In Vivo Assay of Cortical Microcircuitry in Frontotemporal Dementia: A Platform for Experimental Medicine Studies.

Alexander D Shaw,James B Rowe,Tim Rittman,Rosalyn Moran,Laura E Hughes,Ian Coyle-Gilchrist

doi:10.1093/cercor/bhz024

Abstract

The analysis of neural circuits can provide crucial insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioral variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to noninvasive human magnetoencephalography, using dynamic causal modeling, can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case–control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.

Highlights

The impairment of brain circuit physiology occurs early in neurodegeneration
We demonstrate that inversion of canonical microcircuit models to noninvasive human magnetoencephalography, using dynamic causal modeling, can identify the regional- and laminar-specificity of behavioral variant frontotemporal dementia (bvFTD) pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls
We show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy

Summary

Introduction

The impairment of brain circuit physiology occurs early in neurodegeneration. The loss of synapses, synaptic plasticity, and effective information processing in microcircuits precede the onset of atrophy and behavioral change in animal models of neurodegeneration (Rowan et al 2003; Hof and Morrison 2004). There is strong preclinical evidence of functional impairment in neural circuits before cell death or atrophy, including the downstream effects of oligomeric modified and misfolded proteins on axonal transport, synapse density, and plasticity (Wilcock et al 2009; Castillo-Carranza et al 2015). There is growing evidence for the reorganization of brain networks, and change in the efficiency of information processing, in patients with Alzheimer’s disease (Zhou et al 2010; Sami et al 2018), Parkinson’s disease (Crossley et al 2014), progressive supranucelar palsy (Rittman et al 2016; Cope et al 2018), and frontotemporal dementia (Hughes et al 2013, 2018)

Methods

Results

Conclusion