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were assessed. Classification accuracy was explored Kingdom; Department of Clinical Neurosciences, University of
using ROC curves. Cambridge, Cambridge CB2 0SZ, United Kingdom; Depart-
ment of Experimental Psychology, University of Oxford,
RESULTS The MCI group showed intermediate power Oxford OX1 3UD, United Kingdom
values between SCD and AD, except for the alpha
range, where it was higher than both (p < 0.05 and ABSTRACT The multiple demand (MD) system is a
p < 0.001). The largest differences between MCI and network of fronto-parietal brain regions active dur-
SCD were in the theta band, with higher power in MCI ing the organization and control of diverse cognitive
(p < 0.01). The hippocampi showed several unique operations. It has been argued that this activation
group differences, such as higher power in the higher may be a nonspecific signal of task difficulty. However,
alpha band in MCI compared to SCD (p < 0.05). Clas- here we provide convergent evidence for a causal role
sification accuracy (MCI versus SCD) was best for for the MD network in the "simple task" of automatic
absolute theta band power in the right hippocampus auditory change detection, through the impairment
(AUC = 0.87). of top-down control mechanisms. We employ inde-
pendent structure-function mapping, dynamic causal
CONCLUSION In this MEG study, we detected oscilla- modeling (DCM), and frequency-resolved functional
tory abnormalities of the hippocampi in prodromal AD connectivity analyses of MRI and magnetoencepha-
patients. Moreover, hippocampus-based classification lography (MEG) from 75 mixed-sex human patients
performed better than cortex-based classification. We across four neurodegenerative syndromes [behavioral
conclude that a focus on hippocampal MEG may im- variant fronto-temporal dementia (bvFTD), nonfluent
prove early detection of AD-related neuronal dysfunc- variant primary progressive aphasia (nfvPPA), posterior
tion. cortical atrophy (PCA), and Alzheimer's disease mild
cognitive impairment with positive amyloid imaging
Keywords: Alzheimer’s disease, dementia, hippocampus, (ADMCI)] and 48 age-matched controls. We show that
magnetoencephalography, mild cognitive impairment, atrophy of any MD node is sufficient to impair auditory
spectral analysis neurophysiological response to change in frequency,
location, intensity, continuity, or duration. There was no
Journal of Alzheimer's disease: JAD (2022), Vol. 87, No. 1 similar association with atrophy of the cingulo-oper-
(35311705) (0 citations) cular, salience or language networks, or with global
atrophy. MD regions displayed increased functional
but decreased effective connectivity as a function
Causal Evidence for the Multiple Demand of neurodegeneration, suggesting partially effective
Network in Change Detection: Auditory compensation. Overall, we show that damage to any
Mismatch Magnetoencephalography across Focal of the nodes of the MD network is sufficient to impair
Neurodegenerative Diseases (2022) top-down control of sensation, providing a common
mechanism for impaired change detection across de-
Cope, Thomas E; Hughes, Laura E; Phillips, Holly N; mentia syndromes.SIGNIFICANCE STATEMENT Previous
Adams, Natalie E; Jafarian, Amirhossein; Nesbitt, David; evidence for fronto-parietal networks controlling per-
Assem, Moataz; Woolgar, Alexandra; Duncan, John; ception is largely associative and may be confounded
Rowe, James B by task difficulty. Here, we use a preattentive measure
of automatic auditory change detection [mismatch
Cambridge University Hospitals NHS Trust, Cambridge CB2 negativity (MMN) magnetoencephalography (MEG)] to
0SZ, United Kingdom; Cognition and Brain Sciences Unit, show that neurodegeneration in any frontal or parietal
Medical Research Council, Cambridge CB2 7EF, United King- multiple demand (MD) node impairs primary auditory
dom; Cambridge Centre for Ageing and Neuroscience (Cam- cortex (A1) neurophysiological response to change
CAN), University of Cambridge, Cambridge CB2 7EF, United through top-down mechanisms. This explains why the

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