Feasibility of Online Neuromodulation Using Transcranial Alternating Current Stimulation in Schizophrenia.

Abnormalities in resting and event-related brain oscillations are known to be associated with cognitive deficits in schizophrenia. Transcranial alternating current stimulation (tACS) modulates these rhythms across the neuronal circuits and could have a potential therapeutic role in psychiatric disorders. In this report, we describe, for the first time, application of online tACS in a schizophrenia patient with working memory deficits. This case report supports the feasibility and potential utility of online tACS in schizophrenia, which needs further systematic research.

INTRODUCTION

Abnormalities in synchronized neural oscillations play a central role in the pathophysiology of schizophrenia.[1] Synchronization of these brain oscillations is feasible with the application of a novel brain stimulation technique, transcranial alternating current stimulation (tACS), in which alternating current of specified frequency entrains and enhances the brain rhythms to the corresponding frequency.[2]

Working memory impairment is one of the critical cognitive deficits found in schizophrenia patients. Previous studies suggested that working memory and executive function deficits in schizophrenia are associated with reduced low- and high-frequency electroencephalogram (EEG) activity.[3] Exogenously synchronizing the dorsolateral prefrontal cortex and posterior parietal cortex in phase with tACS frequency has been shown to enhance the working memory performance in healthy subjects.[4] Application of theta frequency (3–8 Hz) stimulation over parietal region can increase the working memory load,[5] and gamma frequency (>30 Hz) stimulation over frontal region can enhance the working memory processing.[6] tACS, given its potential to modulate brain oscillations, is postulated to be useful in enhancing the working memory in patients with schizophrenia.[3]

Moreover, the effect of tACS is known to be dependent on the state of the brain.[7] Application of a brain stimulation with the subject being concurrently engaged in a neuropsychological or a psychophysiological task is called “online” stimulation.[8] A cognitive task known to activate a specific brain region (e.g., working memory task and prefrontal cortex) has been shown to change its susceptibility to neuromodulation; hence, application of tACS to this brain region (i.e., prefrontal cortex) while it is engaged in a working memory task can potentially result in resonated effects.[7] Thus, further enhancement of neuromodulation in targeted brain region is feasible with “online tACS.”

Apart from a recent case report in obsessive compulsive disorder,[9] we are unaware of any other description on the application of tACS in psychiatric population. Moreover, there has been no report on the feasibility of “online” tACS in any psychiatric disorder. Given the complexity of online tACS, in this report, we describe the successful application of this neuromodulatory paradigm in a schizophrenia patient who had significant cognitive deficits.

CASE REPORT

Mr. P is a right-handed, 35-year-old male with an engineering degree diagnosed with paranoid schizophrenia (Diagnostic and Statistical Manual of Mental Disorders 4th Edition) with illness duration of 8 years. His symptoms were under partial remission with olanzapine 15 mg/day except for occasional auditory hallucinations. However, he reported significant cognitive deficits (digit symbol substitution test – 203 s for 100 digits; animal fluency test – 8/min; computerized n-back test – 91.6% accuracy in 1-back and 62.5% accuracy in 2-back) and poor occupational functioning.

The patient as well as his primary caregiver was provided with adequate information regarding the tACS procedure, and a video of the related procedural implementation was also shown; following this, the patient agreed to participate in the tACS sessions. We adhered to the ethical principles for medical research involving human subjects as per the World Medical Association Declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/). Two sessions of tACS were administered. The electrodes (35 cm2) were placed at the left dorsolateral prefrontal cortex (F3) and the left posterior parietal region (P3) according to 10–20 system.[10] Two online tACS sessions (first session with theta frequency and second session with gamma frequency) were administered with an inter-session interval of 48 h using standard equipment (Neuroconn DC Stimulator Plus, http://www.neuroconn.de/dc-stimulator_plus_en/) [Figure 1a]. During tACS, the subject performed computerized Sternberg's task that was presented using E-Prime software (https://www.pstnet.com/eprime.cfm). In this task, the patient was shown random sequence of numbers (in sets of 2 or 4 consisting of a random combination of numbers from 0 to 9). Each display sequence was followed by a blank screen for 2 s, following which a target numerical in red color was presented. Then, the patient would respond to the target digit by pressing “Yes” or “No” (left arrow and right arrows in key board) to indicate whether the target digit has been presented in the preceding sequence set. Once the patient responds, feedback will be given with ☒ or ☑ signs to indicate the correct and incorrect responses, respectively [Figure 1b]. Following this feedback, the next sequence of numbers will be presented. The patient was familiarized with the Sternberg's task before the tACS session; cognitive task was initiated after 2 min of initiation of tACS session. During the 20 min tACS session, the patient performed the Sternberg's task for 15 min (3 blocks of 5 min each with 1 min gap between each block).[11]

Figure 1

(a)Schematic representation of online transcranial alternating current stimulation experimental paradigms, (b) schematic representation of Sternberg's task during transcranial alternating current stimulation sessions

Theta transcranial alternating current stimulation

Baseline EEG was acquired, and peak alpha frequency of 11 was noted in the posterior electrodes (O1, O2, P3, P4, PZ, PO7, and PO8). As per the previous description,[10] individual-specific stimulating theta frequency was determined to be 6 Hz (stimulating theta frequency = individual peak alpha frequency –5). To determine the threshold of current strength, we applied tACS stimulation starting with 1 mA and increased the current strength stepwise by 0.25 mA up to a maximum of 2 mA. For every level of selected current strength, the stimulation was applied for 1 min (ramping up and down for 100 cycles). Since the patient was able to tolerate all the levels of current strength, 20 min of sinusoidal tACS was given at 6 Hz frequency at 2 mA current intensity without DC offset, a 0° relative phase, and impedance kept below 15 kΩ. The intensity was gradually ramped up for initial 100 cycles (~16 s) and similarly ramped down during the termination to minimize the adverse effects. Side effects were assessed using a structured questionnaire;[12] except for tolerable mild pricking sensation during the sessions. No other side effects were reported by the patient.[13]

Gamma transcranial alternating current stimulation

The second session of tACS was given after 48 h with a stimulation frequency of 40 Hz.[6] While determining threshold current intensity as described above, at levels above 1.5 mA, the patient experienced phosphenes left eye > right eye as well pricking sensations at the skin underneath the electrodes. Hence, gamma tACS (40 Hz frequency) at 1 mA was administered for 20 min; all other parameters were kept similar to that of theta tACS session. The patient tolerated the session well with flickering sensation during the initiation and only mild pricking sensations during the stimulation. No other side effects such as pressure sensations were noted during or following the gamma tACS session.[13]

During both the tACS sessions, the patient was able to perform the Sternberg's task with fair attentiveness and without cognitive fatigue; this was ascertained using a 10-point Likert scale. The effect of tACS was assessed with computerized numerical n-Back (0-, 1-, and 2-back) test and dual (position and color) 2-back test before the initiation and 20-min after the termination of each tACS session. We noticed improved accuracy of responses in 1-, 2-, and dual 2-back tests after theta tACS session (pre-tACS accuracy of 86.1%, 80.5%, and 9.5%; post-tACS accuracy - 94.4%, 86.1%, and 16%, respectively). Performances in gamma sessions remained unchanged in 1-, 2-, and dual 2-back tests (pre-tACS accuracy of 93.05%, 81.94%, and 25.5%; post-tACS accuracy of 91.66%, 77.78%, and 25%, respectively).

DISCUSSION

This case report offers preliminary support to the feasibility of implementing both theta- and gamma-online tACS in schizophrenia. Given that tACS has the potential to modulate various perceptual and cognitive abnormalities in psychiatric population,[3] it has promising applications in schizophrenia as well. However, we need systematic studies to optimize several tACS parameters (e.g., montage positions, stimulation frequency, current intensity, stimulation duration, state during the stimulation [resting/performing task/sleeping], and phase difference across the stimulation sites).[2] Importantly, these parameters are also related to tolerance and different side effects associated with tACS.[13]

Existing literature suggests that like other noninvasive brain stimulation techniques, tACS is safe and well tolerated; the potential side effects involve skin perceptions, pressure sensations, and phosphenes, which are usually mild and tolerable.[13] This is in tune with the observation that our patient was able to perform the task during the stimulation (online tACS), which encourages further systematic studies in schizophrenia.

Previous studies have reported improvement in performances during tACS at higher working memory load.[10] Similarly, we also observed an improvement in accuracy in dual 2-back tasks than in other tasks. Though the potential confounding influence of practice effect is a possibility, the task differential improvement (i.e., dual 2-back alone showing the improvement) as well as stimulation frequency-specific change (i.e., improvement occurring with theta, but not gamma frequency) in cognitive performance argues against this; however, definitive interpretations on such effects can be done with examination of larger number of subjects in a sham-controlled design that involves multiple sessions.

In summary, this case report highlights the feasibility and potential utility of online tACS as a new therapeutic tool in schizophrenia and this needs further systematic evaluation. Noninvasiveness, safety, and ease of administration of tACS, in addition to this being a relatively less-expensive tool, make it a promising avenue toward targeting different symptom profiles including cognition in several psychiatric disorders including schizophrenia.

Financial support and sponsorship

This work is supported by the Department of Science and Technology (Government of India) Research Grant (SR/CSI/158/2012) to GV and Indian Council of Medical Research Young Scientist Research Grant (DHR/HRD/Young Scientist/Type-VI(2)/2015) to VS. AB is supported by the Welcome Trust/DBT India Alliance.

Conflicts of interest

There are no conflicts of interest.