Online Left-hemispheric Frontoparietal Theta In-phase tACS During Working Memory Training in Schizophrenia Patients: A Pilot Randomized Double-blind, Sham-controlled Study of the Effects on Negative Symptoms

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.