Non-invasive Brain Stimulation Normalizes Dopaminergic Transmission in the Frontostriatal Circuit to Alleviate Depression With Metabolic Disorders.
研究概览
详细说明
Depression and metabolic disorder (MetD) are two of the most common and debilitating disorders worldwide, occurring with significant rates of comorbidity. This is a major clinical challenge as the outcomes of both conditions are worsened. Studies have uncovered that depression and metabolic disorder are associated with chronic, low-grade inflammation. In brain circuit level, patients with depression are characterized with aberrant frontostriatal (FS) circuit connectivity and reduced activity level that also associated with metabolic comorbidity. BD patients also showed functional anomalies in the VS and FS circuits with reduced neural flexibility of hedonic signaling in response to stress. The dysfunctional FS circuits also link to the metabolic comorbidities in patients with mood disorders. Regarding metabolic control, the FS functional connectivity changes affect food craving. And the altered reciprocal loop from the medial prefrontal cortex could regulate eating behavior and metabolic disturbance. In neurotransmitter level, the dopaminergic pathway, that could be feedback regulated by immune and metabolic factors, has long been known to involve in emotional and metabolic homeostasis. More importantly, this dopamine (DA) input is critical to shaping the FS circuit-level dynamic connectivity and plasticity. Disruptions in the dopamine (DA) system have been observed in psychiatric disorders. MDD might involve DA reductions that could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. Therefore this study hypothesizes that inflammatory and metabolic dysregulations on DA transmission link to the aberrant FS function that cause depression and MetD. To clarify the underlying mechanisms, unipolar and bipolar depression patients will be enrolled to measure the FS functional connectivity and activation, before and after receiving 10 Hz repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex. Then systemically analyze participants' clinical symptomology, neurocognitive function, inflammation and metabolic status. Possible correlations between indices, the effects of rTMS and the possible differences between unipolar and bipolar depression patients will be tested. Results could provide a chance for further understanding the pathophysiology and better treatment of depression with MetD, finding biomarkers for subgrouping depression between unipolar depression and bipolar depression, predicting outcomes to brain circuit based personalized rTMS treatment for depression with MetD.
The specific aims of the project are:
Aim 1: To find the biological homogeneousness among depression with MetD by investigate the associations between (1) FS circuit connectivity and clinical (mood and metabolic) symptoms, and (2) FS circuit activation and clinical (mood and metabolic) symptoms in both unipolar and bipolar depressed individuals.
Aim 2: To confirm the role of FS in depression with MetD by applying rTMS to test its effects on (1) clinical symptoms, (2) FS circuit activation, (3) FS circuit connectivity and (4) find predictors for the rTMS treatment response.
Aim 3: To study the bidirectional inflammatory and metabolic feedback regulations of the DA transmission in FS circuit in depression with MetD by investigate the associations between (1) FS circuit activation, and (2) FS circuit connectivity and systemic inflammatory/ metabolic regulators both before and after rTMS treatments.
研究类型
注册 (估计的)
阶段
- 不适用
联系人和位置
学习地点
-
-
-
Tainan、台湾、704
- National Cheng-Kung University
-
-
参与标准
资格标准
适合学习的年龄
接受健康志愿者
描述
Inclusion Criteria:
- (1)Signed informed consent by patient or legal representative;
- (2) male or female patient aged ≧20 and ≦70 years;
- (3) a diagnosis of MDD or BD according to DSM criteria made by a specialist in psychiatry;
- (4) a total score of at least 18 in the Hamilton Rating Scale for Depression (HDRS) at the screening stage;
- (5) patient or a reliable caregiver can be expected to ensure acceptable compliance and visit attendance for the duration of the study.
Exclusion Criteria:
- (1) women of childbearing potential, not using adequate contraception as per investigator judgment or not willing to comply with contraception for the duration of the study;
- (2) females who are pregnant or breast-feeding;
- (3) other major DSM 5 diagnoses other than mood disorders, except for tobacco use disorder and anxiety disorder;
- (4) current evidence of an uncontrolled and/or clinically significant medical condition, e.g. patients with extensive area of ischemic bruise, multiple sclerosis, cardiac, hepatic and renal failure that would compromise patient safety or preclude study participation;
- (5) history of seizure or epilepsy;
- (6) history of neurological diseases or traumatic brain injury;
- (7) history of brain lesion, having received neurosurgery, meningitis or encephalitis;
- (8) exacerbation of symptom severity, presenting severe suicidal ideation or self harm behavior during the screen or study period;
- (9) presence of devices, e.g. pacemakers, cochlear prosthesis, neuro-stimulators, magnetic cochlear prosthesis, intracranial/intraocular metallic fragments;
- (10) patient has received electroconvulsive therapy (ECT) within 3 months prior to the first intervention of the treatment;
- (11) skin lesion at local site receiving rTMS stimulation;
- (12) those who cannot tolerate the side effects or ever developed sleep disorder while receiving rTMS therapy.
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：非随机化
- 介入模型：并行分配
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
|
有源比较器：MDD patient with HRSD score of at least 18
MDD patients who meet the DSM-5 diagnostic criteria of MDD and their current episode show a Hamilton Rating Scale for Depression (HRSD) score of at least 18
|
Real-time MRI-guided neuronavigation with a Visor neuronavigation system (ANT Neuro, Enschede, Netherlands) will be used for coil positioning.
Left dorsolateral prefrontal cortex target is located in each participant.
其他名称：
|
|
有源比较器：BD patient with HRSD score of at least 18
BD patients who meet the DSM-5 diagnostic criteria of BD and their current depression episode show a Hamilton Rating Scale for Depression (HRSD) score of at least 18
|
Real-time MRI-guided neuronavigation with a Visor neuronavigation system (ANT Neuro, Enschede, Netherlands) will be used for coil positioning.
Left dorsolateral prefrontal cortex target is located in each participant.
其他名称：
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Change from baseline mood symptom severity at several timepoints over 3 months
大体时间：Week 0, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12.
|
Evaluation for disease severity by using the Hamilton Rating Scale for Depression (HAM-D) by trained senior psychiatrists.
The same rater administers the scale for each patient.
|
Week 0, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12.
|
|
Iowa gambling task (IGT) with functional MR imaging
大体时间：Week 0
|
The subject will be asked to turn a card from 4-decks voluntarily, and maximize gains and minimize losses during the game.
|
Week 0
|
|
Change from baseline functional connectivity maps at 3 months
大体时间：Week 0, Week 12
|
A 2-sample independent t-test will be employed to analyze the functional connectivity maps using SPM 12. Statistical maps will be computed to identify changes in striatum-seeded functional connectivity for between-group comparisons.
The age will be regressed out as a covariate of non-interest.
Significance will be threshold at the uncorrected voxel level p=0.001, followed by the FWE- corrected cluster level p=0.05.
|
Week 0, Week 12
|
|
Change from baseline homeostasis model assessment-estimated insulin resistance (HOMA-IR) index at several timepoints within 3 months
大体时间：Week 0, Week 4, Week 8, Week 12
|
The homeostasis model assessment-estimated insulin resistance (HOMA-IR) index is calculated as the product of the fasting plasma insulin level (uIn/ml) and the fasting plasma glucose level (mg/dl), divided by 405.
Insulin resistance is defined as HOMA-IR ≥2.5.
|
Week 0, Week 4, Week 8, Week 12
|
|
Change from baseline body mass index (BMI) at several timepoints within 3 months
大体时间：Week 0, Week 4, Week 8, Week 12
|
Body weight (to the nearest 0.1 kg), body height (to the nearest 0.1 cm) will be measured and BMI (kg/m2) will be calculated accordingly.
|
Week 0, Week 4, Week 8, Week 12
|
|
Change from baseline waist and hip circumference at several timepoints within 3 months
大体时间：Week 0, Week 4, Week 8, Week 12
|
Waist and hip circumference (to the nearest 0.1 cm) will be measured.
|
Week 0, Week 4, Week 8, Week 12
|
|
Change from baseline fasting serum leptin level at several timepoints within 3 months
大体时间：Week 0, Week 4, Week 8, Week 12
|
Measured using ELISA method (Linco Research, USA).
The limit of detection was 0.5 ng/mL, and the intra- and interassay coefficients of variation were 7% and 9%, respectively.
|
Week 0, Week 4, Week 8, Week 12
|
|
Change from baseline fasting serum lipid level at several timepoints within 3 months
大体时间：Week 0, Week 4, Week 8, Week 12
|
Fasting total cholesterol, high density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and triglyceride (TG) concentrations will be measured.
|
Week 0, Week 4, Week 8, Week 12
|
|
Change from baseline immunological markers at several timepoints within 3 months
大体时间：Week 0, Week 2, Week 3, Week 4, Week 8, Week 12
|
The fasting plasma CRP level will be assessed using an high-sensitivity CRP ELISA kit (Bender MedSystems, USA), for which the limit of detection was 3 pg/mL and the intra- and inter-assay coefficients of variation were 6.9% and 13.1%, respectively.
The other immunological parameters to be analyzed include TNF-α, TGF-β1, IL-1, IL-8 and IL-10.
|
Week 0, Week 2, Week 3, Week 4, Week 8, Week 12
|
|
Change from baseline neurocognitive performance at 3 months
大体时间：Week 0, Week 12
|
Neurocognitive performance will be assessed using Continuous Performance Test (CPT), Finger-Tapping Test (FTT) and Wisconsin Card-Sorting Test (WCST).
|
Week 0, Week 12
|
|
Change from baseline social cognitive function at 3 months
大体时间：Week 0, Week 12
|
Mayer-Salovey-Caruso emotional Intelligent Test (MSCEIT): four branches: perceiving emotion (consisting of two tasks: face and picture tasks), facilitating emotion, understanding emotion, and managing emotion (Mayer, Salovey, Caruso, & Sitarenios, 2003).
The results will be scaled to a standard score based on the weight from the representative adult population (regarding age, gender, and ethnicity) in an extremely large sample of people (5,000).
The reliability and validity of MSCEIT V2.0 have been proved before.
|
Week 0, Week 12
|
|
Change from baseline autonomic nervous system performance at several timepoints within 3 months
大体时间：Week 0, Week 4, Week 12
|
Cardiac autonomic function will be calculated by the geometric method, which is based on short-term measurements of the interbeat interval (IBI) [82].
Power spectral density analysis of HRV will be performed by fast Fourier transformation [83].
|
Week 0, Week 4, Week 12
|
合作者和调查者
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他研究编号
- A-BR-110-005
药物和器械信息、研究文件
研究美国 FDA 监管的药品
研究美国 FDA 监管的设备产品
此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.