Add-on HD Hf-tRNS Over Bilateral DLPFC for Treating Patients With Schizophrenia

The study aimed to investigate the effects of high-definition transcranial random noise stimulation over bilateral prefrontal cortex on psychopathological symptoms, other clinical outcomes, autonomic functioning ,and brain oscillatory activity in schizophrenia patients.

Negative symptoms of schizophrenia include blunted affect, avolition-apathy, alogia and anhedonia-asociality and are closely linked to neurocognitive deficits. Negative symptoms and neurocognitive impairments are associated with poor functional outcomes. Prefrontal cortical dysfunction, particularly hypoactivity of the dorsolateral prefrontal cortex (DLPFC) has consistently been reported in schizophrenia and suggested to underlie the pathophysiology of negative symptom and neurocognitive impairment. Atypical antipsychotics, the mainstream treatment for schizophrenia, are known to show little effect on patients' hypofrontality and some of them (e.g., strong dopamine receptor antagonists and clozapine) are even associated with a decrease in prefrontal activation. Furthermore, good evidence that atypical antipsychotics have any beneficial effect on negative symptoms or neurocognitive impairments is still lacking. Currently, negative symptoms and cognitive deficits remain the most important unmet therapeutic needs in schizophrenia, which have driven the development of novel and effective treatments targeting the core pathophysiological features of the deficits, e.g., non-invasive brain stimulation (NIBS) of DLPFC.

Transcranial random noise stimulation (tRNS) is a neuromodulation technique that applies a weak alternating current over the brain cortex at random frequencies (0.1- 640 Hz), i.e., the current oscillating randomly in amplitude over time and within defined thresholds, following the Gaussian curve around a midpoint, called "offset". Switching the offset from zero towards positive current strength, e.g.1 mA inhibits negative polarisation during the oscillations and provides a unidirectional current flow. It is well-known that when the neurons are stimulated under a constant electrical field, the neuronal membranes adapt themselves and return to their original resting state (i.e., homeostasis of system or the homeostatic phenomena of ion neuron channels). Given the nature of constantly changing electrical field of tRNS, a potential advantage of this type of NIBS is that it might not result in homeostasis of the neural system, the mechanism thought to account for the limit to additional increases in cortical excitability with prolonged constant electrical stimulation. The pilot study in humans reported that tRNS does not work in a polarity dependent way and can increase cortical excitability under both electrodes placed on the scalp. Specifically, tRNS over the motor area positively modulates cortical excitability and improves motor learning, possibly through the mechanism of long-term potentiation (LTP). Given the particular wave shape of tRNS, it might induce temporal summation of small depolarizing currents, which could interact with the activity of the engaged neurons and therefore improve performance in perceptual learning. Therefore, tRNS of neurons provides the driving force for a synaptic potentiation-like phenomenon. The effect was more pronounced with high frequency (hf)-tRNS, which was possibly related to the range of frequency applied (100-640 Hz). Since the time constant of the neuronal cell body and dendrites has been known between 1-10 ms, stimulation at the frequency range between 100-1000 Hz may be appropriate for exerting a meaningful effect on neuronal communication. In addition, a prolonged opening of the voltage-gated sodium channels is also a possible underlying neuronal correlate for hf-tRNS to elicit more cortical excitability shifts and more pronounced plasticity changes. Another proposed mechanism through which tRNS exerts behavioral effects is the stochastic resonance phenomenon. tRNS represents a stimulation that gives rise to nonfinalized random activity in the system i.e., noise. In a linear system, noise generally reduces behavioral performance, but non-linear systems (e.g., the brain) may apply noise to improve performance via stochastic resonance. That is, neurons become sensitive to a specific range of weak inputs in the presence of an optimal level of neuronal noise, and the behavioral performance is therefore facilitated. To the investigator's knowledge, the treatment of schizophrenia with tRNS has only been reported in case studies as an add-on treatment for negative symptoms in a medicated patient or as a monotherapy in alleviating delusions and enhancing insight of the illness in a drug-free patient.

The study aimed to investigate the effects of add-on high-definition high-frequency transcranial random noise stimulation over bilateral prefrontal cortex on negative symptoms and other psychopathological symptoms, clinical outcomes (insight levels, psychosocial functioning, quality of life, beliefs about medication adherence, severity of extrapyramidal symptoms, neurocognitive function), autonomic functioning ,and brain oscillatory activity in schizophrenia patients.

Study design: randomized double-blind, sham-controlled study design.

Participants: 36 patients having a diagnosis of schizophrenia or schizoaffective were randomly allocated to receive 20 minutes of active 2-mA HD-hf-tRNS or sham stimulation twice a day on 5 consecutive weekdays. These participants were assessed at baseline, after intervention, one-week and one-month follow-ups.

Active or sham stimulation: tRNS was delivered by a battery-operated device (Eldith DC stimulator Plus, neuroConn, Ilmenau, Germany) via 5 carbon rubber electrodes (1 cm radius, high-definition 4 × 1 rings configuration with a gel layer of 2.0 mm), with 2 mA amplitude, offset at 1 mA, frequency 100-640 Hz, for 20 min with 15 s ramp-in/ramp-out. The combined impedance of all electrodes was kept below 15 kΩ, as measured by NeuroConn DC stimulator Plus device, using electrolyte gel. The anode was placed over International 10-10 electrode position AF3 (a point midway between F3 and Fp1), with cathodes (reference electrodes) at AF4, F2, F6 and FC4. The sessions were conducted twice a day on 5 consecutive working days. In the sham group, current was applied for 30 s after upward ramping and then terminated. Immediately after the first stimulation session, all participants were asked to answer the question of whether they received active or sham treatment.

Others: see Arms and Interventions, Eligibility Criteria or Outcome Measures.

Eligibility Criteria:
Inclusion Criteria:

1. Eligible participants aged 20-65 with DSM-V-defined schizophrenia or schizoaffective disorder.
2. Duration of illness ≧ 1 year.
3. Being on an adequate therapeutic dose of antipsychotics for at least 8 weeks prior to enrolment.
4. Positive and Negative Syndrome Scale (PANSS scale) total score \< 120 (at both screening and baseline).
5. Agreement to participate in the study and provide the written informed consent.

Exclusion Criteria:

1. Having current psychiatric comorbidity or active substance use disorder, in exception to caffeine and/or tobacco.
2. Having a history of seizures.
3. Having contraindications for transcranial electrical stimulation or transcranial magnetic stimulation, e.g., implanted brain medical devices or metal in the head.
4. Having a history of intracranial neoplasms or surgery, or a history of severe head injuries or cerebrovascular diseases.
5. Pregnancy or breastfeeding at enrollment.