A neurobiological investigation of cannabis use and misuse in Veterans

在精神病患者中，大麻与更差的预后、精神病的恶化有关 症状、认知受损、功能残疾、暴力、频率增加和持续时间增加 住院和医疗费用上升。尽管如此，大麻的共生率仍然很高。 精神病和退伍军人中大麻使用量的上升。随着合法化、商业化和日益增长 由于大麻的效力和风险感知的下降，有理由感到震惊，特别是对精神病患者。 关键的是，对于精神病患者的大麻使用障碍，还没有得到证实或批准的治疗方法。 虽然抗精神病药物对减轻精神病症状很有用，但对 减少大麻的使用。尽管新的研究表明，重复的经颅磁刺激 (RTMS)和心理社会干预(即激励强化疗法)可减少大麻的使用和/或 对于精神病，人们的反应好坏参半。治疗失败的一个可能原因是他们可能依赖于 完整的同步神经活动是信息处理、学习和记忆所必需的。 越来越多的证据表明，学习和记忆相关区域的神经同步性缺陷 与精神错乱的病理生理学和大麻的精神作用有关。在那些患有精神病的人中， 中枢受累的theta(4-7赫兹)和伽马(30-80赫兹)范围内的协调神经活动缺陷 在学习和认知方面，特别是工作记忆(WM)，已经被观察到。体内外研究 我们在健康对照组中的实验工作表明，大麻素受体1型激动剂降低了 以及伽马同步和增加噪声(随机活动)，以及改变工作中的功能连接 内存网络(WMN)。虽然文献很少，但精神病的实验研究表明大麻素 在学习任务中增加认知功能障碍并降低海马区-纹状体的功能连接性。 尽管有这些初步发现，但还需要进一步研究大麻类物质对这些患者神经同步性的影响。 对于精神病，因为识别牵连的神经机制可能会导致新的干预措施的发展。 以前用于研究神经同步性和功能连接的强大工具(协调 活动)，例如脑电(EEG)和功能磁共振成像，可以 辅以脑磁图(MEG)。脑磁图是一种非侵入性的功能性测量方法。 由神经活动产生的场具有出色的时间和空间分辨率。梅格一直对 了解其他疾病的神经同步性和工作记忆，比如阿尔茨海默病。而梅格 脑电对切向电流敏感，对切向电流和径向电流敏感。一起，梅格和EEG 为更准确地确定神经机制提供补充信息。尽管如此，还有 目前还没有使用MEG/EEG来研究退伍军人的神经同步性、大麻和精神病的研究。 为了解决这些差距，CDA-2旨在比较神经同步性和认知的临床结果， 精神病退伍军人和普通退伍军人的精神症状(即精神病、创伤和焦虑)和功能 使用同时脑磁图/脑电图的大麻使用与不使用的同龄人进行比较，首次在 弗吉尼亚州康涅狄格州。该提案将建立在首席调查员在大麻使用方面的专门知识和 认知和提供独特的技能，以支持她使用高级多式联运的长期职业目标 作为一名独立的VHA调查者，研究大麻类药物对退伍军人的影响的神经科学工具。 这项研究有可能用洞察力揭示这一人群中神经同步的复杂描述 研究它与认知、精神症状和功能的关系。科学知识的这种进步可能 产生显著的翻译临床效用，使得关于改变的同步性区域的发现可以提供 开发新的、更有效的干预措施的目标，如认知补救或rTMS 解决精神病退伍军人的神经同步性和提高认知能力。

In individuals with psychosis cannabis is associated with worse prognosis, exacerbation of psychotic symptoms, impaired cognition, functional disability, violence, increased frequency and duration of hospitalizations, and elevated healthcare costs. Despite this, there are high rates of co-occurring cannabis use in psychosis, and rising cannabis use amongst Veterans. With legalization, commercialization, and increasing potency of cannabis and decreasing risk perception, there is cause for alarm especially for those with psychosis. Critically, there are no proven or approved treatments for cannabis use disorder in individuals with psychosis. While antipsychotic medications are useful for decreasing psychotic symptoms, they have little effect on decreasing cannabis use. Although nascent research suggests that repetitive transcranial magnetic stimulation (rTMS) and psychosocial interventions (i.e., motivational enhancement therapy) may reduce cannabis use and/or psychosis, responses have been mixed. One possible reason that treatments may fail is that they may rely on intact synchronized neural activity necessary for information processing, learning and memory. Converging evidence suggest deficits in neural synchrony in regions involved in learning and memory are implicated in the pathophysiology of psychosis and psychoactive effects of cannabis. In those with psychosis, deficits in coordinated neural activity in theta (4-7Hz) and gamma (30-80Hz) ranges, which are centrally involved in learning and cognition and particularly working memory (WM), have been observed. In vitro and in vivo studies and our experimental work in healthy controls have shown cannabinoid receptor type 1 agonists decrease theta and gamma synchrony and increase noise (random activity), as well as alter functional connectivity in the working memory network (WMN). While a scant literature, experimental studies in psychosis have shown cannabinoids increase cognitive dysfunction and reduced hippocampal-striatal functional connectivity during a learning task. Despite these initial findings, further work is needed on the impact of cannabinoids on neural synchrony in those with psychosis, as identifying implicated neural mechanisms may lead to development of new interventions. Powerful tools previously used to investigate neural synchrony and functional connectivity (coordinated activity), such as electroencephalography (EEG) and functional magnetic resonance imaging, can be complemented with magnetoencephalography (MEG). MEG is a non-invasive, functional measure of magnetic fields produced by neural activity with excellent temporal and spatial resolution. MEG has been critical for understanding neural synchrony and working memory in other disorders, like Alzheimer’s Disease. While MEG is sensitive to tangential currents, EEG is sensitive to tangential and radial currents. Together, MEG and EEG provide complementary information for more accurate determination of neural mechanisms. Despite this, there have been no studies using MEG/EEG to investigate neural synchrony, cannabis, and psychosis in Veterans. To address these gaps, this CDA-2 aims to compare neural synchrony and clinical outcomes of cognition, psychiatric symptoms (i.e., psychosis, trauma, and anxiety), and function in Veterans with psychosis and regular cannabis use compared to non-using peers using simultaneous MEG/EEG, available for the first time within the VA at VA Connecticut. The proposal will build on the Principal Investigator’s expertise in cannabis use and cognition and provide the unique skills to support her long-term career goal of using advanced multimodal neuroscience tools to investigate the impact of cannabinoids on Veterans as an independent VHA investigator. This study has the potential to reveal a sophisticated account of neural synchrony in this population with insight into how it relates to cognition, psychiatric symptoms, and function. This advance in scientific knowledge may yield significant translational clinical utility such that findings about regions of altered synchrony may provide targets for the development of novel, more effective, interventions, such as cognitive remediation or rTMS to address neural synchrony and enhance cognition in Veterans with psychosis and co-occurring cannabis use.