Add-on HD Hf-tRNS Over Bilateral DLPFC for Treating Patients With Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder; Psychotic Symptoms; Neurocognitive Dysfunction; Insight Impaired; Quality of Life; Psychosocial Impairment; Autonomic Imbalance; EEG With Abnormally Slow Frequencies
MeSH terms: Schizophrenia; Psychotic Disorders; Cognitive Dysfunction
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): HD hf-tRNS
Intervention type(s): Device
Intervention description(s): See detail in arm/group descriptions regarding the intervention.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In active tRNS condition, random noise 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. Stimulation was applied at an intensity of 2 milliampere (mA) for 20 min, twice-daily on 5 consecutive weekdays.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment