Epileptogenic networks in extra temporal lobe epilepsy.

Extra temporal lobe epilepsy (eTLE) may involve heterogenous widespread cerebral networks. We investigated the structural network of an eTLE cohort, at the postulated epileptogenic zone later surgically removed, as a network node: the resection zone (RZ). We hypothesized patients with an abnormal connection to/from the RZ to have proportionally increased abnormalities based on topological proximity to the RZ, in addition to poorer post-operative seizure outcome. Structural and diffusion MRI were collected for 22 eTLE patients pre- and post-surgery, and for 29 healthy controls. The structural connectivity of the RZ prior to surgery, measured via generalized fractional anisotropy (gFA), was compared with healthy controls. Abnormal connections were identified as those with substantially reduced gFA (z < -1.96). For patients with one or more abnormal connections to/from the RZ, connections with closer topological distance to the RZ had higher proportion of abnormalities. The minority of the seizure-free patients (3/11) had one or more abnormal connections, while most non-seizure-free patients (8/11) had abnormal connections to the RZ. Our data suggest that eTLE patients with one or more abnormal structural connections to/from the RZ had more proportional abnormal connections based on topological distance to the RZ and associated with reduced chance of seizure freedom post-surgery.

Normative brain mapping of interictal intracranial EEG to localize epileptogenic tissue.

The identification of abnormal electrographic activity is important in a wide range of neurological disorders, including epilepsy for localizing epileptogenic tissue. However, this identification may be challenging during non-seizure (interictal) periods, especially if abnormalities are subtle compared to the repertoire of possible healthy brain dynamics. Here, we investigate if such interictal abnormalities become more salient by quantitatively accounting for the range of healthy brain dynamics in a location-specific manner. To this end, we constructed a normative map of brain dynamics, in terms of relative band power, from interictal intracranial recordings from 234 participants (21 598 electrode contacts). We then compared interictal recordings from 62 patients with epilepsy to the normative map to identify abnormal regions. We proposed that if the most abnormal regions were spared by surgery, then patients would be more likely to experience continued seizures postoperatively. We first confirmed that the spatial variations of band power in the normative map across brain regions were consistent with healthy variations reported in the literature. Second, when accounting for the normative variations, regions that were spared by surgery were more abnormal than those resected only in patients with persistent postoperative seizures (t = -3.6, P = 0.0003), confirming our hypothesis. Third, we found that this effect discriminated patient outcomes (area under curve 0.75 P = 0.0003). Normative mapping is a well-established practice in neuroscientific research. Our study suggests that this approach is feasible to detect interictal abnormalities in intracranial EEG, and of potential clinical value to identify pathological tissue in epilepsy. Finally, we make our normative intracranial map publicly available to facilitate future investigations in epilepsy and beyond.

A Closed-Loop Optogenetic Platform.

Neuromodulation is an established treatment for numerous neurological conditions, but to expand the therapeutic scope there is a need to improve the spatial, temporal and cell-type specificity of stimulation. Optogenetics is a promising area of current research, enabling optical stimulation of genetically-defined cell types without interfering with concurrent electrical recording for closed-loop control of neural activity. We are developing an open-source system to provide a platform for closed-loop optogenetic neuromodulation, incorporating custom integrated circuitry for recording and stimulation, real-time closed-loop algorithms running on a microcontroller and experimental control via a PC interface. We include commercial components to validate performance, with the ultimate aim of translating this approach to humans. In the meantime our system is flexible and expandable for use in a variety of preclinical neuroscientific applications. The platform consists of a Controlling Abnormal Network Dynamics using Optogenetics (CANDO) Control System (CS) that interfaces with up to four CANDO headstages responsible for electrical recording and optical stimulation through custom CANDO LED optrodes. Control of the hardware, inbuilt algorithms and data acquisition is enabled via the CANDO GUI (Graphical User Interface). Here we describe the design and implementation of this system, and demonstrate how it can be used to modulate neuronal oscillations in vitro and in vivo.

Towards simulations of long-term behavior of neural networks: Modeling synaptic plasticity of connections within and between human brain regions.

Simulations of neural networks can be used to study the direct effect of internal or external changes on brain dynamics. However, some changes are not immediate but occur on the timescale of weeks, months, or years. Examples include effects of strokes, surgical tissue removal, or traumatic brain injury but also gradual changes during brain development. Simulating network activity over a long time, even for a small number of nodes, is a computational challenge. Here, we model a coupled network of human brain regions with a modified Wilson-Cowan model representing dynamics for each region and with synaptic plasticity adjusting connection weights within and between regions. Using strategies ranging from different models for plasticity, vectorization and a different differential equation solver setup, we achieved one second runtime for one second biological time.

Computational modelling of the long-term effects of brain stimulation on the local and global structural connectivity of epileptic patients.

Computational studies of the influence of different network parameters on the dynamic and topological network effects of brain stimulation can enhance our understanding of different outcomes between individuals. In this study, a brain stimulation session along with the subsequent post-stimulation brain activity is simulated for a period of one day using a network of modified Wilson-Cowan oscillators coupled according to diffusion imaging based structural connectivity. We use this computational model to examine how differences in the inter-region connectivity and the excitability of stimulated regions at the time of stimulation can affect post-stimulation behaviours. Our findings indicate that the initial inter-region connectivity can heavily affect the changes that stimulation induces in the connectivity of the network. Moreover, differences in the excitability of the stimulated regions seem to lead to different post-stimulation connectivity changes across the model network, including on the internal connectivity of non-stimulated regions.

The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX) Version 2.0: Modelling in vitro electrical stimulation of brain tissue.

Neuronal circuits can be modelled in detail allowing us to predict the effects of stimulation on individual neurons. Electrical stimulation of neuronal circuits in vitro and in vivo excites a range of neurons within the tissue and measurements of neural activity, e.g the local field potential (LFP), are again an aggregate of a large pool of cells. The previous version of our Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX) allowed for the simulation of the LFP generated by a patch of brain tissue. Here, we extend VERTEX to simulate the effect of electrical stimulation through a focal electric field. We observe both direct changes in neural activity and changes in synaptic plasticity. Testing our software in a model of a rat neocortical slice, we determine the currents contributing to the LFP, the effects of paired pulse stimulation to induce short term plasticity (STP), and the effect of theta burst stimulation (TBS) to induce long term potentiation (LTP).

Predicting Surgery Targets in Temporal Lobe Epilepsy through Structural Connectome Based Simulations.

Temporal lobe epilepsy (TLE) is a prevalent neurological disorder resulting in disruptive seizures. In the case of drug resistant epilepsy resective surgery is often considered. This is a procedure hampered by unpredictable success rates, with many patients continuing to have seizures even after surgery. In this study we apply a computational model of epilepsy to patient specific structural connectivity derived from diffusion tensor imaging (DTI) of 22 individuals with left TLE and 39 healthy controls. We validate the model by examining patient-control differences in simulated seizure onset time and network location. We then investigate the potential of the model for surgery prediction by performing in silico surgical resections, removing nodes from patient networks and comparing seizure likelihood post-surgery to pre-surgery simulations. We find that, first, patients tend to transit from non-epileptic to epileptic states more often than controls in the model. Second, regions in the left hemisphere (particularly within temporal and subcortical regions) that are known to be involved in TLE are the most frequent starting points for seizures in patients in the model. In addition, our analysis also implicates regions in the contralateral and frontal locations which may play a role in seizure spreading or surgery resistance. Finally, the model predicts that patient-specific surgery (resection areas chosen on an individual, model-prompted, basis and not following a predefined procedure) may lead to better outcomes than the currently used routine clinical procedure. Taken together this work provides a first step towards patient specific computational modelling of epilepsy surgery in order to inform treatment strategies in individuals.

Computational modeling of neurostimulation in brain diseases.

Neurostimulation as a therapeutic tool has been developed and used for a range of different diseases such as Parkinson's disease, epilepsy, and migraine. However, it is not known why the efficacy of the stimulation varies dramatically across patients or why some patients suffer from severe side effects. This is largely due to the lack of mechanistic understanding of neurostimulation. Hence, theoretical computational approaches to address this issue are in demand. This chapter provides a review of mechanistic computational modeling of brain stimulation. In particular, we will focus on brain diseases, where mechanistic models (e.g., neural population models or detailed neuronal models) have been used to bridge the gap between cellular-level processes of affected neural circuits and the symptomatic expression of disease dynamics. We show how such models have been, and can be, used to investigate the effects of neurostimulation in the diseased brain. We argue that these models are crucial for the mechanistic understanding of the effect of stimulation, allowing for a rational design of stimulation protocols. Based on mechanistic models, we argue that the development of closed-loop stimulation is essential in order to avoid inference with healthy ongoing brain activity. Furthermore, patient-specific data, such as neuroanatomic information and connectivity profiles obtainable from neuroimaging, can be readily incorporated to address the clinical issue of variability in efficacy between subjects. We conclude that mechanistic computational models can and should play a key role in the rational design of effective, fully integrated, patient-specific therapeutic brain stimulation.

GPs should evaluate all children following UTI.

Ten per cent of girls and 3% of boys will have had a UTI by 16 years of age. The majority are acute, isolated illnesses that resolve quickly, with no long-term implications for the patient. However, UTIs may be associated with underlying congenital abnormalities, and recurrent infections can lead to renal scarring. UTI is defined as bacteriuria in the presence of symptoms. Asymptomatic bacteriuria does not require treatment or investigation. The presentation of UTI is extremely variable. The only way to differentiate a UTI from a viral infection is by testing the urine and this should be carried out within 24 hours in children with non-specific fever. UTIs can also present with vomiting, failure to thrive or persistent irritability. A urine infection in the presence of any of the above symptoms is a pyelonephritis (upper UTI). Children may also present with classical symptoms of cystitis (lower UTI) such as urinary frequency, dysuria and abdominal pain. Most children with UTI, even if febrile, can be managed in the community. If the initial assessment shows a high risk of serious illness, there should be an urgent referral to a paediatrician. The same applies to infants under three months with suspected UTI. It is better to obtain a urine sample by the clean catch method, rather than using urine pads or bags. Leucocyte esterase and nitrite dipsticks are not reliable in children under three, so a negative dipstick does not rule out UTI. Not every child needs to be referred after a first UTI. However, they should all be evaluated to help determine which require renal imaging as well as identifying triggers for recurrence. GPs are central to the identification of children at risk of renal pathology. All children who are diagnosed and treated for a UTI must be assessed for risk of renal abnormalities and/or recurrence.