Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke

Abstract

Background and Purpose— Transcranial direct current stimulation is emerging as a promising tool for the treatment of several neurological conditions, including cerebral ischemia. The therapeutic role of this noninvasive treatment is, however, limited to chronic phases of stroke. We thus ought to investigate whether different stimulation protocols could also be beneficial in the acute phase of experimental brain ischemia. Methods— The influence of both cathodal and anodal transcranial direct current stimulation in modifying brain metabolism of healthy mice was first tested by nuclear magnetic resonance spectroscopy. Then, mice undergoing transient proximal middle cerebral artery occlusion were randomized and treated acutely with anodal, cathodal, or sham transcranial direct current stimulation. Brain metabolism, functional outcomes, and ischemic lesion volume, as well as the inflammatory reaction and blood brain barrier functionality, were analyzed. Results— Cathodal stimulation was able, if applied in the acute phase of stroke, to preserve cortical neurons from the ischemic damage, to reduce inflammation, and to promote a better clinical recovery compared with sham and anodal treatments. This finding was attributable to the significant decrease of cortical glutamate, as indicated by nuclear magnetic resonance spectroscopy. Conversely, anodal stimulation induced an increase in the postischemic lesion volume and augmented blood brain barrier derangement. Conclusions— Our data indicate that transcranial direct current stimulation exerts a measurable neuroprotective effect in the acute phase of stroke. However, its timing and polarity should be carefully identified on the base of the pathophysiological context to avoid potential harmful side effects.

The role of the immune system in central nervous system plasticity after acute injury

“…Upon infiltration, neutrophils start producing inducible nitric oxide synthase (iNOS), an enzyme that generates toxic amounts of nitric oxide (NO), and release both matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) (Justicia et al, 2003). Release of MMP-9, as well as the upregulation of MPO within the ischemic tissue, contribute to the further down-regulation of junctional proteins and are the main contributors to the first derangement of the BBB (Bao Dang et al, 2013;Peruzzotti-Jametti et al, 2013). Initial BBB disruption is soon enhanced by ECM degradation, which participates in the secondary ischemic brain damage by permitting serum elements to enter the perivascular space (Asahi et al, 2001;Elali et al, 2011).…”

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“…They also analyzed the endothelial tight junction protein zona occludens-1 (ZO-1) and confirmed a significant decrease in its expression in the anodal tDCS condition. As ZO-1 is fundamental for maintaining the BBB after ischemic stroke 40,41 , these results suggest that the disruption of blood vessel tight junctions occurs in the case of anodal stimulation, but not cathodal stimulation 39 . To put these results in context, these findings were obtained using a charge density of 132,000 C/m 2 for tDCS stimulation, which was about half of that used by Nik-Mohd-Afizan et al 36 .…”

“…Despite the strong evidence reported by Nik-MohdAfizan et al, a different study using a mouse ischemic stroke model reported that anodal tDCS exacerbated dysregulation of BBB during the acute phase of stroke 39 . In this study, Peruzzotti-Jametti et al evaluated the ratio of endogenous immunoglobulin G (IgG) extravasation in the ipsilateral ischemic hemisphere, and found a significant increase in endogenous IgG leakage only in the anodal tDCS group 39 .…”

“…In this study, Peruzzotti-Jametti et al evaluated the ratio of endogenous immunoglobulin G (IgG) extravasation in the ipsilateral ischemic hemisphere, and found a significant increase in endogenous IgG leakage only in the anodal tDCS group 39 . They also analyzed the endothelial tight junction protein zona occludens-1 (ZO-1) and confirmed a significant decrease in its expression in the anodal tDCS condition.…”

“…One possible explanation for this discrepancy could be that Nik-Mohd-Afizan et al performed tDCS on normal healthy brains 36 , whereas Peruzzotti-Jametti et al 39 applied tDCS to the ischemic brain in the acute phase of stroke. These findings suggest that the safety of tDCS may differ between healthy and injured brains, with the severity of brain damage or post-acute/ chronic stages of brain injury affecting patient outcomes.…”