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

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 1day 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 (1)H 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.

[1]  D. Purpura,et al.  INTRACELLULAR ACTIVITIES AND EVOKED POTENTIAL CHANGES DURING POLARIZATION OF MOTOR CORTEX. , 1965, Journal of neurophysiology.

[2]  G. Dawson,et al.  The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines , 2005, Journal of psychopharmacology.

[3]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.

[4]  W. Singer,et al.  Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex , 1990, Nature.

[5]  J. Silver,et al.  Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[6]  Yun-fei Lu,et al.  c-Fos Expression Mediated by N-Methyl-d-aspartate Receptors Following Anodal Polarization in the Rat Brain , 1995, Experimental Neurology.

[7]  T. Schallert,et al.  Use-Dependent Exaggeration of Brain Injury: Is Glutamate Involved? , 1999, Experimental Neurology.

[8]  M. Nitsche,et al.  Safety limits of cathodal transcranial direct current stimulation in rats , 2009, Clinical Neurophysiology.

[9]  T. Jones,et al.  Motor Skills Training Enhances Lesion-Induced Structural Plasticity in the Motor Cortex of Adult Rats , 1999, The Journal of Neuroscience.

[10]  L. Cohen,et al.  Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. , 2005, Brain : a journal of neurology.

[11]  J R Jenner,et al.  Stepping before standing: hip muscle function in stepping and standing balance after stroke , 2000, Journal of neurology, neurosurgery, and psychiatry.

[12]  A. Risedal,et al.  Early Training May Exacerbate Brain Damage after Focal Brain Ischemia in the Rat , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  T. Jones,et al.  Cortical electrical stimulation combined with rehabilitative training: Enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats , 2003, Neurological research.

[14]  P. Weinstein,et al.  Reversible middle cerebral artery occlusion without craniectomy in rats. , 1989, Stroke.

[15]  Yanwen Y Duan,et al.  Cortical electrical stimulation alone enhances functional recovery and dendritic structures after focal cerebral ischemia in rats , 2010, Brain Research.

[16]  Manoel Jacobsen Teixeira,et al.  Functional mapping of the motor cortex of the rat using transdural electrical stimulation , 2009, Behavioural Brain Research.

[17]  Chris Rorden,et al.  Using Transcranial Direct-Current Stimulation to Treat Stroke Patients With Aphasia , 2010, Stroke.

[18]  B. Kolb,et al.  A comparison of different models of stroke on behaviour and brain morphology , 2003, The European journal of neuroscience.

[19]  C. Barnes.  Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. , 1979, Journal of comparative and physiological psychology.

[20]  B. Rosen,et al.  A functional MRI study of subjects recovered from hemiparetic stroke. , 1997, Stroke.

[21]  Heidi M. Schambra,et al.  Direct Current Stimulation Promotes BDNF-Dependent Synaptic Plasticity: Potential Implications for Motor Learning , 2010, Neuron.

[22]  I. Gartside,et al.  Mechanisms of Sustained Increases of Firing Rate of Neurones in the Rat Cerebral Cortex after Polarization: Role of Protein Synthesis , 1968, Nature.

[23]  T. Jones,et al.  "Exuberant" Neuronal Growth After Brain Damage in Adult Rats: The Essential Role of Behavioral Experience , 1993, Journal of neural transplantation & plasticity.

[24]  G. Bernardi,et al.  Cerebral plasticity after stroke as revealed by ipsilateral responses to magnetic stimulation. , 1996, Neuroreport.

[25]  R A Swanson,et al.  A Semiautomated Method for Measuring Brain Infarct Volume , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  J. Garcìa,et al.  Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. , 1995, Stroke.

[27]  L. Leocani,et al.  Brain transcranial direct current stimulation modulates motor excitability in mice , 2010, The European journal of neuroscience.

[28]  W. Fries,et al.  Motor recovery following capsular stroke. Role of descending pathways from multiple motor areas. , 1993, Brain : a journal of neurology.

[29]  M. Nitsche,et al.  Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation , 2000, The Journal of physiology.

[30]  J. Schaechter.  Motor rehabilitation and brain plasticity after hemiparetic stroke , 2004, Progress in Neurobiology.

[31]  Ç. Ulukuş,et al.  Neuroprotective Effect of Erythropoietin on Hypoxic-Ischemic Brain Injury in Neonatal Rats , 2003, Neonatology.

[32]  R. Jope,et al.  The role of microtubule‐associated protein 2 (MAP‐2) in neuronal growth, plasticity, and degeneration , 1992, Journal of neuroscience research.

[33]  Yue Cao,et al.  Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis. , 1998, Stroke.

[34]  L. Bindman,et al.  The action of brief polarizing currents on the cerebral cortex of the rat (1) during current flow and (2) in the production of long‐lasting after‐effects , 1964, The Journal of physiology.

[35]  Edward T. Bullmore,et al.  The relationship between motor deficit and hemisphere activation balance after stroke: A 3T fMRI study , 2007, NeuroImage.

[36]  Richard S. J. Frackowiak,et al.  How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? , 2005, The European journal of neuroscience.

[37]  S. Carmichael,et al.  Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex , 2005, Experimental Neurology.

[38]  O. Creutzfeldt,et al.  Influence of transcortical d-c currents on cortical neuronal activity. , 1962, Experimental neurology.

[39]  R. P. Stroemer,et al.  Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. , 1995, Stroke.

[40]  M. Cuadrado,et al.  Bihemispheric Contribution to Motor Recovery after Stroke: A Longitudinal Study with Transcranial Doppler Ultrasonography , 1999, Cerebrovascular Diseases.

[41]  Richard S. J. Frackowiak,et al.  The functional anatomy of motor recovery after stroke in humans: A study with positron emission tomography , 1991, Annals of neurology.

[42]  R. Lasek,et al.  Astrocytes block axonal regeneration in mammals by activating the physiological stop pathway. , 1987, Science.

[43]  M. Nitsche,et al.  Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. , 2002, Brain : a journal of neurology.

[44]  Sergio P. Rigonatti,et al.  Transcranial direct current stimulation of the unaffected hemisphere in stroke patients , 2005, Neuroreport.

[45]  A. Antal,et al.  Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients , 2007, Brain Research Bulletin.

[46]  T. Jones,et al.  Maladaptive effects of learning with the less-affected forelimb after focal cortical infarcts in rats , 2008, Experimental Neurology.

[47]  Jeff Biernaskie,et al.  Enriched Rehabilitative Training Promotes Improved Forelimb Motor Function and Enhanced Dendritic Growth after Focal Ischemic Injury , 2001, The Journal of Neuroscience.

[48]  Sergio P. Rigonatti,et al.  Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. , 2007, Restorative neurology and neuroscience.

[49]  L. Bindman,et al.  Long-lasting Changes in the Level of the Electrical Activity of the Cerebral Cortex produced by Polarizing Currents , 1962, Nature.

[50]  D. Collen,et al.  Depletion of circulating alpha(2)-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization. , 2001, Blood.

[51]  E. Taub,et al.  A Placebo-Controlled Trial of Constraint-Induced Movement Therapy for Upper Extremity After Stroke , 2006, Stroke.

[52]  P. Matthews,et al.  The role of ipsilateral premotor cortex in hand movement after stroke , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[53]  D. Corbett,et al.  Efficacy of Rehabilitative Experience Declines with Time after Focal Ischemic Brain Injury , 2004, The Journal of Neuroscience.

[54]  Richard S. J. Frackowiak,et al.  Neural correlates of outcome after stroke: a cross-sectional fMRI study. , 2003, Brain : a journal of neurology.

[55]  I. Gartside,et al.  Mechanisms of Sustained Increases of Firing Rate of Neurones in the Rat Cerebral Cortex after Polarization: Reverberating Circuits or Modification of Synaptic Conductance? , 1968, Nature.

[56]  A. Schleicher,et al.  Long-term changes of ionotropic glutamate and GABA receptors after unilateral permanent focal cerebral ischemia in the mouse brain , 1998, Neuroscience.

[57]  M. Nitsche,et al.  Anticonvulsant Effects of Transcranial Direct‐current Stimulation (tDCS) in the Rat Cortical Ramp Model of Focal Epilepsy , 2006, Epilepsia.

[58]  Rick M Dijkhuizen,et al.  Structural and functional plasticity in the somatosensory cortex of chronic stroke patients. , 2006, Brain : a journal of neurology.

[59]  Hidenao Fukuyama,et al.  Movement-related cortical potentials and regional cerebral blood flow change in patients with stroke after motor recovery , 1997, Journal of the Neurological Sciences.

[60]  D. Steindler,et al.  Enhanced expression of the developmentally regulated extracellular matrix molecule tenascin following adult brain injury. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[61]  W Paulus,et al.  Regional modulation of BOLD MRI responses to human sensorimotor activation by transcranial direct current stimulation , 2001, Magnetic resonance in medicine.

[62]  Karl J. Friston,et al.  Functional reorganization of the brain in recovery from striatocapsular infarction in man , 1992, Annals of neurology.

[63]  M. Chopp,et al.  Neuronal damage and plasticity identified by microtubule-associated protein 2, growth-associated protein 43, and cyclin D1 immunoreactivity after focal cerebral ischemia in rats. , 1998, Stroke.

[64]  N. Ward.  Neural plasticity and recovery of function. , 2005, Progress in brain research.

[65]  R. Nudo,et al.  Neural Substrates for the Effects of Rehabilitative Training on Motor Recovery After Ischemic Infarct , 1996, Science.

[66]  M. Nitsche,et al.  Pharmacological Modulation of Cortical Excitability Shifts Induced by Transcranial Direct Current Stimulation in Humans , 2003, The Journal of physiology.

[67]  Myoung-Hwan Ko,et al.  Enhancing the Working Memory of Stroke Patients Using tDCS , 2009, American journal of physical medicine & rehabilitation.

[68]  François Chollet,et al.  Correlation between cerebral reorganization and motor recovery after subcortical infarcts , 2003, NeuroImage.