经颅时间干涉刺激治疗伴有抑郁发作的双相情感障碍 一项可行性研究

汇报人： 浙江大学医学院附属第一医院 罗宇家

01

背景

01 Disease Burden

Bipolar depression is the most common and debilitating phase of bipolar disorder, with a suicide risk 20–30 times higher than the general population.

02 Limitations of Pharmacotherap

Medications show unstable efficacy and significant side effects.

03 Limitations of Physical Treatments

Non-invasive brain stimulation techniques (e.g., tDCS, rTMS) mainly act on the cortex and have difficulty modulating deep brain regions.

01 疾病困扰

双相抑郁(BD-D)是双相障碍中 最常见、最具破坏性的阶段,自 杀风险比普通人群高20–30倍。

02 药物治疗不理想

药物治疗疗效不稳定,副作用大。

03 物理治疗局限性

非侵入性脑刺激(如tDCS、 rTMS)主要作用于皮层,难以调 节深部脑区。

The tTIS technology revolutionarily adopts the innovative principle of dual-channel alternating current interference: By applying two high-frequency alternating currents with a slight frequency difference to the scalp, an interference effect is generated in deep brain regions, forming a lowfrequency envelope wave capable of effectively modulating neuronal activity. In this study, tTIS was used for the first time to achieve non-invasive, precise targeting of deep brain structures such as the nucleus accumbens (NAcc).

tTIS技术革命性地采用了双通道交流电干涉的创新原理： 通过在头部施加两路具有频率差的高频交流电，利用其 在大脑深部产生的干涉效应，形成能够有效调制神经元 活动的低频包络波。 在本研究中，tTIS技术首次真正实现了对伏隔核等深部脑 区的无创精准靶向干预。

Figure. Schematic of Temporal Interference (TI) Technology Temporal interference electrical stimulation applies two highfrequency sinusoidal currents, f1 (red line) and f2 (blue line), with a small frequency difference (Δf) to the human brain, generating a modulated waveform (black envelope).

图：时域干涉（TI）技术原理示意图 时间干涉（ TI ）电刺激以较小的频率差（ ∆f ） 向人脑施加两个高频 正弦电流 f1（红线）和 f2（蓝线），可以产生调制波形（黑色包络）。

02

方法

This study was designed as a single-arm clinical trial, strictly enrolling 25 patients diagnosed with bipolar depression according to DSM-5 criteria.

Stimulation Parameters: • Duration: 20 minutes per session • Schedule: Twice daily, Monday to Friday, for a total of 10 sessions • Maximum current: 2 mA • Envelope frequency: 40 Hz (using 1000 Hz and 1040 Hz)

Inclusion Criteria:

• Age 16–50 • DSM-5 diagnosis of bipolar depression • HAMD-17 score > 17 • Drug-naïve or off medication for at least 1 month, voluntarily participating and providing informed consent

Exclusion Criteria: • Comorbid psychiatric disorders (e.g., anxiety, intellectual disability, substance dependence) • Severe physical or neurological diseases • Risk of epilepsy or structural brain abnormalities • Implanted metal or electronic devices (e.g., pacemaker, cochlear implant) • Prior exposure to tDCS, rTMS, or ECT • Pregnant or breastfeeding women

本研究设计了一项单臂临床试验，研究严格纳入25名符合DSM-5诊断标准的双相抑郁患者。 刺激参数： • 每次20分钟（治疗安排在每周一至周五，每天两次，共计10次） • 最大电流2mA • 包络频率40Hz（1000Hz和1040Hz）

纳入标准：

(1) 年龄16–50岁；

(2) 符合DSM-5双相抑郁诊断标准；

(3) HAMD-17评分 > 17；

(4) 未用药或已停药1个月，自愿参与并签署知情同意书。

排除标准：

（1）合并其他精神障碍（如焦虑、智障、物质依赖）；

(2) 严重躯体疾病或神经系 统疾病；

(3) 有癫痫风险或脑部结构异常；

(4) 体内有金属/电子设备（如起搏器、耳蜗）；

(5) 曾接受tDCS、rTMS、电休克等治疗；

(6) 孕妇或哺乳期女性。

03

结果—— 情绪症状显著改善

A: HAMD-17 score decreased from 23.36 ± 3.20 to 16.16 ± 5.64 (p < 0.0001)

B: MADRS score decreased from 39.12 ± 7.77 to 31.28 ± 9.38 (p < 0.01)

C: 11 participants (44.0%) achieved clinical improvement (≥20% reduction in HAMD-17 or MADRS); 7 participants (28.0%) achieved response criteria (≥50% reduction); No significant difference in mood improvement between drug- naïve and medication-free patients

D: HAMA score decreased from 19.68 ± 5.72 to 15.44 ± 6.74 (p < 0.05)

E: YMRS score decreased from 10.4 ± 6.88 to 7.72 ± 7.33 (not statistically significant)

F: QIDS score decreased from 13.52 ± 3.39 to 9.68 ± 4.00 (p < 0.001)

汉密尔顿抑郁量表-17项（HAMD-17）评分从 23.36 ± 3.20下降至16.16 ± 5.64（p < 0.0001）；

蒙哥马利-阿斯伯格抑郁量表（MADRS）评分从 39.12 ± 7.77下降至31.28 ± 9.38（p < 0.01）；

11人（44.0%）达到临床改善标准（HAMD-17或 MADRS评分下降>20%），7人（28.0%）达到应 答标准（评分下降≥50%）。未曾用药与已停药患 者之间在情绪症状改善方面无显著差异。

汉密尔顿焦虑量表（HAMA）评分从19.68 ± 5.72下 降至15.44 ± 6.74（p < 0.05）；

杨氏躁狂量表（YMRS）评分虽无统计学显著性， 但也从10.4 ± 6.88下降至7.72 ± 7.33。

抑郁症状快速自评清单-16项（QIDS）评分从13.52 ± 3.39下降至9.68 ± 4.00（p < 0.001）；

04

结果 —— 认知功能改善

Using the THINC-it tool to assess cognitive function, participants showed improvement trends in multiple cognitive tasks post-intervention: • Significant improvement in DSST (Digit Symbol Substitution Test) • Significant reduction in reaction time in the N-back task • Improvement trends in PDQ-5-D and CRT, though not statistically significant These results suggest that tTIS may not only alleviate mood symptoms but also enhance cognitive function. Throughout the intervention, only mild and transient scalp discomfort was reported. No serious adverse events occurred. Notably, no manic switching was observed, indicating good safety and tolerability of tTIS in this sensitive population.

使用THINC-it工具对认知功能进行评估，干 预后参与者在多个认知任务中表现出改善趋 势：  DSST（数字符号替换测试）表现显著提 升；  N-back任务中的反应时（NbackRT）显 著缩短；  PDQ-5-D、CRT等项目也呈改善趋势， 但未达统计学显著性。 这些结果表明，tTIS干预不仅对情绪症状有 效，还可能带来认知功能的提升。

05

结果 —— 奖励系统脑激活变化

fMRI Analysis Revealed: • Post-intervention, participants showed significantly increased bilateral NAcc activation during reward anticipation • Right NAcc activation change was positively correlated with HAMD-17 reduction rate (r = 0.712, p = 0.014) • Left NAcc activation change was not significantly correlated with symptom improvement These findings suggest that tTIS may improve mood symptoms in bipolar depression patients by modulating reward system activity.

fMRI分析显示：

干预后，参与者在奖励预期阶 段双侧NAcc（伏隔核）激活 显著增强；

右侧NAcc的激活变化与 HAMD-17评分下降率呈显著 正相关（r = 0.712，p = 0.014）；

左侧NAcc激活变化与症状改 善无显著相关性。这些结果提示，tTIS可能通过调 节奖励系统的神经活动，改善 BD-D患者的情绪状态，尤其是 快感缺失等核心症状。

06

讨论与结论

This is the first study to demonstrate that non-invasive deep brain stimulation using tTIS targeting the left NAcc can significantly reduce acute depressive and anxiety symptoms in bipolar depression, with 44% achieving clinical improvement and 28% achieving response.

Significant improvements in DSST and N-back reaction time, along with reduced subjective cognitive complaints, suggest both objective and subjective cognitive enhancement.

fMRI-MID task revealed increased bilateral NAcc activation during reward anticipation, with right NAcc activation correlating with HAMD-17 reduction, providing neuroimaging evidence for improved anhedonia.

Unlike traditional tDCS/rTMS, which mainly affect cortical areas, tTIS enables low-frequency modulation in the NAcc via interference of two high-frequency currents, potentially enhancing reward circuitry function and alleviating anhedonia.

Only mild, transient scalp discomfort was reported, with no serious or persistent adverse events —indicating good tolerability

Study Limitations

Single-arm design: Lack of sham control prevents ruling out placebo effects

Small sample size: Only 25 completed treatment; fMRI data from 11, limiting statistical power and subgroup analysis

Acute intervention: Only 5-day efficacy observed; long-term maintenance and relapse data lacking

Spatial precision of electric field: Despite individualized modeling, current may affect adjacent structures; behavioral effects may not be solely attributable to NAcc

首次证实「非侵入式深部脑刺激-tTIS」靶向左侧伏隔核，可显著减轻双相抑郁（BD-D）急性期的抑郁与焦 虑症状，44%患者达临床改善、28%达应答。

DSST与N-back反应时显著缩短，主观抱怨减少，提示客观+主观认知同步提升。

fMRI-MID任务发现双侧伏隔核在“奖励预期”阶段激活增强，右侧激活变化与HAMD-17降幅正相关，为“快感 缺失改善”提供神经影像证据。 传统tDCS/rTMS主要作用于皮层，本研究通过tTIS实现两路高频电流包络在 NAcc生成低频调制，局部突触可塑性改变 → 增强奖励回路功能 → 减轻快感缺失。

仅出现短暂头皮刺痛/麻木等轻度不适，无严重或持续不良事件，耐受性良好。

研究局限性：

单臂设计：无假刺激对照，不能排除安慰剂效应。

样本量小：25例完成治疗，fMRI仅11例，统计效能有限，且无法做亚组分析。

急性期干预：仅观察5天疗效，缺乏长期维持与复发数据。

电场空间精度：虽个体化建模，但电流仍可能波及相邻结构，行为效应不一定完全源于NAcc。