The blood-brain barrier (BBB) and the blood-spinal cord barrier (BSCB) are responsible for controlling the microenvironment within neural tissues in humans. These barriers are fundamental to all neurological processes as they provide the extreme nutritional demands of neural tissue, remove wastes, and maintain immune privileged status. Being a semipermeable membrane, both the BBB and BSCB allow the diffusion of certain molecules, whilst restricting others. In amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, these barriers become hyperpermeable, allowing a wider variety of molecules to pass through leading to more severe and more rapidly progressing disease. The intention of this review is to discuss evidence that BBB hyperpermeability is potentially a disease driving feature in ALS and other neurodegenerative diseases. The various biochemical, physiological, and genomic factors that can influence BBB permeability in ALS and other neurodegenerative diseases are also discussed, in addition to novel therapeutic strategies centred upon the BBB.
Purpose. Seizure is a well-recognized complication of both remote and acute ischemic strokes. Predictors of seizure recurrence and epilepsy in patients with ischemic stroke who develop acute symptomatic seizures (ASyS) on continuous electroencephalography (cEEG) have not been well studied. Methods. We present a five-year retrospective study of acute and remote ischemic stroke patients who developed ASyS on cEEG. We then identified risk factors for the development of seizure recurrence. Results. Sixty-five patients with ischemic stroke and ASyS were identified and reviewed. All ASyS were noted to be nonconvulsive seizures. Clinical recurrence of seizures was identified in 19 of these patients (29.2%) at follow-up. Rate of seizure recurrence was higher in remote ischemic stroke patients (84.2%), compared to acute ischemic stroke patients (15.8%, p=0.0116, OR 0.17, 95% CI 0.049–0.65). Sharp waves/spikes on follow-up EEG significantly correlated with seizure recurrence (p=0.006, OR 0, 95% CI 0–0.3926). Patients discharged on ≥3 antiepileptic drugs (AEDs) were at a higher risk of having seizure recurrence (p=0.0015, OR 0.05, 95% CI 0.0089–0.37). Conclusion. We identified risk factors of seizure recurrence in patients with ASyS as remote ischemic stroke, requiring multiple AEDs, and the presence of sharp waves on follow-up EEG. This study highlights the usefulness of cEEG in evaluating patients with acute or remote strokes.
Among the many factors responsible for the cognitive decline in Alzheimer's disease, beta amyloid protein and plaque formation is crucial. This amyloid pathology is associated with activation of glial cells and oxidative stress but whether oxidative stress activates beta amyloid protein in the neurons is not clear. Further the expression of microglia is also known to vary during pathogenesis of beta amyloid plaques. The aim of the present study is to evaluate the antioxidant effect of NAC on amyloid pathology and cognition and also to investigate the link between amyloid pathology and glial cells activation. Intracerebroventricular colchicine in rats known mimics human AD in many aspects including memory loss, oxidative stress, and hyper phosphorylation of tau protein. The animal groups consisted of age matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in active avoidance test; beta amyloid protein, beta amyloid plaques, astrocytes, and microglia cells were quantified using immunohistochemistry in hippocampal and prefrontal cortices. Colchicine has resulted in significant cognitive loss, increased intraneuronal beta amyloid protein expression, increased reactive astrocytes, and activated microglia in all the regions of the hippocampus and prefrontal cortices. The antioxidant NAC has reversed the cognitive deficits and inhibited microglia activation but failed to inhibit BAP expression and astrocytosis. Intraneuronal BAP accumulation is deleterious and known to adversely affect cognition, but in this study in spite of intraneuronal BAP accumulation, the cognition is restored. It can be postulated that NAC might have reversed the effect of intraneuronal beta amyloid protein by acting on some downstream compensatory mechanisms which needs to be explored.
There is an excellent correlation between the age when alcohol consumption begins and the likelihood of lifelong problems with alcohol abuse. Alcohol use often begins in adolescence, a time marked by brain development and maturation of numerous brain systems. Rats are an important model, wherein the emergence of alcohol withdrawal symptoms serves as a gauge of dependency following chronic alcohol consumption. Previous work has shown that adolescent Long-Evans rats consume high levels of alcohol and develop a severe alcohol withdrawal syndrome when fed alcohol as part of a liquid diet. Acutely, alcohol inhibits two important excitatory receptors for glutamate (NMDA and AMPA) and may further decrease glutamate activity through modulatory adenosine receptors. The present study focuses on potential adaptive changes in expression of these receptors that may create a receptor imbalance during chronic alcohol consumption and lead to severe overexcitation of the adolescent brain during alcohol withdrawal. Levels of brain expression of NMDA, AMPA, and adenosine A1 and A2a receptors were determined by Western blotting after adolescent rats consumed an alcohol-containing liquid diet for 4, 11, or 18 days. Severity of alcohol withdrawal was also assessed at these time points. Levels increased for both AMPA and NMDA receptors, significant and approaching maximal by day 11. In contrast, A1 receptor density showed a slow decline reaching significance at 18 days. There were no changes in expression of adenosine A2a receptor. The most severe withdrawal symptoms appear to coincide with the later downregulation of adenosine A1 receptors coming on top of maximal upregulation of excitatory AMPA and NMDA glutamate receptors. Thus, loss of adenosine “brakes” on glutamate excitation may punctuate receptor imbalance in alcohol-consuming adolescents by allowing the upregulation of the excitatory receptors to have full impact during early alcohol withdrawal.
Mammalians have recognition-behavioral stress-coping neuronal module system followed by some humoral glycolipids. A sulfated Galbeta1-4GlcNAc-lipid promotes the serotonergic module regulating the emotional behaviors for not-wasting the physical strength; GalNAcalpha1-3GalNAc-lipid promotes the adrenergic module inducing the behaviors escaping from the uneasy situation, and sulfated Fucalpha1-2Gal-lipid protects the cholinergic module keeping the stressor-memory from the ischemia-stress. Mouse given bathing recognizes the stressors to be coped with in the treatment. We previously observed mouse given CO2-microbubble-bathing increased the behavior escaping from the bathing situation. Mouse given CO2-microbubble-bathing would recognize the other stressors to be coped with in the treatment. We examined stress-coping glycolipids produced by mice given controlled bathing treatments, and got the following results. A sulfated Galbeta1-4GlcNAc-lipid production was increased by the acidic bathing condition and the dissolved CO2, GalNAcalpha1-3GalNAc-lipid production was increased by the dissolved CO2, and sulfated Fucalpha1-2Gal-lipid production was increased by the acidic bathing condition. We understood the mice treated with CO2-microbubble-bathing would recognize the acidic bathing condition and the dissolved CO2, but not the microbubble, as the other stressors to be coped.
Introduction. It is known that cognitive impairment is linked to aging and neurobiological, psychological, and social factors. Recently, however, mastication and the number of teeth has also attracted attention, with a previous case control study reporting a correlation between the loss of teeth and Alzheimer’s disease. Objective. To investigate possible relationships between cognitive function and various demographic variables, stress, medical history, and number of natural teeth in a specified female population. Materials & Methods. A sample of the Saudi female population, 40–65 years of age, who visited the King Khalid University College of Dentistry (Abha, Saudi Arabia), was studied. Education, occupation, perceived stress, and medical history, along with the number of remaining teeth, were assessed. The Mini-Mental State Examination (MMSE) was used to assess cognitive performance and the results were statistically analyzed. Results. Subjects were divided into those with mild, moderate, and severe impairment based on MMSE score; the association between age, education, occupation, medical history, and cognitive function demonstrated statistically significant results. Fifty percent of subjects with 0–16 teeth exhibited severe cognitive impairment. Of the cognitive abilities, attention, recall, and language skills were linked to the number of remaining teeth. When subjects were categorized into only high and low cognitive impairment based on MMSE score, regression analysis did not reveal a significant correlation between any of the studied variables and cognitive impairment. Conclusion. Results of the present study add to the recent data and head towards the theory of likely connection between the number of teeth and hippocampus-dependent cognitive functioning. Results of regression analysis revealed an absence of conclusive relation in the latter part of study. Longitudinal analyses including comprehensive clinical dental data with brain-imaging will shed further light on probable causal relationship(s).
After traumatic brain injury (TBI), multiple ongoing processes contribute to worsening and spreading of the primary injury to create a secondary injury. One major process involves disrupted fluid regulation to create vascular and cytotoxic edema in the affected area. Although understanding of factors that influence edema is incomplete, the astrocyte water channel Aquaporin 4 (AQP4) has been identified as an important mediator and therefore attractive drug target for edema prevention. The FDA-approved drug acetazolamide has been administered safely to patients for years in the United States. To test whether acetazolamide altered AQP4 function after TBI, we utilized in vitro and in vivo models of TBI. Our results suggest that AQP4 localization is altered after TBI, similar to previously published reports. Treatment with acetazolamide prevented AQP4 reorganization, both in human astrocyte in vitro and in mice in vivo. Moreover, acetazolamide eliminated cytotoxic edema in our in vivo mouse TBI model. Our results suggest a possible clinical role for acetazolamide in the treatment of TBI.
Background. Head injuries contribute to almost 50% of all injuries. Head injuries are still one of the major causes of loss of life and loss of function among young adults. Nowadays, head injury has become a major community problem. Recently, head injury has become one of the biggest issues of almost more than 57 million people in the whole world living with the neurological problem raised by TBI, in which 10 million people require hospital base care. Objectives. To determine the epidemiological aspects of patients with head injury (HI) in Aseer Central Hospital (ACH). Materials and Methods. This is a retrospective cross-sectional study. Data were gathered from patients’ files and the registrar’s database of ACH. The study duration was January 2015–December 2017. All patients with head injury admitted to ACH during the study duration were included in the study. SPSS software was used for analysis. Descriptive statistics were obtained (mean SD frequencies, percentages). Statistical tests, t test, and chi-squared test were applied to measure the significant difference among the variables. P-value less than 0.05 was considered as a significant difference. Results. There were 353 patients with head injury, and the mean ± SD of age was 27.01 ± 13.9. Motor vehicle accidents (MVA) accounted for (89.3%) of head injury. A total of 87.3% of the patients were male while 12.7% were female. Conclusion. In this study, we observed that MVA is the leading cause of brain/head injuries in the KSA, despite the implementations of new speed rules. However, with new regulations of forbidding cell phone use while driving and forcing the seat belt regulations, a major impact on these numbers is expected in the future. Thus, a future study is recommended to assess these expectations.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease due to an expansion of a trinucleotide repeats in IT15 gene encoding for the protein huntingtin. Motor dysfunction, cognitive decline, and psychiatric disorder are typical clinical signs of HD. In HD, mutated huntingtin causes a major loss of brain derived neurotrophic factor (BDNF), causing striatal atrophy. Moreover, a key involvement of BDNF was observed in the synaptic plasticity that controls the acquisition and/or consolidation of certain forms of memory. We studied changes in hippocampal BDNF and in CREB in the R6/2 mouse model of HD. Moreover, we investigated if the beneficial effects of systemically administered recombinant BDNF observed in the striatum and cortex had an effect also on the hippocampus. Osmotic minipumps that chronically released recombinant BDNF or saline solution from 4 weeks of age until euthanasia were implanted into R6/2 and wild type mice. Our data show that BDNF is severely decreased in the hippocampus of R6/2 mice, while BDNF treatment restored its physiological levels. Moreover, the chronic administration of recombinant BDNF promoted the increment of phosphorylated CREB protein. Our study demonstrates the involvement of hippocampus in the pathology of R6/2 model of HD and correlates the beneficial effects of BDNF administration with increased hippocampal levels of BDNF and pCREB.
Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia. In light of our recent finding on the misguidance of hippocampal mossy fiber projection in the rodent model of schizophrenia, we discuss whether ectopic mossy fiber projection is a commonality in order to evoke TLE as well as symptoms related to schizophrenia.
BACKGROUND:Parkinson's disease is responsible for decrease of activities of daily living and mobility limitations. Association of strength with physical capacities and disease time can improve training methodologies and predict changes in physical fitness for this population, since the control center of movements and strength is the same.OBJECTIVE:Therefore, the aim of this study is to analyze if there are correlation between strength with functional tests (the sit-to-stand, the six-minute walk, and the timed-up-go) and disease time in people with Parkinson's disease.RESULTS:All functional tests correlations are significant, p < 0.05. The strength is positively correlated with the sit-to-stand and the six-minute walk. The strength is negatively correlated with the timed-up-go.CONCLUSION:There are a correlation between strength with functional tests in people with PD, and changes in strength assessment can be used as predictor to changes in aerobic capacity.
Research in last few years on neurophysiology focused on several areas across the cortex during cognitive processing to determine the dominant direction of electrical activity. However, information about the frequency and direction of episodic synchronization related to higher cognitive functions remain unclear. Our aim was to determine whether neural oscillations carry perceptual information as spatial patterns across the cortex, which could be found in the scalp EEG of human subjects while being engaged in visual sensory stimulation. Magnitude squared coherence of neural activity during task states that "finger movement with Eyes Open (EO) or Eyes Wandering (EW)" among all electrode combinations has the smallest standard deviation and variations. Additionally, the highest coherence among the electrode pairs occurred between alpha (8-12 Hz) and beta (12-16 Hz) ranges. Our results indicate that alpha rhythms seem to be regulated during activities when an individual is focused on a given task. Beta activity, which has also been implicated in cognitive processing to neural oscillations, is seen in our work as a manner to integrate external stimuli to higher cognitive activation. We have found spatial network organization which served to classify the EEG epochs in time with respect to the stimuli class. Our findings suggest that cortical neural signaling utilizes alpha-beta phase coupling during cognitive processing states, where beta activity has been implicated in shifting cognitive states. Significance. Our approach has found frontoparietal attentional mechanisms in shifting brain states which could provide new insights into understanding the global cerebral dynamics of intentional activity and reflect how the brain allocates resources during tasking and cognitive processing states.
Objective Studies have demonstrated the utility of closed-loop neuromodulation in treating focal onset seizures. There is an utmost need of neurostimulation therapy for generalized tonic-clonic seizures. The study goals are to map the thalamocortical network dynamics during the generalized convulsive seizures and identify targets for reliable seizure detection. Methods Local field potentials were recorded from bilateral cortex, hippocampi, and centromedian thalami in Sprague-Dawley rats. Pentylenetetrazol was used to induce multiple convulsive seizures. The performances of two automated seizure detection methods (line length and P-operators) as a function of different cortical and subcortical structures were estimated. Multiple linear correlations-Granger's Causality was used to determine the effective connectivity. Results Of the 29 generalized tonic-clonic seizures analyzed, line length detected 100% of seizures in all the channels while the P-operator detected only 35% of seizures. The detection latencies were shortest in the thalamus in comparison to the cortex. There was a decrease in amplitude correlation within the thalamocortical network during the seizure, and flow of information was decreased from thalamus to hippocampal-parietal nodes. Significance The preclinical study confirms thalamus as a superior target for automated detection of generalized seizures and modulation of synchrony to increase coupling may be a strategy to abate seizures.
Glioblastoma (GB) is the most angiogenic tumor. Nevertheless, antiangiogenic therapy has not shown significant clinical efficacy. The aim of this study was to assess blood vessel characteristics on survival of GB patients. Surgically excised GB tissues were histologically examined for overall proportion of glomeruloid microvascular proliferation (MP) and the total number of blood vessels. Also, immunohistochemical vascular staining intensities of CD133 and ICAM-1 were determined. Vessel parameters were correlated with patients' overall survival. The survival time depended on the number of blood vessels (p = 0.03) but not on the proportion of MP. Median survival times for patients with low (<median) and high (≥median) number of blood vessels were 9.0 months (95% CI: 7.5–10.5) and 12.0 months (95% CI: 9.3–14.7). Also, median survival times for patients with low (<median) and high (≥median) vascular expression level of CD133 were 9.0 months (95% CI: 8.0–10.1) and 12.0 months (95% CI: 10.3–13.7). In contrast, the staining intensity of vascular ICAM-1 did not affect survival. In multivariate analysis, the number of blood vessels emerged as an independent predictor for longer overall survival (HR: 2.4, 95% CI: 1.2–5.0, p = 0.02). For success in antiangiogenic therapy, better understanding about tumor vasculature biology is needed.
Objective. Research continues to highlight variability in hospital policy and documentation of brain death. The aim of our study was to characterize how strictly new guidelines of American Academy of Neurology (AAN) for death by neurological criteria were practiced in our hospital prior to appointment of neurointensivists. Method. This is a retrospective study of adults diagnosed as brain dead from 2011 to 2015. Descriptive statistics compared five categories: preclinical testing, neurological examination, apnea tests, ancillary test, and documentation of time of death. Strict adherence to AAN guidelines for brain death determination was determined. Result. 76 patients were included in this study. Preclinical prerequisites were fulfilled in 53.9% and complete neurological examinations were documented in 76.3%. Apnea test was completed in 39.5%. Ancillary test was completed in 29.8%. Accurate documentation of time of death occurred in 59.2%. Overall, strict adherence to current AAN guidelines for death by neurological criteria was correctly documented in 38.2%. Conclusion. Our study shows wide variability in diagnosing brain death. These findings led us to update our death by neurological criteria policy and increase awareness of brain death determination with the goal of improving our documentation following current AAN guidelines.
The delivery of five stimuli to each cranial site is recommended during transcranial magnetic stimulation (TMS) mapping. However, this time-consuming practice restricts the use of TMS mapping beyond the research environment. While reducing the number of stimuli administered to each cranial site may improve efficiency and decrease physiological demand, doing so may also compromise the procedure's validity. Therefore, the aim of this study was to determine the minimum number of stimuli per cranial site required to obtain valid outcomes during TMS mapping. Map volume and centre of gravity (CoG) recordings obtained using five stimuli per cranial site were retrospectively compared to those obtained using one, two, three, and four stimuli per cranial site. For CoG longitude, one stimulus per cranial site produced valid recordings (ICC = 0.91, 95% CI 0.82 to 0.95). However, this outcome is rarely explored in isolation. As two stimuli per cranial site were required to obtain valid CoG latitude (ICC = 0.99, 95% CI 0.99 to 0.99) and map volume (ICC = 0.99, 95% CI 0.99 to 0.99) recordings, it is recommended that a minimum of two stimuli be delivered to each cranial site during TMS mapping in order to obtain valid outcomes.
In a previous study, we found that chronic mild stress (CMS) paradigm did not induce anhedonia in young-adult male rats but it reduced their body weight gain. These contrasting results encouraged us to explore other indicators of animal's vulnerability to stress such as anxious-like behaviors, since stress is an etiologic factor also for anxiety. Thus, in this study, we evaluated the vulnerability of these animals to CMS using behavioral tests of depression or anxiety and measuring serum corticosterone. Male Wistar rats were exposed to four weeks of CMS; the animals' body weight and sucrose preference (indicator of anhedonia) were assessed after three weeks, and, after the fourth week, some animals were evaluated in a behavioral battery (elevated plus maze, defensive burying behavior, and forced swimming tests); meanwhile, others were used to measure serum corticosterone. We found that CMS (1) did not affect sucrose preference, immobility behavior in the forced swimming test, or serum corticosterone; (2) decreased body weight gain; and (3) increased the rat's entries into closed arms of the plus maze and the cumulative burying behavior. These data indicate that young male rats' vulnerability to CMS is reflected as poor body weight gain and anxious-like instead of depressive-like behaviors.
Background . Many studies have explored the cognitive variation between left- and right-handed individuals; however, the differences remain poorly understood. Aim of the Work . To assess the association between brain lateralization indicated by handedness and cognitive abilities. Material and Methods . A total of 217 students aged between 7 and 10 years of both genders were identified for the study. Males and females were equally distributed. All left-handed students were chosen. An equal group with right-handed students was randomly selected. Handedness was assessed using traditional writing hand approach as well as the WatHand Cabient Test and the Grooved Pegboard Test. Cognition was measured using Cambridge University’s CANTAB eclipse cognitive battery. Pearson Correlation Coefficient Test “ r ” was calculated to measure the strength of association between quantitative data. Results . Right-handed children had superior visuospatial abilities ( p = 0.011, r = 0.253), visual memory ( p = 0.034, r = 0.205), and better scores in reaction time tests which incorporated elements of visual memory ( p = 0.004, r = −0.271). Left-handed children proved to have better simple reaction times ( p = 0.036, r = 0.201). Conclusion . Right-handed children had superior visuospatial abilities and left-handed children have better simple reaction times.
Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerve conduction studies to identify chronic neuropathies. We postulated that this value was significantly elevated in chronic demyelinating neuropathy. Methods. We retrospectively reviewed electrophysiology laboratory records to compare the stimulus intensity values recorded during median and ulnar motor nerve conduction studies. The groups studied included normal controls (n = 42) and the following diagnostic categories: chronic inflammatory demyelinating neuropathy (CIDP) (n = 20), acquired inflammatory demyelinating neuropathy (AIDP) (n = 13), Charcot Marie Tooth (CMT) type 1 or 4C (n = 15), carpal tunnel syndrome (CTS) (n = 11), and amyotrophic lateral sclerosis (ALS) (n = 18). Results. Supramaximal intensities were significantly higher in patients with CMT (median nerve: 43.4 mA) and CIDP (median nerve: 38.9 mA), whereas values similar to normal controls (median nerve: 25.3 mA) were obtained in ALS, CTS, and AIDP. Conclusions. Supramaximal stimulus intensity may be used as an additional criterion to identify the pathophysiology of neuropathy. We postulate that endoneurial hypertrophic changes may increase electrical impedance and thus the threshold of excitation at nodes of Ranvier.
