Prefrontal cortical engagement and clinical effects of non-invasive direct current stimulation for cognitive control impairments in schizophrenia

非侵入性直流电刺激对精神分裂症认知控制障碍的前额皮质参与和临床效果

• 批准号: 9678081
• 负责人: RAYMOND Y CHO
• 金额: $ 42.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-28 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9678081
• 关键词: Prefrontal; cortical; engagement; clinical; effects

 DESCRIPTION (provided by applicant): Cognitive deficits are a strong predictor of functional outcome in schizophrenia, yet poorly remediated by current treatments. Disturbances in dorsolateral prefrontal cortex (DLPFC) function underlie core impairments such as in cognitive control and thus represent a critical target for novel therapeutics. Initial studies indicate transcranial direct-current stimulation (tDCS) may be effective in reducing symptoms due to DLPFC dysfunction. While tDCS potentially represents an exciting, novel therapeutic advance, a number of basic questions should be addressed prior to conducting larger-scale clinical trials, including: verifying therapeutic target engagement, optimizing treatment parameters, and evaluating for meaningful clinical effects. Recent studies employing tDCS to enhance prefrontal cortical function in schizophrenia applied stimulating electrodes over the left frontal scalp regio, putatively targeting the left DLPFC. However, explicit confirmation of such target engagement is lacking. Further, EEG studies have demonstrated close links of frontal cortical gamma oscillations to cognitive control processes but modulation of this critical physiologic process has not been investigated. Accordingly, the primary R61 aim (R61-Aim 1) will employ multimodal imaging to explicitly test for the assumed DLPFC engagement (fMRI) and modulation of frontal gamma activity (EEG) by tDCS. The R61-Aim 2 will investigate the optimization of tDCS application parameters. Analogous to dose-finding investigations in drug studies, we will conduct a parametric investigation of optimal current strengths. Also, while there is extensive evidence for tolerability of single session tDCS, confirmation of feasibility of multi- session optimized protocols in schizophrenia is lacking and so will be explicitly evaluated (R61-Aim 3). The R33 phase will be predicated on initial demonstration of target engagement, namely, tDCS modulation of DLPFC BOLD and frontal gamma oscillatory activity (R61-Aim 1). With such demonstration and equipped with an optimized tDCS protocol (R61-Aim 2) that has been verified to be well-tolerated (R61-Aim 3), the R33 phase would then seek to demonstrate clinical effect, namely, the modulation of cognitive control probed by a cued stimulus-response reversal paradigm (R33-Aim 1). We will also evaluate clinical and functional outcome employing relevant assessment tools (BPRS/SANS/SAPS and SLOF/SFS/UPSA-B, respectively) (R33-Aim 2). Finally, we will investigate whether any observed improvements in cognitive control and functional outcome are mediated by DLPFC and frontal gamma oscillation engagement (R33-Aim 3). In summary, a successful outcome of this study would provide tDCS the sound mechanistic, methodologic and clinical-relevance basis for more definitive testing in large-scale clinical trials as a highly innovative therapeutic intervention for cognitive impairments in schizophrenia.

 描述（由申请人提供）：认知缺陷是精神分裂症功能结局的一个强有力的预测因子，但目前的治疗方法补救不力。背外侧前额叶皮质（DLPFC）功能障碍是核心障碍（如认知控制）的基础，因此代表了新疗法的关键靶标。初步研究表明，经颅直流电刺激（tDCS）可能有效地减少DLPFC功能障碍引起的症状。虽然tDCS可能代表了一种令人兴奋的新型治疗进展，但在进行大规模临床试验之前，应解决一些基本问题，包括：验证治疗靶点参与，优化治疗参数，以及评估有意义的临床效果。最近的研究采用tDCS来增强精神分裂症患者的前额叶皮质功能，在左额叶头皮区域施加刺激电极，靶向左DLPFC。然而，对这种目标接触缺乏明确的确认。此外，EEG研究已经证明了额叶皮层伽马振荡与认知控制过程的密切联系，但是对这一关键生理过程的调制已经被证明是不可能的。 没有被调查。因此，主要R61目标（R61-Aim 1）将采用多模态成像来明确测试假定的DLPFC接合（fMRI）和tDCS对额叶伽马活动（EEG）的调制。R61-Aim 2将研究tDCS应用参数的优化。类似于药物研究中的剂量探索研究，我们将对最佳电流强度进行参数研究。此外，虽然有大量证据表明单次治疗tDCS的耐受性，但缺乏对精神分裂症中多次治疗优化方案可行性的确认，因此将对其进行明确评价（R61-Aim 3）。R33阶段将根据目标接合的初始演示来预测，即DLPFC BOLD和额叶伽马振荡活动（R61-Aim 1）的tDCS调制。有了这样的证明，并配备了优化的tDCS方案（R61-Aim 2），该方案已被证实耐受良好（R61-Aim 3），R33阶段将寻求证明临床效果，即通过线索刺激-反应逆转范式（R33-Aim 1）探测的认知控制的调节。我们还将使用相关评估工具（分别为BPRS/SANS/SAPS和SLOF/SFS/UPSA-B）评价临床和功能结局（R33-Aim 2）。最后，我们将研究是否有任何观察到的认知控制和功能结果的改善是由DLPFC和额叶伽马振荡参与介导的（R33-Aim 3）。总之，本研究的成功结果将为tDCS在大规模临床试验中作为精神分裂症认知障碍的高度创新性治疗干预措施进行更明确的测试提供可靠的机制，方法学和临床相关性基础。