Decoding the Cortical Dynamics of Sound-Meaning Mapping.

Comprehending speech involves the rapid and optimally efficient mapping from sound to meaning. Influential cognitive models of spoken word recognition (Marslen-Wilson and Welsh, 1978) propose that the onset of a spoken word initiates a continuous process of activation of the lexical and semantic properties of the word candidates matching the speech input and competition between them, which continues until the point at which the word is differentiated from all other cohort candidates (the uniqueness point, UP). At this point, the word is recognized uniquely and only the target word's semantics are active. Although it is well established that spoken word recognition engages the superior (Rauschecker and Scott, 2009), middle, and inferior (Hickok and Poeppel, 2007) temporal cortices, little is known about the real-time brain activity that underpins the computations and representations that evolve over time during the transformation from speech to meaning. Here, we test for the first time the spatiotemporal dynamics of these processes by collecting MEG data while human participants listened to spoken words. By constructing quantitative models of competition and access to meaning in combination with spatiotemporal searchlight representational similarity analysis (Kriegeskorte et al., 2006) in source space, we were able to test where and when these models produced significant effects. We found early transient effects ∼400 ms before the UP of lexical competition in left supramarginal gyrus, left superior temporal gyrus, left middle temporal gyrus (MTG), and left inferior frontal gyrus (IFG) and of semantic competition in MTG, left angular gyrus, and IFG. After the UP, there were no competitive effects, only target-specific semantic effects in angular gyrus and MTG. SIGNIFICANCE STATEMENT: Understanding spoken words involves complex processes that transform the auditory input into a meaningful interpretation. This effortless transition occurs on millisecond timescales, with remarkable speed and accuracy and without any awareness of the complex computations involved. Here, we reveal the real-time neural dynamics of these processes by collecting data about listeners' brain activity as they hear spoken words. Using novel statistical models of different aspects of the recognition process, we can locate directly which parts of the brain are accessing the stored form and meaning of words and how the competition between different word candidates is resolved neurally in real time. This gives us a uniquely differentiated picture of the neural substrate for the first 500 ms of word recognition.This work was supported by a European Research Council Advanced Investigator grant under the European Community’s Horizon 2020 Research and Innovation Programme (2014 –2020 ERC Grant 669820 to L.K.T.)

Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful

Evidence and implications of abnormal predictive coding in dementia.

The diversity of cognitive deficits and neuropathological processes associated with dementias has encouraged divergence in pathophysiological explanations of disease. Here, we review an alternative framework that emphasizes convergent critical features of cognitive pathophysiology. Rather than the loss of 'memory centres' or 'language centres', or singular neurotransmitter systems, cognitive deficits are interpreted in terms of aberrant predictive coding in hierarchical neural networks. This builds on advances in normative accounts of brain function, specifically the Bayesian integration of beliefs and sensory evidence in which hierarchical predictions and prediction errors underlie memory, perception, speech and behaviour. We describe how analogous impairments in predictive coding in parallel neurocognitive systems can generate diverse clinical phenomena, including the characteristics of dementias. The review presents evidence from behavioural and neurophysiological studies of perception, language, memory and decision-making. The reformulation of cognitive deficits in terms of predictive coding has several advantages. It brings diverse clinical phenomena into a common framework; it aligns cognitive and movement disorders; and it makes specific predictions on cognitive physiology that support translational and experimental medicine studies. The insights into complex human cognitive disorders from the predictive coding framework may therefore also inform future therapeutic strategies.EK is funded by the Dementias Platform UK and Alzheimer’s Research UK (RG94383/RG89702). JBR is supported by the Wellcome Trust (103838) and Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre. LH is funded by the Wellcome Trust (103838). AKG is funded by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant (798971)

COMPARISON OF THE EFFECT OF TRANSCRANIAL DIRECT CURRENT STIMULATION BETWEEN FOCAL AND GENERALIZED EPILEPSY SYNDROMES

31st International Epilepsy Congress -- SEP 05-09, 2015 -- Istanbul, TURKEYWOS: 000365756500617

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

Funder: NIHR Cambridge Clinical Research Facility and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)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.Cambridge Centre for Parkinson-Plus; a Cambridge Trust Vice-Chancellor’s Award and Fitzwilliam College Scholarship; the Association of British Neurologists – Patrick Berthoud Charitable Trust (RG99368); NIHR Cambridge Clinical Research Facilit

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological “signatures” of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological "signatures" of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies

Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease

Background Synaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo. Methods MRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes. Results The AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD. Conclusions We interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease-associated differences and the feasibility of measuring FISO on commercially available imaging systems makes it a potential surrogate for pathology related to synapse loss that could be used to support early-stage evaluations of novel therapeutics for AD