Pedro Shiozawa

Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review

UNLABELLED We reviewed trigeminal nerve stimulation (TNS) and transcutaneous vagus nerve stimulation (tVNS). All techniques have shown preliminary promising results, although the results are mixed. METHOD We performed a systematic review of the Medline and Embase databases, with no constraint to dates, through June 2013. The keywords were [(1) trigeminal nerve stimulation OR (2) cranial nerve OR (3) trigemin* OR (4) transcutaneous VNS OR (5) transcutaneous cranial nerve stimulation] and (6) mental disorders. RESULTS We included four preclinical and clinical five studies on TNS. All clinical data were based on open-label studies with small samples, which diminished the external validity of the results, thus reflecting the modest impact of TNS in current clinical practice. Of the tVNS clinical trials, three assessed physiological features in healthy volunteers, and one examined patients with epilepsy. CONCLUSION TNS and tVNS improve treatment of particular neuropsychiatric disorders such as depression.

Understanding tDCS effects in schizophrenia: a systematic review of clinical data and an integrated computation modeling analysis

Although recent clinical studies using transcranial direct current stimulation (tDCS) for schizophrenia showed encouraging results, several tDCS montages were employed and their current flow pattern has not been investigated. We performed a systematic review to identify clinical tDCS studies in schizophrenia. We then applied computer head modeling analysis for prediction of current flow. Out of 41 references, we identified 12 relevant studies. The most employed montage was anode and cathode over the left dorsolateral prefrontal and temporoparietal cortex, respectively. Computational model analysis predicted activation and under-activation under the anode and the cathode, respectively, occurring in areas respectively associated with negative and positive symptoms. We also identified tDCS-induced electrical currents in cortical areas between the electrodes (frontoparietal network) and, to a lesser extent, in deeper structures involved in schizophrenia pathophysiology. Mechanisms of tDCS effects in schizophrenia and the usefulness of computer modeling techniques for planning tDCS trials in schizophrenia are discussed.

Transcranial Direct Current Stimulation (tDCS) for the Treatment of Persistent Visual and Auditory Hallucinations in Schizophrenia: A Case Study

or cerebral trauma. She was taking the following medications: sertraline 150 mg/day, olanzapine 75 mg/day, hydroxyzine 25 mg/day. rTMS treatment was delivered by Magstim Magnetic Stimulator (The Magstim Company Ltd., Whitland, UK) with a figure eight coil. The motor threshold was defined as the lowest intensity of TMS required to induce motor response in the contralateral resting abductor pollicis brevis muscle. Motor threshold determination was made with the use of EMG. The coil was placed over the left dorsolateral prefrontal cortex (DLPFC) using the rule of 5 cm. Stimulations were performed with a frequency of 10 Hz, 60 trains of 5 s. inter-train intervals of 25 s and 3000 stimuli per day, 5 days a week for 4 weeks [3]. The event occurred 20 min into the 40 trains for this patient on the 12th day of stimulation. The subject was sitting. The setting was a research laboratory that is placed in the Psychiatry University Central Hospital of Helsinki. The TMS operator was a Medicine physician who first noted slight movements of the subject’s right hand fingers and, a few seconds later, progressive muscular contractions. The subject turned unresponsive and showed a tonic rearing up in her seat lasting for approximately 30 s after which she was smacking and breathing audibly with asymmetrical twitching of both arms with emphasis of her right side. rTMS treatment was stopped immediately. Protective measures were taken tomaintain airway patency and the patient was placed in right lateral decubitus. The subject had post-ictal confusion lasting 15 min. Approximately 60 s later, she recovered spontaneously and was responsive again. Afterward, the medical parameters were stable. A repeat MRI and EKG showed normal findings. Half an hour after the seizure her physical examination including neurological consultation and laboratory tests revealed no abnormal findings. However, the examination revealed a high level (0.20%) of blood alcohol concentration. The patient recovered completely without sequelae. The clinical diagnosis of this event was TMS-related seizure, complicated by alcohol use.

Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: A phase II, sham-controlled, randomized clinical trial

BACKGROUND Considering both the burden determined by major depressive disorder (MDD) itself and the high refractoriness and recurrence index, alternative strategies, such as trigeminal nerve stimulation (TNS), are the cutting edge instruments to optimize clinical response and to avoid treatment discontinuation and relapse of symptoms. Trigeminal nerve stimulation is an incipient simple, low-cost interventional strategy based on the application of an electric current over a branch of the trigeminal nerve with further propagation of the stimuli towards brain areas related to mood symptoms. METHOD The study was a phase II, randomized, sham-controlled trial with 40 patients with MDD. Patients with moderate or severe depressive symptoms as assessed by adequate clinical scales underwent a 10-day intervention protocol. Regarding main clinical outcome, analysis of variance (ANOVA) was performed to evaluate mean change scores in depressive symptoms as assessed by the HDRS-17 between baseline (t1), after intervention protocol (t2), and during one-month follow-up (t3). RESULTS There was a significant interaction between the mean percentage changes in depressive symptoms according to the HDRS in the two groups across the three assessments (F=6.38, df=2, p=0.0033). Post hoc analyses (Bonferroni method) demonstrated a statistically significant difference between depressive symptoms at baseline and t1 (p=0.01) and between depressive symptoms at baseline and t2 (p=0.009). No severe adverse effects were reported. DISCUSSION Our results in the present controlled trial highlight the possibility of more practical treatment protocols for clinical research, which are similar to those for different neuromodulation strategies such as transcranial direct current stimulation (tDCS). The in-office administration of TNS in our protocol is similar to the schedule for repetitive transcranial magnetic stimulation (rTMS), though over fewer treatment sessions. CONCLUSION Further controlled studies will contribute to the establishment of the clinical relevance of this new treatment strategy for MDD.

Reducing transcranial direct current stimulation-induced erythema with skin pretreatment: considerations for sham-controlled clinical trials.

Transcranial direct current stimulation (tDCS)‐induced erythema (skin reddening) has been described as an adverse effect that can harm blinding integrity in sham‐controlled designs. To tackle this issue, we investigated whether the use of topical pretreatments could decrease erythema and other adverse effects associated with tDCS.

Transcranial direct current stimulation for generalized anxiety disorder: a case study.

To the Editor: Generalized anxiety disorder (GAD) is a mental illness with an overall prevalence of 4% to 7% (1). It ts characterized by a subjective sensation of uncontrollable worry and multiple physiological symptoms such as sleep disturbances, muscle tension, and difficulties concentrating. Current treatment strategies are based on both psychological and pharmacologic therapies, although treatment-resistance and low adherence due to adverse effects are some issues that compromise optimal treatment. In fact, only some patients fully respond after an adequate antidepressant drug trial (2). Additional research to improve GAD treatment is therefore neeeded. Regarding new interventional strategies, the development of noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) has shown promising results. This technique is based on the application of a weak, direct electric current delivered over the scalp to induce polaritydependent changes in cortical excitability; anodal and cathodal stimulation induce increasing and decreasing of cortical excitability, respectively (3–5). When applied daily, tDCS displays clinical effects and has been successfully used for the treatment of psychiatric disorders, such as major depression (6), schizophrenia (7), and obsessive-compulsive disorder (8). However, tDCS use has not been reported for GAD. We hereby describe a 58-year-old woman with GAD who successfully underwent a tDCS intervention with amelioration of her symptoms. Ms. C progressively developed anxiety symptoms over the previous 3 years. Despite adequate treatment with several medicines in adequate doses such as venlafaxine, sertraline, amitriptiline and quetiapine, she presented no significant improvement of her symptoms and adverse effects that ultimately lead her to discontinue the use of pharmacotherapy. Considering the severity of her symptoms and the failure of other therapies, tDCS was started after informed consent was provided. We performed 15 consecutive daily tDCS sessions (except for weekends). The cathode was positioned over the right dorsolateral prefrontal cortex (DLPFC), and the anode was placed extracephalic over the contralateral deltoid. We used a direct

Trigeminal nerve stimulation (TNS) protocol for treating major depression: An open-label proof-of-concept trial

BACKGROUND Major depressive disorder (MDD) is an incapacitating mental disorder associated with significant personal, social, and economic impairment. Patients with MDD present lower quality of life and higher prevalence of medical conditions, including epilepsy. Noninvasive brain stimulation (NIBS) is a technique that might aid in overcoming some of the current challenges related to pharmacotherapy. Trigeminal nerve stimulation is an incipient, simple, low-cost interventional strategy based on the application of an electric current over a branch of the trigeminal nerve with further propagation of the stimuli toward brain areas related to mood symptoms. METHODS We performed an open-label proof-of-concept trial using TNS for MDD. To the best of our knowledge, we present a TNS interventional protocol that has not been evaluated for MDD hitherto. RESULTS A total of 11 patients were studied, with a mean age of 50.36 years (sd: 11.8 from 30 to 60). Only one patient was male. Regarding the main outcome, there was a reduction of depressive symptoms with a mean score of 5.72 (sd: 2.24) (p<0.001) on the HDRS-17. Considering a categorical analysis, all patients presented clinical response defined as a reduction of scores of at least 50%. Only one patient did not reach a remission score (defined as an HDRS score lower than 8). DISCUSSION In the current neuromodulation scenario, clinical results have been working as truly hypothesis-driven forces, i.e., empirical observation and data analysis from different studies have been highlighting possible mechanisms related to the neurobiological functioning of neuromodulation strategies. The present results, however significant, need to be taken as hypothesis-driven given the study design. Data generalization is jeopardized due to the present study lacking a control group. Our results, therefore, may be overestimated due to intrinsic characteristics such as the placebo effect and Hawthorne effect. CONCLUSION We present a proof-of-concept trial evaluating a new TNS protocol for depression. Data analysis underscores a significant participation of TNS in ameliorating depressive symptoms of patients with moderate or severe depressive episode. Further controlled studies will contribute to establish the clinical relevance of this new strategy for MDD.

Presentation and treatment of carotid cavernous aneurysms

We analyzed a group of patients with the diagnosis of internal carotid aneurysms in its intracavernous segment, with emphasis in prevalence, clinical features, treatments, evolution and neurological prognosis. Neurological signs and symptoms at initial presentation were registered and compared with final outcome. Patients were divided into two stratified groups, one with 19 patients which underwent interventionist treatment, and another with 21 patients who were conservatively treated. The present study demonstrated that intervention is significantly correlated with a better prognosis considering evolution of pain symptoms secondary to neurovascular compression (p=0,002). Regarding neurological deficits, an interventionist approach was also significantly correlated with better outcome in comparison with initial presentation (p=0,008). These results indicate that interventionist treatment determines improvement or resolution of pain symptoms in comparison with patients conservatively treated, as well as stabilization or partial improvement of neuro-ophthalmological deficits.

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.