Restorative Neurology and Neuroscience

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of stimulating the brain that changes excitability at the site of stimulation as well as at distant anatomically connected sites. Since the effects can outlast the period of stimulation for minutes or hours and are thought to be depend, at least in part, on changes in the efficiency of synaptic connections in the cortex, the method has generated much interest as a potential therapeutic intervention in a wide range of neurological and psychiatric conditions. A symposium on brain stimulation and brain recovery was held in Greifswald (Germany) in 2010 to exchange of state-of-the-art knowledge about rTMS effects from animal experiments to clinical trials in conditions such as stroke, Parkinson disease, and depression. There was enormous interest in the effects of rTMS and signs of therapeutic success in mainly small clinical trials. However, it was also clear that some of our models of the effects of rTMS, such as upregulation or downregulation of specific brain areas may need further development if they are to account for all the observations that have been made so far. The results of the symposium are made available by lab reviews of members of the symposium's faculty. This editorial provides an overview.

Transcranial magnetic stimulation (TMS) can be used in two different ways to manipulate cortical information processing, either by applying a single pulse around the time point of expected task processing or by persistently shifting cortical excitability by repetitive stimulation (rTMS). Single pulses applied when specific cortical processing takes place always impair cortical function due to increased noise or enhanced inhibition, both resulting in decreased signal-to-noise ratio, while repetitive stimulation may allow to weaken or improve cortical processing depending on the type of stimulation. The opposite effects of low- (∼1 Hz) and high-frequency rTMS (5–20 Hz), as well as the opposing effects of continuous versus intermittent theta-burst trains, lowering or raising cortical excitability respectively, have mainly been attributed to synaptic plasticity. As reviewed in this article, in a series of electrophysiological, immunohistochemical and molecular-biological animal experiments we obtained evidence for modulation of inhibitory cortical activity as a further reason of changing cortical excitability following rTMS.

A new patterned repetitive transcranial magnetic stimulation (rTMS) protocol, quadripulse stimulation (QPS), can produce a broad range of motor cortical plasticity ranging from MEP suppression to MEP facilitation depending on the interval of the pulses within a burst. In addition to inducing lasting cortical plastic changes, QPS can also be used to evaluate priming effects: when used as a priming stimulation, which does not induce an LTP- or LTD-like phenomena itself, it can nevertheless change the threshold for LTP- or LTD-like plasticity caused by a consecutive stimulation. This enables us to examine metaplasticity theory in more details in humans. Another application of QPS might be to induce symptomatic relief in patients with neurological or psychiatric disorders, such as Parkinson's disease, depression, or intractable pain.

Repetitive Transcranial Magnetic Stimulation (rTMS) paradigms are showing increasing promise as tools for neurorehabilitation in a variety of chronic neurological and psychiatric conditions. However, the mechanisms by which they modulate cortical activation are still not completely understood. In this review we summarize what non-invasive magnetic resonance imaging techniques can tell us about the cortical effects of rTMS – from changes at a cellular level within the stimulated motor cortex, to modulating activation patterns within the wider motor network. We discuss how variation in these effects in stroke patients may inform our understanding of how rTMS could improve function in these patients.

Background: Disruption of a cortical region can paradoxically improve behavior. After unilateral damage to the primary motor cortex (M1), increased excitability of the unaffected M1 has been shown. The M1 plays a critical role in motor performance and also early aspects of motor skill learning. Repetitive transcranial magnetic stimulation (rTMS) of one motor cortex can lead a temporary reduction in cortical excitability. We hypothesize that unilateral suppression of one M1 by rTMS may increase excitability of the unaffected motor cortex and thus improve motor performance and motor skill learning with the ipsilateral hand by releasing the contralateral motor cortex from transcallosal inhibition.

Methods: Forty healthy volunteers participated in our study; 16 for the experiment I and 24 for the experiment II. In the experiment I, after practicing a sequential simple key-pressing task with the index finger, their motor performance was monitored before and after slow-frequency (1Hz) rTMS, applied on the M1 ipsilateral or contralateral to the hand, ipsilateral premotor area or vertex (Cz). In the experiment II, participants were randomly divided into three stimulation groups: i) ipsilateral M1; ii) contralateral M1; and iii) Cz. rTMS was applied before the initiation of practice and learning of a simple motor skill. Mean execution time and error rate were recorded in 4 sessions distributed over 2 days.

Results: In experiment I: rTMS of M1 shortened execution time of the motor task with the ipsilateral hand, without affecting performance with the contralateral hand. This effect outlasted rTMS by at least 10 min, and was most prominent for M1 stimulation. In experiment II, disruption of M1 with rTMS slowed down skill acquisition with the contralateral hand, but paradoxically accelerated learning with the ipsilateral hand. This effect was evident during the first of 2 days of practice in the group with rTMS over the ipsilateral M1 compared to the other two groups (Cz and contralateral M1).

Conclusions: Our results support the notion of an interhemispheric competition, and demonstrate the utility of rTMS to explore the functional facilitation of the un-stimulated counterpart M1 with effects on motor execution and learning, which may have implications for neurorehabilitation.

Repetitive electrical stimulation has been applied to induce long-term changes in synaptic strength in animal preparations. It is generally believed that such changes in synapses form the basis of neural plasticity. Recently, several techniques, including repetitive transcranial magnetic stimulation (rTMS), have been developed to attempt to replicate similar plasticity effects in the brains of conscious humans. However, traditional paradigms of rTMS usually require lengthy stimulation and relatively high stimulus intensity. In light of these problems, a novel rTMS paradigm- theta burst stimulation (TBS) – was developed. TBS is able to produce plasticity-like effects more efficiently and powerfully than traditional protocols. The excitability of circuits within the motor cortex can be modified not only by TBS over the primary motor cortex but also when it is delivered to the premotor area. Moreover, TBS over the premotor cortex modifies aspects of spinal reflexes. Studies using TBS over the motor and premotor cortices provide further understanding of dystonia, and the results also distinguish the different mechanisms of the effects of TBS given to the primary motor and premotor cortices. In addition, some data also support the hypothesis that TBS is a potential candidate technique to help restore damaged motor functions through brain stimulation.

Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), can modify cortical excitability in a lasting fashion. The modification can be bi-directional in nature and holds considerable therapeutic promise for a number of neurological conditions. However, the effectiveness of these techniques is currently limited by large intra- and inter-subject variability in the response. A number of factors that contribute to response variability have now been identified, with one of the most important being the history of synaptic activity within the cortical region being targeted by stimulation. In this review we discuss what is currently known about the influence of behaviourally, or experimentally, induced changes in synaptic activity in the cortical (or interconnected) region being targeted by stimulation on the response to rTMS techniques. Understanding such influences is a critical step in the development of effective therapeutic paradigms employing such techniques.

Applying functional lesions using functional magnetic resonance imaging (fMRI)-navigated transcranial magnetic stimulation (TMS) is a powerful method for investigation of the functional relevance of a given activation site for motor performance in healthy individuals, and also for investigation of the temporal interactions of particular areas during movement preparation. In patients with good cognitive compliance, this procedure may be useful for detection of functional reorganisation or to plan individual therapy directions. Different protocols for applying functional lesions are presented here and their relevance and usage in different applications are explained.

Transcranial stimulation of the primary motor cortex (M1) for the treatment of pain has attracted much interest in recent years. Non-invasive low frequency and high frequency repetitive transcranial magnetic stimulation (rTMS) over the M1 was reported to reduce both experimentally induced acute and chronic pain. In this paper we summarize the results of several studies from our laboratory and report the antinociceptive effects of a special rTMS paradigm, theta-burst stimulation (TBS). We have applied excitatory (iTBS) and inhibitory (cTBS) paradigms over two cortical locations (M1 and the primary somatosensory cortex (S1)). As evaluation criteria a pain rating scale and the recording of laser evoked potentials (LEPs) were used. Reduced subjective pain perception after cTBS could be objectified by alterations of LEPs that reflect pain related activations in the pain processing in the operculo-insular and anterior cingulate cortex. The stimulation of S1 had physiological effects (LEPs), but did not induce significant reduction in acute pain perception. We believe that the application of cTBS over M1 in pain research has a great potential and as a method it can contribute to a more efficient manipulation of the brain plasticity for therapeutic purposes, for example in chronic pain. Nevertheless, the effectiveness of other types of TBS paradigms should also be tested.

Visuospatial processing refers to the spatial perception, recognition and analysis of visual input. Human functional brain imaging studies have consistently revealed the involvement of fronto-parietal brain areas during the execution of visuospatial tasks. Just as the execution of these tasks activates fronto-parietal regions in the healthy brain, lesions to those structures, e.g. after stroke or brain injury, cause specific spatial deficits. The most prominent of these is known as spatial neglect. There are several competing theories on the neural mechanisms underlying spatial neglect. Although each of these theories postulates different underlying physiological mechanisms, they all account in their own way for the fact that the prevalence of neglect is much higher following right hemisphere lesions. This makes it difficult to distinguish between the different models at a behavioural level. Until today, it was impossible to empirically address these matters and to provide direct and conclusive empirical evidence in favour of one of the competing theories of spatial neglect. This review article describes the neural correlates of intact visuospatial processing as revealed by non-invasive functional brain imaging studies. It subsequently focuses on the approach of using the non-invasive brain inference technique of transcranial magnetic brain stimulation (TMS) to transiently and reversibly disrupt neural activity in these visuospatial processing-related brain regions. Using this approach, we can now imitate specific spatial deficits and neglect-like symptoms in healthy volunteers. Mimicking and manipulating the spatial deficits following unilateral brain lesions, under controlled experimental conditions, may allow for the development of new therapeutic interventions for parietal stroke patients suffering from real spatial neglect. The perspective is to use non-invasive brain interference to guide and promote functional recovery on a brain-system level in stroke and neglect patients, based on knowledge directly derived from fundamental brain research in healthy volunteers.

Hemispatial neglect – defined as the failure to attend, explore, and act upon the contralesional side of space – is a frequent and disabling neurological syndrome. Interhemispheric rivalry is considered as a major pathophysiological mechanism underlying hemispatial neglect. According to this account, the contralesional, intact hemisphere undergoes a pathological hyperactivity due to a deficient transcallosal inhibition from the damaged hemisphere. This model offers a framework for possible therapeutic interventions with repetitive transcranial magnetic stimulation (rTMS), i.e. a reduction of the pathological hyperactivity with a rTMS protocol that has lasting inhibitory effects. In the present work, we will first review evidence for the interhemispheric rivalry account coming from animals and humans. We will then describe studies showing the possibility to perturb and to restore interhemispheric balance in healthy subjects as a proof of concept for therapeutic rTMS application. Finally, we will consider studies applying rTMS as a therapeutic approach in hemispatial neglect. We conclude that rTMS is a promising approach to reduce the interhemispheric imbalance in neglect patients and to ameliorate symptoms. Newly developed protocols such as Theta Burst Stimulation (TBS) – with short stimulation times and long offline effects – seem to be particularly convenient. However, future studies should assess stimulation effects not only in clinical testing, but also on disability, considering combination with traditional therapies as well.

This review of our research with rTMS to treat aphasia contains four parts: Part 1 reviews functional brain imaging studies related to recovery of language in aphasia with emphasis on nonfluent aphasia. Part 2 presents the rationale for using rTMS to treat nonfluent aphasia patients (based on results from functional imaging studies). Part 2 also reviews our current rTMS treatment protocol used with nonfluent aphasia patients, and our functional imaging results from overt naming fMRI scans, obtained pre- and post- a series of rTMS treatments. Part 3 presents results from a pilot study where rTMS treatments were followed immediately by constraint-induced language therapy (CILT). Part 4 reviews our diffusion tensor imaging (DTI) study that examined white matter connections between the horizontal, midportion of the arcuate fasciculus (hAF) to different parts within Broca's area (pars triangularis, PTr; pars opercularis, POp), and the ventral premotor cortex (vPMC) in the RH and in the LH. Part 4 also addresses some of the possible mechanisms involved with improved naming and speech, following rTMS with nonfluent aphasia patients.

Purpose: Upper limb function is the best predictor of long-term disability after stroke. Despite extensive rehabilitation, recovery of upper limb motor function is frequently incomplete after stroke.

Methods: We review the pertinent literature on functional reorganization within the cerebral motor network after stroke and noninvasive techniques to modulate brain function towards beneficial plasticity.

Results: Direct current stimulation and repetitive transcranial magnetic stimulation are powerful tools to (i) modulate cortical excitability, (ii) induce remote changes within the cortical motor system and (iii) thereby improve upper limb motor function after stroke. Today no relevant side effects have been reported.

Conclusions: Neuromodulation, by means of noninvasive brain stimulation techniques, has been shown to be a safe, feasible and effective method to promote recovery of motor function after stroke. However, several methodological and theoretical issues remain to be addressed in future work.

This review discusses the clinical results that were obtained by applying rTMS in acute and chronic ischemic stroke patients. These studies included only the recovery of motor disability and dysphagia. In summary, two approaches have been used when employing rTMS as a potential therapy for the treatment of stroke. The most direct approach involves applying rTMS directly over the affected hemisphere in an attempt to increase excitability and plasticity of damaged circuits to improve motor function. The second approach has taken advantage of the concept of interhemispheric balance in which damage to the stroke hemisphere is exacerbated by increased inhibition from the intact non-stroke hemisphere. In this case, inhibitory rTMS is applied to the non-stroke hemisphere with the intention of reducing interhemispheric inhibition and restoring the balance of excitation between the motor cortices.The overall procedure remains to be optimized, in particular regarding the number of rTMS sessions, frequency and intensity of stimulation and the exact timing of rTMS application after stroke. Cortical stimulation is an effective method for improving functional recovery of acute and chronic stroke.

Long-term therapy with levodopa and dopamine agonists in Parkinson's disease (PD) patients is complicated by the development of fluctuations in motor response, such as levo-dopa induced dyskinesia (LID). Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently put forward as a possible therapeutic tool able to LID in PD. Trains of 1 Hz rTMS applied either over the supplementary motor area (SMA) or the primary motor cortex (M1) were able to induce a transient reduction in the severity of LID, confirming that an over-activity of these areas plays a crucial role in the pathophysiology of LID. However, repeated sessions of rTMS were not effective in inducing persistent beneficial clinical effects. Functional or metabolic changes have been reported in the cerebellum in studies in PD patients treated with procedures known to alleviate LID, such as deep brain stimulation. Therefore, the effects of rTMS applied over the lateral cerebellum has been recently tested in patients with LID. A two-week course of bilateral cerebellar rTMS induced persistent clinical beneficial effects, reducing peak-dose LID for up to four weeks after the end of the daily stimulation period. These findings demonstrate that rTMS is a potential tool in individuating the best cortical targets and the optimal parameters of stimulation able to improve LID in dyskinetic PD patients.

Looking at novelties and advances in medicine in particular in the treatment of major depressive disorder no principally new antidepressant treatment strategy has been established in clinical routine in the last fifty years. However, regarding the considerable issue of treatment resistance in depression, new therapeutic strategies are urgently required. In this context, repetitive transcranial magnetic stimulation above the dorsolateral prefrontal cortex has been proposed as a potential new treatment option for depression; furthermore, in October 2008 a first rTMS-device (NeuroStar TMS Therapy System™) was approved by the FDA for the treatment of treatment resistant major refractory depression in adults. Yet, despite now nearly two decades of research in this field, no final answer concerning its validity for antidepressant treatment in the clinical practice is given. Numerous studies with small sample sizes and heterogeneous designs have been performed in this field yielding to different results. These were subjected to meta-analyses, assessing the antidepressant effect of rTMS, which are briefly summarized in this article. Further, multicentre-trials with larger numbers of patients were performed, which are presented and critically discussed here in more detail. This short review shall thus provide an overview of the current status of knowledge concerning rTMS in depression and it also provides some recommendations for future research in this field.

Since various studies, including multi-centre studies, investigating the effect of repetitive transcranial magnetic stimulation (rTMS) in depression have shown different results, it is now important to research, which symptoms of depression are most responsive to this kind of non-invasive brain stimulation. Furthermore, an increasing interest of rTMS as a potential tool for treatment of neurological and psychiatric disorders should be recorded. Therefore, it is critical to investigate dopaminergic functional interactions in the prefrontal cortex, and in particular, the effect of dorsolateral prefrontal cortex stimulation on clinical symptoms depending on dopaminergic concentrations in various brain regions. This short review summarizes important preliminary data, which focus on the symptom-oriented effects of rTMS in depression.

The greatest therapeutic promise of human embryonic stem cells (hESC) is to generate specialized cells to replace damaged tissue in patients suffering from various degenerative diseases. However, the signaling mechanisms involved in lineage restriction of ESC to adopt various cellular phenotypes are still under investigation. Furthermore, for progression of hESC-based therapies towards clinical applications, appropriate culture conditions must be developed to generate genetically stable homogenous populations of cells, to hinder possible adverse effects following transplantation. Other critical challenges that must be addressed for successful cell implantation include problems related to survival and functional efficacy of the grafted cells. This review initially describes the derivation of hESC and focuses on recent advances in generation, characterization, and maintenance of these cells. We also give an overview of original and emerging differentiation strategies used to convert hESC to different cell types. Finally, we will discuss transplantation studies of hESC-derived cells with respect to safety and functional recovery.