Interpreting and validating complexity and causality in lesion-symptom prognoses.

This paper considers the steps needed to generate pragmatic and interpretable lesion-symptom mappings that can be used for clinically reliable prognoses. The novel contributions are 3-fold. We first define and inter-relate five neurobiological and five methodological constraints that need to be accounted for when interpreting lesion-symptom associations and generating synthetic lesion data. The first implication is that, because of these constraints, lesion-symptom mapping needs to focus on probabilistic relationships between Lesion and Symptom, with Lesion as a multivariate spatial pattern, Symptom as a time-dependent behavioural profile and evidence that Lesion raises the probability of Symptom. The second implication is that in order to assess the strength of probabilistic causality, we need to distinguish between causal lesion sites, incidental lesion sites, spared but dysfunctional sites and intact sites, all of which might affect the accuracy of the predictions and prognoses generated. We then formulate lesion-symptom mappings in logical notations, including combinatorial rules, that are then used to evaluate and better understand complex brain-behaviour relationships. The logical and theoretical framework presented applies to any type of neurological disorder but is primarily discussed in relationship to stroke damage. Accommodating the identified constraints, we discuss how the 1965 Bradford Hill criteria for inferring probabilistic causality, post hoc, from observed correlations in epidemiology-can be applied to lesion-symptom mapping in stroke survivors. Finally, we propose that rather than rely on post hoc evaluation of how well the causality criteria have been met, the neurobiological and methodological constraints should be addressed, a priori, by changing the experimental design of lesion-symptom mappings and setting up an open platform to share and validate the discovery of reliable and accurate lesion rules that are clinically useful.

Combining local and global evolutionary trajectories of brain-behaviour relationships through game theory.

The study of the evolution of brain-behaviour relationships concerns understanding the causes and repercussions of cross- and within-species variability. Understanding such variability is a main objective of evolutionary and cognitive neuroscience, and it may help explaining the appearance of psychopathological phenotypes. Although brain evolution is related to the progressive action of selection and adaptation through multiple paths (e.g. mosaic vs. concerted evolution, metabolic vs. structural and functional constraints), a coherent, integrative framework is needed to combine evolutionary paths and neuroscientific evidence. Here, we review the literature on evolutionary pressures focusing on structural-functional changes and developmental constraints. Taking advantage of recent progress in neuroimaging and cognitive neuroscience, we propose a twofold hypothetical model of brain evolution. Within this model, global and local trajectories imply rearrangements of neural subunits and subsystems and of behavioural repertoires of a species, respectively. We incorporate these two processes in a game in which the global trajectory shapes the structural-functional neural substrates (i.e. players), while the local trajectory shapes the behavioural repertoires (i.e. stochastic payoffs).

Revisiting 'brain modes' in a new computational era: approaches for the characterization of brain-behavioural associations.

The study of brain-function relationships is undergoing a conceptual and methodological transformation due to the emergence of network neuroscience and the development of multivariate methods for lesion-deficit inferences. Anticipating this process, in 1998 Godefroy and co-workers conceptualized the potential of four elementary typologies of brain-behaviour relationships named 'brain modes' (unicity, equivalence, association, summation) as building blocks able to describe the association between intact or lesioned brain regions and cognitive processes or neurological deficits. In the light of new multivariate lesion inference and network approaches, we critically revisit and update the original theoretical notion of brain modes, and provide real-life clinical examples that support their existence. To improve the characterization of elementary units of brain-behavioural relationships further, we extend such conceptualization with a fifth brain mode (mutual inhibition/masking summation). We critically assess the ability of these five brain modes to account for any type of brain-function relationship, and discuss past versus future contributions in redefining the anatomical basis of human cognition. We also address the potential of brain modes for predicting the behavioural consequences of lesions and their future role in the design of cognitive neurorehabilitation therapies.

Executive function and cortical thickness in youths prenatally exposed to cocaine, alcohol and tobacco.

Small and detrimental, albeit inconsistent, effects of prenatal cocaine exposure (PCE) during early childhood have been reported. The teratogenic effects of prenatal alcohol (PAE) and tobacco exposure (PTE) on neurobehavior are more firmly established than PCE. We tested if co-exposure to all three drugs could be related to greater differences in brain structure than exposure to cocaine alone. Participants (n=42, PCE=27; age range=14-16 years) received an executive function battery prior to a T1-weighted 3T structural MRI scan. Cortical thickness was measured using FreeSurfer (v5.1). Fetal drug exposure was quantified through maternal self-reports usage during pregnancy. Using general linear modeling, we found no main effects of PCE on cortical thickness, but significant main effects of PAE and PTE in superior and medial frontal regions, after co-varying for the effects of age, sex, and each drug of exposure. Significant alcohol-by-tobacco interactions, and significant cocaine-by-alcohol interactions on cortical thickness in medial parietal and temporal regions were also observed. Poly-drug exposure and cognitive function also showed significant interactions with cortical thickness: lower cortical thickness was associated with better performance in PCE-exposed adolescents. Results suggest that although children with PCE have subtle but persistent brain cortical differences until mid-to-late adolescence.