Establishing a biomarker for reflective awareness in brain-injured patients

建立脑损伤患者反思意识的生物标志物

• 批准号: 9115922
• 负责人: Benjamin Baird
• 金额: $ 5.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115922
• 关键词: Adult; Anesthesia procedures; Aphasia; Area; Arousal; Awareness; Behavior assessment; Biological Markers; Brain; Brain Injuries; Categories; Cerebrovascular Circulation; Clinical; Cognition; Computer Simulation; Conscious; Consciousness Disorders; Coupled; Degenerative Disorder; Development; Diagnosis; Diagnostic Errors; Disease; Dreams; Electroencephalography; Etiology; Functional Magnetic Resonance Imaging; General anesthetic drugs; Goals; Health; Hearing; Impaired cognition; Impairment; Individual; Lead; Link; Literature; Measures; Metabolism; Modeling; Monitor; Neurology; Pain; Parietal; Patients; Persistent Vegetative State; Population; Prefrontal Cortex; REM Sleep; Rehabilitation therapy; Research; Sensory; Sensory Process; Signal Transduction; Stroke; Syndrome; Testing; Therapeutic; Tracheotomy procedure; Transcranial magnetic stimulation; Traumatic injury; Unconscious State; Vegetative States; Wakefulness; Work; activity marker; base; causal model; density; diagnostic accuracy; experience; improved; information processing; motor impairment; neuroimaging; neuropsychological; neurotransmission; outcome forecast; rapid eye movement; relating to nervous system; research study; response; tool

 DESCRIPTION (provided by applicant): Assessing the level of awareness in patients suffering from disorders of consciousness (DOC) as a result of traumatic injury, strokes, or degenerative diseases remains a central challenge of modern neurology. Current estimates suggest that misdiagnosis occurs in over 40% of patients. This high rate of diagnostic error may partially be explained by the fact that clinicians are currently forced to make inferences about a patient's awareness based solely on overt responses to verbal commands obtained at a patient's bedside, which can be restricted by factors such as cognitive dysfunction, aphasia, motor impairment or tracheotomy. Development of brain activity markers of consciousness holds promise for improving diagnostic accuracy. One of the most important clinical goals is to assess whether an individual is aware of herself and her state (referred to as reflective consciousness (RC)), which is critical to making appropriate therapeutic choices and in determining prognosis. Preliminary studies in healthy adults have shown that RC is associated with activity within a network of frontoparietal (FP) cortices. Consistent with this, patients with presumed global loss of consciousness, such as the unresponsiveness wakefulness syndrome (vegetative state) and certain forms of anesthesia-induced unresponsiveness, have decreased activity in FP cortices. However, alterations in regional activity within FP cortices are insufficient as an unambiguous marker of consciousness because activation in these regions is also observed during unconscious states. Recent findings suggest that a potentially more sensitive marker of global unconsciousness may be a reduction of top-down FP functional connectivity. These findings converge with recent theoretical work and computational modeling, which has suggested a link between consciousness and neural effective connectivity. However, a direct link between RC and top-down FP effective connectivity has yet to be established. The proposed studies use a multimodal approach across two different arousal states to investigate the relationship between RC and FP directional connectivity. We will first examine changes in directional connectivity by applying state-of-the-art measures of Granger Causality (GC) and Dynamic Causal Modeling (DCM) to [high-density electroencephalography (hd-EEG)]. We will then directly assess changes in neural effective connectivity using TMS/hd-EEG to directly perturb targeted neural populations and model changes in neural signal propagation from FP regions. Using this multimodal approach, Aim 1 will examine how modulation of RC during waking influences directional connectivity in FP cortices. Aim 2 will then examine the directional connectivity changes that are associated with loss of RC in REM sleep. Together, we expect that these studies will help establish a brain activity marker for RC that does not depend on an individual's ability to communicate or respond to sensory signals. Identification of such a marker has the potential to both improve diagnostic accuracy as well as extend basic scientific understanding of these disorders, opening new avenues for treatment.

 描述（由申请人提供）：评估因创伤性损伤、中风或退行性疾病而患有意识障碍（DOC）的患者的意识水平仍然是现代神经学的核心挑战。目前的估计表明，误诊发生在40%以上的患者。这种高诊断错误率可能部分地由以下事实来解释：临床医生目前被迫仅基于对在患者床边获得的口头命令的明显反应来推断患者的意识，这可能受到诸如认知功能障碍、失语症、运动障碍或气管切开术等因素的限制。意识的大脑活动标记物的发展有望提高诊断准确性。最重要的临床目标之一是评估个体是否意识到自己和自己的状态（称为反射意识（RC）），这对于做出适当的治疗选择和确定预后至关重要。对健康成年人的初步研究表明，RC与额顶叶（FP）皮质网络内的活动有关。与此相一致的是，具有假定的整体意识丧失的患者，例如无反应性觉醒综合征（植物人状态）和某些形式的麻醉诱导的无反应性，FP皮质的活性降低。然而，FP皮质内区域活动的改变不足以作为意识的明确标记，因为在无意识状态期间也观察到这些区域的激活。最近的研究结果表明，一个潜在的更敏感的标记全球无意识可能是减少自上而下的FP功能连接。这些发现与最近的理论工作和计算模型相吻合，后者表明意识和神经有效连接之间存在联系。然而，驻地协调员与自上而下的FP有效连接之间的直接联系尚未建立。建议的研究使用跨两种不同的唤醒状态的多模态方法来调查RC和FP方向连接之间的关系。我们将首先通过将最先进的格兰杰因果关系（GC）和动态因果模型（DCM）应用于[高密度脑电图（HD-EEG）]来检查方向连接的变化。然后，我们将使用TMS/hd-EEG直接评估神经有效连接的变化，以直接干扰目标神经群体并对FP区域神经信号传播的变化进行建模。使用这种多模式的方法，目标1将研究如何调制RC清醒期间影响FP皮层的方向连接。目标2将检查与REM睡眠中RC丢失相关的方向连接变化。总之，我们希望这些研究将有助于建立一个大脑活动标记RC，不依赖于个人的能力，沟通或响应感官信号。这种标记物的鉴定有可能提高诊断准确性，并扩展对这些疾病的基本科学理解，为治疗开辟新途径。