Posts Tagged rTMS
[Abstract] Virtual reality and non-invasive brain stimulation in stroke: How effective is their combination for upper limb motor improvement?
[ARTICLE] Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients – Full Text
Multimodal assessment of motor system integrity for predicting iTBS-aftereffects
Effective connectivity of M1 predicts behavioral iTBS-aftereffects
No association between iTBS-aftereffects and BOLD activity or RMT/AMT/SICI
Effects of brain stimulation strongly influenced by connectivity of stimulated region
Cerebral plasticity-inducing approaches like repetitive transcranial magnetic stimulation (rTMS) are of high interest in situations where reorganization of neural networks can be observed, e.g., after stroke. However, an increasing number of studies suggest that improvements in motor performance of the stroke-affected hand following modulation of primary motor cortex (M1) excitability by rTMS shows a high interindividual variability. We here tested the hypothesis that in stroke patients the interindividual variability of behavioral response to excitatory rTMS is related to interindividual differences in network connectivity of the stimulated region. Chronic stroke patients (n = 14) and healthy controls (n = 12) were scanned with functional magnetic resonance imaging (fMRI) while performing a simple hand motor task. Dynamic causal modeling (DCM) was used to investigate effective connectivity of key motor regions. On two different days after the fMRI experiment, patients received either intermittent theta-burst stimulation (iTBS) over ipsilesional M1 or control stimulation over the parieto-occipital cortex. Motor performance and TMS parameters of cortical excitability were measured before and after iTBS. Our results revealed that patients with better motor performance of the affected hand showed stronger endogenous coupling from supplemental motor area (SMA) onto M1 before starting the iTBS intervention. Applying iTBS to ipsilesional M1 significantly increased ipsilesional M1 excitability and decreased contralesional M1 excitability as compared to control stimulation. Individual behavioral improvements following iTBS specifically correlated with neural coupling strengths in the stimulated hemisphere prior to stimulation, especially for connections targeting the stimulated M1. Combining endogenous connectivity and behavioral parameters explained 82% of the variance in hand motor performance observed after iTBS. In conclusion, the data suggest that the individual susceptibility to iTBS after stroke is influenced by interindividual differences in motor network connectivity of the lesioned hemisphere.
Recovery of function after stroke is driven by reorganization of neural networks in both the lesioned and unaffected hemispheres (Cramer, 2008). However, spontaneous recovery after stroke often remains incomplete (Kolominsky-Rabas et al., 2006). One strategy to improve the functional outcome of patients suffering from brain lesions is to modulate cerebral plasticity by means of non-invasive brain stimulation such as, e.g., repetitive transcranial magnetic stimulation (rTMS) (Ridding and Rothwell, 2007). Although to date a direct proof is missing, increasing evidence exist that rTMS-effects are mediated by changes in synaptic transmission (Funke and Benali, 2011 ; Hoogendam et al., 2010). One specific strategy to ameliorate motor impairments in stroke patients is to enhance cortical excitability of the motor cortex in the lesioned hemisphere (Khedr et al., 2005). An effective protocol of rTMS to induce such increase in excitability of the motor cortex following a relatively short (i.e., 3.5 min) stimulation period is intermittent theta-burst stimulation (iTBS) (Huang et al., 2005).
Consequently, proof-of-principle studies have been able to demonstrate that iTBS applied to ipsilesional M1 improve hand motor function in stroke patients (Ackerley et al., 2010; Hsu et al., 2012 ; Talelli et al., 2007b). A major issue, however, with rTMS (including iTBS) induced cerebral plasticity is high inter-individual variability of the effects induced in both healthy subjects (Daskalakis et al., 2006; Hamada et al., 2013 ; Muller-Dahlhaus et al., 2008) and stroke patients (Ameli et al., 2009 ; Grefkes and Fink, 2012). For example, Hamada et al. (2013) demonstrated that application of iTBS in healthy subjects leads to an increase of motor-cortical excitability in only 52% subjects, while the other half responded in an opposite way with a decrease of excitability. Likewise, Ameli et al. (2009) reported that in patients suffering from cortical strokes, only half of them showed behavioral improvements after 10 Hz rTMS while the other half even deteriorated with their stroke affected hands. Such opposed stimulation after-effects are likely to contribute to absent overall effects across the entire group (Hamada et al., 2013).
Apart from known sources of response variability following iTBS like age (Freitas et al., 2011), genetic polymorphisms of the brain-derived neurotrophic factor (Cheeran et al., 2008 ; Kleim et al., 2006) and technical aspects such as the direction of current flow, the intensity of stimulation and the number of pulses applied (Gamboa et al., 2010; Gentner et al., 2008 ; Talelli et al., 2007a), clinical factors like lesion location, degree of neurological impairment and time since stroke are also likely to impact on the response to rTMS (Grefkes and Fink, 2012). For example, several studies demonstrated that patients with subcortical lesions have a higher probability to improve after rTMS than patients with cortical lesions (Ameli et al., 2009 ; Hsu et al., 2012). Moreover, the pathomechanisms underlying stroke-induced motor deficits do not only depend on direct tissue damage due to ischemia, but might also comprise network disturbances remote from the stroke lesion (Grefkes and Fink, 2011 ; Grefkes and Fink, 2014). Thus, changes in network interactions are likely to constitute another important factor for the evolution of rTMS-aftereffects as TMS does not only interfere with neural tissue of the stimulated hemisphere but also with neural activity levels of regions that are interconnected with the stimulation site (Bestmann et al., 2005).
Hence, there is good reason to assume that specific inter-individual differences (or abnormalities post-stroke) in network connectivity might – at least in part – influence response to rTMS. Support for this hypothesis stems from studies with patients suffering from dystonia in which reduced functional connectivity between premotor cortex and M1 was indicative for responding to rTMS (Huang et al., 2010 ; Quartarone et al., 2003). Furthermore, changes in motor-evoked potential (MEP) amplitudes following rTMS have been shown to be associated with higher effective connectivity between supplementary motor area (SMA), ventral premotor cortex (vPMC) and M1 of the stimulated hemisphere (Cardenas-Morales et al., 2014).
Therefore, in stroke patients, the variability of the individual response to plasticity-inducing intervention might depend on how the stimulation interacts with the pre-existing connectivity in a given functional network, e.g., the motor system. In order to identify factors that are associated with a positive behavioral effect in response to intermittent theta burst stimulation (here: iTBS) applied to ipsilesional M1, we used a multimodal approach consisting of clinical scales, electrophysiological parameters measured using single- and paired-pulse TMS, as well as functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess effective connectivity of the cortical motor network. We reasoned that the systems level perspective offered by DCM might be useful for identifying predictors that indicate whether or not a patient will respond to non-invasive brain stimulation given that (i) focal brain stimulation also impacts on activity levels of areas connected to the stimulation site (Bestmann et al., 2003 ; Grefkes et al., 2010) and (ii) recovery of motor function depends on changes in the entire motor network rather than changes in M1 only (Rehme et al., 2012 ; Ward et al., 2003). Here, especially the coupling strengths between ipsilesional M1 and premotor areas might be indicative for the behavioral after-effect of iTBS given the role of these connections in motor performance in both healthy subjects and stroke (Pool et al., 2013; Pool et al., 2014 ; Rehme et al., 2011a). […]
[Abstract] Effects of low-frequency repetitive transcranial magnetic stimulation and neuromuscular electrical stimulation on upper extremity motor recovery in the early period after stroke: a preliminary study
Objective: To assess the efficacy of inhibitory repetitive transcranial magnetic stimulation (rTMS) and neuromuscular electrical stimulation (NMES) on upper extremity motor function in patients with acute/subacute ischemic stroke.
Methods: Twenty-five ischemic acute/subacute stroke subjects were enrolled in this randomized controlled trial. Experimental group 1 received low frequency (LF) rTMS to the primary motor cortex of the unaffected side + physical therapy (PT) including activities to improve strength, flexibility, transfers, posture, balance, coordination, and activities of daily living, mainly focusing on upper limb movements; experimental group 2 received the same protocol combined with NMES to hand extensor muscles; and the control group received only PT. Functional magnetic resonance imaging (fMRI) scan was used to evaluate the activation or inhibition of the affected and unaffected primary motor cortex.
Results: No adverse effect was reported. Most of the clinical outcome scores improved significantly in all groups, however no statistically significant difference was found between groups due to the small sample sizes. The highest percent improvement scores were observed in TMS + NMES group (varying between 48 and 99.3%) and the lowest scores in control group (varying between 13.1 and 28.1%). Hand motor recovery was significant in both experimental groups while it did not change in control group. Some motor cortex excitability changes were also observed in fMRI.
Conclusion: LF-rTMS with or without NMES seems to facilitate the motor recovery in the paretic hand of patients with acute/subacute ischemic stroke. TMS or the combination of TMS + NMES may be a promising additional therapy in upper limb motor training. Further studies with larger numbers of patients are needed to establish their effectiveness in upper limb motor rehabilitation of stroke.
Source: Effects of low-frequency repetitive transcranial magnetic stimulation and neuromuscular electrical stimulation on upper extremity motor recovery in the early period after stroke: a preliminary study: Topics in Stroke Rehabilitation: Vol 24, No 5
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.
- motor function,
- repetitive transcranial magnetic stimulation,
[ARTICLE] The Effects of Navigated Repetitive Transcranial Magnetic Simulation and Brunnstrom Movement Therapy on Upper Extremity Proprioceptive Sense and Spasticity in Stroke Patients: A Double-Blind Randomized Trial – Full Text PDF
Purpose: The purpose of this study is to investigate the effects of various treatments (repetitive transcranial magnetic stimulation and Brunnstrom movement therapy) on upper extremity proprioceptive sense and spasticity.
Methods: Twenty-one stroke patients were included in the study. The treatment group (Group 1; n=10) was administered navigated real repetitive transcranial magnetic stimulation (rTMS), and the control group (Group 2; n=11) was administered sham rTMS by the first researcher. The patients in both groups had upper extremity exercises according to Brunnstrom movement therapy (BMT). The patients were assessed using the Brunnstrom recovery stages (BRS), proprioceptive sense assessment, and the modified Ashworth scale (MAS).
Results: Between the treatment group and control group patients, there were no significant statistical differences obtained from pre-treatment and postreatment tenth day, first month, and third month by BRS wrist, hand, and upper extremity stages. The intragroup comparison of the treatment group patients revealed a statistically significant difference between the pre-treatment and post-treatment third month BRS-hand and BRS-upper extremity stages.The pretreatment and postreatment tenth day and first month evaluations of the wrist proprioceptive sense of the groups presented a significant difference. There was no statistically significant difference between the groups in terms of MAS scores before and after treatment evaluations.
Conclusion: The rTMS and BMT approaches that were implemented in the study affected the proprioceptive sense of the wrist after the treatment and in the early period but did not change spasticity.
Keywords: Repetitive transcranial magnetic stimulation, stroke, Brunnstrom recovery stages, proprioceptive sense, spasticity
Proprioceptive sense is the individual’s ability to perceive the position and the motion of his/her body segments in the space via somatosensorial impulses sent by the receptors in the skin, muscles, and joints (1). Researchers have stated that the proprioceptive sense, which is the awareness sense of the body, consists of three fundamental senses: kinesthesia, joint position sense, and neuromuscular control (2). The proprioceptive sense plays a crucial role in carrying out and controlling daily activities, maintaining posture and balance, joint stability, and motor learning (3, 4). Neuromuscular control is affected by proprioceptive inefficiencies apart from motor dysfunctions. It has been shown that proprioceptive knowledge is of extreme importance for the neural control of motion and that the upper extremity proprioceptive sense is commonly decreased or evanished following stroke (5). It has been explained that the proprioceptive deficit incidence rate is 50-65% in stroke patients, which affects daily activities and quality of life negatively (6, 7). It has been stated that proprioceptive and motor deficits have different recovery rates in the first six months following stroke (8). In stroke patients, sensorimotor learning calls for a sound somatosensorial impulse, which is possible through sensorimotor rehabilitation (9). The Bobath, Brunnstrom, Johnstone, and Rood proprioceptive neuromuscular facilitation techniques and the motor learning method, commonly utilized by physiotherapists, are based upon treating sensorimotor functions (10). There exist several recent studies that report that the pain-free, non-invasive transcranial magnetic stimulation (rTMS) application decreases spasticity or that it has no effect (11-13). Stroke rehabilitation is provided by decreasing the transcallosal inhibition from the unaffected motor cortex to the affected motor cortex via 1 Hz rTMS applied on the motor cortex (14, 15). Whereas there is a limited number of studies in the literature with various results on the effects of rTMS and physiotherapy combination on spasticity, a study dealing with the effect of rTMS and physiotherapy combination on proprioceptive sense has not been found. This study was planned to investigate the effect of rTMS and Brunnstrom movement therapy (BMT) on upper extremity proprioceptive sense and spasticity (11, 12).
This narrative review aims to provide an objective view of the non-invasive neuromodulation (NINM) protocols available for treating spasticity, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). On the basis of the relevant randomized controlled trials, we infer that NINM is more effective in reducing spasticity when combined with the conventional therapies than used as a stand-alone treatment. However, the magnitude of NINM aftereffects depends significantly on the applied hemisphere and the underlying pathology. Being in line with these arguments, low-frequency rTMS and cathodal-tDCS over the unaffected hemisphere are more effective in reducing spasticity than high-frequency rTMS and anodal-tDCS over the affected hemisphere in chronic post-stroke. However, most of the studies are heterogeneous in the stimulation setup, patient selection, follow-up duration, and the availability of the sham operation. Therefore, the available data on the usefulness of NINM in reducing spasticity need to be confirmed by further larger and multicentric randomized controlled trials to gather evidence on the efficiency of NINM regimens in reducing spasticity in various neurologic conditions.
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.
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.
[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