Letter to the Editor

Efficacy and safety of fronto-temporal transcranial random noise stimulation (tRNS) in drug-free patients with schizophrenia: A case study

Mental health disorders and substance use disorders are a leading cause of morbidity and mortality worldwide, and one of the most important challenges for public health systems. While evidence-based psychotherapy is generally pursued to address mental health challenges, psychological change is often hampered by non-adherence to treatments, relapses, and practical barriers (e.g., time, cost). In recent decades, Non-invasive brain stimulation (NIBS) techniques have emerged as promising tools to directly target dysfunctional neural circuitry and promote long-lasting plastic changes. While the therapeutic efficacy of NIBS protocols for mental illnesses has been established, neuromodulatory interventions might also be employed to support the processes activated by psychotherapy. Indeed, combining psychotherapy with NIBS might help tailor the treatment to the patient’s unique characteristics and therapeutic goal, and would allow more direct control of the neuronal changes induced by therapy. Herein, we overview emerging evidence on the use of NIBS to enhance the psychotherapeutic effect, while highlighting the next steps in advancing clinical and research methods toward personalized intervention approaches.

High-frequency transcranial random noise stimulation (hf-tRNS) is a non-invasive neuromodulatory technique capable of increasing human cortex excitability. There were only published case reports on the use of hf-tRNS targeting the lateral prefrontal cortex in treating negative symptoms of schizophrenia, thus necessitating systematic investigation. We designed a randomized, double-blind, sham-controlled trial in a cohort of stabilized schizophrenia patients to examine the efficacy of add-on hf-tRNS (100–640 Hz; 2 mA; 20 min) using a high definition 4 × 1 electrode montage (anode AF3, cathodes AF4, F2, F6, and FC4) in treating negative symptoms (ClinicalTrials.gov ID: NCT04038788). Participants received either active hf-tRNS or sham twice daily for 5 consecutive weekdays. Primary outcome measure was the change over time in the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), which was measured at baseline, after 10-session stimulation, and at one-week and one-month follow-ups. Among 36 randomized patients, 35 (97.2%) completed the trial. Intention-to-treat analysis showed a significantly greater decrease in PANSS-FSNS score after active (−17.11%) than after sham stimulation (−1.68%), with a large effect size (Cohen's d = 2.16, p < 0.001). The beneficial effect lasted for up to one month. In secondary-outcome analyses, the authors observed improvements with hf-tRNS of disorganization symptoms, unawareness of negative symptoms, subjective response to taking antipsychotics, and antipsychotic-induced extrapyramidal symptoms. No effects were observed on the neurocognitive performance and other outcome measures. Overall, hf-tRNS was safe and efficacious in improving negative symptoms. Our promising findings should be confirmed in a larger sample of patients with predominant negative symptoms.

Anxiety is characterized by psychological, physiological, and cognitive complaints. Current treatments have significant limitations, and often overlook any potential benefits to common cognitive symptoms, notably attention and executive function issues. The current study aimed to investigate the use of transcranial direct current stimulation (tDCS) on both common anxiety symptoms and executive function abilities in a college aged sample.

As this is one of the first large scale anxiety studies utilizing tDCS, participants were given a single session of tDCS (anodal, cathodal, or sham) for 20 min at 2 mA over the left dorsolateral prefrontal cortex (lDLPFC). Participants also completed a series of self-reported anxiety measures and measures of executive functioning (Rey-O Copy and Wisconsin Card Sorting Task).

While there were no differences in anxiety between tDCS groups, a trend was noted demonstrating better performance on Rey-O Copy for the cathodal group. Anxiety increased pre to post for all groups.

Overall, results suggest that while anodal stimulation of the lDLPFC may benefit cognitive abilities for this population, targeting psychological symptoms of anxiety likely requires stimulation over other cortex, possibly right DLPFC. Further, the use of tDCS, whether active or sham, may be distressing to patients.

A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinson’s disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimer’s disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10–24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.

Random noise stimulation was reported as the more effective and safer type of electrical stimulation techniques in relieving tinnitus symptoms. The multisite protocol of transcranial random noise stimulation has shown additional favorable effects.

Here we will discuss the role of applying eight sessions of multisite transcranial random noise stimulation in decreasing tinnitus loudness and annoyance without exerting additional adverse effects.

Twenty-nine subjects (8 female), the mean age of (45.34 ± 9.57) with chronic tinnitus received transcranial random noise stimulation in the multisite protocol, 10 min of auditory-transcranial random noise stimulation applied over the T3, T4 preceded by 10 min of prefrontal-transcranial random noise stimulation applied over F4, FP1. In the first group, only one session was applied and the multiple-sessions group contained eight repeated sessions. Visual analog scale scores for loudness and distress were recorded before and immediately after the treatment. Multivariate repeated measure ANOVA test was used and minimal detectable change calculated.

There was a statistically and clinically significant reduction in tinnitus loudness and annoyance in both groups (p < 0.05, effect size (η²) > 0.8), while the amount of annoyance suppression in the multiple-sessions group was significantly greater than the single-session group. The patients of the multiple-sessions transcranial random noise stimulation group reported an improvement in their sleep and lower tinnitus handicap inventory scores without experiencing any additional adverse effects of the intervention.

The results of this study showed a substantial improvement in tinnitus symptoms by using the multiple sessions of transcranial random noise stimulation in the multisite protocol without producing any additional side effects. We suggest further clinical trials with long-term follow-up be investigated.

Tem sido relatado que a estimulação transcraniana por ruído aleatório é um tipo mais eficaz e seguro de técnica de estimulação elétrica no alívio dos sintomas do zumbido. O protocolo multissítio da estimulação transcraniana por ruído aleatório mostrou efeitos favoráveis adicionais.

Discutir o papel da aplicação de oito sessões de estimulação transcraniana por ruído aleatório multissítio na diminuição da intensidade (loudness) do som e incômodo (annoyance) do zumbido sem causar efeitos adversos adicionais.

Vinte e nove indivíduos com zumbido crônico (oito do sexo feminino), com média de 45,34 ± 9,57 anos, receberam estimulação transcraniana por ruído aleatório no protocolo multissítio, 10 minutos de estimulação transcraniana por ruído aleatório-auditivo aplicado no T3, T4 precedido por 10 min de estimulação transcraniana por ruído aleatório pré-frontal aplicado sobre F4, FP1. No primeiro grupo, apenas uma sessão foi aplicada e o grupo de múltiplas sessões recebeu oito sessões. Os escores da escala visual analógica para a intensidade do som (loudness) e incômodo (annoyance) do zumbido foram registrados antes e imediatamente após o tratamento. O teste Anova multivariada para medidas repetidas foi utilizado e a mudança mínima detectável foi calculada.

Houve uma redução estatisticamente e clinicamente significante na intensidade e incômodo do zumbido em ambos os grupos (p < 0,05; tamanho do efeito (η2) > 0,8), embora o nível de supressão do incômodo no grupo de sessões múltiplas tenha sido significantemente maior do que no grupo de sessão única. Os pacientes do grupo estimulação transcraniana por ruído aleatório com múltiplas sessões relataram uma melhoria no sono e menores escores no tinnitus handicap inventory, sem experimentar quaisquer efeitos adversos adicionais da intervenção.

Os resultados deste estudo mostraram uma melhora substancial nos sintomas do zumbido utilizando múltiplas sessões de estimulação transcraniana por ruído aleatório no protocolo multissítio sem produzir quaisquer efeitos colaterais adicionais. Sugerimos que novos ensaios clínicos com seguimento de longo prazo sejam realizados.