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1.
medRxiv ; 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38946983

RESUMO

Importance: Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. Distributed white matter (WM) impairments in individuals with heroin use disorder (iHUD) have been associated with increased drug craving, a reliable predictor of treatment outcomes. However, little is known about the extent of whole-brain structural connectivity changes with inpatient treatment and abstinence in iHUD. Objective: To assess WM microstructure and associations with drug craving changes with inpatient treatment in iHUD (effects of time/re-scan compared to controls; CTL). Design: Longitudinal cohort study (12/2020-09/2022) where iHUD and CTL underwent baseline magnetic resonance imaging (MRI#1) and follow-up (MRI#2) scans, (mean interval of 13.9 weeks in all participants combined). Setting: The iHUD and CTL were recruited from urban inpatient treatment facilities and surrounding communities, respectively. Participants: Thirty-four iHUD (42.1yo; 7 women), 25 age-/sex-matched CTL (40.5yo; 9 women). Intervention: Between scans, inpatient iHUD continued their medically-assisted treatment and related clinical interventions. CTL participants were scanned at similar time intervals. Main Outcomes and Measures: Changes in white matter diffusion metrics [fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivities (RD)] in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Results: Main findings showed HUD-specific WM microstructure changes encompassing mostly frontal major callosal, projection, and association tracts, characterized by increased FA (.949<1-p<.986) and decreased MD (.949<1-p<.997) and RD (.949<1-p<.999). The increased FA (r=-0.72, p<.00001) and decreased MD (r=0.69, p<.00001) and RD (r=0.67, p<.0001) in the genu and body of the corpus callosum and the left anterior corona radiata in iHUD were correlated with a reduction in baseline craving (.949<1-p<.999). No other WM correlations with outcome variables reached significance. Conclusions and Relevance: Our findings suggest whole-brain normalization of structural connectivity with inpatient medically-assisted treatment in iHUD encompassing recovery in frontal WM pathways implicated in emotional regulation and top-down executive control. The association with decreases in baseline craving further supports the relevance of these WM markers to a major symptom in drug addiction, with implications for monitoring clinical outcomes.

2.
medRxiv ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38746340

RESUMO

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially as a multi-target biomarker. We used a validated proximity extension assay for relative quantification of 92 cytokines and inflammatory proteins in serum of iHUD on medication assisted therapy (MAT; n=21), versus HC (n=24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison correction (p=0.05). This included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, and PC1 scores were iHUD>HC (p<0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC=91.7% (p<0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, which included demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, and provides a multi-target "cytokine biomarker score" for potential diagnostic purposes, and examination of disease severity.

3.
medRxiv ; 2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37961156

RESUMO

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other reinforcers share a continuous narrative context, fMRI responses in individuals with heroin use disorder (iHUD) will preferentially synchronize during drug scenes. Results revealed such drug-biased synchronization in the orbitofrontal cortex (OFC), ventromedial and ventrolateral prefrontal cortex, and insula. After 15 weeks of inpatient treatment, there was a significant reduction in this drug-biased shared response in the OFC, which correlated with a concomitant reduction in dynamically-measured craving, suggesting synchronized OFC responses to a drug-themed movie as a neural marker of craving and recovery in iHUD.

4.
medRxiv ; 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-37034753

RESUMO

Importance: Heroin addiction and related mortality impose a devastating toll on society, with little known about the neurobiology of this disease or its treatment. Poor inhibitory control is a common manifestation of prefrontal cortex (PFC) impairments in addiction, and its potential recovery following treatment is largely unknown in heroin (or any drug) addiction. Objective: To study inhibitory control brain activity in iHUD and HC, before and after 15 weeks of inpatient treatment in the former. Design: A longitudinal cohort study (11/2020-03/2022) where iHUD and HC underwent baseline and follow-up fMRI scans. Average follow-up duration: 15 weeks. Setting: The iHUD and HC were recruited from treatment facilities and surrounding neighborhoods, respectively. Participants: Twenty-six iHUD [40.6±10.1 years; 7 (29.2%) women] and 24 age-/sex-matched HC [41.1±9.9 years; 9 (37.5%) women]. Intervention: Following the baseline scan, inpatient iHUD continued to participate in a medically-assisted program for an average of 15 weeks (abstinence increased from an initial 183±236 days by 65±82 days). The HC were scanned at similar time intervals. Main Outcomes and Measures: Behavioral performance as measured by the stop-signal response time (SSRT), target detection sensitivity (d', proportion of hits in go vs. false-alarms in stop trials), and brain activity (blood-oxygen level dependent signal differences) during successful vs. failed stops in the stop signal task. Results: As we previously reported, at time 1 and as compared to HC, iHUD exhibited similar SSRT but impaired d' [t(38.7)=2.37, p=.023], and lower anterior and dorsolateral PFC (aPFC, dlPFC) activity (p<.001). Importantly, at time 2, there were significant gains in aPFC and dlPFC activity in the iHUD (group*session interaction, p=.002); the former significantly correlated with increases in d' specifically in iHUD (p=.012). Conclusions and Relevance: Compared to HC, the aPFC and dlPFC impairments in the iHUD at time 1 were normalized at time 2, which was associated with individual differences in improvements in target detection sensitivity. For the first time in any drug addiction, these results indicate a treatment-mediated inhibitory control brain activity recovery. These neurobehavioral results highlight the aPFC and dlPFC as targets for intervention with a potential to enhance self-control recovery in heroin addiction.

5.
Brain ; 146(4): 1662-1671, 2023 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-36200376

RESUMO

Different drugs of abuse impact the morphology of fronto-striatal dopaminergic targets in both common and unique ways. While dorsal striatal volume tracks with addiction severity across drug classes, opiates impact ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAcc) neuroplasticity in preclinical models, and psychostimulants alter inhibitory control, rooted in cortical regions such as the inferior frontal gyrus (IFG). We hypothesized parallel grey matter volume changes associated with human heroin or cocaine use disorder: lower grey matter volume of vmPFC/NAcc in heroin use disorder and IFG in cocaine use disorder, and putamen grey matter volume to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified grey matter volume (P < 0.05-corrected) in age/sex/IQ-matched individuals with heroin use disorder (n = 32, seven females), cocaine use disorder (n = 32, six females) and healthy controls (n = 32, six females) and compared fronto-striatal volume between groups using voxel-wise general linear models and non-parametric permutation-based tests. Overall, individuals with heroin use disorder had smaller vmPFC and NAcc/putamen volumes than healthy controls. Bilateral lower IFG grey matter volume patterns were specifically evident in cocaine versus heroin use disorders. Correlations between addiction severity measures and putamen grey matter volume did not reach nominal significance level in this sample. These results indicate alterations in dopamine-innervated regions (in the vmPFC and NAcc) in heroin addiction. For the first time we demonstrate lower IFG grey matter volume specifically in cocaine compared with heroin use disorder, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioural measures. Overall, results suggest substance-specific volumetric changes in human psychostimulant or opiate addiction, with implications for fine-tuning biomarker and treatment identification by primary drug of abuse.


Assuntos
Cocaína , Heroína , Feminino , Humanos , Estudos Transversais , Corpo Estriado/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Imageamento por Ressonância Magnética
6.
Mol Psychiatry ; 28(2): 780-791, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36369361

RESUMO

Neuroimaging studies in substance use disorder have shown widespread impairments in white matter (WM) microstructure suggesting demyelination and axonal damage. However, substantially fewer studies explored the generalized vs. the acute and/or specific drug effects on WM. Our study assessed whole-brain WM integrity in three subgroups of individuals addicted to drugs, encompassing those with cocaine (CUD) or heroin (HUD) use disorder, compared to healthy controls (CTL). Diffusion MRI was acquired in 58 CTL, 28 current cocaine users/CUD+, 32 abstinent cocaine users/CUD-, and 30 individuals with HUD (urine was positive for cocaine in CUD+ and opiates used for treatment in HUD). Tract-Based Spatial Statistics allowed voxelwise analyses of diffusion metrics [fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)]. Permutation statistics (p-corrected < 0.05) were used for between-group t-tests. Compared to CTL, all individuals with addiction showed widespread decreases in FA, and increases in MD, RD, and AD (19-57% of WM skeleton, p < 0.05). The HUD group showed the most impairments, followed by the CUD+, with only minor FA reductions in CUD- (<0.2% of WM skeleton, p = 0.05). Longer periods of regular use were associated with decreased FA and AD, and higher subjective craving was associated with increased MD, RD, and AD, across all individuals with drug addiction (p < 0.05). These findings demonstrate extensive WM impairments in individuals with drug addiction characterized by decreased anisotropy and increased diffusivity, thought to reflect demyelination and lower axonal packing. Extensive abnormalities in both groups with positive urine status (CUD+ and HUD), and correlations with craving, suggest greater WM impairments with more recent use. Results in CUD-, and correlations with regular use, further imply cumulative and/or persistent WM damage.


Assuntos
Cocaína , Doenças Desmielinizantes , Substância Branca , Humanos , Heroína/farmacologia , Cocaína/farmacologia , Fissura , Imagem de Tensor de Difusão/métodos , Encéfalo , Anisotropia
7.
Neuron ; 110(22): 3820-3832.e4, 2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36206758

RESUMO

The habenula (Hb) is central to adaptive reward- and aversion-driven behaviors, comprising a hub for higher-order processing networks involving the prefrontal cortex (PFC). Despite an established role in preclinical models of cocaine addiction, the translational significance of the Hb and its connectivity with the PFC in humans is unclear. Using diffusion tractography, we detailed PFC structural connectivity with the Hb and two control regions, quantifying tract-specific microstructural features in healthy and cocaine-addicted individuals. White matter was uniquely impaired in PFC-Hb projections in both short-term abstainers and current cocaine users. Abnormalities in this tract further generalized to an independent sample of heroin-addicted individuals and were associated, in an exploratory analysis, with earlier onset of drug use across the addiction subgroups, potentially serving as a predisposing marker amenable for early intervention. Importantly, these findings contextualize a plausible PFC-Hb circuit in the human brain, supporting preclinical evidence for its impairment in cocaine addiction.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Habenula , Dependência de Heroína , Humanos , Transtornos Relacionados ao Uso de Cocaína/diagnóstico por imagem , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/diagnóstico por imagem
8.
Elife ; 102021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448453

RESUMO

Sleep slow waves are studied for their role in brain plasticity, homeostatic regulation, and their changes during aging. Here, we address the possibility that two types of slow waves co-exist in humans. Thirty young and 29 older adults underwent a night of polysomnographic recordings. Using the transition frequency, slow waves with a slow transition (slow switchers) and those with a fast transition (fast switchers) were discovered. Slow switchers had a high electroencephalography (EEG) connectivity along their depolarization transition while fast switchers had a lower connectivity dynamics and dissipated faster during the night. Aging was associated with lower temporal dissipation of sleep pressure in slow and fast switchers and lower EEG connectivity at the microscale of the oscillations, suggesting a decreased flexibility in the connectivity network of older individuals. Our findings show that two different types of slow waves with possible distinct underlying functions coexist in the slow wave spectrum.


Assuntos
Ondas Encefálicas , Encéfalo/fisiologia , Sono de Ondas Lentas , Adulto , Fatores Etários , Idoso , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal , Polissonografia , Fatores de Tempo , Adulto Jovem
9.
Eur J Neurosci ; 53(9): 3212-3230, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33662163

RESUMO

Impaired inhibitory control accompanied by enhanced salience attributed to drug-related cues, both associated with function of the dorsolateral prefrontal cortex (dlPFC), are hallmarks of drug addiction, contributing to worse symptomatology including craving. dlPFC modulation with transcranial direct current stimulation (tDCS) previously showed craving reduction in inpatients with cocaine use disorder (CUD). Our study aimed at assessing feasibility of a longer tDCS protocol in CUD (15 versus the common five/10 sessions) and replicability of previous results. In a randomized double-blind sham-controlled protocol, 17 inpatients with CUD were assigned to either a real-tDCS (right anodal/left cathodal) or a sham-tDCS condition for 15 sessions. Following the previous report, primary outcome measures were self-reported craving, anxiety, depression, and quality of life. Secondary measures included sleepiness, readiness to change drug use, and affect. We also assessed cognitive function including impulsivity. An 88% retention rate demonstrated feasibility. Partially supporting the previous results, there was a trend for self-reported craving to decrease in the real-tDCS group more than the sham-group, an effect that would reach significance with 15 subjects per group. Quality of life and impulsivity improved over time in treatment in both groups. Daytime sleepiness and readiness to change drug use showed significant Group × Time interactions whereby improvements were noted only in the real-tDCS group. One-month follow-up suggested transient effects of tDCS on sleepiness and craving. These preliminary results suggest the need for including more subjects to show a unique effect of real-tDCS on craving and examine the duration of this effect. After replication in larger sample sizes, increased vigilance and motivation to change drug use in the real-tDCS group may suggest fortification of dlPFC-supported executive functions.


Assuntos
Cocaína , Estimulação Transcraniana por Corrente Contínua , Fissura , Método Duplo-Cego , Humanos , Pacientes Internados , Córtex Pré-Frontal , Qualidade de Vida , Sonolência
10.
Sleep ; 43(3)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31691825

RESUMO

STUDY OBJECTIVES: In young adults, sleep is associated with important changes in cerebral connectivity during the first cycle of non-rapid eye movement (NREM) sleep. Our study aimed to evaluate how electroencephalography (EEG) connectivity during sleep differs between young and older individuals, and across the sleep cycles. METHODS: We used imaginary coherence to estimate EEG connectivity during NREM and rapid eye movement (REM) sleep in 30 young (14 women; 20-30 years) and 29 older (18 women; 50-70 years) individuals. We also explored the association between coherence and cognitive measures. RESULTS: Older individuals showed lower EEG connectivity in stage N2 but higher connectivity in REM and stage N3 compared to the younger cohort. Age-related differences in N3 were driven by the first sleep cycle. EEG connectivity was lower in REM than N3, especially in younger individuals. Exploratory analyses, controlling for the effects of age, indicated that higher EEG connectivity in delta during N2 was associated with higher processing speed, whereas, during REM sleep, lower EEG connectivity in delta and sigma was associated with higher verbal memory performance and a higher global averaged intelligence quotient score. CONCLUSION: Our results indicated that age modifies sleep EEG connectivity but the direction and the magnitude of these effects differ between sleep stages and cycles. Results in N3 and REM point to a reduced ability of the older brains to disconnect as compared to the younger ones. Our results also support the notion that cerebral functional connectivity during sleep may be associated with cognitive functions.


Assuntos
Eletroencefalografia , Sono , Encéfalo , Feminino , Humanos , Fases do Sono , Sono REM , Adulto Jovem
11.
Sleep ; 41(9)2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860401

RESUMO

Study Objectives: Sleep is a reliable indicator of cognitive health in older individuals. Sleep spindles (SS) are non-rapid eye movement (NREM) sleep oscillations implicated in sleep-dependent learning. Their generation imply a complex activation of the thalamo-cortico-thalamic loop. Since SS require neuronal synchrony, the integrity of the white matter (WM) underlying these connections is of major importance. During aging, both SS and WM undergo important changes. The goal of this study was to investigate whether WM integrity could predict the age-related reductions in SS characteristics. Methods: Thirty young and 31 older participants underwent a night of polysomnographic recording and a 3T magnetic resonance imaging acquisition including a diffusion sequence. SS were detected in NREM sleep and EEG spectral analysis was performed for the sigma frequency band. WM diffusion metrics were computed in a voxelwise design of analysis. Results: Compared to young participants, older individuals showed lower SS density, amplitude, and sigma power. Diffusion metrics were correlated with SS amplitude and sigma power in tracts connecting the thalamus to the frontal cortex for the young but not for the older group, suggesting a moderation effect. Moderation analyses showed that diffusion metrics explained between 14% and 39% of SS amplitude and sigma power variance in the young participants only. Conclusion: Our results indicate that WM underlying the thalamo-cortico-thalamic loop predicts SS characteristics in young individuals, but does not explain age-related changes in SS. Other neurophysiological factors could better explain the effect of age on SS characteristics.


Assuntos
Envelhecimento/fisiologia , Fases do Sono/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiologia , Adulto , Fatores Etários , Idoso , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , Eletroencefalografia/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Tálamo/diagnóstico por imagem , Tálamo/fisiologia , Adulto Jovem
12.
Sleep ; 39(3): 613-24, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26612390

RESUMO

STUDY OBJECTIVES: Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements. METHODS: EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day. RESULTS: EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice. CONCLUSIONS: Our results suggest that EphA4 is involved in circadian sleep regulation.


Assuntos
Ritmo Circadiano/fisiologia , Receptor EphA4/metabolismo , Privação do Sono/fisiopatologia , Sono/fisiologia , Animais , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Escuridão , Eletrocorticografia , Fenômenos Eletrofisiológicos , Homeostase , Luz , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal , Regiões Promotoras Genéticas/genética , Ratos , Ratos Sprague-Dawley , Receptor EphA4/biossíntese , Receptor EphA4/deficiência , Receptor EphA4/genética , Sono/genética , Privação do Sono/genética , Sono REM/genética , Sono REM/fisiologia , Núcleo Supraquiasmático/metabolismo , Tálamo/metabolismo , Fatores de Tempo , Vigília/genética , Vigília/fisiologia
14.
Brain Behav Immun ; 47: 118-30, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25576803

RESUMO

Traumatic brain injury (TBI), including mild TBI (mTBI), is importantly associated with vigilance and sleep complaints. Because sleep is required for learning, plasticity and recovery, we here evaluated the bidirectional relationship between mTBI and sleep with two specific objectives: (1) Test that mTBI rapidly impairs sleep-wake architecture and the dynamics of the electrophysiological marker of sleep homeostasis (i.e., non-rapid eye movement sleep delta (1-4Hz) activity); (2) evaluate the impact of sleep loss following mTBI on the expression of plasticity markers that have been linked to sleep homeostasis and on genome-wide gene expression. A closed-head injury model was used to perform a 48h electrocorticographic (ECoG) recording in mice submitted to mTBI or Sham surgery. mTBI was found to immediately decrease the capacity to sustain long bouts of wakefulness as well as the amplitude of the time course of ECoG delta activity during wakefulness. Significant changes in ECoG spectral activity during wakefulness, non-rapid eye movement and rapid eye movement sleep were observed mainly on the second recorded day. A second experiment was performed to measure gene expression in the cerebral cortex and hippocampus after a mTBI followed either by two consecutive days of 6h sleep deprivation (SD) or of undisturbed behavior (quantitative PCR and next-generation sequencing). mTBI modified the expression of genes involved in immunity, inflammation and glial function (e.g., chemokines, glial markers) and SD changed that of genes linked to circadian rhythms, synaptic activity/neuronal plasticity, neuroprotection and cell death and survival. SD appeared to affect gene expression in the cerebral cortex more importantly after mTBI than Sham surgery including that of the astrocytic marker Gfap, which was proposed as a marker of clinical outcome after TBI. Interestingly, SD impacted the hippocampal expression of the plasticity elements Arc and EfnA3 only after mTBI. Overall, our findings reveal alterations in spectral signature across all vigilance states in the first days after mTBI, and show that sleep loss post-mTBI reprograms the transcriptome in a brain area-specific manner and in a way that could be deleterious to brain recovery.


Assuntos
Lesões Encefálicas/fisiopatologia , Encéfalo/fisiopatologia , Ritmo Circadiano/fisiologia , Sono/fisiologia , Transcriptoma , Animais , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Eletrocorticografia , Masculino , Camundongos , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia
15.
Proc Natl Acad Sci U S A ; 110(24): 9974-9, 2013 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-23716671

RESUMO

Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Neurônios/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Western Blotting , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Eletroencefalografia , Eletromiografia , Expressão Gênica , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Neurônios/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sono/genética , Privação do Sono/genética , Privação do Sono/fisiopatologia , Especificidade da Espécie , Fatores de Tempo , Vigília/genética
16.
Parkinsonism Relat Disord ; 19(2): 212-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23107557

RESUMO

BACKGROUND: Rapid eye movement sleep behavior disorder is found in 33-46% of patients with Parkinson's disease and was shown to be associated with cognitive deficits. Our goal was to improve our understanding of the role of this sleep disorder in cerebral dysfunction occurring in Parkinson's disease using a visual cognitive task and event-related potentials. METHODS: Sixteen patients with Parkinson's disease and rapid eye movement sleep behavior disorder, 15 patients with Parkinson's disease without rapid eye movement sleep behavior disorder and 16 healthy control subjects were included. The amplitude and latency of event-related potentials were compared between groups. RESULTS: No group differences were found for reaction times or accuracy. A Group effect was found for P2 wave amplitude; patients with rapid eye movement sleep behavior disorder had increased P2 in comparison with the control group (p < 0.05). Patients with Parkinson's disease alone were not different from the two other groups for this component. Prolonged novelty P3 latencies on Cz were associated with longer disease durations among patients with Parkinson's disease (p < 0.01). CONCLUSION: Co-morbid Parkinson's disease and rapid eye movement sleep behavior disorder were associated with abnormal visual P2 component of event-related potentials. Although patients with Parkinson's disease alone were not significantly different from patients with combined Parkinson's disease and rapid eye movement sleep behavior disorder, their P2 amplitudes were not sufficiently abnormal to differ from that of control subjects. This study confirms that rapid eye movement sleep behavior disorder accentuates cerebral dysfunctions in Parkinson's disease.


Assuntos
Potenciais Evocados/fisiologia , Lobo Occipital/fisiopatologia , Doença de Parkinson/fisiopatologia , Transtorno do Comportamento do Sono REM/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Polissonografia , Transtorno do Comportamento do Sono REM/complicações
18.
Am J Emerg Med ; 26(4): 413-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18410808

RESUMO

OBJECTIVES: To assess the prevalence of neurologic and neuropsychological symptoms in the short-term and 1 year after an electric shock and to explore whether any of these were associated with risk factors. METHODS: Patients presenting to one of 21 EDs between October 2000 and November 2004 were eligible to be enrolled in a prospective observational study after an electric shock if they had risk factors for late arrhythmias. Telephone follow-up was done to evaluate the appearance of symptoms. RESULTS: A total of 30 (26%) of 114 patients complained of neurologic or neuropsychological symptoms at a median of 52 days post-electric shock. At 1 year, 24 (28%) of 86 patients complained of neurologic or neuropsychological symptoms. None of the risk factors evaluated were associated with the symptoms. CONCLUSION: The prevalence of the symptoms we observed should alarm all emergency physicians that the effect of electricity can cause late neurologic and neuropsychological manifestations.


Assuntos
Traumatismos por Eletricidade/complicações , Transtornos Mentais/epidemiologia , Doenças do Sistema Nervoso/epidemiologia , Adolescente , Adulto , Arritmias Cardíacas/etiologia , Criança , Humanos , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
19.
J Cutan Med Surg ; 12(1): 27-30, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18258154

RESUMO

BACKGROUND: Soy lecithin is widely used as an emulsifier, not only in topical skin care products but also in various drugs administered either topically, orally, or intravenously or by inhalation. Patients strongly allergic to soy and/or peanuts can develop an anaphylactic reaction when exposed to soy lecithin. METHOD: We report a 3-year-old asthmatic boy, allergic to peanuts, who was treated at the emergency department for an exacerbation of asthma following an upper respiratory tract infection. Within an hour after receiving the second of two inhalations of an ipratropium bromide (Atrovent) metered dose inhaler, he developed respiratory distress and generalized urticaria, an adverse event that regressed within 48 hours of withdrawal of the suspected drug. Soy lecithin, contained as an excipient in the metered dose inhaler, was strongly suspected of being responsible for this reaction. CONCLUSION: Drug products containing soy lecithin can cause severe allergic reactions in patients allergic to peanuts or soy. Physicians should be aware that adverse drug reactions can be due to both the active medical component and the excipient ingredients.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/química , Hipersensibilidade Imediata/etiologia , Hipersensibilidade Imediata/imunologia , Ipratrópio/química , Lecitinas/imunologia , Proteínas de Soja/imunologia , Arachis/imunologia , Asma/imunologia , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Pré-Escolar , Excipientes , Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/imunologia , Humanos , Ipratrópio/administração & dosagem , Ipratrópio/efeitos adversos , Lecitinas/administração & dosagem , Lecitinas/efeitos adversos , Masculino , Nebulizadores e Vaporizadores , Proteínas de Soja/administração & dosagem , Proteínas de Soja/efeitos adversos
20.
Emerg Med J ; 24(5): 348-52, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17452703

RESUMO

OBJECTIVE: To report our experience monitoring patients with previously identified theoretical risk factors of significant electrical injury. METHODS: Patients who presented to one of 21 emergency departments between October 2000 and November 2004 were eligible to be enrolled in a prospective observational cohort study if after an electric shock they had one of several risk factors (transthoracic current, tetany, loss of consciousness or voltage source > or =1000 V) and therefore needed cardiac monitoring. RESULTS: Of the 134 patients enrolled, most were monitored because of transthoracic current (n = 60), transthoracic current and tetany (n = 39), tetany (n = 10), or voltage > or =1000 V (n = 10). There were 15/134 (11%) patients with abnormal initial ECGs. No patient developed potentially lethal late arrhythmia during the 24 hours of cardiac monitoring. CONCLUSION: Although only patients deemed at risk of late arrhythmias were monitored, none developed potentially lethal late arrhythmias. Asymptomatic patients with transthoracic current and/or tetany and a normal initial ECG do not require cardiac monitoring after an electrical injury with voltage <1000 V and no loss of consciousness.


Assuntos
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Traumatismos por Eletricidade/epidemiologia , Monitorização Fisiológica/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Idoso , Dor no Peito/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Creatina Quinase/metabolismo , Traumatismos por Eletricidade/metabolismo , Eletrocardiografia/estatística & dados numéricos , Seguimentos , Humanos , Lactente , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Prevalência , Estudos Prospectivos , Quebeque/epidemiologia , Fatores de Risco
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