Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial

IntroductionWhile current treatments for substance use disorder (SUD) are beneficial, success rates remain low and treatment outcomes are complicated by co-occurring SUDs, many of which are without available medication treatments. Research involving neuromodulation for SUD has recently gained momentum. This study evaluated two doses (60 and 90 W) of Low Intensity Focused Ultrasound (LIFU), targeting the bilateral nucleus accumbens (NAc), in individuals with SUD.MethodsFour participants (three male), who were receiving comprehensive outpatient treatment for opioid use disorder at the time of enrollment and who also had a history of excessive non-opioid substance use, completed this pilot study. After confirming eligibility, these participants received 10 min sham LIFU followed by 20 min active LIFU (10 min to left then right NAc). Outcomes were the safety, tolerability, and feasibility during the LIFU procedure and throughout the 90-day follow-up. Outcomes also included the impact of LIFU on cue-induced substance craving, assessed via Visual Analog Scale (VAS), both acutely (pre-, during and post-procedure) and during the 90-day follow-up. Daily craving ratings (without cues) were also obtained for one-week prior to and one-week following LIFU.ResultsBoth LIFU doses were safe and well-tolerated based on reported adverse events and MRI scans revealed no structural changes (0 min, 24 h, and 1-week post-procedure). For the two participants receiving “enhanced” (90 W) LIFU, VAS craving ratings revealed active LIFU attenuated craving for participants’ primary substances of choice relative to sham sonication. For these participants, reductions were also noted in daily VAS craving ratings (0 = no craving; 10 = most craving ever) across the week following LIFU relative to pre-LIFU; Participant #3 pre- vs. post-LIFU: opioids (3.6 ± 0.6 vs. 1.9 ± 0.4), heroin (4.2 ± 0.8 vs. 1.9 ± 0.4), methamphetamine (3.2 ± 0.4 vs. 0.0 ± 0.0), cocaine (2.4 ± 0.6 vs. 0.0 ± 0.0), benzodiazepines (2.8 ± 0.5 vs. 0.0 ± 0.0), alcohol (6.0 ± 0.7 vs. 2.7 ± 0.8), and nicotine (5.6 ± 1.5 vs. 3.1 ± 0.7); Participant #4: alcohol (3.5 ± 1.3 vs. 0.0 ± 0.0) and nicotine (5.0 ± 1.8 vs. 1.2 ± 0.8) (all p’s < 0.05). Furthermore, relative to screening, longitudinal reductions in cue-induced craving for several substances persisted during the 90-day post-LIFU follow-up evaluation for all participants.DiscussionIn conclusion, LIFU targeting the NAc was safe and acutely reduced substance craving during the LIFU procedure, and potentially had longer-term impact on craving reductions. While early observations are promising, NAc LIFU requires further investigation in a controlled trial to assess the impact on substance craving and ultimately substance use and relapse

215 Laser Thermal Ablation for Mesiotemporal Epilepsy: Relation of Ablation Cavities to Seizure and Neurocognitive Outcomes

Abstract INTRODUCTION Laser interstitial thermal therapy (LiTT) has dramatically changed the management of mesiotemporal epilepsy (mTLE) in recent years. The goal of this study was to identify features of ablations and trajectories that correlate with optimal seizure control and minimize the risk of neurocognitive deficits in patients undergoing LiTT for mTLE. METHODS Clinical and radiographic data were reviewed from a prospectively maintained database of patients undergoing LiTT for epilepsy at the University of Miami. Standard preoperative and postoperative evaluations, including contrast-enhanced MRI and neurocognitive testing, were performed in all patients. Laser trajectory and ablation volumes were computed both by manual tracing of mesiotemporal structures and by nonrigid registration of ablation cavities to a common reference system based on 7T MRI data. RESULTS >Of the 28 patients with at least 1-year follow-up, sparing of the mesial hippocampal head was significantly correlated with persistent disabling seizures (P = 0.01). Projecting all ablation cavities onto a common reference frame showed a clear tendency towards lateral placement of the laser with inadequate mesial hippocampal head ablation in these patients compared to those free of seizures. Patients that suffered deficits in memory, on the other hand, tended to have larger ablations with greater insult to entorrhinal and perirhinal cortex than those free of memory deficits. CONCLUSION Better understanding of the impact of ablation volume and location through the use of image normalization tools could potentially fine-tune this novel technique to improve seizure-freedom rates and associated neurocognitive deficits

Intersurgeon Variability in the Selection of Anterior and Posterior Commissures and Its Potential Effects on Target Localization

Razvojem novih materijala na osnovi polimera, s određenim mehaničkim i tribološkim svojstvima, dolazi do postupnog smanjenja primjene materijala na osnovi metala. Značajan razvoj dogodio se u području kompozitnih materijala, koji se često primjenjuju u svim granama industrije. Predmet rada je usporedba triboloških svojstava kompozitnih materijala s tradicionalnim metalnim materijalima u funkciji kliznog ležaja. Kompozitni ležajni materijali pripadaju skupini nelinearno elastičnih materijala, kod kojih krivulja opterećenja i rasterećenja u dijagramu naprezanje – deformacija nije polinom prvog stupnja. Strukturu kompozitnih materijala čine matrica kao što je npr. matrica od PTFE-a (politetrafloretilen) ili poliestera te ojačalo, koje povezano čine kompozit. Kompleksnost strukture kompozitnih materijala zahtjevno je opisati matematičkim modelima što otežava proračun predviđenog radnog vijeka u funkciji vremena i opterećenja. S ciljem postizanja točnijih vrijednosti predviđenog radnog vijeka kompozitnih ležajnih materijala potrebno je provesti eksperimentalno istraživanje. Rezultate eksperimentalnog mjerenja moguće je usporediti s vrijednostima dobivenim proračunom ili MKE (metoda konačnih elemenata) analizom. U okviru doktorskog rada provest će se istraživanje operetivosti kompozitnih ležajnih materijala.Development of new materials based on a polymers with certain mechanical and tribological properties, leading to a gradual reduction of materials on the metal base. A significant development occurred in the field of composite materials, which are widely used in all branches of industry. The subject of this paper is to compare the tribological properties of composite materials with traditional materials based on metal in function as slide bearing. Composite bearing materials belong to the group of non-linear materials, in which the loading and unloading curve in the stress - strain diagram is not a polynomial of the first degree. The structure of the composite material consists of fabric such as PTFE (polytetrafluoroethylene) and polyester resin, which connects matrix composites in the finish product. The complexity of the composite structure is challenge to describe as mathematical model which makes it difficult for calculation of planned service life in terms of time and work load. To achieve more accurate value of the estimated working life time of the composite bearing material is necessary to conduct experimental research. The results of experimental measurements can be compared with those obtained by calculation or FEM (Finite Element Method) analysis. As part of the doctoral thesis will be carried out research of load on bearing composite material

CranialVault and its CRAVE tools: A clinical computer assistance system for deep brain stimulation (DBS) therapy

Teaching and learning astronomy is known to be both exciting and challenging. To learn astronomy demands not only disciplinary knowledge, but also the ability to discern meaning from disciplinary specific representations (disciplinary discernment). This includes the ability to think spatially, in particular, extrapolating three-dimensionality from a one- or two-dimensional input i.e. to be able to visualize in one’s mind how a three-dimensional astronomical object may look from a one- or two-dimensional input such as from a visual image or a mathematical representation. In this talk I demonstrate that these abilities are deeply intertwined, and that to learn astronomy at any level demands becoming fluent in all three aspects (disciplinary knowledge, disciplinary discernment and spatial thinking). A framework is presented for how these competencies can be described, and combined, as a new and innovative way to frame teaching and learning in astronomy. It is argued that using this framework “Reading the Sky” optimizes the learning outcomes for students. The talk also suggests strategies for how to implement this approach for improving astronomy teaching and learning overall

Predictive modeling of brain tumor laser ablation dynamics

Laser interstitial thermal therapy (LITT) is a novel MR thermometry-guided thermoablative tool revolutionizing the clinical management of brain tumors. A limitation of LITT is our inability to estimate a priori how tissues will respond to thermal energy, which hinders treatment planning and delivery. The aim of this study was to determine whether brain tumor LITT ablation dynamics may be predicted by features of the preoperative MRI and the relevance of these data, if any, to the recurrence of metastases after LITT.Intraoperative thermal damage estimate (TDE) map pixels representative of irreversible damage were retrospectively quantified relative to ablation onset for 101 LITT procedures. Raw TDE pixel counts and TDE pixel counts modelled with first order dynamics were related to eleven independent variables derived from the preoperative MRI, demographics, laser settings, and tumor pathology. Stepwise regression analysis generated predictive models of LITT dynamics, and leave-one-out cross validation evaluated the accuracy of these models at predicting TDE pixel counts solely from the independent variables. Using a deformable atlas, TDE maps were co-registered to the immediate post-ablation MRI, allowing comparison of predicted and actual ablation sizes.Brain tumor TDE pixel counts modelled with first order dynamics, but not raw pixel counts, are correlated with the independent variables. Independent variables showing strong relations to the TDE pixel measures include T1 gadolinium and T2 signal, perfusion, and laser power. Associations with tissue histopathology are minimal. Leave-one-out analysis demonstrates that predictive models using these independent variables account for 77% of the variance observed in TDE pixel counts. Analysis of metastases treated revealed a trend towards the over-estimation of LITT effects by TDE maps during rapid ablations, which was associated with tumor recurrence.Features of the preoperative MRI are predictive of LITT ablation dynamics and could eventually be used to improve the clinical efficacy with which LITT is delivered to brain tumors

Ablation dynamics during laser interstitial thermal therapy for mesiotemporal epilepsy

<div><p>Introduction</p><p>The recent emergence of laser interstitial thermal therapy (LITT) as a frontline surgical tool in the management of brain tumors and epilepsy is a result of advances in MRI thermal imaging. A limitation to further improving LITT is the diversity of brain tissue thermoablative properties, which hinders our ability to predict LITT treatment-related effects. Utilizing the mesiotemporal lobe as a consistent anatomic model system, the goal of this study was to use intraoperative thermal damage estimate (TDE) maps to study short- and long-term effects of LITT and to identify preoperative variables that could be helpful in predicting tissue responses to thermal energy.</p><p>Methods</p><p>For 30 patients with mesiotemporal epilepsy treated with LITT at a single institution, intraoperative TDE maps and pre-, intra- and post-operative MRIs were co-registered in a common reference space using a deformable atlas. The spatial overlap of TDE maps with manually-traced immediate (post-ablation) and delayed (6-month) ablation zones was measured using the dice similarity coefficient (DSC). Then, motivated by simple heat-transfer models, ablation dynamics were quantified at amygdala and hippocampal head from TDE pixel time series fit by first order linear dynamics, permitting analysis of the thermal time constant (<i>τ</i>). The relationships of these measures to 16 independent variables derived from patient demographics, mesiotemporal anatomy, preoperative imaging characteristics and the surgical procedure were examined.</p><p>Results</p><p>TDE maps closely overlapped immediate ablation borders but were significantly larger than the ablation cavities seen on delayed imaging, particularly at the amygdala and hippocampal head. The TDEs more accurately predicted delayed LITT effects in patients with smaller perihippocampal CSF spaces. Analyses of ablation dynamics from intraoperative TDE videos showed variable patterns of lesion progression after laser activation. Ablations tended to be slower for targets with increased preoperative T2 MRI signal and in close proximity to large, surrounding CSF spaces. In addition, greater laser energy was required to ablate mesial versus lateral mesiotemporal structures, an effect associated with laser trajectory and target contrast-enhanced T1 MRI signal.</p><p>Conclusions</p><p>Patient-specific variations in mesiotemporal anatomy and pathology may influence the thermal coagulation of these tissues. We speculate that by incorporating demographic and imaging data into predictive models we may eventually enhance the accuracy and precision with which LITT is delivered, improving outcomes and accelerating adoption of this novel tool.</p></div

Evidence for bone and mineral metabolism alterations in children with autosomal dominant polycystic kidney disease

Context: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Hypophosphatemia was demonstrated in adult patients with preserved renal function, together with high fibroblast growth factor 23 (FGF23) and low soluble Klotho levels. The latter explained the relative FGF23 hyporesponsiveness in this cohort. Objective: Evaluating phosphate and bone mineral metabolism in children with ADPKD compared with what is known in adult ADPKD patients. Design: Observational cross-sectional study. Setting: Multicenter study via ambulatory care in tertiary centers. Participants: Ninety-two children with ADPKD (52 males; mean 6 standard deviation age, 10.2 +/- 5.0 years) and 22 healthy controls (HCs, 10 males; mean 6 standard deviation age, 10.3 +/- 4.1 years). Main Outcome Measures: The predictor was early ADPKD stage. Bone mineral metabolism and renal phosphate handling were the main outcome measures. Performed measurements were serum phosphate, tubular maximum phosphorus reabsorption per glomerular filtration rate, FGF23, soluble Klotho, sclerostin, and bone alkaline phosphatase. Results: ADPKD children had significantly lower serum phosphate levels compared with HC. Low tubular maximum phosphorus reabsorption per glomerular filtration rate was observed in 24% of patients, although not significantly different from HC. Serum FGF23 and soluble Klotho levels were comparable between patients and HC. In addition, we showed decreased bone alkaline phosphatase levels in ADPKD children, suggesting suppressed bone formation. Conclusions: This report demonstrates hypophosphatemia and suppressed bone formation in a pediatric ADPKD cohort, with preserved renal function, compared with HC. Although FGF23 levels were not different from controls, they should be considered inappropriate, given the concomitant hypophosphatemia. Further studies are required to elucidate underlying pathophysiology and potential clinical consequences

Dynamics of irreversible ablation during mesiotemporal LITT.

<p>(A) Different frames of a sample axial TDE video. The larger image on the right shows a lower magnification view, with the white dashed box highlighting the region used in the left panels. Trajectories were traced from the first frame in each video and the appearance of yellow pixels indicating irreversible ablation was quantified relative to the laser using Matlab Image Processing Toolbox. The blue (lateral) and yellow (mesial) rectangles demonstrate regions of interest used to measure pixel counts on each side of the laser. (B) Time course of total (black), lateral (blue), mesial (yellow), and lateral—mesial (red) pixel counts from the same patient as in G. A, anterior; L, lateral.</p