Oh well, generalities galore.
Enhancing Brain Plasticity to Promote Stroke Recovery
Fan Su and 
Wendong Xu*- Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
Stroke disturbs both the structural and functional integrity of the brain. The understanding of stroke pathophysiology has improved greatly in the past several decades. However, effective therapy is still limited, especially for patients who are in the subacute or chronic phase. Multiple novel therapies have been developed to improve clinical outcomes by improving brain plasticity. These approaches either focus on improving brain remodeling and restoration or on constructing a neural bypass to avoid brain injury. This review describes emerging therapies, including modern rehabilitation, brain stimulation, cell therapy, brain-computer interfaces, and peripheral nervous transfer, and highlights treatment-induced plasticity. Key evidence from basic studies on the underlying mechanisms is also briefly discussed. These insights should lead to a deeper understanding of the overall neural circuit changes, the clinical relevance of these changes in stroke, and stroke treatment progress, which will assist in the development of future approaches to enhance brain function after stroke.
Introduction
Stroke represents the leading cause of long-term disability and causes substantial medical and financial burdens. Even with standard rehabilitation after stroke, the majority of stroke patients are disabled when they enter the chronic phase (1). The lack of effective neurorepair and limitations of functional recovery have led researchers to consider other approaches that improve the scope for recovery by enhancing brain plasticity.
Brain plasticity is defined as the intrinsic ability of the brain to reorganize its function and structure in response to stimuli and injuries. After stroke, the plasticity process is initiated in an attempt to compensate for both the lesion itself and its remote effects. Changed neural activity and connectivity in terms of function and structure could be detected in the perilesional and remote regions and even in the contralateral hemisphere, which were assumed to be the mechanisms underlying spontaneous recovery (2, 3). Generally, increased neural activity and connectivity in the ipsilesional hemisphere were reported as indicators of better functional recovery (4). However, the roles of the recruitment of the contralateral hemisphere seem to be mixed, as both supportive and inhibitory influences of the unaffected hemisphere were detected during recovery. Compensatory or maladaptive processes may contribute to the inconsistency; these processes were attributed to, at least partially, the time since stroke, location and size of the lesion, and other biological factors (e.g., age of the patient) (5, 6).
Various post-stroke interventions have been developed to improve recovery, which either intentionally or not promote the plasticity of the remaining neural circuit. In addition to conventional therapies (i.e., physical, occupational, and speech), novel approaches have shown promising effects in clinical trials. Many of the approaches were designed to enhance plasticity in the ipsilesional hemisphere, in which increased activity/connectivity was related to better functional performance. However, the results obtained thus far are complicated, and even when significant improvements were made, the effect sizes were not satisfactory in most cases.
As mentioned above, stroke leads to disturbances across the brain, and interhemispheric interactions have complex influences on functional recovery (6, 7). Accordingly, strategies for recovery may include modulation of the intact hemisphere, and work related to this approach has been performed. In this review, we summarize post-stroke interventions that enhance brain plasticity and functional recovery, placing emphasis on modulation of the intact hemisphere. Acute revascularization and neuroprotection are not included, and approaches that were only utilized in basic researches were also excluded. We searched the PubMed from January 1990 to May 2020. Search key words were combinations of “stroke” and “plasticity or neural plasticity or neuroplasticity or brain remodeling or brain rewire.” The article type was limited to Clinical trial. The final list of references is based on the relevance of the articles to the scope of this review. We did not intend to provide a comprehensive analysis but instead aimed to highlight novel evidence from well-designed trials. In the next section, we discuss the selected examples of promising approaches listed in Figure 1, including modern rehabilitation, brain stimulation, cell therapy, brain-computer interfaces (BCIs), and peripheral nerve transfer. The representative trails that evaluated each intervention were listed in Table 1.
Figure 1. Summary of treatment approaches discussed in this review. The abscissa indicates the readiness of clinical application, and the ordinate indicates the involvement of the healthy hemisphere.
Table 1. Representative clinical trials evaluating novel interventions for stroke recovery.
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