SEEG-Guided DBS for Schizophrenia

Official title

Deep Brain Stimulation for Treatment-Refractory Schizophrenia: Individualized Target Selection and Efficacy

Overview

This is a prospective, randomized, interventional study designed to evaluate the efficacy and safety of SEEG-guided deep brain stimulation (DBS) for symptom improvement in patients with treatment-resistant schizophrenia. Using stereo-electroencephalography (SEEG) to record brain activity, we will identify specific abnormal electrophysiological targets and signal features associated with clinical symptoms, followed by a 12-month open-label stimulation period. The study is conducted in three stages: Stage 1 consists of SEEG brain mapping, screening of intervention targets, and optimization of stimulation parameters; Stage 2 consists of DBS implantation surgery and further optimization of stimulation parameters; Stage 3 is a randomized crossover treatment phase, followed by an open-label treatment period.

Detailed description

This clinical trial aims to systematically evaluate the efficacy and safety of SEEG-guided target screening combined with individualized deep brain stimulation (DBS) for treatment-refractory schizophrenia.

The study first employs Stereoelectroencephalography (SEEG) electrodes as the core tool to establish a personalized, minimally invasive neuromodulation surgical framework. After SEEG electrode implantation, researchers will collect and analyze high-spatiotemporal-resolution electrophysiological data during both resting-state and task-state conditions, as well as identify characteristic electrophysiological biomarkers that correlate with clinical symptoms.

Secondly, electrical stimulation is delivered through the SEEG contacts to functionally verify candidate targets in different brain regions. By stimulating specific targets and observing immediate symptomatic or physiological responses, we validate the effects on neural circuits and confirm their functional relevance prior to any permanent intervention. For targets that show preliminary efficacy, we further apply externalized chronic stimulation to continuously monitor symptom improvement and potential adverse effects.

After determine the optimal targets and the intervention is confirmed to be both effective and safe, we implant a permanent brain pacemaker (DBS device). During the efficacy follow-up phase, we employ a randomized crossover design, which is then followed by an open-label period. These two stages enable thorough assessment of clinical efficacy. Meanwhile, we also collect multidimensional data (clinical symptoms, cognition, and neuroimaging) to explore the circuit mechanisms of stimulation.

Interventions

• Procedure SEEG implantation
  Phase 1 involves the stereotactic implantation of Stereoelectroencephalography (SEEG) electrodes. Following implantation, comprehensive electrophysiological monitoring is conducted, including resting-state and task-state recordings, as well as acute electrical stimulation mapping. This process aims to identify the specific pathological neural circuits and electrophysiological biomarkers associated with the patient's individual psychotic symptoms.
• Device Deep brain stimulation
  Phase 2 involves individualized deep brain stimulation (DBS). Instead of relying solely on standardized anatomical landmarks, the DBS targets and parameters are precisely customized based on the individualized data acquired during the SEEG mapping phase.

Primary outcome measures

• Reduction Rate of PANSS Positive Subscale or SAPS [Time frame: Baseline (pre-operation), 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks post-operation.]

Secondary outcome measures (5)

• Reduction Rate of Auditory Hallucinations (Assessed by PSYRATS-AH) [Time frame: Baseline (pre-operation), 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks post-operation.]
• Reduction Rate of Delusions (Assessed by PSYRATS-D) [Time frame: Baseline (pre-operation), 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks post-operation.]
• Reduction Rate of Depressive Symptoms (Assessed by HAMD) [Time frame: Baseline (pre-operation), 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks post-operation.]
• Reduction Rate of Anxiety Symptoms (Assessed by HAMA) [Time frame: Baseline (pre-operation), 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks post-operation.]
• Improvement Rate of Cognitive Function (Assessed by MoCA) [Time frame: Baseline (pre-operation), 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks post-operation.]

Eligibility criteria

Inclusion criteria

• Meets the International Classification of Diseases, 10th Revision (ICD-10) diagnostic criteria for schizophrenia.
• Male or female, aged 18 to 55 years, with stable vital signs.
• Currently presents with prominent psychotic symptoms, assessed as moderate or severe by the Positive and Negative Syndrome Scale (PANSS) or other equivalent scales.
• Exhibits impaired social functioning, assessed as moderate or severe impairment by the Social and Occupational Functioning Assessment Scale (SOFAS) or other equivalent scales.
• Has a history of sequential treatment with at least two antipsychotic medications of different chemical structures known for strong efficacy against positive symptoms. Treatment must have been at an adequate dose and for an adequate duration (continuous treatment at a therapeutic dose for more than 6 weeks per medication), with good treatment adherence.
• Has been on a stable antipsychotic medication regimen for at least one month prior to enrollment.
• Capable and willing to provide written informed consent.
• Demonstrates good compliance and is able to cooperate with all follow-up procedures.

Exclusion criteria

• Diagnosed with any psychiatric disorder other than schizophrenia.
• Presence of a severe personality disorder.
• History of severe neurological diseases, such as seizures or hemorrhagic stroke.
• Presence of structural brain abnormalities.
• Previous history of stereotactic neurosurgery.
• Contraindications to general anesthesia or stereotactic neurosurgery.
• Any current or anticipated condition-including medical, psychological, social, familial support, or geographical factors-that might compromise patient safety or interfere with successful participation in the study.

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

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Ruijin Hospital, Shanghai JiaoTong University School of Medicine — Shanghai

Publications

• Vilela-Filho O, Ragazzo PC, Canedo D, Barreto US, Oliveira PM, Goulart LC, Reis MD, Campos TM. The impact of subcaudate tractotomy on delusions and hallucinations in psychotic patients. Surg Neurol Int. 2021 Sep 20;12:475. doi: 10.25259/SNI_599_2021. eCollection 2021. PMID 34621590
• Vaernet K, Madsen A. Stereotaxic amygdalotomy and basofrontal tractotomy in psychotics with aggressive behaviour. J Neurol Neurosurg Psychiatry. 1970 Dec;33(6):858-63. doi: 10.1136/jnnp.33.6.858. PMID 5531905
• Liu W, Hao Q, Zhan S, Li D, Pan S, Li Y, Lin G, Pan G, Mahyoub R, Sun B. Long-term follow-up of mri-guided bilateral anterior capsulotomy in patients with refractory schizophrenia. Stereotact Funct Neurosurg. 2014;92(3):145-52. doi: 10.1159/000360861. Epub 2014 May 7. PMID 24818571
• Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, Liu TX, Rao VR, Sellers KK, Dawes HE, Starr PA, Krystal AD, Chang EF. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med. 2021 Oct;27(10):1696-1700. doi: 10.1038/s41591-021-01480-w. Epub 2021 Oct 4. PMID 34608328
• Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron. 2005 Mar 3;45(5):651-60. doi: 10.1016/j.neuron.2005.02.014. PMID 15748841
• Sun FT, Morrell MJ, Wharen RE Jr. Responsive cortical stimulation for the treatment of epilepsy. Neurotherapeutics. 2008 Jan;5(1):68-74. doi: 10.1016/j.nurt.2007.10.069. PMID 18164485
• Motamedi GK, Lesser RP, Miglioretti DL, Mizuno-Matsumoto Y, Gordon B, Webber WR, Jackson DC, Sepkuty JP, Crone NE. Optimizing parameters for terminating cortical afterdischarges with pulse stimulation. Epilepsia. 2002 Aug;43(8):836-46. doi: 10.1046/j.1528-1157.2002.24901.x. PMID 12181002
• Lesser RP, Kim SH, Beyderman L, Miglioretti DL, Webber WR, Bare M, Cysyk B, Krauss G, Gordon B. Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology. 1999 Dec 10;53(9):2073-81. doi: 10.1212/wnl.53.9.2073. PMID 10599784

Identifiers

NCT: NCT07671261 · SEEG-Guided DBS for TRS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗