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See detailTreating severely brain-injured patients with apomorphine: study protocol for a double blind randomized placebo-controlled trial using behavioral and neuroimaging assessments
Sanz, Leandro ULiege; Lejeune, Nicolas; Thibaut, Aurore ULiege et al

in Frontiers in Neuroscience (2018, October)

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of ... [more ▼]

Background: Patients who survive severe brain injury may develop chronic disorders of consciousness. Treating these patients to improve recovery is extremely challenging because of the absence of international guidelines and scarce therapeutic options (Schnakers and Monti, 2017). Among pharmacological treatments, apomorphine, a potent direct non-specific dopamine agonist with a high affinity for D2 receptors, has exhibited promising behavioral effects and safety of use in small-sample pilot studies (Fridman et al., 2009, 2010). However, despite the improvement compared to historical data, the lack of a control group could not eliminate the possibility that the effect was a result of spontaneous recovery, and the true efficacy of apomorphine for the recovery of consciousness remains unclear (Gosseries et al., 2014). In addition, the underlying neural mechanisms of this treatment are still unknown. An upregulation of central thalamic activity through a modulation of the anterior forebrain mesocircuit has been proposed as a possible explanation (Schiff, 2010a, 2010b) but the absence of neuroimaging and neurophysiological data prevent definitive confirmation. This clinical trial aims to 1) verify and quantify the efficacy of apomorphine subcutaneous infusion in patients with disorders of consciousness, 2) better identify the rate and the phenotype of responders to treatment, 3) evaluate tolerance and side effects occurrence in this specific patient population and 4) investigate the neural networks underlying its modulating action on consciousness using multimodal outcome measurements. Methods/design: This study is a prospective double-blind randomized placebo-controlled trial. Forty-eight patients diagnosed with disorders of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state) will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo via daily 12-hour subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, followed by a two-year remote follow-up. In an initial study phase, up to six patients will be treated in an open-label fashion. Behavioral outcome measures will include weekly assessments using standardized scales such as the Coma Recovery Scale – Revised (CRS-R) (Giacino et al., 2004) and the Nociception Coma Scale – Revised (NCS-R) (Chatelle et al., 2012) during the inpatient phase. Tolerance and safety of use will be monitored using a specifically designed Adverse Events Questionnaire filled weekly by the referent physician, from treatment initiation to the end of the inpatient phase. Long-term behavioral follow-up will be performed at 6, 12 and 24 months post-treatment by telephone interview using the Glasgow Outcome Scale – Extended (GOS-E) (Levin et al., 2001) as well as phone-adapted versions of the CRS-R and the Adverse Events Questionnaire. Neurophysiological and neuroimaging measures will complement clinical evaluations and provide data on brain activity. Resting-state high-density electroencephalography (EEG) will be acquired weekly during the whole inpatient phase. In addition, participants will be assessed before and after treatment with Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), EEG during auditory paradigms and 24-hours EEG recordings. To measure changes in circadian rhythm, body core temperature (Matsumoto et al., 2013) and body movements (Cruse et al., 2013) will be recorded with non-invasive portable devices throughout the whole duration of the inpatient phase (Figure 1). Statistical analyses will be performed blindly to detect changes in behavioral status, circadian rhythmicity, brain metabolism and functional connectivity both at the individual level (comparing before and after treatment) and at the group level (comparing the apomorphine and the placebo arms). Behavioral response will be determined by changes of diagnosis using the CRS-R, and further analyses will also look at changes between the non-responding and the responding patient subgroups. Age, gender, etiology, time since injury and diagnosis will also be included as regressors. Hypotheses: Based on the mesocircuit hypothesis, we postulate a modulation in the activity of the network’s anterior forebrain structures following administration of apomorphine (Figure 2), which will translate into the following changes: 1) A behavioral improvement such that the CRS-R diagnosis and total score will improve in responding patients, while NCS-R scores may also increase, reflecting a higher perception of pain; along with long-term functional recovery measured by sustained higher GOS-E and CRS-R scores at follow-up compared to the placebo group; 2) A relative recovery of sleep-wake cycles measured by a normalization of circadian rhythmicity as well as an increase in total body movements; 3) A metabolic improvement with significant increase of whole-brain glucose uptake, with highest increase of values found in the striatum, thalamus and frontoparietal cortical areas measured with PET; 4) A modulation of dynamic connectivity in response to apomorphine measured by resting-state fMRI analyses (seed-based and whole-brain connectivity measures) and changes of resting-state EEG connectivity metrics (notably increased mean alpha spectral connectivity, participation coefficient and delta modularity). Additionally, we can expect improvements after treatment in less specific measures of recovery such as sleep cycle architecture on 24-hours EEG hypnograms and the probability of consciousness given by a machine learning multivariate classifier derived from EEG recordings during auditory paradigms (Engemann et al., 2015). While improvements can be expected as well in the placebo arm due to spontaneous recovery and placebo effect, we hypothesize that responding patients in the apomorphine arm will exhibit significantly higher increases in these different markers of recovery. Discussion: New multimodal approaches using neurophysiology and neuroimaging allow a more accurate diagnosis of patients with disorders of consciousness but the current available treatments remain inefficient. This study aims to verify the efficacy of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal measurement methods. The results will contribute to define the role of dopamine agonists in the treatment of this challenging population of patients and help identify the neural underpinnings underlying the modulation of consciousness networks by apomorphine. Notably, this trial is designed to bring objective neuroimaging and neurophysiological evidence to further assess the validity of the mesocircuit hypothesis and its modulation by pharmacological agents, which may open new therapeutic perspectives. [less ▲]

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See detailRandom Forests based group importance scores and their statistical interpretation: application for Alzheimer’s disease
Wehenkel, Marie ULiege; Sutera, Antonio ULiege; Bastin, Christine ULiege et al

in Frontiers in Neuroscience (2018), 12

Machine learning approaches have been increasingly used in the neuroimaging field for the design of computer-aided diagnosis systems. In this paper, we focus on the ability of these methods to provide ... [more ▼]

Machine learning approaches have been increasingly used in the neuroimaging field for the design of computer-aided diagnosis systems. In this paper, we focus on the ability of these methods to provide interpretable information about the brain regions that are the most informative about the disease or condition of interest. In particular, we investigate the benefit of group-based, instead of voxel-based, analyses in the context of Random forests. Assuming a prior division of the voxels into non overlapping groups (defined by an atlas), we propose several procedures to derive group importances from individual voxel importances derived from random forests models. We then adapt several permutation schemes to turn group importance scores into more interpretable statistical scores that allow to determine the truly relevant groups in the importance rankings. The good behavior of these methods is first assessed on artificial datasets. Then, they are applied on our own dataset of FDG-PET scans to identify the brain regions involved in the prognosis of Alzheimer's disease. [less ▲]

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See detailNeurogenomic profiling reveals distinct gene expression profiles between brain parts that are consistent in Ophthalmotilapia cichlids
Derycke, Sofie; Kever, Loïc ULiege; Van den Berge, K et al

in Frontiers in Neuroscience (2018), 12

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See detailAssessing Command-Following and Communication With Vibro-Tactile P300 Brain-Computer Interface Tools in Patients With Unresponsive Wakefulness Syndrome.
Guger, Christoph; Spataro, Rossella; Pellas, Frederic et al

in Frontiers in Neuroscience (2018), 12

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor disablities, and thus assessing their spared cognitive abilities can be difficult. Recent research from several groups ... [more ▼]

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor disablities, and thus assessing their spared cognitive abilities can be difficult. Recent research from several groups has shown that non-invasive brain-computer interface (BCI) technology can provide assessments of these patients' cognitive function that can supplement information provided through conventional behavioral assessment methods. In rare cases, BCIs may provide a binary communication mechanism. Here, we present results from a vibrotactile BCI assessment aiming at detecting command-following and communication in 12 unresponsive wakefulness syndrome (UWS) patients. Two different paradigms were administered at least once for every patient: (i) VT2 with two vibro-tactile stimulators fixed on the patient's left and right wrists and (ii) VT3 with three vibro-tactile stimulators fixed on both wrists and on the back. The patients were instructed to mentally count either the stimuli on the left or right wrist, which may elicit a robust P300 for the target wrist only. The EEG data from -100 to +600 ms around each stimulus were extracted and sub-divided into 8 data segments. This data was classified with linear discriminant analysis (using a 10 x 10 cross validation) and used to calibrate a BCI to assess command following and YES/NO communication abilities. The grand average VT2 accuracy across all patients was 38.3%, and the VT3 accuracy was 26.3%. Two patients achieved VT3 accuracy >/=80% and went through communication testing. One of these patients answered 4 out of 5 questions correctly in session 1, whereas the other patient answered 6/10 and 7/10 questions correctly in sessions 2 and 4. In 6 other patients, the VT2 or VT3 accuracy was above the significance threshold of 23% for at least one run, while in 4 patients, the accuracy was always below this threshold. The study highlights the importance of repeating EEG assessments to increase the chance of detecting command-following in patients with severe brain injury. Furthermore, the study shows that BCI technology can test command following in chronic UWS patients and can allow some of these patients to answer YES/NO questions. [less ▲]

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See detailBCI performance and brain metabolism profile in severely brain-injured patients without response to command at bedside
Annen, Jitka ULiege; Blandiaux, Séverine ULiege; Lejeune, Nicolas ULiege et al

in Frontiers in Neuroscience (2018)

Detection and interpretation of signs of "covert command following" in patients with disorders of consciousness (DOC) remains a challenge for clinicians. In this study, we used a tactile P3-based BCI in ... [more ▼]

Detection and interpretation of signs of "covert command following" in patients with disorders of consciousness (DOC) remains a challenge for clinicians. In this study, we used a tactile P3-based BCI in 12 patients without behavioral command following, attempting to establish "covert command following." These results were then confronted to cerebral metabolism preservation as measured with glucose PET (FDG-PET). One patient showed "covert command following" (i.e., above-threshold BCI performance) during the active tactile paradigm. This patient also showed a higher cerebral glucose metabolism within the language network (presumably required for command following) when compared with the other patients without "covert command-following" but having a cerebral glucose metabolism indicative of minimally conscious state. Our results suggest that the P3-based BCI might probe "covert command following" in patients without behavioral response to command and therefore could be a valuable addition in the clinical assessment of patients with DOC. [less ▲]

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See detailUnderstanding Negative Results in tDCS Research: The Importance of Neural Targeting and Cortical Engagement
Thibaut, Aurore ULiege; Zafonte, Ross; Morse, Leslie R. et al

in Frontiers in Neuroscience (2017)

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See detailChanges in preoptic estradiol concentrations during male sexual behavior
de Bournonville, Marie-Pierre ULiege; de Bournonville, Catherine; Ball, Gregory et al

in Frontiers in Neuroscience (2017, May 30)

Besides its long-term control by steroids, male sexual behavior is also modulated by membrane-initiated effects of neuroestrogens in the short-term (within minutes). These effects are thought to depend on ... [more ▼]

Besides its long-term control by steroids, male sexual behavior is also modulated by membrane-initiated effects of neuroestrogens in the short-term (within minutes). These effects are thought to depend on short-term variations in the local production of estrogens, through rapid fluctuations of the enzymatic activity of brain aromatase, the enzyme that synthesizes estradiol (E2) from testosterone. Studies in male Japanese quail have shown that a sexual interaction with a female leads to a decrease in the activity of brain aromatase within minutes. These effects occur mainly within the medial preoptic nucleus (POM), a sexually dimorphic structure of the preoptic area that plays a key role in the activation of male sexual behavior and contains the highest aromatase activity (AA) in the brain. However recent studies showed that AA does not always reflect local E2 concentration. For example, while an acute stress decreases AA in the POM, E2 concentration increases in the same conditions. Here we used in vivo microdialysis to quantify changes in E2 concentration in the male POM during sexual interactions with a female. A series of experiments conducted to validate the in vivo dialysis and RIA methods showed that (1) E2 concentration in the dialysate change linearly with the concentration of a bath containing known amounts of E2 in which the probe was placed, (2) an increase in preoptic E2 concentration is observed after retrodialysis of testosterone and (3) preoptic E2 levels also increase after a peripheral injection of E2. Together these results suggest that in vivo dialysis is a suitable method to assay E2 in the range of brain concentrations suspected to be present in physiological conditions. With this approach, we showed during two independent experiments that E2 concentrations increase in the POM during sexual interactions with a female. Birds that had their cannula placed outside the POM did not show any increase in E2 levels. The E2 increase in the POM could serve to maintain motivation during the entire sexual encounter. The decrease of AA observed ex vivo after copulation would then reflect a compensatory mechanism to restore baseline pre-copulatory conditions. [less ▲]

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See detailHow Can Music Influence the Autonomic Nervous System Response in Patients with Severe Disorder of Consciousness?
Riganello, Francesco ULiege; Cortese, Maria Daniela; Arcuri, Francesco et al

in Frontiers in Neuroscience (2015), 9(461),

Activations to pleasant and unpleasant musical stimuli were observed within an extensive neuronal network and different brain structures, as well as in the processing of the syntactic and semantic aspects ... [more ▼]

Activations to pleasant and unpleasant musical stimuli were observed within an extensive neuronal network and different brain structures, as well as in the processing of the syntactic and semantic aspects of the music. Previous studies evidenced a correlation between autonomic activity and emotion evoked by music listening in patients with Disorders of Consciousness (DoC). In this study, we analyzed retrospectively the autonomic response to musical stimuli by mean of normalized units of Low Frequency (nuLF) and Sample Entropy (SampEn) of Heart Rate Variability (HRV) parameters, and their possible correlation to the different complexity of four musical samples (i.e., Mussorgsky, Tchaikovsky, Grieg, and Boccherini) in Healthy subjects and Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients. The complexity of musical sample was based on Formal Complexity and General Dynamics parameters defined by Imberty's semiology studies. The results showed a significant difference between the two groups for SampEn during the listening of Mussorgsky's music and for nuLF during the listening of Boccherini and Mussorgsky's music. Moreover, the VS/UWS group showed a reduction of nuLF as well as SampEn comparing music of increasing Formal Complexity and General Dynamics. These results put in evidence how the internal structure of the music can change the autonomic response in patients with DoC. Further investigations are required to better comprehend how musical stimulation can modify the autonomic response in DoC patients, in order to administer the stimuli in a more effective way. [less ▲]

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See detailLocal modulation of steroid action: rapid control of enzymatic activity.
Charlier, Thierry D.; Cornil, Charlotte ULiege; Patte-Mensah, Christine et al

in Frontiers in Neuroscience (2015), 9

Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects ... [more ▼]

Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17beta-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues. [less ▲]

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See detailMechanisms and Functional Significance of Stroke-Induced Neurogenesis
Marlier, Quentin ULiege; Verteneuil, Sébastien ULiege; Vandenbosch, Renaud ULiege et al

in Frontiers in Neuroscience (2015)

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See detailHeart rate variability: a tool to explore the sleeping brain?
Chouchou, Florian; Desseilles, Martin ULiege

in Frontiers in Neuroscience (2014), 8

Sleep is divided into two main sleep stages: (1) non-rapid eye movement sleep (non-REMS), characterized among others by reduced global brain activity; and (2) rapid eye movement sleep (REMS ... [more ▼]

Sleep is divided into two main sleep stages: (1) non-rapid eye movement sleep (non-REMS), characterized among others by reduced global brain activity; and (2) rapid eye movement sleep (REMS), characterized by global brain activity similar to that of wakefulness. Results of heart rate variability (HRV) analysis, which is widely used to explore autonomic modulation, have revealed higher parasympathetic tone during normal non-REMS and a shift toward sympathetic predominance during normal REMS. Moreover, HRV analysis combined with brain imaging has identified close connectivity between autonomic cardiac modulation and activity in brain areas such as the amygdala and insular cortex during REMS, but no connectivity between brain and cardiac activity during non-REMS. There is also some evidence for an association between HRV and dream intensity and emotionality. Following some technical considerations, this review addresses how brain activity during sleep contributes to changes in autonomic cardiac activity, organized into three parts: (1) the knowledge on autonomic cardiac control, (2) differences in brain and autonomic activity between non-REMS and REMS, and (3) the potential of HRV analysis to explore the sleeping brain, and the implications for psychiatric disorders. [less ▲]

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See detailChanges in cerebral metabolism in patients with a minimally conscious state responding to zolpidem.
Chatelle, Camille ULiege; Thibaut, Aurore ULiege; Gosseries, Olivia ULiege et al

in Frontiers in Neuroscience (2014), 8

BACKGROUND: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of ... [more ▼]

BACKGROUND: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). METHODS: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). RESULTS: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. CONCLUSION: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS. [less ▲]

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See detailProgramming of neuroendocrine self in the thymus and its defect in neuroendocrine autoimmunity
Geenen, Vincent ULiege; Bodart, Gwennaëlle ULiege; Henry, Séverine et al

in Frontiers in Neuroscience (2013), 7

During centuries after its first description by Galen, the thymus has been considered only as a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the ... [more ▼]

During centuries after its first description by Galen, the thymus has been considered only as a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the development of T (thymo-dependent) lymphocytes. A unique thymus appeared for the first time in cartilaginous fishes some 500 millions years ago, in the same time or shortly after the emergence of the adaptive (acquired) immune system. The thymus may be compared to a small brain or a computer highly specialized in the orchestration of central immunological self-tolerance. This latter was a necessity for the survival of species given the potent evolutionary pressure impacted by the high risk of autotoxicity inherent to the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. The new paradigm of neuroendocrine self-peptides has been proposed together with the definition of neuroendocrine self. Neuroendocrine self-peptides are not secreted by thymic epithelial cells (TECs) according to the classic model of neuroendocrine signaling, but processed for a presentation by, or in association with, the thymic major histocompatibility complex (MHC) proteins. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. The presentation of self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells emerging during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). In the same time, self-antigen presentation in the thymus also generates regulatory T (Treg) cells that are able to inhibit in the periphery self-reactive T cells having escaped negative selection in the thymus. Several arguments show that the origin of autoimmunity directed against neuroendocrine glands primarily results from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or acquired during an enteroviral infection, for example. This novel knowledge of normal and pathologic functions of the thymus already constitutes a solid basis for the development of a novel type of tolerogenic/negative self-vaccination against type 1 diabetes (T1D). [less ▲]

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See detailMean Expression of the X-Chromosome is Associated with Neuronal Density.
Swingland, James T.; Durrenberger, Pascal F.; Reynolds, Richard et al

in Frontiers in Neuroscience (2012), 6

Background: Neurodegenerative diseases are characterized by key features such as loss of neurons, astrocytosis, and microglial activation/proliferation. These changes cause differences in the density of ... [more ▼]

Background: Neurodegenerative diseases are characterized by key features such as loss of neurons, astrocytosis, and microglial activation/proliferation. These changes cause differences in the density of cell types between control and disease subjects, confounding results from gene expression studies. Chromosome X (ChrX) is known to be specifically important in the brain. We hypothesized the existence of a chromosomal signature of gene expression associated with the X-chromosome for neurological conditions not normally associated with that chromosome. The hypothesis was investigated using publicly available microarray datasets from studies on Parkinson's disease, Alzheimer's disease, and Huntington's disease. Data were analyzed using Chromowave, an analytical tool for detecting spatially extended expression changes along chromosomes. To examine associations with neuronal density and astrocytosis, the expression of cell specific reporter genes was extracted. The association between these genes and the expression patterns extracted by Chromowave was then analyzed. Further analyses of the X:Autosome ratios for laser dissected neurons, microglia cultures and whole tissue were performed to detect cell specific differences. Results: We observed an extended pattern of low expression of ChrX consistent in all the neurodegenerative disease brain datasets. There was a strong correlation between mean ChrX expression and the pattern extracted from the autosomal genes representing neurons, but not with mean autosomal expression. No chromosomal patterns associated with the neuron specific genes were found on other chromosomes. The chromosomal expression pattern was not present in datasets from blood cells. The X:Autosome expression ratio was also higher in neuronal cells than in tissues with a mix of cell types. Conclusions: The results suggest that neurological disorders show as a reduction in mean expression of many genes along ChrX. The most likely explanation for this finding relates to the documented general up-regulation of ChrX in brain tissue which, this work suggests, occurs primarily in neurons. If validated, this cell specific ChrX expression warrants further research as understanding the biological reasons and mechanisms for this expression, may help to elucidate a connection with the development of neurodegenerative disorders. [less ▲]

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See detailGenetic analysis of cortical thickness and fractional anisotropy of water diffusion in the brain.
Kochunov, Peter; Glahn, David C.; Nichols, Thomas E. et al

in Frontiers in Neuroscience (2011), 5

OBJECTIVES: The thickness of the brain's cortical gray matter (GM) and the fractional anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory with age. The two ... [more ▼]

OBJECTIVES: The thickness of the brain's cortical gray matter (GM) and the fractional anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory with age. The two measures are positively correlated and may be modulated by common biological mechanisms. We employed four types of genetic analyses to localize individual genes acting pleiotropically upon these phenotypes. METHODS: Whole-brain and regional GM thickness and FA values were measured from high-resolution anatomical and diffusion tensor MR images collected from 712, Mexican American participants (438 females, age = 47.9 +/- 13.2 years) recruited from 73 (9.7 +/- 9.3 individuals/family) large families. The significance of the correlation between two traits was estimated using a bivariate genetic correlation analysis. Localization of chromosomal regions that jointly influenced both traits was performed using whole-genome quantitative trait loci (QTL) analysis. Gene localization was performed using SNP genotyping on Illumina 1M chip and correlation with leukocyte-based gene-expression analyses. The gene-expressions were measured using the Illumina BeadChip. These data were available for 371 subjects. RESULTS: Significant genetic correlation was observed among GM thickness and FA values. Significant logarithm of odds (LOD >/= 3.0) QTLs were localized within chromosome 15q22-23. More detailed localization reported no significant association (p < 5.10(-5)) for 1565 SNPs located within the QTLs. Post hoc analysis indicated that 40% of the potentially significant (p </= 10(-3)) SNPs were localized to the related orphan receptor alpha (RORA) and NARG2 genes. A potentially significant association was observed for the rs2456930 polymorphism reported as a significant GWAS finding in Alzheimer's disease neuroimaging initiative subjects. The expression levels for RORA and ADAM10 genes were significantly (p < 0.05) correlated with both FA and GM thickness. NARG2 expressions were significantly correlated with GM thickness (p < 0.05) but failed to show a significant correlation (p = 0.09) with FA. DISCUSSION: This study identified a novel, significant QTL at 15q22-23. SNP correlation with gene-expression analyses indicated that RORA, NARG2, and ADAM10 jointly influence GM thickness and WM-FA values. [less ▲]

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See detailSleep vs Coma
Noirhomme, Quentin ULiege; Laureys, Steven ULiege; Boly, Mélanie ULiege

in Frontiers in Neuroscience (2009), 3(3), 406-407

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