dACC-Targeted Temporal Interference for Negative and Cognitive Symptoms in Schizophrenia

The Brief Assessment of Cognition in Schizophrenia (BACS) is a multidomain battery assessing overall neurocognitive functioning, including verbal learning and memory, working memory, psychomotor speed, verbal fluency, sustained attention and processing speed, and executive function. The constituent subtests include the List Learning Test, Digit Sequencing Task, Token Motor Task, Category Instances and Controlled Oral Word Association Test, Symbol Coding Task, and Tower of London Test. Domain scores are aggregated into a single composite z-score standardized against age- and sex-matched normative data. Lower values reflect greater cognitive impairment.

The Scale for the Assessment of Negative Symptoms (SANS) provides a detailed characterization of negative symptomatology. It comprises 25 clinician-rated items spanning five domains: affective flattening or blunting, alogia, avolition-apathy, anhedonia-asociality, and attentional impairment. Each item is rated on a six-point scale ranging from 0 to 5. The item scores are summed to generate a total score, where higher values denote a more severe negative symptom profile.

The Apathy Evaluation Scale (AES-S) is a self-rated measure used to evaluate apathy. The scale consists of 18 items that probe the cognitive, affective, and behavioral dimensions of apathetic experiences over the preceding four weeks. Responses are summed to yield a total score ranging from 0 to 72. Higher scores indicate more severe apathy, meaning a worse outcome.

The Temporal Experience of Pleasure Scale (TEPS) is used to evaluate hedonic experience by separately indexing the anticipatory and consummatory components of pleasure. The scale consists of 20 items, with each item rated on a six-point Likert scale ranging from 1 ("very false for me") to 6 ("very true for me"). Following the reverse-scoring of designated items, responses are summed to yield a total score, where lower values indicate greater anhedonia. Therefore, higher scores indicate a better outcome.

The Personal and Social Performance Scale (PSP) is a clinician-administered tool used to evaluate real-world social functioning. It appraises four behavioral domains: engagement in socially constructive activities, interpersonal relationships, self-care, and disruptive or aggressive conduct. The total score spans from 1 to 100, with higher scores reflecting superior functional status.

Subjective quality of life will be assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF). This multidimensional instrument covers four domains: physical health, psychological well-being, social relationships, and environment. Higher scores within each domain reflect a more positive self-reported quality of life, meaning a better outcome.

The incidence and severity of adverse events will be assessed throughout the study period, from baseline to the 4-week follow-up, to evaluate treatment safety and tolerability.

Current depressive symptomatology will be quantified using the Patient Health Questionnaire-9 (PHQ-9). It contains nine items, each rated on a scale from 0 to 3, yielding an aggregate score ranging from 0 to 27. Elevated scores reflect a more severe depressive burden.

Participants' perceptions of the credibility of the intervention and their expectations regarding treatment benefit will be assessed using an adapted version of the Credibility/Expectancy Questionnaire (CEQ). Higher scores indicate greater perceived credibility and higher expectations for treatment benefit, which represents a more positive expectancy.

Broader psychopathological status will be assessed using the 30-item Positive and Negative Syndrome Scale (PANSS). Each of the 30 items is rated on a 1 to 7 ordinal scale, yielding a total score ranging from a minimum of 30 to a maximum of 210. Higher scores denote a more severe psychopathological profile, meaning a worse outcome.

Exploratory analyses will investigate treatment-related neural changes using resting-state functional MRI (rs-fMRI).

Response inhibition will be evaluated with the computerized Go/No-Go paradigm. The derived index reported here is overall accuracy, calculated as the percentage of correct responses. Higher accuracy percentages indicate better response inhibition and cognitive control, meaning a better outcome.

Anxiety over the preceding two weeks will be indexed by the Generalized Anxiety Disorder-7 scale (GAD-7). It comprises seven items, each scored from 0 to 3, which are summed to a maximum total score of 21. Higher totals denote greater anxiety severity.

Sleep disturbance will be quantified with the Pittsburgh Sleep Quality Index (PSQI). It is a 19-item self-report measure that generates a composite global score ranging from 0 to 21. Higher values indicate worse sleep quality.

Conflict processing and cognitive control will be evaluated using the Stroop color-word task. The primary metric evaluated is the Stroop interference effect, calculated based on the differences in reaction times between congruent and incongruent trials. A lower interference effect score indicates better conflict processing and cognitive control, meaning a better outcome.

The positive symptom subscale of the 30-item Positive and Negative Syndrome Scale (PANSS) will be evaluated to assess broader psychopathological status. Clinician-assigned ratings for the items in this subscale are each anchored on a 1 to 7 ordinal scale. Higher scores denote a more severe positive symptom profile, meaning a worse outcome.

Exploratory analyses will investigate treatment-related neural changes using diffusion tensor imaging (DTI). Changes in white matter structural connectivity will be evaluated to assess neural target engagement.