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Clifford A Robbins,1 Daniel H Daneshvar,1,2 John D Picano,1,3 Brandon E Gavett,1,4 Christine M Baugh,1,2 David O Riley,1 Christopher J Nowinski,1,2,5 Ann C McKee,1,2,6–8 Robert C Cantu,1,5,9,10 Robert A Stern1,2,8,91Center for the Study of Traumatic Encephalopathy, 2Department of Neurology, Boston University School of Medicine, Boston, MA, USA; 3School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY, USA; 4Department of Psychology, University of Colorado, Colorado Springs, CO, USA; 5Sports Legacy Institute, Waltham MA, USA; 6United States Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA, USA; 7Department of Pathology, 8Alzheimer's Disease Center, 9Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA; 10Department of Neurosurgery, Emerson Hospital, Concord, MA, USABackground: In recent years, the understanding of concussion has evolved in the research and medical communities to include more subtle and transient symptoms. The accepted definition of concussion in these communities has reflected this change. However, it is unclear whether this shift is also reflected in the understanding of the athletic community.What is known about the subject: Self-reported concussion history is an inaccurate assessment of someone's lifetime exposure to concussive brain trauma. However, unfortunately, in many cases it is the only available tool.Hypothesis/purpose: We hypothesize that athletes' self-reported concussion histories will be significantly greater after reading them the current definition of concussion, relative to the reporting when no definition was provided. An increase from baseline to post-definition response will suggest that athletes are unaware of the currently accepted medical definition.Study design: Cross-sectional study of 472 current and former athletes.Methods: Investigators conducted structured telephone interviews with current and former athletes between January 2010 and January 2013, asking participants to report how many concussions they had received in their lives. Interviewers then read participants a current definition of concussion, and asked them to re-estimate based on that definition.Results: The two estimates were significantly different (Wilcoxon signed rank test: z=15.636, P

Blount's disease is an idiopathic developmental abnormality affecting the medial proximal tibia physis resulting in a multi-planar deformity with pronounced tibia varus. A single cause is unknown, and it is currently thought to result from a multifactorial combination of hereditary, mechanical, and developmental factors. Relationships with vitamin D deficiency, early walking, and obesity have been documented. Regardless of the etiology, the clinical and radiographic findings are consistent within the two main groups. Early-onset Blount's disease is often bilateral and affects children in the first few years of life. Late-onset Blount's disease is often unilateral and can be sub-categorized as juvenile tibia vara (ages 4-10), and adolescent tibia vara (ages 11 and older). Early-onset Blount's disease progresses to more severe deformities, including depression of the medial tibial plateau. Additional deformities in both groups include proximal tibial procurvatum, internal tibial torsion, and limb length discrepancy. Compensatory deformities in the distal femur and distal tibia may occur. When non-operative treatment fails the deformities progress through skeletal maturity and can result in pain, gait abnormalities, premature medial compartment knee arthritis, and limb length discrepancy. Surgical options depend on the patient's age, weight, extent of physeal involvement, severity, and number of deformities. They include growth modulation procedures such as guided growth for gradual correction with hemi-epiphysiodesis and physeal closure to prevent recurrence and equalize limb lengths, physeal bar resection, physeal distraction, osteotomies with acute correction and stabilization, gradual correction with multi-planar dynamic external fixation, and various combinations of all modalities. The goals of surgery are to restore normal joint and limb alignment, equalize limb lengths at skeletal maturity, and prevent recurrence. The purpose of this literature review is to delineate basic concepts and reconstructive surgical treatment strategies for patients with Blount's disease.

Mineral scaling is a major constraint that limits the performance of membrane distillation (MD) for hypersaline wastewater treatment. Although the use of antiscalants is a common industrial practice to mitigate mineral scaling, the effectiveness and underlying mechanisms of antiscalants in inhibiting different mineral scaling types have not been systematically investigated. Herein, we perform a comparative investigation to elucidate the efficiencies of antiscalant candidates with varied functional groups for mitigating gypsum scaling and silica scaling in MD desalination. We show that antiscalants with Ca(II)-complexing moieties (e.g., carboxyl group) are the most effective to inhibit gypsum scaling formed via crystallization, whereas amino-enriched antiscalants possess the best performance to mitigate silica scaling created by polymerization. A set of microscopic and spectroscopic analyses reveal distinct mechanisms of antiscalants required for those two common types of scaling. The mitigating effect of antiscalants on gypsum scaling is attributed to the stabilization of scale precursors and nascent CaSO 4 nuclei, which hinders phase transformation of amorphous CaSO 4 toward crystalline gypsum. In contrast, antiscalants facilitate the polymerization of silicic acid, immobilizing active silica precursors and retarding the gelation of silica scale layer on the membrane surface. Our study, for the first time, demonstrates that antiscalants with different functionalities are required for the mitigation of gypsum scaling and silica scaling, providing mechanistic insights on the molecular design of antiscalants tailored to MD applications for the treatment of wastewaters containing different scaling types.

Leveraging waste heat has been considered to have significant potential for promoting the economic feasibility of wastewater treatment in unconventional oil and gas (UOG) production. However, its availability near well sites has not been fully understood and other energy sources may be also feasible. In this work, we quantitatively investigate the viability of using waste heat and well-pad natural gas to power on-site wastewater treatment by membrane distillation (MD) for twenty randomly selected wells located in the Denver-Julesburg (DJ) Basin, U.S. Results show that waste heat produced from on-site electrical loads is insufficient for MD treatment of all the wastewater generated during UOG production (2.2-24.3% of thermal energy required for MD treatment). Waste heat from hydraulic fracturing, which persists only for a short timeframe, is able to meet the full or partial energy requirement during the peak period of wastewater production (17-1005% of thermal energy required for MD treatment within the first two months of production), but this scenario varies among wells and is dependent on the energy efficiency of MD. Compared to waste heat, natural gas is a more consistent energy source. The treatment capacity of MD powered by natural gas at the well pad exceeds full wastewater treatment demands for all the twenty wells, with only two wells requiring short-term wastewater storage. Our work indicates that although waste heat has the potential to reduce the electricity consumption and cost of UOG wastewater treatment, it is unlikely to supply sufficient thermal energy required by MD for long-term treatment. Natural gas can serve as an alternative or complementary energy resource. Further investigations, in particular techno-economic analyses, are needed to identify the best suitable energy source or combination for on-site UOG wastewater treatment., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19-3.91; MI, 2.10,1.17-3.76; CES-D, 3.08,1.65-5.76; AES, 2.39,1.32-4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76-0.97) and CES-D (OR, 95% CI: 0.85, 0.74-0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.

Objective: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease associated with repetitive brain trauma (RBT). Initially described in boxers, CTE has now been found in other contact sport athletes with a history of RBT. In recent years, there has been tremendous media attention regarding CTE, primarily because of the deaths of high profile American football players who were found to have CTE upon neuropathological examination. However, the study of CTE remains in its infancy. This review focuses on research from the Centre for the Study of Traumatic Encephalopathy (CSTE) at Boston University., Methods: This study reviews the formation of the CSTE, major CSTE publications and current ongoing research projects at the CSTE., Results: The neuropathology of CTE has been well-described. Current research focuses on: methods of diagnosing the disease during life (including the development of biomarkers), examination of CTE risk factors (including genetic susceptibility and head impact exposure variables); description of the clinical presentation of CTE; development of research diagnostic criteria for Traumatic Encephalopathy Syndrome; and assessment of mechanism and pathogenesis., Conclusions: Current research at the BU CSTE is aimed at increasing understanding of the long-term consequences of repetitive head impacts and attempting to begin to answer several of the unanswered questions regarding CTE.

Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 × CBACa) and (MOLF × CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17.

Opinion Statement: Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease found in individuals with a history of repetitive head impacts. The neuropathology of CTE is increasingly well defined. Prospective, longitudinal studies with post-mortem neuropathologic validation as well as in vivo diagnostic techniques are needed in order to advance the understanding of CTE clinically. Given the large number of individuals who incur concussions and other forms of brain trauma, this is an important area for scientific and public health inquiry.

The behaviors of other people are often central to envisioning the future. The ability to accurately predict the thoughts and actions of others is essential for successful social interactions, with far-reaching consequences. Despite its importance, little is known about how the brain represents people in order to predict behavior. In this functional magnetic resonance imaging study, participants learned the unique personality of 4 protagonists and imagined how each would behave in different scenarios. The protagonists' personalities were composed of 2 traits: Agreeableness and Extraversion. Which protagonist was being imagined was accurately inferred based solely on activity patterns in the medial prefrontal cortex using multivariate pattern classification, providing novel evidence that brain activity can reveal whom someone is thinking about. Lateral temporal and posterior cingulate cortex discriminated between different degrees of agreeableness and extraversion, respectively. Functional connectivity analysis confirmed that regions associated with trait-processing and individual identities were functionally coupled. Activity during the imagination task, and revealed by functional connectivity, was consistent with the default network. Our results suggest that distinct regions code for personality traits, and that the brain combines these traits to represent individuals. The brain then uses this "personality model" to predict the behavior of others in novel situations., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

In everyday life, people adaptively prepare for the future by simulating dynamic events about impending interactions with people, objects and locations. Previous research has consistently demonstrated that a distributed network of frontal-parietal-temporal brain regions supports this ubiquitous mental activity. Nonetheless, little is known about the manner in which specific regions of this network contribute to component features of future simulation. In two experiments, we used a functional magnetic resonance (fMR)-repetition suppression paradigm to demonstrate that distinct frontal-parietal-temporal regions are sensitive to processing the scenarios or what participants imagined was happening in an event (e.g., medial prefrontal, posterior cingulate, temporal-parietal and middle temporal cortices are sensitive to the scenarios associated with future social events), people (medial prefrontal cortex), objects (inferior frontal and premotor cortices) and locations (posterior cingulate/retrosplenial, parahippocampal and posterior parietal cortices) that typically constitute simulations of personal future events. This pattern of results demonstrates that the neural substrates of these component features of event simulations can be reliably identified in the context of a task that requires participants to simulate complex, everyday future experiences.

Objective: The goal of this study was to examine the clinical presentation of chronic traumatic encephalopathy (CTE) in neuropathologically confirmed cases., Methods: Thirty-six adult male subjects were selected from all cases of neuropathologically confirmed CTE at the Boston University Center for the Study of Traumatic Encephalopathy brain bank. Subjects were all athletes, had no comorbid neurodegenerative or motor neuron disease, and had next-of-kin informants to provide retrospective reports of the subjects' histories and clinical presentations. These interviews were conducted blind to the subjects' neuropathologic findings., Results: A triad of cognitive, behavioral, and mood impairments was common overall, with cognitive deficits reported for almost all subjects. Three subjects were asymptomatic at the time of death. Consistent with earlier case reports of boxers, 2 relatively distinct clinical presentations emerged, with one group whose initial features developed at a younger age and involved behavioral and/or mood disturbance (n = 22), and another group whose initial presentation developed at an older age and involved cognitive impairment (n = 11)., Conclusions: This suggests there are 2 major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.

The interaction between episodic retrieval and visual attention is relatively unexplored. Given that systems mediating attention and episodic memory appear to be segregated, and perhaps even in competition, it is unclear how visual attention is recruited during episodic retrieval. We investigated the recruitment of visual attention during the suppression of gist-based false recognition, the tendency to falsely recognize items that are similar to previously encountered items. Recruitment of visual attention was associated with activity in the dorsal attention network. The inferior parietal lobule, often implicated in episodic retrieval, tracked veridical retrieval of perceptual detail and showed reduced activity during the engagement of visual attention, consistent with a competitive relationship with the dorsal attention network. These findings suggest that the contribution of the parietal cortex to interactions between visual attention and episodic retrieval entails distinct systems that contribute to different components of the task while also suppressing each other., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Voltage-gated K(+) channels (Kv) represent the largest family of genes in the K(+) channel family. The Kv1 subfamily plays an essential role in the initiation and shaping of action potentials, influencing action potential firing patterns and controlling neuronal excitability. Overlapping patterns with differential expression and precise localization of Kv1.1 and Kv1.2 channels targeted to specialized subcellular compartments contribute to distinctive patterns of neuronal excitability. Dynamic regulation of the components in these subcellular domains help to finely tune the cellular and regional networks. Disruption of the expression, distribution, and density of these channels through deletion or mutation of the genes encoding these channels, Kcna1 and Kcna2, is associated with neurologic pathologies including epilepsy and ataxia in humans and in rodent models. Kv1.1 and Kv1.2 knockout mice both have seizures beginning early in development; however, each express a different seizure type (pathway), although the channels are from the same subfamily and are abundantly coexpressed. Voltage-gated ion channels clustered in specific locations may present a novel therapeutic target for influencing excitability in neurologic disorders associated with some channelopathies., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

People often falsely recognize items that are similar to previously encountered items. This robust memory error is referred to as gist-based false recognition. A widely held view is that this error occurs because the details fade rapidly from our memory. Contrary to this view, an initial experiment revealed that, following the same encoding conditions that produce high rates of gist-based false recognition, participants overwhelmingly chose the correct target rather than its related foil when given the option to do so. A second experiment showed that this result is due to increased access to stored details provided by reinstatement of the originally encoded photograph, rather than to increased attention to the details. Collectively, these results suggest that details needed for accurate recognition are, to a large extent, still stored in memory and that a critical factor determining whether false recognition will occur is whether these details can be accessed during retrieval.

Mutations within MYO7A can lead to recessive and dominant forms of inherited hearing loss. We previously identified a large pedigree (referred to as the HL2 family) with hearing loss that first impacts the low and mid frequencies segregating a dominant MYO7A mutation in exon 17 at DNA residue G2164C. The MYO7A(G2164C) mutation predicts a nonconservative glycine-to-arginine (G722R) amino acid substitution at a highly conserved glycine residue. The degree of low and mid frequency hearing loss varies markedly in the family, suggesting the presence of a genetic modifier that either rescues or exacerbates the primary MYO7A(G2164C) mutation. Here we describe a single nucleotide polymorphism (SNP) T/C at position -4128 in the wild-type MYO7A promoter allele that sorts with the degree of hearing loss severity in the pedigree. Electrophoretic mobility shift assay analysis indicates that the SNP differentially regulates the binding of the YY1 transcription factor with the T(-4128) allele creating an YY1 binding site. Immunocytochemistry demonstrates that Yy1 is expressed in hair cell nuclei within the cochlea. Given that Myo7a is also expressed in cochlear hair cells, Yy1 shows the appropriate localization to regulate Myo7a transcription within the inner ear. YY1 appears to be acting as a transcriptional repressor as the MYO7A promoter allele containing the T(-4128) SNP drives 41 and 46% less reporter gene expression compared with the C(-4128) SNP in the ARPE-19 and HeLa cell lines, respectively. The T(-4128) SNP may be contributing to the severe hearing loss phenotype in the HL2 pedigree by reducing expression of the wild-type MYO7A allele.

Voltage-gated potassium (Kv) channels containing Kv1.1 subunits are strongly expressed in neurons that fire temporally precise action potentials (APs). In the auditory system, AP timing is used to localize sound sources by integrating interaural differences in time (ITD) and intensity (IID) using sound arriving at both cochleae. In mammals, the first nucleus to encode IIDs is the lateral superior olive (LSO), which integrates excitation from the ipsilateral ventral cochlear nucleus and contralateral inhibition mediated via the medial nucleus of the trapezoid body. Previously we reported that neurons in this pathway show reduced firing rates, longer latencies and increased jitter in Kv1.1 knockout (Kcna1−/−) mice. Here, we investigate whether these differences have direct impact on IID processing by LSO neurons. Single-unit recordings were made from LSO neurons of wild-type (Kcna1+/+) and from Kcna1−/− mice. IID functions were measured to evaluate genotype-specific changes in integrating excitatory and inhibitory inputs. In Kcna1+/+ mice, IID sensitivity ranged from +27 dB (excitatory ear more intense) to −20 dB (inhibitory ear more intense), thus covering the physiologically relevant range of IIDs. However, the distribution of IID functions in Kcna1−/− mice was skewed towards positive IIDs, favouring ipsilateral sound positions. Our computational model revealed that the reduced performance of IID encoding in the LSO of Kcna1−/− mice is mainly caused by a decrease in temporal fidelity along the inhibitory pathway. These results imply a fundamental role for Kv1.1 in temporal integration of excitation and inhibition during sound source localization.

Usher syndrome is the leading cause of combined deaf-blindness, but the molecular mechanisms underlying the auditory and visual impairment are poorly understood. Usher I is characterized by profound congenital hearing loss, vestibular dysfunction, and progressive retinitis pigmentosa beginning in early adolescence. Using the c.216G>A cryptic splice site mutation in Exon 3 of the USH1C gene found in Acadian Usher I patients in Louisiana, we constructed the first mouse model that develops both deafness and retinal degeneration. The same truncated mRNA transcript found in Usher 1C patients is found in the cochleae and retinas of these knock-in mice. Absent auditory-evoked brainstem responses indicated that the mutant mice are deaf at 1 month of age. Cochlear histology showed disorganized hair cell rows, abnormal bundles, and loss of both inner and outer hair cells in the middle turns and at the base. Retinal dysfunction as evident by an abnormal electroretinogram was seen as early as 1 month of age, with progressive loss of rod photoreceptors between 6 and 12 months of age. This knock-in mouse reproduces the dual sensory loss of human Usher I, providing a novel resource to study the disease mechanism and the development of therapies.

The threshold of toxicologic concern (TTC) concept was developed as a method to identify a chemical intake level that is predicted to be without adverse human health effects assuming daily intake over the course of a 70-yr life span. The TTC values are based on known structure-activity relationships and do not require chemical-specific toxicity data. This allows safety assessment (or prioritization for testing) of chemicals with known molecular structure but little or no toxicity data. Recently, the TTC concept was extended to inhaled substances by converting a TTC expressed in micrograms per person per day to an airborne concentration (ng/m(3)), making allowance for intake by routes in addition to inhalation and implicitly assuming 100% bioavailability of inhaled toxicants. The resulting concentration of no toxicologic concern (CoNTC), 30 ng/m(3), represents a generic airborne concentration that is expected to pose no hazard to humans exposed continuously throughout a 70-yr lifetime. Published data on the levels of mycotoxins in agricultural dusts or in fungal spores, along with measured levels of airborne mycotoxins, spores, or dust in various environments, were used to identify conditions under which mycotoxin exposures might reach the CoNTC. Data demonstrate that airborne concentrations of dusts and mold spores sometimes encountered in agricultural environments have the potential to produce mycotoxin concentrations greater than the CoNTC. On the other hand, these data suggest that common exposures to mycotoxins from airborne molds in daily life, including in the built indoor environment, are below the concentration of no toxicologic concern.

Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage-activated potassium current I Kv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced I Kv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (-/-). The -/- mice exhibited increased seizure susceptibility compared with their +/+ and +/- littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from -/- and +/- mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped -/- MNTB neurons had enlarged I Kv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/- Kv1 channels, and no -/- Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger I Kv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.

Voltage-gated sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.

Purpose: To develop a non-invasive method for exploring seizure initiation and propagation in the brain of intact experimental animals., Methods: We have developed and applied a model-independent statistical method--Hierarchical Cluster Analysis (HCA)--for analyzing BOLD-fMRI data following administration of pentylenetetrazol (PTZ) to intact rats. HCA clusters voxels into groups that share similar time courses and magnitudes of signal change, without any assumptions about when and/or where the seizure begins., Results: Epileptiform spiking activity was monitored by EEG (outside the magnet) following intravenous PTZ (IV-PTZ; n=4) or intraperitoneal PTZ administration (IP-PTZ; n=5). Onset of cortical spiking first occurred at 29+/-16 s (IV-PTZ) and 147+/-29 s (IP-PTZ) following drug delivery. HCA of fMRI data following IV-PTZ (n=4) demonstrated a single dominant cluster, involving the majority of the brain and first activating at 27+/-23s. In contrast, IP-PTZ produced multiple, relatively small, clusters with heterogeneous time courses that varied markedly across animals (n=5); activation of the first cluster (involving cortex) occurred at 130+/-59 s. With both routes of PTZ administration, the timing of the fMRI signal increase correlated with onset of EEG spiking., Conclusions: These experiments demonstrate that fMRI activity associated with seizure activity can be analyzed with a model-independent statistical method. HCA indicated that seizure initiation in the IV- and IP-PTZ models involves multiple regions of sensitivity that vary with route of drug administration and that show significant variability across animal subjects. Even given this heterogeneity, fMRI shows clear differences that are not apparent with typical EEG monitoring procedures, in the activation patterns between IV and IP-PTZ models. These results suggest that fMRI can be used to assess different models and patterns of seizure activation.

This article reviews the relationship deficits experienced by many individuals who have attention deficit hyperactivity disorder (ADHD) and proposes effective strategies, based on Imago Relationship Therapy (IRT), to assist them in communicating more effectively. The neurological underpinnings of the disorder often contribute to the development of poor social and communication skills and can lead to a lifetime of relationship difficulties. IRT, a brain-based approach, is compatible with the neurological challenges of living with ADHD because it slows the communication process, provides structure, reduces reactivity, and helps individuals to be fully present so that their loved one can feel fully heard and understood. The couple's dialogue strengthens relationships by encouraging the development of stronger listening skills, better self-control, and problem solving. Two case examples illustrate the clinical methods used., (Copyright 2005 Wiley Periodicals, Inc)

Tuberous sclerosis (TSC) is an autosomal dominant disorder, caused by mutations of either the TSC1 or TSC2 gene. Characteristic brain pathologies (including cortical tubers and subependymal hamartomas/giant astrocytomas) are thought to cause epilepsy, as well as other neurological dysfunction. The Eker rat, which carries a spontaneous germline mutation of the TSC2 gene (TSC2+/-), provides a unique animal model in which to study the relationship between TSC cortical pathologies and epilepsy. In the present study, we have analyzed the seizure propensity and histopathological features of a modified Eker rat preparation, in which early postnatal irradiation was employed as a "second hit" stimulus in an attempt to exacerbate cortical malformations and increase seizure propensity. Irradiated Eker rats had a tendency toward lower seizure thresholds (latencies to flurothyl-induced seizures) than seen in non-irradiated Eker rats (significant difference) or irradiated wild-type rats (non-significant difference). The majority of irradiated Eker rats exhibited dysplastic cytomegalic neurons and giant astrocyte-like cells, similar to cytopathologies observed in TSC lesions of patients. The most prominent features in these brains were hamartoma-like lesions involving large eosinophilic cells, similar to giant tuber cells in human TSC. In some cells from these hamartomas, immunocytochemistry revealed features of both neuronal and glial phenotypes, suggesting an undifferentiated or immature cell population. Both normal-appearing and dysmorphic neurons, as well as cells in the hamartomas, exhibited immunopositivity for tuberin, the protein product of the TSC2 gene.

Although there is increasing awareness of adverse effects associated with use of the high-fat ketogenic diet, very little is known regarding its long-term clinical consequences, especially in relation to cardiovascular health. Recent reports have highlighted rare but significant cardiac problems in patients treated with the ketogenic diet. Given the inherent limitations in conducting detailed pathologic assessments in patients, we asked whether histologic changes might develop in the brain and skeletal muscle of mice fed a high-fat diet for 2 to 3 months. We found no evidence of gross morphologic or histochemical alterations in muscle or brain after administration of the ketogenic diet. Further, there was no abnormal lipid storage or mitochondrial enzymatic staining. Our data suggest that patients chronically treated with a ketogenic diet are not likely to develop a lipid myopathy or neuronal inclusions.

An exhaustive search of the literature on the growth of mold on fiberglass insulation materials was conducted. Because of the paucity of published material, both peer-reviewed and non-peer-reviewed articles were included. The literature indicates that fiberglass can serve as a support matrix for the collection of debris which, when moist, have the capability of supporting the growth of mold. Further, binding and paper-based moisture barriers from fiberglass resins are also capable of supporting the growth of mold when moist.

Mycotoxins are known to produce veterinary and human diseases when consumed with contaminated foods. Mycotoxins have also been proposed to cause adverse human health effects after inhalation exposure to mold in indoor residential, school, and office environments. Epidemiologic evidence has been inadequate to establish a causal relationship between indoor mold and nonallergic, toxigenic health effects. In this article, the authors model a maximum possible dose of mycotoxins that could be inhaled in 24 h of continuous exposure to a high concentration of mold spores containing the maximum reported concentration of aflatoxins B1 and B2, satratoxins G and H, fumitremorgens B and C, verruculogen, and trichoverrols A and B. These calculated doses are compared to effects data for the same mycotoxins. None of the maximum doses modeled were sufficiently high to cause any adverse effect. The model illustrates the inefficiency of delivery of mycotoxins via inhalation of mold spores, and suggests that the lack of association between mold exposure and mycotoxicoses in indoor environments is due to a requirement for extremely high airborne spore levels and extended periods of exposure to elicit a response. This model is further evidence that human mycotoxicoses are implausible following inhalation exposure to mycotoxins in mold-contaminated home, school, or office environments.

Genetic influences contribute to susceptibility to seizures and to excitotoxic injury, but it is unclear if/how these susceptibilities are linked. This study assessed the impact of genetic background on mouse strain seizure susceptibility, seizure phenotype, mortality, and hippocampal histopathology. A subcutaneous (s.c.) kainic acid multiple injection protocol was developed. Five mouse strains were tested: a and b) C57BL/6J and 129/SvJ, strains commonly used in gene targeting experiments; c) C3HeB/FeJ, a strain with reported sensitivity to the convulsant effects of kainic acid (KA); d) 129/SvEms, a strain reportedly susceptible to hippocampal excitotoxic cell death; and e) a mixed genetic background strain (129/SvJXC57BL/6J) from which targeted gene deletion experiments have been carried out. Histopathological features were examined at early (7-10 day), delayed (2-4 month), and late (6-13 month) time points.Mouse background strains can be genetically segregated based on excitotoxin sensitivity, seizure phenotype, mortality, and hippocampal histopathology. When injected with KA, C3HeB/FeJ and C57BL/6J strains were resistant to cell death and synaptic reorganization despite severe behavioral seizures, while 129/SvEms mice developed marked pyramidal cell loss and mossy fiber sprouting despite limited seizure activity. The mixed background 129/SvJXC57BL/6J group exhibited features of both parental strains. In the mouse strains tested, the duration or severity of seizure activity was not predictive of subsequent hippocampal pyramidal cell death and/or synaptic reorganization. Unlike rats, mice exhibiting prolonged high-grade KA-induced seizure activity did not develop subsequent spontaneous behavioral seizures.

Cortical dysplasia is a major cause of intractable epilepsy in children. However, the precise mechanisms linking cortical malformations to epileptogenesis remain elusive. The neuronal-specific activator of cyclin-dependent kinase 5, p35, has been recognized as a key factor in proper neuronal migration in the neocortex. Deletion of p35 leads to severe neocortical lamination defects associated with sporadic lethality and seizures. Here we demonstrate that p35-deficient mice also exhibit dysplasia/ heterotopia of principal neurons in the hippocampal formation, as well as spontaneous behavioral and electrographic seizures. Morphological analyses using immunocytochemistry, electron microscopy, and intracellular labeling reveal a high degree of abnormality in dentate granule cells, including heterotopic localization of granule cells in the molecular layer and hilus, aberrant dendritic orientation, occurrence of basal dendrites, and abnormal axon origination sites. Dentate granule cells of p35-deficient mice also demonstrate aberrant mossy fiber sprouting. Field potential laminar analysis through the dentate molecular layer reflects the dispersion of granule cells and the structural reorganization of this region. Similar patterns of cortical disorganization have been linked to epileptogenesis in animal models of chronic seizures and in human temporal lobe epilepsy. The p35-deficient mouse may therefore offer an experimental system in which we can dissect out the key morphological features that are causally related to epileptogenesis.

Industrial hygienists (IHs) are called upon to investigate exposures to mold in indoor environments, both residential and commercial. Because exposure standards for molds or mycotoxins do not exist, it is important for the industrial hygienist to have a broad knowledge of the potential for exposure and health effects associated with mold in the indoor environment. This review focuses on the toxic effects of molds associated with the production of mycotoxins, and the putative association between health effects due to mycotoxin exposure in the indoor environment. This article contains background information on molds and mycotoxins, and a brief summary and review of animal exposure studies, case reports, and epidemiological studies from the primary literature concerning inhalation of mycotoxins or potentially toxin-producing molds. The relevance of the findings in the reviewed articles to exposures to mold in indoor, non-agricultural environments is discussed. Although evidence was found of a relationship between high levels of inhalation exposure or direct contact to mycotoxin-containing molds or mycotoxins, and demonstrable effects in animals and health effects in humans, the current literature does not provide compelling evidence that exposure at levels expected in most mold-contaminated indoor environments is likely to result in measurable health effects. Even though there is general agreement that active mold growth in indoor environments is unsanitary and must be corrected, the point at which mold contamination becomes a threat to health is unknown. Research and systematic field investigation are needed to provide an understanding of the health implications of mycotoxin exposures in indoor environments.

Synaptically released zinc has neuromodulatory capabilities that could result in either inhibition or enhancement of neuronal excitability. To determine the net effects of vesicular zinc release in the brain in vivo, we examined seizure susceptibility and seizure-related neuronal damage in mice with targeted disruption of the gene encoding the zinc transporter, ZnT3 (ZnT3-/- mice). ZnT3-/- mice, which lack histochemically reactive zinc in synaptic vesicles, had slightly higher thresholds to seizures elicited by the GABA(A) antagonist, bicuculline, and no differences in seizure threshold were seen in response to pentylenetetrazol or flurothyl. However, ZnT3-/- mice were much more susceptible than wild-type mice to limbic seizures elicited by kainic acid, suggesting that the net effect of hippocampal zinc on acute seizures in vivo is inhibitory. The hippocampi of ZnT3-/- mice showed typical seizure-related neuronal damage in response to kainic acid, demonstrating that damage to the targets of zinc-containing neurons can occur independently of synaptically released zinc. Mice lacking the neuronal zinc-binding protein metallothionein III (MT-III) are also more susceptible to kainic acid-induced seizures. Double knockout (ZnT3 and MT3) mice show the same response to kainic acid as ZnT3-/- mice, suggesting that ZnT3 and MT-III function in the same pathway.

Purpose/methods: Seizures in early life are thought to contribute to the development of human temporal lobe epilepsy. To examine the consequences of early seizures, we elicited status epilepticus in immature, 5.5- to 7.0-month-old pigtailed macaques by unilateral microinfusion of bicuculline methiodide into the entorhinal cortex., Results: This report focuses on neuropathological changes in the hippocampus. Bicuculline infusion consistently elicited limbic-like seizures with prolonged, relatively localized electrographic activity. Magnetic resonance imaging revealed enhanced signal intensity in the ipsilateral hippocampus after seizures; in some cases, there was also progressive hippocampal atrophy. Histological changes were variable; in two of five monkeys, there was significant hippocampal neuron loss, gliosis, granule cell dispersion, and mossy fiber reorganization., Conclusions: The histopathological findings and associated magnetic resonance imaging abnormalities after bicuculline-induced status epilepticus in infant monkeys mimic common aspects of human temporal lobe epilepsy.

In the kainic acid (KA) model of temporal lobe epilepsy, mossy fibers (MFs) are thought to establish recurrent excitatory synaptic contacts onto granule cells. This hypothesis was tested by intracellular labeling of granule cells with biocytin and identifying their synaptic contacts in the dentate molecular layer with electron microscopic (EM) techniques. Twenty-three granule cells from KA-treated animals and 14 granule cells from control rats were examined 2 to 4 months following KA at the light microscopic (LM) level; four cells showing MF sprouting were further characterized at the EM level. Timm staining revealed a time-dependent growth of aberrant MFs into the dentate inner molecular layer. The degree of sprouting was generally (but not invariably) correlated with the severity and frequency of seizures. LM examination of individual biocytin-labeled MF axon collaterals revealed enhanced collateralization and significantly increased numbers of synaptic MF boutons in the hilus compared to controls, as well as aberrant MF growth into the granule cell and molecular layers. EM examination of serially reconstructed, biocytin-labeled MF collaterals in the molecular layer revealed MF boutons that form asymmetrical synapses with dendritic shafts and spines of granule cells, including likely autaptic contacts on parent dendrites of the biocytin-labeled granule cell. These results constitute ultrastructural evidence for newly formed excitatory recurrent circuits, which might provide a structural basis for enhanced excitation and epileptogenesis in the hippocampus of KA-treated rats.

Several lines of evidence suggest that norepinephrine (NE) can modulate seizure activity. However, the experimental methods used in the past cannot exclude the possible role of other neurotransmitters coreleased with NE from noradrenergic terminals. We have assessed the seizure susceptibility of genetically engineered mice that lack NE. Seizure susceptibility was determined in the dopamine beta-hydroxylase null mutant (Dbh -/-) mouse using four different convulsant stimuli: 2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and high-decibel sound. Dbh -/- mice demonstrated enhanced susceptibility (i.e., lower threshold) compared with littermate heterozygous (Dbh +/-) controls to flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was increased in Dbh -/- mice in association with flurothyl-induced seizures. Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos mRNA expression were reversed by pretreatment with L-threo-3, 4-dihydroxyphenylserine, which partially restores the NE content in Dbh -/- mice. These genetically engineered mice confirm unambiguously the potent effects of the noradrenergic system in modulating epileptogenicity and illustrate the unique opportunity offered by Dbh -/- mice for elucidating the pathways through which NE can regulate seizure activity.

Despite strong clinical data confirming the anticonvulsant efficacy of a ketogenic diet (KGD) in pediatric patients, corroborative experimental data in young animals are limited. In the present study, the effects of a KGD on flurothyl seizure susceptibility were examined in normal juvenile mice after a dietary duration of 3, 7, or 12 days, and in adult mice for 15 days. In all groups of KGD-treated mice, blood beta-hydroxybutyrate levels were significantly elevated over those measured in controls. The present KGD was anticonvulsant (i.e. delayed onset) against the first (clonic) flurothyl-induced seizure for juvenile mice treated for either 7 or 12 days, but not for juvenile mice and adult mice fed the diet for 3 and 15 days, respectively. While this KGD was not anticonvulsant against the second (tonic extension) seizure induced by flurothyl in any of the juvenile groups, it significantly delayed tonic extension in the adult group. In addition, juvenile mice fed a KGD exhibited a lower mortality rate following flurothyl-induced seizures compared to mice fed a standard diet. In our discussion of animal models of the KGD, we highlight the need to understand better the impact of important variables such as dietary composition, genetic background, and mode of seizure induction in the study of the KGD.

Seizures, particularly multiple episodes and/or status epilepticus (SE) are prevalent in pediatric patients. Pediatric SE is associated with brain changes that have been hypothesized to contribute to the onset of temporal lobe epilepsy (TLE). In order to gain insight into the effects of seizures on the immature brain and the risk for later TLE, we have developed a model of limbic SE in the pigtailed macaque monkey. In separate studies, bicuculline methiodide or a bicuculline 'cocktail' was infused into three regions of the brain (area tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included MRI, electrophysiology, behavior and morphology. Our results suggest that monkey models of SE may provide useful tools for understanding the effects of prolonged seizures during infancy and the origins of TLE in humans., (Copyright 1999 S. Karger AG, Basel)

Mice lacking the voltage-gated potassium channel alpha subunit, K(V)1.1, display frequent spontaneous seizures throughout adult life. In hippocampal slices from homozygous K(V)1.1 null animals, intrinsic passive properties of CA3 pyramidal cells are normal. However, antidromic action potentials are recruited at lower thresholds in K(V)1.1 null slices. Furthermore, in a subset of slices, mossy fiber stimulation triggers synaptically mediated long-latency epileptiform burst discharges. These data indicate that loss of K(V)1.1 from its normal localization in axons and terminals of the CA3 region results in increased excitability in the CA3 recurrent axon collateral system, perhaps contributing to the limbic and tonic-clonic components of the observed epileptic phenotype. Axonal action potential conduction was altered as well in the sciatic nerve--a deficit potentially related to the pathophysiology of episodic ataxia/myokymia, a disease associated with missense mutations of the human K(V)1.1 gene.

Perinatal hypoxia is associated with both seizures arising acutely and the subsequent development of temporal lobe epilepsy (as determined retrospectively). We therefore attempted to identify acute and chronic morphological and/or electrophysiological hippocampal pathologies associated with experimentally induced hypoxia in immature rats. Pups were exposed to 15 minutes of hypoxia on 3 successive days (starting on postnatal day 8; P8), or to 60 minutes of hypoxia on P10 with either one or multiple hypoxia-induced seizures. For animals experiencing multiple seizures, flurothyl seizure threshold was significantly lower than that of controls at 60 to 80 days, but not at 10 days, after hypoxia. Acutely, there was a treatment-related increase in the number and the density of pyknotic dentate and hilar neurons, in particular in animals experiencing multiple seizures. However, 60 to 80 days after the multiple-seizure protocol, the number of dentate and hilar neurons did not differ between control and experimental animals. Electrophysiological measures of pyramidal cell properties showed no striking difference between experimental and control animals at any time point. These results indicate that early postnatal hypoxia and hypoxia-induced seizure episodes decrease seizure threshold in the adult but produce minimal acute or chronic morphological or functional changes in the hippocampus.

This research evaluated the effect of the polarity of a second vapor on the adsorption of a polar and a nonpolar vapor using the Wheeler model. To examine the effect of polarity, it was also necessary to observe the effect of component boiling point. The 1% breakthrough time (1% tb), kinetic adsorption capacity (W(e)), and rate constant (kv) of the Wheeler model were determined for vapor challenges on carbon beds for both p-xylene and pyrrole (referred to as test vapors) individually, and in equimolar binary mixtures with the polar and nonpolar vapors toluene, p-fluorotoluene, o-dichlorobenzene, and p-dichlorobenzene (referred to as probe vapors). Probe vapor polarity (0 to 2.5 Debye) did not systematically alter the 1% tb, W(e), or kv of the test vapors. The 1% tb and W(e) for test vapors in binary mixtures can be estimated reasonably well, using the Wheeler model, from single-vapor data (1% tb +/- 30%, W(e) +/- 20%). The test vapor 1% tb depended mainly on total vapor concentration in both single and binary systems. W(e) was proportional to test vapor fractional molar concentration (mole fraction) in mixtures. The kv for p-xylene was significantly different (p < or = 0.001) when compared according to probe boiling point; however, these differences were apparently of limited importance in estimating 1% tb for the range of boiling points tested (111 to 180 degrees C). Although the polarity and boiling point of chemicals in the range tested are not practically important in predicting 1% tb with the Wheeler model, an effect due to probe boiling point is suggested, and tests with chemicals of more widely ranging boiling point are warranted. Since the 1% tb, and thus, respirator service life, depends mainly on total vapor concentration, these data underscore the importance of taking into account the presence of other vapors when estimating respirator service life for a vapor in a mixture.

The purposes of this study were to determine: (1) the prevalence of psychoactive medication and alcohol use and (2) the relationship among psychoactive medications, alcohol use, and falls in a sample of 1028 independently living women and men, aged 55 and older. Twenty-six percent of the sample reported falling, 28% were taking one or more psychoactive drugs, and 38% drank alcohol during the past year. Analyses with logistic regression indicate that predictors of falls were psychoactive drug use, age, and number of illnesses. Living alone, frequency of alcohol use, and gender were not significant predictors.

We combined the isolation of gene-enriched genomic DNA with gene prediction by computer to search for genes in a cosmid contig covering one million base pairs in the Huntington disease region on chromosome 4. Our aim was to develop a simple, robust strategy to identify genes adjacent to CpG islands without first characterizing undermethylated regions with multiple rare-cutter restriction enzyme sites. We cloned DNA adjacent to the rare-cutter restriction enzyme sites EagI and SacII, which are predicted to cut more frequently within CpG islands and relied solely on minimal sequence analysis to determine the likely coding potential of the DNA next to these sites. Our results indicated that isolating fragments with a single rare-cutter restriction enzyme site was sufficient to provide a high likelihood of identifying genes. Of the 42 CpG-selected clones analyzed, we determined that 17 contained exons as determined by sequence identity to known genes in this region, sequence identity to gene fragments isolated by direct cDNA selection in our laboratory, and/or their ability to detect transcripts on Northern blots. Analysis of the sequences with the BLAST and GRAIL programs provided additional independent evidence that 15 of these 17 clones contain coding sequences and that nine other clones are likely to contain sequences coding for portions of new genes. By mapping these clones to an EcoRI restriction map of the region, we determined a detailed localization for each of the exons and estimate that there are a minimum of seven genes that contain CpG-rich DNA between D4S126 and D4S181.

The subjects were 1028 respondents from a randomly selected sample of independently living adults aged 55 years and older in the southeastern United States. Data on background characteristics, physical health, life satisfaction, psychological distress, and medication compliance were gathered from structured interviews. Among the 785 subjects in the analysis who were taking prescribed medications, 75% were women, 83% were white, their median income was $12,500 annually, 66% lived alone, their mean age was 73.9 years, and their mean number of years of education was 11.4. Twenty-one percent of all respondents taking medications had been noncompliant during the month preceding the study interview. Noncompliance with prescribed medications was significantly associated with higher socioeconomic status (P < 0.01), greater number of prescribed medications (P < 0.01), and higher psychological stress (P < 0.05). There was no relationship between compliance and living arrangements, health, life satisfaction, number of illnesses, age, or sex.

The analyses reported here draw on recent work on gender and deviance to derive hypotheses concerning sex differences in drinking behavior, reactions of significant others to male and female intoxication, and the psychological consequences of drinking experiences. The hypotheses are evaluated in structural equation models with recent national data on drinking behavior and consequences. Consistent with the gendered deviance perspective, the results suggest that sex differences in style as well as frequency of intoxication mitigate the adverse consequences of female drinking commonly presumed on the basis of biological vulnerability or societal disapproval of female drunkenness. Compared to males, females become intoxicated less frequently and are less likely to abandon personal control while drinking (as indicated by aggression, blackouts, and rapid ingestion). As expected, these sex differences in drinking behavior are smaller among adolescents than among adults. Partly as a result of this different drinking style, significant others are no more likely to criticize girls or women for their drinking than they are to criticize boys or men. Two hypotheses concerning the greater psychological vulnerability of females to depression as a result of drinking or criticism of drinking by significant others are supported among youths but not among adults.

The synaptic events responsible for epileptiform burst discharge are often difficult to define. Blockade of inhibition has been used to produce epileptiform events, but it is unclear whether increased excitatory activity in the presence of normal inhibition can also result in burst discharge. In the hippocampal slice culture preparation, a small percentage of cultures exhibit spontaneous bursts. To determine whether the absence of inhibitory postsynaptic potentials (IPSPs) is responsible for these spontaneous bursts, we applied the glutamate antagonist, kynurenic acid (KYN) to block burst activity, and unmask any underlying IPSPs. KYN (10 mM) quickly reduced synaptic activity with concomitant loss of burst discharge. Washout of KYN resulted in a gradual return of synaptic activity, during which time both fast and slow IPSPs were clearly observed. As burst activity returned to control levels, excitatory postsynaptic potentials (EPSPs) were increasingly superimposed within the inhibitory events, obscuring (but not eliminating) the IPSPs. In these hippocampal slice cultures, therefore, epileptiform bursts appear to be the result of an abnormally high level of excitatory synaptic drive, not a reduction in inhibition.

The GABAA antagonist bicuculline methiodide and the GABAB antagonist phaclofen were used to examine the function of the fast inhibitory postsynaptic potential and slow inhibitory postsynaptic potential, in hippocampal slice cultures in the rat. These cultures form easily-visualized monolayers of nerve cells which maintain the structure and synaptic organization of transverse hippocampal slices. The present study shows that the cellular and synaptic physiological properties of slice cultures are very similar, but not identical, to those observed in acutely-prepared hippocampal slices. The major difference is a higher incidence of fast excitatory postsynaptic potentials and inhibitory postsynaptic potentials compared to slices, and the appearance of spontaneous slow inhibitory postsynaptic potentials. This increase in synaptic drive has been useful for our investigation of the role of GABA-mediated inhibitory postsynaptic potentials. Bath application of 10 microM bicuculline blocked the fast inhibitory postsynaptic potentials and gave rise to bursts 1-11 s in duration. The presence of the slow inhibitory postsynaptic potentials did not prevent bicuculline-induced burst activity. Phaclofen (1 mM) perfused in the bath reversibly blocked the slow inhibitory postsynaptic potential, but did not result in the formation of large paroxysmal depolarizing shift-like bursts as seen with bicuculline. Rather, block of the slow inhibitory postsynaptic potential resulted in the formation of repetitive "afterdischarge bursts". These afterdischarge potentials typically appeared with a delay of 2-15 min following block of the slow inhibitory postsynaptic potential, during which time there was a gradual increase in non-synchronized excitatory activity. Once established, this cycle of increasing excitatory activity culminating in afterdischarge potentials recurred at 2-4 min intervals while phaclofen was present.(ABSTRACT TRUNCATED AT 250 WORDS)

The objects of these experiments were: (a) to determine modal interspike intervals (ISIs) of precentral cells involved in repetitious, gross motor movements; (b) to compare those modal ISIs to the modal ISIs of similar neurons under operant control; and (c) to determine if monkeys could change the modal ISIs of operantly controlled precentral neurons. Data were obtained from 4 monkeys conditioned to produce tonic firing of precentral neurons and one monkey trained to produce repetitious movements of the neck and contralateral limbs. Results are: (a) the modal ISIs from operantly controlled precentral units do not differ significantly from precentral neurons involved in repetitive gross motor movements; and (b) while under operant control, the monkeys cannot modify significantly the modal ISI of the majority of precentral neurons.

Two rhesus monkeys were trained to control firing patterns of single neurons in parietal cortex (areas 1, 2, 3, 5, 7) using an operant task previously applied to the study of precentral units. Twenty-four of 56 (43%) postcentral cells were controlled in contrast to 71 of 136 (52%) precentral units from these and 4 other rhesus monkeys. In addition, monkeys were able to drive precentral units to more sustained tonic firing rates than they could parietal units. An analysis of interspike interval (ISI) distributions showed that, in contrast to precentral units with modal ISIs of 25-50 ms, 50% of parietal units have modal ISIs of 2 ms. Such short ISIs may account for fewer postcentral units reaching control criteria for this particular operant task. Other factors that may contribute to the reduced control of postcentral cells are discussed, particularly the more complex afferent connections to parietal units when compared to precentral pyramidal tract neurons. The data indirectly support conclusions from previous studies that imply that operant control of cortical units is peripherally mediated and does not primarily involve a 'central' or 'open loop' system.

Two Macaca mulatta monkeys were reinforced to operantly control a precentral neuron's firing pattern while a contralateral unit was monitored simultaneously. The results from 38 complete experiments indicate the following: (a) upon altering to the operant task, both the contingent and the non-contingent neurons changed firing patterns from preconditioning levels. However, as the monkey brought the contingent unit under operant control, there were no significant changes in the firing pattern of the non-contingent neuron; (b) when the contingencies were reversed so that the monkeys were reinforced to control the originally non-contingent neuron, the firing pattern off the originally contingent neuron returned to near baseline levels. These data indicate that although many precentral units may change firing patterns when the monkey attends to the operant task, the reinforced changes in firing pattern are not the result of a generalized phenomenon at the spinal level.