Combining noninvasive brain stimulation and neuroimaging to study human brain biology

有很多关于大脑如何工作的理论。这些理论可以通过改变大脑功能并确定其如何影响行为的工具进行测试。这种工具在动物模型中很常见（例如，光遗传学），但对于人类大脑没有这样的工具。我们的长期NSERC支持计划需要开发这样的工具。一种可以非侵入性地测试人类大脑行为因果关系理论的方法将对神经科学产生变革性的影响。经颅电流刺激（TCS）结合MRI可以成为这样的主要工具。 先前的研究观察到TCS在体内调节人类行为，而其他研究则没有发现影响。这些不一致性在很大程度上反映了TCS的无创性。事实上，tCS本身并不能显示它在调节行为时如何影响大脑。这是tCS研究中缺失的一个基本步骤：tCS调节什么，从而影响行为？ 这项为期5年的计划的主要目标是通过同时结合TCS和MRI进行基础研究来表征tDCS如何调节人脑活动。由于之前的发现资助，我们开发了一种同时结合tCS和静息状态MRI的方法。因此，这种方法可以测试TCS是否可以真正调节大脑活动，而不会混淆行为影响。我们发现，TCS的背外侧前额叶皮层的健康成年人在静息状态下功能性MRI和MR波谱增强连接的额顶网络和前额叶NAA和纹状体谷氨酸水平升高。我们的研究提供的证据表明，TCS可以影响刺激过程中的人脑活动。我们最近还观察到，脑形态，特别是体积，影响TCS诱导的神经递质水平的变化。引人注目的是，很少有关于形态测量学和纤维束描记术如何影响TCS对大脑活动的影响的研究。然而，形态测量和纤维束成像是电流通过的主要途径（我们可以在人脑中进行体内评估），以调节大脑活动并因此调节行为。 在本计划中，我们建议专门测试： 1.如果假tDCS是一个良好的对照条件，因为最常用的假tDCS方案之一尚未通过MRI结局进行测试; 2. tDCS在刺激期间和刺激后对静息状态功能连接的影响的个体内可靠性，并表征脑解剖结构（形态测量学、纤维束成像）对这些影响的影响;以及 3. tDCS在刺激期间和刺激后对神经递质水平的影响的个体内可靠性，并表征脑解剖结构（形态测量学、纤维束成像）对这些影响的影响。 同时结合TCS和MRI方法的发展将有助于提供可靠调节特定脑网络的工具。这些工具将具有通过建立大脑行为因果关系来测试人类大脑功能的质量。

There are theories about how the brain works. Those theories can be tested with tools that can change brain function and identify how that affects behaviours. Such tools are common in animal models (e.g., optogenetics), but there are no such tools for the human brain. Our long-term NSERC supported program entails developing such tools. A method that could test theories, noninvasively, on human causal brain-behaviour relationships would have a transformative impact in neuroscience. Transcranial current stimulation (tCS) combined with MRI can become such cardinal tool. Previous studies observed that tCS modulated human behaviours in vivo, whereas others found not effects. These inconsistencies reflect in large part the noninvasive quality of tCS. Indeed, tCS alone does not show how it influences the brain when it modulates behaviours. This is a fundamental step missing in tCS investigations: What does tCS modulate to, consequently, influence behaviours? The main goal of this 5-year program is to characterize how tDCS modulates human brain activity by conducting basic investigations concurrently combining tCS and MRI. Thanks to previous Discovery grants, we developed a method concurrently combining tCS with resting state MRI. This method can thus to test whether tCS can truly modulate brain activity, without confounding behavioural influence. We found that tCS over the dorsolateral prefrontal cortex of healthy adults during resting state functional MRI and MR spectroscopy strengthened connectivity in the frontoparietal network and elevated prefrontal NAA and striatal glutamate levels. Our studies provide evidence that tCS can impact human brain activity during stimulation. We also recently observed that brain morphometry, especially the volume, influences tCS-induced changes on neurotransmitter levels. Strikingly, there are scarce studies on how morphometry and tractography influence tCS effects on brain activity. Yet, morphometry and tractography are the main roads that the current travels through (and that we can assess in vivo in the human brain) to modulate brain activity and consequently behaviours. In this program, we propose to specifically test: 1. If sham tDCS is a good control condition, as one of the most used sham tDCS protocol has yet to be tested with MRI outcomes; 2. Intra-individual reliability of tDCS effects on resting state functional connectivity during and after stimulation and characterize the impact of brain anatomy (morphometry, tractography) on these effects; and 3. Intra-individual reliability of tDCS effects on neurotransmitter levels during and after stimulation and characterize the impact of brain anatomy (morphometry, tractography) on these effects. The development of concurrently combining tCS and MRI methods will contribute at providing tools that will reliably modulate specific brain networks. Such tools will have the quality to test human brain functions by establishing brain-behavioural causal relationships.