Elsevier

Brain Research

Volume 1452, 3 May 2012, Pages 61-72
Brain Research

Research Report
Functional improvement and neuroplastic effects of anodal transcranial direct current stimulation (tDCS) delivered 1 day vs. 1 week after cerebral ischemia in rats

https://doi.org/10.1016/j.brainres.2012.02.062Get rights and content

Abstract

Transcranial direct current stimulation (tDCS) is an emerging tool for improving recovery from stroke. However, there has been no trial to determine whether it has a therapeutic benefit in the early stage of cerebral ischemia, and there is no consensus on the optimal time window of stimulation. Here, we described the effects of anodal tDCS in early cerebral ischemia, assessing functional improvements and changes in neuronal plasticity, and identifying the optimal time window for delivering tDCS to maximize functional gains. Thirty rats were randomly assigned to three groups: sham (n = 10); early tDCS (ET), receiving tDCS 1 day after ischemia for 5 days (n = 10), and late tDCS (LT), receiving tDCS 1 week after ischemia for 5 days (n = 10). Both ET and LT groups showed improved Barnes maze performance and motor behavioral index scores. However, only the LT group exhibited improvement in beam balance test. Immunohistochemical stainings showed that the ET group reinforced notable MAP-2 expression and the LT group enhanced mainly the level of GAP-43 in both peri-lesional and contralesional cortex. These immunohistochemical results had significant correlation with behavioral and cognitive functions. However, brain MRI and 1H MRS showed no significant differences among the three groups in ischemic volume and metabolic alteration. These results suggest that anodal tDCS has the potential to modulate neural plasticity around the ischemic penumbra and even in the contralesional area without aggravating infarction volume and metabolic alteration. The degree of functional improvement was slightly greater when tDCS was applied 1 week rather than 1 day after ischemic injury.

Highlights

► Anodal tDCS had benefits in acute cerebral ischemic rats. ► tDCS at 1 week (LT) was slightly more effective than 1 day after ischemia (ET). ► MAP-2 was increased around the peri-lesional area in ET group. ► GAP-43 was increased in the intact cortex of LT group. ► MRI and 1H MRS showed no differences among groups in ischemic volume and metabolites.

Introduction

Transcranial direct current stimulation (tDCS) is an emerging technique that has currently been applied in cerebral ischemic patients with motor dysfunction, impaired working memory, or aphasia (Baker et al., 2010, Boggio et al., 2007, Fregni et al., 2005, Hummel et al., 2005, Jo et al., 2009). It is a painless stimulation method that delivers subthreshold electrical currents to the brain and manipulates the resting membrane potential of cortical neurons by modulating sodium and calcium channels (Nitsche and Paulus, 2000, Poreisz et al., 2007). However, few clinical trials have been undertaken to evaluate the efficacy of tDCS in providing functional improvement after cerebral ischemia, and have enrolled only chronic stroke patients (Boggio et al., 2007, Fregni et al., 2005, Hummel et al., 2005). As there have been no animal experiments of tDCS in acute cerebral ischemia, DC stimulation is difficult to apply in acute stroke patients without any evidence of its safety.

After a stroke, the brain has the capability to reorganize the damaged tissue by means of dendritic branching, synaptic formation and neuronal sprouting, a process known as ‘neural plasticity’ (Gonzalez and Kolb, 2003, Schallert and Jones, 1993, Stroemer et al., 1995). As these changes are known to be time-dependent, the injured brain is highly plastic during the early stage after a stroke. A recent interesting report showed that neuronal growth-promoting genes such as GAP-43 (growth-associated protein 43) are expressed during the first week after ischemic injury (Carmichael et al., 2005). It also gradually loses its ability to reorganize over time (Nudo et al., 1996, Qu et al., 1998) although functional plasticity could be achieved at any time after stroke (Schaechter, 2004, Schaechter et al., 2006, Ward, 2005). However, peri-lesional neurons in the brain might be more vulnerable to excitation during this highly plastic period. In this context, several previous animal studies have shown that exercise training initiated very early after focal brain ischemia increased cortical infarct volume (Humm et al., 1999, Risedal et al., 1999).

Because no previous trials have been undertaken to determine whether tDCS has a therapeutic benefit in the early stage of cerebral ischemia, there has been no consensus on the optimal time window of tDCS. The purpose of this study is to evaluate the effect of tDCS on functional improvements and neuroplastic changes in a rat model of early stage cerebral ischemia, and determine the optimal time window to apply tDCS to maximize functional gains.

Section snippets

Behavioral and cognitive tests

Results of beam balance, motor behavioral index, rotarod, and Barnes maze are presented in Table 1. In the beam balance test, there was a significant interaction of group × time (F10, 135 = 6.187, p < 0.001, repeated measures ANOVA). The LT group showed significant improvement in beam balance test compared with ET and sham group at 2, 3, and 4 weeks after ischemic injury (p < 0.001, p < 0.001, p < 0.001, respectively; one way ANOVA with Scheffe's post-hoc test and Bonferroni correction; Table 1). A

Discussion

Previous studies using tDCS have been limited to chronic patients whose mean time after stroke was over 1 year (Boggio et al., 2007, Hummel et al., 2005). However, there have been no trials applying tDCS in the early stage of stroke. The present study, which represents the first attempt to elucidate the effects of tDCS on the early stage of cerebral ischemia, showed that both early (ET group) and late (LT group) treatments exerted beneficial effects on cognition, behavioral function, and neural

Animals

Thirty 6-week-old male Sprague–Dawley rats (220–280 g) were used for the investigation. Throughout the experiment, animals were housed in laboratory cage under controlled temperature conditions (22.0 °C–24.0 °C) and maintained under a 12/12 h light/dark cycle with free access to food and water. All protocols used in this study were approved by Institutional Animal Care and Use Committee of Asan Institute for Life Science (IACUC number: 2008-01-063).

Cerebral ischemic model

The cerebral ischemic rat model was made by Longa

Acknowledgments

This work was supported by a Korean Stroke Society young investigator's award (KSS-2008-002) and by a grant from Seoul Medical Center Research Institute (07-C09). The authors would like to thank Ms. Ho Sun Lee at the Asan Institute of Life Science.

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