scholarly journals Neuropathology in the North American sudden unexpected death in epilepsy registry

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Dominique F Leitner ◽  
Arline Faustin ◽  
Chloe Verducci ◽  
Daniel Friedman ◽  
Christopher William ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
North American ◽  
Focal Cortical Dysplasia ◽  
Brain Activity ◽  
Brain Regions ◽  
Sudden Unexpected Death ◽  
Age At Death ◽  
Unexpected Death ◽  
Whole Brain ◽  
The North

Abstract Sudden unexpected death in epilepsy is the leading category of epilepsy-related death and the underlying mechanisms are incompletely understood. Risk factors can include a recent history and high frequency of generalized tonic-clonic seizures, which can depress brain activity postictally, impairing respiration, arousal and protective reflexes. Neuropathological findings in sudden unexpected death in epilepsy cases parallel those in other epilepsy patients, with no implication of novel structures or mechanisms in seizure-related deaths. Few large studies have comprehensively reviewed whole brain examination of such patients. We evaluated 92 North American Sudden unexpected death in epilepsy Registry cases with whole brain neuropathological examination by board-certified neuropathologists blinded to the adjudicated cause of death, with an average of 16 brain regions examined per case. The 92 cases included 61 sudden unexpected death in epilepsy (40 definite, 9 definite plus, 6 probable, 6 possible) and 31 people with epilepsy controls who died from other causes. The mean age at death was 34.4 years and 65.2% (60/92) were male. The average age of death was younger for sudden unexpected death in epilepsy cases than for epilepsy controls (30.0 versus 39.6 years; P = 0.006), and there was no difference in sex distribution respectively (67.3% male versus 64.5%, P = 0.8). Among sudden unexpected death in epilepsy cases, earlier age of epilepsy onset positively correlated with a younger age at death (P = 0.0005) and negatively correlated with epilepsy duration (P = 0.001). Neuropathological findings were identified in 83.7% of the cases in our cohort. The most common findings were dentate gyrus dysgenesis (sudden unexpected death in epilepsy 50.9%, epilepsy controls 54.8%) and focal cortical dysplasia (FCD) (sudden unexpected death in epilepsy 41.8%, epilepsy controls 29.0%). The neuropathological findings in sudden unexpected death in epilepsy paralleled those in epilepsy controls, including the frequency of total neuropathological findings as well as the specific findings in the dentate gyrus, findings pertaining to neurodevelopment (e.g. FCD, heterotopias) and findings in the brainstem (e.g. medullary arcuate or olivary dysgenesis). Thus, like prior studies, we found no neuropathological findings that were more common in sudden unexpected death in epilepsy cases. Future neuropathological studies evaluating larger sudden unexpected death in epilepsy and control cohorts would benefit from inclusion of different epilepsy syndromes with detailed phenotypic information, consensus among pathologists particularly for more subjective findings where observations can be inconsistent, and molecular approaches to identify markers of sudden unexpected death in epilepsy risk or pathogenesis.

scholarly journals Proteomic and Transcriptomic Analyses of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Cases

2020 ◽  
Author(s):  
Dominique F. Leitner ◽  
James D. Mills ◽  
Geoffrey Pires ◽  
Arline Faustin ◽  
Eleanor Drummond ◽  
...  
Keyword(s):  
High Risk ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Brain Activity ◽  
Brain Regions ◽  
Sudden Unexpected Death ◽  
Differentially Expressed ◽  
Unexpected Death ◽  
Protein Coding ◽  
The Brain

AbstractSudden unexpected death in epilepsy (SUDEP) is the leading type of epilepsy-related death. Severely depressed brain activity in these cases may impair respiration, arousal, and protective reflexes, occurring as a prolonged postictal generalized EEG suppression (PGES) and resulting in a high-risk for SUDEP. In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and epilepsy cases, contrasting our previously reported robust differences between epilepsy and controls. Transcriptomics in hippocampus and cortex from surgical epilepsy cases segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. Overall, the SUDEP proteome and high-risk SUDEP transcriptome largely reflected other epilepsy cases in the brain regions analyzed, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Thus, studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

scholarly journals Health news sharing is reflected in distributed reward-related brain activity

2020 ◽  
Vol 15 (10) ◽  
pp. 1111-1119
Author(s):  
B P Doré ◽  
C Scholz ◽  
E C Baek ◽  
E B Falk
Keyword(s):  
Health Information ◽  
Brain Activity ◽  
Population Level ◽  
Brain Regions ◽  
Self Report ◽  
Whole Brain ◽  
Health News ◽  
Brain Responses ◽  
Reward Value ◽  
Reward Valuation

Abstract Neuroimaging has identified individual brain regions, but not yet whole-brain patterns, that correlate with the population impact of health messaging. We used neuroimaging to measure whole-brain responses to health news articles across two studies. Beyond activity in core reward value-related regions (ventral striatum, ventromedial prefrontal cortex), our approach leveraged whole-brain responses to each article, quantifying expression of a distributed pattern meta-analytically associated with reward valuation. The results indicated that expression of this whole-brain pattern was associated with population-level sharing of these articles beyond previously identified brain regions and self-report variables. Further, the efficacy of the meta-analytic pattern was not reducible to patterns within core reward value-related regions but rather depended on larger-scale patterns. Overall, this work shows that a reward-related pattern of whole-brain activity is related to health information sharing, advancing neuroscience models of the mechanisms underlying the spread of health information through a population.

scholarly journals SUDEP in the North American SUDEP Registry

Neurology ◽  
2019 ◽  
Vol 93 (3) ◽  
pp. e227-e236 ◽  
Author(s):  
Chloe Verducci ◽  
Fizza Hussain ◽  
Elizabeth Donner ◽  
Brian D. Moseley ◽  
Jeffrey Buchhalter ◽  
...  
Keyword(s):  
North American ◽  
Medical Records ◽  
Focal Epilepsy ◽  
Seizure Type ◽  
Sufficient Information ◽  
Next Of Kin ◽  
Unexpected Death ◽  
Full Spectrum ◽  
Death Scene ◽  
The North

ObjectiveTo obtain medical records, family interviews, and death-related reports of sudden unexpected death in epilepsy (SUDEP) cases to better understand SUDEP.MethodsAll cases referred to the North American SUDEP Registry (NASR) between October 2011 and June 2018 were reviewed; cause of death was determined by consensus review. Available medical records, death scene investigation reports, autopsy reports, and next-of-kin interviews were reviewed for all cases of SUDEP. Seizure type, EEG, MRI, and SUDEP classification were adjudicated by 2 epileptologists.ResultsThere were 237 definite and probable cases of SUDEP among 530 NASR participants. SUDEP decedents had a median age of 26 (range 1–70) years at death, and 38% were female. In 143 with sufficient information, 40% had generalized and 60% had focal epilepsy. SUDEP affected the full spectrum of epilepsies, from benign epilepsy with centrotemporal spikes (n = 3, 1%) to intractable epileptic encephalopathies (n = 27, 11%). Most (93%) SUDEPs were unwitnessed; 70% occurred during apparent sleep; and 69% of patients were prone. Only 37% of cases of SUDEP took their last dose of antiseizure medications (ASMs). Reported lifetime generalized tonic-clonic seizures (GTCS) were <10 in 33% and 0 in 4%.ConclusionsNASR participants commonly have clinical features that have been previously been associated with SUDEP risk such as young adult age, ASM nonadherence, and frequent GTCS. However, a sizeable minority of SUDEP occurred in patients thought to be treatment responsive or to have benign epilepsies. These results emphasize the importance of SUDEP education across the spectrum of epilepsy severities. We aim to make NASR data and biospecimens available for researchers to advance SUDEP understanding and prevention.

scholarly journals Genetic generalized and focal epilepsy prevalence in the North American SUDEP Registry

Neurology ◽  
2020 ◽  
Vol 94 (16) ◽  
pp. e1757-e1763 ◽  
Author(s):  
Chloe Verducci ◽  
Daniel Friedman ◽  
Elizabeth Donner ◽  
Orrin Devinsky
Keyword(s):  
North American ◽  
Focal Epilepsy ◽  
Seizure Type ◽  
Epilepsy Syndrome ◽  
Next Of Kin ◽  
Unexpected Death ◽  
Sleep State ◽  
The North ◽  
Generalized Epilepsy ◽  
Record Review

ObjectiveTo assess relative rates and clinical features of patients with genetic generalized epilepsy (GGE), focal epilepsy (FE), and developmental encephalopathic epilepsy (DEE) in the North American SUDEP Registry (NASR).MethodsWe identified all adjudicated definite, definite plus, and probable sudden unexpected death in epilepsy (SUDEP) cases (n = 262) and determined epilepsy type (GGE, FE, or DEE) from medical record review including history, imaging and EEG results, genetics, and next-of-kin interviews.ResultsOf the 262 SUDEP cases, 41 occurred in GGE, 95 in FE, 24 in DEE, and 102 were unclassifiable. GGE cases comprised 26% of NASR cases with an epilepsy syndrome diagnosis. The relative frequency of FE:GGE was slightly lower (2.3:1) than in population cohorts (2.1–6:1). Compared to patients with FE, patients with GGE had similar (1) ages at death and epilepsy onset and rates of (2) terminal and historical antiseizure medication adherence; (3) abnormal cardiac pathology; (4) illicit drug/alcohol use histories; and (5) sleep state when SUDEP occurred.ConclusionsGGE cases were relatively overrepresented in NASR. Because GGEs are less often treatment-resistant than FE or DEE, seizure type rather than frequency may be critical. Many people with GGE predominantly have generalized tonic-clonic seizures (GTCS) when they have uncontrolled or breakthrough seizures, whereas patients with FE more commonly experience milder seizures. Future mechanistic SUDEP studies should assess primary and focal-to-bilateral GTCS to identify potential differences in postictal autonomic and arousal disorders and to determine the differential role that lifestyle factors have on breakthrough seizures and seizure types in GGE vs FE to effectively target SUDEP mechanisms and prevention.

scholarly journals Dynamic properties of simulated brain network models and empirical resting-state data

2019 ◽  
Vol 3 (2) ◽  
pp. 405-426 ◽  
Author(s):  
Amrit Kashyap ◽  
Shella Keilholz
Keyword(s):  
Resting State ◽  
Dynamic Properties ◽  
Brain Activity ◽  
Structural Connectivity ◽  
Simulated Data ◽  
Network Models ◽  
Resting State Fmri ◽  
Brain Regions ◽  
Brain Network ◽  
Whole Brain

Brain network models (BNMs) have become a promising theoretical framework for simulating signals that are representative of whole-brain activity such as resting-state fMRI. However, it has been difficult to compare the complex brain activity obtained from simulations to empirical data. Previous studies have used simple metrics to characterize coordination between regions such as functional connectivity. We extend this by applying various different dynamic analysis tools that are currently used to understand empirical resting-state fMRI (rs-fMRI) to the simulated data. We show that certain properties correspond to the structural connectivity input that is shared between the models, and certain dynamic properties relate more to the mathematical description of the brain network model. We conclude that the dynamic properties that explicitly examine patterns of signal as a function of time rather than spatial coordination between different brain regions in the rs-fMRI signal seem to provide the largest contrasts between different BNMs and the unknown empirical dynamical system. Our results will be useful in constraining and developing more realistic simulations of whole-brain activity.

scholarly journals Parcellation-induced variation of empirical and simulated brain connectomes at group and subject levels

2021 ◽  
pp. 1-56
Author(s):  
Justin W.M. Domhof ◽  
Kyesam Jung ◽  
Simon B. Eickhoff ◽  
Oleksandr V. Popovych
Keyword(s):  
Functional Connectivity ◽  
Goodness Of Fit ◽  
Brain Activity ◽  
Brain Regions ◽  
Single Subject ◽  
Whole Brain ◽  
Clear Cut ◽  
Recent Developments ◽  
Network Properties ◽  
Brain Models

Abstract Recent developments of whole-brain models have demonstrated their potential when investigating resting-state brain activity. However, it has not been systematically investigated how alternating derivations of the empirical structural and functional connectivity, serving as the model input, from MRI data influence modelling results. Here, we study the influence from one major element: the brain parcellation scheme that reduces the dimensionality of brain networks by grouping thousands of voxels into a few hundred brain regions. We show graph-theoretical statistics derived from the empirical data and modelling results exhibiting a high heterogeneity across parcellations. Furthermore, the network properties of empirical brain connectomes explain the lion’s share of the variance in the modelling results with respect to the parcellation variation. Such a clear-cut relationship is not observed at the subject-resolved level per parcellation. Finally, the graph-theoretical statistics of the simulated connectome correlate with those of the empirical functional connectivity across parcellations. However, this relation is not one-to-one, and its precision can vary between models. Our results imply that network properties of both empirical connectomes can explain the goodness-of-fit of whole-brain models toempirical data at a global group but not a single-subject level, which provides further insights into the personalisation of whole-brain models.

scholarly journals Brain-wide functional architecture remodeling by alcohol dependence and abstinence

2020 ◽  
Vol 117 (4) ◽  
pp. 2149-2159 ◽  
Author(s):  
Adam Kimbrough ◽  
Daniel J. Lurie ◽  
Andres Collazo ◽  
Max Kreifeldt ◽  
Harpreet Sidhu ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Dependence ◽  
Current Knowledge ◽  
Brain Activity ◽  
Alcohol Exposure ◽  
Brain Regions ◽  
Future Research ◽  
Functional Architecture ◽  
Whole Brain ◽  
Alcohol Abstinence

Alcohol abuse and alcohol dependence are key factors in the development of alcohol use disorder, which is a pervasive societal problem with substantial economic, medical, and psychiatric consequences. Although our understanding of the neurocircuitry that underlies alcohol use has improved, novel brain regions that are involved in alcohol use and novel biomarkers of alcohol use need to be identified. The present study used a single-cell whole-brain imaging approach to 1) assess whether abstinence from alcohol in an animal model of alcohol dependence alters the functional architecture of brain activity and modularity, 2) validate our current knowledge of the neurocircuitry of alcohol abstinence, and 3) discover brain regions that may be involved in alcohol use. Alcohol abstinence resulted in the whole-brain reorganization of functional architecture in mice and a pronounced decrease in modularity that was not observed in nondependent moderate drinkers. Structuring of the alcohol abstinence network revealed three major brain modules: 1) extended amygdala module, 2) midbrain striatal module, and 3) cortico-hippocampo-thalamic module, reminiscent of the three-stage theory. Many hub brain regions that control this network were identified, including several that have been previously overlooked in alcohol research. These results identify brain targets for future research and demonstrate that alcohol use and dependence remodel brain-wide functional architecture to decrease modularity. Further studies are needed to determine whether the changes in coactivation and modularity that are associated with alcohol abstinence are causal features of alcohol dependence or a consequence of excessive drinking and alcohol exposure.

scholarly journals Cavefish brain atlases reveal functional and anatomical convergence across independently evolved populations

2019 ◽  
Author(s):  
James Jaggard ◽  
Evan Lloyd ◽  
Anders Yuiska ◽  
Adam Patch ◽  
Yaouen Fily ◽  
...  
Keyword(s):  
Brain Structure ◽  
Larval Fish ◽  
Brain Activity ◽  
Brain Regions ◽  
Model Systems ◽  
Neural Basis ◽  
Behavioral Evolution ◽  
Whole Brain ◽  
Brain Structure And Function ◽  
Brain Atlases

AbstractEnvironmental perturbation can drive the evolution of behavior and associated changes in brain structure and function. The generation of computationally-derived whole-brain atlases have provided insight into neural connectivity associated with behavior in many model systems. However, these approaches have not been used to study the evolution of brain structure in vertebrates. The Mexican tetra, A. mexicanus, comprises river-dwelling surface fish and multiple independently evolved populations of blind cavefish, providing a unique opportunity to identify neuroanatomical and functional differences associated with behavioral evolution. We employed intact brain imaging and image registration on 684 larval fish to generate neuroanatomical atlases of surface fish and three different cave populations. Analyses of brain regions and neural circuits associated with behavioral regulation identified convergence on hypothalamic expansion, as well as changes in transmitter systems including elevated numbers of catecholamine and hypocretin neurons in cavefish populations. To define evolutionarily-derived changes in brain function, we performed whole brain activity mapping associated with feeding and sleep. Feeding evoked neural activity in different sensory processing centers in surface and cavefish. We also identified multiple brain regions with sleep-associated activity across all four populations, including the rostral zone of the hypothalamus and tegmentum. Together, these atlases represent the first comparative brain-wide study of intraspecies variation in a vertebrate model, and provide a resource for studying the neural basis underlying behavioral evolution.

scholarly journals Proteomic differences in the hippocampus and cortex of epilepsy brain tissue

2021 ◽  
Author(s):  
Geoffrey Pires ◽  
Dominique Leitner ◽  
Eleanor Drummond ◽  
Evgeny Kanshin ◽  
Shruti Nayak ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Frontal Cortex ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
High Rate ◽  
Label Free ◽  
Protein Subunit ◽  
Unexpected Death ◽  
And Control

Abstract Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., sudden unexpected death in epilepsy, accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with seizures in epilepsy with a broad range of etiologies, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry was performed on the hippocampal cornu ammonis 1-3 region (CA1-3), frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n = 14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein subunit beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors in epilepsy. Our results provide insights into common molecular mechanisms underlying epilepsy across various etiologies, which may allow for novel targeted therapeutic strategies.

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