Transcranial Direct Current Stimulation Enhances Neuroplasticity and Accelerates Motor Recovery in a Stroke Mouse Model

Abstract

Background: More effective strategies are needed to promote poststroke functional recovery. Here, we evaluated the impact of bihemispheric transcranial direct current stimulation (tDCS) on forelimb motor function recovery and the underlying mechanisms in mice subjected to focal ischemia of the motor cortex. Methods: Photothrombotic stroke was induced in the forelimb brain motor area, and tDCS was applied once per day for 3 consecutive days, starting 72 hours after stroke. Grid-walking, single pellet reaching, and grip strength tests were conducted to assess motor function. Local field potentials were recorded to evaluate brain connectivity. Western immunoblotting, ELISA, quantitative real-time polymerase chain reaction, and Golgi-Cox staining were used to uncover tDCS-mediated stroke recovery mechanisms. Results: Among our results, tDCS increased the rate of motor recovery, anticipating it at the early subacute stage. In this window, tDCS enhanced BDNF (brain-derived neurotrophic factor) expression and dendritic spine density in the peri-infarct motor cortex, along with increasing functional connectivity between motor and somatosensory cortices. Treatment with the BDNF TrkB (tropomyosin-related tyrosine kinase B) receptor inhibitor, ANA-12, prevented tDCS effects on motor recovery and connectivity as well as the increase of spine density, pERK (phosphorylated extracellular signal-regulated kinase), pCaMKII (phosphorylated calcium/calmodulin-dependent protein kinase II), pMEF (phosphorylated myocyte-enhancer factor), and PSD (postsynaptic density)-95. The tDCS-promoted rescue was paralleled by enhanced plasma BDNF level, suggesting its potential role as circulating prognostic biomarker. Conclusions: The rate of motor recovery is accelerated by tDCS applied in the subacute phase of stroke. Anticipation of motor recovery via vicariate pathways or neural reserve recruitment would potentially enhance the efficacy of standard treatments, such as physical therapy, which is often delayed to a later stage when plastic responses are progressively lower.

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery

“…64 Experimental rodent studies suggested that tDCS in either polarity might reduce neuronal damage, decrease microglia activity, and enhance functional recovery during the acute or subacute phase after stroke. 18-20,47 Our data suggest that 5 sessions of cathodal tDCS applied ipsilesionally starting the first week after focal cortical stroke is most effective in mice. Additional tDCS sessions on days 12 to 16 after stroke did not benefit recovery, the modulation of neuroinflammation, or neurogenesis.…”

“…For future research, we would consider more extensive group sizes, fewer statistical variables, and behavioral tests providing continuous scales such as nest building activity, the cylinder test, or the grip strength test, whose exceptional consistency in detecting functional deficits in mice in the chronic phase after motor cortex lesions has been reported. 20…”

“…[15][16][17][18] Moreover, in line with clinical studies in patients, tDCS accelerates motor recovery in the rodent after stroke. [19][20][21] However, functional recovery after a stroke occurs much faster in rodents than humans, requiring caution in translating results. 22 Besides, to further our understanding of the molecular and cellular processes underlying tDCSenhanced recovery of function, it is crucial to correlate the molecular and cellular effects evoked by tDCS to the time course of functional recovery in the experimental animal due to establish the actual relevance of these observations and ultimately aid translation into the clinic.…”

Tuning brain networks: The emerging role of transcranial direct current stimulation on structural plasticity

“…Considering the aforementioned reviewed synaptic plasticity modifications induced by tDCS and also the activated molecular cascade underlying these effects, some recent works pointed the attention not only at the functional but also the structural changes ( Paciello et al, 2018 ; Barbati et al, 2020 ; Gellner et al, 2020 ; Longo et al, 2022 ).…”

“…Moreover, in a recent preclinical study, Longo et al (2022) applied bilateral tDCS over M1 (35.4 A/m 2 , 20 min, single daily sessions for 3 consecutive days) in a mouse model of ischemic stroke and showed that tDCS accelerated motor recovery by enhancing forelimb strength and ameliorating performances in both skilled and non-skilled motor tasks. The authors looked at possible effects on FC by recording local field potentials through epidurally implanted electrodes over M1 and somatosensory cortices and analyzing total coherence (TotCoh)—an index expressing global functional coupling of the LFP rhythms ( Vecchio et al, 2019 ).…”