tDCS for Cognitive Impairment Associated With Recent-onset Schizophrenia

Not Applicable

Not yet recruiting

• Conditions: Schizophrenia; Psychotic Disorder
• Interventions: Device: left fronto-temporal transcranial Direct Current Stimulation (tDCS)

• Registration Number: NCT05440955
• Lead Sponsor: University Hospital, Grenoble

Brief Summary

Background: In parallel to the traditional symptomatology, deficits in cognition (memory, attention, reasoning, social functioning) contribute significantly to disability and suffering in individuals with schizophrenia. Cognitive deficits have been closely linked to alterations in early auditory processes (EAP) that occur in auditory cortical areas. Preliminary evidence indicates that cognitive deficits in schizophrenia can be improved with a reliable and safe non-invasive brain stimulation technique called tDCS (transcranial Direct Current Stimulation). However, a significant proportion of patients derive no cognitive benefits after tDCS treatment. Further, the neurobiological mechanisms of cognitive changes after tDCS have been poorly explored in trials and are thus still unclear.

Method: The study is designed as a randomized, double-blind, 2-arm parallel-group, sham controlled, 4-centers trial. Sixty participants with recent-onset schizophrenia and cognitive impairment will be randomly allocated to receive either active (n=30) or sham (n=30) tDCS (20-min, 2-mA, 10 sessions during 5 consecutive weekdays). The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left auditory cortex. Cognition, tolerance, symptoms, general outcome and EAP (measured with EEG and multimodal MRI) will be assessed prior to tDCS (baseline), after the 10 sessions, and at 1- and 3-month follow-up. The primary outcome will be the number of responders, defined as participants demonstrating a cognitive improvement ≥Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score at 1-month follow-up. Additionally, we will measure how differences in EAP modulate individual cognitive benefits from active tDCS and whether there are changes in EAP measures in responders after active tDCS.

Discussion: Besides proposing a new fronto-temporal tDCS protocol by targeting the auditory cortical areas, we aim to conduct an RCT with follow-up assessments up to 3-months and a large sample size. In addition, this study will allow identifying and assessing the value of a wide range of neurobiological EAP measures for predicting and explaining cognitive deficits improvement after tDCS. The results of this trial will constitute a step toward the use of tDCS as a therapeutic tool for the treatment of cognitive impairment in recent-onset schizophrenia.

Detailed Description

Not available

Study Timeline

• Status Verified: 2022-05
• Study First Submitted: 2022-05-31
• Study First Submitted QC: 2022-06-27
• Study First Posted: 2022-07-01
• Last Update Submitted: 2023-04-03
• Last Update Posted: 2023-04-04
• Study Start: 2023-06-01
• Primary Completion: 2026-06-01
• Study Completion: 2027-06-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
active tDCS	left fronto-temporal transcranial Direct Current Stimulation (tDCS)	tDCS (transcranial Direct Current Stimulation subjects) is a noninvasive brain stimulation technique that involves the passage of a small electric current through the scalp and skull to modulate brain activity \[10\]. The study intervention consists of ten 20-minutes sessions of active or sham tDCS. Sessions will be delivered twice daily and separated by at least 2 hours for 5 consecutive weekdays. The electric current will be generated by an electric stimulator (class IIa medical device).
sham tDCS	left fronto-temporal transcranial Direct Current Stimulation (tDCS)	The sham procedure is developed by the tDCS device manufacturer, which allows using the same tDCS device and the same procedure (i.e., 10 sessions delivered during five consecutive days) for both the active and sham procedures. In the sham condition, the electrodes will be placed in the same positions as in the active group; however, the stimulator will be only active for initial and final ramp up/ramp down periods, in order to mimic the sensation of active stimulation. In addition, brief pulses of 110 μA will be administered every 550 ms in order to control impedance and keep the manipulator blinded to the active or sham condition.

Primary Outcome Measures

Name	Time	Method
Cognitive response	at 1-month follow-up	Number of responders at 1-month after tDCS, defined as the proportion of patients demonstrating a cognitive improvement greater than or equal to Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score (MCCB). The MCCB is a gold-standard standardized test battery to assess cognitive functions in patients with schizophrenia. This criterion has been used and validated in both antipsychotic and cognitive remediation trials in schizophrenia.

Secondary Outcome Measures

Name	Time	Method
Clinical response 1	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Schizophrenia symptoms will be assessed using the PANSS (Positive and Negative Syndrome Scale) total score.
Response marker 1	at inclusion	The differences at baseline in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • correlations (z-scores) between left prefrontal and temporal cortical areas (i.e., areas stimulated with tDCS) measured with resting-state functional Magnetic Resonance Imaging (MRI).
Response marker 2	at inclusion	The differences at baseline in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • spectral power (dB) in gamma frequency (40-Hz) during specific auditory paradigms (auditory steady-state, oddball, tone-matching) measured with electroencephalography (EEG).
Clinical response 7	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Subjective experiences of cognitive impairment will be assessed using the self-rated Subjective Scale To Investigate Cognition in Schizophrenia (SSTICS) total score.
Response marker 4	at inclusion	The differences at baseline in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • GABA and Glutamate levels (mM) within left prefrontal and temporal cortical areas measured with resting-state Magnetic Resonance Spectroscopy (MRS)
Long term cognitive response	at inclusion; at 3-months follow-up	Number of responders at 3-months after tDCS, defined as the proportion of patients demonstrating a cognitive improvement greater than or equal to Z=0.5 from baseline on the MATRICS Consensus Cognitive Battery total score (MCCB). The MCCB is a gold-standard standardized test battery to assess cognitive functions in patients with schizophrenia. This criterion has been used and validated in both antipsychotic and cognitive remediation trials in schizophrenia.
Clinical response 2	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Auditory hallucinations, one of the key symptoms of schizophrenia, will be assessed using the AHRS (Auditory Hallucination Rating Scale)
Clinical response 3	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Negative symptoms will be additionally assessed using the Brief Negative Symptom Scale (BNSS).
Clinical response 4	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Depressive symptoms will be assessed using the Calgary Depression Scale for Schizophrenia (CDSS) total score.
Outcome response 1	at inclusion; at 1-month follow-up; at 3-months follow-up	Changes from baseline to 1-month and 3-months endpoints in the following general outcome measures: • Functional outcome will be assessed using the FROGS (Functional Remission Observatory Group in Schizophrenia) total score
Tolerance 1	at 1-week	Score after the last tDCS session in the following tolerance measure: • tDCS-AEQ (Adverse Effects Questionnaire)
Tolerance 2	at 1-week	Score after the last tDCS session in the following tolerance measure: • VAMS (Visual Analogue Mood Scale)
Cognitive domain response	at inclusion; at 1-month follow-up; at 3-months follow-up	Changes from baseline to 1-month and 3-months endpoints in each MCCB domains subscores (processing speed, attention/vigilance, working memory, verbal learning, visual learning, problem solving, emotional awareness) and total score.
Clinical response 5	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Global symptom severity and treatment response will be assessed using the Clinical Global Impressions Scale (CGI) total score.
Clinical response 6	at inclusion; at 1-week; at 1-month follow-up; at 3-months follow-up	Changes from baseline to after tDCS, 1-month and 3-months endpoints in the following symptom measure: • Subjective experience of negative symptoms will be assessed using the Self-evaluation of Negative Symptoms (SNS) total score
Outcome response 2	at inclusion; at 1-month follow-up; at 3-months follow-up	Changes from baseline to 1-month and 3-months endpoints in the following general outcome measures: • Quality of life will be assessed by the Schizophrenia Quality of Life Questionnaire Short Form (S-QoL 18) total score
Response marker 3	at inclusion	The differences at baseline in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • inter-assay coherence (%) in gamma frequency (40-Hz) during specific auditory paradigms (auditory steady-state, oddball, tone-matching) measured with electroencephalography (EEG).
Response marker 5	at inclusion	The differences at baseline in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • radiotracer binding potential on GABA-A receptors (Binding Potential) within left prefrontal and temporal cortical areas measured with resting-state \[11C\]flumazenil Positron Emission Tomography MRI (PET-MRI).
Response predictor 3	at inclusion; at 1-month follow-up	Changes from baseline to 1-month in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • inter-assay coherence (%) in gamma frequency (40-Hz) during specific auditory paradigms (auditory steady-state, oddball, tone-matching) measured with electroencephalography (EEG).
Response predictor 4	at inclusion; at 1-month follow-up	Changes from baseline to 1-month in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • GABA and Glutamate levels (mM) within left prefrontal and temporal cortical areas measured with resting-state Magnetic Resonance Spectroscopy (MRS)
Response predictor 1	at inclusion; at 1-month follow-up	Changes from baseline to 1-month in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • correlations (z-scores) between left prefrontal and temporal cortical areas (i.e., areas stimulated with tDCS) measured with resting-state functional Magnetic Resonance Imaging (MRI).
Response predictor 2	at inclusion; at 1-month follow-up	Changes from baseline to 1-month in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • spectral power (dB) in gamma frequency (40-Hz) during specific auditory paradigms (auditory steady-state, oddball, tone-matching) measured with electroencephalography (EEG).
Response predictor 5	at inclusion; at 1-month follow-up	Changes from baseline to 1-month in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • GABA and Glutamate levels (mM) within left prefrontal and temporal cortical areas measured with resting-state Magnetic Resonance Spectroscopy (MRS)
Response predictor 6	at inclusion; at 1-month follow-up	Changes from baseline 1-month in the following early auditory processing (EAP) measure between patients with cognitive improvement and patients without cognitive improvement after active tDCS: • radiotracer binding potential on GABA-A receptors (Binding Potential) within left prefrontal and temporal cortical areas measured with resting-state \[11C\]flumazenil Positron Emission Tomography MRI (PET-MRI).

Trial Locations

Locations (4)

CHU Grenoble Alpes; 🇫🇷 La Tronche, Auvergne-Rhône-Alpes, France

CH Alpes-Isère; 🇫🇷 Saint-Égrève, Rhône-Alpes, France

CH Le Vinatier; 🇫🇷 Bron, France

CHU Saint-Etienne; 🇫🇷 Saint-Étienne, France