Zachary David Threlkeld

All Publications

• 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 DOI 10.1016/j.cortex.2018.05.004

  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 DOI 10.1016/j.jstrokecerebrovasdis.2017.03.004

  View details for Web of Science ID 000407018400022

  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 DOI 10.4049/jimmunol.1202831

  View details for Web of Science ID 000325487700013

  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 DOI 10.1177/0883073811428780

  View details for Web of Science ID 000302231900018

  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 DOI 10.3233/JAD-2011-110206

  View details for Web of Science ID 000297215900017

  View details for PubMedID 21860094

  View details for PubMedCentralID PMC3410647