Prefrontal Cortical Engagement and Clinical Effects of non-invasive Direct Current Stimulation for Cognitive Control Impairments in Schizophrenia

 描述(由申请人提供)：认知缺陷是精神分裂症功能结果的有力预测因素，但目前的治疗方法补救效果不佳。背外侧前额叶皮质(DLPFC)功能障碍是认知控制等核心损伤的基础，因此是新疗法的关键靶点。初步研究表明，经颅直流电刺激(TDC)可能有效地减轻DLPFC功能障碍引起的症状。虽然TDC可能代表着一种令人兴奋的、新颖的治疗进展，但在进行更大规模的临床试验之前，应该解决一些基本问题，包括：验证治疗靶点的参与，优化治疗参数，以及评估有意义的临床效果。最近的研究使用tdcs来增强精神分裂症患者的前额叶皮质功能，将刺激电极应用于左侧额叶头皮区，推测是针对左侧DLPFC。然而，缺乏对这种目标接触的明确确认。此外，脑电研究表明，额叶皮质伽马振荡与认知控制过程有密切联系，但对这一关键生理过程的调节 没有被调查过。因此，主要的R61 AIM(R61-AIM 1)将使用多模式成像来明确测试假定的DLPFC参与(FMRI)和tDC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发现调查，我们将对最佳电流强度进行参数调查。此外，虽然有广泛的证据表明单疗程tdcs的耐受性，但缺乏对多疗程优化方案在精神分裂症中的可行性的确认，因此将明确评估(R61-Aim 3)。R33阶段将基于目标参与的初步演示，即DLPFC BOLD和锋面伽马振荡活动的tDCS调制(R61-AIM 1)。有了这样的演示，并配备了已被证实耐受性良好的优化tDCS方案(R61-Aim 2)，R33阶段将寻求展示临床效果，即，通过线索刺激-反应逆转范式(R33-Aim 1)来探索认知控制的调节。我们还将使用相关评估工具(分别为BPRS/SANS/SAPS和SLOF/SFS/UPSA-B)评估临床和功能结果(R33-AIM 2)。最后，我们将调查是否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(R33-AIM 3)介导的。总而言之，这项研究的成功结果将为TDC提供可靠的机制、方法和临床相关性基础，以便在大规模临床试验中进行更明确的测试，作为一种高度创新的治疗精神分裂症认知障碍的干预措施。

 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.