Sensory sensitivity as a link between concussive traumatic brain injury and PTSD.

Traumatic brain injury (TBI) is one of the most common injuries to military personnel, a population often exposed to stressful stimuli and emotional trauma. Changes in sensory processing after TBI might contribute to TBI-post traumatic stress disorder (PTSD) comorbidity. Combining an animal model of TBI with an animal model of emotional trauma, we reveal an interaction between auditory sensitivity after TBI and fear conditioning where 75 dB white noise alone evokes a phonophobia-like phenotype and when paired with footshocks, fear is robustly enhanced. TBI reduced neuronal activity in the hippocampus but increased activity in the ipsilateral lateral amygdala (LA) when exposed to white noise. The white noise effect in LA was driven by increased activity in neurons projecting from ipsilateral auditory thalamus (medial geniculate nucleus). These data suggest that altered sensory processing within subcortical sensory-emotional circuitry after TBI results in neutral stimuli adopting aversive properties with a corresponding impact on facilitating trauma memories and may contribute to TBI-PTSD comorbidity

Mapping the functional connectome traits of levels of consciousness

Examining task-free functional connectivity (FC) in the human brain offers insights on how spontaneous integration and segregation of information relate to human cognition, and how this organization may be altered in different conditions, and neurological disorders. This is particularly relevant for patients in disorders of consciousness (DOC) following severe acquired brain damage and coma, one of the most devastating conditions in modern medical care. We present a novel data-driven methodology, connICA, which implements Independent Component Analysis (ICA) for the extraction of robust independent FC patterns (FC-traits) from a set of individual functional connectomes, without imposing any a priori data stratification into groups. We here apply connICA to investigate associations between network traits derived from task-free FC and cognitive/clinical features that define levels of consciousness. Three main independent FC-traits were identified and linked to consciousness-related clinical features. The first one represents the functional configuration it is associated to a sedative (sevoflurane), the overall effect of the pathology and the level of arousal. The second FC-trait reflects the disconnection of the visual and sensory-motor connectivity patterns. It also relates to the time since the insult and to the ability of communicating with the external environment. The third FC-trait isolates the connectivity pattern encompassing the fronto-parietal and the default-mode network areas as well as the interaction between left and right hemispheres, which are also associated to the awareness of the self and its surroundings. Each FC-trait represents a distinct functional process with a role in the degradation of conscious states of functional brain networks, shedding further light on the functional subcircuits that get disrupted in severe brain-damage

Brain connectivity and sensory stimulation in patients with disorders of consciousness

This thesis explores brain connectivity and sensory stimulation in patients with disorders of consciousness (DOC). These are serious conditions where massive brain damage can lead to a dissociation between arousal and awareness (e.g., UWS and MCS). Part I explores brain connectivity. We highlight that brain function and structure are intimately related to each other, and to consciousness. The decrease in brain function can be used to distinguish between the clinically indicated states of consciousness. Part II evaluates passive sensory stimulations. Preferred stimuli may have the power to momentarily enhance brain function, and behavioral responses

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Methods and models for brain connectivity assessment across levels of consciousness

The human brain is one of the most complex and fascinating systems in nature. In the last decades, two events have boosted the investigation of its functional and structural properties. Firstly, the emergence of novel noninvasive neuroimaging modalities, which helped improving the spatial and temporal resolution of the data collected from in vivo human brains. Secondly, the development of advanced mathematical tools in network science and graph theory, which has recently translated into modeling the human brain as a network, giving rise to the area of research so called Brain Connectivity or Connectomics. In brain network models, nodes correspond to gray-matter regions (based on functional or structural, atlas-based parcellations that constitute a partition), while links or edges correspond either to structural connections as modeled based on white matter fiber-tracts or to the functional coupling between brain regions by computing statistical dependencies between measured brain activity from different nodes. Indeed, the network approach for studying the brain has several advantages: 1) it eases the study of collective behaviors and interactions between regions; 2) allows to map and study quantitative properties of its anatomical pathways; 3) gives measures to quantify integration and segregation of information processes in the brain, and the flow (i.e. the interacting dynamics) between different cortical and sub-cortical regions. The main contribution of my PhD work was indeed to develop and implement new models and methods for brain connectivity assessment in the human brain, having as primary application the analysis of neuroimaging data coming from subjects at different levels of consciousness. I have here applied these methods to investigate changes in levels of consciousness, from normal wakefulness (healthy human brains) or drug-induced unconsciousness (i.e. anesthesia) to pathological (i.e. patients with disorders of consciousness)

Treating Disorders of Consciousness With Apomorphine: Protocol for a Double-Blind Randomized Controlled Trial Using Multimodal Assessments

Background: There are few available therapeutic options to promote recovery among patients with chronic disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects and safety of use in small-sample pilot studies. The true efficacy of the drug and its neural mechanism are still unclear. Apomorphine may act through a modulation of the anterior forebrain mesocircuit, but neuroimaging and neurophysiological investigations to test this hypothesis are scarce. This clinical trial aims to (1) assess the treatment effect of subcutaneous apomorphine infusions in patients with DOC, (2) better identify the phenotype of responders to treatment, (3) evaluate tolerance and side effects in this population, and (4) examine the neural networks underlying its modulating action on consciousness.Methods/Design: This study is a prospective double-blind randomized parallel placebo-controlled trial. Forty-eight patients diagnosed with DOC will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, using standardized behavioral scales (Coma Recovery Scale-Revised, Nociception Coma Scale-Revised), neurophysiological measures (electroencephalography, body temperature, actigraphy) and brain imaging (magnetic resonance imaging, positron emission tomography). Behavioral follow-up will be performed up to 2 years using structured phone interviews. Analyses will look for changes in behavioral status, circadian rhythmicity, brain metabolism, and functional connectivity at the individual level (comparing before and after treatment) and at the group level (comparing apomorphine and placebo arms, and comparing responder and non-responder groups).Discussion: This study investigates the use of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal assessments. The results will contribute to define the role of dopamine agonists for the treatment of these challenging conditions and identify the neural correlates to their action. Results will bring objective evidence to further assess the modulation of the anterior forebrain mesocircuit by pharmacological agents, which may open new therapeutic perspectives.Clinical Trial Registration: EudraCT n°2018-003144-23; Clinicaltrials.gov n°NCT03623828 (https://clinicaltrials.gov/ct2/show/NCT03623828)

Functional and cognitive outcomes in patients with covert cognition during acute intensive rehabilitation

Background: Disorders of consciousness (DOC) result from focal or extensive brain lesions. Patients suffering from DOC go through neurobehavioral assessments and are classified in different categories: coma, unresponsive wakefulness syndrome (UWS) (also known as vegetative state) and minimally conscious state (MCS). Recently, the broader use of technologies, such as functional neuroimaging and electroencephalography, has allowed the highlighting of preserved cognitive capacities in patients behaviourally categorized as UWS or MCS. Such condition is called cognitive motor dissociation (CMD). Objectives: 1) To investigate the consciousness/functional recovery in patients with disorders of consciousness (DOC) as well as those presenting with cognitive motor dissociation (CMD), 2) to compare the different functional outcomes to see whether those with preserved cognitive capacities differ and 3) to evaluate the patients’ clinical evolution between admission and discharge. Method: We retrospectively included 141 patients admitted to the Acute Neurorehabilitation Unit (NRA) of the University Hospital of Lausanne (CHUV, Lausanne, Switzerland) from November 2011 to August 2018 and investigated their functional outcomes at admission and discharge using 6 different outcome scales. Univariate analyses were then performed to compare the different functional outcomes. Results: Patients presenting with CMD were significantly associated with better functional outcomes and potential of improvement than the patients suffering from DOC. Conclusion: Our findings support the fact that CMD patients constitute a separate category of patients with different potential of improvement and functional outcomes than patients suffering from DOC. This reinforces the need for them to be recognized as soon as possible, as it could have a direct impact on patient care and influence life and death decisions

Structural Network Properties and Their Relation to Cognitive Flexibility and Neurological Risk Factors in Adult Survivors of Pediatric Brain Tumors

Neuroimaging techniques have been used to investigate the neurobiological mechanisms of cognitive deficits in survivors of childhood brain tumors. Graph theory is a quantitative method that characterizes brains as a complex system. By modeling brain regions as ‘nodes’ and white matter tracts between each brain region pair as ‘edges,’ graph theory provides metrics that quantify the topological properties of networks. Given that brain tumor survivorship is associated with focal and diffuse impairments, a network analysis can provide complementary information to previous neuroimaging studies in this clinical group. This study used diffusion-weighted imaging and deterministic tractography to examine the properties of the structural networks in 38 adult survivors of pediatric brain tumors (Mean age=22.5, 55% female, mean years post diagnosis=14.1 (6.2), Range post diagnosis = 4.5-30 years). Results of this study suggest that long term survivorship is associated with altered structural networks with respect to measures of integration, segregation, and centrality. Further, properties of the network mediate differences in cognitive flexibility performance between survivors and healthy peers, and mediate the relationship between cumulative neurological risk and cognitive flexibility performance