Americans spend billions of dollars each year on antidepressants, but the National Institutes of Health estimates that those medications work for only 60 percent to 70 percent of people who take them. In addition, the number of people with depression has increased 18 percent since 2005, according to the World Health Organization, which this year launched a global campaign encouraging people to seek treatment.
The Semel Institute for Neuroscience and Human Behavior at UCLA is one of a handful of hospitals and clinics nationwide that offer a treatment that works in a fundamentally different way than drugs. The technique, transcranial magnetic stimulation, beams targeted magnetic pulses deep inside patients’ brains — an approach that has been likened to rewiring a computer.
TMS has been approved by the FDA for treating depression that doesn’t respond to medications, and UCLA researchers say it has been underused. But new equipment being rolled out this summer promises to make the treatment available to more people.
“We are actually changing how the brain circuits are arranged, how they talk to each other,” said Dr. Ian Cook, director of the UCLA Depression Research and Clinic Program. “The brain is an amazingly changeable organ. In fact, every time people learn something new, there are physical changes in the brain structure that can be detected.”
Nathalie DeGravel, 48, of Los Angeles had tried multiple medications and different types of therapy, not to mention many therapists, for her depression before she heard about magnetic stimulation. She discussed it with her psychiatrist earlier this year, and he readily referred her to UCLA.
Within a few weeks, she noticed relief from the back pain she had been experiencing; shortly thereafter, her depression began to subside. DeGravel says she can now react more “wisely” to life’s daily struggles, feels more resilient and is able to do much more around the house. She even updated her resume to start looking for a job for the first time in years.
During TMS therapy, the patient sits in a reclining chair, much like one used in a dentist’s office, and a technician places a magnetic stimulator against the patient’s head in a predetermined location, based on calibrations from brain imaging.
The stimulator sends a series of magnetic pulses into the brain. People who have undergone the treatment commonly report the sensation is like having someone tapping their head, and because of the clicking sound it makes, patients often wear earphones or earplugs during a session.
TMS therapy normally takes 30 minutes to an hour, and people typically receive the treatment several days a week for six weeks. But the newest generation of equipment could make treatments less time-consuming.
“There are new TMS devices recently approved by the FDA that will allow patients to achieve the benefits of the treatment in a much shorter period of time,” said Dr. Andrew Leuchter, director of the Semel Institute’s TMS clinical and research service. “For some patients, we will have the ability to decrease the length of a treatment session from 37.5 minutes down to 3 minutes, and to complete a whole course of TMS in two weeks.”
Leuchter said some studies have shown that TMS is even better than medication for the treatment of chronic depression. The approach, he says, is underutilized.
“We are used to thinking of psychiatric treatments mostly in terms of either talk therapies, psychotherapy or medications,” Leuchter said. “TMS is a revolutionary kind of treatment.”
Bob Holmes of Los Angeles is one of the 16 million Americans who report having a major depressive episode each year, and he has suffered from depression his entire life. He calls the TMS treatment he received at UCLA Health a lifesaver.
“What this did was sort of reawaken everything, and it provided that kind of jolt to get my brain to start to work again normally,” he said.
Doctors are also exploring whether the treatment could also be used for a variety of other conditions including schizophrenia, epilepsy, Parkinson’s disease and chronic pain.
“We’re still just beginning to scratch the surface of what this treatment might be able to do for patients with a variety of illnesses,” Leuchter said. “It’s completely noninvasive and is usually very well tolerated.”
Orlando Swayne completed a PhD at UCL and a fellowship at the NINDS in the US, investigating mechanisms of post-stroke neuroplasticity. He is a Consultant Neurologist at the National Hospital for Neurology & Neurosurgery (NHNN) on the Neurorehabilitation Unit. He also works as a Neurologist at Northwick Park Hospital and is an Honorary Senior Lecturer at the UCL Institute of Neurology.
Correspondence to: Orlando Swayne, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, UK. Acknowledgments: Orlando received funding from the UCLH Biomedical Research Centre. Conflicts of interest statement: None declared Provenance and peer review: Submitted and externally reviewed. Date submitted: 20/8/17 Date submitted after peer review: 27/10/17 Acceptance date: 9/11/17 To cite: Swayne O. ACNR 2017;17(2):11-13. Published online: 11/12/17
Transcranial Magnetic Stimulation (TMS) is a non-invasive technique whereby an electro-magnetic coil held over the scalp is used to induce a brief electrical current in the cortex of the underlying brain. TMS may be used in a number of ways to gain in vivo insights into brain physiology and has provided a window into the cascade of physiological changes that occur following stroke. When stimulating the primary motor cortex in a healthy subject stimuli of an intensity above the motor threshold will give rise to a detectable evoked potential in a peripheral muscle. As the stimulus intensity is gradually increased the evoked potentials increase in amplitude up to a maximum, giving rise to a measurable recruitment curve. The motor threshold and the recruitment curve both provide measures of the excitability of the corticospinal tract. This incorporates the excitability of axons within the motor cortex, synaptic inputs onto pyramidal cells and the spinal alpha motor neuron pool. In paired pulse TMS a sub-threshold pulse is delivered a few milliseconds before a second suprathreshold pulse, both through the same coil. The first pulse conditions the response to the second, resulting in inhibition or facilitation depending upon the inter-stimulus interval and reflecting the activity in intracortical regulatory circuits. If two separate TMS coils are used then one may use a similar test-conditioning approach to explore inter-regional interactions, such as interhemispheric inhibition between the two primary motor cortices (Figure 1). Alternatively pulses may be delivered during a motor task, and the resulting effect on behaviour used to infer the stimulated region’s role in task performance, for example during a simple reaction time or movement selection task. See Reis et al1 for a summary of these techniques and their physiological basis.
Figure 1. TMS measures of motor cortical physiology. a) Eliciting a Motor Evoked Potential (MEP) from the primary motor cortex, b) Measures of corticospinal tract excitability, c) Using paired pulse stimulation to measure Intracortical inhibition, d) Using two TMS coils to measure Interhemispheric Inhibition.
Paired pulse measures have fairly reliably shown reduced inhibitory activity in the intracortical circuits after stroke. Such apparent disinhibition is hard to interpret in the stroke hemisphere, as these measures depend upon an unconditioned evoked potential of reasonable amplitude which may not be available or may require high stimulus intensities. However no such technical issue affects the intact hemisphere, and the absence or reduction of inhibition when tested in the contralesional primary motor cortex suggests a reduction in the tonic level of GABA-ergic inhibitory activity in intracortical circuits that extends far beyond the site of the stroke. In one study such intracortical disinhibition of the non-stroke hemisphere was seen in patients with cortical but not subcortical infarction,5 suggesting that this phenomenon may relate to interruption of the transcallosal projection between the motor cortices. Few longitudinal studies of intra-cortical excitability have been performed but on the basis of the data available it seems that in the acute period disinhibition is seen regardless of clinical status, but that by three months it has resolved in those patients with a better clinical outcome, such that a clinical–physiological correlation emerges at around that time.6 A recent meta-analysis of TMS studies has shown no overall abnormality of excitability in the intact hemisphere:7 however if disinhibition were seen only in more severely affected patients then one may see clinical correlation without a group effect.
It is recognised that in healthy humans there is tonic inhibition of each hemisphere by its opposite, a situation that is likely to be important in the generation of unimanual versus bimanual movements. When this inter-hemispheric interaction is measured at rest with two TMS coils using a paired pulse conditioning approach there is robust inhibition. When tested in healthy subjects during a reaction time paradigm the baseline inhibition disappears or reverses as the onset of movement approaches. Murase and colleagues8 found that such switching-off of interhemispheric inhibition was impaired in stroke patients, and that the extent of residual interhemispheric inhibition was greater in more severely affected patients. This result has been interpreted as suggesting that after stroke there is an imbalance of such interhemispheric interactions, with pathological inhibition of the recovering stroke hemisphere by the non-stroke hemisphere.
Interpretation of the physiological changes observed after stroke remains a matter of debate. TMS as a technique operates at the level of the whole system, drawing inferences from the effect of manipulations on the overall corticospinal output, but the pathological changes observed may be the result of dysfunction at one or more of several levels. These may include the effects of cytotoxic changes on local neurochemistry, altered inhibitory vs excitatory synaptic activity, or diaschisis due to disruption of inter-regional tracts. The TMS finding of wide- spread intracortical disinhibition is in keeping with MR Spectroscopy studies that show reduced cortical GABA content during this period after stroke.9 A rapid reduction in GABA is also seen in healthy humans as a response to motor training or to experimental deafferentation of one arm by ischaemic nerve block, which likewise causes intracortical disinhibition as assessed by TMS. In those contexts it is felt that such disinhibition creates a more favourable environment for synaptic plasticity to occur, and it is tempting to conclude that the same is occurring in the post-stroke period as a way of driving reorganisation of the motor output. It is also conceivable that disinhibition allows cortical regions that are disconnected from their usual corticospinal output projection to access instead the horizontal cortico-cortical connections that are prevalent in cortical layers 2 and 3, thereby reaching an alternative output projection. Such a phenomenon would allow for the shifts in cortical motor output maps that are well documented after stroke.10 In one longitudinal study the correlation between disinhibition and clinical status was strong at three months but then became weaker in the chronic phase.6 We interpreted this as suggesting that ongoing disinhibition becomes less important for motor function as the reorganised motor network becomes better established with time. Direct evidence for such a process is lacking however, and some would argue that disinhibition is an epiphenomenon rather than an adaptive response to injury. This alternative conclusion would be supported by the observation that reduced intracortical inhibition as measured by paired pulse TMS may be observed in other pathological states, including dystonia and Attention Deficit Hyperactivity Disorder.
The concept of an imbalance between the two hemispheres and of excessive interhemispheric inhibition of the stroke hemisphere has gained a lot of traction and has provided the rationale for therapeutic approaches that aim to redress it. Non-invasive brain stimulation, either by repetitive TMS or transcranial direct current stimulation (tDCS), can induce measurable changes in cortical excitability that outlast the period of stimulation. Depending on the stimulation paradigm used one can induce either increases or reductions lasting minutes or in some cases hours. The most common approaches are either to apply excitatory stimulation to the stroke hemisphere or alternatively inhibitory stimulation to the non-stroke hemisphere (Figure 2), the aim being to enhance the response to conventional therapy by stimulating either before or during treatment. The concept of an overactive non-stroke hemisphere resonates with the widely reproduced functional imaging finding of increased movement-related brain activation on that side in more severely affected patients, which may normalise as clinical recovery progresses.6
Figure 2. The interhemispheric rivalry model, whereby the intact hemisphere exerts a pathological degree of interhemispheric inhibition on the stroke hemisphere and hinders motor function in the paretic limb. This has given rise to the therapeutic strategies of either increasing excitability in the stroke hemisphere or reducing it in the intact hemisphere.
It is by no means clear however that this contralesional activity is the same phenomenon as that which generates pathological inhibition of the recovering hemisphere, or that it is necessarily maladaptive. There is evidence that at least some regions on the non-stroke side may support movement of the paretic side, such as the contralesional dorsal premotor cortex which displays increased functional connectivity to the primary motor cortex of the stroke in more affected patients and appears to support hand movement.11,12Furthermore a recent study suggested that reducing intact hemisphere excitability may in fact be detrimental to upper limb function in more impaired patients.3
As the role of contralesional brain regions in movement appears to differ depending upon factors such as clinical severity, extent of corticospinal tract disruption and possibly stroke location it would seem that reducing excitability on that side equally in all stroke patients may represent rather a blunt therapeutic approach. This is especially true of tDCS, whose effects incorporate most of the stimulated hemisphere. However, positive studies may be found in the literature for both repetitive TMS and tDCS when applied to either side of the brain (sometimes both), and although a comprehensive review of the outcomes is beyond the scope of this article the most promising approach appears to be inhibition of the non-stroke hemisphere by tDCS.13 Non-invasive brain stimulation has not as yet entered routine clinical practice however, and there are a number of reasons why this may be, such as the large number of stimulation protocols available and uncertainty regarding the optimal time to apply stimulation. However, for the reasons discussed above it is important to consider the heterogeneity of the clinical syndrome when designing further trials. Opinions differ as to whether progress will be made using a ‘one size fits all’ design, the hope being that larger sample sizes will take care of heterogeneity, or alternatively whether targeting stimulation according to clinical and physiological factors would have a greater chance of success. This is likely to be worth getting right, as a large negative study would present an obstacle to further investigation in this field. It is likely to be the case that applying brain stimulation to the right patients could significantly enhance the outcome of post-stroke rehabilitation, with a clinically meaningful reduction in resulting impairment and disability.
Reis J, Swayne OB, Vandermeeren Y, Camus M, Dimyan MA, Harris-Love M, Perez MA, Ragert P, Rothwell JC, Cohen LG. Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control. J Physiol 2008; 586(2):325-51.
Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional Potential in chronic stroke patients depends on corticospinal tract integrity. Brain 2007;130:170-180.
Bradnam LV, Stinear CM, Barber PA, Byblow WD. Contralesional hemisphere control of the proximal paretic upper limb following stroke. Cereb Cortex. 2012 Nov;22(11):2662-71.
Traversa R, Cicinelli P, Pasqualetti P, Filippi M, Rossini PM. Follow-up of interhemispheric differences of motor evoked potentials from the ‘affected’ and ‘unaffected’ hemispheres in human stroke. Brain Research 1998; 803:1-8.
Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 2002; 113:936-943.
Swayne OB, Rothwell JC, Ward NS, Greenwood RJ. Stages of Motor Output Reorganization after Hemispheric Stroke Suggested by Longitudinal Studies of Cortical Physiology. Cereb Cortex 2008; 18:1909- 1922.
McDonnell MN, Stinear CM. TMS measures of motor cortex function after stroke: A meta-analysis. Brain Stimul. 2017 Jul – Aug;10(4):721-734.
Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 2004; 55:400-409.
Blicher JU, Near J, Næss-Schmidt E, Stagg CJ, Johansen-Berg H, Nielsen JF, Østergaard L, Ho YC. GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement. Neurorehabil Neural Repair 2015 Mar-Apr;29(3):278-86.
Delvaux V, Alagona G, Gerard P, De Pasqua V, Pennisi G, de Noordhout AM. Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clin Neurophysiol 2003; 114:1217-1225
Bestmann S, Swayne O, Blankenburg F, Ruff CC, Teo J, Weiskopf N, Driver J, Rothwell JC, Ward NS. The role of contralesional dorsal premotor cortex after stroke as studied with concurrent TMS-fMRI. J Neurosci 2010; 30(36):11926-37.
Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A 2002; 99:14518- 14523.
Kang N, Summers JJ, Cauraugh JH. Transcranial direct current stimulation facilitates motor learning post- stroke: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2016 Apr;87(4):345-55.
Stroke is a leading cause of disability. Alternative and more effective techniques for stroke rehabilitation have been sought to overcome limitations of conventional therapies. Repetitive transcranial magnetic stimulation (rTMS) arises as a promising tool in this context. This systematic review aims to provide a state of the art on the application of rTMS in stroke patients and to assess its effectiveness in clinical rehabilitation of motor function.
Studies included in this review were identified by searching PubMed and ISI Web of Science. The search terms were (rTMS OR “repetitive transcranial magnetic stimulation”) AND (stroke OR “cerebrovascular accident” OR CVA) AND (rehab OR rehabilitation OR recover*). The retrieved records were assessed for eligibility and the most relevant features extracted to a summary table.
Seventy out of 691 records were deemed eligible, according to the selection criteria. The majority of the articles report rTMS showing potential in improving motor function, although some negative reports, all from randomized controlled trials, contradict this claim. Future studies are needed because there is a possibility that a bias for non-publication of negative results may be present.
rTMS has been shown to be a promising tool for stroke rehabilitation, in spite of the lack of standard operational procedures and harmonization. Efforts should be devoted to provide a greater understanding of the underlying mechanisms and protocol standardization.
Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.
Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are the most commonly used methods of non-invasive transcranial brain stimulation that has been abbreviated by previous authors as either as NIBS or NTBS. Here we use NIBS since it seems to be the most common term at the present time. When it was first introduced in 1985, TMS was employed primarily as a tool to investigate the integrity and function of the human corticospinal system (Barker et al., 1985). Single pulse stimulation was used to elicit motor evoked potentials (MEPs) that were easily evoked and measured in contralateral muscles (Rothwell et al., 1999). The robustness and repeatability of measures of conduction time, stimulation threshold and “hot spot” location allowed TMS to be developed into a standard tool in clinical neurophysiology.
As we review below, a number of NIBS protocols can lead to effects on brain excitability that outlast the period of stimulation. These may reflect basic synaptic mechanisms involving long-term potentiation (LTP)- or long-term depression (LTD)-like plasticity, and because of this there has been great interest in using the methods as therapeutic interventions in neurological and psychiatric diseases. Furthermore, recently they are more frequently applied to modify memory processes and to enhance cognitive function in healthy individuals. However, apart from success in treating some patients with depression (Lefaucheur et al., 2014; Padberg et al., 2002, 1999), there is little consensus that they have improved outcomes in a clinically meaningful fashion in any other conditions. The reason for this is probably linked to the reason why many other protocols failed to reach routine clinical neurophysiology: they are too variable both within and between individuals to make them practically useful in a health service setting (Goldsworthy et al., 2014; Hamada et al., 2013; Lopez-Alonso et al., 2014, 2015).
Below we review the evidence for the mechanisms underlying the “neuroplastic” effects of NIBS, and then consider the problems in reproducibility and offer some potential ways forward in research. […]
Fig. 1. There are three major lines of evidence supporting NIBS produces effects through mechanisms of synaptic plasticity: (1) Drugs that modulate the function of critical receptors/channels for plasticity, e.g. Ca2+ channels and NMDA receptors, alter the effect of NIBS; (2) NIBS mainly changes I-waves rather than the D-wave in the epidural recording of descending volleys evoked by TMS, suggesting the effect of NIBS occurs trans-synaptically; and (3) NIBS interacts between protocols and with motor practice and cognitive learning processes, suggesting the effect of NIBS is involves in plasticity-related motor and psychological processes.
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). […]
Fig. 4. Neural activity when patients and controls moved the affected or unaffected hand. Fist closures were conducted at a fixed movement frequency of 0.8 Hz and at a frequency adjusted to individual performance levels. Compared to controls, patients featured enhanced activity in both hemispheres during movements of the affected hand. Movements of the unaffected hand yielded a similar activation pattern in patients and controls. T-values are represented by the color bar. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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.
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.
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).
•Spasticity can cause a severe disability and challenge the rehabilitation process.
•A successful treatment of spasticity depends on a pathophysiologic assessment.
•The main therapeutic options include physiotherapy and pharmacological treatments.
•Non-pharmacologic approaches may reduce spasticity and improve quality of life.
The present paper aims at providing an objective narrative review of the existing non-pharmacological treatments for spasticity. Whereas pharmacologic and conventional physiotherapy approaches result well effective in managing spasticity due to stroke, multiple sclerosis, traumatic brain injury, cerebral palsy and incomplete spinal cord injury, the real usefulness of the non-pharmacological ones is still debated. We performed a narrative literature review of the contribution of non-pharmacological treatments to spasticity management, focusing on the role of non-invasive neurostimulation protocols (NINM). Spasticity therapeutic options available to the physicians include various pharmacological and non-pharmacological approaches (including NINM and vibration therapy), aimed at achieving functional goals for patients and their caregivers. A successful treatment of spasticity depends on a clear comprehension of the underlying pathophysiology, the natural history, and the impact on patient’s performances. Even though further studies aimed at validating non-pharmacological treatments for spasticity should be fostered, there is growing evidence supporting the usefulness of non-pharmacologic approaches in significantly helping conventional treatments (physiotherapy and drugs) to reduce spasticity and improving patient’s quality of life. Hence, non-pharmacological treatments should be considered as a crucial part of an effective management of spasticity.
Spasticity can cause a severe disability and challenge the rehabilitation process.
A successful treatment of spasticity depends on a pathophysiologic assessment.
The main therapeutic options include physiotherapy and pharmacological treatments.
Non-pharmacologic approaches may reduce spasticity and improve quality of life.
The present paper aims at providing an objective narrative review of the existing non-pharmacological treatments for spasticity. Whereas pharmacologic and conventional physiotherapy approaches result well effective in managing spasticity due to stroke, multiple sclerosis, traumatic brain injury, cerebral palsy and incomplete spinal cord injury, the real usefulness of the non-pharmacological ones is still debated.
We performed a narrative literature review of the contribution of non-pharmacological treatments to spasticity management, focusing on the role of non-invasive neurostimulation protocols (NINM). Spasticity therapeutic options available to the physicians include various pharmacological and non-pharmacological approaches (including NINM and vibration therapy), aimed at achieving functional goals for patients and their caregivers. A successful treatment of spasticity depends on a clear comprehension of the underlying pathophysiology, the natural history, and the impact on patient’s performances.
Even though further studies aimed at validating non-pharmacological treatments for spasticity should be fostered, there is growing evidence supporting the usefulness of non-pharmacologic approaches in significantly helping conventional treatments (physiotherapy and drugs) to reduce spasticity and improving patient’s quality of life.
Hence, non-pharmacological treatments should be considered as a crucial part of an effective management of spasticity.
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.