[ARTICLE] Noninvasive Brain Stimulation to Enhance Functional Recovery After Stroke: Studies in Animal Models – Full Text

Background. Stroke is the leading cause of adult disability, but treatment options remain limited, leaving most patients with incomplete recovery. Patient and animal studies have shown potential of noninvasive brain stimulation (NIBS) strategies to improve function after stroke. However, mechanisms underlying therapeutic effects of NIBS are unclear and there is no consensus on which NIBS protocols are most effective.

Objective. Provide a review of articles that assessed effects and mechanisms of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in animal stroke models.

Methods. Articles were searched in PubMed, including cross-references.

Results. Nineteen eligible studies reporting effects of rTMS or tDCS after stroke in small rodents were identified. Seventeen of those described improved functional recovery or neuroprotection compared with untreated control or sham-stimulated groups. The effects of rTMS could be related to molecular mechanisms associated with ischemic tolerance, neuroprotection, anti-apoptosis, neurogenesis, angiogenesis, or neuroplasticity. Favorable outcome appeared most effectively when using high-frequency (>5 Hz) rTMS or intermittent theta burst stimulation of the ipsilesional hemisphere. tDCS effects were strongly dependent on stimulation polarity and onset time. Although these findings are promising, most studies did not meet Good Laboratory Practice assessment criteria.

Conclusions. Despite limited data availability, animal stroke model studies demonstrate potential of NIBS to promote stroke recovery through different working mechanisms. Future studies in animal stroke models should adhere to Good Laboratory Practice guidelines and aim to further develop clinically applicable treatment protocols by identifying most favorable stimulation parameters, treatment onset, adjuvant therapies, and underlying modes of action.

Globally, stroke is a devastating neurological disorder and a leading cause of death and acquired disability.1 The majority of stroke patients experience motor impairment, which affects movement of the face, leg, and/or arm on one side of the body.2 Upper limb motor deficiencies are often persistent and disabling, affecting independent functional activities of daily living.3 Unfortunately, most stroke patients recover incompletely after stroke, despite intensive rehabilitation strategies.3,4 Although there is a diverse range of interventions (for overview, see review by Pollock and colleagues4) aimed at improving motor outcome after stoke, there is still a pressing need for novel treatment therapies and continued research to reduce disability and improve functional recovery after stroke.

Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have shown promising therapeutic potential in stroke patient studies.5,6 The rationale behind rTMS or tDCS therapy is to modulate cortical excitability, increase neural plasticity, and improve functional motor outcome. For many studies, this approach has been based on the interhemispheric competition model.7 The interhemispheric competition model suggests that functional recovery in stroke patients is hindered due to reduced output from the affected hemisphere and excessive transcallosal inhibition from the unaffected hemisphere.8 Therefore, improvement in motor deficits may be obtained with NIBS strategies that facilitate excitability in the affected hemisphere or suppress inhibitory activity from the unaffected hemisphere.9,10 Depending on the type and duration of the stimulation protocol, both rTMS and tDCS can be used to increase (>5 Hz rTMS; intermittent theta burst stimulation; anodal tDCS) or decrease (⩽1 Hz rTMS; continuous theta burst stimulation; cathodal tDCS) cortical excitability, with potentially lasting effects beyond the stimulation period, promoting mechanisms of synaptic plasticity.11 Evidence suggests that rTMS and tDCS techniques are able to induce changes in cortical excitability associated with facilitation or long-term potentiation like plasticity via glutamatergic neurotransmission, or inhibition and long-term depression via GABAergic neurotransmission.12,13 Furthermore, effects of rTMS and tDCS are not restricted to the target region of stimulation, but also affect distantly connected cortical areas, allowing for the modulation of large-scale neural networks.14

However, despite accumulating evidence of the potential of NIBS, the precise therapeutic mechanisms of action of rTMS and tDCS are largely unidentified and there is no consensus about standardized treatment protocols. Moreover, when deciding on treatment after stroke with either rTMS or tDCS, the poststroke time and lesion status should be considered, and stimulation intensity and duration must be fine-tuned to prevent further tissue damage or the interruption of beneficial plastic changes.15,16 These uncertainties emphasize the critical need for basic understanding of the (patho)physiological processes that are influenced by rTMS and tDCS paradigms after stroke, which may ideally be explored in well-controllable and reproducible experimental animal models.

In animal models of stroke, similar to the human condition, there is a variable degree of spontaneous functional improvement after stroke, associated with a complex cascade of cellular and molecular processes that are activated within minutes after the insult, both in perilesional tissue and remote brain regions.17,18 These events include changes in genetic transcriptional and translational processes, alterations in neurotransmitter interactions, altered secretion of growth factors, gliosis, vascular remodeling, and structural changes in axons, dendrites, and synapses.19,20 Therefore, assessment of the effects of NIBS on endogenous recovery processes in animal stroke models offer excellent opportunities for the exploration of neuroplastic and neuromodulatory mechanisms, which could aid in the optimization of treatment protocols for clinical applications.

Our goal was to provide an overview of studies that assessed functional outcomes and potential mechanisms of action of rTMS and tDCS in animal models of stroke, which may guide future studies that aim to improve mechanistic insights and therapeutic utilization of NIBS effects after stroke.[…]


Continue —->  Noninvasive Brain Stimulation to Enhance Functional Recovery After Stroke: Studies in Animal Models – Julia Boonzaier, Geralda A. F. van Tilborg, Sebastiaan F. W. Neggers, Rick M. Dijkhuizen, 2018


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