Zachary David Threlkeld

All Publications

• Correction: Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Neuroimaging. Neurocritical care Edlow, B. L., Boerwinkle, V. L., Annen, J., Boly, M., Gosseries, O., Laureys, S., Mukherjee, P., Puybasset, L., Stevens, R. D., Threlkeld, Z. D., Newcombe, V. F., Fernandez-Espejo, D. 2024

  View details for DOI 10.1007/s12028-024-02101-3

  View details for PubMedID 39394544

• Correction: Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Neuroimaging. Neurocritical care Edlow, B. L., Boerwinkle, V. L., Annen, J., Boly, M., Gosseries, O., Laureys, S., Mukherjee, P., Puybasset, L., Stevens, R. D., Threlkeld, Z. D., Newcombe, V. F., Fernandez-Espejo, D. 2023

  View details for DOI 10.1007/s12028-023-01842-x

  View details for PubMedID 37794309

• The Severely Wounded Brain Healed: Outcome Prognostication in Neurology. Seminars in neurology Threlkeld, Z. D., Hwang, D. Y. 2023; 43 (5): 662-663

  View details for DOI 10.1055/s-0043-1775794

  View details for PubMedID 37918443

• Recommendations from the Working Group on Neuroimaging. Neurocritical care Edlow, B. L., Boerwinkle, V. L., Annen, J., Boly, M., Gosseries, O., Laureys, S., Mukherjee, P., Puybasset, L., Stevens, R. D., Threlkeld, Z. D., Newcombe, V. F., Fernandez-Espejo, D., and the Curing Coma Campaignand its Contributing Members, Aiyagari, V., Akbari, Y., Al-Mufti, F., Alexander, S., Alexandrov, A., Alkhachroum, A., Amiri, M., Appavu, B., Gebre, M. A., Bader, M. K., Badjiata, N., Balu, R., Barra, M., Beekman, R., Beghi, E., Bell, K., Beqiri, E., Berlin, T., Bleck, T., Bodien, Y., Boerwinkle, V., Boly, M., Bonnel, A., Brown, E., Caceres, E., Carroll, E., Cediel, E. G., Chou, S., Citerio, G., Classen, J., Condie, C., Cosmas, K., Creutzfeldt, C., Dangayach, N., DeGeorgia, M., Der-Nigoghoss, C., Desai, M., Diringer, M., Dullaway, J., Edlow, B., Ercole, A., Estraneo, A., Falcone, G., Farrokh, S., Ferioli, S., Fernandez-Esp, D., Fink, E., Fins, J., Foreman, B., Frontera, J., Ganesan, R., Ghavam, A., Giacino, J., Gibbons, C., Gilmore, E., Gosseries, O., Green, T., Greer, D., Guanci, M., Hahn, C., Hakimi, R., Hanley, D. F., Hartings, J., Hassan, A., Hemphill, C., Hinson, H., Hirsch, K., Hocker, S., Hu, P., Hu, X., Human, T., Hwang, D., Illes, J., Jaffa, M., James, M. L., Janas, A., Jones, M., Keller, E., Keogh, M., Kim, J., Kim, K., Kirsch, H., Kirschen, M., Ko, N., Kondziella, D., Kreitzer, N., Kromm, J., Kumar, A., Kurtz, P., Laureys, S., Lawson, T., Lejeune, N., Lewis, A., Liang, J., Ling, G., Livesay, S., Luppi, A., Madden, L., Maddux, C., Mahanes, D., Mainali, S., Maldonado, N., Ribeiro, R. M., Massimini, M., Mayer, S., McCredie, V., McNett, M., Mejia-Mantill, J., Menon, D., Meyfroidt, G., Mijangos, J., Moberg, D., Moheet, A., Molteni, E., Monti, M., Morrison, C., Muehlschlegel, S., Murtaugh, B., Naccache, L., Nagayama, M., Nairon, E., Natarajan, G., Newcombe, V., Nielsen, N., Noronha-Falc, F., Nyquist, P., Olson, D., Othman, M., Owen, A., Padayachy, L., Park, S., Pergakis, M., Polizzotto, L., Pouratian, N., Spivack, M. P., Prisco, L., Provencio, J., Puybasset, L., Rasmussen, L., Rass, V., Richardson, R., Shinots, C. R., Robba, C., Robertson, C., Rohaut, B., Rolston, J., Rosanova, M., Rosenthal, E., Russell, M. B., Silva, G. S., Sanz, L., Sarasso, S., Sarwal, A., Schiff, N., Schnakers, C., Seder, D., Shah, V. A., Shapiro-Rosen, A., Shapshak, A., Sharma, K., Sharshar, T., Shutter, L., Sitt, J., Slomine, B., Smielewski, P., Smith, W., Stamatakis, E., Steinberg, A., Stevens, R., Suarez, J., Sussman, B., Taran, S., Thibaut, A., Threlkeld, Z., Tinti, L., Toker, D., Torbey, M., Trevick, S., Turgeon, A., Udy, A., Varelas, P., Venkatasubba, C., Vespa, P., Videtta, W., Voss, H., Vox, F., Wagner, A., Wainwright, M., Whyte, J., Witherspoon, B., Yakhind, A., Zafonte, R., Zahuranec, D., Zammit, C., Zhang, B., Ziai, W., Zimmerman, L., Zink, E. 2023

  Abstract

  BACKGROUND: Over the past 5 decades, advances in neuroimaging have yielded insights into the pathophysiologic mechanisms that cause disorders of consciousness (DoC) in patients with severe brain injuries. Structural, functional, metabolic, and perfusion imaging studies have revealed specific neuroanatomic regions, such as the brainstem tegmentum, thalamus, posterior cingulate cortex, medial prefrontal cortex, and occipital cortex, where lesions correlate with the current or future state of consciousness. Advanced imaging modalities, such as diffusion tensor imaging, resting-state functional magnetic resonance imaging (fMRI), and task-based fMRI, have been used to improve the accuracy of diagnosis and long-term prognosis, culminating in the endorsement of fMRI for the clinical evaluation of patients with DoC in the 2018 US (task-based fMRI) and 2020 European (task-based and resting-state fMRI) guidelines. As diverse neuroimaging techniques are increasingly used for patients with DoC in research and clinical settings, the need for a standardized approach to reporting results is clear. The success of future multicenter collaborations and international trials fundamentally depends on the implementation of a shared nomenclature and infrastructure.METHODS: To address this need, the Neurocritical Care Society's Curing Coma Campaign convened an international panel of DoC neuroimaging experts to propose common data elements (CDEs) for data collection and reporting in this field.RESULTS: We report the recommendations of this CDE development panel and disseminate CDEs to be used in neuroimaging studies of patients with DoC.CONCLUSIONS: These CDEs will support progress in the field of DoC neuroimaging and facilitate international collaboration.

  View details for DOI 10.1007/s12028-023-01794-2

  View details for PubMedID 37552410

• An Electronic Health Record Intervention to Limit Viral Testing of Cerebrospinal Fluid. The Neurohospitalist Lyman, K. A., Madill, E., Thatikunta, P., Threlkeld, Z. D., Banaei, N., Gold, C. A. 2023; 13 (2): 173-177

  Abstract

  Meningitis and encephalitis are neurologic emergencies that require immediate management and current guidelines recommend empiric treatment with broad-spectrum antimicrobials. Cerebrospinal fluid (CSF) testing algorithms are heterogeneous and largely institution-specific, reflecting a lack of consensus on how to effectively identify CSF pathogens while conserving resources and avoiding false positives. Moreover, many lumbar punctures (LPs) performed in the inpatient setting are done for noninfectious workups, such as evaluation for leptomeningeal metastasis. As such, tailoring CSF testing to clinical context has been a focus of multiple prior reports and several healthcare systems have focused on efforts to limit low-yield diagnostic testing when a positive result is unlikely. To curb ordering viral PCRs when pre-test probability is low, some peer institutions have implemented pleocytosis criteria for virus-specific polymerase chain reaction (PCR) tests from CSF. In this report, we retrospectively analyzed the diagnostic testing of CSF from patients who had an LP while admitted to a single, large academic medical center and found that many cases of Herpes Simplex Virus (HSV) meningoencephalitis were diagnosed by non-neurologists. The rate of positive virus-specific PCR tests was very low, and tests were frequently ordered in duplicate with a multiplexed meningitis/encephalitis PCR panel (M/E panel, BioFire, Salt Lake City, UT). We designed and implemented a systems-level intervention to promote a revised stepwise testing algorithm that minimizes unnecessary tests. This intervention led to a significant reduction in the number of low-yield virus-specific PCR tests ordered without implementing a policy of cancelling virus-specific PCRs.

  View details for DOI 10.1177/19418744231152103

  View details for PubMedID 37064939

  View details for PubMedCentralID PMC10091445

• Corrigendum to 'functional networks reemerge during recovery of consciousness after acute severe traumatic brain injury' Cortex 106 (2018) 299-308. Cortex; a journal devoted to the study of the nervous system and behavior Threlkeld, Z. D., Bodien, Y. G., Rosenthal, E. S., Giacino, J. T., Nieto-Castanon, A., Wu, O., Whitfield-Gabrieli, S., Edlow, B. L. 2023

  View details for DOI 10.1016/j.cortex.2023.01.003

  View details for PubMedID 36948917

• Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma. Journal of neuropathology and experimental neurology Nie, E. H., Ahmadian, S. S., Bharadwaj, S. N., Acosta-Alvarez, L., Threlkeld, Z. D., Frank, M. J., Miklos, D. B., Monje, M., Scott, B. J., Vogel, H. 2023

  Abstract

  Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.

  View details for DOI 10.1093/jnen/nlac121

  View details for PubMedID 36592076

• Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with CD19 CAR T-cell lymphoma therapy Nie, E., Ahmadian, S., Bharadwaj, S., Acosta-Alvarez, L., Threlkeld, Z., Frank, M., Miklos, D., Born, D., Scott, B., Monje, M., Vogel, H. OXFORD UNIV PRESS INC. 2022: 464

  View details for Web of Science ID 000798368400099

• Reemergence of the language network during recovery from severe traumatic brain injury: A pilot functional MRI study. Brain injury Coffey, B. J., Threlkeld, Z. D., Foulkes, A. S., Bodien, Y. G., Edlow, B. L. 2021: 1-11

  Abstract

  PRIMARY OBJECTIVE: We hypothesized that, in patients with acute severe traumatic brain injury (TBI) who recover basic language function, speech-evoked blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) responses within the canonical language network increase over the first 6 months post-injury.RESEARCH DESIGN: We conducted aprospective, longitudinal fMRI pilot study of adults with acute severe TBI admitted to the intensive care unit. We also enrolled age- and sex-matchedhealthy subjects.METHODS AND PROCEDURES: We evaluated BOLD signal in bilateral superior temporal gyrus (STG) and inferior frontal gyrus (IFG) regions of interest acutely and approximately 6 months post-injury. Given evidence that regions outside the canonical language network contribute to language processing, we also performed exploratory whole-brain analyses.MAIN OUTCOMES AND RESULTS: Of the 16 patients enrolled, eight returned for follow-up fMRI, all of whom recovered basic language function. We observed speech-evoked longitudinal BOLD increases in the left STG, but not in the right STG, right IFG, or left IFG. Whole-brain analysis revealed increases in the right supramarginal and middle temporal gyri but no differences between patients and healthy subjects (n=16).CONCLUSION: This pilot study suggests that, in patients with severe TBI who recover language function,speech-evoked BOLD responses in bihemispheric language-processing cortex reemerge by 6monthspost-injury.

  View details for DOI 10.1080/02699052.2021.1972455

  View details for PubMedID 34546806

• Diffuse Axonal Injury Grade on Early MRI is Associated with Worse Outcome in Children with Moderate-Severe Traumatic Brain Injury. Neurocritical care Janas, A. M., Qin, F., Hamilton, S., Jiang, B., Baier, N., Wintermark, M., Threlkeld, Z., Lee, S. 2021

  Abstract

  BACKGROUND: Traumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI).METHODS: Pediatric patients (≤19years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score<13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility.RESULT: Of 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone.CONCLUSIONS: A higher DAI grade on early MRI is associated with worse 6-monthfunctional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI.

  View details for DOI 10.1007/s12028-021-01336-8

  View details for PubMedID 34462880

• Neuro-Oncologic Emergencies. Neurologic clinics Threlkeld, Z. D., Scott, B. J. 2021; 39 (2): 545–63

  Abstract

  Cancer and cancer therapies have the potential to affect the nervous system in a host of different ways. Cerebral edema, increased intracranial pressure, cerebrovascular events, status epilepticus, and epidural spinal cord compression are among those most often presenting as emergencies. Neurologic side-effects of cancer therapies are often mild, but occasionally result in serious illness. Immunotherapies cause autoimmune-related neurologic side-effects that are generally responsive to immunosuppressive therapies. Emergency management of neuro-oncologic problems benefits from early identification and close collaboration among interdisciplinary team members and patients or surrogate decision-makers.

  View details for DOI 10.1016/j.ncl.2021.01.012

  View details for PubMedID 33896532

• Cryptogenic new-onset refractory status epilepticus (NORSE) following blood transfusion in a patient with severe anemia. Epileptic disorders : international epilepsy journal with videotape Wu, C. K., Culbertson, C. J., Von Stein, E. L., Walia, S., Krishnamohan, P., Threlkeld, Z. D. 2021

  Abstract

  New-onset refractory status epilepticus (NORSE) is a rare neurological emergency in which a patient without prior seizure disorder develops seemingly unprovoked status epilepticus refractory to treatment. We report the case of a middle-aged woman who developed NORSE after receiving multiple blood transfusions for subacute blood loss anemia secondary to menorrhagia. Although the mechanism is unclear, we propose that sudden changes in blood viscosity and vasogenic tone resulted in cortical edema and irritation. Although seizures have been documented in patients who undergo blood transfusion and develop posterior reversible encephalopathy syndrome (PRES), there was no radiographic evidence of PRES in this case. This is the first reported case of cryptogenic NORSE following blood transfusion.

  View details for DOI 10.1684/epd.2021.1267

  View details for PubMedID 33881399

• Feasibility and acceptability of virtually coaching residents on communication skills: a pilot study. BMC medical education Sasnal, M., Miller-Kuhlmann, R., Merrell, S. B., Beres, S., Kipp, L., Lee, S., Threlkeld, Z., Nassar, A. K., Gold, C. A. 2021; 21 (1): 513

  Abstract

  Developing communication skills is a key competency for residents. Coaching, broadly accepted as a training modality in medical education, has been proven a successful tool for teaching communication skills. Little research is available thus far to investigate virtual coaching on communication skills for telemedicine encounters. The purpose of the study was to test the hypothesis that virtually coaching residents on communication skills is feasible and acceptable. We surveyed 21 resident-faculty pairs participating in a "fully virtual" coaching session (patient, coach, and resident were virtual).We asked 50 neurology resident-faculty coach pairs to complete one "fully virtual" coaching session between May 20 and August 31, 2020. After each session, the resident and coach completed a 15-item survey, including Likert-style scale and open-ended questions, assessing feasibility and acceptability. Descriptive statistics and qualitative content and thematic analyses were performed.Forty-two percent (21/50) of all eligible residents completed "fully virtual" coaching sessions. The overall survey response rate was 91 % (38/42). The majority of respondents agreed that the direct observation and debriefing conversation were easy to schedule and occurred without technical difficulties and that debriefing elements (self-reflection, feedback, takeaways) were useful for residents. Ninety-five percent of respondents rated the coach's virtual presence to be not at all disruptive to the resident-patient interaction. Virtual coaching alleviated resident stress associated with observation and was perceived as an opportunity for immediate feedback and a unique approach for resident education that will persist into the future.In this pilot study, residents and faculty coaches found virtual coaching on communication skills feasible and acceptable for telemedicine encounters. Many elements of our intervention may be adoptable by other residency programs. For example, residents may share their communication goals with clinic faculty supervisors and then invite them to directly observe virtual encounters what could facilitate targeted feedback related to the resident's goals. Moreover, virtual coaching on communication skills in both the in-person and telemedicine settings may particularly benefit residents in challenging encounters such as those with cognitively impaired patients or with surrogate decision-makers.

  View details for DOI 10.1186/s12909-021-02936-w

  View details for PubMedID 34583691

• Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit. Neurocritical care Edlow, B. L., Barra, M. E., Zhou, D. W., Foulkes, A. S., Snider, S. B., Threlkeld, Z. D., Chakravarty, S., Kirsch, J. E., Chan, S., Meisler, S. L., Bleck, T. P., Fins, J. J., Giacino, J. T., Hochberg, L. R., Solt, K., Brown, E. N., Bodien, Y. G. 2020

  Abstract

  There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

  View details for DOI 10.1007/s12028-020-01062-7

  View details for PubMedID 32794142

• Early magnetic resonance imaging as a predictor of outcome in pediatric traumatic brain injury Janas, A., Threlkeld, Z., Wintermark, M., Lee, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058003124

• Cryptogenic new-onset refractory status epilepticus (NORSE) following blood transfusion in a patient with severe anemia Wu, C., Von Stein, E., Culbertson, C., Walia, S., Krishnamohan, P., Threlkeld, Z. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058006056

• Will We Ever Make Headway in Severe Traumatic Brain Injury Treatment Trials? JAMA neurology Murray, N. M., Threlkeld, Z. D., Hirsch, K. G. 2020

  View details for DOI 10.1001/jamaneurol.2019.4672

  View details for PubMedID 31961381

• Early Head Computed Tomography Abnormalities Associated with Elevated Intracranial Pressure in Severe Traumatic Brain Injury. Journal of neuroimaging : official journal of the American Society of Neuroimaging Murray, N. M., Wolman, D. N., Mlynash, M. n., Threlkeld, Z. D., Christensen, S. n., Heit, J. J., Harris, O. A., Hirsch, K. G. 2020

  Abstract

  Intracranial pressure (ICP) monitoring is recommended in severe traumatic brain injury (sTBI), yet invasive monitoring has risks, and many patients do not develop elevated ICP. Tools to identify patients at risk for ICP elevation are limited. We aimed to identify early radiologic biomarkers of ICP elevation.In this retrospective study, we analyzed a prospectively enrolled cohort of patients with a sTBI at an academic level 1 trauma center. Inclusion criteria were nonpenetrating TBI, age ≥16 years, Glasgow Coma Scale (GCS) score ≤8, and presence of an ICP monitor. Two independent reviewers manually evaluated 30 prespecified features on serial head computed tomography (CTs). Patient characteristics and radiologic features were correlated with elevated ICP. The primary outcome was clinically relevant ICP elevation, defined as ICP ≥ 20 mm Hg on at least 5 or more hourly recordings during postinjury days 0-7 with concurrent administration of an ICP-lowering treatment.Among 111 sTBI patients, the median GCS was 6 (interquartile range 3-8), and 45% had elevated ICP. Features associated with elevated ICP were younger age (every 10-year decrease, odds ratio [OR] 1.4), modified Fisher scale (mFS) score at 0-4 hours postinjury (every 1 point, OR 1.8), and combined volume of contusional hemorrhage and peri-hematoma edema (10 ml, OR 1.2) at 4-18 hours postinjury.Younger age, mFS score, and volume of contusion are associated with ICP elevation in patients with a sTBI. Imaging features may stratify patients by their risk of subsequent ICP elevation.

  View details for DOI 10.1111/jon.12799

  View details for PubMedID 33146933

• Intact Brain Network Function in an Unresponsive Patient with COVID-19. Annals of neurology Fischer, D. n., Threlkeld, Z. D., Bodien, Y. G., Kirsch, J. E., Huang, S. Y., Schaefer, P. W., Rapalino, O. n., Hochberg, L. R., Rosen, B. R., Edlow, B. L. 2020

  Abstract

  Many patients with severe coronavirus disease 2019 (COVID-19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID-19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID-19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness.

  View details for DOI 10.1002/ana.25838

  View details for PubMedID 32613682

• A state-space model for dynamic functional connectivity. Conference record. Asilomar Conference on Signals, Systems & Computers Chakravarty, S., Threlkeld, Z. D., Bodien, Y. G., Edlow, B. L., Brown, E. N. 2019; 2019: 240-244

  Abstract

  Dynamic functional connectivity (DFC) analysis involves measuring correlated neural activity over time across multiple brain regions. Significant regional correlations among neural signals, such as those obtained from resting-state functional magnetic resonance imaging (fMRI), may represent neural circuits associated with rest. The conventional approach of estimating the correlation dynamics as a sequence of static correlations from sliding time-windows has statistical limitations. To address this issue, we propose a multivariate stochastic volatility model for estimating DFC inspired by recent work in econometrics research. This model assumes a state-space framework where the correlation dynamics of a multivariate normal observation sequence is governed by a positive-definite matrix-variate latent process. Using this statistical model within a sequential Bayesian estimation framework, we use blood oxygenation level dependent activity from multiple brain regions to estimate posterior distributions on the correlation trajectory. We demonstrate the utility of this DFC estimation framework by analyzing its performance on simulated data, and by estimating correlation dynamics in resting state fMRI data from a patient with a disorder of consciousness (DoC). Our work advances the state-of-the-art in DFC analysis and its principled use in DoC biomarker exploration.

  View details for DOI 10.1109/ieeeconf44664.2019.9048807

  View details for PubMedID 32801606

  View details for PubMedCentralID PMC7425228

• Default mode network dynamics in covert consciousness CORTEX Bodien, Y. G., Threlkeld, Z. D., Edlow, B. L. 2019; 119: 571–74

  View details for DOI 10.1016/j.cortex.2019.01.014

  View details for Web of Science ID 000489035600045

• Functional Reorganization of the Language Network During Recovery from Severe Traumatic Brain Injury: Longitudinal fMRI Study Coffey, B., Threlkeld, Z., Bodien, Y., Edlow, B. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965906139

• Non-electrographic Seizures Due to Subdural Hematoma: A Case Series and Review of the Literature. Neurocritical care Driver, J., DiRisio, A. C., Mitchell, H., Threlkeld, Z. D., Gormley, W. B. 2019; 30 (1): 16–21

  Abstract

  Seizures due to subdural hematoma (SDH) are a common finding, typically diagnosed using electroencephalography (EEG). At times, aggressive management of seizures is necessary to improve neurologic recovery and outcomes. Here, we present three patients who had undergone emergent SDH evacuation and showed postoperative focal deficits without accompanying electrographic epileptiform activity. After infarction and recurrent hemorrhage were ruled out, seizures were suspected despite a negative EEG. Patients were treated aggressively with AEDs and eventually showed clinical improvement. Long-term monitoring with EEG revealed electrographic seizures in a delayed fashion. EEG recordings are an important tool for seizure detection, but should be used as an adjunct to, rather than a replacement for, the clinical examination in the acute setting. At times, aggressive treatment of suspected postoperative seizures is warranted despite lack of corresponding electrographic activity and can improve clinical outcomes.

  View details for PubMedID 29476391

• Default mode network dynamics in covert consciousness. Cortex; a journal devoted to the study of the nervous system and behavior Bodien, Y. G., Threlkeld, Z. D., Edlow, B. L. 2019

  View details for PubMedID 30791975

• A state-space model for dynamic functional connectivity Chakravarty, S., Threlkeld, Z. D., Bodien, Y. G., Edlow, B. L., Brown, E. N., Matthews, M. B. IEEE. 2019: 240–44

  View details for Web of Science ID 000544249200047

• Recovery of Functional Independence After Traumatic Transtentorial Herniation With Duret Hemorrhages. Frontiers in neurology Edlow, B. L., Threlkeld, Z. D., Fehnel, K. P., Bodien, Y. G. 2019; 10: 1077

  Abstract

  Historically, Duret hemorrhages have conferred a devastating prognosis. However, recent case reports suggest that cognitive and functional recovery are possible after Duret hemorrhages. Here, we describe a patient who recovered consciousness, communication, and functional independence after Duret hemorrhages caused by traumatic transtentorial herniation. We performed prospective, standardized behavioral assessments, structural MRI scans and stimulus-based functional MRI (fMRI) scans during the first 2 years of recovery. The multimodal assessments revealed reintegration of neural networks mediating language and consciousness, concurrent with the reemergence of functional independence. These observations provide insights into network-based mechanisms of recovery from coma and add to a growing body of evidence indicating that Duret hemorrhages are not invariably associated with a poor prognosis.

  View details for DOI 10.3389/fneur.2019.01077

  View details for PubMedID 31649617

• Functional networks reemerge during recovery ofconsciousness after acute severe traumatic braininjury. Cortex; a journal devoted to the study of the nervous system and behavior Threlkeld, Z. D., Bodien, Y. G., Rosenthal, E. S., Giacino, J. T., Nieto-Castanon, A., Wu, O., Whitfield-Gabrieli, S., Edlow, B. L. 2018

  Abstract

  Integrity of the default mode network (DMN) is believed to be essential for human consciousness. However, the effects of acute severe traumatic brain injury (TBI) on DMN functional connectivity are poorly understood. Furthermore, the temporal dynamics of DMN reemergence during recovery of consciousness have not been studied longitudinally in patients with acute severe TBI. We performed resting-state functional magnetic resonance imaging (rs-fMRI) to measure DMN connectivity in 17 patients admitted to the intensive care unit (ICU) with acute severe TBI and in 16 healthy control subjects. Eight patients returned for follow-up rs-fMRI and behavioral assessment six months post-injury. At each time point, we analyzed DMN connectivity by measuring intra-network correlations (i.e. positive correlations between DMN nodes) and inter-network anticorrelations (i.e. negative correlations between the DMN and other resting-state networks). All patients were comatose upon arrival to the ICU and had a disorder of consciousness (DoC) at the time of acute rs-fMRI (9.2±4.6 days post-injury): 2 coma, 4 unresponsive wakefulness syndrome, 7 minimally conscious state, and 4 post-traumatic confusional state. We found that, while DMN anticorrelations were absent in patients with acute DoC, patients whorecovered from coma to a minimally conscious or confusional state while in the ICU showed partially preserved DMN correlations. Patients who remained in coma or unresponsive wakefulness syndrome in the ICU showed no DMN correlations. All eight patients assessed longitudinally recovered beyond the confusional state by 6 months post-injury and showed normal DMN correlations and anticorrelations, indistinguishable from those of healthy subjects. Collectively, these findings suggest that recovery of consciousness after acute severe TBI is associated with partial preservation of DMN correlations in the ICU, followed by long-term normalization of DMN correlations and anticorrelations. Both intra-network DMN correlations and inter-network DMN anticorrelations may be necessary for full recovery of consciousness after acute severe TBI.

  View details for PubMedID 29871771

• Collaborative Interventions Reduce Time-to-Thrombolysis for Acute Ischemic Stroke in a Public Safety Net Hospital JOURNAL OF STROKE & CEREBROVASCULAR DISEASES Threlkeld, Z. D., Kozak, B., McCoy, D., Cole, S., Martin, C., Singh, V. 2017; 26 (7): 1500–1505

  Abstract

  Shorter time-to-thrombolysis in acute ischemic stroke (AIS) is associated with improved functional outcome and reduced morbidity. We evaluate the effect of several interventions to reduce time-to-thrombolysis at an urban, public safety net hospital.All patients treated with tissue plasminogen activator for AIS at our institution between 2008 and 2015 were included in a retrospective analysis of door-to-needle (DTN) time and associated factors. Between 2011 and 2014, we implemented 11 distinct interventions to reduce DTN time. Here, we assess the relative impact of each intervention on DTN time.The median DTN time pre- and postintervention decreased from 87 (interquartile range: 68-109) minutes to 49 (interquartile range: 39-63) minutes. The reduction was comprised primarily of a decrease in median time from computed tomography scan order to interpretation. The goal DTN time of 60 minutes or less was achieved in 9% (95% confidence interval: 5%-22%) of cases preintervention, compared with 70% (58%-81%) postintervention. Interventions with the greatest impact on DTN time included the implementation of a stroke group paging system, dedicated emergency department stroke pharmacists, and the development of a stroke code supply box.Multidisciplinary, collaborative interventions are associated with a significant and substantial reduction in time-to-thrombolysis. Such targeted interventions are efficient and achievable in resource-limited settings, where they are most needed.

  View details for PubMedID 28396187

• Continuous Qualitative Electroencephalography as a Noninvasive Neuromonitor. The Neurohospitalist Threlkeld, Z. D., Kottapally, M., Aysenne, A., Ko, N. 2016; 6 (4): 157–60

  Abstract

  Intracranial pressure (ICP) monitoring frequently guides key decisions in the management of diseases causing intracranial hypertension. Although typically measured by invasive means, contraindications may leave the clinician with little recourse for dynamic ICP evaluation-particularly when the patient's mental status is compromised. We describe here a healthy 18-year-old woman who subacutely progressed to coma due to diffuse cerebral venous sinus thrombosis. Heparinization precluded the use of invasive ICP monitoring, and electroencephalography (EEG) was used novelly as a surrogate ICP monitor. She responded well to anticoagulation and hyperosmolar therapy guided by qualitative EEG and was later discharged with a nearly normal neurologic examination. She was found to have Salmonella bacteremia, heterozygous prothrombin and factor V Leiden mutations, and hemoglobin H disease.

  View details for PubMedID 27695597

• Heat Shock Transcription Factor 1 Is Activated as a Consequence of Lymphocyte Activation and Regulates a Major Proteostasis Network in T Cells Critical for Cell Division During Stress JOURNAL OF IMMUNOLOGY Gandhapudi, S. K., Murapa, P., Threlkeld, Z. D., Ward, M., Sarge, K. D., Snow, C., Woodward, J. G. 2013; 191 (8): 4068–79

  Abstract

  Heat shock transcription factor 1 (HSF1) is a major transcriptional regulator of the heat shock response in eukaryotic cells. HSF1 is evoked in response to a variety of cellular stressors, including elevated temperatures, oxidative stress, and other proteotoxic stressors. Previously, we demonstrated that HSF1 is activated in naive T cells at fever range temperatures (39.5°C) and is critical for in vitro T cell proliferation at fever temperatures. In this study, we demonstrated that murine HSF1 became activated to the DNA-binding form and transactivated a large number of genes in lymphoid cells strictly as a consequence of receptor activation in the absence of apparent cellular stress. Microarray analysis comparing HSF1(+/+) and HSF1(-/-) gene expression in T cells activated at 37°C revealed a diverse set of 323 genes significantly regulated by HSF1 in nonstressed T cells. In vivo proliferation studies revealed a significant impairment of HSF1(-/-) T cell expansion under conditions mimicking a robust immune response (staphylococcal enterotoxin B-induced T cell activation). This proliferation defect due to loss of HSF1 is observed even under nonfebrile temperatures. HSF1(-/-) T cells activated at fever temperatures show a dramatic reduction in cyclin E and cyclin A proteins during the cell cycle, although the transcription of these genes was modestly affected. Finally, B cell and hematopoietic stem cell proliferation from HSF1(-/-) mice, but not HSF1(+/+) mice, were also attenuated under stressful conditions, indicating that HSF1 is critical for the cell cycle progression of lymphoid cells activated under stressful conditions.

  View details for PubMedID 24043900

  View details for PubMedCentralID PMC4520533

• Isolated Histoplasma capsulatum Meningoencephalitis in an Immunocompetent Child JOURNAL OF CHILD NEUROLOGY Threlkeld, Z. D., Broughton, R., Khan, G. Q., Berger, J. R. 2012; 27 (4): 532–35

  Abstract

  Histoplasmosis with central nervous system involvement typically arises in the immunocompromised patient with disseminated fungal disease. Rarely, neurologic histoplasmosis may arise as an isolated syndrome in immunocompetent individuals without evidence of general dissemination. The disease often is diagnostically challenging, and a high index of suspicion is required for diagnosis. We describe an immunocompetent 13-year-old girl with atypical symptoms and unusual radiologic findings due to laboratory-confirmed histoplasma meningoencephalitis. She responded well to antifungal therapy.

  View details for PubMedID 22241715

• Task Deactivation Reductions and Atrophy within Parietal Default Mode Regions are Overlapping but Only Weakly Correlated in Mild Cognitive Impairment JOURNAL OF ALZHEIMERS DISEASE Threlkeld, Z. D., Jicha, G. A., Smith, C. D., Gold, B. T. 2011; 27 (2): 415–27

  Abstract

  Reduced task deactivation within regions of the default mode network (DMN) has been frequently reported in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). As task deactivation reductions become increasingly used in the study of early AD states, it is important to understand their relationship to atrophy. To address this issue, the present study compared task deactivation reductions during a lexical decision task and atrophy in aMCI, using a series of parallel voxel-wise and region-wise analyses of fMRI and structural data. Our results identified multiple regions within parietal cortex as convergence areas of task deactivation and atrophy in aMCI. Relationships between parietal regions showing overlapping task deactivation reductions and atrophy in aMCI were then explored. Regression analyses demonstrated minimal correlation between task deactivation reductions and either local or global atrophy in aMCI. In addition, a logistic regression model which combined task deactivation reductions and atrophy in parietal DMN regions showed higher classificatory accuracy of aMCI than separate task deactivation or atrophy models. Results suggest that task deactivation reductions and atrophy in parietal regions provide complementary rather than redundant information in aMCI. Future longitudinal studies will be required to assess the utility of combining task deactivation reductions and atrophy in the detection of early AD.

  View details for PubMedID 21860094