Cerebellothalamocortical connectivity regulates penetrance in dystonia.
Cerebellothalamocortical connectivity regulates penetrance in dystonia.
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DOI：
10.1523/jneurosci.2300-09.2009
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发表时间：
2009-08-05
期刊：
影响因子：
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通讯作者：
Eidelberg D
中科院分区：
文献类型：
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作者：
Argyelan M;Carbon M;Niethammer M;Ulug AM;Voss HU;Bressman SB;Dhawan V;Eidelberg D
肌张力障碍是一种以持续的不自主肌肉收缩为特征的脑部疾病。它通常作为不完全显性的常染色体显性遗传性状遗传。虽然缺乏明确的退行性神经病理学，但原发性肌张力障碍被认为涉及神经元回路的微结构和功能变化。在目前的研究中，我们使用磁共振（MR）扩散张量成像（DTI）和概率纤维束成像，以确定特定的电路异常的基础上，临床表现为这种疾病的基因突变的载体。这种方法揭示了小脑-丘脑-皮质（CbTC）纤维束的完整性降低，可能起源于发育，在表现和临床非表现肌张力障碍突变携带者中。在这些受试者中，小脑-丘脑连接的减少与运动激活反应的增加相关，这与皮质水平的抑制丧失一致。非显性突变携带者的区别是位于通路的丘脑-皮质段远端沿着的纤维束破坏的额外区域，与近端小脑流出异常串联。在个体基因携带者中，临床突变率由在这两个位点测量的连接差异决定。总的来说，这些发现指出了一种新的机制来解释脑部疾病基因携带者临床表达的差异。
Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance (MR) diffusion tensor imaging (DTI) and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebello-thalamo-cortical (CbTC) fiber tracts, likely developmental in origin, in both manifesting and clinically non-manifesting dystonia mutation carriers. In these subjects, reductions in cerebello-thalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Non-manifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamo-cortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.