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

Tri-Service General Hospital

Status: Completed

Conditions: Negative Symptoms in Schizophrenia; Schizophrenia; Schizoaffective Disorder, Mixed Type

Treatments: Device: HD-tDCS

Study type: Interventional

Funder types: Other

Identifiers

NCT05582980

1-108-03-002

Details and patient eligibility

About

In this randomized double-blind trial, the investigators aim to investigate whether online high definition transcranial direct current stimulation (HD-tDCS) over the left dorsolateral prefrontal cortex (DLPFC) during a working memory task improves the severity of negative symptoms in schizophrenia patients with predominant negative symptoms.

Full description

Positive (delusions and hallucinations) and negative (blunted affect, avolition-apathy, alogia and anhedonia-asociality) symptoms are recognized as core features of schizophrenia. Antipsychotic medications as the first-line treatment for schizophrenia can reduce the positive symptoms within 14-28 days but good evidence that antipsychotics have any beneficial effect on negative symptoms is scarce. Negative symptoms remain the most important unmet therapeutic needs in schizophrenia.

Accumulating functional neuroimaging research has linked the correlation between negative symptoms and reduced dorsolateral prefrontal activity. Atypical antipsychotics, the mainstream treatment for schizophrenia, are known to show little effect on patients' hypofrontality and some of them (e.g., strong dopamine receptor antagonists and clozapine) are even associated with a decrease in prefrontal activation. All these findings have driven the development of novel and effective treatments targeting the brain regions implicated in negative symptoms of schizophrenia, e.g., non-invasive brain stimulation (NIBS) of over the left DLPFC.

Transcranial direct current stimulation (tDCS) is a NIBS that has great potential to improve negative symptoms of schizophrenia. tDCS applies a weak direct current on the scalp and through the brain and rapidly leads to changes in cortical excitability by shifting membrane resting potentials, which facilitates either depolarization or hyperpolarization of the brain neurons. Repetitive stimulation during specific time intervals further enhances efficacy and prolongs the after-effects of tDCS through modifying the efficacy of N-methyl-D-aspartate receptor. An increasing number of studies attempted to reduce negative symptoms of schizophrenia by using tDCS.

Most tDCS research delivers direct current to the participants while they are at rest (offline tDCS). There has been a novel stimulation model called "online" stimulation, in which non-invasive brain stimulation is applied while the individuals are concurrently engaged in a neuropsychological task. For example, a cognitive task has been known to activate a specific brain region (e.g., working memory task and prefrontal cortex). The susceptibility of a specific brain region (i.e., prefrontal cortex) to neuro-stimulation will be enhanced if it is simultaneously activated when engaging a working memory task. Compared to the use of tDCS while the subject is at rest (offline tDCS), the application of tDCS to activate the prefrontal cortex while the subject is engaged in a working memory task (online tDCS) can potentially result in resonated effects and further enhance the neuromodulation on the target brain region, aka functional targeting.

High definition tDCS (HD-tDCS) targets cortical areas using arrays of electrodes on the scalp (i.e. a classic 4 × 1 ring configuration) and constrains the electrical current flow to a specific cortical area, allows for more accurate definition of the current field distribution than conventional tDCS and serves to optimize electrode montage to specifically target the brain areas of interest.

Our proof-of-concept study aims to investigate the efficacy of online HD-tDCS over left DLPFC as an add-on therapy to improve negative symptoms severity in schizophrenia patients with predominant negative symptoms. Moreover, it provides data on other secondary outcomes and preliminary neurophysiological data for this intervention condition.

Enrollment: 60 patients

Sex: All

Ages: 20 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Subjects aged 20-65 years and diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5 ) schizophrenia or schizoaffective disorder
• Duration of illness≧1 year
• With a clinical presentation of predominant negative symptoms (according to the clinical judgment of 2 experienced psychiatrists) and the Positive and Negative Syndrome Scale (PANSS) score > 70
• Receiving stable antipsychotic drug regimen >8 weeks.

Exclusion criteria

• Subjects with current psychiatric comorbidity or active substance use disorder with the exception of caffeine and/or tobacco
• Having contraindications for tDCS, e.g., implanted brain medical devices or metal in the head
• Pregnancy at enrollment
• Having a history of seizures, intracranial neoplasms or surgery, severe head injuries, or cerebrovascular diseases

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 2 patient groups

HD-tDCS (active)

Experimental group

Description:

Stimulation will be applied by a battery-operated device (NeuroConn DC Stimulator Plus) via 5 carbon rubber electrodes (1 cm radius, high-definition 4 × 1 rings configuration). To target the left DLPFC, the central electrode (anode) will be placed over International 10-20 electrode position F3, with return peripheral electrodes at Fp1, Fz, C3 and F7. Stimulation will be applied at an intensity of 2 milliamp (mA), 8-sec fade in and 5-sec fade out, for 20 min, two times daily, on 5 consecutive weekdays (total 10 sessions). During each session, the subject has to perform a computerized working memory task (i.e., 2-back task). The two times daily sessions will be separated by at least 2 hours.

Treatment:

Device: HD-tDCS

HD-tDCS (sham)

Sham Comparator group

Description:

In sham stimulation, the electrode montage and protocol will be the same as the active stimulation, except the 2 mA current will be turned on for 30 sec and then ramped down to 0 mA through the remainder of the 20-min time.

Treatment:

Device: HD-tDCS