Combining HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia

Official title

The Efficacy of Combined HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia

Overview

Dysfunction of the dorsolateral prefrontal cortex (DLPFC) is central to the persistence of negative symptoms in schizophrenia. Both HD-tDCS and iTBS targeting the left DLPFC have shown therapeutic benefit. This trial will test the hypothesis that combining HD-tDCS with iTBS yields additive efficacy.

Detailed description

Dysfunction of the left dorsolateral prefrontal cortex (DLPFC) is central to the persistence of negative symptoms in schizophrenia, an area of unmet therapeutic need. High-definition transcranial direct current stimulation (HD-tDCS) and intermittent theta burst stimulation (iTBS), an optimized form of repetitive transcranial magnetic stimulation (rTMS), have each demonstrated efficacy in alleviating negative symptoms when applied to the left DLPFC. However, meta-analyses indicate only moderate effect sizes for these interventions individually. Evidence suggests that combining iTBS with tDCS may enhance cortical plasticity beyond either technique alone, warranting trials to assess additive efficacy. This double-blind, randomized, sham-controlled study will test the hypothesis that combined HD-tDCS and iTBS produce superior therapeutic benefit for negative symptoms in schizophrenia.

Interventions

• Device active iTBS followed by active HD-tDCS
  The active iTBS sessions will be delivered using the Magstim Rapid2 stimulator. The iTBS protocol consists of 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) for 2 s at 8-s intervals for 60 cycles. A 2-s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. The intensity of stimulation will be set at 80% resting motor threshold (RMT). The target will be the left DLPFC with the coil centered at the MNI coordinate \[-38, 44, 26\] calculated from T1-weighted MRI. The a
• Device active iTBS followed by sham HD-tDCS
  The active iTBS sessions will be delivered using the Magstim Rapid2 stimulator. The iTBS protocol consists of 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) for 2 s at 8-s intervals for 60 cycles. A 2-s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. The intensity of stimulation will be set at 80% resting motor threshold (RMT). The target is the left DLPFC with the coil centered at the MNI coordinate \[-38, 44, 26\] calculated from T1-weighted MRI. In the sha
• Device sham iTBS followed by active HD-tDCS
  In the sham iTBS condition, the patients receive the same iTBS regimen and exact positioning of the coil but stimulations will be delivered using a commercial identical looking figure 8 sham coil (Magstim D70 Air film sham coil) that can produce a similar sound and sensation. In the active HD-tDCS condition, 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
• Device sham iTBS followed by sham HD-tDCS
  In the sham iTBS condition, patients receive the same iTBS regimen and exact positioning of the coil but stimulations will be delivered using a commercial identical looking figure 8 sham coil (Magstim D70 Air film sham coil) that can produce a similar sound and sensation. In the sham HD-tDCS condition, short continuous currents without neuromodulatory effects will be applied to mimic real-stimulation sensations. Specifically, sham stimulation will deliver 40-sec, 2 mA normal-like stimulation, fo

Primary outcome measures

• The change in Positive and Negative Syndrome Scale (PANSS) negative subscale score [Time frame: Fifteen weeks]

Secondary outcome measures (12)

• The change in score of the Scale for the Assessment of Negative Symptoms (SANS) [Time frame: Fifteen weeks]
• The change in score of Calgary Depression Rating Scale for Schizophrenia (CDSS) [Time frame: Fifteen weeks]
• The change in the Personal and Social Performance scale (PSP) score [Time frame: Fifteen weeks]
• The change in the score of the Beck Cognitive Insight Scale (BCIS) [Time frame: Fifteen weeks]
• The change in the score of Schizophrenia Quality of Life Scale Revision Four (SQOLR4) [Time frame: Fifteen weeks]
• The changes in the results of the Tower of London Drexel University Test 2nd Edition [Time frame: Three weeks]
• The changes in the results of the Color Trails Test (CTT) [Time frame: Three weeks]
• The changes in the results of the Stroop Color Word Test (SCWT) [Time frame: Three weeks]
• The changes in indices of heart rate variability (HRV) derived from R-R intervals of ECG signals [Time frame: Three weeks]
• The changes in resting-state EEG features [Time frame: Three weeks]
• The changes in fNIRS features [Time frame: Three weeks]
• The changes in resting-state fMRI features [Time frame: Three weeks]

Eligibility criteria

Inclusion criteria

• Subjects diagnosed with DSM-5 schizophrenia or schizoaffective disorder;
• With a clinical presentation characterized by predominant negative symptoms, as determined by psychiatric assessment and a score of at least 20 on the Negative Symptoms Subscale of the Positive and Negative Syndrome Scale (PANSS);
• Stable positive and negative symptoms for at least 4 weeks, as documented in medical records and confirmed by clinical judgment and psychiatric interview;

Exclusion criteria

• Unstable medical conditions;
• Current psychiatric comorbidity or active substance use disorder (except for tobacco use disorders);
• Contraindications for MRI, tDCS or rTMS;
• Pregnancy or breastfeeding at the time of enrollment;
• History of meningitis, encephalitis, seizures, intracranial neoplasms or surgery, severe head injury or cerebrovascular disease, or a family history of seizures;
• rTMS or tDCS treatment within the past 6 months as well as a history of electroconvulsive therapy (ECT);
• Any skin lesion at the stimulation sites;
• Patients receiving medications that significantly change the seizure threshold;
• A history of suicidal behavior within the past 6 months, or symptom worsening and emergence of suicidal ideation during the screening period.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Taiwan · 1 center

• Tri-service general hospital — Taipei

Publications

• Kishi T, Ikuta T, Sakuma K, Hamanaka S, Nishii Y, Hatano M, Kito S, Iwata N. Theta Burst Stimulation Protocols for Schizophrenia: A Systematic Review and Network Meta-Analysis. JAMA Netw Open. 2024 Oct 1;7(10):e2441159. doi: 10.1001/jamanetworkopen.2024.41159. PMID 39446321
• Tong S, Chen S, Chen J, Tong Z, Li W, Liu S, Shi H, Yao L, Zhang C, Zhang X. Efficacy and long-term effects of intermittent theta burst stimulation on negative symptoms in schizophrenia: a systematic review and meta-analysis. Brain Commun. 2026 Jan 29;8(1):fcag027. doi: 10.1093/braincomms/fcag027. eCollection 2026. PMID 41704822
• Gupta R, Sharma A, Goyal N. Breaking the Negative Symptom Barrier: A Novel Neuromodulation Strategy Using HD-tDCS Primed iTBS in Schizophrenia. J ECT. 2026 Jan 20. doi: 10.1097/YCT.0000000000001224. Online ahead of print. PMID 41575458
• Ma CC, Lin YY, Chung YA, Park SY, Huang CC, Chang WC, Chang HA. The two-back task leads to activity in the left dorsolateral prefrontal cortex in schizophrenia patients with predominant negative symptoms: a fNIRS study and its implication for tDCS. Exp Brain Res. 2024 Mar;242(3):585-597. doi: 10.1007/s00221-023-06769-5. Epub 2024 Jan 16. PMID 38227007
• Yeh TC, Lin YY, Tzeng NS, Kao YC, Chung YA, Chang CC, Fang HW, Chang HA. Effects of online high-definition transcranial direct current stimulation over left dorsolateral prefrontal cortex on predominant negative symptoms and EEG functional connectivity in patients with schizophrenia: a randomized, double-blind, controlled trial. Psychiatry Clin Neurosci. 2025 Jan;79(1):2-11. doi: 10.1111/pcn.13745 PMID 39317963
• Lin CE, Chen LF, Sack AT, Chang HA. Task-based fNIRS biomarkers of HD-tDCS treatment for negative symptoms in schizophrenia. Schizophr Res. 2026 Aug;294:35-43. doi: 10.1016/j.schres.2026.04.010. Epub 2026 Apr 17. PMID 42000633

Identifiers

NCT: NCT07680959 · B202303001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗