Time-dependent barriers and first-passage times--different types of neuronal models

To study the phenomenon of spike discharge in a single neuron, first-passage time density of the membrane potential to cross or reach the threshold value in different situations is analyzed. The neuron is taken as a leaky integrator and the inputs are due to Poisson events occurring independently. Closed solutions using the compensation method and imbedding techniques are arrived at. Using Keilson's limiting procedure, diffusion processes with boundaries are solved. To simulate the refractory period of the neuron, thresholds moving linearly or exponentially with time are considered. Very interesting Wald identities are obtained in the case of jump processes which go over to the corresponding identities for diffusion processes obtained by a limiting procedure.     

Quantitative MR analyses of the hippocampus: Unspecific metabolic changes in aging

Abstract The age-related structural changes of the human hippocampus are not entirely understood. The goal of the present investigation was to understand better the nature of age-related hippocampal changes by a comparative MR-analysis of four complementary aspects of hippocampal integrity: total volume, metabolite concentration, neuron to glial cell ratio and amount of extracellular diffusion space for water. To that end, we applied MR-based methods of manual and computerized (voxel-based morphometry) volumetry, diffusion-weighted imaging and ¹H MR spectroscopy to characterize specific age-related hippocampal effects in a group of 22 healthy old adults in comparison with a group of 13 healthy younger adults. Age-related reductions of the hippocampal N-acetyl aspartate to creatine/choline ratio together with only marginal age-related reductions in hippocampal volumes and increases in diffusion parameters suggest that the process of aging affects mainly the metabolic status of the hippocampus with little equivalent age-related changes in hippocampal cell density. The metabolic changes are unspecific as they are not restricted to the hippocampus but equally occur in measures obtained from extrahippocampal temporal lobe regions.     

Repeater F-waves in amyotrophic lateral sclerosis: Electrophysiologic indicators of upper or lower motor neuron involvement?

ObjectiveTo extract insight about the mechanism of repeater F-waves (Frep) by exploring their correlation with electrophysiologic markers of upper and lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS).MethodsThe correlations of Frep parameters with clinical scores and the results of neurophysiological index (NI), MScanfit MUNE, F/M amplitude ratio (F/M%), single and paired-pulse transcranial magnetic stimulation (TMS), and triple stimulation technique (TST) studies, recorded from abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles of 35 patients with ALS were investigated.ResultsFrep parameters were correlated with NI and MScanfit MUNE in ADM muscle and F/M% in both muscles. None of the Frep parameters were correlated with clinical scores or TST and TMS measures. While the CMAP amplitudes were similar in the two recording muscles, there was a more pronounced decrease of F-wave persistence in APB, probably heralding the subsequent split hand phenomenon.ConclusionOur findings suggest that the presence and density of Freps are primarily related to the degree of lower motor neuron loss and show no correlation with any of the relatively extensive set of parameters for upper motor neuron dysfunction.SignificanceFreps are primarily related to lower motor neuron loss in ALS.     

Considering the negatively formed identity: Relationships between negative identity and problematic psychosocial beliefs

IntroductionDeveloping a firm sense of identity is a critical developmental task in adolescence and emerging adulthood, but little or no empirical research exists regarding individuals who firmly form negative identities and psychosocial beliefs. This study examined the formation of negative identities in youth and its association with psychosocial beliefs in terms of variable-oriented psychosocial facets (i.e., dichotomous beliefs, cynicism, and social distrust) and person-oriented psychosocial profiles.MethodsA total of 2313 young Japanese people (70.9% were females) aged 18–25 years answered the self-report questionnaire.ResultsWe consequently found that individuals with negative identities possessed problematic psychosocial facets, such as high dichotomous beliefs and cynicism, as well as low social trust. Furthermore, individuals with negative identities had profile characterized by strong hostility toward others/societies.ConclusionsOverall, our study provided a comprehensive understanding of how youth with negative identities face difficulty in constructing relationships with society, which has been neglected in prior research.     

Macroglossia in primary lateral sclerosis: a case report

Abstract

Purpose/Aim: Macroglossia is a rare condition, especially in patients with motor neuron disease. In this case report, we describe a patient with macroglossia in the early stages of motor neuron disease.

Case report: A 62-year-old woman presented with macroglossia in the early stages of motor neuron disease. She was referred to the department of physical medicine and rehabilitation of a university hospital for rehabilitation with the diagnosis of motor neuron disease, most likely primary lateral sclerosis. Her speech was incomprehensible, and she also showed significant sialorrhea and had difficulty in chewing large solid food. Her tongue was enlarged on examination, and she could not close her mouth fully. No other possible causes of macroglossia were found. She showed nocturnal hypercapnia on overnight capnography examination coupled with desaturation, which was believed to result from the macroglossia. After commencing non-invasive ventilation with pressure control mode, follow-up overnight capnography revealed EtCO₂ values within the normal range.

Conclusions: To the best of our knowledge, this is the first report of macroglossia in PLS. Further study would be needed to ascertain the pathogenesis of this phenomenon.     

Ultrastructural evidence of neurofilament involvement in immune-mediated motor neuron injury

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder. A pathologic hallmark of ALS is accumulation of neurofilaments in proximal axons of affected motor neurones. As the neurofilaments involved in immune-mediated spinal cord ventral horn motor neuron degeneration and loss, we developed immune-mediated motor neuron injury animal model by inoculating Lewis rats with swine spinal cord homogenate and investigated the ultrastructural features of neurofilament accumulation using transmission electron microscopy. Our results showed that there was aberrant accumulation of neurofilaments in perikarya and processes of remaining motor neurons in recipient animals, which is similar to those observed in ALS patients. These findings suggest that immune-mediated motor neuron injury may share a common pathogenesis with ALS.     

Do you need a roadmap or can someone give you directions: When school-focused possible identities change so do academic trajectories

IntroductionDespite the assumed importance of school-focused possible identities for academic motivation and outcomes, interventions rarely assess the effect of intervention on possible identities. This may be due to difficulty coding open-ended text at scale but leaves open a number of questions: 1) how do school-focused possible identities change over the course of the school year, 2) whether these changes are associated with changes in school outcomes, and 3) whether a machine coding approach is viable.MethodsIn Study 1 (n = 247 Chicago 8th-graders) we assess fall-to-spring change in school-focused possible identities. We test whether change in school-focused possible identities predicts 8th-grade academic outcomes. We include robustness checks. Then we examine school context effects. In Study 2 (n = 1006 Chicago 8th-graders) we address the problem of coding at scale, using a separate data set to train a machine-learning algorithm.ResultsOn average, school-focused possible identities decline over the school year. But nearly a third of students have increasing school-focused possible identity scores. Increase is associated with improved grades. School context influences whether linked strategies matter. Our machine-learning algorithm accurately classifies school-focused possible identities in our original sample and this school-focused classification reliably predicts academic trajectories.ConclusionsChange in school-focused possible identities is normative over the course of the school year, interventions should take this into account. On average, students have fewer school-focused possible identities by spring. This decline is associated with declining academic trajectories. However, when school-focused possible identities increase, so do grades. Whether strategies matter is context dependent.     

Are habitual overgeneral recollection and prospection maladaptive?

Background and objectivesIndividuals with depression exhibit difficulty retrieving specific memories and imagining specific future events when instructed to do so relative to non-clinical comparison groups. Instead of specific events, depressed individuals frequently retrieve or imagine “overgeneral” memories that span a long period of time or that denote a category of similar events. Recently, Raes, Hermans, Williams, and Eelen (2007) developed a sentence completion procedure (SCEPT) to assess the tendency to recall overgeneral autobiographical memories. They found that specificity on this measure was associated with depression and rumination. We aimed to replicate these findings and to examine the tendency to imagine overgeneral future events.MethodsWe had 170 subjects complete past (SCEPT) and future-oriented (SCEFT) sentence completion tasks and measures of depression severity, PTSD severity, hopelessness, and repetitive negative thought.ResultsAlthough specificities of past and future events were correlated, neither SCEPT nor SCEFT specificity was negatively associated with depression severity, posttraumatic stress symptoms, repetitive negative thought (RNT), or hopelessness.LimitationsOur data are cross-sectional, preventing any determination of causality and limiting our assessment of whether specificity is associated with psychological distress following a stressful life event. In addition, we observed poor internal consistency for both the SCEPT and SCEFT.ConclusionsThese findings fail to support the hypothesis that overgeneral memory and prospection on these tasks are associated with psychological distress.     

Muscle ultrasonography: a diagnostic tool for amyotrophic lateral sclerosis

ObjectiveIn a prospective study we tested whether muscle ultrasonography can differentiate between amyotrophic lateral sclerosis (ALS) and mimics. Furthermore, we assessed the ability of ultrasonography to identify subclinical lower motor neuron involvement.MethodsIn 59 patients, suspected for adult onset motor neuron disease, ultrasound scans were made of 12 different muscle groups. Echo intensity was determined and each muscle was screened for fasciculations. Ultrasonography was considered diagnostic for ALS when echo intensity was 1.5 SD above normal in at least two muscles and fasciculations were present in at least four muscles.ResultsUltrasonography differentiated between ALS and mimics with 96% sensitivity and 84% specificity. In the 27 ALS patients, ultrasonography detected 15 regions with lower motor neuron involvement that were negative using either clinical examination or needle EMG.ConclusionsMuscle ultrasound can differentiate between amyotrophic lateral sclerosis and mimics with high sensitivity and specificity, and is a sensitive tool to screen for regional lower motor neuron involvement.SignificanceMuscle ultrasonography is a promising tool in the diagnostic work up of ALS.     

Age-related stigma and the golden section hypothesis

Objectives: The present study used the golden section hypothesis, which predicts that people organize information in a ratio of 61.8% positive to 38.2% negative, to examine age-related identities. It was predicted that people would rate identities of the aging population in accordance with a reverse golden section hypothesis. That is, people would assign negative ratings 61.8% of the time and positive ratings 38.2% of the time.

Method: A golden section survey was completed online by 148 participants. Along the top of the survey were 15 identities: child, elderly person, grandparent, middle-aged adult, nurse, musician, adolescent, senior citizen, business person, lawyer, secretary, mental patient, homeless person, retired person, and self. On the left side of the survey were 12 adjective pairs with well-established positive and negative poles: generous–stingy, pleasant–unpleasant, true–false, fair–unfair, active–passive, energetic–lethargic, sharp–dull, excitable–calm, strong–weak, bold–timid, hard–soft, and rugged–delicate.

Results: Elderly person and senior citizen were rated in a manner consistent with the reverse golden section hypothesis. In keeping with previous findings, the self was rated positively precisely 71% of the time. Combined ratings of the remaining identities were consistent with the traditional golden section hypothesis. A prior finding that mental patient and homeless person would produce a reverse golden section pattern was not replicated.

Conclusion: Certain elderly identities evoke a reverse golden section rating pattern. This suggests that such identities have stigma associated with them. Because American society has coupled aging to stigma, people have come to associate negative connotations with certain age-related terms.     

Food activities and identity maintenance in old age: a systematic review and meta-synthesis

Objectives: Services provided to older people should be developed based on active ageing policies. Nutrition is one aspect of active ageing, but little is known about how food activities contribute to psychological well-being in later life. This is a systematic review of qualitative and quantitative research that answers the question ‘What is known about the relationship between food activities and the maintenance of identities in old age?’.

Methods: We followed the preferred reporting items for systematic reviews and meta-analyses guidelines and used quality assessment parameters to complete a systematic review and narrative synthesis. Academic Search Premier, MEDLINE, CINAHL Plus, and PsycINFO databases were searched.

Results: We initially identified 8016 articles, of which 167 full-text articles were screened for inclusion. Twenty-two articles were included in the review. There was moderate evidence from nine qualitative and two quantitative studies, of variable quality, that food activities contribute to the maintenance of women's gendered identities, the ethnic identities of men and women, and community identities. There was moderate evidence from 10 qualitative studies, of variable quality, that a change in food choice and deteriorating health changed food activity participation. These changes threatened identities. Most studies included both younger adults and older adults.

Conclusion: In later life, there are many life experiences leading to change. Further research is needed to develop understanding of how identity and mental well-being are maintained, despite changes in everyday activities like cooking and eating. This may enable health care professionals to meet psychological needs alongside biological needs during nutritional interventions.     

Effects of direct current stimulation on synaptic plasticity in a single neuron

BackgroundTranscranial direct current stimulation (DCS) has lasting effects that may be explained by a boost in synaptic long-term potentiation (LTP). We hypothesized that this boost is the result of a modulation of somatic spiking in the postsynaptic neuron, as opposed to indirect network effects. To test this directly we record somatic spiking in a postsynaptic neuron during LTP induction with concurrent DCS.MethodsWe performed rodent in-vitro patch-clamp recordings at the soma of individual CA1 pyramidal neurons. LTP was induced with theta-burst stimulation (TBS) applied concurrently with DCS. To test the causal role of somatic polarization, we manipulated polarization via current injections. We also used a computational multi-compartment neuron model that captures the effect of electric fields on membrane polarization and activity-dependent synaptic plasticity.ResultsTBS-induced LTP was enhanced when paired with anodal DCS as well as depolarizing current injections. In both cases, somatic spiking during the TBS was increased, suggesting that evoked somatic activity is the primary factor affecting LTP modulation. However, the boost of LTP with DCS was less than expected given the increase in spiking activity alone. In some cells, we also observed DCS-induced spiking, suggesting DCS also modulates LTP via induced network activity. The computational model reproduces these results and suggests that they are driven by both direct changes in postsynaptic spiking and indirect changes due to network activity.ConclusionDCS enhances synaptic plasticity by increasing postsynaptic somatic spiking, but we also find that an increase in network activity may boost but also limit this enhancement.     

Imaging Flow Cytometry Analysis to Identify Differences of Survival Motor Neuron Protein Expression in Patients With Spinal Muscular Atrophy

BackgroundSpinal muscular atrophy is a neurodegenerative disorder caused by the deficient expression of survival motor neuron protein in motor neurons. A major goal of disease-modifying therapy is to increase survival motor neuron expression. Changes in survival motor neuron protein expression can be monitored via peripheral blood cells in patients; therefore we tested the sensitivity and utility of imaging flow cytometry for this purpose.MethodsAfter the immortalization of peripheral blood lymphocytes from a human healthy control subject and two patients with spinal muscular atrophy type 1 with two and three copies of SMN2 gene, respectively, we used imaging flow cytometry analysis to identify significant differences in survival motor neuron expression. A bright detail intensity analysis was used to investigate differences in the cellular localization of survival motor neuron protein.ResultsSurvival motor neuron expression was significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject. Moreover, survival motor neuron expression correlated with the clinical severity of spinal muscular atrophy according to SMN2 copy number. The cellular accumulation of survival motor neuron protein was also significantly decreased in cells derived from patients with spinal muscular atrophy relative to those derived from a healthy control subject.ConclusionsThe benefits of imaging flow cytometry for peripheral blood analysis include its capacities for analyzing heterogeneous cell populations; visualizing cell morphology; and evaluating the accumulation, localization, and expression of a target protein. Imaging flow cytometry analysis should be implemented in future studies to optimize its application as a tool for spinal muscular atrophy clinical trials.     

Steering Toward Normative Wide-Dynamic-Range Neuron Activity in Nerve-Injured Rats With Closed-Loop Peripheral Nerve Stimulation

ObjectivesChronic pain is primarily treated with pharmaceuticals, but the effects remain unsatisfactory. A promising alternative therapy is peripheral nerve stimulation (PNS), but it has been associated with suboptimal efficacy because its modulation mechanisms are not clear and the current therapies are primarily open loop (ie, manually adjusting the stimulation parameters). In this study, we developed a proof-of-concept computational modeling as the first step toward implementing closed-loop PNS in future biological studies. When developing new pain therapies, a useful pain biomarker is the wide-dynamic-range (WDR) neuron activity in the dorsal horn. In healthy animals, the WDR neuron activity occurs in a stereotyped manner; however, this response profile can vary widely after nerve injury to create a chronic pain condition. We hypothesized that if injury-induced changes of neuronal response can be normalized to resemble those of a healthy condition, the pathological aspects of pain may be treated while maintaining protective physiological nociception.Materials and MethodsUsing an in vivo electrophysiology data set of WDR neuron recordings obtained in nerve-injured rats and naïve rats, we constructed sets of linear phenomenologic models of WDR firing rate during windup stimulation for both conditions. Then, we applied robust control systems techniques to identify a closed-loop PNS controller, which can drive the dynamics of WDR neuron response in neuropathic pain model into ranges associated with normal physiological pain.ResultsThe sets of identified linear models can accurately predict, in silico, nonlinear neural responses to electrical stimulation of the peripheral nerve. In addition, we showed that continuous closed-loop control of PNS can be used to normalize WDR neuron firing responses in three injured cases.ConclusionsIn this proof-of-concept study, we show how tractable, linear mathematical models of pain-related neurotransmission can be used to inform the development of closed-loop PNS. This new application of robust control to neurotechnology may also be expanded and applied across other neuromodulation applications.     

Prognostic value of EMG genioglossus involvement in amyotrophic lateral sclerosis

ObjectiveTo evaluate the prognostic value of needle electromyography (EMG) genioglossus involvement in patients with amyotrophic lateral sclerosis (ALS) at diagnosis.MethodsWe separately explored the prognostic value of clinical bulbar lower motor neuron (LMN) signs and EMG genioglossus involvement using Cox proportional hazard models adjusted for age, gender, diagnostic delay, presence of bulbar upper motor neuron (UMN) signs, EMG cervical and lumbosacral region involvement, ALSFRS-R score and C9Orf72 gene status. Then, we compared the prognostic value of EMG masseter and genioglossus abnormalities in a subset of patients in whom both muscles were analysed.Results103 ALS patients were included in the study. Neurophysiological genioglossus involvement was associated with a shorter survival (p = 0.002), a shorter time to moderate dysphagia (p = 0.0001) and to severe dysarthria (p = 0.012). Its prognostic value was still evident in patients without clinical bulbar LMN signs. Bulbar clinical LMN signs were only associated with an earlier onset of moderate dysphagia (p = 0.0001). EMG masseter abnormalities did not reach statistical significance with regard to all the clinical milestones.ConclusionsGenioglossus EMG at diagnosis could provide important information about ALS progression rate. The masseter muscle seems to be less involved in ALS.SignificanceEMG genioglossus involvement is a prognostic factor in ALS.     

A 23-year follow-up report of juvenile-onset Sandhoff disease presenting with a motor neuron disease phenotype and a novel variant

BackgroundThe clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature.Case presentationWe present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances.ConclusionWe need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease.     

Structural and diffusion tensor imaging of the fornix in childhood- and adolescent-onset schizophrenia

ObjectiveThere is emerging evidence that aberrations in the integrity of cerebral white matter tracts, especially those connected to limbic structures, play a role in the pathophysiology of schizophrenia. The fornix is the primary efferent neural pathway of the hippocampus and has been shown to be abnormal in adults with schizophrenia.MethodHigh-resolution structural magnetic resonance imaging and diffusion tensor images were obtained on 15 patients with childhood- and adolescent-onset schizophrenia and 15 age- and sex-matched controls. Measures of cross-sectional area and water diffusion properties were obtained on regions of interest of the fornix performed by a trained radiologist.ResultsThe volume of the fornix was significantly smaller (10.9%) in children and adolescents with schizophrenia compared to controls (Cohen d = 0.87, p = .025). There were no significant differences between the fractional anisotropy or mean diffusivity between the groups.ConclusionsThese findings suggest that the early stages of schizophrenia are associated with a decrease in fornix volume without microstructural white matter changes. The volume differences may reflect an early insult to neighboring brain regions (i.e., hippocampus), that could decrease the number of efferent fibers without necessarily disrupting fiber integrity. J. Am. Acad. Child Adolesc. Psychiatry, 2008; 47(7):826–832.     

Putaminal volume and diffusion in early familial Creutzfeldt–Jakob Disease

BackgroundThe putamen is centrally implicated in the pathophysiology of Creutzfeldt–Jakob Disease (CJD). To our knowledge, its volume has never been measured in this disease. We investigated whether gross putaminal atrophy can be detected by MRI in early stages, when the diffusion is already reduced.MethodsTwelve familial CJD patients with the E200K mutation and 22 healthy controls underwent structural and diffusion MRI scans. The putamen was identified in anatomical scans by two methods: manual tracing by a blinded investigator, and automatic parcellation by a computerized segmentation procedure (FSL FIRST). For each method, volume and mean Apparent Diffusion Coefficient (ADC) were calculated.ResultsADC was significantly lower in CJD patients (697 ± 64 µm²/s vs. 750 ± 31 µm²/s, p < 0.005), as expected, but the volume was not reduced. The computerized FIRST delineation yielded comparable ADC values to the manual method, but computerized volumes were smaller than manual tracing values.ConclusionsWe conclude that significant diffusion reduction in the putamen can be detected by delineating the structure manually or with a computerized algorithm. Our findings confirm and extend previous voxel-based and observational studies. Putaminal volume was not reduced in our early-stage patients, thus confirming that diffusion abnormalities precede detectible atrophy in this structure.     

Growth of rat cortical neurons on DuraGen,a collagen-based dural graft matrix

Abstract

Objectives: DuraGen, a collagen-based dural graft matrix, is frequently used in clinical neurosurgery. In the present study we examined whether DuraGen influenced neuron survival of or process growth from cerebral cortex neurons in culture.

Methods: Dissociated E19 rat cerebral cortical neurons were cultured at low density on poly-L-lysine or on cryostat-sectioned DuraGen. Neuron survival was assessed using morphological criteria, fluorescein diacetate (FDA) and propidium iodide (PI), nuclear staining and TUNEL labeling. Process growth was analysed using specific antibodies against MAP2 and the 200 kDa neurofilament subunit (NF-H) to identify dendrites and axons, respectively.

Results: In immature cultures (3 days in vitro, DIV), nearly 70% of the neurons remained viable in control and DuraGen-exposed cells. In mature cultures (10 DIV), ～45% of the neurons were viable. Survival was similar in DuraGen cultures and controls. Cell viability also was similar when DuraGen conditioned the medium, but was not in contact with the neurons. When 10-day-old cultures were treated with glutamate (100 μmol/l for 24 hours) to elicit excitotoxic injury, a 40% decrease in neuron survival was observed. DuraGen's presence neither exacerbated nor attenuated glutamate-induced excitotoxic neuron death. The amount of necrotic or apoptotic cells also was similar in control and DuraGen cultures. Finally, DuraGen had an equal ability to support both axon and dendrite growth as poly-L-lysine.

Conclusion: Our findings demonstrate that DuraGen has no adverse effect on survival of or process growth from cerebral cortical neurons in vitro. These data support DuraGen's biosafety as a dural substitute in clinical neurosurgery.