# Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2022 · $193,750

## Abstract

This project seeks to develop electrical brain stimulation methods to reverse drug-induced pathological
neuroplasticity. Addictions are difficult to treat in part because drugs of abuse transform reward and decision-
making circuits, persistently remodeling them in ways that lead to persistent cravings. As a result, relapse rates
are high even with gold-standard treatment. Animal studies using optogenetics and related technologies
suggest that drug-induced plasticity can be reversed by targeted circuit manipulations. This is
particularly true in circuits related to the nucleus accumbens (NAc), a “hub” of brain reward circuitry. For
instance, co-PI Thomas showed that chronic morphine exposure in mice strengthened an infralimbic cortex (IL)
to NAc synapse. Weakening this same synapse blocked reinstatement of drug-seeking after a period of
abstinence (a model of relapse). The challenge is that our circuit-directed tools for animals do not translate
readily to humans. Electrical deep brain stimulation (DBS), particularly of the nucleus accumbens (NAc), is
feasible in humans with addiction, but appears not to work reliably in its current form. This is in part because
clinical NAc DBS uses approaches developed for Parkinson disease, without considering addiction biology.
That is, it does not address the neuroplasticity problem.
We propose to develop an electrical intervention that specifically targets pathological IL-NAc
connectivity, based around the concept of timing-dependent plasticity. In short, if one structure (NAc) is
stimulated only in response to changes in another’s (IL’s) activity, the synapses between then can be
specifically strengthened or weakened, based entirely on the timing between the two events. Co-PI Widge has
developed such activity-dependent stimulation methods for modulating fear-related amygdala circuitry. There is
a long tradition of using similar approaches for rehabilitation of spinal cord injury and stroke. We will apply
activity-dependent electrical stimulation to modify the IL-NAc circuit of Long-Evans rats, as a first step
towards a human brain stimulation therapy. We will develop real-time IL-NAc connectivity measurement tools
(Aim 1) and identify the electrical stimulation parameters (timing, intensity) that can de-facilitate the IL-NAc
connection (Aim 2a). We will then apply those optimized methods to rats exposed to morphine in a conditioned
place preference paradigm (Aim 2b), comparing our electrical approach to Dr. Thomas’ existing optogenetic
approach. We hypothesize that this activity-dependent electrical approach will be equally effective, while also
being much easier to translate. Success would have near-term clinical potential. Dr. Widge is both a neural
engineer and a brain stimulation psychiatrist, with specific experience in NAc DBS. Both PIs are affiliated with
state-funded initiatives in addiction treatment development. We are well positioned to translate potential
outcomes from this effort into novel, m...

## Key facts

- **NIH application ID:** 10359133
- **Project number:** 5R21DA052568-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Mark John Thomas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359133

## Citation

> US National Institutes of Health, RePORTER application 10359133, Reversal of Opioid-Induced Pathological Neuroplasticity Through Timed Electrical Stimulation (5R21DA052568-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359133. Licensed CC0.

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