Faculty Bibliography

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system that has aspects of repetitive inflammatory activity as well as a slow neurodegenerative process. The immune assault on the nervous system is triggered by a complex interaction between immunogenetic and environmental factors. Among the different environmental factors, a compelling case, buttressed by strong epidemiological, serological and other data, has been made for the role of Epstein-Barr virus (EBV) in the pathogenesis of MS. However, the ubiquity of EBV, lack of a well understood role in MS pathogenesis, and controversies regarding its presence in brains of people with MS has caused debate as to how exactly it contributes to MS. Recent years have seen the remarkable effect of anti-CD20 therapies on the inflammatory component of MS. How B cell depletion results in a salutary effect in MS remains incompletely understood. It has been proposed that depletion of CD20+ B-cells disrupts other pro-inflammatory pathways in the immune system, especially T-cells. In this paper, we make the case that the robust effect of anti-CD20 therapies on MS activity could actually be from removal of circulating EBV-infected memory B-cells that drive CNS inflammation and not through other immune pathways - in essence that this is from an anti-viral effect, and not necessarily an immuno-modulatory effect.

To derive meaning from sound, the brain must integrate information across many timescales. What computations underlie multiscale integration in human auditory cortex? Evidence suggests that auditory cortex analyses sound using both generic acoustic representations (for example, spectrotemporal modulation tuning) and category-specific computations, but the timescales over which these putatively distinct computations integrate remain unclear. To answer this question, we developed a general method to estimate sensory integration windows-the time window when stimuli alter the neural response-and applied our method to intracranial recordings from neurosurgical patients. We show that human auditory cortex integrates hierarchically across diverse timescales spanning from ~50 to 400 ms. Moreover, we find that neural populations with short and long integration windows exhibit distinct functional properties: short-integration electrodes (less than ~200 ms) show prominent spectrotemporal modulation selectivity, while long-integration electrodes (greater than ~200 ms) show prominent category selectivity. These findings reveal how multiscale integration organizes auditory computation in the human brain.

Departing from traditional linguistic models, advances in deep learning have resulted in a new type of predictive (autoregressive) deep language models (DLMs). Using a self-supervised next-word prediction task, these models generate appropriate linguistic responses in a given context. In the current study, nine participants listened to a 30-min podcast while their brain responses were recorded using electrocorticography (ECoG). We provide empirical evidence that the human brain and autoregressive DLMs share three fundamental computational principles as they process the same natural narrative: (1) both are engaged in continuous next-word prediction before word onset; (2) both match their pre-onset predictions to the incoming word to calculate post-onset surprise; (3) both rely on contextual embeddings to represent words in natural contexts. Together, our findings suggest that autoregressive DLMs provide a new and biologically feasible computational framework for studying the neural basis of language.

The care for the patients with end-stage heart failure has been revolutionized by the introduction of durable left ventricular assist devices, providing a substantial improvement in patient survival and quality of life and an alternative to heart transplantation. The newest devices have lower instances of mechanical dysfunction and associated pump thrombosis. Despite these improvements in complications, the use of continuous flow assist devices is still associated with high rates of thrombotic and hemorrhagic complications, most notably stroke in approximately 10% of continuous flow assist devices patients per year. With the newest HeartMate 3 devices, there have been lower observed rates of stroke, which has in part been achieved by both improvements in pump technology and knowledge of the risk factors for stroke and neurological complications. The therapeutic options available to clinicians to reduce the risk of stroke, including management of hypertension and antithrombotics, will be reviewed in this manuscript.

Background: Sturge-Weber syndrome (SWS) involves the skin, brain, and eyes. The dermatologic manifestation is the facial port wine birthmark (PWB), while there are several potential neurologic and ophthalmologic manifestations, notably epilepsy and glaucoma, respectively. This consensus aims to develop evidence-based expert-defined recommendations for management of the neurologic and ophthalmic features and provides a framework for dermatologists to determine workup for patients with PWB who seek laser treatment. Study Design/Materials and Method: Thirteen national experts in neurology, radiology, and ophthalmology were assembled as part of a larger consensus statement for the management of SWS. Key topics and questions regarding risk stratification, referral indications, and treatment were formulated. A systematic PubMed search was performed. Evidence-based recommendations were developed.
Result(s): High-risk PWB distributions involve the hemifacial, forehead, or median locations, including the upper eyelids, especially when concerned for glaucoma. Any child with a high-risk facial PWB should be referred to a pediatric neurologist and pediatric ophthalmologist for a baseline evaluation, with periodic follow-up. Routine screening for brain involvement is not recommended for newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms but can be performed in cases of extreme parental anxiety, an abnormal EEG, or when presymptomatic treatment is contemplated such as with extensive bilateral PWB. In children with stable neurocognitive symptoms, routine follow-up neuroimaging is not advised. In adults with a high-risk PWB and no prior imaging, neuroimaging should be obtained, but follow-up neuroimaging is not recommended in adults with established SWS and stable neurocognitive symptoms. The treatment of glaucoma varies depending on the patient's age and clinical presentation.
Conclusion(s): Recommendations were developed by experts in neurology, neuroradiology, and ophthalmology. These guidelines can guide evidence-based discussions between patients and providers and increase dermatologists' awareness regarding when and what workup is necessary in patients seeking laser treatment for PWB

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins^1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear³. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.

Purpose/UNASSIGNED:To report 3 otherwise healthy patients with Herpes zoster reactivation shortly after administration of a mRNA vaccine against the novel COVID-19 virus. Observations/UNASSIGNED:Patient 1 is a 54 year old who presented with Herpes zoster meningitis complicated by enhancing nodular leptomeningeal lesions of the spinal cord. The subsequent two patients had Herpes zoster ophthalmicus of the cornea (Case 2) and eyelid (Case 3). All three presented within 2 weeks of receiving the Pfizer/BioNTech COVID-19 vaccine. Conclusions/UNASSIGNED:Herpes zoster may be a side effect of m RNA vaccination against the Sars-CoV2 vaccine and requires further investigation.