Efficacy of Theta Frequency HDtACS for Cognitive Deficits in Schizophrenia: A Randomized Double-Blind Sham-Controlled Study

Schizophrenia is a common and chronic neuropsychiatric disorder. Schizophrenia exerts an enormous personal, social and financial cost and one of the most disabling illness (Harrison, P., et al., 2017). Even with optimal treatment, individuals with schizophrenia are commonly left with cognitive impairments impacting on key functions such as working memory, attention, processing speed & executive function. These functions are recognised to be primarily associated with the prefrontal cortex of brain, and modulating activity in this region forms the basis of different interventional approaches (Lang et al., 2019). HD- tACS is a novel non-invasive brain stimulation technique where alternating current in the range of 0.5 to 4 mA is passed by means of electrode (Sreeraj, V.S., et al., 2019). This thesis examines whether theta frequency transcranial alternating current stimulation would improve cognitive deficits in individuals with schizophrenia.

Cognitive impairment was for many years a neglected component of schizophrenia, however contemporary studies have emphasised its extent and importance (Schaefer, J., et al., 2013). Deficits are seen across all domains of learning and memory, with disproportionate involvement of semantic memory, working memory and attention (Harrison, J., et al., 2017) Cognitive aspects of schizophrenia are a major determinant of poor outcome (Green, M.F., 2016). Working memory can be conceptualized as a memory system that temporarily stores and processes verbal and visuo-spatial information (Baddeley, A., 2003; D’ Esposito, M., 2007). Working memory impairment are common in people with schizophrenia (Forbes, N.F., et al., 2009; Heinrichs, R.W., and Zakzanis, K.K., 1998). There is evidence indicating that the level of working memory impairment is related to functional outcomes in this group (Green, M.F., et al 1996).

Poor working memory in schizophrenia has been linked to abnormal dorsolateral prefrontal cortex (DLPFC) activation (Callicott, J.H., et al., 2003; Minzenberg, M.J., et al., 2009; Potkin, S.G., et al., 2009). In schizophrenia, hypo-activation of the DLPFC during tasks of working memory is commonly reported in the literature (Minzenberg, M.J., et al., 2009). Hypo-activation of the DLPFC appears to be related to encoding and the maintenance of information, especially as the number of items to be remembered increases (Anticevic, A., et al., 2013; Metzak, P.D., et al., 2012). Hyper-activation of the DLPFC has also been reported in schizophrenia (Callicott, J.H., et al., 2003; Potkin, S.G., et al., 2009). Hyper-activation of DLPFC is typically observed when participants with schizophrenia show working memory performance equivalent to healthy controls (Callicott, J.H., et al., 2003).

The neurobiological basis of cognitive deficit are complex (Minzenberg et al., 2009). Nevertheless, recent advances in neuroimaging contributed to probable neural correlates of cognitive deficit. Altered frontal activity is apparent in fMRI and the N-back task studies of schizophrenia, particularly in the prefrontal cortex during performance of working memory tasks (Harrison, P., et al., 2017). In a landmark study, Johnstone et al. (1976) used the novel technique of computerized tomography and found significantly larger ventricles and cerebral atrophy. Study conducted by Ingvar and Franzen (1974), who used injections of radioactive xenon and found decreased perfusion of the frontal cortex compared with the posterior regions in chronic, medicated patients with schizophrenia. Neurodevelopmental hypothesis of schizophrenia supports the cognitive impairment in the children who later develops schizophrenia.

Transcranial alternating current stimulation uses bidirectional biphasic current that periodically fluctuates/alternate from positive to negative charges across the 2 electrodes. Abnormalities in brain oscillations are known to underlie the pathogenesis of neuropsychiatric disorders. (Uhlhaas, P.J., and Singer, W., 2010) It is hypothesized that if sinusoidal current is applied externally, it can increase or decrease the power of endogenous oscillatory rhythms in the brain and can potentially rectify the abnormalities in brain oscillations. The mechanistic basis of HD-tACS might involve synchronization or desynchronization of the peak oscillatory activity in the neuronal networks. This is called neuronal entrainment (Sreeraj, V.S., et al., 2019). It has been postulated that rather than shifting the peak frequency and phase of oscillations, it is the matching of external frequency with the endogenous activity which brings the effect of HD-tACS (Schmidt, S.L., et al.,2014).Different rhythms occur simultaneously in the brain and are known to modulate each other. Hence, the effects might not be simple and unidirectional, as the targeted oscillations can further modulate oscillations of other frequencies, which could mediate the functional changes (Reato, D., et al.,2013).Transcranial electrical stimulation are novel modalities modulates endogenous neural oscillations showing potential to improve cognitive deficits (Ahn, S., et al., 2019)

Role of tDCS in treating cognitive deficit is inconclusive. Transcranial alternating current stimulation (tACS), a non-invasive brain stimulation technique that uses low intensity alternating current, has been postulated to be a potential therapeutic option in treating the cognitive deficits in schizophrenia. tACS synchronises the neural oscillations to the applied stimulation frequency in the stimulated cortical regions. Impaired theta wave activity in the frontoparietal neuronal network has been shown to be associated with working memory (WM) deficits in schizophrenia. Two study has shown tACS improves working memory (Sreeraj, V.S., et al., 2019; Ahn, S., et al., 2019). There is only one case report which found online theta tACS led to improvement in working memory, attention, processing speed (Sloan, N. P., et al., 2020). The beneficial effect of tACS persisted during reassessment of the patient after 50 days (Sreeraj, V.S., et al., 2019).

Need for Study

Cognitive deficits critically contribute to functional disability in schizophrenia; these deficits persist even after adequate treatment with antipsychotics. The synchronization of brain oscillations of prefrontal cortex with other areas like parietal lobe during an executive function task is deemed to be the underlying mechanism of dynamic neuronal binding. Working memory (WM) provides temporary storage and manipulation of information required for a variety of complex cognitive tasks. WM capacity plays a central role in daily life activities and is predictive for a wide range of higher cognitive measures. Transcranial alternating current stimulation has advantage over other techniques of non-invasive brain stimulation such as cost effectiveness, small size of the apparatus, allowing portability, possibility of modulating neuronal activity. Promising results have been obtained in a case report of effect of online theta frequency tACS stimulation for cognitive remediation in schizophrenia. HD-theta tACS has the potential to ameliorate cognitive deficits in schizophrenia.

Aim of the Study

To see the neuromodulatory effect of adjunctive online theta frequency HD-tACS for cognitive remediation in schizophrenia.