Profiling neuronal ion channelopathies with non-invasive brain imaging and dynamic causal models: Case studies of single gene mutations

Jessica R Gilbert,Mkael Symmonds,Michael G Hanna,Raymond J Dolan,Karl J Friston,Rosalyn J Moran

doi:10.1016/j.neuroimage.2015.08.057

Abstract

Clinical assessments of brain function rely upon visual inspection of electroencephalographic waveform abnormalities in tandem with functional magnetic resonance imaging. However, no current technology proffers in vivo assessments of activity at synapses, receptors and ion-channels, the basis of neuronal communication. Using dynamic causal modeling we compared electrophysiological responses from two patients with distinct monogenic ion channelopathies and a large cohort of healthy controls to demonstrate the feasibility of assaying synaptic-level channel communication non-invasively. Synaptic channel abnormality was identified in both patients (100% sensitivity) with assay specificity above 89%, furnishing estimates of neurotransmitter and voltage-gated ion throughput of sodium, calcium, chloride and potassium. This performance indicates a potential novel application as an adjunct for clinical assessments in neurological and psychiatric settings. More broadly, these findings indicate that biophysical models of synaptic channels can be estimated non-invasively, having important implications for advancing human neuroimaging to the level of non-invasive ion channel assays.

Highlights

The balanced flow of ions through synapses is integral to the stability and control of neuronal firing and information transmission in the brain
At the MEG sensor level, we examined evoked responses to mismatch negativity (MMN) standard and deviant tones to assess whether our dynamic causal modeling (DCM) analysis was informed by an appropriate amount of experimental variance (Fig. 2)
The ellipsoid plot of Patient 2 demonstrates that their GABAA-mediated chloride parameter estimate is an outlier, while their presynaptic calcium parameter estimate lies in the negative quartile. These results demonstrate that biophysical models of synaptic channels can be estimated using non-invasive magnetoencephalographic responses to simple auditory stimuli

Summary

Introduction

The balanced flow of ions through synapses is integral to the stability and control of neuronal firing and information transmission in the brain. Abnormalities of ion channels and synaptic function are thought to underlie a range of neurological presentations including seizures, migraine and movement disorders (Catterall et al, 2008), and inform pharmacological treatment strategies (Yogeeswari et al, 2004). While limited assessments of neurotransmitter and synaptic receptor levels are feasible with magnetic resonance spectroscopy (Dager et al, 2008) and positron emission tomography (Lee and Farde, 2006), these techniques do not directly measure neuronal function and can be applied only to a limited set of molecules. We describe how magnetic event-related fields (ERFs), measured at superconducting sensors around the head, can be fit to a biophysical model of neural circuits to recover potential probabilistic markers of an individual's synaptic function

Methods

Results

Conclusion