A novel TMS-EEG study of GABAergic and glutamatergic neurotransmission in antipsychotic treatment response in schizophrenia

精神分裂症患者会出现各种各样的症状，包括妄想（固定的、错误的信念）幻觉（例如幻听）、认知症状（例如记忆困难、注意力不集中、思维迟钝）和消极症状（例如缺乏动力）。精神分裂症的现有药物治疗，抗精神病药物，是通过减少大脑中一种叫做多巴胺的化学物质来起作用的。然而，三分之一到一半的患者尽管接受了抗精神病药物治疗，但仍有明显的症状。这导致患者有副作用，但症状没有改善，包括妄想、幻觉和认知症状。因此，多巴胺的减少并不是对所有的病人和精神分裂症的所有症状都有效，这就是为什么其他的大脑化学物质，如GABA和谷氨酸，正在被研究，希望可以为那些对目前的抗精神病药物没有反应的病人提供替代药物。与大脑化学物质相结合的是，大脑的一种被称为认知控制的认知能力，也可能在减少多巴胺的抗精神病药物对症状无反应的情况下发挥作用。认知控制通过帮助我们根据来自环境的信息改变和调整我们的行为，并将这些信息与我们自己的内部目标、规则或意图进行比较，从而使内部和外部现实同步。这种内外同步被认为是通过充当“大脑的免疫系统”来保护我们免受精神疾病症状的影响，并在精神疾病症状出现时处理它们。这种能力在精神分裂症中受损。在这项研究计划中，我们将研究服用抗精神病药物并对其产生反应的患者和服用抗精神病药物但对其没有反应的患者的大脑中GABA和谷氨酸化学物质的变化。我们将使用一种非侵入性、简单且安全的大脑刺激方法——经颅磁刺激（transcranial magnetic stimulation， TMS）来刺激这些大脑化学物质，这种方法多年来一直被用于抑郁症的临床治疗和精神分裂症的研究。TMS通过放置在头皮特定区域的“线圈”向大脑施加磁脉冲。电流被输送到线圈中，线圈在过程中充当磁场发生器。产生的磁场在大脑中产生电流。我们将用脑电图记录大脑对经颅磁刺激的反应。EEG使用附着在头皮上的小金属圆盘（电极）来检测大脑中的电活动，活动在EEG记录上以波浪线的形式显示出来。两组之间GABA和谷氨酸的差异将提供患者对当前抗精神病药物反应可能性的信息。我们还将研究认知控制是否在两组间GABA和谷氨酸的差异中起作用。这些信息最终将有助于预测哪些患者在诊断后会尽快对哪种药物产生反应。它也可能有助于研究开发对GABA和谷氨酸起作用的新药物，这样病人就可以服用对他们有效的药物，改善他们的症状和生活质量，而不必尝试无效的药物和忍受多年的副作用。

People who suffer from schizophrenia experience a wide range of symptoms, including delusions (fixed, false beliefs) hallucinations (e.g. hearing voices), cognitive symptoms (e.g. difficulties with memory, concentration, slow thinking) and negative symptoms (e.g. lack of motivation). The available pharmacological treatment for schizophrenia, the antipsychotic medications, are working through the reduction of a brain chemical called dopamine. However, a third to half of the patients still experience significant symptoms despite treatment with antipsychotics. This results in patients having side effects without improvement of their symptoms, including delusions, hallucinations and cognitive symptoms. Dopamine reduction is therefore not working for all patients and for all symptoms of schizophrenia and that's why other brain chemicals, such as GABA and glutamate, are being studied in the hope that alternative medications can be made available for those patients who do not respond to the current antipsychotics. In conjunction with the brain chemicals, a cognitive ability of the brain called cognitive control, may also play a role in the non-response of the symptoms to dopamine reducing antipsychotics. Cognitive control synchronises the internal and external realities by helping us to change and adapt our behaviour based on information from the environment and comparing this information with our own internal goals, rules or intentions. This internal-external synchronisation is thought to protect us from symptoms of mental illness by acting as the "immune system of brain" and dealing with the symptoms of mental illness as they arise. This ability is impaired in schizophrenia. In this research proposal we will study how GABA and glutamate chemicals in the brain change in patients who take antipsychotics and respond to them and in patients who take antipsychotics but have not responded to them. We will use a non-invasive, simple and safe stimulation of the brain called transcranial magnetic stimulation (TMS), which has been used for years in clinical practice as treatment for depression and research in schizophrenia, to stimulate these brain chemicals. TMS applies magnetic pulses to the brain via a 'coil" placed on specific areas on the scalp. An electric current is delivered to the coil, which acts as the magnetic field generator in the procedure. The generated magnetic field induces an electrical current in the brain. We will record the response of the brain to the TMS stimulation with electroencephalogram (EEG). EEG detects electrical activity in the brain using small, metal discs (electrodes) attached to the scalp and the activity shows up as wavy lines on an EEG recording. The differences in GABA and glutamate between the two groups will provide information on the likelihood of a patient to respond to the current antipsychotics. We will also study if cognitive control plays a role in the differences in GABA and glutamate between the two groups. This information will ultimately help to predict which patient will respond to which medication as soon as possible after the diagnosis. It may also contribute to the research for development of new medications acting on GABA and glutamate, so that patients will be able to take the mediations that work for them and improve their symptoms and quality of life without having to try ineffective medications and suffer side effects for years.