Faculty Bibliography

Background and Purpose- The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours. Methods- We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score-24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score-24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95-100 and modified Rankin Scale score of 0-1), good 3-month functional outcome (modified Rankin Scale score of 0-2), and 3-month infarct volume. Results- There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%; P=0.045) but not median delta NIHSS (3 versus 2; P=0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROC_percent) was better than delta NIHSS (ROC_delta) and admission NIHSS (ROC_admission) with regards to excellent 3-month Barthel Index (ROC_percent, 0.83; ROC_delta, 0.76; ROC_admission, 0.75), excellent 3-month modified Rankin Scale (ROC_percent, 0.83; ROC_delta, 0.74; ROC_admission, 0.78), and good 3-month modified Rankin Scale (ROC_percent, 0.83; ROC_delta, 0.76; ROC_admission, 0.78). Conclusions- In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.

INTRODUCTION/BACKGROUND:Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has been shown to reliably improve several symptoms of Parkinson's disease (PD) in appropriately selected patients. Various factors may preclude patients from undergoing DBS and for them, non-invasive lesion-based therapies such as focused ultrasound and Gamma Knife (GK) radiosurgery may present a safer alternative. MATERIALS AND METHODS/METHODS:Based on preliminary positive reports of STN GK for PD, we conducted a prospective, open-label, single-center, pilot study in PD patients deemed potential candidates for unilateral DBS based on their disease characteristics, but contraindicated due to age >74, an irreversible bleeding diathesis, or significant comorbid medical disease. Stereotactic MRI-guided GK radiosurgery was performed using a single 110- or 120-Gy dose targeting the STN contralateral to the more symptomatic extremity. Clinical follow-up and imaging assessed the safety and efficacy of the procedure over a 12-month period. RESULTS:Four PD patients with medication-refractory tremors and disabling dyskinesias underwent unilateral STN GK radiosurgery. Contraindications to DBS included high-risk comorbid cardiovas-cular disease in 3 patients and an irreversible bleeding diathesis in 1. There were no immediate post-procedural adverse events. One patient who underwent left STN GK radiosurgery developed right hemiparesis and dysarthria 7 months post-procedure followed by hospitalization at 9 months for bacterial endocarditis and liver failure from which he died. The remaining 3 patients were free of adverse events up to 12 months post-procedure and experienced a reduction in contralateral rigidity, bradykinesia, and tremor. Upon extended follow-up, 2 patients developed subacute worsening of gait. One died at 16 months due to complications of a fall whereas the other saw no change in gait up to 42 months post-procedure. All 3 patients with adverse events demonstrated a hyper-response in the targeted area on follow-up neuroimaging. DISCUSSION/CONCLUSION/CONCLUSIONS:Despite the potential for clinical improvement, our results suggest that unilateral STN GK radiosurgery should be approached cautiously in medically frail PD patients who may be at higher risk of GK hyper-response and neurologic complications.

OBJECTIVE:To investigate clinical characteristics and treatment patterns in persistent post-traumatic headache attributed to mild traumatic brain injury. METHODS:A total of 100 individuals with persistent post-traumatic headache attributed to mild traumatic brain injury were enrolled between July 2018 and June 2019. Deep phenotyping was performed using a semi-structured interview while allodynia was assessed using the 12-item Allodynia Symptom Checklist. RESULTS:In 100 subjects with persistent post-traumatic headache, the mean headache frequency was 25.4 ± 7.1 days per month. The most common headache phenotype was chronic migraine-like headache (n = 61) followed by combined episodic migraine-like and tension-type-like headache (n = 29) while nine subjects reported "pure" chronic tension-type-like headache. The most frequent trigger factors were stress, lack of sleep, and bright lights. A history of preventive medication use was reported by 63 subjects, of which 79% reported failure of at least one preventive drug, while 19% reported failure of at least four preventive drugs. Cutaneous allodynia was absent in 54% of the subjects, mild in 23%, moderate in 17%, and severe in 6%. CONCLUSIONS:The headache profile of individuals with persistent post-traumatic headache most often resembled a chronic migraine-like phenotype or a combined episodic migraine-like and tension-type-like headache phenotype. Migraine-specific preventive medications were largely reported to be ineffective. Therefore, there is a pressing need for pathophysiological insights and disease-specific therapies.

Memory consolidation is hypothesized to involve the distribution and restructuring of memory representations across hippocampal and cortical regions. Theories suggest that, through extended hippocampal-cortical interactions, cortical ensembles come to represent more integrated, or overlapping, memory traces that prioritize commonalities across related memories. Sleep processes, particularly fast sleep spindles, are thought to support consolidation, but evidence for this relationship has been mostly limited to memory retention benefits. Whether fast spindles provide a mechanism for neural changes hypothesized to support consolidation, including the strengthening of hippocampal-cortical networks and integration across memory representations, remains unclear, as does the specificity of regions involved. Using functional connectivity analyses of human fMRI data (both sexes), we show that fast spindle density during overnight sleep is related to enhanced hippocampal-cortical functional connectivity the next day, when re-studying information learned before sleep. Spindle density modulated connectivity in distinct hippocampal-cortical networks depending on the category of the consolidated stimuli. Specifically, spindle density correlated with functional connectivity between anterior hippocampus and ventromedial prefrontal cortex (vmPFC) for object-word pairs, and posterior hippocampus and posteromedial cortex (PMC) for scene-word pairs. Using multivariate pattern analyses, we also show fast spindle density during post-learning sleep is associated with greater pattern similarity, or representational overlap, across individual object-word memories in vmPFC the next day. Further, the relationship between fast spindle density and representational overlap in vmPFC was mediated by the degree of anterior hippocampal-vmPFC functional connectivity. Together, these results suggest fast spindles support the network distribution of memory traces, potentially restructuring memory representations in vmPFC.SIGNIFICANCE STATEMENTHow new experiences are transformed into long-term memories remains a fundamental question for neuroscience research. Theories suggest that memories are stabilized as they are reorganized in the brain, a process thought to be supported by sleep oscillations, particularly sleep spindles. Although sleep spindles have been associated with benefits in memory retention, it is not well understood how spindles modify neural memory traces. This study found that spindles during overnight sleep correlate with changes in neural memory traces, including enhanced functional connectivity in distinct hippocampal-cortical networks and increased pattern similarity amongst memories in the cortex. The results provide critical evidence that spindles during overnight sleep may act as a physiological mechanism for the restructuring of neural memory traces.

INTRODUCTION/BACKGROUND:Horner's syndrome has been reported after carotid artery endarterectomy (CEA) and carotid artery stenting (CS). This study evaluates pupillary changes after these procedures using automated pupillometry. METHODS:Retrospective analysis from a prospective database of pupillometry readings. Cases (14 patients with CEA/CS) were matched to controls (14 patients without CEA/CS). t test models were constructed to examine pupillary light reflex measures for CEA, CS, and controls. RESULTS:The 28 subjects had a mean age of 70 years, 50% were male, and 96% were Caucasian. There was no significant difference in the mean pupil size, constriction velocity (CV), dilation velocity (DV) between the procedural side compared to the contralateral side. However, the mean DV in the left eye after a left sided procedure among CS patients (.67) was lower than mean DV in left eye among controls (.88; P < .0001) and patients undergoing CEA (1.03; P < .0001). DISCUSSION/CONCLUSIONS:CS may result in disruption of the carotid artery plexus and decreased sympathetic response thereby reducing DV in the ipsilateral pupil. In addition, decreased CV can also been seen. CONCLUSION/CONCLUSIONS:The findings confirm and extend those of previous authors suggesting that pupillary changes may be seen after CS and automated handheld pupillometry may aid in the detection of Horner Syndrome.

OBJECTIVE:Individuals with a diagnosis of multiple sclerosis (MS) often present with cognitive and motor deficits, and thus the ability to perform tasks that rely on both domains may be particularly impaired. Yet, dual-task walking studies yield mixed results. Individual variance in the ability to cope with brain insult and mobilize additional brain resources may contribute to mixed findings. METHODS:To test this hypothesis, we acquired event-related potentials (ERP) in individuals with MS and healthy controls (HCs) performing a Go/NoGo task while sitting (i.e., single task) or walking (i.e., dual-task) and looked at the relationship between task related modulation of the brain response and performance. RESULTS:On the Go/NoGo task the MS group showed dual-task costs when walking, whereas HCs showed a dual-task benefit. Further, whereas the HC group showed modulation of the brain response as a function of task load, this was not the case in the MS group. Analysis for the pooled sample revealed a positive correlation between load-related ERP effects and dual-task performance. CONCLUSIONS:These data suggest a neurophysiological marker of cognitive-motor dysfunction in MS. SIGNIFICANCE/CONCLUSIONS:Understanding neural processes underlying dual-task walking will help identify objective brain measurements of real-world issues and may improve assessment of MS.

Medicines currently used in the management of epilepsy have been developed to suppress seizures, and they have no known impact on the underlying disease. Using the term "antiepileptic" to describe these compounds is misleading because it suggests an action on the epilepsy itself. Pharmacological agents that have a merely symptomatic effect should be referred to as antiseizure medicines. Using appropriate terminology is especially important at a time innovative treatments targeting the development of epilepsy and its comorbidities are being actively pursued.

There has been considerable public interest in the topic of traumatic brain injury (TBI) as a risk factor for development of late-life dementia. A review was performed on empirical studies examining the relationship between these two conditions. Although results from a number of studies clearly demonstrate that TBI is a positive risk factor for developing dementia, there are an equivalent number of studies that obtain inconclusive or negative findings. Inconsistencies across studies are often the result of methodological findings including the nature of the investigational design, choice of comparison groups, and criteria used to define cases. In many studies, the diagnosis of TBI is obtained retrospectively in a manner that is subject to bias. Accurate identification of dementia cases is often compromised by the use of inappropriately brief follow-up periods and variations in diagnostic methods. There remains no universally accepted neurobiological mechanism to explain the transition from acute TBI to the chronic effects of dementia. Studies of specialty populations, including athletes and military personnel are beset by secular and cohort effects, raising questions about the applicability of findings to the general population. No existing studies have been able to exclude the possible effects of confounding medical or lifestyle factors in facilitating the onset of dementia following TBI. Although the research findings suggest a general association between TBI and dementia, the specifics of the relationship remain poorly defined.

Causal Structure Discovery (CSD) is the problem of identifying causal relationships from large quantities of data through computational methods. With the limited ability of traditional association-based computational methods to discover causal relationships, CSD methodologies are gaining popularity. The goal of the study was to systematically examine whether (i) CSD methods can discover the known causal relationships from observational clinical data and (ii) to offer guidance to accurately discover known causal relationships. We used Alzheimer's disease (AD), a complex progressive disease, as a model because the well-established evidence provides a "gold-standard" causal graph for evaluation. We evaluated two CSD methods, Fast Causal Inference (FCI) and Fast Greedy Equivalence Search (FGES) in their ability to discover this structure from data collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used structural equation models (which is not designed for CSD) as control. We applied these methods under three scenarios defined by increasing amounts of background knowledge provided to the methods. The methods were evaluated by comparing the resulting causal relationships with the "gold standard" graph that was constructed from literature. Dedicated CSD methods managed to discover graphs that nearly coincided with the gold standard. For best results, CSD algorithms should be used with longitudinal data providing as much prior knowledge as possible.