Probabilistic outlier identification for RNA sequencing generalized linear models.

Relative transcript abundance has proven to be a valuable tool for understanding the function of genes in biological systems. For the differential analysis of transcript abundance using RNA sequencing data, the negative binomial model is by far the most frequently adopted. However, common methods that are based on a negative binomial model are not robust to extreme outliers, which we found to be abundant in public datasets. So far, no rigorous and probabilistic methods for detection of outliers have been developed for RNA sequencing data, leaving the identification mostly to visual inspection. Recent advances in Bayesian computation allow large-scale comparison of observed data against its theoretical distribution given in a statistical model. Here we propose ppcseq, a key quality-control tool for identifying transcripts that include outlier data points in differential expression analysis, which do not follow a negative binomial distribution. Applying ppcseq to analyse several publicly available datasets using popular tools, we show that from 3 to 10 percent of differentially abundant transcripts across algorithms and datasets had statistics inflated by the presence of outliers.

User-centered design of an air quality feedback technology to promote adoption of clean cookstoves.

BACKGROUND: Recent work has examined behavioral reactivity associated with personal awareness of electronic sensors monitoring the use of environmental health products, including cookstoves. These studies suggest that sensors could be used as behavior change tools. OBJECTIVE: We present a human-centered design approach toward the development of a household air quality feedback technology intended to improve consistent and exclusive use of liquid petroleum gas (LPG) stoves provided as part of a health efficacy study. METHODS: We found through a consultation process that households may be behaviorally triggered by reminders of the health and environmental impacts of cooking practices and may respond to both auditory and visual feedback. Based on these insights, we designed and validated a system linking air particulate monitoring with persistent visual feedback and a dynamic audio alarm. RESULTS: Data collected over 14 days in participants households show that the system is able to detect sudden rises in household indoor air pollution and to communicate that information to household members. SIGNIFICANCE: This device could be used as a tool to raise awareness of air pollution associated in order to stimulate adoption of cleaner cooking technologies.

Effects of a large-scale distribution of water filters and natural draft rocket-style cookstoves on diarrhea and acute respiratory infection: A cluster-randomized controlled trial in Western Province, Rwanda.

BACKGROUND: Unsafe drinking water and household air pollution (HAP) are major causes of morbidity and mortality among children under 5 in low and middle-income countries. Household water filters and higher-efficiency biomass-burning cookstoves have been widely promoted to improve water quality and reduce fuel use, but there is limited evidence of their health effects when delivered programmatically at scale. METHODS AND FINDINGS: In a large-scale program in Western Province, Rwanda, water filters and portable biomass-burning natural draft rocket-style cookstoves were distributed between September and December 2014 and promoted to over 101,000 households in the poorest economic quartile in 72 (of 96) randomly selected sectors in Western Province. To assess the effects of the intervention, between August and December, 2014, we enrolled 1,582 households that included a child under 4 years from 174 randomly selected village-sized clusters, half from intervention sectors and half from nonintervention sectors. At baseline, 76% of households relied primarily on an improved source for drinking water (piped, borehole, protected spring/well, or rainwater) and over 99% cooked primarily on traditional biomass-burning stoves. We conducted follow-up at 3 time-points between February 2015 and March 2016 to assess reported diarrhea and acute respiratory infections (ARIs) among children <5 years in the preceding 7 days (primary outcomes) and patterns of intervention use, drinking water quality, and air quality. The intervention reduced the prevalence of reported child diarrhea by 29% (prevalence ratio [PR] 0.71, 95% confidence interval [CI] 0.59-0.87, p = 0.001) and reported child ARI by 25% (PR 0.75, 95% CI 0.60-0.93, p = 0.009). Overall, more than 62% of households were observed to have water in their filters at follow-up, while 65% reported using the intervention stove every day, and 55% reported using it primarily outdoors. Use of both the intervention filter and intervention stove decreased throughout follow-up, while reported traditional stove use increased. The intervention reduced the prevalence of households with detectable fecal contamination in drinking water samples by 38% (PR 0.62, 95% CI 0.57-0.68, p < 0.0001) but had no significant impact on 48-hour personal exposure to log-transformed fine particulate matter (PM2.5) concentrations among cooks (ß = -0.089, p = 0.486) or children (ß = -0.228, p = 0.127). The main limitations of this trial include the unblinded nature of the intervention, limited PM2.5 exposure measurement, and a reliance on reported intervention use and reported health outcomes. CONCLUSIONS: Our findings indicate that the intervention improved household drinking water quality and reduced caregiver-reported diarrhea among children <5 years. It also reduced caregiver-reported ARI despite no evidence of improved air quality. Further research is necessary to ascertain longer-term intervention use and benefits and to explore the potential synergistic effects between diarrhea and ARI. TRIAL REGISTRATION: Clinical Trials.gov NCT02239250.

Quantifying increased groundwater demand from prolonged drought in the East African Rift Valley.

Millions of people in the arid regions of Kenya and Ethiopia face water scarcity and frequent drought. Water resource forecasting and reliable operation of groundwater distribution systems may improve drought resilience. In this study, we examined three remote sensing data sets against in-situ sensor-collected groundwater extraction data from 221 water points serving over 1.34 million people across northern Kenya and Afar, Ethiopia between January 1, 2017 and August 31, 2018. In models containing rainfall as a binary variable, we observed an overall 23% increase in borehole runtime following weeks with no rainfall compared to weeks preceded by some rainfall. Further, a 1 mm increase in rainfall was associated with a 1% decrease in borehole use the following week. When surface water availability is reduced during the dry seasons, groundwater demand increases. Our findings emphasize the imperative to maintain functionality of groundwater boreholes in these regions which often suffer drought related emergencies. Funding provided by the United States Agency for International Development, the World Bank, the National Science Foundation, and the Cisco Foundation. The views expressed in this article do not necessarily reflect the views of the United States Agency for International Development or the United States Government.

Ensemble machine learning and forecasting can achieve 99% uptime for rural handpumps.

Broken water pumps continue to impede efforts to deliver clean and economically-viable water to the global poor. The literature has demonstrated that customers' health benefits and willingness to pay for clean water are best realized when clean water infrastructure performs extremely well (>99% uptime). In this paper, we used sensor data from 42 Afridev-brand handpumps observed for 14 months in western Kenya to demonstrate how sensors and supervised ensemble machine learning could be used to increase total fleet uptime from a best-practices baseline of about 70% to >99%. We accomplish this increase in uptime by forecasting pump failures and identifying existing failures very quickly. Comparing the costs of operating the pump per functional year over a lifetime of 10 years, we estimate that implementing this algorithm would save 7% on the levelized cost of water relative to a sensor-less scheduled maintenance program. Combined with a rigorous system for dispatching maintenance personnel, implementing this algorithm in a real-world program could significantly improve health outcomes and customers' willingness to pay for water services.

Comparison of respondent-reported and sensor-recorded latrine utilization measures in rural Bangladesh: a cross-sectional study.

Background: Health improvements realized through sanitation are likely achieved through high levels of facilities utilization by all household members. However, measurements of sanitation often rely on either the presence of latrines, which does not guarantee use, or respondent-reported utilization of sanitation facilities, which is prone to response bias. Overstatement of sanitation metrics limits the accuracy of program outcome measures, and has implications for the interpretation of related health impact data. Methods: We conducted a cross-sectional study of 213 households in 14 village water, sanitation and hygiene committee clusters throughout rural Bangladesh and used a combined data- and relationship-scale approach to assess agreement between respondent-reported latrine utilization and sensor-recorded measurement. Results: Four-day household-level respondent-reported defecation averaged 28 events (inter-quartile range [IQR] 20-40), while sensor-recorded defecation averaged 17 events (IQR 11-29). Comparative analyses suggest moderately high accuracy (bias correction factor=0.84), but imprecision in the data (broad scatter of data, Pearson's r=0.35) and thus only weak concordance between measures (ρc=0.29 [95% BCa CI 0.15 to 0.43]). Conclusions: Respondent-reported latrine utilization data should be interpreted with caution, as evidence suggests use is exaggerated. Coupling reported utilization data with objective measures of use may aid in the estimation of latrine use.

Use, microbiological effectiveness and health impact of a household water filter intervention in rural Rwanda-A matched cohort study.

Unsafe drinking water is a substantial health risk contributing to child diarrhoea. We investigated impacts of a program that provided a water filter to households in rural Rwandan villages. We assessed drinking water quality and reported diarrhoea 12-24 months after intervention delivery among 269 households in the poorest tertile with a child under 5 from 9 intervention villages and 9 matched control villages. We also documented filter coverage and use. In Round 1 (12-18 months after delivery), 97.4% of intervention households reported receiving the filter, 84.5% were working, and 86.0% of working filters contained water. Sensors confirmed half of households with working filters filled them at least once every other day on average. Coverage and usage was similar in Round 2 (19-24 months after delivery). The odds of detecting faecal indicator bacteria in drinking water were 78% lower in the intervention arm than the control arm (odds ratio (OR) 0.22, 95% credible interval (CrI) 0.10-0.39, p<0.001). The intervention arm also had 50% lower odds of reported diarrhoea among children <5 than the control arm (OR=0.50, 95% CrI 0.23-0.90, p=0.03). The protective effect of the filter is also suggested by reduced odds of reported diarrhoea-related visits to community health workers or clinics, although these did not reach statistical significance.

Comparing Sanitation Delivery Modalities in Urban Informal Settlement Schools: A Randomized Trial in Nairobi, Kenya.

The provision of safely managed sanitation in informal settlements is a challenge, especially in schools that require durable, clean, sex-segregated facilities for a large number of children. In informal settlements in Nairobi, school sanitation facilities demand considerable capital costs, yet are prone to breakage and often unhygienic. The private sector may be able to provide quality facilities and services to schools at lower costs as an alternative to the sanitation that is traditionally provided by the government. We conducted a randomized trial comparing private sector service delivery (PSSD) of urine-diverting dry latrines with routine waste collection and maintenance and government standard delivery (GSD) of cistern-flush toilets or ventilated improved pit latrines. The primary outcomes were facility maintenance, use, exposure to fecal contamination, and cost. Schools were followed for one school year. There were few differences in maintenance and pathogen exposure between PSSD and GSD toilets. Use of the PSSD toilets was 128% higher than GSD toilets, as measured with electronic motion detectors. The initial cost of private sector service delivery was USD 2053 (KES 210,000) per school, which was lower than the average cost of rehabilitating the government standard flush-type toilets (USD 9306 (KES 922,638)) and constructing new facilities (USD 114,889 (KES 1,169,668)). The private sector delivery of dry sanitation provided a feasible alternative to the delivery of sewage sanitation in Nairobi informal settlements and might elsewhere in sub-Saharan Africa.

Process evaluation and assessment of use of a large scale water filter and cookstove program in Rwanda.

BACKGROUND: In an effort to reduce the disease burden in rural Rwanda, decrease poverty associated with expenditures for fuel, and minimize the environmental impact on forests and greenhouse gases from inefficient combustion of biomass, the Rwanda Ministry of Health (MOH) partnered with DelAgua Health (DelAgua), a private social enterprise, to distribute and promote the use of improved cookstoves and advanced water filters to the poorest quarter of households (Ubudehe 1 and 2) nationally, beginning in Western Province under a program branded Tubeho Neza ("Live Well"). The project is privately financed and earns revenue from carbon credits under the United Nations Clean Development Mechanism. METHODS: During a 3-month period in late 2014, over 470,000 people living in over 101,000 households were provided free water filters and cookstoves. Following the distribution, community health workers visited nearly 98 % of households to perform household level education and training activities. Over 87 % of households were visited again within 6 months with a basic survey conducted. Detailed adoption surveys were conducted among a sample of households, 1000 in the first round, 187 in the second. RESULTS: Approximately a year after distribution, reported water filter use was above 90 % (+/-4 % CI) and water present in filter was observed in over 76 % (+/-6 % CI) of households, while the reported primary stove was nearly 90 % (+/-4.4 % CI) and of households cooking at the time of the visit, over 83 % (+/-5.3 % CI) were on the improved stove. There was no observed association between household size and stove stacking behavior. CONCLUSIONS: This program suggests that free distribution is not a determinant of low adoption. It is plausible that continued engagement in households, enabled by Ministry of Health support and carbon financed revenue, contributed to high adoption rates. Overall, the program was able to demonstrate a privately financed, public health intervention can achieve high levels of initial adoption and usage of household level water filtration and improved cookstoves at a large scale.

Behavioral Reactivity Associated With Electronic Monitoring of Environmental Health Interventions--A Cluster Randomized Trial with Water Filters and Cookstoves.

Subject reactivity--when research participants change their behavior in response to being observed--has been documented showing the effect of human observers. Electronics sensors are increasingly used to monitor environmental health interventions, but the effect of sensors on behavior has not been assessed. We conducted a cluster randomized controlled trial in Rwanda among 170 households (70 blinded to the presence of the sensor, 100 open) testing whether awareness of an electronic monitor would result in a difference in weekly use of household water filters and improved cookstoves over a four-week surveillance period. A 63% increase in number of uses of the water filter per week between the groups was observed in week 1, an average of 4.4 times in the open group and 2.83 times in the blind group, declining in week 4 to an insignificant 55% difference of 2.82 uses in the open, and 1.93 in the blind. There were no significant differences in the number of stove uses per week between the two groups. For both filters and stoves, use decreased in both groups over four-week installation periods. This study suggests behavioral monitoring should attempt to account for reactivity to awareness of electronic monitors that persists for weeks or more.

Study design of a cluster-randomized controlled trial to evaluate a large-scale distribution of cook stoves and water filters in Western Province, Rwanda.

BACKGROUND: In Rwanda, pneumonia and diarrhea are the first and second leading causes of death, respectively, among children under five. Household air pollution (HAP) resultant from cooking indoors with biomass fuels on traditional stoves is a significant risk factor for pneumonia, while consumption of contaminated drinking water is a primary cause of diarrheal disease. To date, there have been no large-scale effectiveness trials of programmatic efforts to provide either improved cookstoves or household water filters at scale in a low-income country. In this paper we describe the design of a cluster-randomized trial to evaluate the impact of a national-level program to distribute and promote the use of improved cookstoves and advanced water filters to the poorest quarter of households in Rwanda. METHODS/DESIGN: We randomly allocated 72 sectors (administratively defined units) in Western Province to the intervention, with the remaining 24 sectors in the province serving as controls. In the intervention sectors, roughly 100,000 households received improved cookstoves and household water filters through a government-sponsored program targeting the poorest quarter of households nationally. The primary outcome measures are the incidence of acute respiratory infection (ARI) and diarrhea among children under five years of age. Over a one-year surveillance period, all cases of acute respiratory infection (ARI) and diarrhea identified by health workers in the study area will be extracted from records maintained at health facilities and by community health workers (CHW). In addition, we are conducting intensive, longitudinal data collection among a random sample of households in the study area for in-depth assessment of coverage, use, environmental exposures, and additional health measures. DISCUSSION: Although previous research has examined the impact of providing household water treatment and improved cookstoves on child health, there have been no studies of national-level programs to deliver these interventions at scale in a developing country. The results of this study, the first RCT of a large-scale programmatic cookstove or household water filter intervention, will inform global efforts to reduce childhood morbidity and mortality from diarrheal disease and pneumonia. TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT02239250).

Evaluating Cellular Instrumentation on Rural Handpumps to Improve Service Delivery-A Longitudinal Study in Rural Rwanda.

In rural sub-Saharan Africa, where handpumps are common, 10-67% are nonfunctional at any one time, and many never get repaired. Increased reliability requires improved monitoring and responsiveness of maintenance providers. In 2014, 181 cellular enabled water pump use sensors were installed in three provinces of Rwanda. In three arms, the nominal maintenance model was compared against a "best practice" circuit rider model, and an "ambulance" service model. In only the ambulance model was the sensor data available to the implementer, and used to dispatch technicians. The study ran for seven months in 2014-2015. In the study period, the nominal maintenance group had a median time to successful repair of approximately 152 days, with a mean per-pump functionality of about 68%. In the circuit rider group, the median time to successful repair was nearly 57 days, with a per-pump functionality mean of nearly 73%. In the ambulance service group, the successful repair interval was nearly 21 days with a functionality mean of nearly 91%. An indicative cost analysis suggests that the cost per functional pump per year is approximately similar between the three models. However, the benefits of reliable water service may justify greater focus on servicing models over installation models.

A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract.

Intrinsic sensory neurons (ISNs) of the enteric nervous system respond to stimuli such as muscle tension, muscle length, distortion of the mucosa, and the chemical content in the lumen. ISNs form recurrent networks that probably drive many intestinal motor patterns and reflexes. ISNs express a large number of voltage- and calcium-gated ion channels, some of which are modified by inflammation or repeated physiological stimuli, but how interactions between different ionic currents in ISNs produce both normal and pathological behaviors in the intestine remains unclear. We constructed a model of ISNs including voltage-gated sodium and potassium channels, N-type calcium channels, big conductance calcium-dependent potassium (BK) channels, calcium-dependent nonspecific cation channels (NSCa), intermediate conductance calcium-dependent potassium (IK) channels, hyperpolarization-activated cation (Ih) channels, and internal calcium dynamics. The model was based on data from the literature and our electrophysiological studies. The model reproduced responses to short or long depolarizing current pulses and responses to long hyperpolarizing current pulses. Sensitivity analysis showed that Ih, IK, NSCa, and BK have the largest influence on the number of action potentials observed during prolonged depolarizations. The model also predicts that changes to the voltage of activation for Ih have a large influence on excitability, but changes to the time constant of activation for Ih have a minor effect. Our model identifies how interactions between different iconic currents influence the excitability of ISNs and highlights an important role for Ih in enteric neuroplasticity resulting from disease.

Designing and piloting a program to provide water filters and improved cookstoves in Rwanda.

BACKGROUND: In environmental health interventions addressing water and indoor air quality, multiple determinants contribute to adoption. These may include technology selection, technology distribution and education methods, community engagement with behavior change, and duration and magnitude of implementer engagement. In Rwanda, while the country has the fastest annual reduction in child mortality in the world, the population is still exposed to a disease burden associated with environmental health challenges. Rwanda relies both on direct donor funding and coordination of programs managed by international non-profits and health sector businesses working on these challenges. METHODS AND FINDINGS: This paper describes the design, implementation and outcomes of a pilot program in 1,943 households across 15 villages in the western province of Rwanda to distribute and monitor the use of household water filters and improved cookstoves. Three key program design criteria include a.) an investment in behavior change messaging and monitoring through community health workers, b.) free distributions to encourage community-wide engagement, and c.) a private-public partnership incentivized by a business model designed to encourage "pay for performance". Over a 5-month period of rigorous monitoring, reported uptake was maintained at greater than 90% for both technologies, although exclusive use of the stove was reported in only 28.5% of households and reported water volume was 1.27 liters per person per day. On-going qualitative monitoring suggest maintenance of comparable adoption rates through at least 16 months after the intervention. CONCLUSION: High uptake and sustained adoption of a water filter and improved cookstove was measured over a five-month period with indications of continued comparable adoption 16 months after the intervention. The design attributes applied by the implementers may be sufficient in a longer term. In particular, sustained and comprehensive engagement by the program implementer is enabled by a pay-for-performance business model that rewards sustained behavior change.

Mathematical modelling of enteric neural motor patterns.

1. The enteric nervous system modulates intestinal behaviours, such as motor patterns and secretion. Although much is known about different types of neurons and simple reflexes in the intestine, it remains unclear how complex behaviours are generated. 2. Mathematical modelling is an important tool for assisting the understanding of how the neurons and reflexes can be pieced together to generate intestinal behaviours. 3. Models have identified a functional role for slow excitatory post-synaptic potentials (EPSPs) by distinguishing between fast and slow EPSPs in the ascending excitation reflex. These models also discovered coordinated firing of similarly located neurons as emergent properties of feed-forward networks of interneurons in the intestine. A model of the recurrent network of intrinsic sensory neurons identified important control mechanisms to prevent uncontrolled firing due to positive feedback and that the interaction between these control mechanisms and slow EPSPs is necessary for the networks to encode ongoing sensory stimuli. This model also showed that such networks may mediate migrating motor complexes. 4. A network model of vasoactive intestinal peptide neurons in the submucosal plexus found this relatively sparse recurrent network could produce uncontrolled firing under conditions that appear to be related to cholera toxin-induced hypersecretion. 5. Abstract modelling of the intestinal fed-state motor patterns has identified how stationary contractions can arise from a polarized network. 6. These models have also helped predict and/or explained pharmacological evidence for two rhythm generators and the requirement of feedback from contractions in the circular muscle.

Use of remotely reporting electronic sensors for assessing use of water filters and cookstoves in Rwanda.

Remotely reporting electronic sensors offer the potential to reduce bias in monitoring use of environmental health interventions. In the context of a five-month randomized controlled trial of household water filters and improved cookstoves in rural Rwanda, we collected data from intervention households on product compliance using (i) monthly surveys and direct observations by community health workers and environmental health officers, and (ii) sensor-equipped filters and cookstoves deployed for about two weeks in each household. The adoption rate interpreted by the sensors varied from the household reporting: 90.5% of households reported primarily using the intervention stove, while the sensors interpreted 73.2% use, and 96.5% of households reported using the intervention filter regularly, while the sensors interpreted no more than 90.2%. The sensor-collected data estimated use to be lower than conventionally collected data both for water filters (approximately 36% less water volume per day) and cookstoves (approximately 40% fewer uses per week). An evaluation of intrahousehold consistency in use suggests that households are not using their filters or stoves on an exclusive basis, and may be both drinking untreated water at times and using other stoves ("stove-stacking"). These results provide additional evidence that surveys and direct observation may exaggerate compliance with household-based environmental interventions.

Network-specific mechanisms may explain the paradoxical effects of carbamazepine and phenytoin.

PURPOSE: A common notion of the mechanism by which the antiepileptic drugs (AEDs) carbamazepine and phenytoin act is that they block sodium channels by binding preferentially to the inactivated state, thereby allowing normal neuronal firing while blocking ictal activity. However, these drugs have unpredictable efficacy and, in some cases, may exacerbate seizures. Previous studies have suggested that reducing sodium channel availability in the dentate gyrus (DG) paradoxically increases excitability. We used a biophysically detailed computer model of the DG to test the hypothesis that AEDs increase excitability by disproportionately reducing negative feedback mechanisms. METHODS: We built a Markov model of sodium channel gating that reproduces responses to voltage clamp experiments in the presence of carbamazepine and phenytoin. We incorporated this validated Markov model into a biophysically realistic computer model of DG neurons and networks. Simulated drug concentrations were similar to those measured in cerebral spinal fluid in medicated patients. Single neuron models were stimulated with current injections, and networks were stimulated with perforant path synaptic input. In the network model, environmental effects were studied by introducing mossy fiber sprouting. KEY FINDINGS: As expected, drugs reduced sodium channel availability, which in turn reduced action potential amplitude. This had only a small effect on action potential (AP) firing rate during brief (100 msec) current injections. Paradoxically, long current injections (2,500 msec) increased AP firing rates. This was caused by reduced calcium entry and consequently reduced activation of calcium activated potassium channels. It is important to note that the main determinant of drug effect was resting membrane potential (RMP) and not action potential firing rate. Binding of phenytoin and carbamazepine is slow and, thus drug effects are largely determined by the long term state of the RMP. This paradoxical AP firing increase was dependent on the unusually large calcium-activated potassium conductances expressed by DG granule cells. This predicts that drug efficacy in a given network will depend on the precise makeup of conductances in the network. RMP is expected to vary with the level of activity in the network. We simulated the effects of drugs on single shot stimulus responses in networks with mossy fiber sprouting and varied the RMP in all neurons as a model for network activity. For an RMP of -50 mV, representing an active network, drugs had no effect, or in some cases, increased excitability. Drugs had an increasingly larger inhibitory effect on network responses as RMP decreased. An important prediction is that drugs will be unable to block ictal activity invading an active network. SIGNIFICANCE: Our key findings are that drug effects depend on both intrinsic properties of the network and its behavioral state. This may explain the paradoxical and unpredictable effects of some AEDs on seizure control in some patients.

Axon initial segment structural plasticity in animal models of genetic and acquired epilepsy.

A novel form of neuronal plasticity, occurring at the axon initial segment (AIS), has recently been described. Lengthening of the AIS and movement away from the soma are consequences of changes in neuronal input and result in alterations in neuronal excitability. We hypothesised that AIS plasticity may play a role in epilepsy, due to chronic changes in neuronal activity. Immunohistochemistry and confocal microscopy were used to analyse AIS length and position in pyramidal neurons in deep layer 5 of the somatosensory cortex from 5 mice with genetic epilepsy and 4 controls, and from 3 rats subjected to amygdala kindling and 3 controls. The effect of a subtle alteration of AIS position was modelled computationally. We identified a difference in the position of the AIS in animals with seizures: in mice the AIS was positioned 0.2 µm further away from the soma, and in rats the AIS was positioned 0.6 µm closer to the soma compared with controls. Computational modelling indicated that a subtle alteration in AIS position could result in a change in action potential firing threshold. The identification of AIS plasticity in animal models of epilepsy is significant in furthering our understanding of the pathophysiological mechanisms involved in this disorder.

Parametric computation predicts a multiplicative interaction between synaptic strength parameters that control gamma oscillations.

Gamma oscillations are thought to be critical for a number of behavioral functions, they occur in many regions of the brain and through a variety of mechanisms. Fast repetitive bursting (FRB) neurons in layer 2 of the cortex are able to drive gamma oscillations over long periods of time. Even though the oscillation is driven by FRB neurons, strong feedback within the rest of the cortex must modulate properties of the oscillation such as frequency and power. We used a highly detailed model of the cortex to determine how a cohort of 33 parameters controlling synaptic drive might modulate gamma oscillation properties. We were interested in determining not just the effects of parameters individually, but we also wanted to reveal interactions between parameters beyond additive effects. To prevent a combinatorial explosion in parameter combinations that might need to be simulated, we used a fractional factorial design (FFD) that estimated the effects of individual parameters and two parameter interactions. This experiment required only 4096 model runs. We found that the largest effects on both gamma power and frequency came from a complex interaction between efficacy of synaptic connections from layer 2 inhibitory neurons to layer 2 excitatory neurons and the parameter for the reciprocal connection. As well as the effect of the individual parameters determining synaptic efficacy, there was an interaction between these parameters beyond the additive effects of the parameters alone. The magnitude of this effect was similar to that of the individual parameters, predicting that it is physiologically important in setting gamma oscillation properties.

Multiple neural oscillators and muscle feedback are required for the intestinal fed state motor program.

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40-60 s and separated by quiescent episodes lasting 40-200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle.