Page 77 - MEGIN Book Of Abstracts - 2023

high-field magnetic resonance spectroscopy confirmed netoencephalography (MEG) activity in human early-
lower concentrations of GABA in the right inferior stage AD patients.
frontal gyrus of people with frontotemporal lobar
degeneration. While memantine showed a subtle effect METHODS To simulate spontaneous electrophysi-
on early-auditory processing in patients, there was no ological activity, we used a whole-brain computational
significant main effect of memantine on the magnitude network model comprised of 78 neural masses coupled
of the mismatch negativity (MMN) response in the right according to human structural brain topology. We
frontotemporal cortex in patients or controls. However, modified relevant model parameters to simulate six
the change in the right auditory cortex MMN response literature-based cellular scenarios of AD and compare
to memantine (vs. placebo) in patients correlated with them to one healthy and six contrast (non-AD-like)
individuals' prefrontal GABA concentration. There scenarios. The parameters include excitability, postsyn-
was no moderating effect of glutamate concentra- aptic potentials, and coupling strength of excitatory
tion or cortical atrophy. This proof-of-concept study and inhibitory neuronal populations. Whole-brain spike
demonstrates the potential for baseline dependency density and spectral power analyses of the simulated
in the pharmacological restoration of neurotransmit- data reveal mechanisms of neuronal hyperactivity that
ter deficits to influence cognitive neurophysiology in lead to oscillatory changes similar to those observed
neurodegenerative disease. With changes to multiple in MEG data of 18 human prodromal AD patients
neurotransmitters in frontotemporal lobar degenera- compared to 18 age-matched subjects with subjective
tion, we suggest that individuals' balance of excita- cognitive decline.
tion and inhibition may determine drug efficacy, with
implications for drug selection and patient stratification RESULTS All but one of the AD-like scenarios showed
in future clinical trials. higher spike density levels, and all but one of these
scenarios had a lower peak frequency, higher spectral
Translational psychiatry (2022), Vol. 12, No. 1 (36030249) (0 power in slower (theta, 4-8Hz) frequencies, and greater
citations) total power. Non-AD-like scenarios showed opposite
patterns mainly, including reduced spike density and
faster oscillatory activity. Human AD patients showed
A multiscale brain network model links Alzheimer's oscillatory slowing (i.e., higher relative power in the
disease-mediated neuronal hyperactivity to large- theta band mainly), a trend for lower peak frequency
scale oscillatory slowing (2022) and higher total power compared to controls. Combin-
ing model and human data, the findings indicate that
van Nifterick, Anne M; Gouw, Alida A; van Kesteren, neuronal hyperactivity can lead to oscillatory slowing,
Ronald E; Scheltens, Philip; Stam, Cornelis J; de Haan, likely due to hyperexcitation (by hyperexcitability of
Willem pyramidal neurons or greater long-range excitatory
coupling) and/or disinhibition (by reduced excitability
Amsterdam Neuroscience, Neurodegeneration, Amster- of inhibitory interneurons or weaker local inhibitory
dam, The Netherlands. [email protected]; coupling strength) in early AD.
Department of Molecular and Cellular Neurobiology, Center
for Neurogenomics and Cognitive Research, Vrije Universiteit CONCLUSIONS Using a computational brain network
Amsterdam, Amsterdam, The Netherlands model, we link findings from different scales and mod-
els and support the hypothesis of early-stage neuronal
BACKGROUND Neuronal hyperexcitability and inhibi- hyperactivity underlying E/I imbalance and whole-
tory interneuron dysfunction are frequently observed brain network dysfunction in prodromal AD.
in preclinical animal models of Alzheimer's disease
(AD). This study investigates whether these microscale
abnormalities explain characteristic large-scale mag-

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