Long term retention of retigabine in a cohort of people with drug resistant epilepsy

PurposeTo assess the utility of retigabine (RTG) for epilepsy in clinical practice at a single UK tertiary centre.MethodsWe identified all individuals who were offered RTG from April 2011 to May 2013. We collected demographics, seizure types, previous and current antiepileptic drugs (AEDs), starting and maximum attained daily dose of RTG, clinical benefits, side effects, and reason to discontinue RTG from in- and outpatient encounters until February 28, 2014.Results145 people who had failed a median of 11 AEDs took at least one dose of RTG. One year retention was 32% and decreased following the safety alert by the US Federal Drug Administration (FDA) in April 2013. None became seizure free. 34 people (24%) reported a benefit that was ongoing at last assessment in five (3%). The most relevant benefit was the significant reduction or cessation of drop attacks or seizure-related falls in four women, this persisted at last assessment in two. The presence of simple partial seizures was associated with longer retention, as was a higher attained dose of RTG. Adverse effects were seen in 74% and largely CNS-related or nonspecific and affected the genitourinary system in 13%.ConclusionRetention of RTG was less favourable compared to data from open label extension studies of the regulatory trials. In comparison with historical data on similar retention audits retention of RTG at one year appears to be less than lamotrigine, topiramate, levetiracetam, pregabalin, zonisamide, and lacosamide, and slightly higher than gabapentin.     

Epigenetics of stress adaptations in the brain

Recent findings in epigenetics shed new light on the regulation of gene expression in the central nervous system (CNS) during stress. The most frequently studied epigenetic mechanisms are DNA methylation, histone modifications and microRNA activity. These mechanisms stably determine cell phenotype but can also be responsible for dynamic molecular adaptations of the CNS to stressors. The limbic–hypothalamic–pituitary–adrenal axis (LHPA) is the primary circuit that initiates, regulates and terminates a stress response. The same brain areas that control stress also react to stress dynamically and with long-term consequences. One of the biological processes evoking potent adaptive changes in the CNS such as changes in behavior, gene activity or synaptic plasticity in the hippocampus is psychogenic stress. This review summarizes the current data regarding the epigenetic basis of molecular adaptations in the brain including genome-wide epigenetic changes of DNA methylation and particular genes involved in epigenetic responses that participate in the brain response to chronic psychogenic stressors. It is concluded that specific epigenetic mechanisms in the CNS are involved in the stress response.     

Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function

Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain’s glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease.     

Examining the relationship between motor assessments and handwriting consistency in children with and without probable Developmental Coordination Disorder

Children with Developmental Coordination Disorder (DCD) often experience difficulties in handwriting. The current study examined the relationships between three motor assessments and the spatial and temporal consistency of handwriting. Twelve children with probable DCD and 29 children from 7 to 12 years who were typically developing wrote the lowercase letters “e” and “l” in cursive and printed forms repetitively on a digitizing tablet. Three behavioral assessments, including the Beery–Buktenica Developmental Test of Visual-Motor Integration (VMI), the Minnesota Handwriting Assessment (MHA) and the Movement Assessment Battery for Children (MABC), were administered. Children with probable DCD had low scores on the VMI, MABC and MHA and showed high temporal, not spatial, variability in the letter-writing task. Their MABC scores related to temporal consistency in all handwriting conditions, and the Legibility scores in their MHA correlated with temporal consistency in cursive “e” and printed “l”. It appears that children with probable DCD have prominent difficulties on the temporal aspect of handwriting. While the MHA is a good product-oriented assessment for measuring handwriting deficits, the MABC shows promise as a good assessment for capturing the temporal process of handwriting in children with DCD.     

A systematic review of mirror neuron system function in developmental coordination disorder: Imitation,motor imagery,and neuroimaging evidence

PURPOSEThe aim of this systematic review was to investigate the evidence of abnormal functioning of the mirror neuron system (MNS) in children and adults with developmental coordination disorder (DCD), through examination of imitation, motor imagery, and neuroimaging literature.METHODSThe following databases were comprehensively searched for relevant articles: CINAHL Plus, Embase, MEDLINE, PsycINFO, Pubmed, and Web of Science. Full-text articles of all potentially relevant citations were obtained and assessed for eligibility by two authors. Outcome measures of interest at a motor behaviour level were any measures of imitation or motor imagery proficiency and, at a neurological level, were any measures of neural activity in MNS brain regions. Due to differences in outcome measures between studies and the variables reported, a narrative review was undertaken to synthesise findings from the studies.RESULTSOverall, 31 articles met the inclusion criteria. Children and adults with DCD display deficits imitating meaningful and novel gestures and demonstrate different response patterns to controls when undertaking complex motor imagery tasks. Children with DCD present reduced activation and connectivity of frontal, parietal, and temporal MNS regions.CONCLUSIONSPreliminary evidence indicates some deficit in the functioning of the MNS at a motor behaviour and neurological level. As no published neuroimaging studies have been designed specifically to explore MNS function, these results must be interpreted with caution. Further research to explore the MNS hypothesis in greater detail, particularly from a neuroimaging perspective, has the potential to provide information on the underlying mechanisms of DCD, inform future research into the aetiology of this disorder, and inform intervention approaches.     

Diet,behavior and immunity across the lifespan

It is increasingly appreciated that perinatal events can set an organism on a life-long trajectory for either health or disease, resilience or risk. One early life variable that has proven critical for optimal development is the nutritional environment in which the organism develops. Extensive research has documented the effects of both undernutrition and overnutrition, with strong links evident for an increased risk for obesity and metabolic disorders, as well as adverse mental health outcomes. Recent work has highlighted a critical role of the immune system, in linking diet with long term health and behavioral outcomes. The present review will summarize the recent literature regarding the interactions of diet, immunity, and behavior.     

Smartphone-based tactile cueing improves motor performance in Parkinson's disease

IntroductionVisual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water).MethodsTen PD patients (71 ± 9 years) and 10 healthy controls (69 ± 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application.ResultsPD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R² = 0.56) than healthy controls (R² = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)).ConclusionThis study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid.     

Molecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases

The structure and dynamics of dendritic spines reflect the strength of synapses, which are severely affected in different brain diseases. Therefore, understanding the ultra-structure, molecular signaling mechanism(s) regulating dendritic spine dynamics is crucial. Although, since last century, dynamics of spine have been explored by several investigators in different neurological diseases, but despite countless efforts, a comprehensive understanding of the fundamental etiology and molecular signaling pathways involved in spine pathology is lacking. The purpose of this review is to provide a contextual framework of our current understanding of the molecular mechanisms of dendritic spine signaling, as well as their potential impact on different neurodegenerative and psychiatric diseases, as a format for highlighting some commonalities in function, as well as providing a format for new insights and perspectives into this critical area of research. Additionally, the potential strategies to restore spine structure–function in different diseases are also pointed out. Overall, these informations should help researchers to design new drugs to restore the structure–function of dendritic spine, a “hot site” of synaptic plasticity.     

Effects of methylmercury on spinal cord afferents and efferents—A review

Methylmercury (MeHg) is an environmental neurotoxicant of public health concern. It readily accumulates in exposed humans, primarily in neuronal tissue. Exposure to MeHg, either acutely or chronically, causes severe neuronal dysfunction in the central nervous system and spinal neurons; dysfunction of susceptible neuronal populations results in neurodegeneration, at least in part through Ca²⁺-mediated pathways. Biochemical and morphologic changes in peripheral neurons precede those in central brain regions, despite the fact that MeHg readily crosses the blood-brain barrier. Consequently, it is suggested that unique characteristics of spinal cord afferents and efferents could heighten their susceptibility to MeHg toxicity. Transient receptor potential (TRP) ion channels are a class of Ca²⁺-permeable cation channels that are highly expressed in spinal afferents, among other sensory and visceral organs. These channels can be activated in numerous ways, including directly via chemical irritants or indirectly via Ca²⁺ release from intracellular storage organelles. Early studies demonstrated that MeHg interacts with heterologous TRP channels, though definitive mechanisms of MeHg toxicity on sensory neurons may involve more complex interaction with, and among, differentially-expressed TRP populations. In spinal efferents, glutamate receptors of the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and possibly kainic acid (KA) classes are thought to play a major role in MeHg-induced neurotoxicity. Specifically, the Ca²⁺-permeable AMPA receptors, which are abundant in motor neurons, have been identified as being involved in MeHg-induced neurotoxicity. In this review, we will describe the mechanisms that could contribute to MeHg-induced spinal cord afferent and efferent neuronal degeneration, including the possible mediators, such as uniquely expressed Ca²⁺-permeable ion channels.     

Responses to voluntary hyperventilation in children with separation anxiety disorder: Implications for the link to panic disorder

BackgroundBiological theories on respiratory regulation have linked separation anxiety disorder (SAD) to panic disorder (PD). We tested if SAD children show similarly increased anxious and psychophysiological responding to voluntary hyperventilation and compromised recovery thereafter as has been observed in PD patients.MethodsParticipants were 49 children (5–14 years old) with SAD, 21 clinical controls with other anxiety disorders, and 39 healthy controls. We assessed cardiac sympathetic and parasympathetic, respiratory (including pCO₂), electrodermal, electromyographic, and self-report variables during baseline, paced hyperventilation, and recovery.ResultsSAD children did not react with increased anxiety or panic symptoms and did not show signs of slowed recovery. However, during hyperventilation they exhibited elevated reactivity in respiratory variability, heart rate, and musculus corrugator supercilii activity indicating difficulty with respiratory regulation.ConclusionsReactions to hyperventilation are much less pronounced in children with SAD than in PD patients. SAD children showed voluntary breathing regulation deficits.     

Developmental programing of thirst and sodium appetite

Thirst and sodium appetite are the sensations responsible for the motivated behaviors of water and salt intake, respectively, and both are essential responses for the maintenance of hydromineral homeostasis in animals. These sensations and their related behaviors develop very early in the postnatal period in animals. Many studies have demonstrated several pre- and postnatal stimuli that are responsible for the developmental programing of thirst and sodium appetite and, consequently, the pattern of water and salt intake in adulthood in need-free or need-induced conditions. The literature systematically reports the involvement of dietary changes, hydromineral and cardiovascular challenges, renin–angiotensin system and steroid hormone disturbances, and lifestyle in these developmental factors. Therefore, this review will address how pre- and postnatal challenges can program lifelong thirst and sodium appetite in animals and humans, as well as which neuroendocrine substrates are involved. In addition, the possible epigenetic molecular mechanisms responsible for the developmental programing of drinking behavior, the clinical implications of hydromineral disturbances during pre- and postnatal periods, and the developmental origins of adult hydromineral behavior will be discussed.     

Tissue oxidative stress induced by patulin and protective effect of crocin

Patulin (PAT) is a secondary toxic metabolite produced principally by Penicillium expansum. This mycotoxin is known to be teratogenic, mutagenic, immunotoxic and neurotoxic, and it has been shown to cause damage in several organs in laboratory animals. This study focuses on the prevention of experimental murine PAT-induced nephrotoxicity and hepatotoxicity. We investigate the ability of a natural product, crocin (CRO), to counteract the toxic effects of PAT. Pre-treatment of mice with CRO prevented PAT-induced oxidative damage in both liver and kidney. CRO reduced lipid peroxidation, protein oxidation and restored redox status by regulating the endogenous antioxidant enzymatic system. These data corroborate and extend findings in PAT-induced nephrotoxicity and hepatotoxicity, and further suggest that preventive effect of CRO towards other forms of PAT toxicity, including neurotoxicity, may be warranted.     

Early life exposure to sevoflurane impairs adulthood spatial memory in the rat

Sevoflurane is a general anesthetic commonly used in the pediatric setting because it is sweet-smelling, nonflammable, fast acting and has a very short recovery time. Although recent clinical data suggest that early anesthesia exposure is associated with subsequent learning and memory problems, it is difficult to determine the exact scope of developmental neurotoxicity associated with exposure to specific anesthetics such as sevoflurane. This is largely due to inconsistencies in the literature. Thus, in the present studies we evaluated the effect of early life exposure to sevoflurane (1%, 2%, 3% or 4%) on adulthood memory impairment in Sprague-Dawley rats. Animals were exposed to different regimens of sevoflurane anesthesia on postnatal days (PNDs) 3, 7, or 14 or at 7 weeks (P7W) of age and spatial memory performance was assessed in adulthood using the Morris Water Maze (MWM). Rats exposed to sevoflurane exhibited significant memory impairment which was concentration and exposure duration dependent. Disruption of MWM performance was more severe in animals exposed on both PNDs 3 and 7 than in animals exposed on both PNDs 3 and 14. The younger the animal's age at the time of exposure, the more significant the effect on later MWM performance. Compared to the neonates, animals exposed at P7W were relatively insensitive to sevoflurane: memory was impaired in this group only after repeated exposures to low doses or single exposures to high doses. Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit.     

The clinimetric properties of aerobic and anaerobic fitness measures in adults with cerebral palsy: A systematic review of the literature

ObjectiveTo analyze the clinimetric properties of maximal aerobic and anaerobic fitness measurement protocols in adults with cerebral palsy (CP).Data SourcesA systematic search through March 2015 of databases PubMed, Embase, SPORTDiscus and PsycINFO was performed with medical subject heading terms for ‘cerebral palsy’ combined with search terms adults or adolescents and multiple text words for fitness and exercise tests that yielded 864 articles.Study SelectionAbstracts were screened by two reviewers to identify use of maximal fitness measurements in adolescents (14–18 yrs) or adults (>18 yrs) with CP of all abilities. Ninety-four articles were reviewed. No studies of adolescent (14–18 yrs) qualified. Eight articles reported clinimetric properties for adults with CP who walk or propel a wheelchair independently. Five articles reported on aerobic capacity, one reported on anaerobic capacity and two reported on both.Data ExtractionMethodological quality of the studies was rated using portions of the COSMIN (COnsensus-based Standards for the selection of health status Measurement INstruments) checklist. Quality of the measurement protocols was evaluated based on statistical strength of the clinimetrics. Synthesis of the overall evidence was based on the Cochrane review group guidelines which combine methodological quality and statistical strength.Data SynthesisEight articles reported on 4 aerobic and 1 anaerobic protocols. Overall synthesis revealed that for ambulatory adults with CP there is (i) moderate evidence for good reliability and good construct validity of maximal aerobic and anaerobic cycle tests, (ii) moderate evidence for good criterion validity of sub-maximal aerobic cycle tests, and (iii) strong evidence for poor criterion validity of the six-minute walk test as a maximal aerobic test. And for adults who propel a wheelchair there is limited evidence of good reliability for maximal aerobic wheelchair ergometer tests.ConclusionsLimited quality research exists on the clinimetric properties of aerobic and anaerobic capacity measures for adults with CP who have independent mobility. Quality aerobic and anaerobic measures for adults with more severe mobility impairments are absent.