Chronic 30-Hz Deep Cerebellar Stimulation Coupled With Training Enhances Post-ischemia Motor Recovery and Peri-infarct Synaptophysin Expression in Rodents

Machado, André G.; Cooperrider, Jessica; Furmaga, Havan; Baker, Kenneth B.; Park, Hyun Joo; Chen, Zhihong; Gale, John T.

doi:10.1227/01.neu.0000430766.80102.ac

Cited by 54 publications

(49 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Placement of deep cerebellar electrodes and focal ischemia were conducted as detailed previously (Baker et al, 2010;Machado et al, 2013). Briefly, animals were anesthetized with ketamine (50 mg/kg) and medetomidine (0.5 mg/kg) and fixed in a stereotaxic frame (David Kopf Instruments).…”

Section: Ischemia and Electrode Implantationmentioning

confidence: 99%

“…Our group previously showed that motor rehabilitation associated with chronic stimulation of the dentatothalamocortical pathway is paralleled by greater expression of synaptophysin in immunohistochemistry ( Machado et al, 2013). In this experiment, the effects of stimulation on a family of proteins that play a key role in long-term potentiation (LTP) and synaptic plasticity were evaluated, namely synaptophysin, CaMKII, PSD95, and NMDAR1.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Every other cerebellar slice was mounted and Perls-DAB stained for evaluation of electrode location. Stroke volume was then quantified and plotted with the corresponding location over the atlas (Paxinos and Watson, 1998), as previously described (Park et al, 2013). Electrode location relative to the lateral cerebellar nucleus was verified for each animal.…”

Section: Stroke Volume Quantification and Electrode Location Verificamentioning

confidence: 99%

“…Chronic, electrical stimulation of the brain is now standard of care for managing certain movement disorders (Sjöberg and Blomstedt, 2011), with proven clinical efficacy for suppressing symptoms such as tremor or dyskinesia. However, implementing deep brain stimulation (DBS) to augment rehabilitation from lost neurological function resulting in paralysis or reduced level of consciousness has proven to be a much harder task (Baker et al, 2010;Machado et al, 2013). To date, improvements in level of consciousness and functional measures have been reported in a single patient in minimally conscious state by means of bilateral medial thalamic DBS (Schiff et al, 2007;Yamamoto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Chronic Deep Cerebellar Stimulation Promotes Long-Term Potentiation, Microstructural Plasticity, and Reorganization of Perilesional Cortical Representation in a Rodent Model

Cooperrider

Furmaga

Plow

et al. 2014

Journal of Neuroscience

View full text Add to dashboard Cite

Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of the cerebellar output, a treatment approach that has been shown to improve postischemia motor recovery in a rodent model of cortical infarcts. Long-Evans rats were pretrained on the pasta-matrix retrieval task, followed by induction of focal cortical ischemia and implantation of a macroelectrode in the contralesional lateral cerebellar nucleus. Animals were assigned to one of three treatment groups pseudorandomly to balance severity of poststroke motor deficits: REGULAR stimulation, BURST stimulation, or SHAM. Treatment initiated 2 weeks post surgery and continued for 5 weeks. At the end, animals were randomly selected for perilesional intracortical microstimulation mapping and tissue sampling for Western blot analysis or contributed tissue for 3D electron microscopy.Evidence of enhanced cortical plasticity with therapeutically effective stimulation is shown, marked by greater perilesional reorganization in stimulation-treated animals versus SHAM. BURST stimulation was significantly effective for promoting distal forepaw cortical representation. Stimulation-treated animals showed a twofold increase in synaptic density compared with SHAM. In addition, treated animals demonstrated increased expression of synaptic markers of long-term potentiation and plasticity, including synaptophysin, NMDAR1, CaMKII, and PSD95. These findings provide a critical foundation of how deep cerebellar stimulation may guide plastic reparative reorganization after nonprogressive brain injury and indicate strong translational potential.

show abstract

Section: Ischemia and Electrode Implantationmentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Stroke Volume Quantification and Electrode Location Verificamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chronic Deep Cerebellar Stimulation Promotes Long-Term Potentiation, Microstructural Plasticity, and Reorganization of Perilesional Cortical Representation in a Rodent Model

Cooperrider

Furmaga

Plow

et al. 2014

Journal of Neuroscience

View full text Add to dashboard Cite

show abstract

“…By targeting it at its node of origin in the dentate nucleus or the ascending pathway, the majority of the tract can be activated with a single implanted multipolar electrode [69]. Invasive, subthreshold stimulation, delivered chronically at lower frequencies (in the beta range) can generate sustained facilitatory effects upon excitability of M1 [70] and promote recovery of the impaired forelimb to a significantly greater degree than in a control [71,72].…”

Section: Methodological: Targeting Peri-lesional Substrates Even Whilmentioning

confidence: 99%

Invasive Neurostimulation in Stroke Rehabilitation

Plow

Machado

2014

Neurotherapeutics

View full text Add to dashboard Cite

The last decade has seen a growing interest in adjuvant treatments that synergistically influence mechanisms underlying rehabilitation of paretic upper limb in stroke. One such approach is invasive neurostimulation of spared cortices at the periphery of a lesion. Studies in animals have shown that during training of paretic limb, adjuvant stimulation targeting the peri-infarct circuitry enhances mechanisms of its reorganization, generating functional advantage. Success of early animal studies and clinical reports, however, failed to translate to a phase III clinical trial. As lesions in humans are diffuse, unlike many animal models, peri-infarct circuitry may not be a feasible, or consistent target across most. Instead, alternate mechanisms, such as changing transcallosal inhibition between hemispheres, or reorganization of other viable regions in motor control, may hold greater potential. Here, we review comprehensive mechanisms of clinical recovery and factors that govern which mechanism(s) become operative when. We suggest novel approaches that take into account a patient's initial clinical-functional state, and findings from neuroimaging and neurophysiology to guide to their most suitable mechanism for ideal targeting. Further, we suggest new localization schemes, and bypass strategies that indirectly target peri-lesional circuitry, and methods that serve to counter technical and theoretical challenge in identifying and stimulating such targets at the periphery of infarcts in humans. Last, we describe how stimulation may modulate mechanisms differentially across varying phases of recovery-a temporal effect that may explain missed advantage in clinical trials and help plan for the next stage. With information presented here, future trials would effectively be able to target patient's specific mechanism(s) with invasive (or noninvasive) neurostimulation for the greatest, most consistent benefit. [2], which remains one of the most important predictors of disability and poor quality of life [3]. Disability adds to the costs of disease management that total $74 billion/ year [4]. Developing methods to effectively alleviate residual deficits will reduce health and economic burden of stroke.Several evidence-based rehabilitative approaches have been developed with prominent ones, including neuromuscular electrical stimulation [5], motor learning [6], robotic training [7] constraint-induced movement therapy [8], and bilateral arm training [9], etc. In spite of extensive therapy, recovery is frequently incomplete [10]. There is a critical need for adjuvant strategies that augment rehabilitative outcomes of paretic hand.The last decade has seen a growing interest in the promise of adjuvant treatments that synergistically influence mechanisms associated with rehabilitation. 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 reh...

show abstract

Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke

et al. 2019

View full text Add to dashboard Cite

IMPORTANCE Gait and balance impairment is associated with poorer functional recovery after stroke. The cerebellum is known to be strongly implicated in the functional reorganization of motor networks in patients with stroke, especially for gait and balance functions. OBJECTIVE To determine whether cerebellar intermittent θ-burst stimulation (CRB-iTBS) can improve balance and gait functions in patients with hemiparesis due to stroke. DESIGN, SETTING, PARTICIPANTS This randomized, double-blind, sham-controlled phase IIa trial investigated efficacy and safety of a 3-week treatment of CRB-iTBS coupled with physiotherapy in promoting gait and balance recovery in patients with stroke. Thirty-six patients with consecutive ischemic chronic stroke in the territory of the contralateral middle cerebral artery with hemiparesis were recruited from a neuro-rehabilitation hospital. Participants were screened and enrolled from March 2013 to June 2017. Intention-to-treat analysis was performed.INTERVENTIONS Patients were randomly assigned to treatment with CRB-iTBS or sham iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side immediately before physiotherapy daily during 3 weeks. MAIN OUTCOMES AND MEASURESThe primary outcome was the between-group difference in change from baseline in the Berg Balance Scale. Secondary exploratory measures included the between-group difference in change from baseline in Fugl-Meyer Assessment scale, Barthel Index, and locomotion assessment with gait analysis and cortical activity measured by transcranial magnetic stimulation in combination with electroencephalogram. RESULTSA total of 34 patients (mean [SD] age, 64 [11.3] years; 13 women [38.2%]) completed the study. Patients treated with CRB-iTBS, but not with sham iTBS, showed an improvement of gait and balance functions, as revealed by a pronounced increase in the mean (SE) Berg Balance Scale score (baseline: 34.5 [3.4]; 3 weeks after treatment: 43.4 [2.6]; 3 weeks after the end of treatment: 47.5 [1.8]; P < .001). No overall treatment-associated differences were noted in the Fugl-Meyer Assessment (mean [SE], baseline: 163.8 [6.8]; 3 weeks after treatment: 171.1 [7.2]; 3 weeks after the end of treatment: 173.5 [6.9]; P > .05) and Barthel Index scores (mean [SE], baseline: 71.1 [4.92]; 3 weeks after treatment: 88.8 [2.1]; 3 weeks after the end of treatment: 92.2 [2.4]; P > .05). Patients treated with CRB-iTBS, but not sham iTBS, showed a reduction of step width at the gait analysis (mean [SE], baseline: 16.8 [4.8] cm; 3 weeks after treatment: 14.3 [6.2] cm; P < .05) and an increase of neural activity over the posterior parietal cortex.CONCLUSIONS AND RELEVANCE Cerebellar intermittent θ-burst stimulation promotes gait and balance recovery in patients with stroke by acting on cerebello-cortical plasticity. These results are important to increase the level of independent walking and reduce the risk of falling.

show abstract

Chronic 30-Hz Deep Cerebellar Stimulation Coupled With Training Enhances Post-ischemia Motor Recovery and Peri-infarct Synaptophysin Expression in Rodents

Abstract: These results indicate that chronic activation of ascending cerebellofugal pathways enhances motor recovery after focal cortical ischemia. The recovery was associated with an increase in perilesional cortical plasticity relative to nontreated controls.

Cited by 54 publications

References 21 publications

Chronic Deep Cerebellar Stimulation Promotes Long-Term Potentiation, Microstructural Plasticity, and Reorganization of Perilesional Cortical Representation in a Rodent Model

Chronic Deep Cerebellar Stimulation Promotes Long-Term Potentiation, Microstructural Plasticity, and Reorganization of Perilesional Cortical Representation in a Rodent Model

Invasive Neurostimulation in Stroke Rehabilitation

Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke

Contact Info

Product

Resources

About