Zachary David Threlkeld

All Publications

• 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

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

• 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., Threlkeld, Z. D., Christensen, S., 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

• 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

• 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: 240–44

  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

• 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