Local cortical dynamics of burst suppression in the anaesthetized brain

Burst suppression is an electroencephalogram pattern that consists of a quasi-periodic alternation between isoelectric ‘suppressions’ lasting seconds or minutes, and high-voltage ‘bursts’. It is characteristic of a profoundly inactivated brain, occurring in conditions including hypothermia, deep general anaesthesia, infant encephalopathy and coma. It is also used in neurology as an electrophysiological endpoint in pharmacologically induced coma for brain protection after traumatic injury and during status epilepticus.

Classically, burst suppression has been regarded as a ‘global’ state with synchronous activity throughout cortex. This assumption has influenced the clinical use of burst suppression as a way to broadly reduce neural activity. However, the extent of spatial homogeneity has not been fully explored due to the challenges in recording from multiple cortical sites simultaneously. The neurophysiological dynamics of large-scale cortical circuits during burst suppression are therefore not well understood. To address this question, we recorded intracranial electrocorticograms from patients who entered burst suppression while receiving propofol general anaesthesia. The electrodes were broadly distributed across cortex, enabling us to examine both the dynamics of burst suppression within local cortical regions and larger-scale network interactions. We found that in contrast to previous characterizations, bursts could be substantially asynchronous across the cortex. Furthermore, the state of burst suppression itself could occur in a limited cortical region while other areas exhibited ongoing continuous activity. In addition, we found a complex temporal structure within bursts, which recapitulated the spectral dynamics of the state preceding burst suppression, and evolved throughout the course of a single burst. Our observations imply that local cortical dynamics are not homogeneous, even during significant brain inactivation. Instead, cortical and, implicitly, subcortical circuits express seemingly different sensitivities to high doses of anaesthetics that suggest a hierarchy governing how the brain enters burst suppression, and emphasize the role of local dynamics in what has previously been regarded as a global state. These findings suggest a conceptual shift in how neurologists could assess the brain function of patients undergoing burst suppression. First, analysing spatial variation in burst suppression could provide insight into the circuit dysfunction underlying a given pathology, and could improve monitoring of medically-induced coma. Second, analysing the temporal dynamics within a burst could help assess the underlying brain state. This approach could be explored as a prognostic tool for recovery from coma, and for guiding treatment of status epilepticus. Overall, these results suggest new research directions and methods that could improve patient monitoring in clinical practice.

Brain September 2013

http://brain.oxfordjournals.org/content/136/9/2727.full.pdf+html

Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia

Many individuals with abnormalities of mitochondrial respiratory chain complex III remain genetically undefined. Here, we report mutations (c.288G>T [p.Trp96Cys] and c.643C>T [p.Leu215Phe]) in CYC1, encoding the cytochrome c₁ subunit of complex III, in two unrelated children presenting with recurrent episodes of ketoacidosis and insulin-responsive hyperglycemia. Cytochrome c₁, the heme-containing component of complex III, mediates the transfer of electrons from the Rieske iron-sulfur protein to cytochrome c. Cytochrome c₁ is present at reduced levels in the skeletal muscle and skin fibroblasts of affected individuals. Moreover, studies on yeast mutants and affected individuals’ fibroblasts have shown that exogenous expression of wild-type CYC1 rescues complex III activity, demonstrating the deleterious effect of each mutation on cytochrome c₁ stability and complex III activity.

AJHC August 2013

Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: a cohort study

Background

Although patients with type 2 diabetes are twice as likely to develop dementia as those without this disease, prediction of who has the highest future risk is difficult. We therefore created and validated a practical summary risk score that can be used to provide an estimate of the 10 year dementia risk for individuals with type 2 diabetes.

Methods

Using data from two longitudinal cohorts of patients with type 2 diabetes (aged ≥60 years) with 10 years of follow-up, we created (n=29 961) and validated (n=2413) the risk score. We built our prediction model by evaluating 45 candidate predictors using Cox proportional hazard models and developed a point system for the risk score based on the size of the predictor's β coefficient. Model prediction was tested by discrimination and calibration methods. Dementia risk per sum score was calculated with Kaplan-Meier estimates.

Findings

Microvascular disease, diabetic foot, cerebrovascular disease, cardiovascular disease, acute metabolic events, depression, age, and education were most strongly predictive of dementia and constituted the risk score (C statistic 0·736 for creation cohort and 0·746 for validation cohort). The dementia risk was 5·3% (95% CI 4·2—6·3) for the lowest score (—1) and 73·3% (64·8—81·8) for the highest (12—19) sum scores.

Interpretation

To the best of our knowledge, this is the first risk score for the prediction of 10 year dementia risk in patients with type 2 diabetes mellitus. The risk score can be used to increase vigilance for cognitive deterioration and for selection of high-risk patients for participation in clinical trials.

The Lancet 2013

Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
Science 341, (2013);

T-cell homeostasis in pediatric multiple sclerosis

Objective: To assess pediatric patients with multiple sclerosis (MS) for early signs of homeostatic and functional abnormalities in conventional (T_con) and regulatory T cells (T_reg).

Methods: We studied the composition of the peripheral T-cell compartment and T_reg function in a cross-sectional study with 30 pediatric MS (pMS) patients by multicolor flow cytometry and proliferation assays. Data were compared to those obtained from adult patients (n = 26) and age-matched control donors (n = 67).

Results: Proportions of naive T cells were 10%–20% higher in children than in adults, reflecting the age-related decline. pMS patients, however, had clearly lower numbers of naive T cells, among them recent thymic emigrants (RTE), whereas percentages of memory T cells were increased. In the T_reg compartment, reduced RTE numbers coincided with markedly dampened suppressive capacities of total T_reg. These homeostatic changes in circulating T cells precisely paralleled the pattern seen in adult MS. As in adults, treatment with immunomodulatory drugs attenuated these alterations.

Conclusion: The homeostatic changes detected in the T-cell compartment in pMS are similar to those in adult-onset disease. With ratios between naive and memory T-cell subsets matching those of 20- to 30-years-older controls, signs of early thymic involution are already found in pMS, suggesting that an intrinsic compromise in thymic-dependent T-cell neogenesis might contribute to MS pathogenesis.

Neurology August 27, 2013 vol. 81 no. 9 784-792

Discovering rare diseases: Beauce Ataxia

JAMA Neurol. 2013 Aug 19. doi: 10.1001/jamaneurol.2013.3268. [Epub ahead of print]

SYNE1 Mutations in Autosomal Recessive Cerebellar Ataxia.

Noreau A, Bourassa CV, Szuto A, Levert A, Dobrzeniecka S, Gauthier J, Forlani S, Durr A, Anheim M, Stevanin G, Brice A, Bouchard JP,Dion PA, Dupré N, Rouleau GA.

Source

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada2Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Abstract

IMPORTANCE Autosomal recessive cerebellar ataxia type I, also known as recessive ataxia of Beauce, is a slowly progressive ataxia that leads to moderate disability with gait ataxia, dysarthria, dysmetria, mild oculomotor abnormalities, and diffuse cerebellar atrophy on brain imaging. Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene, located on chromosome 6p25, were first reported in patients who originated from a region known as "Beauce" in the province of Quebec, Canada. OBJECTIVE To better evaluate the prevalence of SYNE1 mutations in individuals with mild pure cerebellar ataxia and cerebellar atrophy, we screened the gene in additional French-Canadian (FC) families and individuals from other populations. DESIGN, SETTING, AND PARTICIPANTS Study participants were referred by their treating physician on the basis of core features of autosomal recessive cerebellar ataxia type I. After excluding individuals with known SYNE1 mutations, our cohort was composed mainly of 19 FCs and 21 individuals from other ethnic backgrounds. INTERVENTIONS Extraction of DNA from blood samples and complete resequencing of the SYNE1 gene. MAIN OUTCOMES AND MEASURES The involvement of SYNE1 mutations in individuals with ataxia worldwide by resequencing the SYNE1 gene. RESULTS Two novel truncating mutations were found among the FC participants, and 2 other novel mutations were found in a patient from France and a patient from Brazil (1 mutation each). CONCLUSIONS AND RELEVANCE This is the second report, to our knowledge, of SYNE1 gene mutations in a population other than FCs. These data suggest that mutations in SYNE1 should be investigated in families with cerebellar ataxia who live outside the FC region.

Nat Rev Neurol. 2013 Aug;9(8):474-81. doi: 10.1038/nrneurol.2013.129. Epub 2013 Jul 2.

New treatments for mitochondrial disease-no time to drop our standards.

Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, Hirano M, Zeviani M, Bindoff LA, Yu-Wai-Man P, Hanna M,Carelli V, McFarland R, Majamaa K, Turnbull DM, Smeitink J, Chinnery PF.

Source

Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Ageing and Health, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

Abstract

Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new biomarkers of mitochondrial disease. In this Perspectives article, we make recommendations for the design of future treatment trials in mitochondrial diseases. Patients and physicians should no longer rely on potentially biased data, with the associated costs and risks.