Deep Brain Stimulation for Chronic Auditory Hallucinations in Treatment-Resistant Schizophrenia: an early-stage clinical trial

深部脑刺激治疗难治性精神分裂症慢性幻听：一项早期临床试验

• 批准号: 10644871
• 负责人: NICOLA G CASCELLA
• 金额: $ 79.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644871
• 关键词: Acute; Aggressive behavior; Antipsychotic Agents; Auditory; Auditory Hallucination; Basal Ganglia; Behavioral; Bilateral; Brain; Brief Psychiatric Rating Scale; Chronic; Clinic; Clinical; Clinical Research; Clozapine; Cognitive; Data; Deep Brain Stimulation; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease remission; Distress; Double-Blind Method; Ecological momentary assessment; Electroencephalography; Enrollment; Hallucinations; Home; Image; Impairment; Ketamine; Lead; Left; Lesion; Link; Measurement; Measures; Medial Dorsal Nucleus; Mediating; Methods; Microelectrodes; Modeling; Obsessive-Compulsive Disorder; Operative Surgical Procedures; Parkinson Disease; Pathologic; Patients; Persons; Phase; Phase I Clinical Trials; Public Health; Quality of life; Rattus; Refractory; Resistance; Saccades; Sample Size; Schizophrenia; Sensory; Serious Adverse Event; Speech; Substantia nigra structure; Suicide; Superior temporal gyrus; Symptoms; System; Techniques; Thalamic structure; Tissues; Verbal Auditory Hallucinations; Work; cohort; connectome; conventional therapy; design; effective therapy; follow-up; implantation; improved; inhibitory neuron; motor impairment; neuroimaging; neuromechanism; neurophysiology; neuropsychiatric disorder; safety study; suicidal behavior; suicidal risk; tractography

SUMMARY Auditory verbal hallucinations (AVH) afflict more than 80% of schizophrenia (SZ) patients and are treatment resistant up to 40-45%. AVHs increase the risk of suicidal, aggressive behavior, reduced work attainment and impairment in specific cognitive domains. Considering that 25-50% of persons with SZ are treatment-resistant (TR-SZ), there is unmet public health need to treat persistent AVH in TR-SZ. SZ is a disorder with disruptions within corticostriatothalamic circuits ((CST) thus potentially amenable to modulation via Deep Brain Stimulation (DBS). DBS-SZ may hypothetically modulate AVH through its effect on projections from superior temporal gyrus (STG) to basal ganglia (BG), via the substantia nigra pars reticulata (SNr) and mediodorsal nucleus of the thalamus (MDN). There is evidence that the SNr-MDN-STG loop is dysfunctional in SZ and lesions within this loop cause new onset SZ-like hallucinations. Modulation of the SNr-MDN-STG loop could result in treatment of persistent hallucinations in SZ. In support of this hypothesis, we have preliminary evidence that bilateral SNr DBS induces sustained remission of chronic AVH in a TR-SZ patient and their improvement in a second patient. We hypothesize (Aim 1) that SNr DBS decreases AVH measured by in-clinic BPRS, and at-home-Ecological momentary assessment technique by at least 20% without serious adverse events when comparing baseline to 60 weeks DBS stimulation. For more granular examination of DBS effect on AVH, we will use in-clinic Auditory Vocal Hallucinations Rating Scale (AVHRS), and the Scale for the Assessment of Positive Symptoms (SAPS) (Aim 1). A potential neural mechanism of SNr DBS modulation for AVH might be restoring oscillatory activity in the SNr-MDN-STG loop. Abnormalities in γ oscillations (30–100 Hz) of the electroencephalogram are ubiquitous in SZ. SNr recordings in persons with SZ is uncharted, but low-γ oscillations have been recorded from the SNr in ketamine- treated rats, a well-established SZ model--these are hypothesized to reflect cognitive and sensory, rather than motor impairment. We hypothesize that AVHs in SZ are associated with excessive gamma power in the SNr, and that these abnormal SNr gamma oscillations can be targeted with bilateral SNr DBS resulting in reduced AVH. We will collect home LFP recordings to assess changes in SNr LFP gamma power in DBS on vs off and explore if DBS-related oscillatory changes correlate with AVH changes (Aim 2). Since AVH are associated with impairments in saccadic eye-movements s, we will also explore if DBS-related oscillatory changes correlate with saccadic impairments and their improvements Aim 2.)

概括 听觉言语幻觉（AVH）受苦超过80％的精神分裂症（SZ）患者，并且是 耐药性高达40-45％。 AVH会增加自杀，侵略性行为的风险， 减少特定认知领域的工作属性和损害。考虑到25-50％ SZ患者具有耐药性（TR-SZ），需要治疗未满足的公共卫生 在Tr-Sz中持续的AVH。 SZ是一种疾病，在皮质纹状体丘脑电路内部有干扰 （（CST）因此可能通过深脑刺激（DBS）进行调节。DBS-SZ可能 假设通过其对上级临时回（STG）项目的影响来调节AVH 到基底神经节（BG），通过黑质Nigra pars网状（SNR）和培养基核的核 丘脑（MDN）。有证据表明SNR-MDN-STG循环在SZ中功能失调，并且 该循环中的病变会引起新的SZ样幻觉。 SNR-MDN-STG的调节 循环可能导致SZ持续幻觉的治疗。为了支持这一假设，我们 有初步的证据表明，双边SNR DB会诱导慢性AVH持续缓解 TR-SZ患者及其在第二名患者中的改善。我们假设（AIM 1）SNR DBS通过临界BPR和在家生态时期衡量的AVH降低 比较基线时，评估技术至少为20％而没有严重的不利事件 到60周的DBS刺激。为了对DBS对AVH的影响进行更多的颗粒状检查，我们将使用 临界听觉声音幻觉评分量表（AVHRS）和评估量表 积极症状（SAPS）（AIM 1）。 SNR DBS调制的潜在神经机制 AVH可能正在恢复SNR-MDN-STG循环中的振荡活动。 γ异常 脑电图的振荡（30-100 Hz）在SZ中无处不在。 SNR记录中 具有SZ的人是未知的，但是在氯胺酮的SNR中记录了低γ的振荡。 经过治疗的大鼠，一种公认的SZ模型 - 假设这些大鼠反映了认知和 感官，而不是运动障碍。我们假设SZ中的AVH与 SNR中的伽马功率过多，并且这些异常SNRγ振荡可能是 用双侧SNR DBS靶向，导致AVH降低。我们将收集家庭LFP录音 评估vs Off DBS中SNR LFP伽马功率的变化，并探索与DBS相关的是否相关 振荡变化与AVH变化相关（AIM 2）。因为AVH与 Sacadic眼动损伤S，我们还将探索是否与DBS相关的振荡性变化 与囊性障碍及其改进相关的目的2.）