Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases

Cope, Thomas; Hughes, Laura E.; Phillips, Holly N.; Adams, Natalie; Jafarian, Amirhossein; Nesbitt, David J.; Assem, Moataz; Woolgar, Alexandra; Duncan, John; Rowe, James B.

doi:10.1523/jneurosci.1622-21.2022

Cited by 18 publications

(9 citation statements)

References 105 publications

(168 reference statements)

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“…We chose to use a reflexive, pre-attentive measure of gap detection: gap-PPI of the acoustic startle response. PPI, a measure of detection rather than perception, is not influenced by attentional factors provided the interval between stimulus and startle is ≤ 60 ms (Li et al, 2009), but see (Cope et al, 2022). This allows measurement of auditory processing without the potentially confounding contribution of cognition or attention, both of which can be affected by stress.…”

Section: Resultsmentioning

confidence: 99%

Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway

Mattingly

Sunthimer

et al. 2022

Preprint

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In children, early ear infections are a risk factor for later speech perception deficits. This is likely because auditory deprivation during a developmental critical period (CP) induces long-lasting deficits in perception and ACx encoding of temporally-varying sounds. CPs also create susceptibility to early-life stress (ELS) in neural regions involved with cognition and anxiety. As CP mechanisms are shared by sensory cortices and higher neural regions, ACx and temporal encoding may also be susceptible to ELS. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in ACx, the auditory periphery, and auditory brainstem. These ELS effects presumably degrade the fidelity of sensory representations available to higher regions, and could contribute to ELS-induced problems with cognition.

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Section: Resultsmentioning

confidence: 99%

Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway

Mattingly

Sunthimer

et al. 2022

Preprint

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“…Six of these regions are based on a series of prior studies with healthy adults and those with non-Alzheimer dementia (Garrido et al ., 2008; Phillips et al ., 2015; Rosch et al ., 2019; Adams et al ., 2021). We extended the network to include the inferior parietal cortex (Lappe et al ., 2013), given the impact of Alzheimer’s disease on parietal cortex (Jacobs et al ., 2012; Talwar et al ., 2021) and recent evidence of mismatch negativity responses from parietal cortex (Lappe et al ., 2013; Cope et al ., 2022). We defined multiple, alternative, symmetric model architectures, each representing plausible alternative hierarchical relationships between regions and their connectivity to include the inferior parietal cortex ( Figure 2 ).…”

Section: Methodsmentioning

confidence: 99%

The effect of Alzheimer’s disease and its progression on pyramidal cell gain and connectivity

Lanskey,

Jafarian,

Karadag

et al. 2024

Preprint

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Alzheimer's disease affects our cognitive neurophysiology by loss of neurones, synapses and neurotransmitters. An improved mechanistic understanding of the human disease will facilitate new treatments. To this end, biophysically-informed dynamic causal models can support inferences around laminar and cell-specific disease effects from human non-invasive imaging. Based on pre-clinical models and effects of cholinesterase inhibitors, we hypothesised that Alzheimer's disease would affect the modulation of superficial pyramidal cell gain and extrinsic connectivity between pyramidal cells of different regions in hierarchical cognitive networks. Magnetoencephalography (MEG) was recorded during an auditory mismatch negativity task from healthy adults (n=14) and people with symptomatic Alzheimer's disease or mild cognitive impairment (n=45, all amyloid-biomarker positive) at baseline and after 16 months. Fourteen people from the symptomatic group had repeat magnetoencephalography at two weeks to assess test-retest reliability. Sensor-level data were analysed using t-tests of the mismatch negativity amplitude from 140ms to 160ms. The repetition effect was assessed with repeated-measures analysis of covariance, using the average evoked response in the mismatch negativity time window as the repeated measure. An absolute, intraclass correlation model of the test-retest data assessed mismatch negativity amplitude reliability. We then fitted dynamic causal models to the evoked responses over 500ms. Second-level parametric empirical Bayes across participants examined the effect of (1) group, patients vs controls, and (2) progression, baseline vs follow-up, on the model parameters reflecting pyramidal cell gain modulation and extrinsic connectivity. There was a significant effect of both disease and progression on the mismatch negativity amplitude (patients vs controls, T=-1.80, p=0.04; patient baseline vs follow-up, T=-2.72, p=.005), which had excellent reliability (ICC=0.95, p<.001). Parametric empirical Bayes revealed strong evidence (posterior probability>95%) that Alzheimer's disease reduced extrinsic connectivity and superficial pyramidal cell gain modulation, which was reduced further at follow up assessment. The mechanistic modelling confirmed the hypothesis that reduced superficial pyramidal cell gain modulation and extrinsic connectivity can explain the observed neurophysiological effect of Alzheimer's disease. This approach to non-invasive magnetoencephalography data may be used for experimental medicine studies of candidate treatments, and bridge clinical to preclinical models of drug efficacy.

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“…Twenty individuals per group are in line with previous neurophysiological studies of crossover drug-placebo effects of bvFTD and PSP [ 8 , 75 ], and memantine in schizophrenia [ 41 ]. Using a different mismatch paradigm, Cope et al [ 76 ] and Hughes et al [ 9 ] reported 30–40% reductions in amplitude with bvFTD (Cohen’s d > 1.6). In this context, for frequentists tests, N = 20 provides >80% power with alpha 0.05 to detect a restorative crossover drug intervention versus placebo with effect size d ≥ 0.6 [ 77 ] (noting the smaller d = 0.3 reported by [ 41 ] in control participants); and >80% power with alpha 0.05 to detect a correlation r ≥ 0.5 with GABA.…”

Section: Methodsmentioning

confidence: 99%

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

et al. 2022

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There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioural variant frontotemporal dementia, 10 progressive supranuclear palsy) and 19 healthy age- and gender-matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10 mg memantine, an uncompetitive NMDA-receptor antagonist. Ultra-high-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. While memantine showed a subtle effect on early-auditory processing in patients, there was no significant main effect of memantine on the magnitude of the mismatch negativity (MMN) response in the right frontotemporal cortex in patients or controls. However, the change in the right auditory cortex MMN response to memantine (vs. placebo) in patients correlated with individuals’ prefrontal GABA concentration. There was no moderating effect of glutamate concentration or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline dependency in the pharmacological restoration of neurotransmitter deficits to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals’ balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

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Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases

Abstract: Title: Causal evidence for the multiple demand network in change detection: auditory mismatch magnetoencephalography across focal neurodegenerative diseases.

Cited by 18 publications

References 105 publications

Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway

Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway

The effect of Alzheimer’s disease and its progression on pyramidal cell gain and connectivity

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

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