Theta tACS During Working Memory Training: A Pilot Study of the Effects on Negative Symptoms of Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder; Negative Symptoms; Working Memory Training; Psychosocial Impairment; Autonomic Imbalance; EEG
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional

Summary: 
      In this randomized double-blind trial, we investigated whether externally induced
      left-hemispheric frontoparietal theta synchronization by multi-electrode online theta (6Hz)
      transcranial alternating current stimulation (tACS) would enhance the influence of a working
      memory training on negative symptoms of schizophrenia.
    

Detailed description: 
      Negative symptoms have a negative impact on the prognosis of schizophrenia, but effective
      treatment for this symptom dimension is still under investigation. Identifying a treatment
      target that has a close link to negative symptoms or highly impacts negative symptoms may
      help to develop an effective therapy to counteract negative symptoms of schizophrenia. Recent
      theoretical and empirical work linking negative symptoms and cognitive impairment in
      schizophrenia has identified a potential treatment target: cognitive deficits. Evidence has
      indicated that cognitive remediation (CR) has a positive effect on improving negative
      symptoms of schizophrenia, in particular behavioural negative symptoms.

      Although it is still debated which active components of CR contribute to the improvements in
      negative symptoms. The framework proposed by Gold and colleagues may be a candidate to
      explain how CR improves negative symptoms (i.e., possible through improving working memory).
      Anhedonia (i.e., the diminished ability to experience pleasure and reduced reactivity to
      pleasurable stimuli) represents a challenging negative symptom in schizophrenia.The
      impairment in hedonic processing has been associated with reduced motivation to engage in
      potentially rewarding events. Working memory (WM) plays an important role in the formation,
      maintenance, and retrieval of affective and value representations, all of which are essential
      for anticipatory pleasure. Individuals represent events and forecast pleasure by using WM in
      order to recruit motivational resources. It has been suggested that there is a hedonic
      detector system within the WM model and that WM serves as a potential underlying cognitive
      mechanism for anticipatory pleasure and goal-related behaviours. Problems in WM may reduce
      the ability to retrieve and manipulate information to motivate and guide future behaviour,
      thereby contributing to diminished motivation and the pleasure experience. It is known that
      the recruitment of the prefrontal-striatal system (including dorsolateral prefrontal cortex,
      cingulate cortex, insula, and ventral striatum) implicates in hedonic processing. It is also
      known that the same brain regions can be viewed as core brain regions of the WM network
      because they are activated during WM load. The overlap in activation of the
      prefrontal-striatal system during hedonic processing and WM provides robust evidence
      supporting the relationship between hedonic capacity and WM. Evidence indicated a correlation
      between the activity in WM brain networks and the improvement in negative symptoms following
      antipsychotic treatment, suggesting a mediating effect of WM on negative symptoms improvement
      in the context of a pharmacological intervention. More recently, studies indicated that 20
      sessions of WM training (dual n-back task training) showed neural transfer effect to enhance
      hedonic processing in individuals with high social anhedonia and ameliorate hedonic
      dysfunction in schizophrenia patients with prominent negative symptoms.

      In addition to WM training, non-invasive brain stimulation (NIBS) is also a
      non-pharmacological method to improve brain neural plasticity. For example, repetitive
      transcranial magnetic stimulation (rTMS) can change the activity of cortical nerve
      temporarily or continuously and enhance neural plasticity. However, the ability of rTMS alone
      to improve cognitive function in schizophrenia is frequently limited to some extent,
      necessitating a combination with WM training to boost cognitive functions.

      Transcranial alternating current stimulation (tACS), a safe NIBS technique that applies
      low-intensity alternating current, is also a potential therapeutic option in treating the
      cognitive impairment in schizophrenia. The stimulation frequency of tACS is usually set to
      coincide with the targeted brain endogenous rhythms. It would synchronize the neural
      oscillations in the stimulated cortical regions to the applied stimulation frequency.
      Different tACS current intensity (0.5 to 4 mA), stimulation frequency (0.1 to 80 Hz),
      electrode montages, phase difference across the stimulation site, with/without DC offset, and
      the states (e.g., at rest or concurrently under the tasks) during stimulation contribute to
      its different effects. If both the target electrode and the reference electrode are in the
      same phase of the cycle of the current at any given time, the phase difference will be 0
      degree (i.e., in-phase). The phase difference will be 180 degrees (i.e., anti-phase) if the
      electrodes are in the opposite phase. In-phase and anti-phase tACS over brain regions elicits
      synchronization and desynchronization of neuronal activity across the brain regions,
      respectively.

      The state-dependent tACS effects indicate that the effects of tACS are enhanced when the
      state of the targeted brain regions is active. Specifically, synchronization of
      frontoparietal regions at theta frequencies dominates during an executive task. tACS at the
      frequency close to the theta oscillation activated by an executive task would elicit more
      resonance and may, in turn, help to enhance executive function. tACS applied when an
      individual is concurrently engaged in a specific cognitive task is defined as online tACS. In
      healthy subjects, online theta (6Hz) in-phase tACS facilitated frontoparietal phase coupling
      (synchronization) resulting in improved WM performance, whereas online theta (6Hz) anti-phase
      tACS disrupted theta phase-coupling (desynchonization) resulting in impaired WM performance.

      The prolonged after-effects of tACS may be related to a phenomenon called
      spike-timing-dependent plasticity (STDP), a process that modifies the connection strengths
      based on the relative timing of the input and output spikes (or action potentials) of a
      neuron. STDP means that synapse will be strengthened if input action potentials occur
      immediately before the output action potentials, and synapse will be made weaker if an input
      action potentials occur immediately after an output action potentials. The STDP process is
      known to explain in part long-term depression (LTD) and long-term potentiation (LTP) of
      nervous systems. To sum up, tACS at a frequency close to that of resonance frequency during
      tACS may intensify the synapses across the stimulated regions through the mechanism of STDP.
      Repetitive (multiple-session) tACS during specific time intervals may consolidate the
      neuroplasticity effects, and may, in turn, elicit a long-lasting effect for further clinical
      application in treating neuropsychiatric disorders. In schizophrenia patients, a few case
      reports indicated 1-5 sessions of online theta in-phase tACS over left frontoparietal regions
      improved the performance of WM and several other cognitive domains.

      So far, there is no relevant research report exploring whether and how the joint intervention
      (i.e., online theta (6Hz) in-phase tACS over the left frontoparietal regions plus WM
      training) will have a combined effect on improving the performance of WM and other cognitive
      domains in schizophrenic patients. Neither is any research investigating whether online theta
      (6Hz) in-phase tACS over the left frontoparietal regions can potentiate the effects of WM
      training on improving negative symptoms of schizophrenia. To sum up, we hypothesize that the
      combination training mode of active online theta tACS plus WM training would have a greater
      ability to reduce negative symptoms of schizophrenia compared to the training mode of sham
      online theta tACS plus WM training. The study aims to test the efficacy of "active online
      theta tACS plus WM" versus "sham online theta tACS plus WM training" in improving negative
      symptoms, WM performance, and other cognitive domains performance of schizophrenia using a
      double-blinded, randomized sham-controlled trial design. In order to evaluate the efficacy of
      the interventions, we will use behavioral outcomes (e.g., negative symptoms assessment and
      neurocognitive assessment) and neurophysiological outcomes (e.g., EEG and heart rate
      variability).

      Methods

      Dual N back training

      The study will use a dual n-back task for WM training. In this task, squares at 8 different
      locations will show up sequentially (stimulus length, 500 ms; inter-stimulus interval, 2,500
      ms) on a computer screen every 3 seconds. Simultaneously with the presentation of the
      squares, one of eight consonants will show up sequentially through a speaker. Participants
      will have to judge whether the location of a square and the consonant they heard matches the
      one n-back before (the same n value for both visual and auditory targets). Each training
      session has 20 blocks consisting of 20 + n trials and takes around 25 min. Each block
      includes six auditory and six visual targets (four appearing in only one modality, and two
      appearing in both modalities simultaneously) whose locations are random. Participants will
      have to make responses manually by pressing the mouse left-click button for visual targets
      and the right-click button for auditory targets. No responses were required for non-targets.
      If a target is correctly detected, a green flash will be given, which constitutes a positive
      feedback. If a target is falsely detected, a blue flash will be given, which constitutes a
      negative feedback. The dual N back training is designed to continuously vary its difficulty
      by modifying the WM load (i.e., the level of n) and thereby track the participants'
      performance. Each training session begins at n = 1. Participants' performance will be
      analyzed after each block and the level of n for the next block will be adapted according to
      the following principle. The level of n increases by 1 in the next block if the mistakes per
      modality made by the participant are<3. Conversely, n would decrease by 1 if the mistakes per
      modality made by the participant are>5. In all other cases, the n is kept unchanged.
      Participants will come to the laboratory and take part in the WM training sessions twice
      daily for 5 weekdays (total 10 sessions), with each session lasting for approximately 25
      minutes. The time interval between twice-daily sessions will be >3 hours.

      Online left-hemispheric frontoparietal theta (6Hz) in-phase tACS

      θ tACS will be administered during the dual n-back task, starting at the beginning of each
      task and lasting for 20 min. In the active θ tACS condition, sinusoidal tACS will be
      delivered by two battery-operated devices connected with two 4 × 1 wire adaptors (Equalizer
      Box, NeuroConn, Ilmenau, Germany). The electrode montages used for θ tACS will be positioned
      at left frontoparietal locations. The stimulation electrodes of the 1st stimulator will be
      placed at the International 10-10 electrode position F1, F5, AF3, and FC3 (stimulation
      electrodes) and CPz (return electrode) to cover the left frontal cortex. For the 2nd
      stimulator, the stimulation electrodes will be placed at P1, P5, CP3, and PO3 (stimulation
      electrodes) and FCz (return electrode) to cover the left parietal cortex. A NeuroConn digital
      to analog converter (DAQ) will control the two stimulators and create an in-phase
      (synchronous) setup (0° relative phase difference between the output signals of the two
      tACS-stimulators).
    

Intervention name(s): Theta tACS
Intervention type(s): Device
Intervention description(s): See detail in arm/group descriptions regarding the intervention.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Schizophrenia; Schizoaffective Disorder; Transcranial alternating current stimulation; Theta oscillatory rhythm; Theta Phase-Coupling; Negative symptoms; Working memory training