Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions.

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.

Olfactory learning alters navigation strategies and behavioral variability in C. elegans.

Animals adjust their behavioral response to sensory input adaptively depending on past experiences. The flexible brain computation is crucial for survival and is of great interest in neuroscience. The nematode C. elegans modulates its navigation behavior depending on the association of odor butanone with food (appetitive training) or starvation (aversive training), and will then climb up the butanone gradient or ignore it, respectively. However, the exact change in navigation strategy in response to learning is still unknown. Here we study the learned odor navigation in worms by combining precise experimental measurement and a novel descriptive model of navigation. Our model consists of two known navigation strategies in worms: biased random walk and weathervaning. We infer weights on these strategies by applying the model to worm navigation trajectories and the exact odor concentration it experiences. Compared to naive worms, appetitive trained worms up-regulate the biased random walk strategy, and aversive trained worms down-regulate the weathervaning strategy. The statistical model provides prediction with $>90 \%$ accuracy of the past training condition given navigation data, which outperforms the classical chemotaxis metric. We find that the behavioral variability is altered by learning, such that worms are less variable after training compared to naive ones. The model further predicts the learning-dependent response and variability under optogenetic perturbation of the olfactory neuron AWC$^\mathrm{ON}$. Lastly, we investigate neural circuits downstream from AWC$^\mathrm{ON}$ that are differentially recruited for learned odor-guided navigation. Together, we provide a new paradigm to quantify flexible navigation algorithms and pinpoint the underlying neural substrates.

Human neural stem cells restore spatial memory in a transgenic Alzheimer's disease mouse model by an immunomodulating mechanism.

Introduction: Stem cells are a promising therapeutic in Alzheimer's disease (AD) given the complex pathophysiologic pathways involved. However, the therapeutic mechanisms of stem cells remain unclear. Here, we used spatial transcriptomics to elucidate therapeutic mechanisms of human neural stem cells (hNSCs) in an animal model of AD. Methods: hNSCs were transplanted into the fimbria fornix of the hippocampus using the 5XFAD mouse model. Spatial memory was assessed by Morris water maze. Amyloid plaque burden was quantified. Spatial transcriptomics was performed and differentially expressed genes (DEGs) identified both globally and within the hippocampus. Subsequent pathway enrichment and ligand-receptor network analysis was performed. Results: hNSC transplantation restored learning curves of 5XFAD mice. However, there were no changes in amyloid plaque burden. Spatial transcriptomics showed 1,061 DEGs normalized in hippocampal subregions. Plaque induced genes in microglia, along with populations of stage 1 and stage 2 disease associated microglia (DAM), were normalized upon hNSC transplantation. Pathologic signaling between hippocampus and DAM was also restored. Discussion: hNSCs normalized many dysregulated genes, although this was not mediated by a change in amyloid plaque levels. Rather, hNSCs appear to exert beneficial effects in part by modulating microglia-mediated neuroinflammation and signaling in AD.

Human neural stem cells restore spatial memory in a transgenic Alzheimer's disease mouse model by an immunomodulating mechanism.

INTRODUCTION: Stem cells are a promising therapeutic in Alzheimer's disease (AD) given the complex pathophysiologic pathways involved. However, the therapeutic mechanisms of stem cells remain unclear. Here, we used spatial transcriptomics to elucidate therapeutic mechanisms of human neural stem cells (hNSCs) in an animal model of AD. METHODS: hNSCs were transplanted into the fimbria fornix of the hippocampus using the 5XFAD mouse model. Spatial memory was assessed by Morris water maze. Amyloid plaque burden was quantified. Spatial transcriptomics was performed and differentially expressed genes (DEGs) identified both globally and within the hippocampus. Subsequent pathway enrichment and ligand-receptor network analysis was performed. RESULTS: hNSC transplantation restored learning curves of 5XFAD mice. However, there were no changes in amyloid plaque burden. Spatial transcriptomics showed 1061 DEGs normalized in hippocampal subregions. Plaque induced genes in microglia, along with populations of stage 1 and stage 2 disease associated microglia (DAM), were normalized upon hNSC transplantation. Pathologic signaling between hippocampus and DAM was also restored. DISCUSSION: hNSCs normalized many dysregulated genes, although this was not mediated by a change in amyloid plaque levels. Rather, hNSCs appear to exert beneficial effects in part by modulating microglia-mediated neuroinflammation and signaling in AD.

Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and leading cause of dementia, characterized by neuronal and synapse loss, amyloid-ß and tau protein aggregates, and a multifactorial pathology involving neuroinflammation, vascular dysfunction, and disrupted metabolism. Additionally, there is growing evidence of imbalance between neuronal excitation and inhibition in the AD brain secondary to dysfunction of parvalbumin (PV)- and somatostatin (SST)-positive interneurons, which differentially modulate neuronal activity. Importantly, impaired interneuron activity in AD may occur upstream of amyloid-ß pathology rendering it a potential therapeutic target. To determine the underlying pathologic processes involved in interneuron dysfunction, we spatially profiled the brain transcriptome of the 5XFAD AD mouse model versus controls, across four brain regions, dentate gyrus, hippocampal CA1 and CA3, and cortex, at early-stage (12 weeks-of-age) and late-stage (30 weeks-of-age) disease. Global comparison of differentially expressed genes (DEGs) followed by enrichment analysis of 5XFAD versus control highlighted various biological pathways related to RNA and protein processing, transport, and clearance in early-stage disease and neurodegeneration pathways at late-stage disease. Early-stage DEGs examination found shared, e.g ., RNA and protein biology, and distinct, e.g ., N-glycan biosynthesis, pathways enriched in PV-versus somatostatin SST-positive interneurons and in excitatory neurons, which expressed neurodegenerative and axon- and synapse-related pathways. At late-stage disease, PV-positive interneurons featured cancer and cancer signaling pathways along with neuronal and synapse pathways, whereas SST-positive interneurons showcased glycan biosynthesis and various infection pathways. Late-state excitatory neurons were primarily characterized by neurodegenerative pathways. These fine-grained transcriptomic profiles for PV- and SST-positive interneurons in a time- and spatial-dependent manner offer new insight into potential AD pathophysiology and therapeutic targets.

Continuous odor profile monitoring to study olfactory navigation in small animals.

Olfactory navigation is observed across species and plays a crucial role in locating resources for survival. In the laboratory, understanding the behavioral strategies and neural circuits underlying odor-taxis requires a detailed understanding of the animal's sensory environment. For small model organisms like Caenorhabditis elegans and larval Drosophila melanogaster, controlling and measuring the odor environment experienced by the animal can be challenging, especially for airborne odors, which are subject to subtle effects from airflow, temperature variation, and from the odor's adhesion, adsorption, or reemission. Here, we present a method to control and measure airborne odor concentration in an arena compatible with an agar substrate. Our method allows continuous controlling and monitoring of the odor profile while imaging animal behavior. We construct stationary chemical landscapes in an odor flow chamber through spatially patterned odorized air. The odor concentration is measured with a spatially distributed array of digital gas sensors. Careful placement of the sensors allows the odor concentration across the arena to be continuously inferred in space and monitored through time. We use this approach to measure the odor concentration that each animal experiences as it undergoes chemotaxis behavior and report chemotaxis strategies for C. elegans and D. melanogaster larvae populations as they navigate spatial odor landscapes.

Diabetes and dementia: Clinical perspective, innovation, knowledge gaps.

The world faces a pandemic-level prevalence of type 2 diabetes. In parallel with this massive burden of metabolic disease is the growing prevalence of dementia as the population ages. The two health issues are intertwined. The Lancet Commission on dementia prevention, intervention, and care was convened to tackle the growing global concern of dementia by identifying risk factors. It concluded, along with other studies, that diabetes as well as obesity and the metabolic syndrome more broadly, which are frequently comorbid, raise the risk of developing dementia. Type 2 diabetes is a modifiable risk factor; however, it is uncertain whether anti-diabetic drugs mitigate risk of developing dementia. Reasons are manifold but constitute a critical knowledge gap in the field. This review outlines studies of type 2 diabetes on risk of dementia, illustrating key concepts. Moreover, it identifies knowledge gaps, reviews strategies to help fill these gaps, and concludes with a series of recommendations to mitigate risk and advance understanding of type 2 diabetes and dementia.

Correcting motion induced fluorescence artifacts in two-channel neural imaging.

Imaging neural activity in a behaving animal presents unique challenges in part because motion from an animal's movement creates artifacts in fluorescence intensity time-series that are difficult to distinguish from neural signals of interest. One approach to mitigating these artifacts is to image two channels simultaneously: one that captures an activity-dependent fluorophore, such as GCaMP, and another that captures an activity-independent fluorophore such as RFP. Because the activity-independent channel contains the same motion artifacts as the activity-dependent channel, but no neural signals, the two together can be used to identify and remove the artifacts. However, existing approaches for this correction, such as taking the ratio of the two channels, do not account for channel-independent noise in the measured fluorescence. Here, we present Two-channel Motion Artifact Correction (TMAC), a method which seeks to remove artifacts by specifying a generative model of the two channel fluorescence that incorporates motion artifact, neural activity, and noise. We use Bayesian inference to infer latent neural activity under this model, thus reducing the motion artifact present in the measured fluorescence traces. We further present a novel method for evaluating ground-truth performance of motion correction algorithms by comparing the decodability of behavior from two types of neural recordings; a recording that had both an activity-dependent fluorophore and an activity-independent fluorophore (GCaMP and RFP) and a recording where both fluorophores were activity-independent (GFP and RFP). A successful motion correction method should decode behavior from the first type of recording, but not the second. We use this metric to systematically compare five models for removing motion artifacts from fluorescent time traces. We decode locomotion from a GCaMP expressing animal 20x more accurately on average than from control when using TMAC inferred activity and outperforms all other methods of motion correction tested, the best of which were ~8x more accurate than control.

Monoclonal antibody-mediated immunosuppression enables long-term survival of transplanted human neural stem cells in mouse brain.

BACKGROUND: As the field of stem cell therapy advances, it is important to develop reliable methods to overcome host immune responses in animal models. This ensures survival of transplanted human stem cell grafts and enables predictive efficacy testing. Immunosuppressive drugs derived from clinical protocols are frequently used but are often inconsistent and associated with toxic side effects. Here, using a molecular imaging approach, we show that immunosuppression targeting costimulatory molecules CD4 and CD40L enables robust survival of human xenografts in mouse brain, as compared to conventional tacrolimus and mycophenolate mofetil. METHODS: Human neural stem cells were modified to express green fluorescent protein and firefly luciferase. Cells were implanted in the fimbria fornix of the hippocampus and viability assessed by non-invasive bioluminescent imaging. Cell survival was assessed using traditional pharmacologic immunosuppression as compared to monoclonal antibodies directed against CD4 and CD40L. This paradigm was also implemented in a transgenic Alzheimer's disease mouse model. RESULTS: Graft rejection occurs within 7 days in non-immunosuppressed mice and within 14 days in mice on a traditional regimen. The addition of dual monoclonal antibody immunosuppression extends graft survival past 7 weeks (p < .001) on initial studies. We confirm dual monoclonal antibody treatment is superior to either antibody alone (p < .001). Finally, we demonstrate robust xenograft survival at multiple cell doses up to 6 months in both C57BL/6J mice and a transgenic Alzheimer's disease model (p < .001). The dual monoclonal antibody protocol demonstrated no significant adverse effects, as determined by complete blood counts and toxicity screen. CONCLUSIONS: This study demonstrates an effective immunosuppression protocol for preclinical testing of stem cell therapies. A transition towards antibody-based strategies may be advantageous by enabling stem cell survival in preclinical studies that could inform future clinical trials.

Stem cell therapy for central nervous system disorders: Metabolic interactions between transplanted cells and local microenvironments.

Stem cell therapy is a promising and rapidly advancing treatment strategy for a multitude of neurologic disorders. Yet, while early phase clinical trials are being pursued in many disorders, the mechanism of action often remains unclear. One important potential mechanism by which stem cells provide neuroprotection is through metabolic signaling with diseased neurons, glia, and other cell types in the nervous system microenvironment. Early studies exploring such interactions report normalization of glucose metabolism, induction of protective mitochondrial genes, and even interactions with supportive neurovasculature. Local metabolic conditions also impact stem cell biology, which can have a large impact on transplant viability and efficacy. Epigenetic changes that occur in the donor prior to collection of stem cells, and even during in vitro culture conditions, may have effects on stem cell biology that are carried into the host upon stem cell transplantation. Transplanted stem cells also face potentially toxic metabolic microenvironments at the targeted transplant site. Novel approaches for metabolically "preconditioning" stem cells prior to transplant harness metabolic machinery to optimize stem cell survival upon transplant. Ultimately, an improved understanding of the metabolic cross-talk between implanted stem cells and the local nervous system environment, in both disease and injury states, will increase the likelihood of success in translating stem cell therapy to early trials in neurological disease.

Optimal Population Coding for Dynamic Input by Nonequilibrium Networks.

The efficient coding hypothesis states that neural response should maximize its information about the external input. Theoretical studies focus on optimal response in single neuron and population code in networks with weak pairwise interactions. However, more biological settings with asymmetric connectivity and the encoding for dynamical stimuli have not been well-characterized. Here, we study the collective response in a kinetic Ising model that encodes the dynamic input. We apply gradient-based method and mean-field approximation to reconstruct networks given the neural code that encodes dynamic input patterns. We measure network asymmetry, decoding performance, and entropy production from networks that generate optimal population code. We analyze how stimulus correlation, time scale, and reliability of the network affect optimal encoding networks. Specifically, we find network dynamics altered by statistics of the dynamic input, identify stimulus encoding strategies, and show optimal effective temperature in the asymmetric networks. We further discuss how this approach connects to the Bayesian framework and continuous recurrent neural networks. Together, these results bridge concepts of nonequilibrium physics with the analyses of dynamics and coding in networks.

Novel stimuli evoke excess activity in the mouse primary visual cortex.

To explore how neural circuits represent novel versus familiar inputs, we presented mice with repeated sets of images with novel images sparsely substituted. Using two-photon calcium imaging to record from layer 2/3 neurons in the mouse primary visual cortex, we found that novel images evoked excess activity in the majority of neurons. This novelty response rapidly emerged, arising with a time constant of 2.6 ± 0.9 s. When a new image set was repeatedly presented, a majority of neurons had similarly elevated activity for the first few presentations, which decayed to steady state with a time constant of 1.4 ± 0.4 s. When we increased the number of images in the set, the novelty response's amplitude decreased, defining a capacity to store ∼15 familiar images under our conditions. These results could be explained quantitatively using an adaptive subunit model in which presynaptic neurons have individual tuning and gain control. This result shows that local neural circuits can create different representations for novel versus familiar inputs using generic, widely available mechanisms.

Small molecule inhibitors of α-synuclein oligomers identified by targeting early dopamine-mediated motor impairment in C. elegans.

BACKGROUND: Parkinson's disease is a disabling neurodegenerative movement disorder characterized by dopaminergic neuron loss induced by α-synuclein oligomers. There is an urgent need for disease-modifying therapies for Parkinson's disease, but drug discovery is challenged by lack of in vivo models that recapitulate early stages of neurodegeneration. Invertebrate organisms, such as the nematode worm Caenorhabditis elegans, provide in vivo models of human disease processes that can be instrumental for initial pharmacological studies. METHODS: To identify early motor impairment of animals expressing α-synuclein in dopaminergic neurons, we first used a custom-built tracking microscope that captures locomotion of single C. elegans with high spatial and temporal resolution. Next, we devised a method for semi-automated and blinded quantification of motor impairment for a population of simultaneously recorded animals with multi-worm tracking and custom image processing. We then used genetic and pharmacological methods to define the features of early motor dysfunction of α-synuclein-expressing C. elegans. Finally, we applied the C. elegans model to a drug repurposing screen by combining it with an artificial intelligence platform and cell culture system to identify small molecules that inhibit α-synuclein oligomers. Screen hits were validated using in vitro and in vivo mammalian models. RESULTS: We found a previously undescribed motor phenotype in transgenic α-synuclein C. elegans that correlates with mutant or wild-type α-synuclein protein levels and results from dopaminergic neuron dysfunction, but precedes neuronal loss. Together with artificial intelligence-driven in silico and in vitro screening, this C. elegans model identified five compounds that reduced motor dysfunction induced by α-synuclein. Three of these compounds also decreased α-synuclein oligomers in mammalian neurons, including rifabutin which has not been previously investigated for Parkinson's disease. We found that treatment with rifabutin reduced nigrostriatal dopaminergic neurodegeneration due to α-synuclein in a rat model. CONCLUSIONS: We identified a C. elegans locomotor abnormality due to dopaminergic neuron dysfunction that models early α-synuclein-mediated neurodegeneration. Our innovative approach applying this in vivo model to a multi-step drug repurposing screen, with artificial intelligence-driven in silico and in vitro methods, resulted in the discovery of at least one drug that may be repurposed as a disease-modifying therapy for Parkinson's disease.

Cholinergic transmission from the basal forebrain modulates social memory in male mice.

Disruptions in social behaviour are prevalent in many neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism spectrum disorders. However, the underlying neurochemical regulation of social behaviour is still not well understood. The central cholinergic system has been proposed to contribute to the regulation of social behaviour. For instance, decreased global levels of acetylcholine release in the brain leads to decreased social interaction and an impairment of social memory in mice. Nonetheless, it has been difficult to ascertain the specific brain areas where cholinergic signalling influences social preference and social memory. In this study, we investigated the impact of different forebrain cholinergic regions on social behaviour by examining mouse lines that differ in their regional expression level of the vesicular acetylcholine transporter-the protein that regulates acetylcholine secretion. We found that when cholinergic signalling is highly disrupted in the striatum, hippocampus, cortex and amygdala mice have intact social preference but are impaired in social memory, as they cannot remember a familiar conspecific nor recognize a novel one. A similar pattern emerges when acetylcholine release is disrupted mainly in the striatum, cortex, and amygdala; however, the ability to recognize novel conspecifics is retained. In contrast, cholinergic signalling of the striatum and amygdala does not appear to significantly contribute to the modulation of social memory and social preference. Furthermore, we demonstrated that increasing global cholinergic tone does not increase social behaviours. Together, these data suggest that cholinergic transmission from the hippocampus and cortex are important for regulating social memory.

Magnetic resonance imaging of human neural stem cells in rodent and primate brain.

Stem cell transplantation therapies are currently under investigation for central nervous system disorders. Although preclinical models show benefit, clinical translation is somewhat limited by the absence of reliable noninvasive methods to confirm targeting and monitor transplanted cells in vivo. Here, we assess a novel magnetic resonance imaging (MRI) contrast agent derived from magnetotactic bacteria, magneto-endosymbionts (MEs), as a translatable methodology for in vivo tracking of stem cells after intracranial transplantation. We show that ME labeling provides robust MRI contrast without impairment of cell viability or other important therapeutic features. Labeled cells were visualized immediately post-transplantation and over time by serial MRI in nonhuman primate and mouse brain. Postmortem tissue analysis confirmed on-target grft location, and linear correlations were observed between MRI signal, cell engraftment, and tissue ME levels, suggesting that MEs may be useful for determining graft survival or rejection. Overall, these findings indicate that MEs are an effective tool for in vivo tracking and monitoring of cell transplantation therapies with potential relevance to many cellular therapy applications.

Contemporaneous evaluation of patient experience, surgical strategy, and seizure outcomes in patients undergoing stereoelectroencephalography or subdural electrode monitoring.

OBJECTIVE: Intracranial electrographic localization of the seizure onset zone (SOZ) can guide surgical approaches for medically refractory epilepsy patients, especially when the presurgical workup is discordant or functional cortical mapping is required. Minimally invasive stereotactic placement of depth electrodes, stereoelectroencephalography (SEEG), has garnered increasing use, but limited data exist to evaluate its postoperative outcomes in the context of the contemporaneous availability of both SEEG and subdural electrode (SDE) monitoring. We aimed to assess the patient experience, surgical intervention, and seizure outcomes associated with these two epileptic focus mapping techniques during a period of rapid adoption of neuromodulatory and ablative epilepsy treatments. METHODS: We retrospectively reviewed 66 consecutive adult intracranial electrode monitoring cases at our institution between 2014 and 2017. Monitoring was performed with either SEEG (n = 47) or SDEs (n = 19). RESULTS: Both groups had high rates of SOZ identification (SEEG 91.5%, SDE 88.2%, P = .69). The majority of patients achieved Engel class I (SEEG 29.3%, SDE 35.3%) or II outcomes (SEEG 31.7%, SDE 29.4%) after epilepsy surgery, with no significant difference between groups (P = .79). SEEG patients reported lower median pain scores (P = .03) and required less narcotic pain medication (median = 94.5 vs 594.6 milligram morphine equivalents, P = .0003). Both groups had low rates of symptomatic hemorrhage (SEEG 0%, SDE 5.3%, P = .11). On multivariate logistic regression, undergoing resection or ablation (vs responsive neurostimulation/vagus nerve stimulation) was the only significant independent predictor of a favorable outcome (adjusted odds ratio = 25.4, 95% confidence interval = 3.48-185.7, P = .001). SIGNIFICANCE: Although both SEEG and SDE monitoring result in favorable seizure control, SEEG has the advantage of superior pain control, decreased narcotic usage, and lack of routine need for intensive care unit stay. Despite a heterogenous collection of epileptic semiologies, seizure outcome was associated with the therapeutic surgical modality and not the intracranial monitoring technique. The potential for an improved postoperative experience makes SEEG a promising method for intracranial electrode monitoring.

BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62.

Molecular chaperones are critical to maintaining intracellular proteostasis and have been shown to have a protective role against alpha-synuclein-mediated toxicity. Co-chaperone proteins regulate the activity of molecular chaperones and connect the chaperone network to protein degradation and cell death pathways. Bcl-2 associated athanogene 5 (BAG5) is a co-chaperone that modulates proteostasis by inhibiting the activity of Heat shock protein 70 (Hsp70) and several E3 ubiquitin ligases, resulting in enhanced neurodegeneration in models of Parkinson's disease (PD). Here we identify a novel interaction between BAG5 and p62/sequestosome-1 (SQSTM1), suggesting that BAG5 may bridge the chaperone network to autophagy-mediated protein degradation. We found that BAG5 enhanced the formation of pathogenic alpha-synuclein oligomers and regulated the levels and subcellular distribution of p62. These results extend the role of BAG5 in alpha-synuclein processing and intracellular proteostasis.

Robot-assisted versus manual navigated stereoelectroencephalography in adult medically-refractory epilepsy patients.

OBJECTIVE: Stereoelectroencephalography (SEEG) has experienced a recent growth in adoption for epileptogenic zone (EZ) localization. Advances in robotics have the potential to improve the efficiency and safety of this intracranial seizure monitoring method. We present our institutional experience employing robot-assisted SEEG and compare its operative efficiency, seizure reduction outcomes, and direct hospital costs with SEEG performed without robotic assistance using navigated stereotaxy. METHODS: We retrospectively identified 50 consecutive adult SEEG cases at our institution in this IRB-approved study, of which 25 were navigated with image guidance (hereafter referred to as "navigated") (02/2014-10/2016) and 25 were robot-assisted (09/2016-12/2017). A thorough review of medical/surgical history and operative records with imaging and trajectory plans was done for each patient. Direct inpatient costs related to each technique were compared. RESULTS: Most common seizure etiologies for patients undergoing navigated and robot-assisted SEEG included non-lesional and benign temporal lesions. Despite having a higher mean number of leads-per-patient (10.2 ± 3.5 versus 7.2 ± 2.6, P = 0.002), robot-assisted cases had a significantly shorter mean operative time than navigated cases (125.5±48.5 versus 173.4±84.3 min, P = 0.02). Comparison of robot-assisted cases over the study interval revealed no significant difference in mean operative time (136.4±51.4 min for the first ten cases versus 109.9±75.8 min for the last ten cases, P = 0.25) and estimated operative time-per-lead (13.4±6.0 min for the first ten cases versus 12.9±7.7 min for the last ten cases, P = 0.86). The mean depth, radial, target, and entry point errors for robot-assisted cases were 2.12±1.89, 1.66±1.58, 3.05±2.02 mm, and 1.39 ± 0.75 mm, respectively. The two techniques resulted in equivalent EZ localization rate (navigated 88 %, robot-assisted 96 %, P = 0.30). Common types of epilepsy surgery performed consisted of implantation of responsive neurostimulation (RNS) device (56 %), resection (19.1 %), and laser ablation (23.8 %) for navigated SEEG. For robot-assisted SEEG, either RNS implantation (68.2 %) or laser ablation (22.7 %) were performed or offered. A majority of navigated and robot-assisted patients who underwent epilepsy surgery achieved either Engel Class I (navigated 36.8 %, robot-assisted 31.6 %) or II (navigated 36.8 %, robot-assisted 15.8 %) outcome with no significant difference between the groups (P = 0.14). Direct hospital cost for robot-assisted SEEG was 10 % higher than non-robotic cases. CONCLUSION: This single-institutional study suggests that robotic assistance can enhance efficiency of SEEG without compromising safety or precision when compared to image guidance only. Adoption of this technique with uniform safety and efficacy over a short period of time is feasible with favorable epilepsy outcomes.

Asymptomatic Versus Symptomatic Idiopathic Intracranial Hypertension in Children.

BACKGROUND: Idiopathic intracranial hypertension is a rare neurologic condition characterized by elevated intracranial pressure with normal cerebrospinal fluid analysis and neuroimaging. A subset of pediatric idiopathic intracranial hypertension patients are coincidentally found to have papilledema and elevated intracranial pressure without symptoms (eg, headache, visual blurring, tinnitus). This study aims to investigate the features of asymptomatic pediatric idiopathic intracranial hypertension. METHODS: Retrospective case-control study of patients aged 0 to 18 years who received idiopathic intracranial hypertension diagnosis from 2005 to 2016. Subjects were included if they met established diagnostic criteria for idiopathic intracranial hypertension diagnosis. Subjects were classified as symptomatic if they presented with 1 symptom related to elevated intracranial pressure, and asymptomatic if no symptoms were present. Statistical analysis was performed to compare the 2 groups. RESULTS: 12 (22.6%) of 53 pediatric idiopathic intracranial hypertension subjects were asymptomatic. Compared to symptomatic idiopathic intracranial hypertension, asymptomatic idiopathic intracranial hypertension had younger age of onset, lower initial opening pressure on lumbar puncture, lower optic nerve edema grades bilaterally, lower likelihood of globe flattening on magnetic resonance imaging (MRI), and smaller required dose of acetazolamide for resolution of papilledema (all P < .05). CONCLUSION: Asymptomatic idiopathic intracranial hypertension is common among pediatric patients with papilledema and is an important disease entity that requires special clinical management. It may exist as a milder version of idiopathic intracranial hypertension that occurs in younger children, or as a precursor state that later evolves into symptomatic disease.

Impact of skull density ratio on efficacy and safety of magnetic resonance-guided focused ultrasound treatment of essential tremor.

OBJECTIVE: Skull density ratio (SDR) assesses the transparency of the skull to ultrasound. Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in essential tremor (ET) patients with a lower SDR may be less effective, and the risk for complications may be increased. To address these questions, the authors analyzed clinical outcomes of MRgFUS thalamotomy based on SDRs. METHODS: In 189 patients, 3 outcomes were correlated with SDRs. Efficacy was based on improvement in Clinical Rating Scale for Tremor (CRST) scores 1 year after MRgFUS. Procedural efficiency was determined by the ease of achieving a peak voxel temperature of 54°C. Safety was based on the rate of the most severe procedure-related adverse event. SDRs were categorized at thresholds of 0.45 and 0.40, selected based on published criteria. RESULTS: Of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. There was no significant difference in improvement in CRST scores between those with an SDR ≥ 0.45 (58% ± 24%), 0.40 ≤ SDR < 0.45 (i.e., SDR ≥ 0.40 but < 0.45) (63% ± 27%), and SDR < 0.40 (49% ± 28%; p = 0.0744). Target temperature was achieved more often in those with an SDR ≥ 0.45 (p < 0.001). Rates of adverse events were lower in the groups with an SDR < 0.45 (p = 0.013), with no severe adverse events in these groups. CONCLUSIONS: MRgFUS treatment of ET can be effectively and safely performed in patients with an SDR < 0.45 and an SDR < 0.40, although the procedure is more efficient when SDR ≥ 0.45.