Faculty Bibliography

Recent neuroimaging research on disorders of consciousness provides direct evidence of covert consciousness otherwise not detected clinically in a subset of severely brain-injured patients. These findings have motivated strategic development of binary communication paradigms, from which researchers interpret voluntary modulations in brain activity to glean information about patients' residual cognitive functions and emotions. The discovery of such responsiveness raises ethical and legal issues concerning the exercise of autonomy and capacity for decisionmaking on matters such as healthcare, involvement in research, and end of life. These advances have generated demands for access to the technology against a complex background of continued scientific advancement, questions about just allocation of healthcare resources, and unresolved legal issues. Interviews with professionals whose work is relevant to patients with disorders of consciousness reveal priorities concerning further basic research, legal and policy issues, and clinical considerations.

Background/Purpose: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and European Union at 200 mg daily dose in combination with a xanthine oxidase inhibitor (XOI) for treatment of hyperuricemia associated with gout in patients unable to achieve target serum uric acid on XOI (allopurinol or febuxostat) alone. Approval of lesinurad was based on three pivotal, placebo-controlled, 12-month phase III (core) studies evaluating lesinurad 200 mg (LESU200) and 400 mg (LESU400) in combination with XOI. Patients completing core studies were eligible to enter extension studies, continuing LESU+XOI at the same dose or randomized from placebo to LESU200 or LESU400 plus XOI. Methods: Renal-related and kidney stone safety data were pooled from core studies to compare LESU200+XOI and LESU400+XOI with XOI alone and from core studies + extension studies to evaluate the impact on renal safety of extended LESU+XOI treatment. Renal-related treatment-emergent adverse events (TEAEs) were a customized list of 36 preferred terms selected from the Medical Dictionary for Regulatory Activities (MedRA) Renal and Urinary Disorders System Organ Class (SOC), the Investigations SOC and the Acute Renal Failure MedRA Standardized MedRA Query (SMQ). Descriptive statistics are provided for patients receiving >1 dose of study medication. To adjust for varying treatment duration, TEAEs are expressed as exposure-adjusted incidence rates (EAIRs; subjects with events per 100 person-years). Results: In the core studies, EAIRs for any renal-related TEAE, serious renal-related TEAEs, and renal-related TEAEs leading to discontinuation were similar with XOI alone and LESU200+XOI and lower than with LESU400 +XOI (Table 1). Similar results were found for kidney stone and serious kidney stone TEAEs. The most common renal-related TEAE was increased serum creatinine (sCr). EAIRs for sCr elevations >1.5x baseline were higher with LESU+XOI than XOI alone (Table 1). Overall, 75% and 84% of sCr elevations in the XOI alone and LESU+XOI groups, respectively, were resolved at last study assessment; 75% and 66% resolved without interruption of medication. Exposure to extended LESU+XOI treatment in core+extension studies did not show an increase from core studies in EAIRs for any renal-related or kidney stone adverse event category (Table 2). Conclusion: Lesinurad at the approved dose of 200 mg once-daily combined with XOI demonstrated comparable rate of adverse events to XOI alone. There was no clinically relevant increase in these adverse events with the extension of treatment beyond 1 year. (Table presented)

Background: Infusion of vasoactive agents in the assessment of orthostatic intolerance in the autonomic laboratory is controversial. The technique of lower body negative pressure (LBNP) was described two decades ago. LBNP exaggerates orthostatic stress by closely mimicking a physiologic stimulus, and has the advantage of being quickly reversible. However, it is not routinely used in clinical practice.
Objective(s): To describe our experience using LBNP in the clinical autonomic laboratory in patients with orthostatic intolerance of unclear origin.
Method(s): We used a customized airtight cover, sealed to a tilttable and to the subject at the level of the iliac crest. After 30 min of asymptomatic passive head-up tilt, LBNP was applied while the patient was still upright. Suction was briefly initiated at -20 mmHg for 1-min and then increased to -40 mmHg for the following 10-min. Blood pressure, heart rate and plasma catecholamines when supine, after 10-min of head up tilt, and during syncope or other paroxysmal event, were measured. Time from LBNP onset to episode was recorded.
Result(s): Fifteen subjects (8 men; aged 40 +/- 20 years, range: 12-75 years) were enrolled. During LBNP, 7 subjects developed typical vasovagal syncope (after 3.8 +/- 1.3 min of LBNP) with hypotension and bradycardia and marked increases in plasma levels of epinephrine and vasopressin. Six tolerated the procedure uneventfully. One patient became unresponsive and his head stooped forward but BP and HR remained stable without changes in plasma catecholamines. The remaining patient had flailing bilateral movements with no changes in consciousness, BP or HR, but a significant increase in plasma epinephrine levels. All patients recovered without sequelae.
Conclusion(s): LBNP is a useful technique in the differential diagnosis of patients with orthostatic intolerance of unclear origin and can be easily implemented in the clinical setting. In addition to its wellknown value to induce vasovagal syncope, this technique can also be useful to induce psychogenic episodes

BACKGROUND: TUBB8 is a primate-specific beta-tubulin isotype whose expression is confined to oocytes and the early embryo. We previously found that mutations in TUBB8 caused oocyte maturation arrest. The objective was to describe newly discovered mutations in TUBB8 and to characterise the accompanying spectrum of phenotypes and modes of inheritance. METHODS AND RESULTS: Patients with oocyte maturation arrest were sequenced with respect to TUBB8. We investigated the effects of identified mutations in vitro, in cultured cells and in mouse oocytes. Seven heterozygous missense and two homozygous mutations were identified. These mutations cause a range of folding defects in vitro, different degrees of microtubule disruption upon expression in cultured cells and interfere to varying extents in the proper assembly of the meiotic spindle in mouse oocytes. Several of the newly discovered TUBB8 mutations result in phenotypic variability. For example, oocytes harbouring any of three missense mutations (I210V, T238M and N348S) could extrude the first polar body. Moreover, they could be fertilised, although the ensuing embryos became developmentally arrested. Surprisingly, oocytes from patients harbouring homozygous TUBB8 mutations that in either case preclude the expression of a functional TUBB8 polypeptide nonetheless contained identifiable spindles. CONCLUSIONS: Our data substantially expand the range of dysfunctional oocyte phenotypes incurred by mutation in TUBB8, underscore the independent nature of human oocyte meiosis and differentiation, extend the class of genetic diseases known as the tubulinopathies and provide new criteria for the qualitative evaluation of meiosis II (MII) oocytes for in vitro fertilization (IVF).

Background: In synucleinopathies, deposits of alpha-synuclein occur in sympathetic neurons innervating sweat glands, leading to impaired sudomotor function. Hence, measurement of sweat production may be relevant as a diagnostic biomarker. We hypothesized that patients with synucleinopathies have decreased electrodermal activity, and that this is associated with sympathetic adrenergic impairment.
Objective(s): To evaluate electrodermal activity in subjects with synucleinopathies.
Method(s): Cross-sectional study including 106 patients with synucleinopathies (55 with idiopathic Parkinson disease-PD-, 18 with probable multiple system atrophy-MSA-, 25 with pure autonomic failure-PAF-, and 8 with idiopathic REM behavior disorder-RBD-) and 57 healthy controls enrolled in New York University (New York, NY) and Hospital de Cruces (Bilbao, Spain). Electrodermal activity was assessed with a device (Sudoscan). Standard cardiovascular autonomic testing (in all subjects) and I¹²³metaiodobenzylguanidine myocardial scintigraphy (in 30 patients with PD) were performed to quantify sympathetic adrenergic dysfunction.
Result(s): Electrodermal activity both in the palms and in the soles was lower in patients than in controls (p<0.01). When considered separately, MSA, PAF and RBD had lower electrodermal activity in the palms than in controls (p<0.001), whereas electrodermal activity in the soles was lower in MSA, PAF and PD (p<0.05). Linear regressions showed that reduced electrodermal activity was associated with markers of sympathetic adrenergic impairment (p<0.05), but not with disease duration.
Conclusion(s): Decreased electrodermal activity in palms and soles is a frequent finding in synucleinopathies. Decreased electrodermal activity was associated with decreased sympathetic adrenergic function, suggesting a parallel degeneration of both adrenergic and cholinergic sympathetic fibers

Background: Normally, during sleep, when cortical influences are minimized, blood pressure (BP) and heart rate (HR) fall (i.e., nocturnal dipping). In patients with afferent baroreflex failure, in whom BP and HR are highly dependent on cortical influences, this nocturnal dipping is usually preserved. There are, however, a number of patients with afferent baroreflex failure in whom BP does not dip at night. The reasons for this are unknown.
Method(s): We examined the 24-hour ambulatory BP profiles in 50 patients with afferent baroreflex failure of acquired (n = 6) or genetic origin (familial dysautonomia n = 44). BP and HR were captured at 30-minute intervals over a 24-h period. Nighttime sleep periods were identified from the patient's diary. Dipping was defined as a 10 % or greater fall in systolic and diastolic blood pressure at night.
Result(s): Normal BP nocturnal dipping was present in only 50 % of the patients; 33 % of patients had reversal of the circadian rhythm with higher blood pressures at night. In the remaining 17 %, nocturnal BP was similar to daytime BP. Patients with preserved nocturnal dipping had a significantly higher glomerular filtration rate (8430 mL/ min) than those that did not dip at night (6130 mL/min, p = 0.043).
Conclusion(s): Lack of nocturnal BP dipping in patients with afferent baroreflex failure was associated with impaired renal function. These findings suggest that in patients with FD, a non-dipping profile may involve abnormalities in extracellular volume and/or impaired regulation of vascular resistance (i.e., abnormal endothelial function)

Uncertainty, which is ubiquitous in decision-making, can be fractionated into known probabilities (risk) and unknown probabilities (ambiguity). Although research has illustrated that individuals more often avoid decisions associated with ambiguity compared to risk, it remains unclear why ambiguity is perceived as more aversive. Here we examine the role of arousal in shaping the representation of value and subsequent choice under risky and ambiguous decisions. To investigate the relationship between arousal and decisions of uncertainty, we measure skin conductance response-a quantifiable measure reflecting sympathetic nervous system arousal-during choices to gamble under risk and ambiguity. To quantify the discrete influences of risk and ambiguity sensitivity and the subjective value of each option under consideration, we model fluctuating uncertainty, as well as the amount of money that can be gained by taking the gamble. Results reveal that although arousal tracks the subjective value of a lottery regardless of uncertainty type, arousal differentially contributes to the computation of value-that is, choice-depending on whether the uncertainty is risky or ambiguous: Enhanced arousal adaptively decreases risk-taking only when the lottery is highly risky but increases risk-taking when the probability of winning is ambiguous (even after controlling for subjective value). Together, this suggests that the role of arousal during decisions of uncertainty is modulatory and highly dependent on the context in which the decision is framed. (PsycINFO Database Record

INTRODUCTION: Tau immunotherapy has emerged as a promising approach to clear tau aggregates from the brain. Our previous findings suggest that tau antibodies may act outside and within neurons to promote such clearance. METHODS: We have developed an approach using flow cytometry, a human neuroblastoma cell model overexpressing tau with the P301L mutation, and paired helical filament (PHF)-enriched pathologic tau to effectively screen uptake and retention of tau antibodies in conjunction with PHF. RESULTS: The flow cytometry approach correlates well with Western blot analysis to detect internalized antibodies in naive and transfected SH-SY5Y cells (r2 = 0.958, and r2 = 0.968, P = .021 and P = .016, respectively). In transfected cells, more antibodies are taken up/retained as pathologic tau load increases, both under co-treated conditions and when the cells are pretreated with PHF before antibody administration (r2 = 0.999 and r2 = 0.999, P = .013 and P = .011, respectively). DISCUSSION: This approach allows rapid in vitro screening of antibody uptake and retention in conjunction with pathologic tau protein before more detailed studies in animals or other more complex model systems.

The journal Hippocampus has passed the milestone of 25 years of publications on the topic of a highly studied brain structure, and its closely associated brain areas. In a recent celebration of this event, a Boston memory group invited 16 speakers to address the question of progress in understanding the hippocampus that has been achieved. Here we present a summary of these talks organized as progress on four main themes: (1) Understanding the hippocampus in terms of its interactions with multiple cortical areas within the medial temporal lobe memory system, (2) understanding the relationship between memory and spatial information processing functions of the hippocampal region, (3) understanding the role of temporal organization in spatial and memory processing by the hippocampus, and (4) understanding how the hippocampus integrates related events into networks of memories. (c) 2016 Wiley Periodicals, Inc.

The thalamus is the major source of cortical inputs shaping sensation, action, and cognition. Thalamic circuits are targeted by two major inhibitory systems: the thalamic reticular nucleus (TRN) and extrathalamic inhibitory (ETI) inputs. A unifying framework of how these systems operate is currently lacking. Here, we propose that TRN circuits are specialized to exert thalamic control at different spatiotemporal scales. Local inhibition of thalamic spike rates prevails during attentional selection, whereas global inhibition more likely prevails during sleep. In contrast, the ETI (arising from basal ganglia, zona incerta (ZI), anterior pretectum, and pontine reticular formation) provides temporally precise and focal inhibition, impacting spike timing. Together, these inhibitory systems allow graded control of thalamic output, enabling thalamocortical operations to dynamically match ongoing behavioral demands.