Fiber Pathway Pathology, Synapse Loss and Decline of Cortical Function in Schizophrenia

A quantitative cortical model is developed, based on both computational and simulation approaches, which relates measured changes in cortical activity of gray matter with changes in the integrity of longitudinal fiber pathways. The model consists of modules of up to 5,000 neurons each, 80% excitatory and 20% inhibitory, with these having different degrees of synaptic connectiveness both within a module as well as between modules. It is shown that if the inter-modular synaptic connections are reduced to zero while maintaining the intra-modular synaptic connections constant, then activity in the modules is reduced by about 50%. This agrees with experimental observations in which cortical electrical activity in a region of interest, measured using the rate of oxidative glucose metabolism (CMRglc(ox)), is reduced by about 50% when the cortical region is isolated, either by surgical means or by transient cold block. There is also a 50% decrease in measured cortical activity following inactivation of the nucleus of Meynert and the intra-laminar nuclei of the thalamus, which arise either following appropriate lesions or in sleep. This occurs in the model if the inter-modular synaptic connections require input from these nuclei in order to function. In schizophrenia there is a 24% decrease in functional anisotropy of longitudinal fasciculi accompanied by a 7% decrease in cortical activity (CMRglc(ox)).The cortical model predicts this, namely for a 24% decrease in the functioning of the inter-modular connections, either through the complete loss of 24% of axons subserving the connections or due to such a decrease in the efficacy of all the inter-modular connections, there will be about a 7% decrease in the activity of the modules. This work suggests that deterioration of longitudinal fasciculi in schizophrenia explains the loss of activity in the gray matter.

本研究基于计算建模与仿真模拟双路径，构建了一套量化皮层模型，该模型将灰质皮层活动的实测变化与纵向纤维通路（longitudinal fiber pathways）完整性的改变建立关联。该模型由多个神经元模块组成，每个模块最多包含5000个神经元，其中80%为兴奋性神经元，20%为抑制性神经元；各神经元在模块内部及跨模块间均存在不同程度的突触连接特性。实验结果显示，若在保持模块内部突触连接不变的前提下，将模块间突触连接强度降至零，则模块内的皮层活动水平将下降约50%。该模型结果与实验观测结果一致：当通过手术或暂时性低温阻滞手段隔离目标皮层区域时，利用氧化葡萄糖代谢率（CMRglc(ox)）测得的该区域皮层电活动将降低约50%。此外，当迈内特核（nucleus of Meynert）与丘脑板内核团（intra-laminar nuclei of the thalamus）失活后，实测皮层活动同样会出现50%的下降——这类失活可由针对性脑损伤或睡眠状态引发。若在模型中设定模块间突触连接需上述核团提供输入才能正常运作，则可复现该实验现象。精神分裂症患者的纵向束（longitudinal fasciculi）功能各向异性会出现24%的下降，同时皮层活动水平（CMRglc(ox)）降低7%。本量化皮层模型可对该现象做出预测：当模块间连接功能出现24%的衰减时，无论是介导该连接的轴突完全丢失24%，还是所有模块间连接的效能均下降相应比例，模块的活动水平均会出现约7%的下降。本研究结果提示，精神分裂症患者纵向束的退行性改变可解释其灰质皮层活动的减退。