Deep Variational Lesion-Deficit Mapping

Causal mapping of the functional organisation of the human brain requires evidence of \textit{necessity} available at adequate scale only from pathological lesions of natural origin. This demands inferential models with sufficient flexibility to capture both the observable distribution of pathological damage and the unobserved distribution of the neural substrate. Current model frameworks -- both mass-univariate and multivariate -- either ignore distributed lesion-deficit relations or do not model them explicitly, relying on featurization incidental to a predictive task. Here we initiate the application of deep generative neural network architectures to the task of lesion-deficit inference, formulating it as the estimation of an expressive hierarchical model of the joint lesion and deficit distributions conditioned on a latent neural substrate. We implement such deep lesion deficit inference with variational convolutional volumetric auto-encoders. We introduce a comprehensive framework for lesion-deficit model comparison, incorporating diverse candidate substrates, forms of substrate interactions, sample sizes, noise corruption, and population heterogeneity. Drawing on 5500 volume images of ischaemic stroke, we show that our model outperforms established methods by a substantial margin across all simulation scenarios, including comparatively small-scale and noisy data regimes. Our analysis justifies the widespread adoption of this approach, for which we provide an open source implementation: https://github.com/guilherme-pombo/vae_lesion_defici

Thalamostriatal disconnection underpins long-term seizure freedom in frontal lobe epilepsy surgery

Around 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure free post-operatively; however, only about 30% of patients remain seizure free in the long-term. Early seizure recurrence is likely to be caused by partial resection of the epileptogenic lesion, whilst delayed seizure recurrence can occur even if the epileptogenic lesion has been completely excised. This suggests a coexistent epileptogenic network facilitating ictogenesis in close or distant dormant epileptic foci. As thalamic and striatal dysregulation can support epileptogenesis and disconnection of cortico-thalamostriatal pathways through hemispherotomy or neuromodulation can improve seizure outcome regardless of focality, we hypothesize that projections from the striatum and the thalamus to the cortex may contribute to this common epileptogenic network. To this end, we retrospectively reviewed a series of 47 consecutive individuals who underwent surgery for drug-resistant frontal lobe epilepsy. We performed voxel-based and tractography disconnectome analyses to investigate shared patterns of disconnection associated with long-term seizure freedom. Seizure freedom after 3 and 5 years was independently associated with disconnection of the anterior thalamic radiation and anterior cortico-striatal projections. This was also confirmed in a subgroup of 29 patients with complete resections, suggesting these pathways may play a critical role in supporting the development of novel epileptic networks. Our study indicates that network dysfunction in frontal lobe epilepsy may extend beyond the resection and putative epileptogenic zone. This may be critical in the pathogenesis of delayed seizure recurrence as thalamic and striatal networks may promote epileptogenesis and disconnection may underpin long-term seizure freedom

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Implémentation d'analyses néo-associationnistes avancées du cerveau

Les nouvelles techniques d’imagerie cérébrales, notamment les différentes modalités de l’imagerie par résonance magnétique (IRM), permettent pour la première fois dans l’histoire des neurosciences, d’étudier le cerveau humain in vivo. Ces technologies rendent désormais possible l’étude des symptômes provoquées par des lésions cérébrales chez les patients vivants. Mais ceci requiert le développement de nouvelles analyses, adaptées à ces données encore inaccessibles quelques décennies plus tôt. La plupart des méthodes actuelles pour relier des déficits neuropsychologiques aux dommages cérébraux se concentrent sur la région lésée elle même, négligeant les connexions structurelles et fonctionnelles affectées. Dans cette thèse, nous présentons tout d’abord un ensemble de méthodes, implémentées dans notre logiciel, le BCBtoolkit, permettant l’étude des déconnexions à la fois structurelles et fonctionnelles, ainsi que leur impact sur le comportement. Nous avons utilisé ces analyses pour cartographier les effets de lésions focales frontales sur la performance dans la tâche de fluence catégorielle. Nous présentons ensuite deux études dans lesquelles nous avons utilisé ces approches pour étudier les mécanismes cérébraux de plusieurs fonctions associées à la créativité. Et nous terminons cette thèse par une discussion sur les interactions entre les différentes structures du cerveau, qui permettent de générer les comportements humains. Nos études dévoilent la participation de nombreux réseaux, aussi bien structurels que fonctionnels, dans les différentes fonctions cognitives de haut niveau. Nous tentons, ultimement, de modéliser théoriquement leurs interactions.The new brain imaging techniques, notably the different magnetic resonance imaging (MRI) modalities, allow the study of the human brain in vivo for the first time in neuroscience's history. These technologies now make possible to study the symptoms caused by brain lesions in living patients. However, it requires the development of new analyses adapted for this new kind of data which was not available a few decades ago. Most of the classical lesion--symptom analyses are focused on the lesioned area, often neglecting the affected structural and functional connections. In this thesis, we begin by presenting a set of methods, implemented in our software the BCBtoolkit, enabling the study of both structural and functional disconnections and their effect on the behaviour. We applied these analyses to map the impact of focal brain lesions on the performance in category fluency. We then present two studies using this approach to investigate the underlying mechanisms of several cognitive functions associated with creativity. We finally discuss the possible interaction between the different brain structures, which generate human behaviours. Our studies unveil numerous networks, both structural or functional, participating in the different high-level cognitive functions. Ultimately, we propose a theoretical model for these interactions

Implémentation d'analyses néo-associationnistes avancées du cerveau

The new brain imaging techniques, notably the different magnetic resonance imaging (MRI) modalities, allow the study of the human brain in vivo for the first time in neuroscience's history. These technologies now make possible to study the symptoms caused by brain lesions in living patients. However, it requires the development of new analyses adapted for this new kind of data which was not available a few decades ago. Most of the classical lesion--symptom analyses are focused on the lesioned area, often neglecting the affected structural and functional connections. In this thesis, we begin by presenting a set of methods, implemented in our software the BCBtoolkit, enabling the study of both structural and functional disconnections and their effect on the behaviour. We applied these analyses to map the impact of focal brain lesions on the performance in category fluency. We then present two studies using this approach to investigate the underlying mechanisms of several cognitive functions associated with creativity. We finally discuss the possible interaction between the different brain structures, which generate human behaviours. Our studies unveil numerous networks, both structural or functional, participating in the different high-level cognitive functions. Ultimately, we propose a theoretical model for these interactions.Les nouvelles techniques d’imagerie cérébrales, notamment les différentes modalités de l’imagerie par résonance magnétique (IRM), permettent pour la première fois dans l’histoire des neurosciences, d’étudier le cerveau humain in vivo. Ces technologies rendent désormais possible l’étude des symptômes provoquées par des lésions cérébrales chez les patients vivants. Mais ceci requiert le développement de nouvelles analyses, adaptées à ces données encore inaccessibles quelques décennies plus tôt. La plupart des méthodes actuelles pour relier des déficits neuropsychologiques aux dommages cérébraux se concentrent sur la région lésée elle même, négligeant les connexions structurelles et fonctionnelles affectées. Dans cette thèse, nous présentons tout d’abord un ensemble de méthodes, implémentées dans notre logiciel, le BCBtoolkit, permettant l’étude des déconnexions à la fois structurelles et fonctionnelles, ainsi que leur impact sur le comportement. Nous avons utilisé ces analyses pour cartographier les effets de lésions focales frontales sur la performance dans la tâche de fluence catégorielle. Nous présentons ensuite deux études dans lesquelles nous avons utilisé ces approches pour étudier les mécanismes cérébraux de plusieurs fonctions associées à la créativité. Et nous terminons cette thèse par une discussion sur les interactions entre les différentes structures du cerveau, qui permettent de générer les comportements humains. Nos études dévoilent la participation de nombreux réseaux, aussi bien structurels que fonctionnels, dans les différentes fonctions cognitives de haut niveau. Nous tentons, ultimement, de modéliser théoriquement leurs interactions

The rise of a new associationist school for lesion-symptom mapping

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The human cost of ethical artificial intelligence

Foundational models such as ChatGPT critically depend on vast data scales the internet uniquely enables. This implies exposure to material varying widely in logical sense, factual fidelity, moral value, and even legal status. Whereas data scaling is a technical challenge, soluble with greater computational resource, complex semantic filtering cannot be performed reliably without human intervention: the self-supervision that makes foundational models possible at least in part presupposes the abilities they seek to acquire. This unavoidably introduces the need for large-scale human supervision-not just of training input but also model output-and imbues any model with subjectivity reflecting the beliefs of its creator. The pressure to minimize the cost of the former is in direct conflict with the pressure to maximise the quality of the latter. Moreover, it is unclear how complex semantics, especially in the realm of the moral, could ever be reduced to an objective function any machine could plausibly maximise. We suggest the development of foundational models necessitates urgent innovation in quantitative ethics and outline possible avenues for its realisation

Brain disconnections link structural connectivity with function and behaviour

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Functionnectome as a framework to analyse the contribution of brain circuits to fMRI.

International audienceIn recent years, the field of functional neuroimaging has moved away from a pure localisationist approach of isolated functional brain regions to a more integrated view of these regions within functional networks. However, the methods used to investigate functional networks rely on local signals in grey matter and are limited in identifying anatomical circuitries supporting the interaction between brain regions. Mapping the brain circuits mediating the functional signal between brain regions would propel our understanding of the brain's functional signatures and dysfunctions. We developed a method to unravel the relationship between brain circuits and functions: The Functionnectome. The Functionnectome combines the functional signal from fMRI with white matter circuits' anatomy to unlock and chart the first maps of functional white matter. To showcase this method's versatility, we provide the first functional white matter maps revealing the joint contribution of connected areas to motor, working memory, and language functions. The Functionnectome comes with an open-source companion software and opens new avenues into studying functional networks by applying the method to already existing datasets and beyond task fMRI

An improved neuroanatomical model of the default-mode network reconciles previous neuroimaging and neuropathological findings

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