Faculty Bibliography

Objective: Network analysis is the utilization of mathematical techniques to analyze the relationships of information within a network. We conducted a network analysis of the International Classification of Headache Disorders, 3rd Edition (ICHD3). Our goal is to better understand individual disease entity based on the interconnectedness inherent in the ICHD hierarchy.
Method(s): A network is defined by a set of objects, called "nodes", and the connections between them. If two nodes are connected, an "edge" exists between them. We define a node as a headache diagnosis identified by at least one ICHD3 diagnosis criterium. An edge between two headache disorders exists if one disorder is mentioned explicitly by the other in the "notes" or "comments" section of the ICHD3. We identify key nodes in a network by measuring mathematically a node's interconnectedness in three ways: degree centrality, between-ness centrality, and closeness centrality. To examine how hierarchy affects classification, we developed two models for the ICHD3, a non-hierarchical model and a hierarchical model. In the non-hierarchical model, only cross-references in the subsections qualify as edges. In the hierarchical model, the structure of the ICHD3 is taken into account by establishing additional edges between sections and their subsections.
Result(s): There are 396 nodes in both of our models. In the non-hierarchical model, there are 718 edges with average degree of separation of 3.63. In the hierarchical model, there are 1385 edges with average degree of 6.99. In both models, migraine and medication-overuse headache (MOH) are in the top 10 diagnoses according to the three centrality measurements. The choice of nonhierarchical or hierarchical model affects which diagnoses occupy the top 10 centrality nodes; specifically, there are more secondary headache diagnoses in the top 10 position in the hierarchy model compared to the non-hierarchical model.
Conclusion(s): Migraine and MOH are the most well connected nodes in ICHD3. Diagnostic hierarchy allows for unification of secondary headaches that would otherwise be considered isolated diagnoses. Once connected in a hierarchical fashion, secondary headache diagnoses form a majority of the most well-connected nodes in our field

Objective: To use quantitative metrics from a large heterogenous population of MS PATHS (Partners Advancing Technology for Health Solutions) patients to derive an integrated view of MS disease course.
Background(s): A commonly used diagram to describe MS disease course shows how various measures change over time. The curves are derived hypothetically, and the best fit patterns, e.g. linear, accelerating, are uncertain. It is also unknown whether the diagrams reflect the current era of disease modifying therapies.
Method(s): In MS PATHS, 2 standardized MRI acquisition sequences (3D FLAIR and 3D T1 on Siemens 3T scanners) were incorporated into routine MS MRI protocols at all participating institutions. A software prototype (MSPie) was developed for automated calculation of brain parenchymal fraction (BPF), total T2 lesion volume (T2LV), and new T2 lesion counts (newT2). The Multiple Sclerosis Performance Test (MSPT) was used to complete neuroperformance tests and questionnaires, including Patient Determined Disease Steps (PDDS) and self-reported relapses. Serum was collected as part of an MS PATHS biomarker sub-study and analyzed by SIMOA kit assay to measure serum neurofilament light (sNfL). Cross-sectional data from patients with MRI metrics were analyzed using linear regression to calculate slopes, and tests for quadratic terms to test linearity, for each measure vs disease duration.
Result(s): 5215 unique patients (mean[sd] age=45.9[11.9]; disease duration=11.9[8.8] years) had MRI metrics. Over nearly 4 decades of MS, BPF showed a linear decrease (slope=-0.16%/year) while PDDS and T2LV showed a linear increase, with annual slopes of 0.076/year and 0.51ml/year, respectively. Linear terms (slopes) were highly significant (p< 10^-15); whereas quadratic terms were weak (p< 0.05). Markers of inflammatory activity, including newT2 and relapses, stayed constant/decreased over the course of MS, with annual slopes of -0.01 (p=0.174) and -0.01 (p< 10^-6), respectively. Log(sNfL) increased linearly (slope= 0.015/year, p< 10^-14).
Conclusion(s): Standardization of MRIs across an international network is feasible, enabling high quality MRI-based metrics and systematic learning from routine patient care. Although limited by the cross-sectional nature of the analyses, these results show strong linearity observed for various measures of disease progression, suggesting that MS neither stabilizes nor accelerates in later stages, unlike some hypothetical diagrams of disease evolution

Introduction: Travel to clinic can be difficult due to barriers of time and cost and becomes even more burdensome for MS patients living with disabilities. Telemedicine platforms present a solution by providing supervised treatment and rehabilitation at home. Without barriers to access, patients may be more compliant and adherent to daily rehabilitation exercises. We have a large telerehabilitation research program in MS that pairs rehabilitation with transcranial direct current stimulation (tDCS), an emerging non-invasive brain stimulation technique used to improve outcomes. We provide real-time treatment administration and supervision via HIPAA compliant videoconference, termed remotely supervised tDCS or RS-tDCS.
Objective(s): To characterize the advantages of telemedicine for patients with MS in an urban setting.
Aim(s): To measure barriers to access for participants in our RS-tDCS telerehabilitation program, as well as compliance and adherence to a remotely supervised intervention.
Method(s): Participants with MS were recruited to complete a trial of cognitive remediation paired with RS-tDCS at-home. Participants were surveyed following completion of the intervention and asked to rate their difficulty in attending the clinic (on a 1-5 ordinal scale, 1 = no difficulty and 5 = nearly impossible difficulty) as well as the typical cost of attending clinic. Descriptive statistics and ordinal logistic regression models were used to evaluate the factors driving difficulty of travel.
Result(s): Participants (n=44) reported that round trip travel to the clinic requires an average of 2.3+/-2.3 hours of time and $27.04+/-38.13. Participants rated the difficulty associated with attending clinic as being moderate to significant (2.5+/-1.3). Regression analyses that included disease features produced better models and accounted for greater variance in difficulty attending the clinic, (p< 0.001, McFadden pseudo R2 = .515), as compared with socioeconomic variables alone (p< 0.001, McFadden pseudo R2 = .140). The RS-tDCS protocol was successful in providing treatment (95% compliance to treatment) and 93% of participants reported satisfaction with the treatment and remote protocols.
Conclusion(s): Participants with MS face considerable difficulty reaching the clinic, largely due to increasing neurologic disability. Telemedicine techniques such as RS-tDCS can increase treatment access, reduce physical and financial burden of travel and maintain high rates of treatment adherence

BACKGROUND:Botulinum neurotoxin type A, an FDA-approved prophylactic drug for chronic migraine, is thought to achieve its therapeutic effect through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with myelinated nociceptors and potentially the vasculature and immune cells. Prior investigations to determine botulinum neurotoxin type A effects on meningeal nociceptors were carried out in male rats and tested with stimuli that act outside the blood brain barrier. Here, we sought to explore the effects of extracranial injections of botulinum neurotoxin type A on activation of meningeal nociceptors by cortical spreading depression, an event which occurs inside the blood brain barrier, in female rats. MATERIAL AND METHODS/METHODS:Using single-unit recording, we studied myelinated C- and unmyelinated Aδ-meningeal nociceptors' responses to cortical spreading depression 7-14 days after injection of botulinum neurotoxin type A or saline along calvarial sutures. RESULTS:In female rats, responses to cortical spreading depression were typically more prolonged and, in some cases, began at relatively longer latencies post-cortical spreading depression, than had been observed in previous studies in male rats. Extracranial administration of botulinum neurotoxin type A reduced significantly the prolonged firing of the meningeal nociceptors, in the combined sample of Aδ- and C-fiber, but not their response probability. DISCUSSION/CONCLUSIONS:The findings suggest that the mechanism of action by which botulinum neurotoxin type A prevents migraine differ from the one by which calcitonin gene-related peptide monoclonal antibodies prevent migraine and that even when the origin of migraine is central (i.e. in the cortex), a peripherally acting drug can intercept/prevent the headache.

Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson's disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia. Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones. Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH. Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a severe neurodevelopmental disorder, CDKL5 deficiency disorder (CDD). CDKL5 is fundamental for correct brain development and function, but the molecular mechanisms underlying aberrant neurologic dysfunction in CDD are incompletely understood. Here we show a dysregulation of hippocampal and cortical serotonergic (5-HT) receptor expression in heterozygous Cdkl5 knockout (KO) female mice, suggesting that impaired 5-HT neurotransmission contributes to CDD. We demonstrate that targeting impaired 5-HT signaling via the selective serotonin reuptake inhibitor (SSRI) sertraline rescues CDD-related neurodevelopmental and behavioral defects in heterozygous Cdkl5 KO female mice. In particular, chronic treatment with sertraline normalized locomotion, stereotypic and autistic-like features, and spatial memory in Cdkl5 KO mice. These positive behavioral effects were accompanied by restored neuronal survival, dendritic development and synaptic connectivity. At a molecular level, sertraline increased brain-derived neurotrophic factor (BDNF) expression and restored abnormal phosphorylation levels of tyrosine kinase B (TrkB) and its downstream target the extracellular signal-regulated kinase (ERK1/2). Since sertraline is an FDA-approved drug with an extensive safety and tolerability data package, even for children, our findings suggest that sertraline may improve neurodevelopment in children with CDD.

Reactive oxygen species (ROS) can act as second messengers in various signaling pathways, and abnormal oxidation contributes to multiple diseases, including cancer. Detecting and quantifying protein oxidation is crucial for a detailed understanding of reduction-oxidation reaction (redox) signaling. We developed an Activated Thiol Sepharose-based proteomic (ATSP) approach to quantify reversible protein oxidation. ATSP can enrich H₂O₂-sensitive thiol peptides, which are more likely to contain reactive cysteines involved in redox signaling. We applied our approach to analyze hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a type of kidney cancer that harbors fumarate hydratase (FH)-inactivating mutations and has elevated ROS levels. Multiple proteins were oxidized in FH-deficient cells, including many metabolic proteins such as the pyruvate kinase M2 isoform (PKM2). Treatment of HLRCC cells with dimethyl fumarate or PKM2 activators altered PKM2 oxidation levels. Finally, we found that ATSP could detect Src homology region 2 domain-containing phosphatase-2 and PKM2 oxidation in cells stimulated with platelet-derived growth factor. This newly developed redox proteomics workflow can detect reversible oxidation of reactive cysteines and can be employed to analyze multiple physiologic and pathologic conditions.-Xu, Y., Andrade, J., Ueberheide, B., Neel, B. G. Activated Thiol Sepharose-based proteomic approach to quantify reversible protein oxidation.

PURPOSE OF REVIEW/OBJECTIVE:The purpose of this review is to examine the impact of pupillometer assessment on care and research of patients with neurological injury. RECENT FINDINGS/RESULTS:Recent studies demonstrate that automated pupillometry outperforms manual penlight pupil examination in neurocritical care populations. Further research has identified specific changes in the pupillary light reflex associated with pathologic conditions, and pupillometry has been used to successfully identify early changes in neurologic function, intracranial pressure, treatment response to osmotherapy, and prognosis after cardiac arrest. Automated pupillometry is being increasingly adopted as a routine part of the neurologic examination, supported by a growing body of literature demonstrating its reliability, accuracy, and ease of use. Automated pupillometry allows rapid, non-invasive, reliable, and quantifiable assessment of pupillary function which may allow rapid diagnosis of intracranial pathology that affects clinical decision making.