The role of ventral tegmental area in chronic stroke rehabilitation: an exploratory study

You wouldn't need reward strategies if you blithering idiots actually thought for once! 

Motivation is extremely easy to understand and implement. 

Write up 100% recovery protocols on this and survivors will do the millions of reps needed, no external motivation required. You don't understand one goddamn thing about stroke survivors, DO YOU? The problem is stroke researchers are not motivated to solve stroke. What the fuck is your solution to that failure? We still don't know how to motivate stroke medical 'professionals' to solve stroke to 100% recovery!

The role of ventral tegmental area in chronic stroke rehabilitation: an exploratory study

Loukas G. Astrakas¹ Sabrina Elbach^2,3 Irini Giannopulu⁴ Shasha Li^2,3 Howard Benjafield⁵ A. Aria Tzika^2,3*

• ¹Medical Physics, Faculty of Medicine, University of Ioannina, Ioannina, Greece
• ²Athinoula A. Martinos Center of Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
• ³NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
• ⁴Clinical Research and Technological Innovation, Paris, France
• ⁵School of Social Sciences and Professions – Psychology, London Metropolitan University, London, United Kingdom

Introduction: The acknowledged role of external rewards in chronic stroke rehabilitation, offering positive reinforcement and motivation, has significantly contributed to patient engagement and perseverance. However, the exploration of self-reward’s importance in this context remains limited. This study aims to investigate the functional connectivity of the ventral tegmental area (VTA), a key node in the brain’s reward circuitry, during motor task-based rehabilitation and its correlation with the recovery process.

Methods: Twelve right-handed healthy volunteers (4 men, 8 women, aged 57.4 ± 11.3 years) and twelve chronic stroke patients (5 men, 7 women, aged 48.1 ± 11.1 years) with clinically significant right-sided motor impairment (mean FM-UE score of 27.6 ± 8.7) participated. The analysis employed the CONN toolbox to assess the association between motor tasks and VTA connectivity using psychophysiological interaction (PPI).

Results: PPI analysis revealed motor-dependent changes in VTA connectivity, particularly with regions within the motor circuitry, cerebellum, and prefrontal cortex. Notably, stronger connectivity between the ipsilesional VTA and cerebellum was observed in healthy controls compared to chronic stroke patients, highlighting the importance of VTA-cerebellum interactions in motor function. Stroke patients’ motor performance was associated with VTA modulation in areas related to both motor tasks and reward processing, emphasizing the role of self-reward processes in rehabilitation. Changes in VTA influence on motor circuitry were linked to improvements in motor performance resulting from rehabilitation.

Discussion: Our findings underscore the potential of neuroimaging techniques in quantifying and predicting rehabilitation outcomes by examining self-reward processes. The observed associations between VTA connectivity and motor performance in both healthy and stroke-affected individuals emphasize the role of psychological factors, particularly self-reward, in the rehabilitation process. This study contributes valuable insights into the intricate interplay between reward circuits and motor function, highlighting the importance of addressing psychological dimensions in neurorehabilitation strategies.

1 Introduction

Stroke is a devastating event, recognized as the second leading cause of mortality worldwide and a major cause of chronic disability. Current evidence supports the hypothesis that long-term post-stroke disabilities can potentially be improved through rehabilitation interventions (1). However, the triage of chronic patients who could benefit from rehabilitation and the customization of rehabilitation programs remain critical medical challenges (2). This is primarily due to the complex nature of stroke recovery, which relies on multiple factors such as genetics, pathophysiology, sociodemographics, and therapeutic interventions. Of particular significance are the mood problems and psychological factors, including anxiety and depression, which are commonly observed in chronic stroke patients and heavily influence rehabilitation outcomes (3). These issues can negatively impact patient adherence and the level of participation in rehabilitation programs, highlighting the importance of addressing them in the overall treatment approach.

Introducing rewards has been proved to be a successful strategy to boost motivation, increase engagement, and improve performance during a motor task (4, 5). Human studies have shown that motor cortex excitability depends on motivation (5) and reward probability (6, 7). These results illustrate that motor cortical physiology integrates cognitive mechanisms related to reward valuation. In neuroanatomical terms, this is supported by the dense innervation of the motor cortex from the ventral tegmental area (VTA), which is one of the principal dopaminergic areas of the brain’s reward system. Many animal studies have demonstrated the role of dopamine in motor learning and in modulating motor responses to reward cues (8–11). Other studies suggest that stroke impairs the dopaminergic pathways, resulting in recovery problems (12). In stroke, levodopa treatment showed promising results in rats (13) but clinically unconvincing outcomes in humans (14). In contrast, endogenous dopamine appears crucial for motor skill recovery after stroke, both for animals (15) and humans performing tasks with reward feedback (4, 16–18).

The role of reward brain areas in neurorehabilitation is not yet fully understood. Specifically, it remains unclear whether the dopaminergic regions respond to a rehabilitation task even without extrinsic reward, and whether they contribute to the recovery potential through intrinsic reward processes. Although functional neuroimaging provides connectivity tools to directly assess the association between motor tasks and connectivity of reward areas, these tools have remained largely unexploited. To bridge this knowledge gap, we employed an analysis of psychophysiological interaction (PPI) to reveal areas that undergo motor-dependent changes in their connectivity with VTA in both chronic stroke patients (CSPs) and healthy age-matched control subjects (HCs). Unlike common resting-state connectivity methods, PPI is more suitable for rehabilitation studies as it allows for the exploration of task-dependent connectivity changes between brain regions (19, 20). Using a rehabilitation protocol based on an MR-compatible robotic device (21), we conducted an exploratory study to test the hypothesis that the functional connectivity of the VTA would be modulated by the motor task during rehabilitation and would be related to the recovery process.