Alisson Paulino Trevizol

Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: An Updated Systematic Review and Meta-analysis.

Background Transcranial magnetic stimulation (TMS) is a promising noninvasive brain stimulation intervention. Transcranial magnetic stimulation has been proposed for obsessive-compulsive disorder (OCD) with auspicious results. Objective To assess the efficacy of TMS for OCD in randomized clinical trials (RCTs). Methods Systematic review using MEDLINE and EMBASE from the first RCT available until March 11, 2016. The main outcome was the Hedges g for continuous scores for Yale-Brown Obsessive Compulsive Scale in a random-effects model. Heterogeneity was evaluated with the I2 and the &khgr;2 test. Publication bias was evaluated using the Begg funnel plot. Metaregression was performed using the random-effects model modified by Knapp and Hartung. Results We included 15 RCTs (n = 483), most had small-to-modest sample sizes. Comparing active versus sham TMS, active stimulation was significantly superior for OCD symptoms (Hedges g = 0.45; 95% confidence interval, 0.2–0.71). The funnel plot showed that the risk of publication bias was low and between-study heterogeneity was low (I2 = 43%, P = 0.039 for the &khgr;2 test). Metaregression showed no particular influence of any variable on the results. Conclusions Transcranial magnetic stimulation active was superior to sham stimulation for the amelioration of OCD symptoms. Trials had moderate heterogeneity results, despite different protocols of stimulation used. Further RCTs with larger sample sizes are fundamentally needed to clarify the precise impact of TMS in OCD symptoms.

Left Dorsolateral Prefrontal Cortex Anodal tDCS Effects on Negative Symptoms in Schizophrenia

Cognitive functions maintained stable (20 at baseline and 24 at the final outcome) as assessed by MOCA, with improvement on memory tasks. MDD symptoms substantially improved during the 10day treatment course and remained stable after three months follow-up, and the patient reported significant global clinical gains (see the Fig. 1). The patient was followed on a monthly basis and no risk issues were observed, such as gestational diabetes or hypertension. Caesarean section was performed opted by the gynecology and obstetrics team due to be considered high-risk pregnancy because of the MDD treatment. No complications during child-birth occurred. The neonate was a healthy full-term, 8 pounds newborn, with APGAR 10/10 and no malformations. The TNS protocol is based on a “bottom up” mechanism [7]. The electric stimuli follows the peripheral nerves pathway through central structures [7] such as the amygdala and the hippocampus, toward higher cortical area such as the dorsolateral prefrontal cortex, previously demonstrated to be involved in MDDwith symptoms amelioration when stimulated with other neuromodulation techniques [8]. Data on the use of cranial nerve stimulation for MDD during pregnancy is scant. In fact, TNS was not evaluated before. Only one case of vagus nerve stimulation (VNS) for the treatment of MDD in pregnancy was performedwith no safety issues [9]. Safety evaluation on the use of VNS in an animal model (pilot study of the teratogenicity) was performed with 10 rabbits with no safety issues reported [10]. We present the first report using TNS in a pregnant patient with successful amelioration of MDD symptoms and no considerable side effects to the newborn. TNS is a focused electrical stimulation technique without likely electric stimulation propagation to the fetus. Our findings are based on a case study, thus having limited generalizability. Nonetheless, these encouraging results should be seen as hypothesis-driven for further controlled, randomized trials exploring the safety and impact of TNS in the treatment of MDD in pregnancy.

Trigeminal Nerve Stimulation (TNS) for Generalized Anxiety Disorder: A Case Study.

Letters to the Editor / Brain Stimulation 8 (2015) 655e683 [2] Wang Z, Maia TV, Marsh R, Colibazzi T, Gerber A, Peterson BS. The neural cir- cuits that generate tics in Tourette’s syndrome. Am J Psychiatry 2011;168(12): 1326e37. [3] Neuner I, Werner CJ, Arrubla J, et al. Imaging the where and when of tic gener- ation and resting state networks in adult Tourette patients. Front Hum Neurosci [4] Lavoie ME, Imbriglio TV, Stip E, O’Connor KP. Neurocognitive changes following cognitive-behavioral treatment in Tourette syndrome and Chronic Tic Disorder. Int J Cogn Ther 2011;4(1):34e50. [5] Nitsche MA, Cohen LG, Wassermann EM, et al. Transcranial direct current stim- ulation: state of the art 2008. Brain Stimul 2008;1(3):206e23. [6] Soares JM, Sampaio A, Marques P, et al. Plasticity of resting state brain networks in recovery from stress. Front Hum Neurosci 2013;7(919). [7] Rickards H. Functional neuroimaging in Tourette syndrome. J Psychosom Res 2009;67(6):575e84. [8] McCairn KW, Iriki A, Isoda M. Global dysrhythmia of cerebro-basal gangliae cerebellar networks underlies motor tics following striatal disinhibition. J Neurosci 2013;33(2):697e708. Trigeminal Nerve Stimulation (TNS) for Generalized Anxiety Disorder: A Case Study Dear Editor, Generalized anxiety disorder (GAD) [1] presents with an overall prevalence of 4e7%. Although available treatment is effective in many patients, treatment-resistance and low adherence due to adverse effects are some issues that compromise optimal treat- ment. In fact about 25% of patients reportedly fail to respond to treatment [2,3]. Brain stimulation techniques have shown prom- ising results for anxiety symptoms [4,5]. Following previous results of different neuromodulation strategies, Trigeminal Nerve Stimula- tion (TNS) may also be able to exert anxiolytic effects in the clinical scenario. TNS is a non-invasive strategy based on the application of an low-energy electric signal to stimulate branches of the trigemi- nal nerve with further propagation of the stimuli toward brain areas related to mood and anxiety symptoms [6]. TNS has been reported to reduce anxiety symptoms in patients with a primary diagnosis of major depression [7] but has not been previously examined as a treatment for primary GAD. Here, we describe the management of a 39-year-old female patient diagnosed with GAD accordingly to DSM-V criteria. The patient did not present with any psychiatric comorbidity at clinical evaluation. Moreover, no other psychiatric history was reported rather than the development of anxiety symptoms over the last three years. During this period the patient failed to respond to different adequate pharmacological protocols (such as venlafaxine, sertraline, fluoxetine and escitalopram). Considering the severity of her symptoms and lack of clinical response to pharmacotherapy, a experimental TNS protocol was started after written informed consent was provided utilizing IRB-approved materials and procedures. The patient was not under any pharmacological approach at the time she underwent the experimental protocol. Ten consecutive daily TNS sessions (except for weekends) were performed. Electric stimulation was performed at 120 Hz with a pulse wave duration of 250 m s for 30 min per day. The 25 cm 2 conductive rubber electrodes were wrapped in cotton material, which was moistened with saline so as to reduce impedance. For assessment of anxiety symptoms we used the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Hamilton Anxiety Rating Scale (HARS). We also assessed cognitive functions with the Montreal Cognitive Assessment (MoCA). At the end of the experi- mental protocol, Ms. E presented with symptomatic remission of her symptoms. Cognitive function exhibited a minor improvement (from 25 at baseline to 27 at final outcome) as assessed by MoCA. Anxiety symptoms substantially improved during the 10-day treat- ment course (reduction of 93.7% and 88.3% according to GAD-7 and HARS, respectively) and remained stable during one-month follow- up (Fig. 1). Zwanzger et al. and Pallanti et al. reviewed the use of transcranial magnetic stimulation (TMS) to treat anxiety symptoms, with interesting positive results. Improvements were observed on anxiety symptoms in panic disorder with depression and treatment-resistant depression [4,5]. Trigeminal nerve stimulation may modulate brain activity through bottom- up mechanisms by stimulating a cranial nerve whose nuclei lie in the brain stem, and which, in turn, make extensive connec- tions to the limbic cortex and monoaminergic nuclei. There are a growing number of publications on the use of TNS for psychiatric disorders [6e8]. Figure 1. Clinical assessment at baseline, 10 days and 40 days follow up. GAD-7: Generalized Anxiety Disorder clinical scale; HARS Hamilton Anxiety Rating Scale. Treatment was administered during the period from Day 0 to Day 10; Day 45 measurements show continued remission one month after the last treatment administration.

Establishing an effective TMS protocol for craving in substance addiction: Is it possible?

BACKGROUND AND OBJECTIVES Repetitive transcranial magnetic stimulation (TMS) is a non-invasive tool with known therapeutic efficacy in various neuropsychiatric disorders, such as depression, schizophrenia, mania, and anxiety disorders. We hereby, briefly present a brief review and meta-analysis on the use of TMS for craving in substance addiction. METHODS We present our brief review and meta-analysis following the recommendations of the Cochrane group. A total of eight randomized controlled trials fulfilled eligibility criteria and were selected. A total of 199 patients were studied. RESULTS We found active stimulation to be superior than sham protocols only for trials focused on right DLPFC (with Hedges g = 1.48; ES (95%CI: 0.126-2.834), p = 0.032. DISCUSSION AND SCIENTIFIC SIGNIFICANCE Main meta-analysis limitations include small number of studies, high heterogeneity among studies, and high publication bias. However challenging, our exploratory analysis underscored the amelioration of craving in substance addiction for trials using high frequency TMS protocols over the right DLPFC. We hereby, propose the use of this particular TMS protocol as a promising tool in clinical research.

Trigeminal Nerve Stimulation (TNS) for Post-traumatic Stress Disorder: A Case Study.

Letters to the Editor / Brain Stimulation 8 (2015) 655e683 The participant began experiencing adverse effects as he was traveling home from the laboratory, approximately 30 min after the conclusion of the protocol. The adverse effects started gradually, and included transient paresthesia, hemiparesis of the left side of the body, slurred speech, and ataxia. Due to prolonged hemiparesis for several hours, the participant presented to the emergency department of his local hospital. The treating physician adminis- tered a brief neurological screening measure that did not reveal any neurological abnormalities; however the participant requested a second opinion. During this time, the participant experienced several additional symptoms, including: severe headache pain in the right frontal and temporal regions, in addition to pain in the “stem” region; sensitivity to light and sound; hot and cold flashes (without associated fever); nausea; and vomiting. The participant underwent a computerized tomography (CT) brain scan, but no ab- normalities were detected. The participant remained in hospital for observation, at the request of the participant’s family, for a total of 6 h. Overall, the symptoms lasted for approximately 8 h with the participant returning to normal functioning within 24 h, with no long-lasting side effects. Although a formal clinical diagnosis was not made, treating physicians agreed that the symptoms were indicative of a severe migraine. As a result of the adverse event, the participant was excluded from further participation in the study. The event was reported to the Deakin University Human Research Ethics Committee. To our knowledge, this is the first report of a combination of TMS and tDCS inducing transient paresthesia. Due to the methodology employed, it is difficult to elucidate which technique is most likely to have caused the adverse event. Both techniques have been previ- ously shown to be safe when applied using accepted parameters, such as those used in this study. The participant had experienced one migraine a year previously, though the symptoms were less extensive and more localized than those experienced following the testing procedure. The previous migraine, which lasted several hours, involved pain around the right temple area and the base of the skull, and photosensitivity. The participant did not seek medical attention for this migraine. Both TMS (in its repetitive form) and anodal M1 tDCS have been investigated as treatments for migraine with no ill effects [1,2]. It is possible that the combination of tech- niques triggered the adverse event, although TMS is commonly used in conjunction with tDCS as a laboratory measurement of tDCS-induced effects [3] without issue. The occurrence of headache and other minor adverse effects following non-invasive brain stimulation has been reported under experimental conditions in the literature [1e3]. To the authors’ knowledge, there have been no reports of migraine occurrence (with or without transient paresthesia) following single- and paired-pulse TMS and/or tDCS application. However, it has been sug- gested that anodal tDCS could induce migraine in susceptible individ- uals via a net increase in cortical hyperexcitability (e.g. Refs. [4,5]). Due to this possibility, Liebetanz et al. [4] concluded that special care should be taken when applying tDCS in migraine patients. The possibility exists that the symptoms were psychogenic, however this is difficult to determine after just a single episode. It is also possible that psychological factors, such as anxiety or stress, interacted with physiological processes to trigger the migraine. For example, heightened anxiety is a known precipitant for migraine [6]. Anxiety as a trigger seems unlikely in this case, as the partici- pant reported no nervousness on an 11-point numerical rating scale four times throughout the session. However, due to the nature of self-report this possibility cannot be excluded. In conclusion, though unprecedented, this event highlights the need for continued participant monitoring following tDCS and TMS application. Both techniques should be applied with caution. Participants should be briefed on the possibility of migraine induction following tDCS and/or TMS, particularly in those with a history of migraine. Hannah G.K. Bereznicki * Cognitive Neuroscience Unit, School of Psychology, Faculty of Health, Deakin University, Waterfront Campus, Geelong, VIC 3220, Australia Aleksandar Milosev Alan J. Pearce Cognitive Neuroscience Unit, School of Psychology, Faculty of Health, Deakin University, Burwood, VIC 3125, Australia Greg A. Tooley School of Psychology, Faculty of Health, Deakin University, Burwood, VIC 3125, Australia Peter G. Enticott Cognitive Neuroscience Unit, School of Psychology, Faculty of Health, Deakin University, Burwood, VIC 3125, Australia * Corresponding author. Tel.: þ61 3 52278715. E-mail address: hannah.bereznicki@deakin.edu.au Received 20 January 2015 Available online 18 March 2015 http://dx.doi.org/10.1016/j.brs.2015.02.006 References [1] Rossi S, Hallett M, Rossini P, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120(12):2008e39. http://dx.doi.org/10.1016/j.clinph.2009.08.016. [2] DaSilva A, Mendonca M, Zaghi S, et al. tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. Headache 2012; 52(8):1283e95. http://dx.doi.org/10.1111/j.1526-4610.2012.02141.x. [3] Brunoni A, Amadera J, Berbel B, Volz M, Rizzerio B, Fregni F. A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol 2011;14(8):1133e45. http://dx.doi.org/10.1017/s1461145710001690. [4] Liebetanz D, Fregni F, Monte-Silva KK, et al. After-effects of transcranial direct current stimulation (tDCS) on cortical spreading depression. Neurosci Lett 2006;298(1e2):85e90. http://dx.doi.org/10.1016/j.neulet. [5] Chadaide Z, Arlt S, Antal A, Nitsche MA, Lang N, Paulus W. Transcranial direct current stimulation reveals inhibitory deficiency in migraine. Cepha- lalgia 2007;27:833e9. http://dx.doi.org/10.1111/j.1468-2982.2007.01337.x. [6] Fukui P, Goncalves T, Strabelli C, et al. Trigger factors in migraine patients. Arq Neuropsiquiatr 2008;66(3A):494e9. http://dx.doi.org/10.1590/s0004- 282x2008000400011. Trigeminal Nerve Stimulation (TNS) for Post-traumatic Stress Disorder: A Case Study Dear Editor, Posttraumatic stress disorder (PTSD) is an anxiety disorder following a potentially traumatic event. It is best characterized by intrusive thoughts related to the event, avoidance behavior and symptoms of hyperarousal such as sleep disorders, hyper- vigilance and panic attacks [1]. The lifetime prevalence is estimated to be 7.8% in the United States, with annual costs of about

Pregabalin for generalized anxiety disorder: an updated systematic review and meta-analysis.

3 billion [2]. There is no definitive pharmacotherapy for PTSD nuclear

Vagus nerve stimulation in neuropsychiatry: Targeting anatomy-based stimulation sites

Generalized anxiety disorder (GAD), characterized by pervasive and highly distressing anxiety and worries, is associated with severe impairment. Although numerous agents from various drug classes are available to treat GAD, as many as 50% of patients have inadequate response, constituting an important medical frontier. In the face of this challenge, new pharmacological alternatives need to be further studied aiming at clinical improvement and better quality of life for patients. To assess the efficacy of pregabalin (PGB) compared with placebo for amelioration of anxiety symptoms in patients with GAD. A systematic literature search was performed using databases such as MEDLINE and EMBASE and other sources. The main outcome was Hedges’ g for continuous scores. We used a random-effects model. Heterogeneity was evaluated with the I2 (moderate heterogeneity was assumed if I2 was >50% and high heterogeneity if I2 was >75%) and the &khgr;2-test (P<0.10 for heterogeneity). Publication bias was evaluated using the funnel plot. Meta-regression was performed using the random-effects model. For safety evaluation, we compared patients’ dropout rates. We included eight randomized-controlled trials (n=2299) in our study, comparing the use of PGB in different dosages and placebo. In terms of the main outcome, PGB was found to be superior to the placebo group (Hedges’ g=0.37; 95% confidence interval 0.30–0.44). The funnel plot assessment showed a low risk of publication bias. Between-study heterogeneity was not significant (I2=0%), strengthening our results. Meta-regression showed no particular influence of any variable on the results. A categorical analysis of safety, using dropout as the most severe possible outcome, was carried out. No difference between PGB and placebo groups was observed in terms of the dropout rates. PGB was superior to placebo for the amelioration of GAD symptoms. In addition, the dropout rate was not significantly higher than that of the placebo groups. PGB was comparable to benzodiazepines in clinical response, but had lower dropout rates than benzodiazepine.

Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: An Open Label Proof-of-Concept Trial

The vagus nerve (VN) is the longest cranial nerve, extending from the brain to the abdominal cavity. The VN consists of both afferent and efferent fibers (respectively 80% and 20%). Vagus nerve stimulation (VNS) is a neuromodulation strategy first developed in the 1980s for epilepsy. More recently, growing efforts in clinical research have been underscoring possible clinical benefits of VNS for different medical conditions such as epilepsy, major depression, anxiety disorders, and Tourette syndrome. Following the rational of VN anatomy and cranial innervation presented above, we hereby hypothesize that transcutaneously placing electrodes over the mastoid process could be a useful study protocol for future tVNS trials.

Integrity of cognitive functions in trigeminal nerve stimulation trials in neuropsychiatry

Despite recent advances in pharmacological treatments, Major Depressive Disorder (MDD) remains an incapacitating psychiatric condition with increasing prevalence and economic burden [1]. New therapeutical strategies such as vagus nerve stimulation (VNS) are being studied [2]. Different brain sites can be modulated by using electrical currents, which can theoretically restore balance to impaired circuits leading to clinical amelioration of symptoms. VNS involves the direct stimulation of the vagus nerve leading to further modulation of impaired brain areas related to psychiatric disorders [3,4]. Target stimulated areas include solitary tract nucleus, dorsal raphe, locus coeruleus, parabrachial area, amygdala, nucleus accumbent, hippocampus and the dorsolateral prefrontal cortex (DLPFC) [5]. Non-invasive VNS stimulation protocols have been assessed with promising results [6]. In fact, our group and others have recently proposed a hypothetically safer non-invasive approach for transcutaneously stimulating the vagus nerve in the ear, transcutaneous auricular VNS (taVNS) [7]. There are also methods for noninvasively stimulating the vagus nerve in the neck, or cervical region, called transcutaneous cervical VNS (tcVNS).We undertook this proofof-concept study to evaluate both the safety and potential clinical efficacy of this new experimental protocol with taVNS for treating patients with MDD. The present protocol had approval from institutional review board. Patients diagnosed with MDD according to the DSM-V criteria were recruited in an outpatient university hospital clinic. Symptom severity was assessed by the 17-itemHamilton Depression Rating Scale (HDRS). Exploratory analyses assessed depressive symptoms through the Beck Depression Inventory (BDI), anxiety symptoms through the Hamilton Anxiety Rating Scale (HAMA) and the Beck Anxiety Inventory (BAI), sleep quality through the Pittsburgh Sleep Quality Index (PSQI), and somatic symptoms through the Somatic Symptom Inventory (SSI) and the Somatoform Disorders Screening Instrument-7 days (SOMS-7). We also assessed cognitive functions with the Montreal Cognitive Assessment instrument (MoCA). Inclusion criteria were as follows: (1) 18to 59-year-old patients, (2) patients diagnosed with MDD following DSM-V criteria, (3) agreement to participate in the trial with written informed consent. Exclusion criteria were the following: (1) imminent need for psychiatric hospitalization, (2) any other [current or lifetime] psychiatric diagnosis, (3) neurologic or other severe diseases such as neoplastic syndromes and neurodegenerative and uncompensated chronic comorbidities, and (4) pregnancy. Clinical assessment was performed by a trained psychiatrist at baseline, at the last day of the stimulation protocol and one month after. The primary outcome was assessed by the mean difference in HDRS scores between baseline and the last day of stimulation. Participants were required to have at least four weeks without a change in psychiatric medication before the beginning of taVNS stimulation until the end of the one-month follow-up period. All patients underwent a 10-session taVNS protocol during a twoweek period. Electrical stimulationwas performed using the Ibramed Neurodyn II external neurostimulator to deliver electric current through the auricular branch of the vagus nerve at 120 Hz with a pulse wave duration of 250 μs for 30 minutes per day. The intensity was set at 12mA, which provoked a nonpainful mild paresthesia without muscle contraction for all patients. We performed the stimulation placing the electrodes bilaterally over the mastoid process area (anode to the left and cathode to the right), juxtaposed to the ear, near the tympanomastoid fissure (see Fig. 1) [8]. We used 15 cm2 auto-adhesive rubber electrodes to deliver the current. The present work was performed at the Interdisciplinary Center for Clinical Neuromodulation, Santa Casa School of Medical Sciences, São Paulo, Brazil. Figure 1. Anode positioning over the mastoid process area, juxtaposed to the ear. The cathode was positioned in the same way over the right mastoid process area.

Trigeminal nerve stimulation (TNS) for posttraumatic stress disorder and major depressive disorder: An open-label proof-of-concept trial☆

It is common for both practitioners and patients to have concerns about the possible neurocognitive side effects of neuromodulation techniques and these may also be related to poor adherence.1 Electroconvulsive therapy (ECT) is currently considered the most effective treatment for severe depression. However, effects such as anterograde and retrograde amnesia and impairment of orientation, processing speed, attention, verbal fluency, and executive functions have been reported after ECT sessions.1 Clinical trials investigating neuropsychological outcomes after neuromodulation strategies therefore tend to focus on cognitive safety. Trigeminal nerve stimulation (TNS) is a transcutaneous neuromodulation technique based on the “bottom-up mechanism” in which alternating electric current is administered over the supraorbitary branch of the trigeminal nerve and stimuli propagate towards brain areas related to symptoms of depression and anxiety, modulating their activities. The efficacy of TNS for major depressive disorder has been studied and the results are interesting.2,3 However, investigations are still ongoing into safety issues related to TNS, such as compromise to skin integrity.4 We present an exploratory analysis of cognitive assessments conducted in clinical trials undertaken by our neuromodulation group. As part of clinical trials performed to investigate the efficacy of TNS for neuropsychiatric disorders such as depression, generalized anxiety, fibromyalgia, panic disorder, posttraumatic stress disorder5 and obsessivecompulsive disorder, 64 patients have been evaluated for cognitive function before and after a TNS protocol, using the Montreal Cognitive Assessment (MOCA). The TNS protocol used was as proposed by Shiozawa et al.3 and involves using an external neurostimulator to deliver an electric current with a frequency of 120 Hz and a pulse duration of 200 ms for 30 minutes. Intensity is Integridade das funções cognitivas em ensaios clínicos de estimulação do nervo trigêmeo em neuropsiquiatria