Posts Tagged rTMS

[Abstract] The treatment of fatigue by non-invasive brain stimulation


The use of non-invasive brain neurostimulation (NIBS) techniques to treat neurological or psychiatric diseases is currently under development. Fatigue is a commonly observed symptom in the field of potentially treatable pathologies by NIBS, yet very little data has been published regarding its treatment. We conducted a review of the literature until the end of February 2017 to analyze all the studies that reported a clinical assessment of the effects of NIBS techniques on fatigue. We have limited our analysis to repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). We found only 15 studies on this subject, including 8 tDCS studies and 7 rTMS studies. Of the tDCS studies, 6 concerned patients with multiple sclerosis while 6 rTMS studies concerned fibromyalgia or chronic fatigue syndrome. The remaining 3 studies included patients with post-polio syndrome, Parkinson’s disease and amyotrophic lateral sclerosis. Three cortical regions were targeted: the primary sensorimotor cortex, the dorsolateral prefrontal cortex and the posterior parietal cortex. In all cases, tDCS protocols were performed according to a bipolar montage with the anode over the cortical target. On the other hand, rTMS protocols consisted of either high-frequency phasic stimulation or low-frequency tonic stimulation. The results available to date are still too few, partial and heterogeneous as to the methods applied, the clinical profile of the patients and the variables studied (different fatigue scores) in order to draw any conclusion. However, the effects obtained, especially in multiple sclerosis and fibromyalgia, are really carriers of therapeutic hope.

Source: The treatment of fatigue by non-invasive brain stimulation

, , , , , , , , ,

Leave a comment

[Abstract] Importance and Difficulties of Pursuing rTMS Research in Acute Stroke


Although much research has been done on repetitive transcranial magnetic stimulation (rTMS) in chronic stroke, only sparse research has been done in acute stroke despite the particularly rich potential for neuroplasticity in this stage.

We attempted a preliminary clinical trial in one active, high-quality inpatient rehabilitation facility (IRF) in the U.S. But after enrolling only four patients in the grant period, the study was stopped because of low enrollment.

The purpose of this paper is to offer a perspective describing the important physiologic rationale for including rTMS in the early phase of stroke, the reasons for our poor patient enrollment in our attempted study, and recommendations to help future studies succeed.

We conclude that, if scientists and clinicians hope to enhance stroke outcomes, more attention must be directed to leveraging conventional rehabilitation with neuromodulation in the acute phase of stroke when the capacity for neuroplasticity is optimal. Difficulties with patient enrollment must be addressed by reassessing traditional inclusion and exclusion criteria. Factors that shorten patients’ length of stay in the IRF must also be reassessed at all policy-making levels to make ethical decisions that promote higher functional outcomes while retaining cost consciousness.

Source: Importance and Difficulties of Pursuing rTMS Research in Acute Stroke | Physical Therapy | Oxford Academic

, , , , ,

Leave a comment

[ARTICLE] Short- and Long-term Effects of Repetitive Transcranial Magnetic Stimulation on Upper Limb Motor Function after Stroke: a Systematic Review and Meta-Analysis – Full Text

The aim of this study was to evaluate the short- and long-term effects as well as other parameters of repetitive transcranial magnetic stimulation (rTMS) on upper limb motor functional recovery after stroke.

The databases of PubMed, Medline, Science Direct, Cochrane, and Embase were searched for randomized controlled studies reporting effects of rTMS on upper limb motor recovery published before October 30, 2016.

The short- and long-term mean effect sizes as well as the effect size of rTMS frequency of pulse, post-stroke onset, and theta burst stimulation patterns were summarized by calculating the standardized mean difference (SMD) and the 95% confidence interval using fixed/random effect models as appropriate.

Thirty-four studies with 904 participants were included in this systematic review. Pooled estimates show that rTMS significantly improved short-term (SMD, 0.43; P < 0.001) and long-term (SMD, 0.49; P < 0.001) manual dexterity. More pronounced effects were found for rTMS administered in the acute phase of stroke (SMD, 0.69), subcortical stroke (SMD, 0.66), 5-session rTMS treatment (SMD, 0.67) and intermittent theta burst stimulation (SMD, 0.60). Only three studies reported mild adverse events such as headache and increased anxiety .

Five-session rTMS treatment could best improve stroke-induced upper limb dyskinesia acutely and in a long-lasting manner. Intermittent theta burst stimulation is more beneficial than continuous theta burst stimulation. rTMS applied in the acute phase of stroke is more effective than rTMS applied in the chronic phase. Subcortical lesion benefit more from rTMS than other lesion site.

Continue —> Short- and Long-term Effects of Repetitive Transcranial Magnetic Stimulation on Upper Limb Motor Function after Stroke: a Systematic Review and Meta-Analysis – Feb 17, 2017


Figure 1. The flow diagram of the selection process.



, , , , , , , , , ,

Leave a comment

[ARTICLE] Does a combined intervention program of repetitive transcranial magnetic stimulation and intensive occupational therapy affect cognitive function in patients with post-stroke upper limb hemiparesis? – Full Text HTML



Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) to the contralesional hemisphere and intensive occupational therapy (iOT) have been shown to contribute to a significant improvement in upper limb hemiparesis in patients with chronic stroke. However, the effect of the combined intervention program of LF-rTMS and iOT on cognitive function is unknown. We retrospectively investigated whether the combined treatment influence patient’s Trail-Making Test part B (TMT-B) performance, which is a group of easy and inexpensive neuropsychological tests that evaluate several cognitive functions. Twenty-five patients received 11 sessions of LF-rTMS to the contralesional hemisphere and 2 sessions of iOT per day over 15 successive days. Patients with right- and left-sided hemiparesis demonstrated significant improvements in upper limb motor function following the combined intervention program. Only patients with right-sided hemiparesis exhibited improved TMT-B performance following the combined intervention program, and there was a significant negative correlation between Fugl-Meyer Assessment scale total score change and TMT-B performance. The results indicate the possibility that LF-rTMS to the contralesional hemisphere combined with iOT improves the upper limb motor function and cognitive function of patients with right-sided hemiparesis. However, further studies are necessary to elucidate the mechanism of improved cognitive function.


Upper limb hemiparesis is reported to be observed in 55–75% of post-stroke patients, and affects the patient’s activities of daily living and quality of life (Nichols-Larsen et al., 2005; Wolf et al., 2006). Duncan et al. (1992) reported that dramatic recovery of motor function was completed by 1month post-stroke, and that recovery often plateaued by 6 months. In recent years, repetitive transcranial magnetic stimulation (rTMS) has attracted attention as a treatment technique for the sequelae of stroke. It is a non-invasive, painless method to stimulate regions of the cerebral cortex, in which a figure-8 or a round coil converts electrical current into a rapidly variable magnetic field that is orthogonal to the current. Eddy currents generated by the changes of the magnetic field directly affect neurons (Barker, 1999). In addition, it has been known that different stimulation frequencies have different effects on the activities of the cerebral cortex, with high-frequency (> 5 Hz) stimulation facilitating local neuronal excitability and low-frequency (< 1 Hz) stimulation showing inhibitory effects (Lefaucheur, 2006; Butler and Wolf, 2007). Low-frequency rTMS (LF-rTMS) aims at increasing the excitability of the ipsilesional hemisphere by exerting its effects on the disrupted interhemispheric inhibition following stroke and thereby providing inhibitory stimulation to the contralesional hemisphere. Meta-analyses of rTMS in patients with stroke indicate that LF-rTMS is recommended for stroke patients in the chronic phase (> 6 months post-stroke), showing a strong possibility of a significant improvement of their upper limb function (Hsu et al., 2012; Le et al., 2014). In the past, our research group implemented a 15-day treatment protocol consisting of LF-rTMS and an intensive individualized rehabilitation program for patients with upper limb hemiparesis following stroke, and demonstrated a significant improvement of upper limb hemiparesis (Kakuda et al., 2011, 2012, 2016). Furthermore, we investigated the effects of our treatment protocol on brain activity and demonstrated a significant increase in the fMRI laterality index, indicating increased neuronal activity in the ipsilesional hemisphere (Yamada et al., 2013). Our single photon emission computed tomography (SPECT) study also demonstrated a significant decrease in perfusion in the middle frontal gyrus (Brodmann area; BA6), precentralgyrus (BA4), and post central gyrus (BA3) of the contralesional hemisphere, as well as an increased perfusion in the insula (BA13) and precentral gyrus (BA44) of the ipsilesional hemisphere (Hara et al., 2013). Thus, we demonstrated changes in brain activity between pre- and post-treatment that combined LF-rTMS and an intensive occupational therapy (iOT) program.

In recent studies, rTMS was used not only in treating upper limb hemiparesis after stroke, but also for other conditions, including neurological and psychiatric disorders, pain, and Parkinson’s disease (Lefaucheur et al., 2014). Furthermore, some studies conducted neuropsychological examinations at the time of rTMS to evaluate its effect on cognitive function (Nardone et al., 2014; Drumond Marra et al., 2015). One study reported an improvement in cognitive function following rTMS in patients with mild cognitive impairment (Nardone et al., 2014). Drumond Marra et al. (2015) reported an improved performance on the Rivermead Behavioral Memory Test following high-frequency rTMS (HF-rTMS) to the left dorsolateral prefrontal cortex (DLPFC).

Furthermore, the effects of rTMS on cognitive function in addition to motor disorders, aphasia, and affective disorders have been attracting attention (Lefaucheur et al., 2014; Nardone et al., 2014; Drumond Marra et al., 2015). One study reported an improvement in Trail-Making Test part B (TMT-B) performance by HF-rTMS, while another study reported a lack of significant improvement relative to a control group (Moser et al., 2002; Mittrach et al., 2010). However, few studies have investigated the effects of LF-rTMS on cognitive function. As described earlier, LF-rTMS exerts an inhibitory stimulation to the side of administration and is considered to affect the contralateral cerebral cortices via a modulation of interhemispheric inhibition. Therefore, LF-rTMS possibly affects a broader region than that affected by HF-rTMS. Meta-analyses of rTMS in patients with stroke indicate that LF-rTMS is recommended for stroke patients in the chronic phase (> 6 months post-stroke).

Although previous studies indicate a possibility of positive effects of rTMS on cognitive function; however, to the best of our knowledge, there has been no report describing the effect of a combined intervention program of LF-rTMS and intensive occupational therapy (iOT) on cognitive function in post-stroke patients. Therefore, the present study aimed to explore the therapeutic effect of the combined intervention program on patients with post-stroke upper limb hemiparesis.

Continue —> Does a combined intervention program of repetitive transcranial magnetic stimulation and intensive occupational therapy affect cognitive function in patients with post-stroke upper limb hemiparesis? Hara T, Abo M, Kakita K, Masuda T, Yamazaki R – Neural Regen Res

, , , , , , , , , ,

Leave a comment

[ARTICLE] The Effect of rTMS with Rehabilitation on Hand Function and Corticomotor Excitability in Sub-Acute Stroke – Full Text PDF


Objectives: Stroke is the leading cause of long-term disability. Hand motor impairment resulting from chronic stroke may have extensive physical, psychological, financial, and social implications despite available rehabilitative treatments. The best time to start treatment for stroke, is in sub-acute period. Repetitive transcranial magnetic stimulation (rTMS) is a method of stimulating and augmenting the neurophysiology of the motor cortex in order to promote the neuroplastic changes that are associated with motor recovery. The purpose of this study was to compare the effects of repetitive transcranial magnetic stimulation protocols plus routine rehabilitation on hand motor functions and hand corticomotor excitability in stroke patients with hemiplegia with pure routine rehabilitation programs.

Methods: This study was a randomized clinical trial which was performed on 24 patients with hemiplegia who were randomly divided in to three groups. One group (n=7), received high frequency repetitive transcranial magnetic stimulation (Hf rTMS) on lesioned M1 with routine rehabilitation program, and the other group (n=7), received rehabilitation program with low frequency repetitive transcranial magnetic stimulation stimulation (Lf rTMS) on nonlesined M1, and a control group (n=10), who were given only routine rehabilitation programs. The treatment was performed for 10 sessions, three times peri-test, Post and follow-up about neurophysiological contralesional hemisphere evaluations using record of MEP wave indices by single pulse TMS, and assessing functional wolf test and hand grip power of disabled hand by dynamometer.

Results: The results demonstrated that the rest MEP threshold reduction in experimental group which received high frequency magnetic stimulation was statistically significant (P<0.05). There was similar finding for active MEP threshold in the both high and low frequency but not in control group (P<0.05). Also there were more significant relation between obtained results from WOLF test and grip power with MEP mentioned parameters, in high frequency group, but not in low frequency and control group.

Discussion: According to the results, However it seems that Hf rTMS combined with routin physiotherapy can significantly improve hand functions and brain neurophysiology via specifically increase of contralesional corticomotor excitability in sever stroke patients that is representative of the role of neuroplasticity in nonlesioned hemisphere but the hypothesis of movement improvement related cognitive balance can’t be eliminated by exploring powerful approved effect of Hf rTMS on mood regulation.

Source: The Effect of rTMS with Rehabilitation on Hand Function and Corticomotor Excitability in Sub-Acute Stroke – Iranian Rehabilitation Journal

, , , , , , , , ,

Leave a comment

[ARTICLE] Systems Biology of Immunomodulation for Post-Stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation – Full Text

AIMS: Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using antiinflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke. METHODS: We develop a computational systems biology approach from preclinical data using ordinary differential equations, to study the behavior of both phenotypes of microglia such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in NF-κB (nuclear factor kappa beta) signaling and neurorehabilitation therapy using tDCS and rTMS which act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways. RESULTS: We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated microglia and neuroprotection together with improved neurogenesis, synaptogenesis and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, Trk-B and Calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-D-aspartate (NMDA) receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS. CONCLUSION: Additive beneficial effect is thus noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation and neurorestoration.

Continue —> Frontiers | Systems Biology of Immunomodulation for Post-Stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation | Stroke

Figure 3. BDNF and TrkB signaling pathway.

, , , , , , ,

Leave a comment

[ARTICLE] Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation – Full Text

The primary aim of this study was to evaluate and compare the effectiveness of two specific Non-Invasive Brain Stimulation (NIBS) paradigms, the repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial Direct Current Stimulation (tDCS), in the upper limb rehabilitation of patients with stroke.

Short and long term outcomes (after 3 and 6 months, respectively) were evaluated. We measured, at multiple time points, the manual dexterity using a validated clinical scale (ARAT), electroencephalography auditory event related potentials, and neuropsychological performances in patients with chronic stroke of middle severity.

Thirty four patients were enrolled and randomized. The intervention group was treated with a NIBS protocol longer than usual, applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS). We compared the results with a control group treated with sham stimulation. We split the data analysis into three studies. In this first study we examined if a cumulative effect was clinically visible. In the second study we compared the effects of the two techniques. In the third study we explored if patients with minor cognitive impairment have most benefit from the treatment and if cognitive and motor outcomes were correlated.

We found that the impairment in some cognitive domains cannot be considered an exclusion criterion for rehabilitation with NIBS. ERP improved, related to cognitive and attentional processes after stimulation on the motor cortex, but transitorily. This effect could be linked to the restoration of hemispheric balance or by the effects of distant connections. In our study the effects of the two NIBS were comparable, with some advantages using tDCS vs. rTMS in stroke rehabilitation. Finally we found that more than one cycle (2–4 weeks), spaced out by washout periods, should be used, only in responder patients, to obtain clinical relevant results.


Motor and cognitive impairment are frequent aftermaths of brain damage after a stroke. Many authors reports cognitive deficits in 12–56% of stroke patients and reduced performances in several cognitive domains in 32% (Ebrahim et al., 1985; Tatemichi et al., 1994; Patel et al., 2002). Moreover, dysfunctions in the use of upper limb and in functional walking are among the more common consequences for many stroke survivors. Of note, only 5% of adult stroke survivors regain full function of the upper limb and 20% do not recover any functional use.

The severity of cognitive impairment negatively correlates with motor and functional recovery achieved in stroke patients after rehabilitation. Indeed, a cognitive assessment should be used to select patients that could have the best benefits from rehabilitation (Patel et al., 2002; Mehta et al., 2003; Saxena et al., 2007; Rabadi et al., 2008).

Event Related Potentials (ERP) are a reproducible electrophysiological response to an external stimulus (visual or auditory), representing the brain activity associated with various cognitive processes such as selective attention, memory, or decision making. Interestingly, ERP can be valuable in the diagnosis of cognitive impairment and are able to track the cognitive changes during the follow-up in stroke patients (Trinka et al., 2000; Alonso-Prieto et al., 2002; Yamagata et al., 2004; Stahlhut et al., 2014).

Recently, Non-Invasive Brain Stimulation (NIBS) techniques have been proposed as support of standard cognitive and motor rehabilitation. The application of NIBS in stroke rehabilitation arises from the observation that cortical excitability can be modulated after electrical or magnetic brain stimulation. It can be reduced or enhanced (Miniussi et al., 2008; Sandrini and Cohen, 2013) depending on many factors (stimulation parameters, type of stimulation technique, timing of the stimulation, brain target region, and state of mind).

The physiological mechanisms underlying brain stimulation effects are still partially unknown, but several evidences explain these effects with Long Term Potentiation (LTP) and Long Term Depression (LTD) like mechanisms (Thickbroom, 2007; Fritsch et al., 2010; Bliss and Cooke, 2011).

Repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS) are the most used NIBS techniques in rehabilitation (Hummel et al., 2005; Miniussi et al., 2008; Bolognini et al., 2009). Both can induce long lasting effect on cortical plasticity (30–90 min). Modification of cortical activity may improve the subject’s ability to relearn or acquire new strategies for carrying out motor or behavioral task, by facilitating perilesional activity or by suppressing maladaptive interfering activity from other brain areas (Miniussi et al., 2008). Even if most of the effects are transient, NIBS during or before a learning process may yield the behavioral improvements more robust and stable (Rossi and Rossini, 2004;Pascual-Leone, 2006). Indeed, during motor learning not only the fast (intra-sessions) and slow (inter-sessions) learning during training are relevant, but also the memory consolidation and the savings (Wessel et al., 2015). Plasticity induced by NIBS could thus have important effects not only in the online phase of motor rehabilitation, but also in the offline phases.

A growing number of studies indicates that NIBS could be useful in chronic stroke rehabilitation (Hummel and Cohen, 2006;Sandrini and Cohen, 2013; Liew et al., 2014; Wessel et al., 2015), but no one compared directly the two techniques or explored the link between cognitive and motor improvement. TMS is able to directly induce action potentials in the axons while the currents used in tDCS (1–2 mA) cannot. The first technique is, therefore, best suited to be used offline, while the second can be used online in conjunction with other rehabilitation techniques or tasks (Wessel et al., 2015). Simis et al. (2013) compared rTMS and tDCS in healthy subjects, observing that both techniques induced similar motor gains. The comparison of brain plasticity induced by NIBS in pathologic subjects could thus extend significantly the Simis’ results.

In this paper, the primary aim was to evaluate and compare the motor and cognitive changes induced by rTMS and tDCS in the upper limb rehabilitation in patients with stroke, both in short and in long term outcome. Secondarily we searched for a possible link between motor and cognitive measures.

We chose the most effective paradigm of rTMS in chronic stroke according to meta-analyses and consensus papers (Lefaucheur et al., 2014), a low-frequency protocol applied onto the controlesional motor cortex (M1). For tDCS, in the absence of a gold standard, we chose a paradigm with a dual sites montage validated in non-inferiority trials (Schlaug et al., 2008; Lüdemann-Podubecká et al., 2014). The tDCS was performed in conjunction with a cognitive training focused on the brain representation of the hands, the mirror-box therapy (MT), to direct the neuromodulation effect as wished. Our aim was to create a paradigm easy to apply in a clinical setting.

To compare the NIBS techniques in the same patients we created a treatment longer than usual applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS).

A randomized clinical trial divided into three studies was designed to explore the following issues:

A longer NIBS stimulation could be beneficial in stroke rehabilitation?

What are the differences between rTMS and tDCS in stroke rehabilitation?

NIBS motor stimulation effects can modulate or be modulated by patients’ cognitive status?

In the first study we evaluated if a cumulative effect, mediated by an offline improvement (consolidation or savings), was clinically detectable. We also evaluated the differences between a first priming cycle with rTMS followed by tDCS and first priming with tDCS followed by rTMS.

In the second study we compared the effects of the two techniques to test if brain plasticity effects could depend on the type of NIBS. In the third study, we searched for a possible link between motor and cognition changes, evaluating if cognitive measures changed in patients with motor improvement differently from the patients without motor improvement.

Continue —> Frontiers | Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation | Frontiers in Behavioral Neuroscience

Figure 1. Experimental design. After screening the patients were randomized into three groups with different interventions: MT, Mirror Therapy; tDCS, transcranial Direct Current Stimulation; rTMS, repetitive Transranial Magnetic Stimulation. In the scheme the outcome measures: ARAT, Action Research Arm Test; P300, cognitive auditory evoked response potentials; NPS, neuropsychological test where assessed in multiple time frames; w, week; mos, months.

, , , , , , , , , , , ,

Leave a comment

[ARTICLE] Role of Brain-Derived Neurotrophic Factor in Beneficial Effects of Repetitive Transcranial Magnetic Stimulation for Upper Limb Hemiparesis after Stroke.



Repetitive transcranial magnetic stimulation (rTMS) can improve upper limb hemiparesis after stroke but the mechanism underlying its efficacy remains elusive. rTMS seems to alter brain-derived neurotrophic factor (BDNF) and such effect is influenced by BDNF gene polymorphism.


To investigate the molecular effects of rTMS on serum levels of BDNF, its precursor proBDNF and matrix metalloproteinase-9 (MMP-9) in poststroke patients with upper limb hemiparesis.


Poststroke patients with upper limb hemiparesis were studied. Sixty-two patients underwent rehabilitation plus rTMS combination therapy and 33 patients underwent rehabilitation monotherapy without rTMS for 14 days at our hospital. One Hz rTMS was applied over the motor representation of the first dorsal interosseous muscle on the non-lesional hemisphere. Fugl-Meyer Assessment and Wolf Motor Function (WMFT) were used to evaluate motor function on the affected upper limb before and after intervention. Blood samples were collected for analysis of BDNF polymorphism and measurement of BDNF, proBDNF and MMP-9 levels.


Two-week combination therapy increased BDNF and MMP-9 serum levels, but not serum proBDNF. Serum BDNF and MMP-9 levels did not correlate with motor function improvement, though baseline serum proBDNF levels correlated negatively and significantly with improvement in WMFT (ρ = -0.422, p = 0.002). The outcome of rTMS therapy was not altered by BDNFgene polymorphism.


The combination therapy of rehabilitation plus low-frequency rTMS seems to improve motor function in the affected limb, by activating BDNF processing. BDNF and its precursor proBDNF could be potentially suitable biomarkers for poststroke motor recovery.

Continue —> PLOS ONE: Role of Brain-Derived Neurotrophic Factor in Beneficial Effects of Repetitive Transcranial Magnetic Stimulation for Upper Limb Hemiparesis after Stroke


, , , , , , , ,

Leave a comment

[ARTICLE] Combining Robotic Training and Non-Invasive Brain Stimulation in Severe Upper Limb-Impaired Chronic Stroke Patients – Full Text HTML/PDF

Previous studies suggested that both robot-assisted rehabilitation and non-invasive brain stimulation can produce a slight improvement in severe chronic stroke patients. It is still unknown whether their combination can produce synergistic and more consistent improvements. Safety and efficacy of this combination has been assessed within a proof-of-principle, double-blinded, semi-randomized, sham-controlled trial. Inhibitory continuous Theta Burst Stimulation (cTBS) was delivered on the affected hemisphere, in order to improve the response to the following robot-assisted therapy via a homeostatic increase of learning capacity. Twenty severe upper limb-impaired chronic stroke patients were randomized to robot-assisted therapy associated with real or sham cTBS, delivered for 10 working days. Eight real and nine sham patients completed the study. Change in Fugl-Meyer was chosen as primary outcome, while changes in several quantitative indicators of motor performance extracted by the robot as secondary outcomes. The treatment was well-tolerated by the patients and there were no adverse events. All patients achieved a small, but significant, Fugl-Meyer improvement (about 5%). The difference between the real and the sham cTBS groups was not significant. Among several secondary end points, only the Success Rate (percentage of targets reached by the patient) improved more in the real than in the sham cTBS group. This study shows that a short intensive robot-assisted rehabilitation produces a slight improvement in severe upper-limb impaired, even years after the stroke. The association with homeostatic metaplasticity-promoting non-invasive brain stimulation does not augment the clinical gain in patients with severe stroke.


Severe upper limb impairment in chronic stroke patients does not respond to standard rehabilitation strategies; for this reason there is the need of new treatments that might be effective in patients with drastically limited residual movement capacity. In patients with moderate to severe upper-limb impairment, a slight improvement have been reported using robot-assisted rehabilitative treatment, even years after a stroke (Lo et al., 2010). Another innovative approach for the enhancement of motor recovery is represented by non-invasive human brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). These techniques can induce long-lasting changes in the excitability of central motor circuits via long-term potentiation/depression (LTP/LTD)-like phenomena (Di Pino et al., 2014b). A recent study reported a mild motor improvement after 10 sessions of rTMS in a group of severe chronic stroke patients (Demirtas-Tatlidedea et al., 2015).

Aim of present study was to explore whether the combination of these two approaches might enhance their positive effects on motor recovery. To the end of assessing safety and potential efficacy of the combination of robot-assisted rehabilitation and non-invasive brain stimulation in a group of chronic stroke patients with severe upper limb impairment, we designed a proof-of-principle double blinded semi-randomized sham-controlled trial. We used continuous theta burst stimulation (cTBS), a robust form of inhibitory rTMS inducing LTD-like changes lasting for about 1 h [8]. The choice of employing cTBS on the affected hemisphere was based on the findings of our recent study, which suggested that this inhibitory protocol can improve the response to physical therapy (Di Lazzaro et al., 2013). Moreover, rTMS protocols suppressing cortical excitability have been shown to strongly facilitate motor learning in normal subjects (Jung and Ziemann, 2009). Jung and Ziemann suggested that such enhancement might involve the phenomenon of “homeostatic” plasticity, which can be induced in the human brain using a variety of brain stimulation protocols (Karabanov et al., 2015). Considering the close link between LTP and mammalian learning and memory (Malenka and Bear, 2004), an enhancement of learning after LTD induction might appear a paradox. However, the experimental studies by Rioult-Pedotti et al. demonstrated the existence of a homeostatic balance between learning and the induction of LTP/LTD (Rioult-Pedotti et al., 2000), thus showing that the ease of producing synaptic LTP/LTD depends on the prior history of neural activity. In the context of stroke, this predicts that by delivering a rTMS protocol that induces LTD-like effects on the stroke-affected hemisphere before performing rehabilitation, would luckily result in better relearning (Di Pino et al., 2014a).

Download Full Text PDF


Continue —> Frontiers | Combining Robotic Training and Non-Invasive Brain Stimulation in Severe Upper Limb-Impaired Chronic Stroke Patients | Neurodegeneration

Figure 1. Figurative illustration representing the algorithm of the study design, the evaluations carried out, and the treatments delivered. Treatment (real/sham cTBS + physical therapy) was delivered for 10 consecutive working days. Baseline evaluation was performed in the first day of treatment.

, , , , , , , , , ,

Leave a comment

[Abstract] Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: A systematic review – Epilepsy & Behavior


We reviewed the crude risk of seizures and other adverse events of rTMS in patients with epilepsy.

A crude per-subject risk of 2.9% (95% CI: 1.3–4.5) was estimated for seizures occurring during or shortly after.

The safety of rTMS applied to patients with epilepsy appears to be the same as in other conditions.


Approximately one-third of patients with epilepsy remain with pharmacologically intractable seizures. An emerging therapeutic modality for seizure suppression is repetitive transcranial magnetic stimulation (rTMS). Despite being considered a safe technique, rTMS carries the risk of inducing seizures, among other milder adverse events, and thus, its safety in the population with epilepsy should be continuously assessed.

We performed an updated systematic review on the safety and tolerability of rTMS in patients with epilepsy, similar to a previous report published in 2007 (Bae EH, Schrader LM, Machii K, Alonso-Alonso M, Riviello JJ, Pascual-Leone A, Rotenberg A. Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature. Epilepsy Behav. 2007; 10 (4): 521–8), and estimated the risk of seizures and other adverse events during or shortly after rTMS application.

We searched the literature for reports of rTMS being applied on patients with epilepsy, with no time or language restrictions, and obtained studies published from January 1990 to August 2015. A total of 46 publications were identified, of which 16 were new studies published after the previous safety review of 2007.

We noted the total number of subjects with epilepsy undergoing rTMS, medication usage, incidence of adverse events, and rTMS protocol parameters: frequency, intensity, total number of stimuli, train duration, intertrain intervals, coil type, and stimulation site.

Our main data analysis included separate calculations for crude per subject risk of seizure and other adverse events, as well as risk per 1000 stimuli. We also performed an exploratory, secondary analysis on the risk of seizure and other adverse events according to the type of coil used (figure-of-8 or circular), stimulation frequency (≤1 Hz or >1 Hz), pulse intensity in terms of motor threshold (<100% or ≥100%), and number of stimuli per session (<500 or ≥ 500).

Presence or absence of adverse events was reported in 40 studies (n = 426 subjects). A total of 78 (18.3%) subjects reported adverse events, of which 85% were mild. Headache or dizziness was the most common one, occurring in 8.9%. We found a crude per subject seizure risk of 2.9% (95% CI: 1.3–4.5), given that 12 subjects reported seizures out of 410 subjects included in the analysis after data of patients with epilepsia partialis continua or status epilepticus were excluded from the estimate.

Only one of the reported seizures was considered atypical in terms of the clinical characteristics of the patients’ baseline seizures. The atypical seizure happened during high-frequency rTMS with maximum stimulator output for speech arrest, clinically arising from the region of stimulation. Although we estimated a larger crude per subject seizure risk compared with the previous safety review, the corresponding confidence intervals contained both risks. Furthermore, the exclusive case of atypical seizure was the same as reported in the previous report. We conclude that the risk of seizure induction in patients with epilepsy undergoing rTMS is small and that the risk of other adverse events is similar to that of rTMS applied to other conditions and to healthy subjects.

Our results should be interpreted with caution, given the need for adjusted analysis controlling for potential confounders, such as baseline seizure frequency. The similarity between the safety profiles of rTMS applied to the population with epilepsy and to individuals without epilepsy supports further investigation of rTMS as a therapy for seizure suppression.

Source: Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: A systematic review – Epilepsy & Behavior

, , , , ,

Leave a comment

%d bloggers like this: