Intraoperative changes in large-scale thalamic circuitry following laser ablation of hypothalamic hamartomas.

BACKGROUND AND OBJECTIVES: Gelastic seizures due to hypothalamic hamartomas (HH) are challenging to treat, in part due to an incomplete understanding of seizure propagation pathways. Although magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) is a promising intervention to disconnect HH from ictal propagation networks, the optimal site of ablation to achieve seizure freedom is not known. In this study, we investigated intraoperative post-ablation changes in resting-state functional connectivity to identify large-scale networks associated with successful disconnection of HH. METHODS: Children who underwent MRgLITT for HH at two institutions were consecutively recruited and followed for a minimum of one year. Seizure freedom was defined as Engel score of 1A at the last available follow-up. Immediate pre- and post- ablation resting-state functional MRI scans were acquired while maintaining a constant depth of general anesthetic. Multivariable generalized linear models were used to identify intraoperative changes in large-scale connectivity associated with seizure outcomes. RESULTS: Twelve patients underwent MRgLITT for HH, five of whom were seizure-free at their last follow-up. Intraprocedural changes in thalamocortical circuitry involving the anterior cingulate cortex were associated with seizure-freedom. Children who were seizure-free demonstrated an increase and decrease in connectivity to the pregenual and dorsal anterior cingulate cortices, respectively. In addition, children who became seizure-free demonstrated increased thalamic connectivity to the periaqueductal gray immediately following MRgLITT. DISCUSSION: Successful disconnection of HH is associated with intraoperative, large-scale changes in thalamocortical connectivity. These changes provide novel insights into the large-scale basis of gelastic seizures and may represent intraoperative biomarkers of treatment success.

Chronic Pallidal Local Field Potentials Are Associated With Dystonic Symptoms in Children.

BACKGROUND: Novel deep brain stimulation devices can record local field potentials (LFPs), which represent the synchronous synaptic activity of neuronal populations. The clinical relevance of LFPs in patients with dystonia remains unclear. OBJECTIVES: We sought to determine whether chronic LFPs recorded from the globus pallidus internus (GPi) were associated with symptoms of dystonia in children. MATERIALS AND METHODS: Ten patients with heterogeneous forms of dystonia (genetic and acquired) were implanted with neurostimulators that recorded LFP spectral snapshots. Spectra were compared across parent-reported asymptomatic and symptomatic periods, with daily narrowband data superimposed in 24 one-hour bins. RESULTS: Spectral power increased during periods of registered dystonic symptoms: mean increase = 102%, CI: (76.7, 132). Circadian rhythms within the LFP narrowband time series correlated with dystonic symptoms: for delta/theta-waves, correlation = 0.33, CI: (0.18, 0.47) and for alpha waves, correlation = 0.27, CI: (0.14, 0.40). CONCLUSIONS: LFP spectra recorded in the GPi indicate a circadian pattern and are associated with the manifestation of dystonic symptoms.

Which is more deleterious to cognitive performance? Interictal epileptiform discharges vs anti-seizure medication.

Children with epilepsy commonly have comorbid neurocognitive impairments that severely affect their psychosocial well-being, education, and future career prospects. Although the provenance of these deficits is multifactorial, the effects of interictal epileptiform discharges (IEDs) and anti-seizure medications (ASMs) are thought to be particularly severe. Although certain ASMs can be leveraged to inhibit IED occurrence, it remains unclear whether epileptiform discharges or the medications themselves are most deleterious to cognition. To examine this question, 25 children undergoing invasive monitoring for refractory focal epilepsy performed one or more sessions of a cognitive flexibility task. Electrophysiological data were recorded to detect IEDs. Between repeated sessions, prescribed ASMs were either continued or titrated to <50% of the baseline dose. Hierarchical mixed-effects modeling assessed the relationship between task reaction time (RT), IED occurrence, ASM type, and dose while controlling for seizure frequency. Both presence (ß ± SE = 49.91 ± 16.55 ms, p = .003) and number of IEDs (ß ± SE = 49.84 ± 12.51 ms, p < .001) were associated with slowed task RT. Higher dose oxcarbazepine significantly reduced IED frequency (p = .009) and improved task performance (ß ± SE = -107.43 ± 39.54 ms, p = .007). These results emphasize the neurocognitive consequences of IEDs independent of seizure effects. Furthermore, we demonstrate that inhibition of IEDs following treatment with select ASMs is associated with improved neurocognitive function.

Interictal discharges delay target-directed eye movements and impair attentional set-shifting in children with epilepsy.

OBJECTIVE: The theory of transient cognitive impairment in epilepsy posits that lapses in attention result from ephemeral disruption of attentional circuitry by interictal events. Eye movements are intimately associated with human attention and can be monitored in real time using eye-tracking technologies. Here, we sought to characterize the associations between interictal epileptiform discharges (IEDs), gaze, and attentional behavior in children with epilepsy. METHODS: Eleven consecutive children undergoing invasive monitoring with stereotactic electrodes for localization-related epilepsy performed an attentional set-shifting task while tandem intracranial electroencephalographic signals and eye-tracking data were recorded. Using an established algorithm, IEDs were detected across all intracranial electrodes on a trial-by-trial basis. Hierarchical mixed-effects modeling was performed to delineate associations between trial reaction time (RT), eye movements, and IEDs. RESULTS: Hierarchical mixed-effects modeling revealed that both the presence of an IED (ß ± SE = 72.74 ± 24.21 ms, p = .003) and the frequency of epileptiform events (ß ± SE = 67.54 ± 17.30 ms, p < .001) were associated with prolonged RT on the attentional set-shifting task. IED occurrence at the time of stimulus presentation was associated with delays in gaze initiation toward the visual targets (p = .017). SIGNIFICANCE: The occurrence of epileptiform activity in close temporal association with stimulus presentation is associated with delays in target-directed gaze and prolonged response time, hallmarks of momentary lapses in attention. These findings provide novel insights into the mechanisms of transient impairments in children and support the use of visual tracking as a correlate of higher order attentional behavior.

Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists.

Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.

Overlapping community detection using Bayesian non-negative matrix factorization.

Identifying overlapping communities in networks is a challenging task. In this work we present a probabilistic approach to community detection that utilizes a Bayesian non-negative matrix factorization model to extract overlapping modules from a network. The scheme has the advantage of soft-partitioning solutions, assignment of node participation scores to modules, and an intuitive foundation. We present the performance of the method against a variety of benchmark problems and compare and contrast it to several other algorithms for community detection.

Evaluation of a series of bicyclic CXCR2 antagonists.

The CXCR2 SAR of a series of bicyclic antagonists such as the 2-aminothiazolo[4,5-d]pyrimidine 3b was investigated by systematic variation of the fused pyrimidine-based heterocyclic cores. Replacement of the aminothiazole ring with a 2-thiazolone alternative led to a series of thiazolo[4,5-d]pyrimidine-2(3H)-one antagonists with markedly improved biological and pharmacokinetic properties, which are suitable pharmacological tools to probe the in vivo effects of CXCR2 antagonism combined with the associated CCR2 activity.

A synaptic input portal for a mapped clock oscillator model of neuronal electrical rhythmic activity.

Neuronal electrical oscillations play a central role in a variety of situations, such as epilepsy and learning. The mapped clock oscillator (MCO) model is a general model of transmembrane voltage oscillations in excitable cells. In order to be able to investigate the behaviour of neuronal oscillator populations, we present a neuronal version of the model. The neuronal MCO includes an extra input portal, the synaptic portal, which can reflect the biological relationships in a chemical synapse between the frequency of the presynaptic action potentials and the postsynaptic resting level, which in turn affects the frequency of the postsynaptic potentials. We propose that the synaptic input-output relationship must include a power function in order to be able to reproduce physiological behaviour such as resting level saturation. One linear and two power functions (Butterworth and sigmoidal) are investigated, using the case of an inhibitory synapse. The linear relation was not able to produce physiologically plausible behaviour, whereas both the power function examples were appropriate. The resulting neuronal MCO model can be tailored to a variety of neuronal cell types, and can be used to investigate complex population behaviour, such as the influence of network topology and stochastic resonance.