Add-on HD Hf-tRNS Over Bilateral DLPFC for Treating Patients With Schizophrenia

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.

GAF is a numeric scale used by mental health clinicians and physicians to rate subjectively the social, occupational, and psychological functioning of an individual, e.g., how well one is meeting various problems-in-living. Scores range from 100 (extremely high functioning) to 1 (severely impaired). GAF serves as a valid tool of assessing global psychosocial and occupational functioning for schizophrenia patients.

Illness severity was assessed with the Clinical Global Impression (CGI) rating scales. The Clinical Global Impression

• Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. The patient is rated from 1 to 7 and a higher score indicates greater illness severity.

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.

This translated SAIQ comprises a three-factor explanation. The three factors correspond to worry (score 7-28), the need for treatment (score 5-20), and presence/outcome (score 5-20) subscales. Higher SAIQ subscale scores indicate more awareness of mental illness.

The overall quality of life (QoL) and the specific domains of QoL was measured with the self-administered World Health Organization Questionnaire on Quality of Life: Short Form-Taiwan version (WHOQOL-BREF) which was developed by the WHO in 1998 and was adapted to Taiwan's culture. The WHOQOL-BREF is of well-established validity and reliability, containing 28 five-point Likert items that assessed general (two items) and four specific domains of QoL, including 7 items in physical health, 6 in psychological, 4 in social relationships, and 9 in environmental domains. Higher scores indicate a better QoL.

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.

An index of autonomic functioning. The ECG signals were acquired, stored, pre-processed according to the recommended procedures [36] and processed by an HRV analyser (LR8Z11, Yangyin Corp., Taipei, Taiwan). The power spectrum of HRV was quantified into the standard frequency-domain measurements including variance (variance of R-R-interval values), very low-frequency power (VLF, 0.003-0.04 Hz), low-frequency power (LF, 0.04-0.15 Hz), high-frequency power (HF, 0.15-0.40 Hz), the ratio of LF/HF, normalized HF (HF%) and LF (LF%).

Global cognition was assessed with the Mini-Mental State Examination (MMSE).

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.

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. Item 1-5 formed the medication adherence subscale and item 6-10 formed the subjective response to taking medication subscale. The scores from MARS subscales were 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.

The Extrapyramidal Symptoms Rating Scale (ESRS) total score was used to quantitatively measure antipsychotic-induced movement disorders including Parkinsonism, akathisia, dystonia, and tardive dyskinesia. The ESRS 41 items includes 7 items of Subscale I (questionnaire), 17 items of Subscale II (Parkinsonism/Akathisia), 10 items of Part III (dystonia), and 7 items of Part IV (dyskinesia). For inter-rater reliability certification, the ESRS 41 item total score also includes the 4 CGI-S's and thus becomes ESRS 45 item total. The ESRS total score ranges from 0 to 257.

In a recliner in a dimly lit, electrically shielded room, patients' resting EEGs were recorded before (baseline) and immediately after the first session of HD hf-tRNS and 3 hours after the final session of HD hf-tRNS by using the Neuro Prax® TMS/tDCS full-band DC-EEG system with 32 electrodes in the standard 10-20 International placement. EEG Ag/AgCl electrodes and HD hf-tRNS electrodes were mounted in a custom-made elastic cap for 64 electrodes. Data were collected eyes-closed and collection took ~ 10 mins and 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. For the real-time recording of EEG during the first session of HD hf-tRNS, a closed-loop stimulation protocol and removal of tRNS-artefacts by using NeuroPrax's built-in algorithm were applied.