Isa Albuquerque Sato

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.

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.

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

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

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

Trigeminal nerve stimulation (TNS) for social anxiety disorder: A case study

It is estimated that 7.8% of the United States population experience posttraumatic stress disorder (PTSD) at some point in their lifetime [1,2]. Medications and psychotherapy have been shown to reduce anxiety symptoms in these individuals. Nonetheless, approximately one-third of patients remain symptomatic despite treatment [3]. To address this unmet medical need, trigeminal nerve stimulation (TNS) has been previously proposed for PTSD, based upon the knownneurobiology of trauma-related [4] and anxiety disorders [5,6]. Trigeminal nerve stimulation is based on the application of a pulsed electric current using external electrodes on the surface of the forehead, to stimulate branches of the ophthalmic division (V1) of the trigeminal nerve. Nerve impulses propagate along the trigeminal pathway to the brain stem and, from there, toward brain areas such as amygdala, hippocampus, and prefrontal lobes, which are areas related to depressive and anxiety symptoms [7]. Previously, TNS has been successfully used for the treatment of depressive disorders [8,9]. Recently, Cook et al. [10] presented the first clinical trial on TNS for PTSD and major depression disorder (MDD) with positive results for both PTSD and mood symptoms. The protocol was performed on an eight-week nocturnal daily basis [10]. We have previously examined a brief, 10-day treatment protocol using TNS during the day [4,5,8]. Therefore, we present the first proof-of-concept trial to evaluate both safety and clinical efficacy of a 10-day daily TNS protocol for treating depressive and PTSD core symptoms. The study protocol had institutional review board approval and followed accepted ethical principles. Patients diagnosed with PTSD and MDD according to the DSM-V were recruited in an outpatient university hospital. The PTSD symptom severity was assessed by the PTSD Check List Scale (PCL-C), the Treatment Outcome PTSD Scale (TOP-8), and the Impact of Event Scale— Revised (IES-R). For assessing anxiety symptoms, we used both the Hamilton Anxiety Rating Scale (HARS) and the Beck Anxiety Inventory (BAI). We also assessed depressive symptoms through the Hamilton Depression Rating Scale (HDRS) — 17 item version and the Beck Depression Inventory (BDI-II) and cognitive functions with the Montreal Cognitive Assessment (MoCA). Inclusion criteria were the following: (1) 18to 59-year-old patients, (2) patients diagnosed with PTSD and MDD according to DSM-V criteria, and (3) agreement to participate in the trial by giving written informed consent, as approved by our IRB. Exclusion criteria were the following: (1) any indication for acute psychiatric hospitalization, (2) no other psychiatric comorbidities, (3) personality disorder diagnosis, (4) neurologic or severe clinical diseases such as neoplastic syndromes and neurodegenerative and uncompensated chronic

Transcranial Magnetic Stimulation for Anxiety Symptoms: An Updated Systematic Review and Meta-Analysis

Social anxiety disorder (SAD) is a common psychiatric condition with a lifetime prevalence rate of around 10%. Patients diagnosed with SAD present with marked occupational and social impairments as well as high comorbiditywith other psychiatric disorders such as depression and drug abuse/addiction [1]. Studies of neuromodulation strategies for anxiety disorders are in initial stages, lacking robust evidence. To the best of our knowledge, no study has evaluated the use of a neuromodulation strategy for SAD. In this report, we describe a 33-year-old male patient diagnosed with SAD according to DSM-V who successfully underwent a trigeminal nerve stimulation (TNS) intervention protocol, with amelioration of his symptoms. “Mr. C.” described that since hewas a little boy, he suffered from SAD, being forced to undergo home schooling since he was ten. The patient reported significant distress and occupational impairment that led him to quit college and work in socially isolated jobs. Prior to the TNS stimulation protocol, the patient had undergone pharmacological therapywith sertraline and venlafaxine aswell as cognitive–behavioral therapy for one year with poor clinical response. His medical presentation was unremarkable. The patient did not present any other psychiatric disorder. His family history was positive for SAD (father). Considering the severity of his symptoms and lack of clinical improvement with pharmacotherapy and psychotherapy, we proposed experimental TNS and the patient provided written informed consent (IRB-approved). During the stimulation protocol, the patient was not under any pharmacological treatment or psychotherapy and had not been so for the previous three months. Ten consecutive daily TNS sessions were performed. Electric stimulation was performed at 120 Hz with a pulse wave duration of 250 μs, continuously for 30 min per day. We used square auto-adhesive rubber electrodes of 25 cm placed over supraorbital trigeminal branches (V1) bilaterally following our previously tested protocol [2]. To assess the symptoms of SAD, we used the Social Phobia Inventory (SPIN) and the Liebowitz Social Anxiety Disorder Scale (LSAS).We also assessed cognitive functions with the Montreal Cognitive Assessment (MOCA). Cognitive functions were unaltered (23 at baseline and 24 at final outcome). Symptoms of SAD substantially improved during the 10-day treatment course and remained stable at the three-month follow-up. The patient reported significant global clinical gains (see Fig. 1). During the tenday period of stimulation, the patient reported gradual improvements on fear and anxiety that enabled him to face in part the avoidance. By the three-month follow-up, the patient reported significant

Trigeminal Nerve Stimulation (TNS) for Panic Disorder: An Open Label Proof-of-Concept Trial

Background: Transcranial magnetic stimulation (TMS) is a promising non-invasive brain stimulation intervention. TMS has been proposed for the treatment of Anxiety Disorders and disorders in which anxiety symptoms are prevalent, such as Obsessive-Compulsive Disorder (OCD) and Post-traumatic Stress Disorder (PTSD). Objective: To assess the efficacy of TMS for anxiety symptoms in Specific and Social Phobia, Generalized Anxiety Disorder, Panic Disorder (PD), OCD and PTSD in randomized clinical trials (RCTs). Methods: Systematic review using MEDLINE from the first RCT available until January 2015. The main outcome was the Hedges’ g for continuous scores for anxiety symptoms scales in a random-effects model. Heterogeneity was evaluated with the I2 and the χ2 test. Publication bias was evaluated using the Begg’s funnel plot. Metaregression was performed using the random-effects model modified by Knapp and Hartung. Results: We included 14 RCTs (n=395); most had small-to-modest sample sizes. Comparing active vs. sham TMS, active stimulation was not significantly superior for anxiety symptoms (Hedges’ g = -0.02; 95% CI -0.24- 0.20). The funnel plot showed that the risk of publication bias was low and between-study heterogeneity was not significantly (I2=12%). Meta-regression showed no particular influence of any variable on the results. Conclusion: TMS active was not superior to sham stimulation for the amelioration of anxiety symptoms. Trials had homogeneous results, despite different protocols of stimulation used. Further RCTs with larger sample sizes are fundamentally needed to clarify the precise impact of TMS in anxiety symptoms. Highlights • We present a systematic review and meta-analysis on results of TMS for anxiety symptoms in anxiety disorders • Four-teen studies (395 patients) were selected for the quantitative analysis • We found that active TMS was not significantly superior to sham TMS in this dataset (Hedges’ g = -0.02; 95% CI -0.24-0.20) • Heterogeneity was not significant in our analysis (I2=12% and p=0.361 for the χ2 test) • Meta-regression showed no particular influence of any variable on the results • The funnel plot displayed that studies were evenly distributed, with all studies within the limits deter-mined by the graphic except for one, indicating low bias.