Examining transcranial random noise stimulation as an add-on treatment for persistent symptoms in schizophrenia (STIM’Zo): a study protocol for a multicentre, double-blind, randomized sham-controlled clinical trial

Background One out of three patients with schizophrenia failed to respond adequately to antipsychotics and continue to experience debilitating symptoms such as auditory hallucinations and negative symptoms. The development of additional therapeutic approaches for these persistent symptoms constitutes a major goal for patients. Here, we develop a randomized-controlled trial testing the efficacy of high-frequency transcranial random noise stimulation (hf-tRNS) for the treatment of resistant/persistent symptoms of schizophrenia in patients with various profiles of symptoms, cognitive deficits and illness duration. We also aim to investigate the biological and cognitive effects of hf-tRNS and to identify the predictors of clinical response. Methods In a randomized, double-blind, 2-arm parallel-group, controlled, multicentre study, 144 patients with schizophrenia and persistent symptoms despite the prescription of at least one antipsychotic treatment will be randomly allocated to receive either active (n = 72) or sham (n = 72) hf-tRNS. hf-tRNS (100–500 Hz) will be delivered for 20 min with a current intensity of 2 mA and a 1-mA offset twice a day on 5 consecutive weekdays. The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Patients’ symptoms will be assessed prior to hf-tRNS (baseline), after the 10 sessions, and at 1-, 3- and 6-month follow-up. The primary outcome will be the number of responders defined as a reduction of at least 25% from the baseline scores on the Positive and Negative Syndrome Scale (PANSS) after the 10 sessions. Secondary outcomes will include brain activity and connectivity, source monitoring performances, social cognition, other clinical (including auditory hallucinations) and biological variables, and attitude toward treatment. Discussion The results of this trial will constitute a first step toward establishing the usefulness of hf-tRNS in schizophrenia whatever the stage of the illness and the level of treatment resistance. We hypothesize a long-lasting effect of active hf-tRNS on the severity of schizophrenia symptoms as compared to sham. This trial will also have implications for the use of hf-tRNS as a preventive intervention of relapse in patients with schizophrenia. Trial registration ClinicalTrials.gov NCT02744989. Prospectively registered on 20 April 2016

Attention network modulation via tRNS correlates with attention gain

Transcranial random noise stimulation (tRNS) can enhance vision in the healthy and diseased brain. Yet, the impact of multi-day tRNS on large-scale cortical networks is still unknown. We investigated the impact of tRNS coupled with behavioral training on resting-state functional connectivity and attention. We trained human subjects for 4 consecutive days on two attention tasks, while receiving tRNS over the intraparietal sulci, the middle temporal areas, or Sham stimulation. We measured resting-state functional connectivity of nodes of the dorsal and ventral attention network (DVAN) before and after training. We found a strong behavioral improvement and increased connectivity within the DVAN after parietal stimulation only. Crucially, behavioral improvement positively correlated with connectivity measures. We conclude changes in connectivity are a marker for the enduring effect of tRNS upon behavior. Our results suggest that tRNS has strong potential to augment cognitive capacity in healthy individuals and promote recovery in the neurological population.

Boosting Numerical Cognition in Children and Adolescents with Mathematical Learning Disabilities by a Brain-Based Intervention: A Study Protocol for a Randomized, Sham-Controlled Clinical Trial

Numbers are everywhere, and supporting difficulties in numerical cognition (e.g., mathematical learning disability (MLD)) in a timely, effective manner is critical for their daily use. To date, only low-efficacy cognitive-based interventions are available. The extensive data on the neurobiology of MLD have increased interest in brain-directed approaches. The overarching goal of this study protocol is to provide the scientific foundation for devising brain-based and evidence-based treatments in children and adolescents with MLD. In this double-blind, between-subject, sham-controlled, randomized clinical trial, transcranial random noise stimulation (tRNS) plus cognitive training will be delivered to participants. Arithmetic, neuropsychological, psychological, and electrophysiological measures will be collected at baseline (T0), at the end of the interventions (T1), one week (T2) and three months later (T3). We expect that tRNS plus cognitive training will significantly improve arithmetic measures at T1 and at each follow-up (T2, T3) compared with placebo and that such improvements will correlate robustly and positively with changes in the neuropsychological, psychological, and electrophysiological measures. We firmly believe that this clinical trial will produce reliable and positive results to accelerate the validation of brain-based treatments for MLD that have the potential to impact quality of life.

The application of vagus nerve stimulation in individuals with misophonia

Stimulating the Vagus nerve helps maintain the autonomic tone, indicating stabilising any hyperactivity in the nervous system. The vagus nerve stimulation is applied in individuals with seizures, depression, sepsis, pain, obesity, cardiovascular disease, lung disease, diabetes, stroke, and traumatic brain injury. Auditory neuroscience has been widely applied in individuals with tinnitus and has been demonstrated as a successful neuromodulation technique. Individuals with peripheral lesions of the hair cells induce a maladaptive change in the plasticity resulting in hyperactivity in the auditory and non-auditory structures. In order to reduce this hyperactivity, neuromodulation techniques such as; transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, transcranial random noise stimulation, neurofeedback, epidural and subdural cortical and deep brain stimulation. The vagus nerve stimulation is also one form of neuromodulation technique considered to reduce the symptoms of tinnitus. It is believed that the ramus Auricularis Nervi vagi, an afferent sensory branch of the vagus nerve, innervates the afferent sensory branch of the vagus nerve, the ramus auricularis nervi vagi also innervate the outer ear canal and parts of the auricle. This auricular branch of the vagus nerve also called Arnold's nerve, which gives a projection to the nucleus of the solitary tract. The vagus nerve stimulation in individuals with tinnitus works to activate the auricular branch of the vagus nerve to reduce its symptoms. A similar principle of vagus nerve stimulation can be tried upon in individuals with misophonia. Literatures states that individuals with misophonia have hyperactivity in their non-classical auditory pathway that can be suppressed with the help of vagus nerve stimulation. The article discusses the possible effects of vagus nerve stimulation in individuals with misophonia.

Transcranial Electric And Acoustic Stimulation For Tinnitus: Study Protocol For A Randomized Double-Blind Controlled Trial Assessing The Influence of Combined Transcranial Random Noise And Acoustic Stimulation On Tinnitus Loudness And Distress

Background: Tinnitus is the result of aberrant neuronal activity. As a novel treatment form, neuromodulation is used to modify neuronal activity of brain areas involved in tinnitus generation. Among the different forms of electric stimulation, transcranial Random Noise Stimulation (tRNS) has been shown to be a promising treatment option for tinnitus. In addition, recent studies indicate that the reduction in tinnitus can be more pronounced when different modalities of stimulation techniques are combined (“bimodal stimulation”). TRNS can be used in combination with acoustic stimulation (AS), a further treatment option recognized in the literature. The aim of the proposed study is to investigate whether simultaneous tRNS and AS improve levels of tinnitus loudness and distress. Methods: The intervention consists of bilateral HD-tRNS over the auditory cortex combined with the application of AS which is studied in a cross-over design. The visits will be performed in 26 sessions. There will be 20 treatment sessions, divided into two blocks: active and sham HD-tRNS. Within the blocks, the interventions are divided into Group A: HD-tRNS and AS, and Group B: HD-tRNS alone. Furthermore, in addition to the assessments directly following the intervention sessions, there will be six extra sessions performed subsequently at the end of each block, after a period of some days (Follow-ups 1 and 2) and a month after the last intervention (C). Primary outcome measures are analogue scales for evaluation of subjective tinnitus loudness and distress, and the audiological measurement of Minimum Masking Level (MML). Secondary outcome measures are brain activity as measured by electroencephalography and standardized questionnaires for evaluating tinnitus distress and severity. Discussion: To the best of our knowledge, this is the first study, which uses HD-tRNS combined with AS for tinnitus treatment. The cross-over design permits the comparison between HD-tRNS active vs. sham and with vs. without AS. Thus, it will be possible to evaluate the efficacy of the combined approach to HD-tRNS alone. In addition, the use of different objective and subjective evaluations for tinnitus enable more reliable and valid results. Trial registration: Swiss Ethics Committee (BASEC-Nr. 2020-02027); Swiss Federal Complementary Database (kofam.ch: SNCTP000004051); and ClinicalTrials.gov (clinicaltrials.gov: NCT04551404).