Online HD-tDCS Over the Left DLPFC During a Working Memory Task for Treating Negative Symptoms of Schizophrenia

The Scale for the Assessment of Negative Symptoms (SANS) is used to assess negative symptoms in schizophrenia on a 25 item, 6-point scale. The SANS measures five domains of the negative symptoms including affective flattening or blunting, alogia, avolition - apathy, anhedonia - Asociality, Attention. In each domain, separate symptoms are rated from 0 (absent) to 5 (severe). A total SANS score ranges from 0 to 125.

PANSS is a clinician-administered rating scale to measure the severity of psychopathological symptoms of the patients with schizophrenia spectrum disorder, ranging from 30 to 210. A higher score indicates greater psychopathological symptom severity. Two subdomains of negative symptoms were identified from the PANSS: the Expressive Deficit domain (EXP domain, the sum of items of N1, N3, N6, G5, G7 and G13) including features of blunted affect and alogia and the Avolition-Apathy domain (AA domain, the sum of items of N2, N4, and G16) including manifestations of anhedonia, asociality and avolition.

PANSS is a clinician-administered rating scale to measure the severity of psychopathological symptoms of the patients with schizophrenia spectrum disorder, ranging from 30 to 210. A higher score indicates greater psychopathological symptom severity. The scores of five-factor PANSS model other than FSNS can be obtained by calculating from 26 of 30 items of PANSS: positive (5 items, P1+P3+P5+P6+G9,score 5-35), grandiosity/excitement (4 items, score 4-28), disorganization (5 items, score 5-35), and depression (4 items, score 4-28) factor scores.

A clinician-administered rating scale to measure the psychosocial functioning of the patients with schizophrenia spectrum disorder. The PSP scale measures psychosocial functioning within four domains: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior.The patient is rated from 1 to 6 on each item of the four domains. A higher score indicates greater psychosocial functioning in any of the four domains.

The final global score is defined according to a summary instruction table. This scale provides a single, overall rating from 1 to 100, where a higher score represents better personal and social function.

The SRG-PSP is a self-rating scale of proven validity and reliability, comprising both male and female versions of cartoon-like pictures that are derived from the narrative text of the four domains of Personal and Social Performance (PSP) scale including the sub-items of socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviour.

An expert-rating scale based on a patient interview to measure patients' clinical insight. The abbreviated version of SUMD comprises 9 items measuring current states of awareness as follows: (1) a mental disorder, (2) consequences of a mental disorder, (3) effects of drugs, (4) hallucinatory experiences, (5) delusional ideas, (6) disorganized thoughts, (7) blunted affect, (8) anhedonia, and (9) lack of sociability. Scores on each item range from 0 to 3. A score of 0 indicates 'not applicable'; 1, 'aware'; 2, 'somewhat aware/unaware' and 3, 'severely unaware.' Based on the 3 dimensions approach of the abbreviated version of SUMD, the scores on the items 1-3, 4-6 and 7-9 were averaged to obtain the dimension score of 'awareness of the disease', 'awareness of positive symptoms', and 'awareness of negative symptoms', respectively. All dimension scores were linearized on a 0-100 scale, with 0 and 100 indicating the lowest and highest level of unawareness, respectively.

Cognitive insight was measured by the Taiwanese version of the Beck Cognitive Insight Scale (BCIS), a self-reported instrument comprising 15 items.The Taiwanese BCIS is composed of 2 subscales including reflective attitude (9 items) and certain attitude (6 items). We obtained a R-C (reflective attitude minus certain attitude) index of the Taiwanese BCIS, representing the measurement of cognitive insight by subtracting the score of the certain attitude subscale from that of the reflective attitude subscale. Lower R-C index scores indicate poorer cognitive insight.

The Taiwanese version of the Self-Appraisal of Illness Questionnaire (SAIQ) was used to assess attitudes toward mental illness and experience of psychiatric treatment.This self-administered tool was composed of 17 items. The patients rated the extent to which they agreed with each statement of the item by using a four-point Likert scale, ranging from 1, ''do not agree at all'', to 4, ''completely agree''. Whether the scale score is in order from least to most or from the most to least depends on the content of the item statement. The total score of SAIQ ranges from 17 to 68.

The Chinese version of the Schizophrenia Quality of Life Scale Revision Four is a self-administered questionnaire of 33 items in two domains: psychosocial and vitality. All but four items are coded on a scale of 0-4 according to the frequency of occurrence during the previous 7 days (0 = always, 4 = never; the four exceptions are coded 0 = never, 4

= always). A higher score indicates higher health-related QoL.

The Taiwanese version of Medication Adherence Rating Scale (MARS), translated from the original MARS, was used to assess patients' beliefs about medication adherence. The translated MARS contains 10 yes/no items. Items 1-5 form the medication adherence subscale and items 6-10 form the subjective response to taking medication subscale. The scores from MARS subscales are summed to yield a total MARS score ranging from 0 (poor adherence to treatment) to 10 (good adherence to treatment), indicating a broad measure of medication compliance.

Extrapyramidal Symptoms Rating Scale (ESRS) is a quantitative measure of antipsychotic-induced extrapyramidal movement symptoms. The ESRS is composed of the patient-assessed ESRS questionnaire and the physician-rated subscales for assessing parkinsonism/akathisia, dystonia movement, and dyskinesia movement.

A test to measure the capacity of working memory of the patients

A neuropsychological test that examines motor functioning, specifically, motor speed and lateralized coordination.

A neuropsychological test that examines the performance of prefrontal-mediated task.

A neuropsychological test of "set-shifting", i.e. the ability to display flexibility in the face of changing schedules of reinforcement.

A neuropsychological test for the assessment of executive functioning specifically to detect deficits in planning, which may occur due to a variety of medical and neuropsychiatric conditions.

The CTT, a culture-neutral version of the Trail Making Test, was selected to measure sustained visual attention. The CTT consists of two parts (CTT-1 and CTT-2). The CTT-1 requires participants to connect a series of numbered circles that are randomly printed on a sheet of paper. In the CTT-2, numbered circles of 1 to 25 are shown twice (printed in pink and in yellow) randomly on a sheet of paper. Participants are asked to connect the numbers from 1 to 25 alternating between the two colors.

Stroop Color Word Test (SCWT), Chinese version; was administered to measure selective attention and cognitive flexibility. SCWT is composed of three parts, each lasting for 45 seconds.

HRV indices represent autonomic functioning. ECG electrodes were placed on bilateral arms just below the elbows, with a ground electrode placed just above the right wrist bone. Lead I electrocardiogram of each patient was taken for 5 min after sitting and having a rest for 20 min in a soundproof, dim-lighted room with thermostatic control. At the four timepoints (baseline, after 10-session HD-tDCS, at 1-week and 1-month follow-ups), HRV will be collected during resting and during a dual 2-back task. The ECG signals were acquired, stored, pre-processed according to the recommended procedures and processed by an HRV analyser (LR8Z11, Yangyin Corp., Taipei, Taiwan). The time domain of HRV is obtained: Standard deviation of NN intervals (SDNN). Power spectrum of HRV is quantified into the standard frequency-domain measurements including low-frequency power (LF, 0.04-0.15 Hz), high-frequency power (HF, 0.15- 0.40 Hz).

In a recliner in a dimly lit, electrically shielded room, patients' EEGs were recorded at baseline and at the end of stimulation by using the Neuro Prax® TMS/tDCS full-band DC-EEG system with 32 EEG Ag/AgCl electrodes in the standard 10-20 International placement. EEG will be collected with eye opened (5min) and closed (5min). Signals will be amplified in the dynamic input range of ± 140 mV at a resolution of 0.5 μV by using EEG amplifiers and stored for offline analyses. Eye or muscle artifacts were automatically detected and removed using NeuroPrax's built-in software.

Cognitive task protocol used for the functional near infrared spectroscopy (fNIRS) system to measure the relative changes in oxy Hb and deoxy Hb. Hemoglobin Hb changes will be measured during 2 different cognitive tasks: semantic verbal fluency task (SVFT) and and a 2 back task . An SVFT involves generating as many words as possible within a certain time frame and hints at the semantic category of the words generated. The task measures the amount of information regarding categorization and the number of words that can be retrieved from memory in 1 min. The task involved generating as many words as possible in relation to the keywords. The 2 back task is used to evaluate participants' working memory. The examiner presents the words while the participant performs the working memory, and the number of memorized words is measured afterward. In this task, participants de