Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance.
Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance.
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DOI：
10.1016/j.nicl.2015.02.009
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发表时间：
2015
影响因子：
4.2
通讯作者：
Gallagher, Michela
中科院分区：
文献类型：
--
作者：
Bakker, Arnold;Albert, Marilyn S.;Krauss, Gregory;Speck, Caroline L.;Gallagher, Michela
对遗忘型轻度认知障碍（aMCI）患者的研究发现，在任务相关的功能性磁共振成像（fMRI）过程中，海马体活动过度。在执行旨在检测这些海马回路对情景记忆的计算贡献的任务期间，这种升高的激活已定位于海马齿状回/CA 3（DG/CA 3）。目前的调查进行测试的假设，更大的海马激活aMCI代表DG/CA 3区域的正常计算平衡的功能失调的转变，增强CA 3驱动的模式完成的模式分离介导的齿状回为代价。我们使用基于动物研究的干预来验证这一假设，该干预通过使用低剂量的非典型抗癫痫药物左乙拉西坦减少过量的海马神经活动来证明对认知的有益作用。在受试者内设计中，我们评估了左乙拉西坦在三个aMCI参与者队列中的作用，每个队列接受不同剂量的左乙拉西坦。相对于老年对照组，在每个aMCI队列中检测到DG/CA 3区域的激活升高以及任务表现受损。我们观察到在62.5和125 mg BID左乙拉西坦剂量下，aMCI队列中药物治疗相对于安慰剂的记忆任务表现显著改善。在这些队列中，药物治疗增加了依赖于模式分离过程的准确性，并减少了归因于模式完成的压倒性影响的错误，同时使DG/CA 3和内嗅皮层的fMRI激活正常化。与动物研究中的结果相似，250 mg BID的较高剂量对任务表现或fMRI激活均无显著益处。与基于在基础动物研究中阐明的DG/CA 3的计算功能的预测一致，这些数据支持通过fMRI在aMCI个体中检测到的功能失调的编码机制，以及使用fMRI检测响应于治疗的目标参与的治疗干预。与对照组相比，aMCI患者DG/CA 3的fMRI激活增加。低剂量左乙拉西坦治疗降低了aMCI中过量的DG/CA 3活化。低剂量左乙拉西坦治疗使aMCI中降低的内嗅激活正常化。低剂量左乙拉西坦治疗改善aMCI中任务相关记忆表现。靶向过量的海马活动在遗忘型MCI中具有治疗潜力。
Studies of individuals with amnestic mild cognitive impairment (aMCI) have detected hyperactivity in the hippocampus during task-related functional magnetic resonance imaging (fMRI). Such elevated activation has been localized to the hippocampal dentate gyrus/CA3 (DG/CA3) during performance of a task designed to detect the computational contributions of those hippocampal circuits to episodic memory. The current investigation was conducted to test the hypothesis that greater hippocampal activation in aMCI represents a dysfunctional shift in the normal computational balance of the DG/CA3 regions, augmenting CA3-driven pattern completion at the expense of pattern separation mediated by the dentate gyrus. We tested this hypothesis using an intervention based on animal research demonstrating a beneficial effect on cognition by reducing excess hippocampal neural activity with low doses of the atypical anti-epileptic levetiracetam. In a within-subject design we assessed the effects of levetiracetam in three cohorts of aMCI participants, each receiving a different dose of levetiracetam. Elevated activation in the DG/CA3 region, together with impaired task performance, was detected in each aMCI cohort relative to an aged control group. We observed significant improvement in memory task performance under drug treatment relative to placebo in the aMCI cohorts at the 62.5 and 125 mg BID doses of levetiracetam. Drug treatment in those cohorts increased accuracy dependent on pattern separation processes and reduced errors attributable to an over-riding effect of pattern completion while normalizing fMRI activation in the DG/CA3 and entorhinal cortex. Similar to findings in animal studies, higher dosing at 250 mg BID had no significant benefit on either task performance or fMRI activation. Consistent with predictions based on the computational functions of the DG/CA3 elucidated in basic animal research, these data support a dysfunctional encoding mechanism detected by fMRI in individuals with aMCI and therapeutic intervention using fMRI to detect target engagement in response to treatment. Patients with aMCI show increased fMRI activation in DG/CA3 relative to controls. Low dose levetiracetam treatment decreases excess DG/CA3 activation in aMCI. Low dose levetiracetam treatment normalizes decreased entorhinal activation in aMCI. Low dose levetiracetam treatment improves task related memory performance in aMCI. Targeting excess hippocampal activity has therapeutic potential in amnestic MCI.
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影响因子：
11
作者：
Miller, S. L.;Fenstermacher, E.;Dickerson, B. C.
通讯作者：
Dickerson, B. C.
影响因子：
16.2
作者：
Neunuebel JP;Knierim JJ
通讯作者：
Knierim JJ
影响因子：
3.5
作者：
OREILLY, RC;MCCLELLAND, JL
通讯作者：
MCCLELLAND, JL
影响因子：
5.7
作者：
Malykhin, N. V.;Lebel, R. M.;Carter, R.
通讯作者：
Carter, R.
DOI：
10.1073/pnas.1421056111
发表时间：
2014-12-30
影响因子：
11.1
作者：
Alme, Charlotte B.;Miao, Chenglin;Moser, May-Britt
通讯作者：
Moser, May-Britt