of distant regions connected to the site of stimulation. As such, utilizing these causal
sources of information requires a map of human brain connectivity. Due to NIH initiatives like the human
connectome project and high powered MRI scanners, such maps are now available. I’ve recently developed a
technique that uses these brain connectivity maps to better localize lesion-induced symptoms and identify
regions mediating response to focal brain stimulation. Because this technique utilizes existing connectivity
data, it does not require connectivity imaging of the patients themselves. As such, the technique can be
applied to any lesion or stimulation dataset and has already lent insight into a variety of neuropsychiatric
symptoms. Here, I leverage this technique to identify brain regions causing depression symptoms (Aim 1) and
brain regions mediating anti-depressant response to focal brain stimulation (Aim 2). Successful completion of
these aims will lend insight into the causal neuroanatomical substrate of depression symptoms. Such
knowledge will facilitate identification of biomarkers for evaluating future therapies, optimal therapeutic targets
for invasive and noninvasive brain stimulation, and individualized targets based on patient-specific symptom
profiles. These treatment targets can then be empirically tested in future therapeutic trials.

## Key facts

- **NIH application ID:** 10242694
- **Project number:** 5R01MH113929-06
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MICHAEL D FOX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $661,868
- **Award type:** 5
- **Project period:** 2017-09-19 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242694

## Citation

> US National Institutes of Health, RePORTER application 10242694, Using human brain connectivity to identify the causal neuroanatomical substrate of depression symptoms (5R01MH113929-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242694. Licensed CC0.

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