Profiling neuronal ion channelopathies with non-invasive brain imaging and dynamic causal models: Case studies of single gene mutations.
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.
Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA. Electronic address: jessg@vtc.vt.edu.
Jessica R
JR
Gilbert
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK.
Mkael
M
Symmonds
Institute of Neurology, University College London, 9 Queen Square, London WC1N 3BG, UK.
Michael G
MG
Hanna
Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Russell Square House, 10-12 Russell Square, London WC1B 5EH, UK.
Raymond J
RJ
Dolan
Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, 12 Queen Square, London WC1N 3BG, UK.
Karl J
KJ
Friston
Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA; Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Rosalyn J
RJ
Moran
D000161:Acoustic Stimulation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001303:Auditory Cortex / Q000503:physiopathology; D001307:Auditory Perception / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D015220:Calcium Channels / Q000235:genetics; D053447:Channelopathies / Q000235:genetics* / Q000503:physiopathology*; D003198:Computer Simulation; D005072:Evoked Potentials, Auditory; D005260:Female; D006801:Humans; D015225:Magnetoencephalography / Q000379:methods*; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D013569:Synapses / Q000502:physiology; D055815:Young Adult; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D024661:Potassium Channels, Inwardly Rectifying; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C489457:KCNJ2 protein, human
Biophysical models; Channelopathies; Dynamic causal modeling; Ion channel signaling; Magnetoencephalography