The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018).

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.

[Mood disorders: When should we use repetitive transcranial magnetic stimulation?] / Troubles de l'humeur : quand recourir à la stimulation magnétique transcrânienne ?

Repeated transcranial magnetic stimulation (rTMS) is still a recent treatment in psychiatry. This article aims at updating the clinicians'knowledge about rTMS in the treatment of mood disorders (uni and bipolar depressive disorders, manic/mixed states, suicidal risk, catatonia). It is intended for clinicians who are required to indicate and/or use rTMS in their current practice. rTMShas the highest level of evidence for the treatment of unipolar depression, provided that effective parameters are used, that is to say, for classical high frequency protocols: 20 to 30 sessions, 1000 pulses/session, 5 to 20Hz, and 110 % of the motor threshold. Low frequency protocol are also efficient and well tolerated. The duration of the efficacy varies with relapses rates around 50 % at one year. Pharmacological treatment generally remains associated. With regard to manic states, and mixed states the results are preliminary and limited to a possible reduction in symptoms. In the suicidal risk associated with mood disorders, the interest of rTMS is still to demonstrate, as well as in catatonia. The current place of the rTMS is no longer disputed in the curative treatment of major depressive disorder, preferentially used after one or two lines of antidepressants upstream. Further studies are needed to confirm preliminary positive findings in other aspects of mood disorders.

Repetitive transcranial magnetic stimulation treatment for depressive disorders: current knowledge and future directions.

PURPOSE OF REVIEW: After three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS), major depressive disorder (MDD) has proven to be the primary field of application. MDD poses a major challenge for health systems worldwide, emphasizing the need for improving clinical efficacy of existing rTMS applications and promoting the development of novel evidence-based rTMS treatment approaches. RECENT FINDINGS: Several promising new avenues have been proposed: novel stimulation patterns, targets, and coils; combinatory treatments and maintenance; and personalization and stratification of rTMS parameters, and treatment of subpopulations. SUMMARY: This opinion review summarizes current knowledge in the field and addresses the future direction of rTMS treatment in MDD, facilitating the establishment of this clinical intervention method as a standard treatment option and continuing to improve response and remission rates, and take the necessary steps to personalize rTMS-based treatment approaches.

Accelerated transcranial magnetic stimulation for the treatment of Patients with depression: A review.

Major depressive disorder is a highly prevalent and profoundly disabling psychiatric disorder with significant morbidity and mortality and it is very often resistant to antidepressants, electroconvulsive therapy and psychotherapy. Therapeutic alternatives include repetitive transcranial magnetic stimulation which may be an effective choice for treatment-resistant depression but requires prolonged treatments for at least four to six weeks. Shorter exposure to this technique might be more advantageous for certain cases. The purpose of this review is to describe and discuss studies that have evaluated the safety and efficacy of accelerated transcranial magnetic stimulation (aTMS) in the acute treatment of depression. Methods: The electronic literature (NCBI Pubmed; Science Direct) on aTMS for the treatment of depression was reviewed. In the last years, a limited number of controlled and open-label studies have been published on the subject. The majority of these studies have shown promising results with aTMS, this protocol probably being at least as safe and as efficacious as conventional rTMS (five sessions per week) in the treatment of treatment-resistant depression (TRD) with a trend for faster response rates when more intensive protocols are used (15 sessions over two days). Future well-designed sham-controlled studies with larger samples are needed to confirm the safety and efficacy of aTMS in the treatment of depression.

Repetitive Transcranial Magnetic Stimulation in the Treatment of a Difficult to Treat Condition, Borderline Personality Disorder.

BACKGROUND: Borderline personality disorder (BPD) is a serious mental disorder characterized by a pervasive pattern of instability in affect regulation and interpersonal relationships, poor self-image and behavioral control, self-injurious behavior, suicidality, and other high-risk behaviors. It is also characterized by a high mortality rate by suicide. METHODS: The published literature on repetitive transcranial magnetic stimulation (TMS), theta-burst stimulation (TBS), and deep TMS in the treatment of BPD were reviewed. RESULTS: Four clinical studies (2 randomized trials and 2 case studies) with limited sample sizes found that TMS and TBS were safe and potentially effective in the reduction of symptoms of BPD. CONCLUSIONS: Given the limited clinical evidence for efficacy on the basis of the results of these studies, future controlled studies involving larger samples and optimal stimulus parameters should be designed to confirm the short-term and long-term safety and efficacy of repetitive TMS and TBS in the treatment of BPD.

Transcranial direct current stimulation for the treatment of obsessive-compulsive disorder? A qualitative review of safety and efficacy.

Obsessive-compulsive disorder (OCD) is a highly disabling psychiatric disorder characterized by recurrent obsessions and compulsions. It has a lifetime prevalence of 1-3% in the general population and commonly has a chronic course. First-line treatments consist of selective serotonin reuptake inhibitors and cognitive-behavioral therapy but up to 60% of patients respond partially or not at all to these treatments. This paper reviewed the literature on the safety and efficacy of transcranial direct current stimulation (tDCS) for the treatment of obsessive-compulsive disorder and discussed future directions for research and clinical application. Criteria for inclusion were open or controlled studies on tDCS and OCD that used validated rating scales along with well-described stimulus parameters. In the majority of the limited number of published studies, most patients with treatment-resistant obsessive-compulsive disorder had either moderate or marked benefit with this technique different stimulation targets, sometimes sustained for many months. This technique might be efficacious in the treatment of obsessive-compulsive disorder, although it is difficult to draw definitive conclusions about its efficacy, future well-designed sham-controlled studies are needed to confirm the safety and efficacy of tDCS for the treatment of this condition.

Repetitive transcranial magnetic stimulation in the treatment of eating disorders: A review of safety and efficacy.

Eating disorders are a significant public health concern accounting for significant morbidity and mortality. Therapeutic approaches are available to treat eating disorders but less than half of the patients recover. Therapeutic alternatives are needed such as repetitive transcranial magnetic stimulation. I reviewed studies that evaluated the safety and efficacy of this technique for the treatment of eating disorders. The electronic literature on repetitive transcranial magnetic stimulation, theta burst and deep transcranial magnetic stimulation in the treatment of eating disorders was retrieved. The findings were quite heterogeneous in results with some studies showing relatively positive results with reduction of both craving and eating behaviors with active stimulation versus sham. Repetitive transcranial magnetic stimulation was safe. Research in this field was limited by the small number of studies and sample sizes, diversity of stimulation parameters, questionable placebo conditions, the lack of a sham-controlled design and the use of subjective scales lacking in sensitivity. The evidence supporting rTMS for eating disorders is somewhat promising. Future studies on high frequency rTMS of the LDLPFC/DMPFC with increased statistical power, rigorous randomization, outcome measures and optimal parameters are needed to confirm the short- and long-term safety and efficacy of rTMS for the treatment of eating disorders.

Maintenance repetitive transcranial magnetic stimulation (rTMS) for relapse prevention in with depression: A review.

Major depressive disorder is a highly prevalent condition with significant morbidity and mortality. Recurrent episodes occur in greater than 50% of patients within a one year period despite treatment with antidepressant medications, electroconvulsive therapy and psychotherapy. Longer antidepressant treatment may prevent relapses and recurrences. Urgent therapeutic alternatives are needed such as maintenance repetitive transcranial magnetic stimulation. The purpose of this review is to describe and discuss studies that have evaluated the safety and efficacy of this technique in the long-term treatment and relapse prevention of depression. The electronic literature on maintenance repetitive transcranial magnetic stimulation for depression was reviewed. A limited number of controlled, open-label studies as well as case series have been published on maintenance rTMS after successful response to acute rTMS. In the majority of these studies, most patients with treatment-resistant unipolar or bipolar depression with or without medications experienced either moderate or marked benefit with maintenance rTMS, sometimes remission for three months and up to eight years. Many of the reviewed studies have shown promising results, however, future well-designed sham-controlled studies are needed to confirm the long-term safety and efficacy of maintenance rTMS in the relapse prevention of depression.

Neurostimulation techniques in the treatment of cocaine dependence: A review of the literature.

OBJECTIVE: Cocaine use disorder is a very common condition that represents a substantial public health problem, and no effective pharmacological or psychological therapies have been identified to date. Urgent therapeutic alternatives are therefore needed such as neurostimulation techniques. The purpose of this review is to describe and discuss studies that have evaluated the safety and efficacy of these techniques for the treatment of cocaine dependence. METHODS: The electronic literature on repetitive transcranial magnetic stimulation, theta-burst stimulation, deep transcranial magnetic stimulation, transcranial direct current stimulation, magnetic seizure therapy, electroconvulsive therapy, cranial electro-stimulation, and deep brain stimulation in the treatment of cocaine addiction were reviewed. RESULTS: Most of these studies which are few in numbers and with limited sample sizes found that some of these neurostimulation techniques, particularly transcranial magnetic stimulation, and transcranial direct current stimulation are safe and potentially effective in the reduction of craving to cocaine. Although deep brain stimulation showed some good results in one patient, no conclusion can be drawn so far concerning the efficacy and safety of this approach. CONCLUSION: Given the somewhat promising results of some of the studies, future controlled studies with larger samples, and optimal stimulus parameters should be designed to confirm the short- and long-term safety and efficacy of neurostimulation techniques to treat cocaine addiction.

Safety and Efficacy of Theta-Burst Stimulation in the Treatment of Psychiatric Disorders: A Review of the Literature.

Theta-burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation and is thought to induce more rapid and longer-lasting effects on synaptic plasticity than conventional repetitive transcranial magnetic stimulation protocols. TBS is being used as an investigational and more recently as a therapeutic tool. The purpose of this review is to describe and discuss the studies that have evaluated the safety and efficacy of this technique in the treatment of various psychiatric disorders such as depression, schizophrenia, obsessive-compulsive disorder, Tourette's disorder, nicotine and cocaine addiction, and pathological gambling. Studies have reported mild adverse effects but no cases of seizures or mania. Despite the fact that studies were heterogeneous in terms of design and results, some of them are promising mostly for treatment-resistant depression and auditory hallucinations. Future well-designed sham-controlled studies are needed to confirm the long-term safety and efficacy of TBS in the treatment of such conditions.

Repetitive Transcranial Magnetic Stimulation (5 and 10 Hz) With Modified Parameters in the Treatment of Resistant Unipolar and Bipolar Depression in a Private Practice Setting.

BACKGROUND: A limited number of studies have investigated the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of resistant depression in an outpatient private practice setting. We hypothesized that rTMS would be safe and effective in the treatment of resistant depression in a nonresearch population. METHODS: We treated 22 outpatients with unipolar or bipolar depression who were experiencing a moderate to severe treatment-resistant major depressive episode (MDE). Treatment was based on a flexible dose schedule of either 5 Hz or 10 Hz rTMS applied over the left dorsolateral prefrontal cortex with modified parameters. Assessments were performed at baseline, then on a weekly basis. The patients had received at least 2 trials of antidepressant medication of an adequate dose and duration without satisfactory improvement in the index MDE. RESULTS: There was a significant change in Montgomery-Asberg Depression Rating Scale scores from baseline (29.14±5.85) to the end of week 4 (16.27±11.20); 50.00% (11/22) were responders and 40.9% (9/22) achieved remission. No major side effects were observed aside from mild headache in some patients. CONCLUSIONS: rTMS applied to the left dorsolateral prefrontal cortex was safe and effective in an important subset of outpatients with a moderate to severe MDE in a naturalistic setting. Outcomes demonstrated response rates similar to research populations. Further larger studies are needed to confirm the safety and effectiveness of rTMS in naturalistic conditions.

Treatment of a Patient With Depersonalization Disorder With Low Frequency Repetitive Transcranial Magnetic Stimulation of the Right Temporo-Parietal Junction in a Private Practice Setting.

Depersonalization disorder (DPD) is a debilitating dissociative condition with no proven treatments. Although the pathophysiology of DPD is poorly understood, there are reports of increased excitability of the prefrontal cortex in patients with this condition. The temporo-parietal junction may also play a major role in the conscious experience of the spatial unity of the normal self and body. Repetitive transcranial magnetic stimulation has been shown in some case studies to effectively treat this condition. This report describes an additional such case, a 26-year-old man with a 6-month history of DPD who responded safely and significantly to repetitive transcranial magnetic stimulation to the right temporo-parietal junction.

Repetitive Transcranial Magnetic Stimulation and Treatment-emergent Mania and Hypomania: A Review of the Literature.

BACKGROUND: This review focuses on treatment-emergent mania/hypomania (TEM) associated with repetitive transcranial magnetic stimulation (rTMS). METHODS: English-language studies involving possible rTMS-induced mania/hypomania published between 1966 and 2015 were retrieved through a Medline search using the search terms mania, hypomania, mixed affective state, treatment-emergent, repetitive transcranial magnetic stimulation, and rTMS. Fifteen case series and controlled studies describing TEM associated with rTMS treatment have been published involving 24 individuals, most of whom were diagnosed with either bipolar I or II disorder or major depressive disorder. RESULTS: rTMS has been shown to possibly induce manic or hypomanic episodes in patients with depression, who are sometimes also taking antidepressants. Both high-frequency and low-frequency rTMS with different stimulus parameters may be associated with TEM in both males and females. CONCLUSIONS: Given these findings, it is highly recommended that patients with bipolar disorder who are experiencing a depressive episode be prescribed a mood stabilizer and that patients diagnosed with major depressive disorder be reevaluated to consider the possibility that they might have bipolar disorder, before rTMS treatment is initiated. If TEM occurs, discontinuation of rTMS should be considered, while continuing mood-stabilizing medications. Further research is needed concerning the underlying neurobiological mechanisms and epidemiologic characteristics of TEM associated with rTMS.

Neurostimulation techniques in the treatment of nicotine dependence: A review.

OBJECTIVE: Nicotine dependence accounts for significant mortality, morbidity, and socio-economic burdens. It remains a significant public health concern since it is among the leading causes of mortality worldwide and of preventable deaths in developed countries. Despite the availability of approved medications to treat nicotine dependence, along with cognitive behavioral therapy, only 6% of the total number of smokers who report wanting to quit each year are successful in doing so for more than a month mostly with poor abstinence rates. Urgent therapeutic alternatives are therefore needed such as neurostimulation techniques. The purpose of this review is to describe studies that have evaluated the safety and efficacy of these techniques for the treatment of nicotine dependence. METHODS: The electronic literature on repetitive transcranial magnetic stimulation, theta-burst stimulation, deep transcranial magnetic stimulation, transcranial direct current stimulation, magnetic seizure therapy, electroconvulsive therapy, cranial electro-stimulation, and deep brain stimulation in the treatment of nicotine addiction were reviewed. RESULTS: Most of these studies found that some of these neurostimulation techniques are safe and potentially effective in the reduction of craving to nicotine as well as in the reduction of cigarette consumption. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Given the promising results of some of the studies particularly with repetitive transcranial magnetic stimulation, theta-burst stimulation, transcranial direct current stimulation and, possibly, deep transcranial magnetic stimulation, future controlled studies with larger samples, and optimal stimulus parameters should be designed to confirm these findings. (Am J Addict 2016;25:436-451).