Person: Khanna, Arjun
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Khanna
First Name
Arjun
Name
Khanna, Arjun
10 results
Search Results
Now showing 1 - 10 of 10
Publication Glioblastoma Mimicking an Arteriovenous Malformation(Frontiers Media S.A., 2013) Khanna, Arjun; Venteicher, Andrew S; Walcott, Brian; Kahle, Kristopher T.; Mordes, Daniel; William, Christopher M.; Ghogawala, Zoher; Ogilvy, ChristopherAbnormal cerebral vasculature can be a manifestation of a vascular malformation or a neoplastic process. We report the case of a patient with angiography-negative subarachnoid hemorrhage (SAH) who re-presented 3 years later with a large intraparenchymal hemorrhage. Although imaging following the intraparenchymal hemorrhage was suggestive of arteriovenous malformation, the patient was ultimately found to have an extensive glioblastoma associated with abnormal tumor vasculature. The case emphasizes the need for magnetic resonance imaging to investigate angiography-negative SAH in suspicious cases to rule out occult etiologies, such as neoplasm. We also discuss diagnostic pitfalls when brain tumors are associated with hemorrhage and abnormal vasculature.Publication Limitations of Current GABA Agonists in Neonatal Seizures: Toward GABA Modulation Via the Targeting of Neuronal Cl− Transport(Frontiers Media S.A., 2013) Khanna, Arjun; Walcott, Brian; Kahle, Kristopher T.Neonatal intensive care has advanced rapidly in the last 40 years, with dramatic decreases in mortality and morbidity; however, for neonatal seizures, neither therapies nor outcomes have changed significantly. Basic and clinical studies indicate that seizures in neonates have long-term neurodevelopmental and psychiatric consequences, highlighting the need for novel pharmacotherapeutics. First-line treatments targeting GABAA receptors, like barbiturates and benzodiazepines, are limited in their efficacy and carry significant risks to the developing brain. Here, we review the use of current GABA agonist therapies for neonatal seizures and suggest other treatment strategies given recent developments in the understanding of disease pathogenesis. One promising avenue is the indirect manipulation of the GABAergic system, via the modulation of neuronal Cl− gradients, by targeting the cation-Cl− cotransporters (NKCC1 and KCC2) or their regulatory signaling molecules. This strategy might yield a novel class of more efficacious anti-epileptics with fewer side effects by specifically addressing disease pathophysiology. Moreover, this strategy may have ramifications for other adult seizure syndromes in which GABA receptor-mediated depolarizations play a pathogenic role, such as temporal lobe epilepsy.Publication Reliability of Resting-State Microstate Features in Electroencephalography(Public Library of Science, 2014) Khanna, Arjun; Pascual-Leone, Alvaro; Farzan, FaranakBackground: Electroencephalographic (EEG) microstate analysis is a method of identifying quasi-stable functional brain states (“microstates”) that are altered in a number of neuropsychiatric disorders, suggesting their potential use as biomarkers of neurophysiological health and disease. However, use of EEG microstates as neurophysiological biomarkers requires assessment of the test-retest reliability of microstate analysis. Methods: We analyzed resting-state, eyes-closed, 30-channel EEG from 10 healthy subjects over 3 sessions spaced approximately 48 hours apart. We identified four microstate classes and calculated the average duration, frequency, and coverage fraction of these microstates. Using Cronbach's α and the standard error of measurement (SEM) as indicators of reliability, we examined: (1) the test-retest reliability of microstate features using a variety of different approaches; (2) the consistency between TAAHC and k-means clustering algorithms; and (3) whether microstate analysis can be reliably conducted with 19 and 8 electrodes. Results: The approach of identifying a single set of “global” microstate maps showed the highest reliability (mean Cronbach's α>0.8, SEM ≈10% of mean values) compared to microstates derived by each session or each recording. There was notably low reliability in features calculated from maps extracted individually for each recording, suggesting that the analysis is most reliable when maps are held constant. Features were highly consistent across clustering methods (Cronbach's α>0.9). All features had high test-retest reliability with 19 and 8 electrodes. Conclusions: High test-retest reliability and cross-method consistency of microstate features suggests their potential as biomarkers for assessment of the brain's neurophysiological health.Publication Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis(Frontiers Media S.A., 2015) Adragna, Norma C.; Ravilla, Nagendra B.; Lauf, Peter K.; Begum, Gulnaz; Khanna, Arjun; Sun, Dandan; Kahle, Kristopher T.The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K+ and Cl− efflux via activation of K+ channels, volume-regulated anion channels (VRACs), and the K+-Cl− cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na+-K+-2Cl− cotransporter isoform 1 (NKCC1). This results in a rapid (<10 min) and significant (>90%) reduction in intracellular K+ content (Ki) via both Cl-dependent (KCC3a + NKCC1) and Cl-independent [DCPIB (VRAC inhibitor)-sensitive] pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in KCC3a encodes a potent switch of transporter activity, Ki homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD.Publication Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia(Frontiers Media S.A., 2015) Merner, Nancy D.; Chandler, Madison R.; Bourassa, Cynthia; Liang, Bo; Khanna, Arjun; Dion, Patrick; Rouleau, Guy A.; Kahle, Kristopher T.Many encoded gene products responsible for neurodevelopmental disorders (NDs) like autism spectrum disorders (ASD), schizophrenia (SCZ), intellectual disability (ID), and idiopathic generalized epilepsy (IGE) converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5) Cl− transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non-synonymous (NS), functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD) in human ASD (R952H and R1049C) and SCZ (R952H) previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W) with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection (SSC) revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs.Publication Electroencephalographic Microstate Correlates of Fluid Intelligence(2016-05-17) Khanna, ArjunThe neurobiological correlates of human fluid intelligence (Gf) remain elusive. Converging lines of evidence suggest a pivotal role for the efficiency and connectivity of anatomically-defined brain networks, but little is known about Gf-related electrophysiological dynamics of these networks occurring at native timescales, such as those measured via electroencephalography (EEG). Spatiotemporal analysis of state-space dynamics of the EEG signal, involving examination of fast-changing, recurring, topographically-defined electric patterns termed “microstates,” may enable investigation of the electrophysiological activity of distributed cortical networks and their relation to brain characteristics, including Gf. Here, we correlated EEG microstate patterns with multiple fluid intelligence measures, and assessed changes in microstate patterns after cognitive training aimed at improving intelligence. We found that the frequency of activation of specific brain topographies, spatially associated with visual (microstate B) and executive control (microstate C) networks, were inversely related to Gf scores. When Gf scores were separated into two distinct “dimensions” of intelligence using latent factor analysis, each “dimension” correlated with a different microstate, suggesting that each microstate class represents a distinct cognitive modality. Cognitive training resulted in a posterior shift in the topography of microstate C, possibly reflecting increased prefrontal inhibitory control over parietal brain regions. These results highlight the role of fast-changing brain electrical states related to visual and executive functions in Gf, as well as the mechanisms behind Gf enhancement after cognitive training.Publication Time interval to surgery and outcomes following the surgical treatment of acute traumatic subdural hematoma(Elsevier BV, 2014) Walcott, Brian; Khanna, Arjun; Kwon, Churl-Su; Phillips, H. Westley; Nahed, Brian; Coumans, Jean-ValeryAlthough the pre-surgical management of patients with acute traumatic subdural hematoma prioritizes rapid transport to the operating room, there is conflicting evidence regarding the importance of time interval from injury to surgery with regards to outcomes. We sought to determine the association of surgical timing with outcomes for subdural hematoma. A retrospective review was performed of 522 consecutive patients admitted to a single center from 2006–2012 who underwent emergent craniectomy for acute subdural hematoma. After excluding patients with unknown time of injury, penetrating trauma, concurrent cerebrovascular injury, epidural hematoma, or intraparenchymal hemorrhage greater than 30 mL, there remained 45 patients identified for analysis. Using a multiple regression model, we examined the effect of surgical timing, in addition to other variables on in-hospital mortality (primary outcome), as well as the need for tracheostomy or gastrostomy (secondary outcome). We found that increasing injury severity score (odds ratio [OR] 1.146; 95% confidence interval [CI] 1.035–1.270; p = 0.009) and age (OR1.066; 95%CI 1.006–1.129; p = 0.031) were associated with in-hospital mortality in multivariate analysis. In this model, increasing time to surgery was not associated with mortality, and in fact had a significant effect in decreasing mortality (OR 0.984; 95%CI 0.971–0.997; p = 0.018). Premorbid aspirin use was associated with a paradoxical decrease in mortality (OR 0.019; 95%CI 0.001–0.392; p = 0.010). In this patient sample, shorter time interval from injury to surgery was not associated with better outcomes. While there are potential confounding factors, these findings support the evaluation of rigorous preoperative resuscitation as a priority in future study.Publication Functional kinomics establishes a critical node of volume-sensitive cation-Cl− cotransporter regulation in the mammalian brain(Nature Publishing Group, 2016) Zhang, Jinwei; Gao, Geng; Begum, Gulnaz; Wang, Jinhua; Khanna, Arjun; Shmukler, Boris; Daubner, Gerrit M.; de los Heros, Paola; Davies, Paul; Varghese, Joby; Bhuiyan, Mohammad Iqbal H.; Duan, Jinjing; Zhang, Jin; Duran, Daniel; Alper, Seth; Sun, Dandan; Elledge, Stephen; Alessi, Dario R.; Kahle, Kristopher T.Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr991/Thr1048 phosphorylation – a key signaling event in cell swelling-induced regulatory volume decrease (RVD). In the mammalian brain, we found the Cl−-sensitive WNK3-SPAK kinase complex, required for cell shrinkage-induced regulatory volume decrease (RVI) via the stimulatory phosphorylation of NKCC1 (Thr203/Thr207/Thr212), is also essential for the inhibitory phosphorylation of KCC3 (Thr991/Thr1048). This is mediated in vivo by an interaction between the CCT domain in SPAK and RFXV/I domains in WNK3 and NKCC1/KCC3. Accordingly, genetic or pharmacologic WNK3-SPAK inhibition prevents cell swelling in response to osmotic stress and ameliorates post-ischemic brain swelling through a simultaneous inhibition of NKCC1-mediated Cl− uptake and stimulation of KCC3-mediated Cl− extrusion. We conclude that WNK3-SPAK is an integral component of the long-sought “Cl−/volume-sensitive kinase” of the cation-Cl− cotransporters, and functions as a molecular rheostat of cell volume in the mammalian brain.Publication Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing(Oxford University Press, 2017) Piantadosi, Anne; Kanjilal, Sanjat; Ganesh, Vijay; Khanna, Arjun; Hyle, Emily; Rosand, Jonathan; Bold, Tyler; Metsky, Hayden C; Lemieux, Jacob; Leone, Michael J; Freimark, Lisa; Matranga, Christian B; Adams, Gordon; McGrath, Graham; Zamirpour, Siavash; Telford, Sam; Rosenberg, Eric; Cho, Tracey Alexander; Frosch, Matthew; Goldberg, Marcia; Mukerji, Shibani; Sabeti, PardisAbstract We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.Publication Semantic encoding during language comprehension at single-cell resolution(Springer Science and Business Media LLC, 2024-07-03) Jamali, Mohsen; Grannan, Benjamin; Cai, Jing; Khanna, Arjun; Munoz Miranda, William; Caprara, Irene; Paulk, Angelique; Cash, Sydney; Fedorenko, Evelina; Williams, ZivFrom sequences of speech sounds, or letters, humans can extract rich and nuanced meaning through language. This capacity is essential for human communication. Yet, despite a growing understanding of the brain areas that support linguistic and semantic processing, the derivation of linguistic meaning in neural tissue at the cellular level and over the timescale of action potentials remains largely unknown. Here, we recorded from single cells in the left language-dominant prefrontal cortex as participants listened to semantically diverse sentences and naturalistic stories. By tracking their activities during natural speech processing, we discover a remarkably fine scale representation of semantic information by individual neurons. These neurons responded selectively to specific word meanings and reliably distinguished words from nonwords. Their activities were also dynamic, reflecting the words’ meanings based on their specific sentence contexts and independent of their phonetic form. Modeled collectively, we show how these cell ensembles accurately predicted the broad semantic categories of the words as they were heard in real-time during speech. We also show how they encoded the hierarchical structure of these meaning representations and how they mapped onto the population’s response patterns. Together, these findings reveal a detailed organization of semantic representations by prefrontal neurons in humans and begin to illuminate the cellular-level processing of meaning during language comprehension.