Faculty Bibliography

Distorted representations of the body are observed in healthy individuals as well as in neurological and psychiatric disorders. Distortions of the body model have been attributed to the somatotopic cerebral representation. Recently, it has been demonstrated that visual biases also contribute to those distortions. To better understand the sources of such distortions, we compared the metric representations across five body parts affording different degrees of tactile sensitivity and visual accessibility. We evaluated their perceived dimensions using a Line Length Judgment task. We found that most body parts were underestimated in their dimensions. The estimation error relative to their length was predicted by their tactile acuity, supporting the influence of the cortical somatotopy on the body model. However, tactile acuity did not explain the distortions observed for the width. Visual accessibility in turn does appear to mediate body distortions, as we observed that the dimensions of the dorsal portion of the neck were the only ones accurately perceived. Coherent with the multisensory nature of body representations, we argue that the perceived dimensions of body parts are estimated by integrating visual and somatosensory information, each weighted differently, based on their availability for a given body part and a given spatial dimension.

Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.

PURPOSE:We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS:-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS:These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Background and Purpose- Allergic reactions, including anaphylaxis, can sometimes occur after intravenous thrombolysis in patients with acute ischemic stroke. However, it remains unclear whether patients with stroke who receive thrombolytic agents face a higher risk of anaphylaxis than those who do not receive thrombolytics. Methods- We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included patients who were ≥65 years old and hospitalized with acute ischemic stroke, defined by validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Our exposure was treated with an intravenous thrombolytic agent during the index hospitalization (International Classification of Diseases, Ninth Revision, Clinical Modification code 99.10). Our primary outcome was anaphylaxis, defined using an accepted International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm (989.5, 995.0-4, 995.6x, E905, E905.3, E905.5, or E905.8-9). A secondary outcome was anaphylactic shock (995.0 or 995.6x). Multiple logistic regression was used to evaluate the association between intravenous thrombolysis and anaphylaxis after adjustment for demographics, vascular risk factors, the Charlson comorbidity index, exposure to intravenous contrast dye, treatment with mechanical thrombectomy, and history of allergic reactions. Results- Among 66 989 patients with stroke, the 3176 (4.7%) who underwent intravenous thrombolysis more often had atrial fibrillation (47.7% versus 37.4%) and more often received intravenous contrast dye (44.3% versus 21.9%) but were otherwise similar in terms of demographics and comorbidities. Anaphylaxis developed in 17 (0.54%; 95% CI, 0.31%-0.86%) patients who received intravenous thrombolysis versus 45 (0.07%; 95% CI, 0.05%-0.09%) who did not. After adjustment for demographics, comorbidities, contrast dye, mechanical thrombectomy, and history of allergies, there was a significant association between receipt of intravenous thrombolysis and anaphylaxis (odds ratio, 7.8; 95% CI, 4.3-13.9). We found a similar association for anaphylactic shock. Conclusions- Although a rare occurrence, the risk of anaphylaxis among patients with acute ischemic stroke was significantly higher among those who received intravenous thrombolysis.

The enhanced electrochemical activity of nanostructured materials is readily exploited in energy devices, but their utility in scalable and human-compatible implantable neural interfaces can significantly advance the performance of clinical and research electrodes. We utilize low-temperature selective dealloying to develop scalable and biocompatible 1D platinum nanorod (PtNR) arrays that exhibit superb electrochemical properties at various length scales, stability, and biocompatibility for high performance neurotechnologies. PtNR arrays record brain activity with cellular resolution from the cortical surfaces in birds and non-human primates. Significantly, strong modulation of surface recorded single unit activity by auditory stimuli is demonstrated in European Starling birds as well as the modulation of local field potentials in the visual cortex by light stimuli in a non-human primate, and as well as responses to electrical stimulation in mice. PtNRs record behaviorally and physiologically relevant neuronal dynamics from the surface of the brain with high spatiotemporal resolution which paves the way for less invasive brain-machine interfaces.

OBJECTIVE:Behavior is encoded across multiple scales of brain activity, from binary neuronal spikes to continuous fields including local field potentials (LFP). Multiscale models need to describe both the encoding of behavior and the conditional dependencies in simultaneously recorded spike and field signals, which form a high-dimensional multiscale network. However, learning spike-field dependencies in high-dimensional recordings is challenging due to the prohibitively large number of spike-field signal pairs, which makes standard learning techniques subject to overfitting. APPROACH/METHODS:We present a sparse model-based estimation algorithm to learn these multiscale network dependencies. We develop a multiscale encoding model consisting of a point process model of binary spikes for each neuron whose firing rate is a function of the LFP network features and behavioral states. Doing so, spike-field dependencies constitute the model parameters to be learned. We resolve the parameter learning challenge by forming a constrained optimization problem to maximize the likelihood with an L1 penalty term that eases the detection of significant spike-LFP dependencies. We then apply the Akaike information criterion (AIC) to force a sparse number of nonzero dependency parameters in the model. MAIN RESULTS/RESULTS:We validate the algorithm using simulations and spike-field data from two non-human primates (NHP) in a 3D motor task with motor cortical recordings and a pro-saccade visual task with prefrontal recordings. We find that by identifying a model with a sparse set of dependency parameters, the algorithm improves spike prediction compared with models without dependencies. Further, the algorithm identifies significantly fewer dependency parameters compared with standard methods while improving their spike prediction likely due to detecting fewer spurious dependencies. Also, spike prediction on any electrode improves by including LFP features from all electrodes compared with using only those on the same electrode. Finally, unlike standard methods, the algorithm uncovers patterns of spike-field network dependencies as a function of distance, brain region, and frequency band. SIGNIFICANCE/CONCLUSIONS:This algorithm can help study functional dependencies in high-dimensional spike-field networks and leads to more accurate multiscale encoding models.

BACKGROUND:Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p19q status. METHODS:We analyzed 412 histologic oligodendroglial tumors with use of 1p19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p19q was performed. Polysomy was defined as >2 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS). RESULTS:In our cohort, 333 tumors (81%) had 1p19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p19q loss had significantly better PFS and OS than did the group with 1p19q maintenance (p < 0.0001 each). Patients with 1p19q loss and polysomy showed significantly shorter PFS survival than patients with 1p19q co-deletion only (p-<0.0001), but longer PFS and OS than patients with 1p19q maintenance (p < 0.01 and p<0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% of polysomic cells. Polysomy had no prognostic significance on progression-free or overall survival in patients with 1p19q maintenance. CONCLUSIONS:The presence of polysomy in oligodendroglial tumors with co-deletion of 1p19q predicts early recurrence and short survival in patients with 1p19q co-deleted tumors.