# Imaging the hypothalamus and motivation deficits in cocaine addiction

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $220,500

## Abstract

ABSTRACT/SUMMARY
Individuals with cocaine dependence (CD) are characterized by motivation deficits and under-responsiveness
to natural reinforcers. Enhancement of intrinsic motivation is a critical component in cognitive behavioral
treatment of drug addiction. As part of the core limbic circuit, the hypothalamus is implicated in a wide range of
motivated behaviors. On the other hand, the neural bases of intrinsic motivation and how hypothalamic circuit
dysfunction contributes to motivation deficits in addiction remain largely unknown.
 Motivation hinges on an internal drive to engage in actions that do not dictate explicit or immediate
reward. Extant studies in addiction neuroscience have focused on cerebral responses to drug cues and
explicit reward, but there is a dearth of information regarding the neural bases of intrinsic motivation – cerebral
responses to motivated behavior independent of performance outcomes and reward. To address this gap of
research, we will study CD and non-drug using controls (HC) in a behavioral paradigm that engages self
choice and controls for performance outcomes and external reward. Self versus forced choice involves
activation of the hypothalamus and ventromedial prefrontal cortex (vmPFC), suggesting the role of
hypothalamus-vmPFC circuit in intrinsic motivation. Further, preclinical work showed distinct and interacting
functions of the lateral hypothalamus (LH) and medial hypothalamus (MH). In human imaging, the LH and MH
each responds to negative and positive emotions. Following an atlas of the human hypothalamus we
distinguished resting state functional connectivity of the LH and MH, with LH and MH each connected to the
dorsal anterior cingulate cortex and vmPFC. Importantly, compared to HC, CD showed altered LH and MH
connectivity in association with the severity of cocaine use.
 Building on these findings, we will investigate how the hypothalamus responds to external emotional
and intrinsic motivation challenges, with concurrent recording of physiological arousal. Specifically, in
conjunction with an ongoing K25 study, we will examine a) how CD and HC differ in LH and MH responses
each to negative and positive emotions and in MH/vmPFC responses to intrinsic motivation challenges; b) how
CD and HC differ in task-modulated LH and MH functional connectivity in association with changes in
physiological arousal; c) how hypothalamic dysfunction predicts relapse in cocaine addiction. By combining
MR imaging and multiple behavioral paradigms to examine hypothalamus function, the study will provide
critical information on motivation deficits in cocaine addiction.

## Key facts

- **NIH application ID:** 9856428
- **Project number:** 5R21DA045743-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SHENG ZHANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $220,500
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856428

## Citation

> US National Institutes of Health, RePORTER application 9856428, Imaging the hypothalamus and motivation deficits in cocaine addiction (5R21DA045743-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856428. Licensed CC0.

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