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

Abstract

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.

Neurodevelopmental sequelae associated with gray and white matter changes and their cellular basis: A comparison between Autism Spectrum Disorder, ADHD and dyslexia

“…It has been suggested that many psychiatric diseases, such as major depression and schizophrenia, are accompanied by particular patterns of gray matter changes in the cortex that are primarily due to a structural pathology of synapses and their dendrites (Bennett, 2011a,b) and of white matter loss primarily due to failure of myelination by oligodendrocytes (Bennett et al, 2013). Here the possibility has been briefly examined that such a generalization might also hold for ASD.…”

Cortical network models of impulse firing in the resting and active states predict cortical energetics

“…18; see also ref. 7). In addition to the introduction of appropriate delays on the intermodular synaptic connections, these were taken as capable of modification by another source external to the modular network, one which may be identified with the cholinergic projections to the cortex from the basal nucleus of Meynert (7).…”

“…We first give the formalism for the network in a single isolated module, following that of ref. 7, which in turn was based on refs. 48 and 49.…”

“…3). The question then arises as to whether it is possible that a quantitative relationship exists between the level of action potential and synaptic activity in a cortical area and the extent to which this area receives associational fiber connections.Correlations of signals between brain areas of subjects in the resting state have been taken to characterize resting-state functional networks (6), with the correlations probably mediated in many cases by synapses formed by associational fiber axons (7,8). During sleep and anesthesia, some of these correlations are lost, indicating changes in synaptic transmission mediated by these fibers (9, 10).…”

“…Correlations of signals between brain areas of subjects in the resting state have been taken to characterize resting-state functional networks (6), with the correlations probably mediated in many cases by synapses formed by associational fiber axons (7,8). During sleep and anesthesia, some of these correlations are lost, indicating changes in synaptic transmission mediated by these fibers (9, 10).…”