Transcranial alternating current stimulation for cognitive deficit in schizophrenia: effects and electrophysiological changes
| ISRCTN | ISRCTN56047723 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN56047723 |
| Secondary identifying numbers | SUKL: VLTAVA_01; File No. sukls301462/2023 |
- Submission date
- 24/01/2024
- Registration date
- 23/02/2024
- Last edited
- 07/05/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Mental and Behavioural Disorders
Plain English summary of protocol
Background and study aims
Cognitive impairment is one of the major symptom groups in patients with schizophrenia (SCH), along with positive and negative symptoms. Reviews suggest that 80% of SCH patients suffer from some kind of cognitive impairment. Impairment in particular cognitive domains is associated with changes in brain network dynamics and endogenous oscillations. Whereas the positive and negative symptoms can be treated with a range of pharmacological agents, pharmacological treatment of cognitive symptoms does not produce sufficient results. Therefore, there is a demand for other methods and therapeutic approaches, as well as for a more detailed understanding of the underlying pathology and mechanisms of action of the proposed intervention methods. One of the possible interventions is transcranial alternating current stimulation (tACS).
TACS is one of the non-invasive brain stimulation (NIBS) methods. Using electrodes, placed on the scalp, alternating current is applied to predefined areas of the brain, and interferes with endogenous oscillations in brain networks. Dysfunctions in endogenous network oscillations have been found in SCH and linked to several SCH symptoms. As for the cognitive domain, studies suggest hyperactivation of resting-state theta phase-gamma amplitude coupling as one of the mechanisms of cognitive dysfunction, or theta band and gamma band oscillations reduction and gamma band shift in working memory (WM) task. Gamma-band oscillations over the prefrontal cortex are a correlate of performing a WM task, with a gamma power increase in higher load WM task. For SCH, tACS has a greater effect when administered in multiple sessions.
Cognitive impairment is one of the major symptom groups in patients with SCH, with a significant lack of effective treatment strategies. The underlying pathology seems to be related to disturbances in endogenous oscillations, but the exact mechanisms are not yet known. TACS might be able through manipulation of endogenous oscillations improve this cognitive impairment. The purpose of the proposed study is to evaluate the effect of 10 sessions of tACS on cognition in SCH patients. If successful, the results could help introduce tACS into clinical practice and represent a safe intervention method. Electrophysiological changes, measured on EEG, TMS and fMRI-EEG, when correlated with the results of cognitive tests, could give insights into the pathology of cognitive impairment in SCH, with possible translation into other disorders. FMRI-EEG can distinguish the effect of tACS, which helps in gaining a deeper knowledge of brain network organization and can be used for the creation of tACS predictive models. These could potentially help stratify responders from non-responders.
Who can participate?
Adults aged 18-70 years old with SCH
What does the study involve?
The study includes a 2-week tACS treatment with ongoing assessment of clinical status and fMRI-EEG and EEG examinations before and after tACS treatment.
What are the possible benefits and risks of participating?
Benefits:
Improvement of cognition and/or overall status after tACS treatment.
Risks:
Adverse effects (AE) during tACS treatment are usually very low, with discomfort, burning feeling and phosphenes being the most common AE. This AE should not lead to withdrawal.
Where is the study run from?
National Institute of Mental Health (Czechia), Psychiatrická nemocnice Bohnice Hospital (Czechia)
When is the study starting, and how long is it expected to run for?
November 2023 to February 2029
Who is funding the study?
National Institute of Mental Health (Czechia)
Who is the main contact?
Assoc. Prof. Monika Klírová M.D., Ph.D., monika.klirova@nudz.cz
Contact information
Public, Scientific, Principal Investigator
National Institute of Mental Health
Topolová 748
Klecany
25067
Czech Republic
 ORCID ID |
0000-0002-8092-9586 |
|---|---|
| Phone | +420283088140 |
| monika.klirova@nudz.cz |
Study information
| Study design | Randomized parallel-group interventional double-blind placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment, Efficacy |
| Participant information sheet | 44938_PIS_PNB.pdf |
| Scientific title | EVaLuation of TAcs effect by adVanced neurocomputational methods in schizophreniA |
| Study acronym | VLTAVA |
| Study objectives | Current study hypothesis as of 07/05/2025: We hypothesize that an active transcranial alternating current stimulation (tACS) protocol will enhance cognitive functions, which will be reflected in improved performance in cognitive tests, namely in: a higher number of correct responses, fewer errors, and shorter reaction times. We predict that these changes in cognitive functions will be related to electrophysiological changes measured in electroencephalogram – EEG (such as event-related potentials (ERPs), functional connectivity, power spectral density, etc.), and transcranial magnetic stimulation – TMS. Previous study hypothesis: We hypothesize that an active transcranial alternating current stimulation (tACS) protocol will enhance cognitive functions, which will be reflected in improved performance in cognitive tests, namely in: a higher number of correct responses, fewer errors, and shorter reaction times. We predict that these changes in cognitive functions will be related to electrophysiological changes measured in electroencephalogram – EEG (such as event-related potentials (ERPs), functional connectivity, power spectral density, etc.), transcranial magnetic stimulation – TMS, and combined functional magnetic resonance imaging and EEG – fMRI-EEG. |
| Ethics approval(s) |
Approved 18/01/2024, National Institute of Mental Health Ethics Committee (Topolova 748, Klecany, 25067, Czech Republic; +420 (0)283 088 312; ek@nudz.cz), ref: 11/24 |
| Health condition(s) or problem(s) studied | Schizophrenia |
| Intervention | Patients diagnosed with schizophrenia will be included in the study. Patients will be randomly allocated according to permuted block design to one of two intervention groups: active transcranial alternating current stimulation (tACS) or placebo tACS. The study is divided into two work packages (WP): WP 1: Randomized controlled trial with active (n=10) and sham (n=10) groups WP 2: Randomized controlled trial with active (n=20) and sham (n=20) groups First, the total subject count in WP1 will be recruited, subsequently moving on to WP2. Description of Visits: Screening Visit (V-1) Signed informed consent Confirm inclusion and exclusion criteria Complete physical examination Complete medical history, review of concomitant medications, check the adequate maintenance treatment Randomization Only subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible for enrollment into the study. An investigator will perform a thorough medical history evaluation, mainly focused on any possible contraindications, to exclude subjects with a possible confounding condition. Baseline Visit (V0) WP1 The following procedures/assessments will be performed: EEG Measurement (Resting state), RBANS, TMT, WCST, PANSS, Speech abilities testing WP2 The following procedures/assessments will be performed: EEG Measurement (Resting state, Auditory Oddball Task, Sternberg Memory Test), RBANS, TMT, WCST, PANSS, Signed informed consent for fMRI-EEG, fMRI-EEG examination, TMS Measurement Intervention Visits (Day 1 – Day 14) The following procedures/assessments will be performed: Confirmation of inclusion and exclusion criteria, Study treatment administration, Recording of adverse events, if any Intervention The intervention parameters for each session are recommended as follows: 10 applications One session per day, five times a week Area of stimulation: F3/F4 electrode according to the 10-20 system Patient position of application: sitting position 6-80Hz, 2mA, 20 min duration Concomitant cognitive testing – N-back test End-of-Intervention Visit (V1) WP1 The following procedures/assessments will be performed: EEG Measurement (Resting state), RBANS, TMT, WCST, PANSS, Speech abilities testing WP2 The following procedures/assessments will be performed: EEG Measurement (Resting state, Auditory Oddball Task, Sternberg Memory Test), RBANS, TMT, WCST, PANSS, fMRI-EEG examination, TMS Measurement Follow-up Visit (V2) During the follow-up visit, the Investigator will question the subject if any reaction or adverse event after the treatment appeared. WP1 The following procedures/assessments will be performed: EEG Measurement (Resting state), RBANS, TMT, WCST, PANSS, Speech abilities testing WP2 The following procedures/assessments will be performed: EEG Measurement (Resting state, Auditory Oddball Task, Sternberg Memory Test), RBANS, TMT, WCST, PANSS, TMS Measurement Subjects who will not respond in the acute phase of the study will be treated as usual according to their psychiatrists. If the patient withdraws consent within follow-up (late drop-out), an unscheduled visit X-FU will be carried out to exclude side effects or worsening of clinical status and to record reasons for withdrawal. |
| Intervention type | Device |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | DC Stimulator Mobile (Neuroconn, Germany) |
| Primary outcome measure | Current primary outcome measure as of 07/05/2025: Attention domain and Total score in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score at baseline (V0) and week two (V1) Previous primary outcome measure: Delayed memory Index measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score at baseline (V0) and week two (V1) |
| Secondary outcome measures | Current secondary outcome measure as of 07/05/2025: 1. Changes in cognition, measured using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) subdomains score (Immediate memory, Delayed memory, Visuospatial abilities, Language and Attention), Trail Making Test – TMT score, Sternberg Memory Test score, Wisconsin Card Sorting Test – WCST score at baseline (V0), week two (V1), and week six (V2) 2. Changes in speech abilities, measured using reading of text, free speech production, reproduction of emotional and neutral speech, and picture description at baseline (V0), week two (V1), and week six (V2) 3. Symptom severity, measured using the Positive and Negative Syndrome Scale (PANSS) at baseline (V0), week two (V1), and week six (V2) 4. Neurophysiological changes, measured using EEG and TMS signal change at baseline (V0), week two (V1), and week six (V2) 5. Cognition changes in the RBANS Attention domain and Total score at baseline (V0) and week six (V2) Previous secondary outcome measure: 1. Changes in cognition, measured using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) overall score, RBANS subdomains score (Immediate memory, Visuospatial abilities, Language and Attention), Trail Making Test – TMT score, Sternberg Memory Test score, Wisconsin Card Sorting Test – WCST score at baseline (V0), week two (V1), and week six (V2) 2. Changes in speech abilities, measured using reading of text, free speech production, reproduction of emotional and neutral speech, and picture description at baseline (V0), week two (V1), and week six (V2) 3. Symptom severity, measured using the Positive and Negative Syndrome Scale (PANSS) scale at baseline (V0), week two (V1), and week six (V2) 4. Neurophysiological changes, measured using EEG, fMRI-EEG, and TMS signal change at baseline (V0), week two (V1), and week six (V2) 5. Cognition changes in the RBANS subdomains Delayed memory domain at baseline (V0) and week six (V2) |
| Overall study start date | 01/11/2023 |
| Completion date | 31/07/2029 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 70 Years |
| Sex | Both |
| Target number of participants | 60 |
| Key inclusion criteria | 1. Male and female outpatients at ages 18-70 years old 2. Meet DSM-V criteria for schizophrenia as determined by Structured Clinical Interview for DSM-V (SCID-5) 3. The mental ability to understand and sign the Informed Consent Form 4. Being on a stable and adequate dose of antipsychotics and/or antidepressants (monotherapy or combination) for at least four weeks before enrollment |
| Key exclusion criteria | 1. Psychiatric comorbidity on axes I and II according to DSM-V six months before enrollment to the study except for SCH-related disorders 2. Personality disorder that makes participation in the trial difficult 3. Substance dependence except for nicotine 4. Substantial suicidal risk as judged by the treating psychiatrist 5. Sensory and motor disabilities precluding participation in computer-based tests 6. Electronic or metal implants in the head |
| Date of first enrolment | 01/04/2024 |
| Date of final enrolment | 28/02/2029 |
Locations
Countries of recruitment
- Czech Republic
Study participating centre
Klecany
25067
Czech Republic
Sponsor information
Research organisation
Topolova 748
Klecany
25067
Czech Republic
| Phone | +420 283 088 111 |
|---|---|
| pavlina.gembicky@nudz.cz | |
| Website | https://www.nudz.cz/en/ |
"ROR" |
https://ror.org/05xj56w78 |
Funders
Funder type
Not defined
No information available
Results and Publications
| Intention to publish date | 31/12/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Data will be published in peer-reviewed journals with IF (Q1, Q2) after completion of the study. Preliminary and final results will also be communicated at scientific international conferences and to the public at educational public lectures. |
| IPD sharing plan | After the article's publication, de-anonymized data will be made available for non-commercial academic projects. Data can be obtained by request to the corresponding author (Monika Klírová, monika.klirova@nudz.cz). The de-anonymized data files with a dictionary will be provided via a secure data transfer service. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | Bohnice Psychiatric Hospital (Psychiatrické nemocnici Bohnice; PNB) in Czech | 30/01/2024 | No | Yes | |
| Participant information sheet | in Czech | 30/01/2024 | No | Yes | |
| Participant information sheet | in Czech | 30/01/2024 | No | Yes |
Additional files
- 44938_PIS_PNB.pdf
- Bohnice Psychiatric Hospital (Psychiatrické nemocnici Bohnice; PNB) in Czech
- 44938_PIS_WP1.pdf
- in Czech
- 44938_PIS_WP2.pdf
- in Czech
Editorial Notes
07/05/2025: The following changes were made:
1. The public title was changed from "Evaluation of transcranial alternating current stimulation effect by advanced neurocomputational methods in schizophrenia".
2. The study hypothesis was updated.
3. Ethics approval information for Ethics Committee of the Bohnice Psychiatric Hospital (Etická komise Psychiatrické nemocnice Bohnice), Prague, Czech Republic, was removed, and Bohnice Psychiatric Hospital (Psychiatrická nemocnice Bohnice) was removed from the study participating centres.
4. The primary and secondary outcome measures were updated.
25/01/2024: Study's existence confirmed by the Ethics Committee of the Bohnice Psychiatric Hospital.
