Effects of concomitant neuromuscular electrical stimulation during repetitive transcranial magnetic stimulation before repetitive facilitation exercise on the hemiparetic hand.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) and Repetitive facilitative exercise (RFE) improves motor impairment after stroke. OBJECTIVE: To investigate whether neuromuscular electrical stimulation (NMES) can facilitate the effects of rTMS and RFE on the function of the hemiparetic hand in stroke patients. METHODS: This randomized double-blinded crossover study divided 20 patients with hemiparesis into two groups and provided treatment for 4 weeks at 5 days/week. NMES-before-sham group and NMES-following-sham group performed NMES sessions and sham NMES sessions for each 2 weeks. Patients received NMES or sham NMES for the affected extensor muscle concurrently with 1 Hz rTMS for the unaffected motor cortex for 10 min and performed RFE for 60 min. The Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), Box and Block Test (BBT) and Modified Ashworth Scale (MAS) were used for evaluation. RESULTS: FMA and ARAT improved significantly during both sessions. The gains in the BBT during an NMES session were significantly greater than those during a sham NMES session. MAS for the wrist and finger significantly decreased only during an NMES session. CONCLUSIONS: NMES combined with rTMS might facilitate, at least in part, the beneficial effects of RFE on motor function and spasticity of the affected upper limb.

The Current and Future Potential of Transcranial Magnetic Stimulation With Electroencephalography in Psychiatry.

The search for biological targets in psychiatric disorders is essential to better understand illness mechanisms and also to monitor and predict response to currently available therapeutic interventions. To this end, the combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) has emerged as a powerful clinical research tool. TMS-EEG allows cortical properties, such as excitability, inhibition, oscillatory activity, and connectivity, to be directly probed within a specific region of the cortex. This review will summarize the state of the current literature on TMS-EEG and its potential to uncover biological targets in psychiatric illnesses, with a focus on major depressive disorder, bipolar disorder, and schizophrenia. Collectively, the reviewed studies suggest that alterations in gamma-aminobutyric acid-mediated inhibition and gamma oscillations in the dorsolateral prefrontal cortex and neighboring frontal regions are potential shared biomarkers in psychiatry, highlighting the potential of TMS-EEG to help identify translational biomarkers.

Surgical Neuromodulation of Tinnitus: A Review of Current Therapies and Future Applications.

INTRODUCTION: Tinnitus is the conscious perception of an auditory sensation in the absence of external stimulus. Proposed theories are based on neuroplastic changes that occur due to sensory deprivation. The authors review the relevant literature on functional imaging and neuromodulation of tinnitus and describe potential targets for deep brain stimulation (DBS). MATERIALS AND METHODS: A MEDLINE keyword and Medical Subject Heading term literature search was performed using PubMed for tinnitus, neuromodulation, DBS, transcranial magnetic stimulation, epidural electrode stimulation, intradural electrode stimulation, functional imaging, and connectivity. Data from these reports were extracted and reviewed. RESULTS: Multiple imaging studies are employed to understand the pathophysiology of tinnitus. Abnormal regions and altered connectivity implicated in tinnitus include auditory pathway and limbic structures. Neuromodulation attempts to correct this hyperexcitable state by disrupting these aberrant oscillations and returning activity to baseline. Applied treatment modalities include transcranial magnetic stimulation, epidural/intradural electrode stimulation, and DBS. More recently, modulation of autonomic pathways through vagus nerve stimulation and paired auditory sounds has demonstrated tinnitus improvement via plasticity changes. CONCLUSIONS: DBS shows much promise as a therapeutic option for tinnitus. Stimulation of the auditory pathway, particularly the medial geniculate body, could counteract thalamocortical dysrhythmias and reduce gamma activity implicated in the tinnitus percept. Stimulation of the limbic pathway could decrease attention to and perception of tinnitus. Additional studies, focusing on the involvement of thalamic and limbic structures in the pathophysiology of tinnitus, are needed to support the use of DBS.

The Future of Brain Stimulation Treatments.

Trends in brain stimulation include becoming less invasive, more focal, and more durable with less toxicity. Several of the more interesting new potentially disruptive technologies that are just making their way through basic and sometimes clinical research studies include low-intensity focused ultrasound and temporally interfering electric fields. It is possible, and even likely, that noninvasive brain stimulation may become the dominant form of brain treatments over the next 20 years. The future of brain stimulation therapeutics is bright.

[Therapeutic applications of closed-loop brain stimulation. Success and expectations]. / Therapeutischer Einsatz von Closed-loop-Hirnstimulation. Erfolge und Erwartungen.

The therapeutic application of brain stimulation is still limited to relatively few indications and small groups of patients due to variable efficacy. Individualization of stimulation parameters by employing a closed-loop system, i.e. synchronization of stimulation with endogenous brain activity with millisecond precision, has the potential to significantly improve the therapeutic efficacy when compared to open-loop systems. In this article the theoretical and experimental results are reviewed including first clinical trials that support the superiority of closed-loop brain stimulation, fundamental aspects in the development of closed loop methods are discussed and clinical studies which could quantify an increase in effectiveness are summarized. A significant increase in the indications for therapeutic applications of closed-loop systems is to be expected in the near future.

Magnetic flimmers: 'light in the electromagnetic darkness'.

Transcranial magnetic stimulation has become an important field for both research in neuroscience and for therapy since Barker in 1985 showed that it was possible to stimulate the human motor cortex with an electromagnet. Today for instance, transcranial magnetic stimulation can be used to measure nerve conduction velocities and to create virtual lesions in the brain. The latter option creates the possibility to inactivate parts of the brain temporarily without permanent damage. In 2008, the American Food and Drugs Administration approved repetitive transcranial magnetic stimulation as a therapy for major depression under strict conditions. Repetitive transcranial magnetic stimulation has not yet been cleared for treatment of other diseases, including schizophrenia, anxiety disorders, obesity and Parkinson's disease, but results seem promising. Transcranial magnetic stimulation, however, was not invented at the end of the 20th century. The discovery of electromagnetism, the enthusiasm for electricity and electrotherapy, and the interest in Beard's concept of neurasthenia already resulted in the first electromagnetic treatments in the late 19th and early 20th century. In this article, we provide a history of electromagnetic stimulation circa 1900. From the data, we conclude that Mesmer's late 18th century ideas of 'animal magnetism' and the 19th century absence of physiological proof had a negative influence on the acceptance of this therapy during the first decades of the 20th century. Electromagnetism disappeared from neurological textbooks in the early 20th century to recur at the end of that century.

Neuromodulation: a more comprehensive concept beyond deep brain stimulation.

As currently understood, neuromodulation comprises not only electrical and magnetic stimulation but also chemical and genetic manipulations. The fact that adverse events induced by some of these treatments are largely reversible has sparked great interest in the development of new applications and targets for neuromodulatory treatments. As the number of indications and studies increases, so does research in associated fields. This chapter provides a brief introduction and discusses the overall contents of this volume of the International Review of Neurobiology.

Stroke rehabilitation using noninvasive cortical stimulation: motor deficit.

Noninvasive cortical stimulation (NICS) has been used during the acute, postacute and chronic poststroke phases to improve motor recovery in stroke patients having upper- and/or lower-limb paresis. This paper reviews the rationale for using the different NICS modalities to promote motor stroke rehabilitation. The changes in cortical excitability after stroke and the possible mechanisms of action of cortical stimulation in this context are outlined. A number of open and placebo-controlled trials have investigated the clinical effect of repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) of the primary motor cortex in patients with motor stroke. These studies attempted to improve motor performance by increasing cortical excitability in the stroke-affected hemisphere (via high-frequency rTMS or anodal tDCS) or by decreasing cortical excitability in the contralateral hemisphere (via low-frequency rTMS or cathodal tDCS). The goal of these studies was to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and to then restore a normal balance of interhemispheric inhibition. All these NICS techniques administered alone or in combination with various methods of neurorehabilitation were found to be safe and equally effective at the short term on various aspects of poststroke motor abilities. However, the long-term effect of NICS on motor stroke needs to be further evaluated before considering the use of such a technique in the daily routine management of stroke.

Stroke rehabilitation using noninvasive cortical stimulation: aphasia.

Poststroke aphasia results from the lesion of cortical areas involved in the motor production of speech (Broca's aphasia) or in the semantic aspects of language comprehension (Wernicke's aphasia). Such lesions produce an important reorganization of speech/language-specific brain networks due to an imbalance between cortical facilitation and inhibition. In fact, functional recovery is associated with changes in the excitability of the damaged neural structures and their connections. Two main mechanisms are involved in poststroke aphasia recovery: the recruitment of perilesional regions of the left hemisphere in case of small lesion and the acquisition of language processing ability in homotopic areas of the nondominant right hemisphere when left hemispheric language abilities are permanently lost. There is some evidence that noninvasive cortical stimulation, especially when combined with language therapy or other therapeutic approaches, can promote aphasia recovery. Cortical stimulation was mainly used to either increase perilesional excitability or reduce contralesional activity based on the concept of reciprocal inhibition and maladaptive plasticity. However, recent studies also showed some positive effects of the reinforcement of neural activities in the contralateral right hemisphere, based on the potential compensatory role of the nondominant hemisphere in stroke recovery.

Stroke rehabilitation using noninvasive cortical stimulation: hemispatial neglect.

The rehabilitation of neuropsychological sequels of cerebral stroke such as hemispatial neglect by noninvasive cortical stimulation (NICS) attracts increasing attention from the scientific community. The NICS techniques include primarily repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). They are based on the concept of either reactivating a hypoactive cortical region affected by the stroke (the right hemisphere in case of neglect) or reducing cortical hyperactivity of the corresponding cortical region in the contralateral hemisphere (the left hemisphere). In the studies published to date on the topic of neglect rehabilitation, rTMS was used to inhibit the left parietal cortex and tDCS to either activate the right or inhibit the left parietal cortex. Sham-controlled NICS studies assessed short-term effects, whereas long-term effects were only assessed in noncontrolled rTMS studies. Further controlled studies of large series of patients are necessary to determine the best parameters of stimulation (including the optimal cortical target location) according to each subtype of neglect presentation and to the time course of stroke recovery. To date, even if there are serious therapeutic perspectives based on imaging data and experimental studies, the evidence is not compelling enough to recommend any particular NICS protocol to treat this disabling condition in clinical practice.

Validation and the future of stimulation therapy of the primary motor cortex.

The use of electrical motor cortex stimulation (EMCS) for post-stroke pain was established in Japan and has spread globally. EMCS has been used for the treatment of neuropathic pain, Parkinson's syndrome, and recovery of motor paresis. Since 2000, repetitive transcranial magnetic stimulation (rTMS) has been developed for the treatment of various neurological disorders. rTMS is a non-invasive method with almost no adverse effects. In the USA, rTMS of the left dorsolateral prefrontal cortex was approved for the treatment of major depression in 2008. rTMS of the primary motor cortex (M1) has been studied worldwide for the treatment of neuropathic pain, Parkinson's disease, motor paresis after stroke, and other neurological problems. New methods and devices for rTMS therapy are under development, and rTMS of the M1 is likely to be established as an effective therapy for some neurological disorders. The present review discusses EMCS and rTMS of the M1 concisely.

Neurostimulation therapies for primary headache disorders: present and future.

PURPOSE OF REVIEW: Most pharmacological treatments of primary headache disorders are partially effective and have cumbersome side effects. Therapies with better efficacy and tolerance are needed. Neurostimulation techniques may have this potential. This is an attempt to summarize the latest clinical trial results published in the field. RECENT FINDINGS: Hypothalamic deep brain stimulation is effective in drug-resistant chronic cluster headache (drCCH) but not riskless. Recent anatomical MRI studies indicate that the effective stimulation sites are rather widespread. Occipital nerve stimulation (ONS) seems to be effective in up to 76% of drCCH patients and its benefit long-lasting. A minority of patients are able to abandon preventive drugs. Its mechanism of action appears nonspecific. In chronic migraine, randomized controlled trials of ONS showed recently encouraging results, but long-term studies are missing. An ongoing sham-controlled trial suggests sphenopalatine ganglion neurostimulation (SPGS) efficacy in drCCH acute treatment, but possibly also in preventive therapy. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) modulate cortical excitability and connectivity. TMS could prevent headache when applied over the occipital cortex during the migraine aura. Repetitive TMS and tDCS have provided mixed results in a few small studies and warrant further trials. SUMMARY: Neurostimulation therapies inaugurate a new era in headache management and offer a promising alternative to medications. Future studies are necessary to provide evidence-based efficacy data, knowledge on their mode of action and information about their pharmaco-economic advantages.

Somatic treatments for mood disorders.

Somatic treatments for mood disorders represent a class of interventions available either as a stand-alone option, or in combination with psychopharmacology and/or psychotherapy. Here, we review the currently available techniques, including those already in clinical use and those still under research. Techniques are grouped into the following categories: (1) seizure therapies, including electroconvulsive therapy and magnetic seizure therapy, (2) noninvasive techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and cranial electric stimulation, (3) surgical approaches, including vagus nerve stimulation, epidural electrical stimulation, and deep brain stimulation, and (4) technologies on the horizon. Additionally, we discuss novel approaches to the optimization of each treatment, and new techniques that are under active investigation.

Brain stimulation: new vistas for the exploration and treatment of tinnitus.

AIMS: Tinnitus, the perception of sounds or noise in the absence of auditory stimuli, is a frequent and often severely disabling symptom of different disorders of the auditory system. Attempts to develop evidence-based therapies have been thwarted by a poor understanding of the underlying pathophysiology. However, recent work points toward a pivotal role of maladaptive cortical reorganization in the generation and perpetuation of tinnitus. Changes in the representation of sounds, abnormalities of oscillatory activity, and hyperactivity in higher order areas of auditory processing have been linked with the perception of tinnitus. Brain stimulation techniques have entered the field and have opened exciting new perspectives for the modulation of dysfunctional brain activity. In this review, a comprehensive overview on the use of brain-stimulation techniques in the exploration and experimental treatment of tinnitus is provided. DISCUSSIONS: Noninvasive and invasive brain stimulation techniques, for example, transcranial magnetic stimulation (TMS), direct current stimulation (tDCS), and direct electrical cortical stimulation gave rise to a new line of investigation in tinnitus research. First, it has been shown that focal interference with presumably pathological cortical function can reduce tinnitus at least transiently. Second, the reduction of tinnitus-associated enhancement of cortical activity by neuronavigated TMS has been demonstrated to ameliorate tinnitus. Third, preliminary data suggest that repeated application of TMS or continuous cortical stimulation may lead to a longer lasting suppression of tinnitus. CONCLUSIONS: These proof of principle studies point toward a new option for the investigation and neurophysiology based treatment of tinnitus. Based on these findings, larger scale randomized clinical trials are needed to explore the efficacy of different brain stimulation techniques and parameters as well as the optimal target sites and treatment schedules. Particularly, a careful evaluation of clinical relevance under consideration of an adequate sham control and attention to possible unwanted side effects of these new interventions are indispensable.

Recovery of function in humans: cortical stimulation and pharmacological treatments after stroke.

In this contribution, we first provide an overview of general principles of reorganisation in the human brain, and point out possible biomarkers of recovery. Subsequently, we expand on possibilities of adjuvant therapy in human rehabilitation using cortical stimulation and pharmacological treatments. Finally, we suggest future directions for research in this field.

Promising avenues of therapeutics for bipolar illness.

Basic scientific advances in understanding the neuropsychobiology of bipolar disorder have given us a multitude of opportunities to explore and exploit new avenues of therapeutics. Pharmacotherapeutic approaches include: neuropeptides (agonists such as thyrotropin-releasing hormone and antagonists such as corticotropin-releasing hormone), neurotrophic factors (especially brain-derived neurotrophic factor), and glutamatergic mechanisms (such as riluzole, ketamine, and antagonists of the NR-2B subunit of the glutamate receptor). Physiological interventions that would offer alternatives to electroconvulsive therapy include: repeated transcranial magnetic stimulation, especially at more intense stimulation parameters; magnetic stimulation therapy (seizures induced more focally by magnetic rather than electrical stimulation with resulting reduced meaning loss); vagal nerve stimulation, and deep brain stimulation. However, these, as well as the panoply of existing treatments, require further intensive investigation to place each of them in the proper therapeutic sequence and combination for the individual patient, based on development of better clinical and biological predictors of response. Large clinical trial networks and development of systematic research in clinical practice settings, such as that featured by the National Cancer Institute for cancer chemotherapy, would greatly accelerate the progress in incorporating new, as well as existing, agents into the best treatment strategies. The bipolar disorders, which are increasingly recognized as complex, highly comorbid conditions with a high morbidity and mortality, of which the majority start in childhood and adolescence, are not likely to respond completely to any single new treatment agent, and new public health initiatives and research strategies are needed as much as any new single treatment advance.

[Applications of magnetic stimulation in biomedicine].

Magnetic stimulation as an efficient and non-invasive technique has been applied broadly in clinical practice. It is mostly used in determination of nerve centre motor conduct and evaluation of motor cortex excitability; in inspection of central nervous system function by measuring peripheral nerve conduct; and in study of pallium nerve distribution. These are conducted in an attempt to control brain activity and provide new methods for the diagnosis and treatment of some brain diseases. This paper reviews the physical theory and functional mechanism of magnetic stimulation, as well as the applications of magnetic stimulation in biomedical examination and treatment.

Does brain stimulation after stroke have a future?

PURPOSE OF REVIEW: Transcranial methods of cortical stimulation can induce long-term changes in excitability of the cerebral cortex in humans and may be useful as therapeutic interventions in stroke rehabilitation. RECENT FINDINGS: Two approaches have been tested: (1) increasing excitability of the cortex in the stroke hemisphere and (2) suppression of the non-stroke hemisphere to reduce potential interference with function of the stroke hemisphere. The interventions have been transcranial direct current stimulation, transcranial magnetic stimulation and implanted epidural stimulation. All have been reported to give 10-20% functional improvement in small numbers of patients in single-session studies as well as in a small number of longer-term therapeutic trials. Preliminary experiments in aphasic patients using transcranial magnetic stimulation in an interference design show, however, that stimulation of the nonstroke hemisphere can in some patients reduce verbal fluency, questioning the general applicability of the second approach. SUMMARY: Cortical stimulation appears to be a safe and promising intervention for stroke patients. More studies are needed to assess its long-term benefits on substantial numbers of patients. We need to know what type of intervention is best, which patients are likely to benefit, the optimum time to intervene and the duration of any benefits.