A Randomised Controlled Trial of Concurrent Cognitive Training and Transcranial Direct Current Stimulation or Cognitive Training Alone in Patients With Schizophrenia.
Phase: NA
Conditions: Schizophrenia
Sponsor: CHAN SAU MAN, SANDRA

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 1 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
 
 
 
 
 
 
 
 
Project topic: 
A Randomised Controlled Trial of Concurrent Cognitive Training with online Transcranial 
Direct Current Stimulation (tDCS) and Cognitive Training Alone in Patients with 
Schizophrenia 
 
 

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 2 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Background: 
i.Cognitive Deficits in Schizophrenia and Current Treatment Options  
Schizophrenia is a disabling mental illness characterized by a wide range of impairments 
across multiple cognitive domains. [1-6] There is substantial evidence that cognitive deficits 
represent a ‘glass ceiling’ preventing functional recovery and impact on utilization of hospital 
service. [7, 8] It is expected that even small improvements in cognitive performance could 
facilitate their transition to independent living and working, and improve their wellbeing.  
Schizophrenia patients show significant cognitive deficits across all domains with the greatest 
deficits in working memory, visual spatial learning , attention/ vigilance and speed of 
processing. [9-11]  It is suggested that dorsolateral prefrontal cortex (DLPFC) is responsible 
for the deficits in the cognitive domains based on recent functional magnetic resonance 
imaging studies. [12] On neurobiological level to increase DLPFC activity , current 
pharmacological options have shown no or only weak effects in schizophrenia. [13, 14] . 
Intensive training might ameliorate the cognition in modest effect size,  but it has limited 
viability to be used on much larger scale. [15] Considering the burden, severity and 
functional outcome of schizophrenia including the explosion of technological advances 
underused in mental healthcare, new cognitive enhancement techniques to improve their 
wellbeing are needed.  
ii.Role of tDCS in Schizophrenia  
The breakthrough findings in therapeutic applications of repetitive transcranial magnetic 
stimulation(rTMS) have revived the popularity of exploring neuromodulation strategies. In 
particular, tDCS is a non-invasive brain stimulation that uses small electric current (usually 
2mA) to specific areas of the brain, and alters excitability of brain cells through polarity 
dependent stimulation. Anodal stimulation of the brain areas generally enhances excitability, 
whereas cathodal stimulation reduces it. [16] Similar to rTMS, the manipulation of electrode 
positions and polarity would lead to different targeted effects in the brain. Nonetheless, 
unlike rTMS, tDCS is easier to use with behavioral techniques to enhance learning, because it 
is less likely to influence attention, produces less scalp sensation [17] and being portable with 
wide clinical utility with remote control setting. [18, 19]  
In the past randomized controlled trials, it had been reported that anodal stimulation of the 
dorsal lateral prefrontal cortex (DLPFC) is effective in enhancing working memory.[20-22] 
One randomized-controlled study in 2015 showed that 5 tDCS sessions has the potential to 
enhance cognitive function in schizophrenia , particularly working memory[23]. However, 
other studies have yielded inconsistent results. In the most recent meta-analysis in 2017,  it 
was concluded that ‘due to plaucity of available data, much remains unknown regarding the 
clinical efficacy of tDCS in schizophrenia’.[24] Furthermore, none of these studies used the 
Cambridge Neuropsychological Test Automated Battery (CANTAB), which was developed 
at the University of Cambridge as the international standard in detecting changes in cognitive 
performances in schizophrenia[10]. Therefore, it is important to explore strategies that may 
augment and consolidate cognitive benefits of tDCS with more sensitive measurement.  
iii.Role of Cognitive Training in Schizophrenia  
Available evidence suggests that cognitive training is able to improve cognitive performance, 
at least in the domain being trained (near transfer). Specifically designed cognitive training 

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 3 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
may have an additional role of transferrable cognitive benefits to other cognitive domains 
(distal transfer).[25-27] Of particular interest, recent computer-assisted cognitive 
rehabilitation and training studies have successfully shown improvements. [28-33] In 
particular, Professor Sahakian at the University of Cambridge developed a computerized 
cognitive training to improve cognition in schizophrenia, which is available on iOS as part of 
the online app ‘ the Peak’ . It was evidenced that patients with schizophrenia improve 
cognitive performance after the game. [33, 34] 
iv.Potential to Enhance Cognitive Training in tDCS in ‘Online Mode’  
Our brain is responsive to mental stimulation with enhanced function. Electrical stimulation 
to the brain appeared to alter neuronal activities with corresponding changes in 
neuroplasticity , that would modulate the neural response to mental stimulation through 
cognitive training. A further line of investigation has involved using tDCS to enhance the 
effects of cognitive training, based on the principle that anodal tDCS lowers the threshold for 
neuronal activation, and thus stimulation before or during the cognitive training may facilitate 
the activation and reinforcement of the specific neural circuits involved. [35-37].  
Based on current evidence, ‘online’ tDCS (tDCS is applied concurrently with cognitive 
training) is superior to ‘offline’ tDCS (tDCS is applied immediately before cognitive 
training). It was suggested that ‘online’ tDCS was superior in the combination of tDCS and 
cognitive training protocols in cognitive rehabilitation. [36] It is postulated that the neurons 
involved in cognitive training are more sensitive to the polarizing effects of tDCS and 
potentiate the impact of tDCS. [38] There is a dearth of data on ‘online’ tDCS to induce 
cognitive improvements in schizophrenia. A single-blinded randomized-control trial in 2016 
[39] explored the role of tDCS combined with cognitive training. The study included both 
‘online’ and ‘offline’ tDCS, the effect size extracted from pre-post assessment suggested 
cognitive functions might be more modifiable with ‘online’ tDCS in patients with 
schizophrenia. However, ‘online’ tDCS was not the center of interest in its study design.  
Therefore, the present study aims to focus on ‘online’ tDCS (when tDCS is administered 
concurrently with cognitive training) and examine the incremental gain of specific cognitive 
domain performance in patients with schizophrenia.  
 
Objectives:  
 
The primary objective of the study is to investigate the adjunct effect of online tDCS with 
cognitive training on specific cognitive domains in stable schizophrenia patients. (i) right 
after the intervention (ii) whether maintenance effect at 1 month after intervention.  
 
The secondary objective of the study is to probe (i) any effects on affective , psychotic and 
negative symptoms; (ii) psychosocial functioning, cognitive insight, subjective quality of life 
(QOL); (iii) the motivation and enjoyment of continuing playing the computerized cognitive 
training; (iv) the tolerability and adverse events of tDCS among patients with schizophrenia.  
 
Hypotheses:  
 
1. Concurrent cognitive training with online transcranial direct current 
stimulation(tDCS) will result in greater incremental training effect in specific 
cognitive domains as compared to cognitive training alone.  

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 4 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
2. The cognitive effect in concurrent cognitive training with online tDCS will be 
maintained over time.  
3. tDCS will have no effect on the affective, psychotic or negative symptoms, as 
compared to the control group(sham stimulation). 
 
Methodology:  
 
Study design 
 
It will be a parallel-group, double-blinded, randomized controlled trial. It will be a 1-week 
intervention (5-week observation). Subjects will be randomized into two groups:  
1. The intervention group- active stimulation of tDCS in ‘online’ mode +cognitive 
training  
2. The control group- sham stimulation of tDCS + cognitive training  
Subjects will be blinded to the allocation with group ratio of 1:1. The schedule, environment 
and equipment used for both groups will be identical. The study will observe the CONSORT 
guideline.  
 
Study population and recruitment 
 
Recruitment strategies include a convenience sample of patients with stable schizophrenia 
who will attend Psychiatric Day Hospitals in Tai Po Hospital. Informed consent will be 
obtained from each eligible subject.  
 
Inclusion criteria: aged 18-65,  right handed, understand and speak in Cantonese, diagnosis of 
schizophrenia meeting the diagnostic criteria of the World Health Organization’s 10th version 
of the International Statistical Classification of Disease and Related Health Problems (ICD-
10). The screening of subjects will be made clinically by the study psychiatrist based on ICD-
10. 
 
Exclusion criteria: 1) History of significant head trauma; 2) active abuse of alcohol or illegal 
substances; 3) significant neurologic history such as dementia, stroke, seizure, Parkinson’s 
disease, multiple sclerosis; 4) concurrent use of cognitive-enhancing medications e.g. 
acetylcholinesterase inhibitors  ; 5) documented history of learning disability; 6) implanted 
with pacemakers, intracranial electrodes, defibrillators;  7) changes in medication regime 
over the 2 weeks before or during the study period.  
 
 
Ethical consideration 
 
The study will be performed in accordance with the Declaration of Helsinki (1964). All 
participants should take part in the study under voluntary basis. Written, informed consent 
will be obtained from all participants before inclusion in study, which will be submitted to 
the CUHK-NTEC Clinical Research Ethics Committee for approval. The study will be 
conducted in the Psychiatric Day Hospital in Tai Po Hospital. Any participant can withdraw 
from the study at any time point without the need of explanation. It will not affect the usual 
care of the participant. 
 
Intervention 
 

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 5 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
Within one week, subjects will receive 5 tDCS sessions applied concurrently with cognitive 
training on 5 consecutive days (a total of 5 sessions, each 20 minutes) . Participants will have 
20 minutes of tDCS stimulation concurrently with 20 minutes of computerized cognitive 
training.  
 
Based on the most recent metanalysis on tDCS in neuropsychological measures 
schizophrenia, when the number of tDCS session is not fewer than 5 sessions, no direct trend 
is identified between the amount of tDCS sessions and neuropsychological measures [24] .  
 
Intervention apparatus: 
 
tDCS Apparatus 
 
tDCS will be applied using the StarStim 8 (NeuroElectrics, Barcelona, Spain). The StarStim8 
system consists of a Neoprene head cap with marked positions for electrode placement, a 
wireless cap-mounted stimulator and a lap-top control computer. tDCS with strength of 2mA 
for 20 minutes will be applied based on similar previous studies. [40] The stimulation 
electrode will be applied according to international EEG system 10-20. The anode will be 
applied at the left dorsolateral prefrontal cortex , which is located at F3; the cathode will be 
applied at the right dorsolateral prefrontal cortex , which is located at F4.  For electrode 
placement, saline-soaked , 5cm diameter sponge electrodes will be used. The intervention 
sessions will be conducted in dedicated consultation rooms of the psychiatric day hospital. 
The rooms are standard consultation rooms with satisfactory sound-proof quality and 
comfort.  
 
Sham stimulation will be essentially the same setup and procedure, except that the loading 
protocol will be different. The electric current will ramp up and ramp down, and will 
stimulate at 0mA for the remainder of the stimulation time. Because it ramps up in the same 
way as the real stimulation for a short period of time, the subjects will find it difficult to 
distinguish between the active and sham tDCS. Sham stimulation is generally regarded as an 
effective blinding technique, especially for those who have never experienced tDCS 
before[41]. 
 
Cognitive Training  
 
All subjects will have ‘online tDCS’ during computerized cognitive training.  Each training 
session lasts for 20 minutes. Subjects will play an app ‘the Peak’ designed by Professor 
Sahakian with computerized cognitive training on a hand held portable iPad. The traditional 
Chinese version with Cantonese instructions will be selected. The progress, the errors and the 
sum scores will be kept track in the personal profile. Subjects will play a few exercises 
supplied by the computerized cognitive training in pseudorandomized order within each 
session.  
 
Randomization procedure   
 
The subjects will be randomly allocated to the intervention group or the control group by a 
block randomization procedure (1:1 allocation) . The randomization sequence will be 
generated by an online randomization tool (www.sealedenvelop.com) . A code (either ‘a’ or 
‘s’) will be generated for each patient and the code corresponds to whether ‘a’ (active) or ‘s’ 
(sham) tDCS will be administered.  

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 6 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Both the assessor and the subjects will be blinded to the procedure. All subjects are assessed 
by the study psychiatrist who is blinded to the group allocation.  Sham stimulation is 
generally regarded as an effective blinding technique, especially for those who have never 
experienced tDCS before[41]. All subjects will not be informed of the group allocation 
neither. 
 
Definitions and Time Point of Measurements   
 
At baseline(T0, at week-0),  after the eligibility of the subjects are confirmed and consent to 
participate is obtained, the following will be assessed 1) clinical and demographic 
characteristics of the sample include 2) the primary outcome measure and 3) the secondary 
outcome measures. At completion of the intervention (T1, at week-1), and one month after 
the intervention (T2, at week-5), the primary and secondary outcome measures of the subjects 
will be measured.  
 
i.Clinical and Demographic Characteristics 
 
The subject characteristics include age, gender, handedness, years of education and 
employment status will be collected. Clinical data, including diagnosis, duration of illness, 
dosage of medications, daily exercise level and insight will be assessed.  
 
ii. Primary Outcome Measure  
Cambridge Neuropsychological Test Automated Battery (CANTAB) will be used as the 
primary outcome measure. [10] CANTAB is a computerized assessment that is automated 
and does not rely on the assessors’ subjective assessment. It has standardized automated test 
delivery with systematic scoring and automated saving. Practice effects are eliminated with 
parallel mode and stimuli randomization. It has concurrent validity same as the MATRICS 
consensus cognitive battery (MCCB). Due to the sensitivity of CANTAB, it can detect effects 
in small effect size over shorter period of time. Test-retest reliability is > 0.7 , which is 
consensed opinion for cognitive evaluation in schizophrenia. Computerized CANTAB tasks 
on specific cognitive domains on paired associates learning, working memory, processing 
speeds and executive function will be selected.  
 
iii. Secondary Outcomes Measures  
Measures on Affective , Psychotic and Negative Symptoms 
- 
Positive and Negative Syndrome Scale (PANSS) [42] is a 30-item clinician rated 
questionnaire to assess the symptoms in schizophrenia patient. It has 3 sub-
categories of positive symptoms, negative symptoms and general 
psychopathology. It is shown to have good construct validity , internal reliability 
and inter rater reliability. [43] It is also shown to be sensitive to change. [44] The 
assessment time is around 40-50 minutes.  
 
- 
Calgary Depression Scale for Schizophrenia [45, 46] is a 9-item clinician rated 
and is administered following a semi-structured interview. It has been used by 
other tDCS studies in schizophrenia, and it has been shown to be reliable , valid 
and sensitive to depressive symptoms separate from positive, negative and 
extrapyramidal symptoms in schizophrenia. A score above 6 has 82% specificity 
and 85% sensitivity for predicting the presence of a major depressive episode.   
 

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 7 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
- 
Clinical Global Impression Scale (CGI) [47]- Schizophrenia  is a 3-item clinician 
rated questionnaire to assess illness severity, global improvement or change, and 
treatment response.  
Measures on Psychosocial Functioning  
- 
Social and Occupational Functioning Assessment scale (SOFAS)[48] 
- 
World Health Organization Five Well-Being Index (WHO-5) is a 5-item self 
reported questionnaire of subjective quality of life (QOL).  [49, 50] 
 
Ratings on Motivation and Enjoyment on Cognitive Training  
- 
Visual Analog Scale to rate their motivation and enjoyment to continue playing 
the computerized cognitive training game (scores ranged from 0-100, with higher 
scores indicating enhanced enjoyment/ willingness to come)  
 
Tolerability on tDCS  
- 
An Adverse Effects Questionnaire associated with t-DCS administration, which is 
generated from a systematic review in 2011 by Brunoni. [51] 
 
Clinical Insight 
- 
Beck Cognitive Insight Scale Taiwanese Version is 15-tem self reported 
questionnaire with two subscales (nine items tapping self-reflectiveness and six on 
self-certainty); it is shown to have Cronbach’s alpha values of >0.70 for both 
subscales and moderate stability.[52, 53] 
 
Statistical Analyses:  
 
The data will be collected according to the Intention-to-treat(ITT) protocol, with last 
observation carried forward (LOCF) design i.e. all subjects whose baseline date collected and 
performed at least 1 day of stimulation will be included in the analysis. The missing 
observation due to non-compliance will be imputed accordingly to the last assessment 
performed.  
 
The baseline demographics and baseline clinical characteristics (T0)will be compared 
between the group of active tDCS and sham tDCs with Pearson’s chi-square test (for 
categorical variables) and independent-sample t tests (for continuous variables).  
Linear mixed effect models will be used for each outcome measures, using the covariates of 
group (tDCS versus sham) and time (T0, T1 and T2).   
Pearson’s correlation test will be performed to evaluate whether there will be correlation 
between change in cognitive performance vs demographics and baseline clinical 
characteristics.  
 
Statistical significance will be referred to a two tailed p-value of less than 0.05.  
All computations will be performed using SPSS for Mac OS and Microsoft for excel. 
 
Data Management: 
 
Raw data and electronic data will be stored in locked space and password protected 
computers respectively. All data will be destroyed 5 years after completion of study and 
submission for publication. 
  

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 8 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
Sample size estimation :  
 
The effect in difference found in the specific cognitive domains between the tDCS and 
sham group before and after the intervention in the similar studies was 0.31 (Smith et al., 2015), 
0.21 (Lam, 2016), 0.6 (Nienow et al., 2016) represented by partial eta square. Considering the 
medium to large effect size of the studies, it is difficult to replicate a study with a large effect 
size. Hence, the rule-of-thumb medium effect size Cohen’s F 0.25 was chosen as the partial eta 
square. Considering a power of 80% and a critical alpha of 5%, it was estimated that a total of 
44 patients would be needed in total. .   
 
Safety Consideration: 
Concerning the safety profile, tDCS is generally regarded as safe for short-term 
administration. There is no published report that tDCS has to be discontinued for safety 
reasons. The adverse effects of tDCS have been reported to be minimal and its risk of 
inducing seizure is minimal. Meta-analysis suggested that tDCS is associated with mild 
adverse effects only, such as itching, tingling, mild burning or pain sensations. [51]In 
particular, mild burning is related to administration of electric current with higher contact 
impedence.  In our study, we will use the StarStim 8 (NeuroElectrics, Barcelona, Spain).  
StarStim 8 will not operate if the contact impedance is above 20 kOhm, which is the far from 
the threshold for tissue damage.  
Safety studies showed that the concentration of serum neuron-specific enolase, a marker of 
neuronal damage, is not raised immediate or 1-hour after tDCS. [54, 55]It was also shown 
that tDCS did not induce changes in diffusion-weighted or contrast-enhanced magnetic 
resonance imaging (MRI) measures[56] or electroencephalogram (EEG) [57].  
 
The long term safety of tDCS is yet to be evaluated through systemic long term studies. 
Notably, there is a single case report of safe and effective use of daily to twice-daily 
domiciliary use of tDCS sessions for 3 years for disabling and clozapine-resistant auditory 
hallucinations in a patient with schizophrenia. [58] 
 
In the unlikely event that adverse effects or complication arise during the tDCS sessions, 
subjects will be immediately attended by an on-site medical professional. 
References:   
1. 
Kalkstein, S., I. Hurford, and R.C. Gur, Neurocognition in schizophrenia. Curr Top 
Behav Neurosci, 2010. 4: p. 373-90. 
2. 
Gur, R.C., et al., Neurocognitive performance in family-based and case-control studies 
of schizophrenia. Schizophr Res, 2015. 163(1-3): p. 17-23. 
3. 
Kurtz, M.M., Neurocognitive impairment across the lifespan in schizophrenia: an 
update. Schizophr Res, 2005. 74(1): p. 15-26. 
4. 
Kremen, W.S., et al., Cognitive decline in schizophrenia from childhood to midlife: a 
33-year longitudinal birth cohort study. Schizophr Res, 2010. 118(1-3): p. 1-5. 
5. 
Meier, M.H., et al., Neuropsychological decline in schizophrenia from the premorbid 
to the postonset period: evidence from a population-representative longitudinal 
study. Am J Psychiatry, 2014. 171(1): p. 91-101. 
已註解 [l1]: Change font  

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 9 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
6. 
Barch, D.M. and A. Ceaser, Cognition in schizophrenia: core psychological and neural 
mechanisms. Trends Cogn Sci, 2012. 16(1): p. 27-34. 
7. 
Sevy, S. and M. Davidson, The cost of cognitive impairment in schizophrenia. 
Schizophr Res, 1995. 17(1): p. 1-3. 
8. 
Green, M.F., et al., Neurocognitive deficits and functional outcome in schizophrenia: 
are we measuring the "right stuff"? Schizophr Bull, 2000. 26(1): p. 119-36. 
9. 
Kern, R.S., et al., The MCCB impairment profile for schizophrenia outpatients: results 
from the MATRICS psychometric and standardization study. Schizophr Res, 2011. 
126(1-3): p. 124-31. 
10. 
Barnett, J.H., et al., Assessing cognitive function in clinical trials of schizophrenia. 
Neurosci Biobehav Rev, 2010. 34(8): p. 1161-77. 
11. 
Lustig, C. and M. Sarter, Attention and the Cholinergic System: Relevance to 
Schizophrenia. Curr Top Behav Neurosci, 2016. 28: p. 327-62. 
12. 
Glahn, D.C., et al., Beyond hypofrontality: a quantitative meta-analysis of functional 
neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp, 2005. 
25(1): p. 60-9. 
13. 
Rosenthal, M.H. and S.L. Bryant, Benefits of adjunct modafinil in an open-label, pilot 
study in patients with schizophrenia. Clin Neuropharmacol, 2004. 27(1): p. 38-43. 
14. 
Hunter, M.D., et al., Impact of modafinil on prefrontal executive function in 
schizophrenia. Am J Psychiatry, 2006. 163(12): p. 2184-6. 
15. 
Wykes, T., et al., A meta-analysis of cognitive remediation for schizophrenia: 
methodology and effect sizes. Am J Psychiatry, 2011. 168(5): p. 472-85. 
16. 
Stagg, C.J. and M.A. Nitsche, Physiological basis of transcranial direct current 
stimulation. Neuroscientist, 2011. 17(1): p. 37-53. 
17. 
Miniussi, C., et al., Efficacy of repetitive transcranial magnetic 
stimulation/transcranial direct current stimulation in cognitive neurorehabilitation. 
Brain Stimul, 2008. 1(4): p. 326-36. 
18. 
Charvet, L.E., et al., Remotely-supervised transcranial direct current stimulation 
(tDCS) for clinical trials: guidelines for technology and protocols. Front Syst Neurosci, 
2015. 9: p. 26. 
19. 
Palm, U., et al., Home Use, Remotely Supervised, and Remotely Controlled 
Transcranial Direct Current Stimulation: A Systematic Review of the Available 
Evidence. Neuromodulation, 2018. 21(4): p. 323-333. 
20. 
Fregni, F., et al., Anodal transcranial direct current stimulation of prefrontal cortex 
enhances working memory. Exp Brain Res, 2005. 166(1): p. 23-30. 
21. 
Ohn, S.H., et al., Time-dependent effect of transcranial direct current stimulation on 
the enhancement of working memory. Neuroreport, 2008. 19(1): p. 43-7. 
22. 
Brunoni, A.R. and M.A. Vanderhasselt, Working memory improvement with non-
invasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review 
and meta-analysis. Brain Cogn, 2014. 86: p. 1-9. 
23. 
Smith, R.C., et al., Effects of transcranial direct current stimulation (tDCS) on 
cognition, symptoms, and smoking in schizophrenia: A randomized controlled study. 
Schizophr Res, 2015. 168(1-2): p. 260-6. 
24. 
Mervis, J.E., et al., Transcranial Direct Current Stimulation over the Dorsolateral 
Prefrontal Cortex in Schizophrenia: A Quantitative Review of Cognitive Outcomes. 
Front Hum Neurosci, 2017. 11: p. 44. 

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 10 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
25. 
Schubert, T., T. Strobach, and J. Karbach, New directions in cognitive training: on 
methods, transfer, and application. Psychol Res, 2014. 78(6): p. 749-55. 
26. 
Greenwood, P.M. and R. Parasuraman, The mechanisms of far transfer from cognitive 
training: Review and hypothesis. Neuropsychology, 2016. 30(6): p. 742-755. 
27. 
Olfers, K.J.F. and G.P.H. Band, Game-based training of flexibility and attention 
improves task-switch performance: near and far transfer of cognitive training in an 
EEG study. Psychol Res, 2018. 82(1): p. 186-202. 
28. 
Subramaniam, K., et al., Computerized cognitive training restores neural activity 
within the reality monitoring network in schizophrenia. Neuron, 2012. 73(4): p. 842-
53. 
29. 
McGurk, S.R., et al., Cognitive training for supported employment: 2-3 year outcomes 
of a randomized controlled trial. Am J Psychiatry, 2007. 164(3): p. 437-41. 
30. 
Cavallaro, R., et al., Computer-aided neurocognitive remediation as an enhancing 
strategy for schizophrenia rehabilitation. Psychiatry Res, 2009. 169(3): p. 191-6. 
31. 
Hochberger, W.C., et al., Neurophysiologic measures of target engagement predict 
response to auditory-based cognitive training in treatment refractory schizophrenia. 
Neuropsychopharmacology, 2019. 44(3): p. 606-612. 
32. 
Thomas, M.L., et al., Targeted cognitive training improves auditory and verbal 
outcomes among treatment refractory schizophrenia patients mandated to 
residential care. Schizophr Res, 2018. 202: p. 378-384. 
33. 
Savulich, G., et al., Improvements in Attention Following Cognitive Training With the 
Novel "Decoder" Game on an iPad. Front Behav Neurosci, 2019. 13: p. 2. 
34. 
Sahakian, B.J., et al., The impact of neuroscience on society: cognitive enhancement 
in neuropsychiatric disorders and in healthy people. Philos Trans R Soc Lond B Biol Sci, 
2015. 370(1677): p. 20140214. 
35. 
Park, S.H., et al., Long-term effects of transcranial direct current stimulation 
combined with computer-assisted cognitive training in healthy older adults. 
Neuroreport, 2014. 25(2): p. 122-6. 
36. 
Martin, D.M., et al., Use of transcranial direct current stimulation (tDCS) to enhance 
cognitive training: effect of timing of stimulation. Exp Brain Res, 2014. 232(10): p. 
3345-51. 
37. 
Lippold, O.C. and J.W. Redfearn, Mental Changes Resulting from the Passage of Small 
Direct Currents through the Human Brain. Br J Psychiatry, 1964. 110: p. 768-72. 
38. 
Bikson, M., A. Name, and A. Rahman, Origins of specificity during tDCS: anatomical, 
activity-selective, and input-bias mechanisms. Front Hum Neurosci, 2013. 7: p. 688. 
39. 
Nienow, T.M., A.W. MacDonald, 3rd, and K.O. Lim, TDCS produces incremental gain 
when combined with working memory training in patients with schizophrenia: A 
proof of concept pilot study. Schizophr Res, 2016. 172(1-3): p. 218-9. 
40. 
Thair, H., et al., Transcranial Direct Current Stimulation (tDCS): A Beginner's Guide for 
Design and Implementation. Front Neurosci, 2017. 11: p. 641. 
41. 
Ambrus, G.G., W. Paulus, and A. Antal, Cutaneous perception thresholds of electrical 
stimulation methods: comparison of tDCS and tRNS. Clin Neurophysiol, 2010. 
121(11): p. 1908-14. 
42. 
Kay, S.R., A. Fiszbein, and L.A. Opler, The positive and negative syndrome scale 
(PANSS) for schizophrenia. Schizophr Bull, 1987. 13(2): p. 261-76. 

                             RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
 
Page 11 of 11 
  
RCT_CCT_online_tDCS_Schizophrenia_version2_21June2019 
43. 
Lindstrom, E., I.M. Wieselgren, and L. von Knorring, Interrater reliability of the 
Structured Clinical Interview for the Positive and Negative Syndrome Scale for 
schizophrenia. Acta Psychiatr Scand, 1994. 89(3): p. 192-5. 
44. 
Santor, D.A., et al., Item response analysis of the Positive and Negative Syndrome 
Scale. BMC Psychiatry, 2007. 7: p. 66. 
45. 
Addington, D., J. Addington, and E. Maticka-Tyndale, Assessing depression in 
schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl, 1993(22): p. 39-
44. 
46. 
Addington, D., J. Addington, and E. Maticka-Tyndale, Specificity of the Calgary 
Depression Scale for schizophrenics. Schizophr Res, 1994. 11(3): p. 239-44. 
47. 
Haro, J.M., et al., The Clinical Global Impression-Schizophrenia scale: a simple 
instrument to measure the diversity of symptoms present in schizophrenia. Acta 
Psychiatr Scand Suppl, 2003(416): p. 16-23. 
48. 
Morosini, P.L., et al., Development, reliability and acceptability of a new version of the 
DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess 
routine social functioning. Acta Psychiatr Scand, 2000. 101(4): p. 323-9. 
49. 
Topp, C.W., et al., The WHO-5 Well-Being Index: a systematic review of the literature. 
Psychother Psychosom, 2015. 84(3): p. 167-76. 
50. 
Kong, C.L., et al., Validation of the Hong Kong Cantonese Version of World Health 
Organization Five Well-Being Index for People with Severe Mental Illness. East Asian 
Arch Psychiatry, 2016. 26(1): p. 18-21. 
51. 
Brunoni, A.R., et al., A systematic review on reporting and assessment of adverse 
effects associated with transcranial direct current stimulation. Int J 
Neuropsychopharmacol, 2011. 14(8): p. 1133-45. 
52. 
Beck, A.T., et al., A new instrument for measuring insight: the Beck Cognitive Insight 
Scale. Schizophr Res, 2004. 68(2-3): p. 319-29. 
53. 
Kao, Y.C. and Y.P. Liu, The Beck Cognitive Insight Scale (BCIS): translation and 
validation of the Taiwanese version. BMC Psychiatry, 2010. 10: p. 27. 
54. 
Nitsche, M.A. and W. Paulus, Sustained excitability elevations induced by transcranial 
DC motor cortex stimulation in humans. Neurology, 2001. 57(10): p. 1899-901. 
55. 
Nitsche, M.A., et al., Modulation of cortical excitability by weak direct current 
stimulation--technical, safety and functional aspects. Suppl Clin Neurophysiol, 2003. 
56: p. 255-76. 
56. 
Nitsche, M.A., et al., MRI study of human brain exposed to weak direct current 
stimulation of the frontal cortex. Clin Neurophysiol, 2004. 115(10): p. 2419-23. 
57. 
Iyer, M.B., et al., Safety and cognitive effect of frontal DC brain polarization in healthy 
individuals. Neurology, 2005. 64(5): p. 872-5. 
58. 
Andrade, C., Once- to twice-daily, 3-year domiciliary maintenance transcranial direct 
current stimulation for severe, disabling, clozapine-refractory continuous auditory 
hallucinations in schizophrenia. J ECT, 2013. 29(3): p. 239-42.