Faculty Bibliography

BACKGROUND:Considerable evidence suggests that posttraumatic stress disorder (PTSD) is a heterogeneous construct despite often being treated as a homogeneous diagnostic entity. PTSD in response to cardiac arrest is common and may differ from PTSD following other medical traumas. Most patients are amnesic from the cardiac event, and it is unclear if and how certain PTSD symptoms may manifest. METHODS:We examined the latent structure of PTSD symptoms in 104 consecutive cardiac arrest survivors who were admitted to Columbia University Medical Center. PTSD symptoms were assessed via the PTSD Checklist-Specific at hospital discharge. We performed a confirmatory factor analysis (CFA) to compare 4-factor dysphoria, 4-factor numbing, and 5-factor dysphoric arousal models of PTSD with our data. RESULTS: (113) = 151.59, p < .01, CFI = 0.94, RMSEA = 0.057, 90% CI: [0.032, 0.081]) as most representative of the data, after considering a between-factor correlation of 0.99 in the 5-factor dysphoric arousal model, and greater fit statistics than the 4-factor dysphoria model. LIMITATIONS/CONCLUSIONS:Certain factors were defined by only two items. Additionally, PTSD was assessed at discharge (median = 21 days); those assessed before 30 days could be displaying symptoms of acute stress disorder. CONCLUSIONS:Our findings suggest that PTSD symptoms after cardiac arrest are best represented by a 4-factor numbing model of PTSD. PTSD assessment and intervention efforts for cardiac arrest survivors should consider the underlying dimensions of PTSD.

The objective analysis of eye movements has a significant history and has been long proven to be an important research tool in the setting of brain injury. Quantitative recordings have a strong capacity to screen diagnostically. Concurrent examinations of the eye and upper limb movements directed toward shared functional goals (e.g., eye-hand coordination) serve as an additional robust biomarker-laden path to capture and interrogate neural injury, including acquired brain injury (ABI). While quantitative dual-effector recordings in 3-D afford ample opportunities within ocular-manual motor investigations in the setting of ABI, the feasibility of such dual recordings for both eye and hand is challenging in pathological settings, particularly when approached with research-grade rigor. Here we describe the integration of an eye tracking system with a motion tracking system intended primarily for limb control research to study a natural behavior. The protocol enables the investigation of unrestricted, three-dimensional (3D) eye-hand coordination tasks. More specifically, we review a method to assess eye-hand coordination in visually guided saccade-to-reach tasks in subjects with chronic middle cerebral artery (MCA) stroke and compare them to healthy controls. Special attention is paid to the specific eye- and limb-tracking system properties in order to obtain high fidelity data from participants post-injury. Sampling rate, accuracy, permissible head movement range given anticipated tolerance and the feasibility of use were several of the critical properties considered when selecting an eye tracker and an approach. The limb tracker was selected based on a similar rubric but included the need for 3-D recording, dynamic interaction and a miniaturized physical footprint. The quantitative data provided by this method and the overall approach when executed correctly has tremendous potential to further refine our mechanistic understanding of eye-hand control and help inform feasible diagnostic and pragmatic interventions within the neurological and rehabilitative practice.

The Receptor for Advanced Glycation End Products (RAGE) is expressed by multiple cell types in the brain and spinal cord that are linked to the pathogenesis of neurovascular and neurodegenerative disorders, including neurons, glia (microglia and astrocytes) and vascular cells (endothelial cells, smooth muscle cells and pericytes). Mounting structural and functional evidence implicates the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous1 (DIAPH1), as the key cytoplasmic hub for RAGE ligand-mediated activation of cellular signaling. In aging and diabetes, the ligands of the receptor abound, both in the central nervous system (CNS) and in the periphery. Such accumulation of RAGE ligands triggers multiple downstream events, including upregulation of RAGE itself. Once set in motion, cell intrinsic and cell-cell communication mechanisms, at least in part via RAGE, trigger dysfunction in the CNS. A key outcome of endothelial dysfunction is reduction in cerebral blood flow and increased permeability of the blood brain barrier, conditions that facilitate entry of activated leukocytes into the CNS, thereby amplifying primary nodes of CNS cellular stress. This contribution details a review of the ligands of RAGE, the mechanisms and consequences of RAGE signal transduction, and cites multiple examples of published work in which RAGE contributes to the pathogenesis of neurovascular perturbation. Insights into potential therapeutic modalities targeting the RAGE signal transduction axis for disorders of CNS vascular dysfunction and neurodegeneration are also discussed.

PURPOSE/OBJECTIVE:Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS:This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS:and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION/CONCLUSIONS:Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

BACKGROUND:Progressive cerebellar ataxia is a neurodegenerative disorder without effective treatment options that seriously hinders quality of life. Previously, transcranial direct current stimulation (tDCS) has been demonstrated to benefit cerebellar functions (including improved motor control, learning and emotional processing) in healthy individuals and patients with neurological disorders. While tDCS is an emerging therapy, multiple daily sessions are needed for optimal clinical benefit. This case study tests the symptomatic benefit of remotely supervised tDCS (RS-tDCS) for a patient with cerebellar ataxia. METHODS:We report a case of a 71-year-old female patient with progressive cerebellar ataxia, who presented with unsteady gait and balance impairment, treated with tDCS. tDCS was administered using our RS-tDCS protocol and was completed daily in the patient's home (Monday - Friday) with the help of a trained study technician. tDCS was paired with 20 min of simultaneous cognitive training, followed by 20 min of physical exercises directed by a physical therapist. Stimulation consisted of 20 min of 2.5 mA direct current targeting the cerebellum via an anodal electrode and a cathodal electrode placed over the right shoulder. The patient completed baseline and treatment end visits with neurological, cognitive, and motor (Lafayette Grooved Pegboard Test, 25 ft walk test and Timed Up and Go Test) assessments. RESULTS:The patient successfully completed sixty tDCS sessions, 59 of which were administered remotely at the patient's home with the use of real time supervision as enabled by video conferencing. Mild improvement was observed in the patient's gait with a 7% improvement in walking speed, which she completed without a walking-aid at treatment end, which was in stark contrast to her baseline assessment. Improvements were also achieved in manual dexterity, with an increase in pegboard scores bilaterally compared to baseline. CONCLUSIONS:Results from this case report suggest that consecutively administered tDCS treatments paired with cognitive and physical exercise hold promise for improving balance, gait, and manual dexterity in patients with progressive ataxia. Remotely supervised tDCS provides home access to enable the administration over an extended period. Further controlled study in a large group of those with cerebellar ataxia is needed to replicate these findings. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT03049969 . Registered 10 February 2017- Retrospectively registered.

Background and Purpose- Protease/antiprotease imbalance is implicated in the pathogenesis of emphysema and may also lead to vessel wall weakening, aneurysm development, and rupture. However, it is unclear whether emphysema is associated with cerebral and aortic aneurysm rupture. Methods- We performed a retrospective cohort study using outpatient and inpatient claims data from 2008 to 2014 from a nationally representative sample of Medicare beneficiaries ≥66 years of age. Our predictor variable was emphysema, and our outcome was hospitalization for either aneurysmal subarachnoid hemorrhage or a ruptured aortic aneurysm. All predictors and outcomes were defined using previously reported International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code algorithms. Survival statistics and Cox regression were used to compare risk between patients with and without emphysema. Results- We identified 1 670 915 patients, of whom 133 972 had a diagnosis of emphysema. During a mean follow-up period of 4.3 (±1.9) years, we identified 4835 cases of aneurysm rupture, 433 of which occurred in patients with emphysema. The annual incidence of aneurysm rupture was 6.5 (95% CI, 6.4-6.8) per 10 000 in patients without emphysema and 14.6 (95% CI, 13.3-16.0) per 10 000 in patients with emphysema. After adjustment for demographics and known risk factors for aneurysmal disease, emphysema was independently associated with aneurysm rupture (hazard ratio, 1.7; 95% CI, 1.5-1.9). Emphysema was associated with both aneurysmal subarachnoid hemorrhage (hazard ratio, 1.5; 95% CI, 1.3-1.7) and ruptured aortic aneurysm (hazard ratio, 2.3; 95% CI, 1.9-2.8). Conclusions- Patients with emphysema face an increased risk of developing subarachnoid hemorrhage and aortic aneurysm rupture, potentially consistent with shared pathways in pathogenesis.

Neurofibrillary tangles consisting of hyperphosphorylated tau (P-tau) are the neuropathological hallmark of Alzheimer's disease (AD), and olfaction disorder is an early symptom of AD. However, the link between P-tau aggregation and olfaction disorder remains unclear. In this study, the expression of P-tau in the olfactory bulb (OB), particularly in the mitral cell layer (MCL), external plexiform layer (EPL), and granule cell layer (GCL), of AD patients was found to be significantly higher than that in the OB of normal aging subjects, which suggested that these layers in the OB were susceptible to P-tau. The P301S tau transgenic mice (P301S mice) exhibit AD-like features, which can be characterized by olfactory dysfunction that precedes cognitive disorder. Importantly, the excessive P-tau expression in the OB of P301S mice, particularly in MCs, was associated with MC loss at 9 months of age, and decreased MC firing activities started to be observed at 2 months of age. Our results revealed that MCs might contribute to olfactory dysfunction in P301S mice. Furthermore, we described an aberrant dendro-dendritic synaptic structure between granule cells (GCs) and MCs and abnormal gamma oscillations in the EPL of the OB, and these findings indicated that P-tau might disrupt the regulation of MCs by GCs in P301S mice starting at 5 months of age. These data showed that the reduction in the MC firing frequency at 2 months of age might not be caused by GC suppression. Based on these findings, we speculated that MCs are a putative target for the treatment of P-tau-induced early olfactory dysfunction, and thus, an exploration of the specific causes and mechanisms of MC functional changes in P301S mice is crucial.

The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread.

BACKGROUND:Sleep spindles are involved in memory consolidation and other cognitive functions. Numerous automated methods for detection of spindles have been proposed; most of these rely on spectral analysis in some form. However, none of these approaches are ideal, and novel approaches to the problem could provide additional insights. NEW METHOD/UNASSIGNED:Here, we apply delay differential analysis (DDA), a time-domain technique based on nonlinear dynamics to detect sleep spindles in human intracranial sleep data, including laminar electrode, stereoelectroencephalogram (sEEG), and electrocorticogram (ECoG) recordings. RESULTS:We show that this approach is computationally fast, generalizable, requires minimal preprocessing, and provides excellent agreement with human scoring. COMPARISON WITH EXISTING METHODS/UNASSIGNED:score than all other tested methods except the automated detections published with the DREAMS data. Further, in addition to being a fast and reliable method for spindle detection, DDA also provides a novel characterization of spindle activity based on nonlinear dynamical content of the data. CONCLUSIONS:This additional, non-frequency-based perspective could prove particularly useful for certain atypical spindles, or identifying spindles of different types.

INTRODUCTION/BACKGROUND:Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief, lightning-like involuntary jerks. There are many possible causes of myoclonus and both the etiology and characteristics of the myoclonus are important in securing the diagnosis and treatment. Myoclonus may be challenging to treat, as it frequently requires multiple medications for acceptable results. Few randomized controlled trials investigating the optimal treatment for myoclonus are available, and expert experience and case series guide treatment. Areas Covered: In this article, the authors review the basics of myoclonus and its classification. The authors discuss the current management of myoclonus and then focus on recent updates in the literature, including both pharmacologic and surgical options. Expert opinion: Myoclonus remains a challenge to manage, and there is a paucity of rigorous clinical trials guiding treatment paradigms. Furthermore, due to the etiological heterogeneity of myoclonus, defining the appropriate scope for high quality clinical trials is challenging. In order to advance the field, the myoclonus study group needs to be revived in the US and abroad so that interested investigators can collaborate on multicenter clinical trials for myoclonus treatments.