Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions

Abstract

Cortical stimulation (CS) as a means to modulate regional activity and excitability in cortex is emerging as a promising approach for facilitating rehabilitative interventions after brain damage, including stroke. In this study, we investigated whether CS-induced functional improvements are linked with synaptic plasticity in peri-infarct cortex and vary with the severity of impairments. Adult rats that were proficient in skilled reaching received subtotal unilateral ischemic sensorimotor cortex (SMC) lesions and implantation of chronic epidural electrodes over remaining motor cortex. Based on the initial magnitude of reaching deficits, rats were divided into severely and moderately impaired subgroups. Beginning two weeks post-surgery, rats received 100 Hz cathodal CS at 50% of movement thresholds or no-stimulation control procedures (NoCS) during 18 days of rehabilitative training on a reaching task. Stereological electron microscopy methods were used to quantify axodendritic synapse subtypes in motor cortical layer V underlying the electrode. In moderately, but not severely impaired rats, CS significantly enhanced recovery of reaching success. Sensitive movement analyses revealed that CS partially normalized reaching movements in both impairment subgroups compared to NoCS. Additionally, both CS subgroups had significantly greater density of axodendritic synapses and moderately impaired CS rats had increases in presumed efficacious synapse subtypes (perforated and multiple synapses) in stimulated cortex compared to NoCS. Synaptic density was positively correlated with postrehabilitation reaching success. In addition to providing further support that CS can promote functional recovery, these findings suggest that CS-induced functional improvements may be mediated by synaptic structural plasticity in stimulated cortex.Keywords motor rehabilitation; skilled reaching; synaptic plasticity; perforated synapses; multisynaptic boutons; stroke Motor impairments are among the most common disabilities caused by stroke (Thom et al., 2006). Motor rehabilitative training can reduce these impairments but it is often insufficient * Corresponding author. The University of Texas, 1 University Station A8000, Austin, TX 78712. Phone: +1 512 475-7763, Fax: +1 512 475-7765, dladkins@mail.utexas.edu. ‡ D.L.A and J.E.H. contributed equally to this work.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptExp Neurol. Author manuscript; available in PMC 2011 January 10. to restore normal levels of function (Duncan et al., 2000;Dobkin, 2004). Recent studies in ...

Invasive Neurostimulation in Stroke Rehabilitation

“…Even though restoration of peri-infarct circuitry may represent the best basis for stroke motor recovery in animal models with well-defined lesions [11][12][13][14][15][16], this prospect is not feasible for many patients. Motor representations in peri-infarct cortices are mostly spared in the subset of patients who experience small, focal infarcts in M1 or sensory cortex [34,35], similar to experimental models of stroke.…”

“…Is peri-infarct cortical reorganization sufficient to effectuate recovery? Even though they experience key peri-infarct reorganization, animals with severe impairments do not show benefits of adjunctive stimulation [13]. It may be that their descending pathways are so compromised that stimulation of periinfarct mechanisms can still not enhance use of the impaired limb.…”

“…Subthreshold (40-70 % of motor evoked potential threshold), variable frequency , and monopolar or bipolar stimulation has typically been employed. The nature of paired training has varied from skilled reaching or grasping [12][13][14][15][16] to precise manipulation of wrist/digits [11]. In training of paretic limb, paired stimulation of peri-lesional M1 has invariably been advantageous in animals [11][12][13][14][15][16].…”

“…For instance, representations devoted to paretic distal forelimb can re-emerge adjacent to the lesion or, at times, at remote distances [11]. Morphologic and physiologic plasticity underlies gross reorganization; regions in the vicinity of the lesion express higher dendritic density [14], and, ultimately, greater synaptogenesis and enhanced synaptic efficacy [13,16]. The edge offered by concurrent stimulation in rehabilitation thus appears to involve re-mapping of function to targeted and interconnected regions [11,15], potentially mediated by longterm potentiation-like synaptic plasticity [16].…”

“…One such approach is invasive neuromodulation, involving electrical stimulation applied to cortical or subcortical targets spared by stroke. By directly stimulating viable targets, it is believed that potential for plasticity underlying rehabilitation can be enhanced to further recovery [11][12][13][14][15][16]. Evidence for such emerges from pioneering work in animals [11][12][13][14][15][16] and clinical trials [17][18][19][20][21].…”