La capacité à évaluer les résultats nos actions est fondamentale pour adapter et optimiser notre comportement et dépend d’un système superviseur chargé d’évaluer l’action, détecter les erreurs, déclencher des corrections.Le réseau neuronal sous-jacent la supervision de l’action n’a pas été complètement caractérisé chez l’homme.Dans une première étude nous avons enregistré dans l’Aire Motrice Supplémentaire (AMS) des LFP évoqués par les réponses et modulés par la performance. Des LFP évoqués exclusivement par les erreurs ont été enregistrés plus tardivement dans le cortex préfrontal médian.Dans la deuxième étude, nous avons observé que les activités de hautes-fréquences gamma sont, elles aussi, modulées par la performance des sujets, mais dans un vaste réseau frontal et extra-frontal.Dans une troisième étude, utilisant des enregistrements simultanés électroencéphalographiques (EEG) et magnétoencéphalographiques (MEG), nous observé une activité évoquée par un feedback interne sur l’EEG (mais pas en MEG), alors qu'une activité évoquée par le feedback externe était bien visible sur les enregistrements MEG, indiquant que les générateurs de ces deux activités cérébrales, sont différents. Nos résultats montrent une implication de l’AMSp dans la supervision de l’action chez l’homme, bien plus importante que ce que l’on soupçonnait auparavant. L’AMS évalue précocement, et de façon continue, l’action en cours et elle engage vraisemblablement des structures préfrontales en cas d’erreur seulement. Le traitement de l’erreur d’action, selon qu'il se fonde sur des informations internes ou externes est certainement sous-tendu par des réseaux corticaux différents. / The capacity to evaluate the outcome of our actions is fundamental for adapting and optimizing behaviour. This capability depends on an action monitoring system in charge of assessing ongoing actions, detecting errors, and evaluating outcomes.Electrical brain activity evoked by negative outcomes is thought to originate within the medial part of the frontal cortex. Nonetheless, the underlying neuronal network is incompletely characterised in humans.In the two first studies, we investigated the anatomical substrates of action monitoring in humans using intracerebral local field potential (LFP) recordings of cerebral cortex from epileptic patients. Response evoked LFPs sensitive to outcome were recorded from the Supplementary Motor Area proper (SMA), while LFPs evoked exclusively by errors were recorded later in the medial prefrontal cortex. High-gamma-frequency activity (60-180 Hz) was modulated as a function of action outcome in a vast frontal and extra-frontal network.In a third study using simultaneous recording of electroencephalography (EEG) and magnetoencephalography (MEG), we found that error related activity was detected by EEG (but not by MEG), while feedback-related activity was detected by MEG, indicating that the sources of these two forms of outcome-modulated brain activity are different.To conclude the SMA is much more involved in action monitoring than previously thought. SMA rapidly and continuously assesses ongoing actions and likely engages more rostral prefrontal structures in the case of error. Processing of action errors and of negative externally delivered feedback therefore appears to be supported by distinct cortical networks.

The dementias are persistent or progressive disorders affecting more than one cognitive domain that interfere with an individual’s ability to function at work or home, and represent a decline from a previous level of function. In this thesis I consider the neurophysiology of dementia at a number of levels. I investigate the ways in which the connectivity and function of the brain predisposes to the specific focal patterns of neurodegeneration seen in the various dementias. I aim to identify the mesoscopic changes that occur in individuals with neurodegeneration and how these relate to their cognitive difficulties. I show how, by assessing patients in whom there is focal disruption of brain networks and observing the outcomes in comparison to controls, I can gain insight into the mechanisms by which the normal brain makes predictions and processes language. In Chapter 1, I set the scene for the focussed experimental investigations of model diseases by beginning with an introductory, clinically-focussed review that sets out the features, aetiology, management, epidemiology and prognosis of the dementias. This places these model diseases in the context of the broader clinical challenge posed by the dementias. In Chapter 2, I turn to ‘prototypical’ model diseases that represent neurodegenerative tauopathies with predominantly cortical (Alzheimer’s disease, AD) and subcortical (Progressive Supranuclear Palsy, PSP) disease burdens. I investigate the neurophysiological causes and consequences of Tau accumulation by combining graph theoretical analyses of resting state functional MR imaging and in vivo ‘Tau’ PET imaging using the ligand AV-1451. By relating Tau distribution to the functional connectome I provide in vivo evidence consistent with ‘prion-like’ trans-neuronal spread of Tau in AD but not PSP. This provides important validation of disease modification strategies that aim to halt or slow down the progression of AD by sequestration of pathological Tau in the synapse. In contrast, I demonstrate associations consistent with regional vulnerability to Tau accumulation due to metabolic demand and a lack of trophic support in PSP but not AD. With a cross-sectional approach, using Tau burden as a surrogate marker of disease severity, I then go on to show how the changes in functional connectivity that occur as disease progresses account for the contrasting cognitive phenotypes in AD and PSP. In advancing AD, functional connectivity across the whole brain becomes increasingly random and disorganised, accounting for symptomatology across multiple cognitive domains. In advancing PSP, by contrast, disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer passed through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Together, this resulted in increasingly modular processing with inter-network communication taking less direct paths, accounting for the bradyphrenia characteristic of the ‘subcortical dementias’. From chapter 3 onwards, I turn to the in-depth study of a model disease called non-fluent variant Primary Progressive Aphasia (nfvPPA). This disease has a clear clinical phenotype of speech apraxia and agrammatism, associated with a focal pattern of mild atrophy in frontal lobes. Importantly, general cognition is usually well preserved until late disease. In chapter 3 itself, I relate an experiment in which patients with nfvPPA and matched controls performed a receptive language task while having their brain activity recorded with magnetoencephalography. I manipulated expectations and sensory detail to explore the role of top-down frontal contributions to predictive processes in speech perception. I demonstrate that frontal neurodegeneration led to inflexible and excessively precise predictions, and that fronto-temporal interactions play a causal role in reconciling prior predictions with degraded sensory signals. The discussion here concentrates on the insights provided by neurodegenerative disease into the normal function of the brain in processing language. Overall, I demonstrate that higher level frontal mechanisms for cognitive and behavioural flexibility make a critical functional contribution to the hierarchical generative models underlying speech perception In chapter 4, I precisely define the sequence processing and statistical learning abilities of patients with nfvPPA in comparison to patients with non-fluent aphasia due to stroke and neurological controls. I do this by exposing participants to a novel, mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships, and then assessing the degree of implicit rule learning. I demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently in health and disease. In chapter 5, I summarise the synergies between the experimental chapters, and explain how I have applied a systems identification framework to a diverse set of experimental methods, with the common goal of defining the physiology of dementia. I then return to the results of chapter 3 with a clinical focus to explain how inflexible predictions can account for subjective speech comprehension difficulties, auditory processing abnormalities and (in synthesis with chapter 4) receptive agrammatism in nfvPPA. Overall, this body of work has contributed to knowledge in several ways. It has achieved its tripartite aims by: 1) Providing in vivo evidence consistent with theoretical models of trans-neuronal Tau spread (chapter 2), and a comprehensive clinical account of the previously poorly-understood receptive symptomatology of nfvPPA (chapter 5), thus demonstrating that systems neuroscience can provide a translational bridge between the molecular biology of dementia and clinical trials of therapies and medications. In this way, I begin to disentangle the network-level causes of neurodegeneration from its consequences. 2) Providing evidence for a causal role for fronto-temporal interactions in language processing (chapter 3), and demonstrating domain separation of statistical learning between linguistic and non-linguistic sequences (chapter 4), thus demonstrating that studies of patients with neurodegenerative disease can further our understanding of normative brain function. 3) Successfully integrating neuropsychology, behavioural psychophysics, functional MRI, structural MRI, magnetoencephalography and computational modelling to provide comprehensive research training, as the platform for a future research programme in the physiology of dementia.