Faculty Bibliography

Background: Research based Developmental Theory of Somatoform/Centralized Pain (S/CP) (Landa et al., 2012) suggests that early interpersonal adversity(EIA) interacts with multigenerational factors leading to neural predisposition to S/CP. Interpersonal affect regulation between infant and caregiver is crucial for optimal maturation of nervous system; EIA may impede development of capacities for emotion-somatic sensation differentiation, awareness, expression and regulation of emotions, leading to experiencing distress in somaticaly. These mechanisms of symptom formation suggest that psychotherapies targeting development of these capacities can help treat S/CP; studies show that psychotherapies that focus on emotion expression and working through interpersonal traumas can alleviate S/CP. However, the exact neurophysiologic mechanisms underlying these effects are not yet fully understood. In our previous study, 90% of S/CP patients (vs 10% of controls) presented with the Unmet Need for Closeness with Others (UNCO) as main representation of relationships. We now present the data on autonomic regulation (HRV) and verbally expressed emotions/alexithymia during patient's interviews on interpersonal relationships.
Method(s): Twenty patients with S/CP from Pain, Neurology, and Primary Care clinics, and 20 age-, sex-, ethnicity-, and level of education-matched healthy controls completed the Relationship Anecdotes Paradigm (RAP)-a semi-structured interview coded for representations of relationships (Core Conflictual Relationship Theme method). HRV was measured continuously during RAP. RAP narratives were coded for Verbally Expressed Emotion using coding method adapted from Levels of Emotional Awareness Scale.
Result(s): S/CP patients had higher levels of UNCO and RAP alexithymia, and significant increase in HRV during RAP vs controls. Relationship between these dimensions and history of interpersonal traumas will be explored.
Discussion(s): Talking about interpersonal relationships and expressing UNCO to others was associated with HRV increase among S/CP patients, which has direct implications for psychophysiologic mechanisms underlying change in psychotherapeutic interventions for S/CP, therefore helping reverse effects of EIA suggested by the Developmental Theory of S/CP. Implications for diagnosis and treatment of S/CP will be discussed

There has been extraordinary research in the blood-brain barrier. Once considered a static anatomic barrier to the traffic of molecules in and out of the central nervous system when fully developed in adults, the blood-brain barrier is now known to be not only fully functional in development but also vital in cerebrovascular angiogenesis. Blood-brain barrier breakdown has been recognized as an important factor in a variety of primary neurologic diseases; however, such disturbances have yet to be critically analyzed. This article reviews the history, neurodevelopment, ultrastructure, function, and clinicopathologic correlation and relevance to central nervous system vasculitis.

Objective/UNASSIGNED:The amyotrophic lateral sclerosis (ALS) trial outcome measures are clinic based. Active and passive smartphone data can provide important longitudinal information about ALS progression outside the clinic. Methods/UNASSIGNED:We used Beiwe, a research platform for smartphone-based digital phenotyping, to collect active (self-report ALSFRS-R surveys and speech recordings) and passive (phone sensors and logs) data from patients with ALS for approximately 24 weeks. In clinics, at baseline and every 3 months, we collected vital capacity, ALSFRS-R, and ALS-CBS at enrollment, week 12, and week 24. We also collected ALSFRS-R by telephone at week 6. Results/UNASSIGNED: < 0.001). ALSFRS-R slopes were equivalent and within-subject standard deviation was smaller for smartphone-based self-report (0.26 vs. 0.56). Use of Beiwe afforded weekly collection of speech samples amenable to a variety of analyses, and we found mean pause time to increase by 0.02 sec per month across the sample. Interpretation/UNASSIGNED:Smartphone-based digital phenotyping in people with ALS is feasible and informative. Self-administered smartphone ALSFRS-R scores correlate highly with clinic-based ALSFRS-R scores, have low variability, and could be used in clinical trials. More research is required to fully analyze speech recordings and passive data, and to identify optimal digital markers for use in future ALS clinical trials.

There have been significant advances in the understanding of the vasculitides in the past several years, leading to more precise classification and nosology. Ophthalmologic manifestations may be the presenting feature of and a clue to the diagnosis of vasculitis, or develop in the course of the illness owing to a common disease mechanism. Precise diagnosis and prompt treatment prevents short- and long-term ophthalmologic sequela.

Interactions between axons and Schwann cells are essential for the acquisition of Schwann cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann cell interactions are mediated by the Nectin-like (Necl) cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann cell membrane and coprecipitate from Schwann cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann cell adaxonal membrane and the establishment of Schwann cell radial polarity.

PURPOSE/OBJECTIVE:Posttraumatic stress disorder (PTSD) often co-occurs with panic disorder (PD), with some etiological models positing a causal role of panic reactivity in PTSD onset; however, data addressing the temporal ordering of these conditions are lacking. The aim of this study was to examine the bi-directional associations between PD and PTSD in a nationally representative, epidemiologic sample of trauma-exposed adults. METHODS: = 48.9, SD 16.3) with lifetime DSM-IV PTSD criterion A trauma exposure drawn from the 2001/2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and re-interviewed in 2004/5 (N = 12,467). Cox discrete-time proportional hazards models with time-varying covariates were used to investigate the bi-directional associations between lifetime PD and PTSD, accounting for demographic characteristics, trauma load, and lifetime history of major depression, generalized anxiety disorder, and social anxiety disorder. RESULTS:PD was significantly associated with subsequent onset of PTSD (HR 1.210, 95%CI = 1.207-1.214, p < .001), and PTSD was significantly associated with onset of PD (HR 1.601, 95% CI 1.597-1.604, p < .001). The association between PTSD and subsequent PD was stronger in magnitude than that between PD and subsequent PTSD (Z = - 275.21, p < .01). Men evidenced stronger associations between PD and PTSD compared to women. CONCLUSIONS:Results were consistent with a bidirectional pathway of risk, whereby PD significantly increased risk for the development of PTSD, and PTSD significantly increased risk for PD. Given the association between PTSD and subsequent PD, particularly among men, clinicians may consider supplementing PTSD treatment with panic-specific interventions, such as interoceptive exposure, to prevent or treat this disabling comorbidity.

PURPOSE/OBJECTIVE:Patients undergoing epilepsy surgery often require invasive EEG, but few studies have examined the signal characteristics of contacts on the surface of the brain (electrocorticography, ECOG) versus depth contacts, used in stereoelectroencephalography (SEEG). As SEEG and ECOG have significant differences in complication rates, it is important to determine whether both modalities produce similar signals for analysis, to ultimately guide management of medically intractable epilepsy. METHODS:Twenty-seven patients who underwent SEEG (19), ECOG (6), or both (2) were analyzed for quantitative measures of activity including spectral power and phase-amplitude coupling during approximately 1 hour of wakefulness. The position of the contacts was calculated by coregistering the postoperative computed tomography with a reconstructed preoperative MRI. Using two types of referencing schemes-local versus common average reference-the brain regions where any quantitative measure differed systematically with contact depth were established. RESULTS:Using even the most permissive statistical criterion, few quantitative measures were significantly correlated with contact depth in either ECOG or SEEG contacts. The factors that predicted changes in spectral power and phase-amplitude coupling with contact depth were failing to baseline correct spectral power measures, use of a local rather than common average reference, using baseline correction for phase-amplitude coupling measures, and proximity of other grey matter structures near the region where the contact was located. CONCLUSIONS:The signals recorded by ECOG and SEEG have very similar spectral power and phase-amplitude coupling, suggesting that both modalities are comparable from an electrodiagnostic standpoint in delineation of the epileptogenic network.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

OBJECTIVE:To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. METHODS:UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. RESULTS:= 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. CONCLUSIONS:Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.