Authors (including presenting author) :
Lo, Ka Ying Heidi, kayinglo@cuhk.edu.hk c
Chan, Sheung Chun, csc407@ha.org.hkc
Chau, Steven Wai Ho, stevenwaihouchau@cuhk.edu.hka
Cheng, Pak Wing Calvin, chengpsy@hku.hkb
Cheung, Kam Yee, cky321@ha.org.hkc
Lam, Hiu Ha, lamdebby@gmail.comc
Mo, Yi Man, mym311@ha.org.hkc
Wong, Wing Ho Oscar, oscarwhwong@cuhk.edu.hka
Wong, Yip Chau, wyc461@ha.org.hkc
Chan, Sau Man Sandra, schan@cuhk.edu.hka
Affiliation :
a Department of Psychiatry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR China
b Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong Island, Hong Kong SAR China
c Tai Po Hospital, Tai Po, New Territories, Hong Kong SAR China
Introduction :
Working memory has been defined as a system of components that holds a limited amount of information temporarily in a heightened state of availability for use in ongoing processing. Impaired working memory in schizophrenia patients has been associated with poorer functional outcomes. Therefore, it has been suggested that remediation of working memory impairments could be a valuable treatment for schizophrenia.
tDCS is a safe and non-invasive neuromodulation technique that induces subthreshold stimulation that can modulate brain networks and enhance cognitive performance. More specifically, research showed that tDCS alters the threshold of membrane polarization and can either enhance or reduce synaptic excitability by applying anodal or cathodal stimulation, respectively. However, a recent meta-analysis that investigated the effect of anodal tDCS over one of the key nodes of the cognitive control network (dorsolateral prefrontal cortex; DLPFC) on cognition in schizophrenia showed no reliable improvement in working memory in schizophrenia. It is urgently needed to investigate tDCS protocols by modifying several components of currently available tDCS protocols, such as the dosage, location, and state-dependency. Several studies indicated that the effect of tDCS highly depends on the subject’s brain state, known as state-dependency. In healthy subjects, CT augmented tDCS showed superior effects on cognition compared to tDCS during rest. CT has been defined as a behavioral training-based intervention that aims to improve cognitive processes with the goal of durability and generalization. Although research suggests that CT modulate dysfunctional neuronal systems in schizophrenia, the efficacy of CT is overcast by feasibility concern including undesirably high attrition rates and only small short-term effects on cognition in most CT studies.
Given the superior effects of CT augmented tDCS in healthy subjects, a handful of studies investigated whether the state-dependent tDCS protocol would benefit schizophrenia patients. These studies had inconclusive results and varied in terms of loose outcome measures, missing data, and lack of proper randomization and blinding. To fill the knowledge gap in investigating the effects of concurrent CT with tDCS in patients with schizophrenia, the present study is a double-blinded randomized controlled using validated cognitive batteries. The outcomes were examined at baseline (T0), immediately after the intervention (T1), and one-month post-intervention (T2). It was hypothesized that concurrent CT with tDCS would result in greater and more sustainable cognitive improvement than CT alone because of increased susceptibility to neuroplasticity changes of the underlying
Objectives :
The primary objective of the study was to investigate the effect of ‘online’ tDCS with cognitive training on specific cognitive domains in stable schizophrenia patients at two time-points, (i) immediately after the intervention (ii) at one month after intervention.
The secondary objectives of the study were to evaluate the effects of ‘online’ tDCS with cognitive training on non-cognitive measures, namely (i) changes in affective, psychotic and negative symptoms; (ii) psychosocial functioning, subjective quality of life (QOL); (iii) the motivation to participate in the gamified cognitive training; and (iv) the tolerability and adverse events of tDCS among patients with schizophrenia.
Hypotheses
1. Concurrent cognitive training with active tDCS would result in greater incremental effect in cognitive domains as compared to the concurrent cognitive training with sham tDCS.
2. As compared to the cognitive training with sham tDCS, the cognitive effects after concurrent cognitive training with active tDCS intervention would be sustainable at one-month follow-up.
3. Concurrent cognitive training with active tDCS intervention would have superior effect on improving (i) psychotic, (ii) negative symptoms, and (iii) affective symptoms than cognitive training with sham tDCS.
4. As compared to the cognitive training with sham tDCS, concurrent cognitive training with active tDCS would be associated with superior improvement of (i) psychosocial functioning, and (ii) subjective quality of life (QOL).
5. Active tDCS would be as tolerable as sham tDCS in terms of adverse side effects and low attrition rate.
Methodology :
Participants
Forty-six clinically stable patients with schizophrenia participated in the study (24 female, all right-handed, mean age ± SD = 41.32 ±11.28 years, table 1). All met the criteria for a current ICD-10 defined Schizophrenia at study entry which was endorsed by two psychiatrists. Exclusion criteria were a history of neurologic disorders, neurosurgery or diagnosed learning disabilities, current active abuse of alcohol or illicit substances, pacemakers, intracranial electrodes, defibrillators, metal implants in the head or neck area, pregnancy, and breastfeeding. The use of cognitive-enhancing medications such as acetylcholinesterase inhibitors was not allowed. All patients had been stable on the same medication at the same dose for a minimum of two weeks before the study period [26].
Informed consent was obtained from each eligible subject. The study has been carried out in accordance with the Declaration of Helsinki and received approval from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee on 28 June 2019 (Reference: CREC 2019.239). It was also registered at clinicaltrials.gov (Reference: NCT04870996) and the Chinese Clinical Trial Registry (Reference: ChiCTR1900025550).
Study Design
Participants were randomly allocated to one of the two groups using a predetermined randomization sequence and block randomization generator (blocks of 6). Group 1 received active tDCS stimulation and CT and will be referred to as the active tDCS + CT group. Group 2 received sham tDCS and CT and will be referred to as the sham tDCS + CT group. Both groups consisted of 23 participants and received five treatment sessions on five consecutive days.
The stimulation protocol with the corresponding randomization code was set up by an independent psychiatrist. The double-blind administration panel of the StarStim8 system of tDCS ensured effective blinding; both the principal investigator and the participants were blinded to the group allocation until the statistical analysis stage. All outcome measures were assessed at three occasions (T0, baseline; T1, end-treatment course; and T2, one-month post-intervention).
Five treatment sessions were administered on five consecutive days and blinded assessments of cognitive and clinical outcomes were conducted at baseline, upon completion of the intervention, and one-month post-intervention. The cognitive outcomes included processing speed, working memory, sustained attention, and visual memory and new learning using standardized cognitive paradigms from the CANTAB, Trail Making Test A, and Backward Digit Span.
Result & Outcome :
Primary Analysis: Cognitive Measures.
For the most part, repeated-measures ANOVA revealed no differences between conditions for cognitive or secondary clinical or functional outcome measures.
For Backward Digit Span score (illustrated in Figure 1), we observed a statistically significant effect of time (F (2, 84) = 15.91, p < .001, η_p^2 = .28). Post hoc analyses with Bonferroni correction (p ≤ .0167*) revealed improvements at T1 compared to baseline were fairly similar for both groups, but only change in the active group reached significance (t(21) = -3.86, p = 0.001). This group further improved at T2 (t(21)= -4.58, p < .001), while the sham group did not show any significant improvements over time. It was in favor of the active tDCS group with concurrent CT as an immediate and sustained improvement.
Secondary Outcome Measures: Clinical Measures
For the secondary outcome measures, there was no significant difference in the clinical effects of active tDCS + CT versus sham tDCS + CT after adjusting for the baseline difference using ANCOVA (Table S7).
Adverse Events in tDCS
Adverse events for all conditions, which are presented in Table S11, had no significant difference (p=.132-.312). The experiment protocol was well-tolerated, with no significant difference in adverse event proportion.
The current study utilized a longitudinal double-blind randomized controlled design. This is the highest standard in intervention studies, minimizing the impact of unknown or immeasurable confounding variables that may induce bias or lead to overestimated effect sizes. Further, this is the first study that suggested a plausible effect of add-on tDCS in the outcome measure of working memory in an almost complete dataset up to at least one-month after the treatment. This fills the pre-existing knowledge gap about the durability of potential cognitive effects of tDCS + CT and substantiates the safety and tolerability of the intervention.
Conclusion
The current mixed low-intensity tDCS and gamified cognitive training utilized a longitudinal double-blind randomized controlled design with an almost complete dataset up to at least one month after the treatment. This proof-of-concept study demonstrated tolerability, low attrition and supported a plausible sustained effect of tDCS+CT on a selected aspect on working memory in a group of cognitively impaired patients with schizophrenia.
