Page 95 - MEGIN Book Of Abstracts - 2023

ability to distinguish SMC from HC. However, we did magnetoencephalography study. We analysed 17
not find a significant association between SG ratios and patients with bvFTD, 15 patients with progressive
cognitive function requiring inhibitory control either supranuclear palsy, and 20 healthy age- and gender-
in the HC or SMC group. In conclusion, although SMC matched controls. In addition to neuropsychological
subjects have intact cognitive functioning revealed by assessment and structural MRI, participants undertook
objective neuropsychological tests, their deficits in au- two magnetoencephalography sessions using a rov-
tomatic inhibitory function could be detected through ing auditory oddball paradigm: once on placebo and
neurophysiological recordings. Our results suggest that once on 10 mg of the oral GABA reuptake inhibitor
altered brain function occurs in SMC prior to the obvi- tiagabine. A subgroup underwent ultrahigh-field mag-
ous decline of cognitive performance. netic resonance spectroscopy measurement of GABA
concentration, which was reduced among patients.
Keywords: Alzheimer's disease, inferior parietal lobule, We identified deficits in frontotemporal processing
magnetoencephalography, sensory gating, subjective using conductance-based biophysical models of local
cognitive decline, subjective memory complaint and global neuronal networks. The clinical relevance
of this physiological deficit is indicated by the correla-
The European journal of neuroscience (2021), Vol. 53, No. tion between top-down connectivity from frontal to
10 (33754412) (3 citations) temporal cortex and clinical measures of cognitive and
behavioural change. A critical validation of the biophys-
ical modelling approach was evidence from parametric
GABAergic cortical network physiology in empirical Bayes analysis that GABA levels in patients,
frontotemporal lobar degeneration (2021) measured by spectroscopy, were related to posterior
estimates of patients' GABAergic synaptic connectivity.
Adams, Natalie E; Hughes, Laura E; Rouse, Matthew Further evidence for the role of GABA in frontotempo-
A; Phillips, Holly N; Shaw, Alexander D; Murley, ral lobar degeneration came from confirmation that the
Alexander G; Cope, Thomas E; Bevan-Jones, W Richard; effects of tiagabine on local circuits depended not only
Passamonti, Luca; Street, Duncan; Holland, Negin; on participant group, but also on individual baseline
Nesbitt, David; Friston, Karl; Rowe, James B GABA levels. Specifically, the phasic inhibition of deep
cortico-cortical pyramidal neurons following tiagabine,
Department of Clinical Neurosciences, Cambridge Biomedi- but not placebo, was a function of GABA concentration.
cal Campus, University of Cambridge, Cambridge CB2 0QQ, The study provides proof-of-concept for the potential
UK; MMRC Cognition and Brain Sciences Unit, Cambridge of dynamic causal modelling to elucidate mechanisms
CB2 7EF, UK; Cambridge University Hospitals, Cambridge, of human neurodegenerative disease, and explains the
CB2 0QQ, UK; Wellcome Centre for Human Neuroimaging, variation in response to candidate therapies among
University College London, London WC1N 3AR, UK patients. The laminar- and neurotransmitter-specific
features of the modelling framework, can be used to
ABSTRACT The clinical syndromes caused by fron- study other treatment approaches and disorders. In
totemporal lobar degeneration are heterogeneous, the context of frontotemporal lobar degeneration, we
including the behavioural variant frontotemporal suggest that neurophysiological restoration in selected
dementia (bvFTD) and progressive supranuclear palsy. patients, by targeting neurotransmitter deficits, could
Although pathologically distinct, they share many be used to bridge between clinical and preclinical mod-
behavioural, cognitive and physiological features, els of disease, and inform the personalized selection
which may in part arise from common deficits of of drugs and stratification of patients for future clinical
major neurotransmitters such as γ-aminobutyric acid trials.
(GABA). Here, we quantify the GABAergic impairment
and its restoration with dynamic causal modelling of a
double-blind placebo-controlled crossover pharmaco-

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