Identifying sources of human interictal discharges with travelling wave and white matter propagation.

Interictal epileptiform discharges have been shown to propagate from focal epileptogenic sources as travelling waves or through more rapid white matter conduction. We hypothesize that both modes of propagation are necessary to explain interictal discharge timing delays. We propose a method that, for the first time, incorporates both propagation modes to identify unique potential sources of interictal activity. We retrospectively analysed 38 focal epilepsy patients who underwent intracranial EEG recordings and diffusion-weighted imaging for epilepsy surgery evaluation. Interictal discharges were detected and localized to the most likely source based on relative delays in time of arrival across electrodes, incorporating travelling waves and white matter propagation. We assessed the influence of white matter propagation on distance of spread, timing and clinical interpretation of interictal activity. To evaluate accuracy, we compared our source localization results to earliest spiking regions to predict seizure outcomes. White matter propagation helps to explain the timing delays observed in interictal discharge sequences, underlying rapid and distant propagation. Sources identified based on differences in time of receipt of interictal discharges are often distinct from the leading electrode location. Receipt of activity propagating rapidly via white matter can occur earlier than more local activity propagating via slower cortical travelling waves. In our cohort, our source localization approach was more accurate in predicting seizure outcomes than the leading electrode location. Inclusion of white matter in addition to travelling wave propagation in our model of discharge spread did not improve overall accuracy but allowed for identification of unique and at times distant potential sources of activity, particularly in patients with persistent postoperative seizures. Since distant white matter propagation can occur more rapidly than local travelling wave propagation, combined modes of propagation within an interictal discharge sequence can decouple the commonly assumed relationship between spike timing and distance from the source. Our findings thus highlight the clinical importance of recognizing the presence of dual modes of propagation during interictal discharges, as this may be a cause of clinical mislocalization.

Critical role of the ventral temporal lobe in naming.

OBJECTIVE: Lexical retrieval deficits are characteristic of a variety of different neurological disorders. However, the exact substrates responsible for this are not known. We studied a large cohort of patients undergoing surgery in the dominant temporal lobe for medically intractable epilepsy (n = 95) to localize brain regions that were associated with anomia. METHODS: We performed a multivariate voxel-based lesion-symptom mapping analysis to correlate surgical lesions within the temporal lobe with changes in naming ability. Additionally, we used a surface-based mixed-effects multilevel analysis to estimate group-level broadband gamma activity during naming across a subset of patients with electrocorticographic recordings and integrated these results with lesion-deficit findings. RESULTS: We observed that ventral temporal regions, centered around the middle fusiform gyrus, were significantly associated with a decline in naming. Furthermore, we found that the ventral aspect of temporal lobectomies was linearly correlated to a decline in naming, with a clinically significant decline occurring once the resection extended 6 cm from the anterior tip of the temporal lobe on the ventral surface. On electrocorticography, the majority of these cortical regions were functionally active following visual processing. These loci coincide with the sites of susceptibility artifacts during echoplanar imaging, which may explain why this region has been previously underappreciated as the locus responsible for postoperative naming deficits. SIGNIFICANCE: Taken together, these data highlight the crucial contribution of the ventral temporal cortex in naming and its important role in the pathophysiology of anomia following temporal lobe resections. As such, surgical strategies should attempt to preserve this region to mitigate postoperative language deficits.

Vinegar-amended anaerobic biosand filter for the removal of arsenic and nitrate from groundwater.

The performance of a vinegar-amended anaerobic biosand filter was evaluated for future application as point-of-use water treatment in rural areas for the removal of arsenic and nitrate from groundwater containing common ions. Due to the importance of sulfate and iron in arsenic removal and their variable concentrations in groundwater, influent sulfate and iron concentrations were varied. Complete removal of influent nitrate (50 mg/L) and over 50% removal of influent arsenic (200 µg/L) occurred. Of all conditions tested, the lowest median effluent arsenic concentration was 88 µg/L. Iron removal occurred completely when 4 mg/L was added, and sulfate concentrations were lowered to a median concentration <2 mg/L from influent concentrations of 22 and 50 mg/L. Despite iron and sulfate removal and the establishment of reducing conditions, arsenic concentrations remained above the World Health Organization's arsenic drinking water standard. Further research is necessary to determine if anaerobic biosand filters can be improved to meet the arsenic drinking water standard and to evaluate practical implementation challenges.

The spatiotemporal dynamics of semantic integration in the human brain.

Language depends critically on the integration of lexical information across multiple words to derive semantic concepts. Limitations of spatiotemporal resolution have previously rendered it difficult to isolate processes involved in semantic integration. We utilized intracranial recordings in epilepsy patients (n = 58) who read written word definitions. Descriptions were either referential or non-referential to a common object. Semantically referential sentences enabled high frequency broadband gamma activation (70-150 Hz) of the inferior frontal sulcus (IFS), medial parietal cortex, orbitofrontal cortex (OFC) and medial temporal lobe in the left, language-dominant hemisphere. IFS, OFC and posterior middle temporal gyrus activity was modulated by the semantic coherence of non-referential sentences, exposing semantic effects that were independent of task-based referential status. Components of this network, alongside posterior superior temporal sulcus, were engaged for referential sentences that did not clearly reduce the lexical search space by the final word. These results indicate the existence of complementary cortical mosaics for semantic integration in posterior temporal and inferior frontal cortex.

Lateralization of interictal temporal lobe hypoperfusion in lesional and non-lesional temporal lobe epilepsy using arterial spin labeling MRI.

PURPOSE: Non-invasive imaging studies play a critical role in the presurgical evaluation of patients with drug-resistant temporal lobe epilepsy (TLE), particularly in helping to lateralize the seizure focus. Arterial Spin Labeling (ASL) MRI has been widely used to non-invasively study cerebral blood flow (CBF), with somewhat variable interictal alterations reported in TLE. Here, we compare temporal lobe subregional interictal perfusion and symmetry in lesional (MRI+) and non-lesional (MRI-) TLE compared to healthy volunteers (HVs). METHODS: Twenty TLE patients (9 MRI+, 11 MRI-) and 14 HVs under went 3 T Pseudo-Continuous ASL MRI through an epilepsy imaging research protocol at the NIH Clinical Center. We compared normalized CBF and absolute asymmetry indices in multiple temporal lobe subregions. RESULTS: Compared to HVs, both MRI+ and MRI- TLE groups demonstrated significant ipsilateral mesial and lateral temporal hypoperfusion, specifically in the hippocampal and anterior temporal neocortical subregions, with additional hypoperfusion in the ipsilateral parahippocampal gyrus in the MRI+ and contralateral hippocampus in the MRI- TLE groups. Contralateral to the seizure focus, there was significant relative hypoperfusion in multiple subregions in the MRI- compared to the MRI+ TLE groups. The MRI+ group therefore had significantly greater asymmetry across multiple temporal subregions compared to the MRI- TLE and HV groups. No significant differences in asymmetry were found between the MRI- TLE and HV groups. CONCLUSION: We found a similar extent of interictal ipsilateral temporal hypoperfusion in MRI+ and MRI- TLE. However, significantly increased asymmetries were found only in the MRI+ group due to differences in perfusion contralateral to the seizure focus between the patient groups. The lack of asymmetry in the MRI- group may negatively impact the utility of interictal ASL for seizure focus lateralization in this patient population.

Intraoperative cortical localization of music and language reveals signatures of structural complexity in posterior temporal cortex.

Language and music involve the productive combination of basic units into structures. It remains unclear whether brain regions sensitive to linguistic and musical structure are co-localized. We report an intraoperative awake craniotomy in which a left-hemispheric language-dominant professional musician underwent cortical stimulation mapping (CSM) and electrocorticography of music and language perception and production during repetition tasks. Musical sequences were melodic or amelodic, and differed in algorithmic compressibility (Lempel-Ziv complexity). Auditory recordings of sentences differed in syntactic complexity (single vs. multiple phrasal embeddings). CSM of posterior superior temporal gyrus (pSTG) disrupted music perception and production, along with speech production. pSTG and posterior middle temporal gyrus (pMTG) activated for language and music (broadband gamma; 70-150 Hz). pMTG activity was modulated by musical complexity, while pSTG activity was modulated by syntactic complexity. This points to shared resources for music and language comprehension, but distinct neural signatures for the processing of domain-specific structural features.

Inhalation aromatherapy in children and adolescents undergoing stem cell infusion: results of a placebo-controlled double-blind trial.

OBJECTIVE: Though often lifesaving, stem cell transplantation (SCT) is a period of great distress for both child and parent. METHODS: We conducted a double-blind, placebo-controlled randomized study evaluating the effect of the respiratory administration of bergamot essential oil on the anxiety, nausea, and pain of 37 pediatric patients with malignant and non-malignant disorders undergoing stem cell infusion and their parents. Patients were assessed at the time of recruitment, prior to infusion, upon infusion completion, and one hour post-infusion using the Spielberger State-Trait Anxiety Inventory (STAI) for parents and the STAIC, Children's Behavioral Style Scale (CBSS), visual analogue scale (VAS) for pain and nausea, and the Emotionality Activity Sociability and Impulsivity instrument (EASI) for children. RESULTS: Children and adolescents in the treatment group experienced greater anxiety (p = 0.05) and nausea (p = 0.03) one hour post-infusion. Reported pain in both groups was no longer significant one hour post-infusion. Parental anxiety declined in both groups but did not reach statistical significance. Child's monitoring coping style was significantly predictive of transitory anxiety post-infusion (p = 0.01). CONCLUSIONS: Although this trial did not report a benefit of inhalation aromatherapy for reducing anxiety, nausea, or pain when added to standard supportive care, it provides the first experimental rather than descriptive report on testing a single therapeutic essential oil among children and adolescents undergoing stem cell infusion. Future research may consider exploring the cutaneous application of essential oil through massage or other psychoeducational counseling interventions among parents with elevated anxiety and patients with greater information seeking coping styles during SCT.

Optimally targeting the centromedian nucleus of the thalamus for generalized epilepsy: A meta-analysis.

BACKGROUND: Deep brain stimulation (DBS) of the centromedian nucleus (CM) is an effective therapeutic option for select patients with generalized epilepsy. However, several studies suggest that success varies with active contact location within the CM and the exact target remains undefined. OBJECTIVE: To quantify the association between active contact location and outcomes across all published series of CM DBS. METHODS: A literature search using PRISMA criteria was performed to identify all studies that reported active contact locations PLUS outcomes following DBS of the CM for epilepsy. Patient, disease, treatment, and outcome data were extracted for statistical analysis. Active contact locations were analyzed on a common reference frame and weighted by percent seizure reduction at last follow-up. RESULTS: From 184 studies that were screened for review, 3 studies comprising 47 patients met criteria for inclusion and were analyzed. At time of surgery, mean duration of epilepsy was 18 years. Pooled rates of atonic, atypical absence, generalized tonic-clonic, myoclonic, and tonic epilepsies were 38%, 74%, 68%, 14%, and 60%, respectively. Indirect targeting was used in all these studies. After a mean follow-up duration of 2.3 years, 87% of patients were deemed to be responders with mean seizure reduction of 73% (95% CI: [64%-81%]). Optimal location of the active contact was found to be at the dorsal border of the CM. CONCLUSIONS: Success following DBS of the CM for epilepsy varies by active contact location, even within the CM. Our findings suggest that stimulation within the dorsal region of the CM improves outcomes. Additional studies are needed to further refine these findings.

Optimal targeting of the anterior nucleus of the thalamus for epilepsy: a meta-analysis.

OBJECTIVE: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has been shown to be an effective therapeutic option for select patients with limbic epilepsy. However, the optimal target and electrode position for this indication remains undefined. Therefore, the objective of this systematic review and meta-analysis is to quantify the association between active contact location and outcomes across all published series of ANT DBS. METHODS: A literature search using PRISMA criteria was performed to identify all studies that reported both active contact locations and outcomes of DBS in the ANT for epilepsy. Patient, disease, treatment, and outcome data were extracted for statistical analysis. Contact locations of responders (defined as ≥ 50% seizure reduction at last follow-up) versus nonresponders to DBS were analyzed on a common reference frame. Centers of mass, weighted by clinical response, were computed for the contacts in each cohort. RESULTS: From 555 studies that were screened for review, a total of 7 studies comprising 162 patients met criteria for inclusion and were analyzed. Across the cohort, the mean duration of epilepsy was 23 years and the mean pre-DBS seizure frequency was 56 seizures per month. DBS electrodes were implanted using direct targeting in 5 studies (n = 62, 38% of patient cohort) via a transventricular electrode trajectory in 4 studies (n = 123, 76%). At the mean follow-up duration of 2.3 years, 56% of patients were considered responders. Active contacts of responders were 1.6 mm anterior (95% CI 1.5-1.6 mm, p < 0.001) compared to those of nonresponders and were adjacent to the mammillothalamic tract (MTT). CONCLUSIONS: Accurate targeting of the ANT is crucial to successful DBS outcomes in epilepsy. These findings suggest that stimulation within the ANT subregions adjacent to the MTT improves outcomes.

Intraoperative localization and preservation of reading in ventral occipitotemporal cortex.

OBJECTIVE: Resective surgery in language-dominant ventral occipitotemporal cortex (vOTC) carries the risk of causing impairment to reading. Because it is not on the lateral surface, it is not easily accessible for intraoperative mapping, and extensive stimulation mapping can be time-consuming. Here the authors assess the feasibility of using task-based electrocorticography (ECoG) recordings intraoperatively to help guide stimulation mapping of reading in vOTC. METHODS: In 11 patients undergoing extraoperative, intracranial seizure mapping, the authors recorded induced broadband gamma activation (70-150 Hz) during a visual category localizer. In 2 additional patients, whose pathologies necessitated resections in language-dominant vOTC, task-based functional mapping was performed intraoperatively using subdural ECoG alongside direct cortical stimulation. RESULTS: Word-responsive cortex localized using ECoG showed a high sensitivity (72%) to stimulation-induced reading deficits, and the confluence of ECoG and stimulation-positive sites appears to demarcate the visual word form area. Intraoperative task-based ECoG mapping was possible in < 3 minutes, providing a high signal quality, and initial intraoperative data analysis took < 3 minutes, allowing for rapid assessment of broad areas of cortex. Cortical areas critical for reading were mapped and successfully preserved, while also enabling pathological tissue to be completely removed. CONCLUSIONS: Eloquent cortex in ventral visual cortex can be rapidly mapped intraoperatively using ECoG. This method acts to guide high-probability targets for stimulation with limited patient participation and can be used to avoid iatrogenic dyslexia following surgery.

Distinguishing type II focal cortical dysplasias from normal cortex: A novel normative modeling approach.

OBJECTIVE: Focal cortical dysplasias (FCDs) are a common cause of apparently non-lesional drug-resistant focal epilepsy. Visual detection of subtle FCDs on MRI is clinically important and often challenging. In this study, we implement a set of 3D local image filters adapted from computer vision applications to characterize the appearance of normal cortex surrounding the gray-white junction. We create a normative model to serve as the basis for a novel multivariate constrained outlier approach to automated FCD detection. METHODS: Standardized MPRAGE, T2 and FLAIR MR images were obtained in 15 patients with radiologically or histologically diagnosed FCDs and 30 healthy volunteers. Multiscale 3D local image filters were computed for each MR contrast then sampled onto the gray-white junction surface. Using an iterative Gaussianization procedure, we created a normative model of cortical variability in healthy volunteers, allowing for identification of outlier regions and estimates of similarity in normal cortex and FCD lesions. We used a constrained outlier approach following local normalization to automatically detect FCD lesions based on projection onto the mean FCD feature vector. RESULTS: FCDs as well as some normal cortical regions such as primary sensorimotor and paralimbic regions appear as outliers. Regions such as the paralimbic regions and the anterior insula have similar features to FCDs. Our constrained outlier approach allows for automated FCD detection with 80% sensitivity and 70% specificity. SIGNIFICANCE: A normative model using multiscale local image filters can be used to describe the normal cortical variability. Although FCDs appear similar to some cortical regions such as the anterior insula and paralimbic cortices, they can be identified using a constrained outlier detection approach. Our method for detecting outliers and estimating similarity is generic and could be extended to identification of other types of lesions or atypical cortical areas.

South African healthcare provider perspectives on transitioning adolescents into adult HIV care.

BACKGROUND: The first generation of South African (SA) children perinatally infected with HIV is entering adulthood, and there is now a pressing need for systematised transfer of these patients from paediatric to adult care. OBJECTIVES: Previous research has investigated the HIV healthcare transition in North America and Europe, yet none has been conducted in SA. Our study is the first to describe the perspectives of healthcare providers overseeing the transition in resource-limited settings. METHODS: We approached healthcare providers working in government paediatric HIV clinics and hospitals in the Western Cape Province, SA. Seven physicians and counsellors in adolescent/paediatric care, representing five clinics, were interviewed, and 43 completed a written survey. Interviews addressed the current state of the transition, barriers and facilitators, and model components. Interviews were assessed for major themes using framework analysis, while logistic regression was applied to survey responses to identify associations with measured covariates. RESULTS: Analysis of interview transcripts revealed several overarching perspectives that were corroborated by survey responses. One barrier identified was the healthcare providers' difficulty in letting go of their relationships with the adolescent patients. Since healthcare providers regarded their patients as particularly vulnerable, they felt a strong and protective attachment towards them. A second barrier identified was a lack of structure and effective communication between adult and paediatric providers; accordingly, healthcare providers feared that they were transferring their adolescents unprepared, to a judgemental, depersonalised and overburdened environment. All interviewees and a majority of survey respondents (>80%) agreed that the formation of adolescent support groups in adult care clinics as well as a later transition age would improve the transition process. CONCLUSION: This study highlights the need for a systematic healthcare transition for HIV-positive adolescents cared for in the Western Cape, while acknowledging the limitations of the current healthcare infrastructure. Several feasible recommendations have been identified, including forming support groups and greater involvement of adolescent healthcare providers to facilitate the transition.

Evaluating the cement stabilization of arsenic-bearing iron wastes from drinking water treatment.

Cement stabilization of arsenic-bearing wastes is recommended to limit arsenic release from wastes following disposal. Such stabilization has been demonstrated to reduce the arsenic concentration in the Toxicity Characteristic Leaching Procedure (TCLP), which regulates landfill disposal of arsenic waste. However, few studies have evaluated leaching from actual wastes under conditions similar to ultimate disposal environments. In this study, land disposal in areas where flooding is likely was simulated to test arsenic release from cement stabilized arsenic-bearing iron oxide wastes. After 406 days submersed in chemically simulated rainwater, <0.4% of total arsenic was leached, which was comparable to the amount leached during the TCLP (<0.3%). Short-term (18 h) modified TCLP tests (pH 3-12) found that cement stabilization lowered arsenic leaching at high pH, but increased leaching at pH<4.2 compared to non-stabilized wastes. Presenting the first characterization of cement stabilized waste using µXRF, these results revealed the majority of arsenic in cement stabilized waste remained associated with iron. This distribution of arsenic differed from previous observations of calcium-arsenic solid phases when arsenic salts were stabilized with cement, illustrating that the initial waste form influences the stabilized form. Overall, cement stabilization is effective for arsenic-bearing wastes when acidic conditions can be avoided.

The large pediatric scrotum: ultrasound technique and differential considerations.

Scrotal enlargement in the pediatric population is caused by a variety of pathologic processes including hydroceles, hernias, varicoceles, testicular torsion, testicular or paratesticular infection, trauma, or neoplasm; adrenal rests; or scrotal skin edema. The clinical presentation of scrotal enlargement is often nonspecific, and ultrasound plays a key role in making the correct diagnosis. In this pictorial review, we review the ultrasound protocol for performing scrotal ultrasound in pediatric patients and illustrate the ultrasound appearance of conditions resulting in scrotal enlargement.

Effect of air-assisted backwashing on the performance of an anaerobic fixed-bed bioreactor that simultaneously removes nitrate and arsenic from drinking water sources.

Contaminant removal from drinking water sources under reducing conditions conducive for the growth of denitrifying, arsenate reducing, and sulfate reducing microbes using a fixed-bed bioreactor may require oxygen-free gas (e.g., N2 gas) during backwashing. However, the use of air-assisted backwashing has practical advantages, including simpler operation, improved safety, and lower cost. A study was conducted to evaluate whether replacing N2 gas with air during backwashing would impact performance in a nitrate and arsenic removing anaerobic bioreactor system that consisted of two biologically active carbon reactors in series. Gas-assisted backwashing, comprised of 2 min of gas injection to fluidize the bed and dislodge biomass and solid phase products, was performed in the first reactor (reactor A) every two days. The second reactor (reactor B) was subjected to N2 gas-assisted backwashing every 3-4 months. Complete removal of 50 mg/L NO3- was achieved in reactor A before and after the switch from N2-assisted backwashing (NAB) to air-assisted backwashing (AAB). Substantial sulfate removal was achieved with both backwashing strategies. Prolonged practice of AAB (more than two months), however, diminished sulfate reduction in reactor B somewhat. Arsenic removal in reactor A was impacted slightly by long-term use of AAB, but arsenic removals achieved by the entire system during NAB and AAB periods were not significantly different (p>0.05) and arsenic concentrations were reduced from approximately 200 µg/L to below 20 µg/L. These results indicate that AAB can be implemented in anaerobic nitrate and arsenic removal systems.

Accelerated infliximab infusions for inflammatory bowel disease improve effectiveness.

AIM: To study the safety and effectiveness associated with accelerated infliximab infusion protocols in patients with inflammatory bowel disease (IBD). METHODS: Original protocols and infusion rates were developed for the administration of infliximab over 90-min and 60-min. Then the IBD patients on stable maintenance infliximab therapy were offered accelerated infusions. To be eligible for the study, patients needed a minimum of four prior infusions. An initial infusion of 90-min was given to each patient; those tolerating the accelerated infusion were transitioned to a 60-min infusion protocol at their next and all subsequent visits. Any patient having significant infusion reactions would be reverted to the standard 120-min protocol. A change in a patient's dose mandated a single 120-min infusion before accelerated infusions could be administered again. RESULTS: The University of Virginia Medical Center's Institutional Review Board approved this study. Fifty IBD patients treated with infliximab 5 mg/kg, 7.5 mg/kg and 10 mg/kg were offered accelerated infusions. Forty-six patients consented to participate in the study. Nineteen (41.3%) were female, five (10.9%) were African American and nine (19.6%) had ulcerative colitis. The mean age was 42.6 years old. Patients under age 18 were excluded. Ten patients used immunosuppressive drugs concurrently out of which six were taking azathioprine, three were taking 6-mercaptopurine and one was taking methotrexate. One of the 46 study patients used corticosteroid therapy for his IBD. Seventeen of the patients used prophylactic medications prior to receiving infusions; six patients received corticosteroids as pre-medication. Four patients had a history of distant transfusion reactions to infliximab. These reactions included shortness of breath, chest tightness, flushing, pruritus and urticaria. These patients all took prophylactic medications before receiving infusions. 46 patients (27 males and 19 females) received a total of fifty 90-min infusions and ninety-three 60-min infusions. No infusion reactions were reported. There were no adverse events, including drug-related infections. None of the patients developed cancer of any type during the study timeframe. Total cost savings for administration of the both 90-min and 60-min accelerated infusions compared to standard 120-min infusions was estimated to be $53 632 ($116 965 vs $63 333, P = 0.001). One hundred and eighteen hours were saved in the administration of the accelerated infusions (17 160 min vs 10 080 min, P = 0.001). In the study population, overweight females [body mass index (BMI) > 25.00 kg/m(2)] were found to have statistically higher BMIs than overweight males (mean BMI 35.07 ± 2.66 kg/m(2) vs 30.08 ± 0.99 kg/m(2), P = 0.05), finding which is of significance since obesity was described as being one of the risk factors for Crohn's disease. CONCLUSION: We are the first US group to report substantial cost savings, increased safety and patient satisfaction associated with accelerated infliximab infusion.