New advances in the rehabilitation of CNS diseases applying rTMS

Transcranial magnetic stimulation (TMS) can directly stimulate the CNS, modifying the brain's plasticity to enhance the behavior of the paretic extremities. Studies with low-frequency repetitive TMS (rTMS) on the intact hemisphere and those with high frequencies on the affected hemisphere could increase the speed of movement in the hand affected by CNS injury. Stimulation of the motor pathway may contribute to faster improvement in patients with spinal cord injury. Symptoms of Parkinson's disease (such as cognition and working memory, neglect syndrome and global aphasia) can be influenced by rTMS. However, the site of stimulation and the parameters of rTMS are different. Processes that contribute to the behavior of rTMS include the modification of brain plasticity, induction of neurogenesis, growth of new fibers in the spinal cord or all of these together. According to previous research, rTMS may be suitable as an add-on therapy to rehabilitation in CNS diseases.     

Modulating cortical excitability in acute stroke: a repetitive TMS study.

OBJECTIVE: Changes in cerebral cortex excitability have been demonstrated after a stroke and are considered relevant for recovery. Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate cerebral cortex excitability and, when rTMS is given as theta burst stimulation (TBS), LTP- or LTD-like changes can be induced. The aim of present study was to evaluate the effects of TBS on cortical excitability in acute stroke. METHODS: In 12 acute stroke patients, we explored the effects of facilitatory TBS of the affected hemisphere and of inhibitory TBS of the unaffected hemisphere on cortical excitability to single-pulse transcranial magnetic stimulation (TMS) on both sides. The effects produced by TBS in patients were compared with those observed in a control group of age-matched healthy individuals. RESULTS: In patients, both the facilitatory TBS of the affected motor cortex and the inhibitory TBS of the unaffected motor cortex produced a significant increase of the amplitude of MEPs evoked by stimulation of the affected hemisphere. The effects observed in patients were comparable to those observed in controls. CONCLUSIONS: Facilitatory TBS over the stroke hemisphere and inhibitory TBS over the intact hemisphere in acute phase enhance the excitability of the lesioned motor cortex. SIGNIFICANCE: TBS might be useful to promote cortical plasticity in stroke patients.     

Transcranial magnetic stimulation in mild to severe hemiparesis early after stroke: a proof of principle and novel approach to improve motor function

Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the unaffected hemisphere can enhance function of the paretic hand in patients with mild motor impairment. Effects of low-frequency rTMS to the contralesional motor cortex at an early stage of mild to severe hemiparesis after stroke are unknown. In this pilot, randomized, double-blind clinical trial we compared the effects of low-frequency rTMS or sham rTMS as add-on therapies to outpatient customary rehabilitation, in 30 patients within 5-45 days after ischemic stroke, and mild to severe hand paresis. The primary feasibility outcome was compliance with the interventions. The primary safety outcome was the proportion of intervention-related adverse events. Performance of the paretic hand in the Jebsen-Taylor test and pinch strength were secondary outcomes. Outcomes were assessed at baseline, after ten sessions of treatment administered over 2 weeks and at 1 month after end of treatment. Baseline clinical features were comparable across groups. For the primary feasibility outcome, compliance with treatment was 100% in the active group and 94% in the sham group. There were no serious intervention-related adverse events. There were significant improvements in performance in the Jebsen-Taylor test (mean, 12.3% 1 month after treatment) and pinch force (mean, 0.5 Newtons) in the active group, but not in the sham group. Low-frequency rTMS to the contralesional motor cortex early after stroke is feasible, safe and potentially effective to improve function of the paretic hand, in patients with mild to severe hemiparesis. These promising results will be valuable to design larger randomized clinical trials.     

Dysphagia and hemispheric stroke: A transcranial magnetic study

INTRODUCTION: Dysphagia is a common and distressing consequence of hemispheric stroke. STUDY AIM: To verify the usefulness of transcranial magnetic stimulation (TMS) studies of swallowing in healthy subjects and in stroke patients. MATERIAL AND METHODS: TMS studies of the motor cortical projections to the upper esophageal sphincter were performed in 45 patients with acute mono-hemispheric stroke (26 patients with dysphagia) and 20 healthy adult volunteers. RESULTS: TMS of either hemisphere in normal volunteers evoked motor evoked potentials (MEP) in the esophagus. The average point of optimal excitability was slightly more anterior in the right hemisphere; otherwise, MEP amplitudes and latencies were similar from both hemispheres as were the areas of the cortical map. The cortical map area and amplitude of MEPs were significantly smaller and the latencies longer after stimulation of the affected hemisphere compared with the unaffected hemisphere and pooled control data. Twenty-four dysphagic patients (92.3%) had abnormalities of MEP of the affected hemisphere, while only five non-dysphagic patients (26%) had these abnormalities. Dysphagic patients were older and had more disability compared with non-dysphagic patients. MEPs of the affected hemisphere of patients with dysphagia were later and smaller in amplitude than MEPs of non-dysphagic patients. The cortical map area was also smaller. CONCLUSION: The esophagus is represented bilaterally in motor cortex, but the hot spot lies more anterior to Cz in right hemisphere compared to left hemisphere. Both the severity of stroke and neuroplasticity of the unaffected hemisphere have implications in the development of dysphagia.     

Contribution of the ipsilateral motor cortex to recovery after chronic stroke

It has been proposed that the intact (ipsilateral) motor cortex play a significant role mediating recovery of motor function in the paretic hand of chronic stroke patients, but this hypothesis has not been tested experimentally. Here, we evaluated the effects of transcranial magnetic stimulation (TMS) on motor performance of the paretic hand of chronic stroke patients and healthy controls. We hypothesized that, if activity in the intact hemisphere contributes to functional recovery, TMS should result in abnormal motor behavior in the paretic hand. We found that stimulation of the intact hemisphere resulted in delayed simple reaction times (RTs) in the contralateral healthy but not in the ipsilateral paretic hand, whereas stimulation of the lesioned hemisphere led to a marked delay in RT in the contralateral paretic hand but not in the ipsilateral healthy hand. RT delays in the paretic hand correlated well with functional recovery. Finger tapping in the paretic hand was affected by TMS of the lesioned but not the intact hemisphere. These results are consistent with the idea that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere.     

Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke.

OBJECTIVE: To explore the effects of a single session of repetitive Transcranial Magnetic Stimulation, given as Theta Burst Stimulation, on behavioural and physiological measures of hand function in chronic stroke patients. METHODS: Six chronic stroke patients with incomplete recovery of the hand were tested under three conditions: excitatory TBS over the stroke hemisphere (iTBS(SH)), inhibitory TBS (cTBS(IH)) over the intact hemisphere and sham stimulation. Behavioural outcomes included simple and choice reaction time paradigms. Physiological effects were assessed using single pulse TMS on both sides. Changes were sought for up to 40min after TBS. RESULTS: Immediately after iTBS(SH) simple reaction times in the paretic hands were decreased and, compared to sham stimulation, remained significantly shorter throughout the testing period. The amplitude of the MEPs at rest and during background contraction and the area under the Input-Output curves were also increased on the stroke side after iTBS(SH). cTBS(IH) suppressed the MEPs evoked in the healthy hands but did not change motor behaviour or the electrophysiology of the paretic hands. No side effects were encountered. CONCLUSIONS: TBS seems safe in chronic stroke patients. iTBS over the stroke hemisphere transiently improved motor behaviour and corticospinal output in the paretic hands. SIGNIFICANCE: Excitatory TBS may represent a useful rTMS protocol to apply to the stroke hemisphere in future longer term therapy trials.     

Motor representation in patients rapidly recovering after stroke: a functional magnetic resonance imaging and transcranial magnetic stimulation study

OBJECTIVE: Neuroimaging studies have suggested an evolution of the brain activation pattern in the course of motor recovery after stroke. Initially poor motor performance is correlated with an recruitment of the uninjured hemisphere that continuously vanished until a nearly normal (contralateral) activation pattern is achieved and motor performance is good. Here we were interested in the early brain activation pattern in patients who showed a good and rapid recovery after stroke. METHODS: Ten patients with first-ever ischemic stroke affecting motor areas had to perform self-paced simple or more complex movements with the affected or the unaffected hand during functional magnetic resonance imaging (fMRI). The location and number of activated voxels above threshold were determined. To study possible changes in the cortical motor output map the amplitude of the motor evoked potentials (MEP) and the extent of the excitable area were determined using transcranial magnetic stimulation (TMS). RESULTS: The pattern of activation observed with movements of the affected and the unaffected hand was similar. In the simple motor task significant (P<0.05) increases were found in the primary motor cortex ipsilateral to the movement, the supplementary motor area and the cerebellar hemisphere contralateral to the movement during performance with the affected hand compared to movements with the unaffected hand. When comparing simple with more complex movements performed with either the affected or the unaffected hand, a further tendency to increased activation in motor areas was observed. The amplitude of MEPs obtained from the affected hemisphere was smaller and the extent of cortical output maps was decreased compared to the unaffected hemisphere; but none of the patients showed MEPs at the affected hand when the ipsilateral unaffected motor cortex was stimulated. CONCLUSIONS: Despite a rapid and nearly complete motor recovery the brain activation pattern was associated with increased activity in (bilateral) motor areas as revealed with fMRI. TMS revealed impaired motor output properties, but failed to demonstrate ipsilateral motor pathways. Successful recovery in our patients may therefore rely on the increased bilateral activation of existing motor networks spared by the injury.     

Motor cortex excitability in stroke before and after constraint-induced movement therapy.

OBJECTIVE: To investigate motor cortex excitability in stroke patients and explore excitability changes induced by an intense physiotherapy. METHODS: We studied 12 chronic stroke patients (6 cortical, 6 subcortical lesions) before and after participation in 12 days of constraint-induced movement therapy. Transcranial magnetic stimulation was applied to test intracortical inhibition (ICI), intracortical facilitation, silent periods, amplitudes of motor evoked potentials, and motor thresholds. Motor function was assessed by the Motor Activity Log, the Wolf Motor Function Test, and the Modified Ashworth Scale for spasticity. RESULTS: Motor evoked potential amplitudes and motor thresholds were inversely correlated, indicating that both parameters reflect the function of corticospinal pathways. Before therapy, a motor cortex disinhibition was found in the affected hemisphere. This disinhibition was stronger in patients with cortical lesions. The amount of disinhibition was correlated with the degree of spasticity. After therapy, ICI changes were more pronounced in the affected hemisphere compared with the unaffected side. Both ICI decreases and increases were observed. Motor function tests indicated an improvement in all patients. CONCLUSIONS: Motor cortical disinhibition is present in chronic stroke patients. Therapy-associated changes of motor cortex excitability mainly occur in the lesioned hemisphere by up-regulation or down-regulation of ICI. We replicate that constraint-induced movement therapy improves motor functions in the chronic stage after stroke.     

Low‐frequency rTMS of the unaffected hemisphere in stroke patients: A systematic review

The aim of this review was to summarize the evidence for the effectiveness of low‐frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over the unaffected hemisphere in promoting functional recovery after stroke. We performed a systematic search of the studies using LF‐rTMS over the contralesional hemisphere in stroke patients and reviewed the 67 identified articles. The studies have been gathered together according to the time interval that had elapsed between the stroke onset and the beginning of the rTMS treatment. Inhibitory rTMS of the contralesional hemisphere can induce beneficial effects on stroke patients with motor impairment, spasticity, aphasia, hemispatial neglect and dysphagia, but the therapeutic clinical significance is unclear. We observed considerable heterogeneity across studies in the stimulation protocols. The use of different patient populations, regardless of lesion site and stroke aetiology, different stimulation parameters and outcome measures means that the studies are not readily comparable, and estimating real effectiveness or reproducibility is very difficult. It seems that careful experimental design is needed and it should consider patient selection aspects, rTMS parameters and clinical assessment tools. Consecutive sessions of rTMS, as well as the combination with conventional rehabilitation therapy, may increase the magnitude and duration of the beneficial effects. In an increasing number of studies, the patients have been enrolled early after stroke. The prolonged follow‐up in these patients suggests that the effects of contralesional LF‐rTMS can be long‐lasting. However, physiological evidence indicating increased synaptic plasticity, and thus, a more favourable outcome, in the early enrolled patients, is still lacking. Carefully designed clinical trials designed are required to address this question. LF rTMS over unaffected hemisphere may have therapeutic utility, but the evidence is still preliminary and the findings need to be confirmed in further randomized controlled trials.     

Transcranial direct current stimulation of the unaffected hemisphere in stroke patients

Recovery of function after a stroke is determined by a balance of activity in the neural network involving both the affected and the unaffected brain hemispheres. Increased activity in the affected hemisphere can promote recovery, while excessive activity in the unaffected hemisphere may represent a maladaptive strategy. We therefore investigated whether reduction of the excitability in the unaffected hemisphere by cathodal transcranial direct current stimulation could result in motor performance improvement in stroke patients. We compared these results with excitability-enhancing anodal transcranial direct current stimulation of the affected hemisphere and sham transcranial direct current stimulation. Both cathodal stimulation of the unaffected hemisphere and anodal stimulation of the affected hemisphere (but not sham transcranial direct current stimulation) improved motor performance significantly. These results suggest that the appropriate modulation of bihemispheric brain structures can promote motor function recovery.