fMRI Analysis of Aging and Awareness in Conditioning

描述（由申请人提供）：本研究的总体目标是利用功能性磁共振成像（fMRI）阐明人类衰老如何影响对眨眼调节至关重要的神经系统，包括小脑和内侧颞叶（MTL）。虽然小脑对于条件反射的眨眼反应是必不可少的，但MTL对于一种被称为“痕迹”条件反射的特定类型的学习也是必要的，在这种学习中，条件刺激（CS）的偏移和非条件刺激（US）的开始之间存在时间间隔。在老年受试者中，以及在条件反射训练中没有获得刺激偶然性意识的老年和年轻受试者中，微量条件反射也受到损害。我们的假设是，在微量条件反射中，MTL激活的差异，以及新皮层和皮层下结构之间功能连接模式的差异，将解释老年人和未意识到的受试者在微量条件反射行为表现上的差异。我们预测，当没有时间差（即“延迟”条件反射）时，意识对表现或小脑激活的影响较小，小脑激活的年龄组差异比MTL激活的年龄组差异更能解释条件反射眨眼表现的年龄差异，功能连接模式的年龄组差异将与微量条件反射中观察到的差异不同。我们计划首先使用未配对的CS和US表现来表征CS和US通路的年龄相关变化，并假设在追踪期间，在短CS和MTL的小脑中观察到任何年龄差异。我们将研究延迟条件反射和痕迹条件反射过程中大脑激活的年龄相关变化，并假设小脑和MTL激活分别对延迟条件反射和痕迹条件反射表现的年龄相关变化具有不同的重要性。最后，我们将通过(a)破坏意识的获得并观察其对条件反射和脑激活的影响，以及(b)测量意识、眨眼条件反射和脑激活的同步发展，来研究意识在眨眼条件反射下脑激活的年龄相关变化中的作用。我们预测，在痕量条件反射中，习得意识的被试比未习得意识的被试条件反射更好，MTL激活更大，条件反射和MTL激活的年龄差异将在意识相等后减少或消除，年龄相关的功能连接变化将在延迟条件反射和痕量条件反射之间不同，功能连接模式将随着意识的变化而改变。左前额叶皮层将是意识相关功能回路的关键节点。最后，我们将研究微量条件反射的年龄相关差异与其他类型的年龄相关认知衰退之间的联系，我们将使用经颅磁刺激测试MTL/新皮层参与微量条件反射和意识的模型。

DESCRIPTION (provided by applicant): The overall goal of this research is to elucidate, using functional magnetic resonance imaging (fMRI), how aging in humans affects neural systems critical for eyeblink conditioning, including the cerebellum and the medial temporal lobe (MTL). While the cerebellum is essential for conditioned eyeblink responses, the MTL is also necessary for a specific type of learning referred to as "trace" conditioning, in which there is a gap in time between the offset of the conditioned stimulus (CS) and the onset of the unconditioned stimulus (US). Trace conditioning is also impaired in older subjects, and in both older and younger subjects who do not acquire awareness of the stimulus contingencies during the conditioning training. Our hypothesis is that in trace conditioning differences in MTL activation, along with differences in patterns of functional connectivity among neocortical and subcortical structures, will account for differences in trace conditioning behavioral performance in both older and unaware subjects. We predict that when the gap in time is absent (i.e., "delay" conditioning), awareness will have less effect on either performance or cerebellar activations, age group differences in cerebellar activation will account for more of the age differences in conditioned eyeblink performance than will MTL activation differences, and age group differences in patterns of functional connectivity will differ from those observed in trace conditioning. We plan to first characterize age-related changes in CS and US pathways using unpaired CS and US presentations, and hypothesize that any age differences will be observed in the cerebellum for short CSs and in the MTL during the trace period. We will investigate age-related changes in brain activation during delay and trace conditioning protocols, and hypothesize differential importance of cerebellar and MTL activations, respectively, for age-related changes in performance of delay and trace conditioning. Finally, we will investigate the role of awareness in age-related changes in brain activation underlying eyeblink conditioning by (a) disrupting the acquisition of awareness and observing its effect on conditioning and brain activation and (b) measuring the concurrent development of awareness, eyeblink conditioning, and brain activation. We predict that in trace conditioning, subjects that acquire awareness will condition better and exhibit greater MTL activation than unaware subjects, age differences in conditioning and MTL activation will be reduced or eliminated after equating for awareness, age-related changes in functional connectivity will differ between delay and trace conditioning, patterns of functional connectivity will change as a function of awareness for trace conditioning, and left prefrontal cortex will be a critical node in awareness-related functional circuits. Finally, we will examine the link between age-related differences in trace conditioning and other types of age-related cognitive decline, and we will test a model of MTL/neocortical involvement in trace conditioning and awareness using transcranial magnetic stimulation.