Diazepam induced sleep spindle increase correlates with cognitive recovery in a child with epileptic encephalopathy.

BACKGROUND: Continuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies. CASE PRESENTATION: We describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient's disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry. CONCLUSIONS: Epileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.

The effect of inhibition on the existence of traveling wave solutions for a neural field model of human seizure termination.

In this paper we study the influence of inhibition on an activity-based neural field model consisting of an excitatory population with a linear adaptation term that directly regulates the activity of the excitatory population. Such a model has been used to replicate traveling wave data as observed in high density local field potential recordings (González-Ramírez et al. PLoS Computational Biology, 11(2), e1004065, 2015). In this work, we show that by adding an inhibitory population to this model we can still replicate wave properties as observed in human clinical data preceding seizure termination, but the parameter range over which such waves exist becomes more restricted. This restriction depends on the strength of the inhibition and the timescale at which the inhibition acts. In particular, if inhibition acts on a slower timescale relative to excitation then it is possible to still replicate traveling wave patterns as observed in the clinical data even with a relatively strong effect of inhibition. However, if inhibition acts on the same timescale as the excitation, or faster, then traveling wave patterns with the desired characteristics cease to exist when the inhibition becomes sufficiently strong.

EEG functional connectivity is partially predicted by underlying white matter connectivity.

Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales.

Neuronal assembly dynamics in the beta1 frequency range permits short-term memory.

Cell assemblies have long been thought to be associated with brain rhythms, notably the gamma rhythm. Here, we use a computational model to show that the beta1 frequency band, as found in rat association cortex, has properties complementary to the gamma band for the creation and manipulation of cell assemblies. We focus on the ability of the beta1 rhythm to respond differently to familiar and novel stimuli, and to provide a framework for combining the two. Simulations predict that assemblies of superficial layer pyramidal cells can be maintained in the absence of continuing input or synaptic plasticity. Instead, the formation of these assemblies relies on the nesting of activity within a beta1 rhythm. In addition, cells receiving further input after assembly formation produce coexistent spiking activity, unlike the competitive spiking activity characteristic of assembly formation with gamma rhythms.

Spike height improves prediction of future seizure risk.

OBJECTIVE: We evaluated whether interictal epileptiform discharge (IED) rate and morphological characteristics predict seizure risk. METHODS: We evaluated 10 features from automatically detectable IEDs in a stereotyped population with self-limited epilepsy with centrotemporal spikes (SeLECTS). We tested whether the average value or the most extreme values from each feature predicted future seizure risk in cross-sectional and longitudinal models. RESULTS: 10,748 individual centrotemporal IEDs were analyzed from 59 subjects at 81 timepoints. In cross-sectional models, increases in average spike height, spike duration, slow wave rising slope, slow wave falling slope, and the most extreme values of slow wave rising slope each improved prediction of an increased risk of a future seizure compared to a model with age alone (p < 0.05, each). In longitudinal model, spike rising height improved prediction of future seizure risk compared to a model with age alone (p = 0.04) CONCLUSIONS: Spike height improves prediction of future seizure risk in SeLECTS. Several other morphological features may also improve prediction and should be explored in larger studies. SIGNIFICANCE: Discovery of a relationship between novel IED features and seizure risk may improve clinical prognostication, visual and automated IED detection strategies, and provide insights into the underlying neuronal mechanisms that contribute to IED pathology.

Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.

BACKGROUND: We estimated the multiple sclerosis (MS) incidence in the Netherlands for better active monitoring of potential vaccine safety signals. METHODS: A retrospective cohort study (1996-2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases. RESULTS: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2-7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3-5) in 1996-2004 to 9/100,000 py in 2007/8 (95% CI, 6-16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005). CONCLUSIONS: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly.

Robust dynamic community detection with applications to human brain functional networks.

While current technology permits inference of dynamic brain networks over long time periods at high temporal resolution, the detailed structure of dynamic network communities during human seizures remains poorly understood. We introduce a new methodology that addresses critical aspects unique to the analysis of dynamic functional networks inferred from noisy data. We propose a dynamic plex percolation method (DPPM) that is robust to edge noise, and yields well-defined spatiotemporal communities that span forward and backwards in time. We show in simulation that DPPM outperforms existing methods in accurately capturing certain stereotypical dynamic community behaviors in noisy situations. We then illustrate the ability of this method to track dynamic community organization during human seizures, using invasive brain voltage recordings at seizure onset. We conjecture that application of this method will yield new targets for surgical treatment of epilepsy, and more generally could provide new insights in other network neuroscience applications.

Disassortative sexual mixing among migrant populations in The Netherlands: a potential for HIV/STI transmission?

To gain insight into the transmission of HIV and sexually transmitted infection (STI) among large migrant groups in The Netherlands, we studied the associations between their demographic and sexual characteristics, in particular condom use, and their sexual mixing patterns with other ethnic groups. In 2002-2005, cross-sectional surveys were conducted among migrants from Surinam (Afro- and Hindo-), the Netherlands Antilles, Cape Verde, and Ghana at social venues in three large cities. A questionnaire was administrated and a saliva sample was collected for HIV antibody testing. Of 2105 migrants recruited, 1680 reported sexual contacts, of whom 41% mixed sexually with other ethnicities, including the indigenous Dutch population. Such disassortative mixing was associated with being second-generation migrant, having several sexual partners, and having a steady and concurrent casual partner. Less disassortative mixing occurred in participants reporting visiting the country of origin. The association between condom use and sexual mixing differed by gender, with men using condoms inconsistently being most likely to be mixing with the Dutch indigenous population. HIV infection and recent STI treatment were not associated with disassortative mixing. This study shows substantial sexual mixing among migrant groups. Since disassortative mixing is more prevalent in second-generation migrants, it might increase in the upcoming years. The mixing patterns in relation to concurrency and the reported condom use in this study suggest a possibly increased level of HIV/STI transmission not only within migrant groups but also between migrant groups, especially via men who mix with the indigenous population and via migrant women who mix with non-Dutch casual partners. Although the observed HIV prevalence in migrants (0.6%) is probably too low to lead to much HIV transmission between ethnicity groups, targeted prevention measures are needed to prevent transmission of other STI.

Migrants travelling to their country of origin: a bridge population for HIV transmission?

BACKGROUND: By having unprotected heterosexual contact in both The Netherlands and their homeland, migrants who travel to their homeland might form a bridge population for HIV and sexually transmitted infection (STI) transmission. We studied the determinants for such a population in two large migrant communities in The Netherlands. METHODS: From 2003 to 2005, 1938 people of Surinamese and Antillean origin were recruited at social venues in two large cities, interviewed and their saliva samples tested for HIV antibodies. We used multivariate multinomial logistic regression to explore characteristics of groups with four risk levels (no, low, moderate and high) for cross-border transmission. RESULTS: 1159/1938 (60%) participants had travelled from The Netherlands to their homeland in the previous 5 years and 1092 (94%) of them reported partnerships and condom use in both countries. Of these 9.2% reported having unprotected sex with partners in both countries. People in this high-risk or bridge population group were more likely to be male, frequent travellers and older compared with people who had no sex or had sexual contact solely in one country in the past 5 years. CONCLUSIONS: Older male travellers of Surinamese and Antillean origin are at high risk for cross-border heterosexual transmission of HIV/STIs. They should be targeted by prevention programmes, which are focused on sexual health education and HIV/STI testing, to raise their risk awareness and prevent transmission.

Ethnic differences in HSV1 and HSV2 seroprevalence in Amsterdam, the Netherlands.

Herpes simplex virus type 1 (HSV1) and 2 (HSV2) infection can lead to significant morbidity, and HSV2 is considered a risk factor for HIV transmission. The majority of HSV-infected people are asymptomatic and unaware of their infection. We aimed to determine the HSV1 and HSV2 prevalence among various ethnic groups in a large urban area in the Netherlands. In 2004, serum samples from a population-based serum repository of 1,325 people over 18 years living in Amsterdam were tested for HSV1 and HSV2 antibodies in order to determine high-risk groups. Prevalence ratios were estimated and all analyses were weighted by sex, age, and ethnicity. In the general population of Amsterdam, 67% had HSV1 antibodies, 22% had HSV2 antibodies, 15% had HSV1 and HSV2 antibodies, and 26% had no indication of HSV infection. In multivariate analyses, HSV1 seroprevalence increased with age, and was higher among people of Turkish and Moroccan origin, homosexual men, and individuals with low educational level. HSV2 seroprevalence was associated with increasing age, Surinamese/Antillean background, and having a history of sexually transmitted infections (STI). These differences between ethnic groups in Amsterdam regarding the distribution of HSV1 and HSV2 infection emphasise the importance of an ethnic-specific approach of serological testing as well as campaigns aimed at behavioural change and counselling to raise awareness of the risk of HSV transmission.

A procedure to increase the power of Granger-causal analysis through temporal smoothing.

BACKGROUND: How the human brain coordinates network activity to support cognition and behavior remains poorly understood. New high-resolution recording modalities facilitate a more detailed understanding of the human brain network. Several approaches have been proposed to infer functional networks, indicating the transient coordination of activity between brain regions, from neural time series. One category of approach is based on statistical modeling of time series recorded from multiple sensors (e.g., multivariate Granger causality). However, fitting such models remains computationally challenging as the history structure may be long in neural activity, requiring many model parameters to fully capture the dynamics. NEW METHOD: We develop a method based on Granger causality that makes the assumption that the history dependence varies smoothly. We fit multivariate autoregressive models such that the coefficients of the lagged history terms are smooth functions. We do so by modelling the history terms with a lower dimensional spline basis, which requires many fewer parameters than the standard approach and increases the statistical power of the model. RESULTS: We show that this procedure allows accurate estimation of brain dynamics and functional networks in simulations and examples of brain voltage activity recorded from a patient with pharmacoresistant epilepsy. COMPARISON WITH EXISTING METHOD: The proposed method has more statistical power than the Granger method for networks of signals that exhibit extended and smooth history dependencies. CONCLUSIONS: The proposed tool permits conditional inference of functional networks from many brain regions with extended history dependence, furthering the applicability of Granger causality to brain network science.

Human seizures couple across spatial scales through travelling wave dynamics.

Epilepsy-the propensity toward recurrent, unprovoked seizures-is a devastating disease affecting 65 million people worldwide. Understanding and treating this disease remains a challenge, as seizures manifest through mechanisms and features that span spatial and temporal scales. Here we address this challenge through the analysis and modelling of human brain voltage activity recorded simultaneously across microscopic and macroscopic spatial scales. We show that during seizure large-scale neural populations spanning centimetres of cortex coordinate with small neural groups spanning cortical columns, and provide evidence that rapidly propagating waves of activity underlie this increased inter-scale coupling. We develop a corresponding computational model to propose specific mechanisms-namely, the effects of an increased extracellular potassium concentration diffusing in space-that support the observed spatiotemporal dynamics. Understanding the multi-scale, spatiotemporal dynamics of human seizures-and connecting these dynamics to specific biological mechanisms-promises new insights to treat this devastating disease.

Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir.

The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.

A prospective randomized study of acyclovir versus ganciclovir plus human immune globulin prophylaxis of cytomegalovirus infection after solid organ transplantation.

Cytomegalovirus disease occurs frequently after solid organ transplantation and has been associated with decreased patient and allograft survival. We hypothesized that CMV transmission or reactivation begins immediately or soon after transplantation, and that a short-duration ganciclovir (GCV)-based regimen would obviate the need for long-term antiviral agent administration, perhaps serving to interdict CMV infection and disease as well as, or perhaps even more effectively than, a more prolonged, oral acyclovir (ACV)-based form of prophylaxis. A total of 311 patients were stratified according to allograft type, age, and presence or absence or diabetes mellitus, and were then randomized to receive either long-duration ACV prophylaxis (800 mg orally or 400 mg i.v. q.i.d. for 12 weeks after transplantation or 6 weeks after any antirejection therapy) versus short-duration GCV (5 mg/kg/12 hr i.v. for 7 days after transplant or after any antirejection therapy) plus human immune globulin (HIg; Sandoglobulin or Minnesota CMV immune globulin) 100 mg/kg i.v. administered on days 1, 4, and 7 after transplant or after any antirejection therapy. A total of 266 patients (ACV, n = 133; GCV+HIg, n = 133) completed the protocol and were available for follow-up. CMV disease occurred in fewer patients (n = 28, 21.0%) in the ACV group, while significantly more patients (n = 42, 31.6%) in the GCV + HIg group developed group developed CMV disease slightly later (2.83 +/- 0.70 months) than those who received GCV/HIg (2.15 +/- 0.21 months, P > 0.01). Multivariate analysis demonstrated (2.15 +/- 0.21 months, P > 0.1). Multivariate analysis demonstrated that receiving antirejection therapy, a liver transplant, or a donor organ from a CMV-seropositive individual if the recipient was CMV seronegative were major risk factors for the development of CMV disease (P < 0.001), while the difference between ACV versus GCV + HIg prophylaxis was also significant (P = 0.054). No differences in actuarial patient or allograft survival, however, were noted between the 2 prophylaxis groups. Overall, ACV prophylaxis appeared to be more effective in reducing the incidence of posttransplant CMV disease, although this effect was diminished in high-risk groups of patients. Our findings indicate that CMV transmission or reactivation may best be prevented by long-term antiviral agent administration, and that the primary morbidity of CMV disease is the need for rehospitalization when either prolonged ACV or short-duration GCV + HIg prophylaxis is used in this patient population.

Treatment of recurrent cytomegalovirus disease in patients receiving solid organ transplants.

Tissue-invasive cytomegalovirus (TI-CMV) disease occurs commonly after solid organ transplantation and has been associated with increased allograft loss and patient mortality. Although ganciclovir has been demonstrated to be an effective form of treatment for TI-CMV disease, therapy may be followed by recurrence. The purpose of this study was to determine the impact of recurrent TI-CMV disease on patient and allograft survival. We studied 619 patients who underwent solid organ transplantation (535 kidney transplants [253 from living related donors and 282 from cadavers] and 84 combined cadaveric kidney-pancreas transplants) during a 3 1/2-year period. One hundred fourteen patients (18.4%) developed TI-CMV disease and were treated with a standardized regimen of intravenous ganciclovir for 14 to 21 days. Of the 114 patients in whom primary TI-CMV disease developed, 28 (24.6%) developed recurrent TI-CMV disease more than 30 days after the initial episode, and these patients were retreated with ganciclovir. Cure rates at 30 days were 98.9% in patients with primary TI-CMV disease and 100% in patients with recurrent TI-CMV disease. Patients who underwent cadaveric kidney or kidney-pancreas transplantation were more likely to develop recurrent TI-CMV disease than were recipients of kidney transplants from living related donors; antirejection therapy also was associated with a higher incidence of recurrent TI-CMV disease. Patients who developed TI-CMV disease exhibited lower rates of graft and patient survival at 3 years than patients without TI-CMV disease or with solely asymptomatic CMV infection, although recurrent TI-CMV disease did not appear to exacerbate morbidity or mortality. We conclude that recurrent episodes of TI-CMV disease do not appear to further adversely affect patient or graft survival in comparison with primary TI-CMV disease in ganciclovir-treated patients.

Diagnosis and treatment of cytomegalovirus disease in transplant patients based on gastrointestinal tract manifestations.

Infection due to cytomegalovirus is a substantial cause of morbidity and mortality in immunocompromised patients. In particular, cytomegalovirus infection has been associated with a significant detrimental effect on patient and allograft survival after solid-organ transplantation. We are evaluating a new antiviral agent, ganciclovir 9-[1,3-dihydroxy-2-2 propoxymethyl] guanine (DHPG), used in solid-organ transplant recipients who developed life-threatening cytomegalovirus infections. Between March 1, 1987, and June 30, 1989, we treated 93 solid-organ transplant patients who developed tissue-invasive cytomegalovirus disease. From this group of patients we have identified 14 patients with primary gastrointestinal cytomegalovirus disease who received treatment with DHPG. Tissue diagnosis was made by endoscopy of the upper gastrointestinal tract (11 patients) or colonoscopy (three patients). Invasive cytomegalovirus disease was identified prior to severe complications of the gastrointestinal tract in all but one patient, who suffered colonic perforation prior to treatment with DHPG and subsequently died of bacterial sepsis. While 13 of the 14 patients improved after treatment with DHPG, four patients required additional treatments for recurrent cytomegalovirus disease and recovered. No DHPG toxicity was observed. We believe treatment with DHPG is indicated in this patient population, but that further studies are indicated to fully define the impact of this recommendation on both patient and allograft survival after solid-organ transplantation.

The effects of MK801 on place conditioning.

The appetitive properties of MK801 were investigated using the conditioned place preference paradigm. Male Sprague-Dawley rats received conditioned place preference training for a four-day period. The conditioning box consisted of three chambers with distinctive visual and tactile cues, separated by removable doors. On alternating days rats received MK801 (0.05, 0.1, 0.25, 0.5 and 0.75 mg/kg) paired with one side of the chamber and saline paired with the other side. On the fifth day, rats were placed in the center chamber and the time spent in each chamber, as well as entries into each chamber were recorded by a trained observer. MK801 produced a conditioned place preference for side paired with drug for the four highest doses. Contrary to previous findings, these results indicate that MK801 is appetitive at doses higher than has previously been assumed.

Using radial basis functions to approximate a function and its error bounds.

A novel network called the validity index network (VI net) is presented. The VI net, derived from radial basis function networks, fits functions and calculates confidence intervals for its predictions, indicating local regions of poor fit and extrapolation.

Higher frequency of left-breast cancer: a possible explanation.

A study of 1027 women with unilateral breast cancer showed that ipsilateral breast cancer was more common before age 45 and contralateral thereafter. The data suggest a possible explanation of the higher incidence of left-breast cancer in American women. A higher percentage of left-handed women developed breast cancer before age 45, but the over-all incidence of unilateral breast cancer was not greater in left-handed women than in right-handed or ambihanded subjects.

A team approach to nursing research.

The study of the relationship of handedness to the laterality of breast cancer in women is intriguing. Results may affect facets of breast cancer diagnosis and therapy. Maybe not in same way as the discovery of the relationship of high oxygen concentrations to the development of blindness in premature infants, but the study may identify women at higher risk and provide new insights to scientists studying the pathophysiology of breast oncogenesis. It is the belief of the authors that laterality research is one of the fields that could easily lend itself to investigation by large numbers of nurses in hospitals across the country if a national organization became involved in it. If nursing is to be successful in its quest for recognition as one of the professions making a serious contribution to theory, it must mobilize its forces. Nursing, recognized as the largest single health profession in the United States, has great potential for accomplishment if the talent of every member of the profession is recognized and utilized in efforts to build up the science of nursing.