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Recently, a case has been made for the safety, tolerability and clinical utility of accelerated protocol for tDCS (acctDCS) (greater number of sessions over a shorter duration) in schizophrenia [
]. In this case report, we describe neurophysiological changes with acctDCS in (a) corollary discharge profile that is relevant to auditory hallucination (AH) pathophysiology and is a reliable indicator of tDCS treatment response [
Effect of fronto-temporal transcranial direct current stimulation on corollary discharge in schizophrenia: a randomized, double-blind, sham-controlled mediation analysis study.
Ms S, a 33 years-old-female patient, presented to us with a six years history of second and third-person auditory hallucinations, alongside significant persecutory, referential, religious, and grandiose delusions. Psychopathology examination elicited derailment, tangentiality, word approximations and sometimes neologism in speech. Poor compliance to oral olanzapine during the first three years of illness prompted treatment with depot injection of olanzapine of 300mg/month for three years. Due to recent non-adherence with resultant worsening of symptoms, the dose of olanzapine injection was increased to 405mg/month for the previous two months; nonetheless, the patient persisted in being symptomatic. At baseline, Positive and Negative Syndrome Scale (PANSS) score was 137 (Positive Scale = 32; Negative Scale = 39; General psychopathology Scale = 66; Supplementary Table 1), and Auditory Hallucination Rating Scale (AHRS) score was 34.
Because of significantly distressing symptoms requiring faster clinical improvement, the patient was treated with add-on acctDCS. AcctDCS protocol involved 10 sessions of 2mA direct current stimulation 20 minutes each over two consecutive days; 5 sessions/day with a 20-min inter-session interval using 7x5-cm electrodes covered with saline-soaked sponges; anode: left prefrontal; cathode: left temporo-parietal junction [
] event-related potential (ERP) paradigms as per the previous descriptions. The clinical outcome was assessed using AHRS and PANSS scales.
The patient tolerated the sessions well, reported no side effects and indicated a significant (44%) reduction in AH severity (AHRS = 19). But, given persistent higher overall psychopathology (PANSS = 112), another three days (15 sessions) of acctDCS (2nd course) was administered following which further decline was noted in AH severity (AHRS = 17; 50% reduction from baseline). There was a gap of two days between the 1st and 2nd course of acctDCS sessions. Overall, 25 tDCS sessions (5-sessions/day) were given to the patient. Both ERP paradigms were repeated after 25 sessions.
AcctDCS sessions were well-tolerated. At the start of the sessions, current appreciation was noted as a mild pricking sensation for a few sessions. An incremental response was noted in clinical symptoms from the 1st to the 2nd course of acctDCS, with a rapid reduction in AH in the first course but progressive improvement in negative and general psychopathology scores by the end of the 2nd course. (Supplementary Table 1).
Both CD and rMMN profiles were aberrant at baseline (Fig. 1). CD is the ability of an organism to discount the sensory consequences of self-generated action [
]. For auditory CD to be adequate, the Talk N100 amplitude should be attenuated (more + ve), indicating less responsiveness of the auditory cortex towards actively self-generated sounds. The Listen N100 amplitude should be robust (more -ve), indicating adequate arousal of the auditory cortex to passive speech sounds. At baseline, Talk and Listen N100 amplitudes were similar [Fig. 1(a). Talk = 0.58μV; Listen = 0.11μV] indicating neurophysiological activity linked to severe AH. Following the acctDCS-1st Course, the correction in the CD profile was prominent [Fig. 1(b). Talk = 2.04μV; Listen = −7.93μV]. This improvement persisted, albeit with lesser magnitude, after the acctDCS-2nd Course [Fig. 1(c). Talk = 0.22μV; Listen = −2.27μV]. The observed change in the CD profile indicates a correction of CD deficiency linked to the improvement of AH [
Effect of fronto-temporal transcranial direct current stimulation on corollary discharge in schizophrenia: a randomized, double-blind, sham-controlled mediation analysis study.
Fig. 11(a) & 1(b) Correction of Corollary Discharge profile after AcctDCS sessions. The N100 component (–ve peak occurring between 60-150ms) should be attenuated in Talk condition but not in Listen condition indicating adequate corollary discharge. 1(c) Attenuation of correction of Corollary Discharge profile following extended acctDCS sessions. 1(d) & 1(e) rMMN profile correction following AcctDCS sessions. Roving MMN profile should be MMN33>MMN8>MMN3 in decreasing order of negativity as measured by N1 component (–ve peak occurring between 100-200ms). 1(f) Enhancement of rMMN amplitudes (more –ve peaks) and negligible change in rMMN profile (MMN33>MMN8>MMN3 pattern) following extended acctDCS sessions.
rMMN is a nuanced measure of prediction error. In the rMMN paradigm, the deviant tone becomes the new standard over the course of stimuli presentation. The strength of prediction error signalling via the deviant stimuli varies as a function of the length of the standard stimuli's strain preceding it. rMMN paradigm allows examination of 1) repetition positivity (RP)–the strength of standard stimulus's memory trace that increases with repetition; 2) deviant negativity (DN)–the strength of prediction error signalling; and MMN that is derived from DN–RP [6]. The magnitude of prediction error signalling is higher when the train of preceding standard stimuli is longer. Stimuli differing in duration or frequency are presented in sets of 3, 8 and 33. Therefore, the expected MMN profile is MMN33>MMN8>MMN3 in the order of decreasing negativity of N1 amplitude. At baseline, the patient's rMMN profile notably deviated from the MMN33>MMN8>MMN3 pattern [Fig. 1(d)]. Following acctDCS-1st course, the correct pattern was established [Fig. 1(e)]. After the acctDCS-2nd Course, there was an enhancement of all MMN amplitudes (amplitudes became more -ve), indicating stronger prediction error signalling [Fig. 1(f)]. Correction of rMMN profile possibly reflects the ability of acctDCS to address deficient prediction error signalling and concomitant aberrant salience in schizophrenia.
The present case study supports the safety, tolerability, and potential clinical utility of extended acctDCS (25 sessions over 5 days) for treating severe AH and psychopathology in schizophrenia. As indicated by the correction of CD and rMMN, acctDCS is capable of rapid neuroplasticity modulation that likely underscores the clinical benefit. Redressal of CD and rMMN profiles may have facilitated more accurate auditory signal processing leading to a reduction in AH and internal misrepresentations of environmental stimuli, paving the way for overall improvement in psychopathology. The incremental clinical and pathophysiological response noted over two courses of acctDCS could be a latent/delayed effect of the 1st course, and additional benefits of extended sessions need to be systematically studied. Future studies should compare the effect of acctDCS to standard tDCS for clinical benefit and potential for neuroplasticity modulation.
Funding
This work is supported by the Department of Biotechnology (DBT) - Wellcome Trust India Alliance grants to GV (IA/CRC/19/1/610005) & AB (IA/CPHE/19/1/504591).
Declaration of competing interest
None.
Acknowledgements
Swarna Buddha Nayok acknowledges the support of the Indian Council of Medical Research (ICMR). Anushree Bose is supported by Department of Biotechnology (DBT)-Wellcome Trust India Alliance Early Career Fellowship grant (IA/CPHE/19/1/504591). Kiran Basawaraj Bagali & Ketaki Maity are supported by the Department of Biotechnology (DBT) - Wellcome Trust India Alliance (IA/CRC/19/1/610005). Venkataram Shivakumar acknowledges the support of Department of Biotechnology (DBT) - Wellcome Trust India Alliance Early Career Fellowship grant (IA/CPHE/18/1/503956). Vanteemar S Sreeraj acknowledges the support of the India-Korea joint program cooperation of science and technology by the National Research Foundation (NRF) Korea (2020K1A3A1A68093469), the Ministry of Science and ICT (MSIT) Korea, and the Department of Biotechnology (India) (DBT/IC-12031(22)-ICD-DBT). Ganesan Venkatasubramanian acknowledges the support of Department of Biotechnology (DBT) - Wellcome Trust India Alliance (IA/CRC/19/1/610005) and Department of Biotechnology, Government of India (BT/HRD-NBA-NWB/38/2019-20(6)).
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Effect of fronto-temporal transcranial direct current stimulation on corollary discharge in schizophrenia: a randomized, double-blind, sham-controlled mediation analysis study.
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