All Publications

  • Intracortical dynamics underlying repetitive stimulation predicts changes in network connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience Huang, Y., Hajnal, B., Entz, L., Fabo, D., Herrero, J. L., Mehta, A. D., Keller, C. J. 2019


    Targeted stimulation can be used to modulate the activity of brain networks. Previously we demonstrated that direct electrical stimulation produces predictable post-stimulation changes in brain excitability. However, understanding the neural dynamics during stimulation and its relationship to post-stimulation effects is limited but critical for treatment optimization. Here, we applied 10Hz direct electrical stimulation across several cortical regions in 14 human subjects (6 males) implanted with intracranial electrodes for seizure monitoring. The stimulation train was characterized by a consistent increase in high gamma (70-170Hz) power. Immediately post-train, low-frequency (1-8Hz) power increased, resulting in an evoked response that was highly correlated with the neural response during stimulation. Using two measures of network connectivity, cortico-cortical evoked potentials (indexing effective connectivity) and theta coherence (indexing functional connectivity), we found a stronger response to stimulation in regions that were highly connected to the stimulation site. In these regions, repeated cycles of stimulation trains and rest progressively altered the stimulation response. Finally, after just two minutes (10%) of repetitive stimulation, we were able to predict post-stimulation connectivity changes with high discriminability. Taken together, this work reveals a relationship between stimulation dynamics and post-stimulation connectivity changes in humans. Thus, measuring neural activity during stimulation can inform future plasticity-inducing protocols.SIGNIFICANCE STATEMENTBrain stimulation tools have the potential to revolutionize the treatment of neuropsychiatric disorders. Despite the widespread use of brain stimulation techniques such as transcranial magnetic stimulation, the therapeutic efficacy of these technologies remains suboptimal. This is in part due to a lack of understanding of the dynamic neural changes that occur during stimulation. In this study, we provide the first detailed characterization of neural activity during plasticity induction through intracranial electrode stimulation and recording in 14 medication-resistant seizure patients. These results fill a missing gap in our understanding of stimulation-induced plasticity in humans. In the longer term, these data will also guide our translational efforts toward non-invasive, personalized, closed-loop neuromodulation therapy for neurological and psychiatric disorders in humans.

    View details for DOI 10.1523/JNEUROSCI.0535-19.2019

    View details for PubMedID 31182638

  • Towards a Mechanistic Understanding of Brain Stimulation Keller, C., Huang, D., Mehta, A., Entz, L., Hajnal, B. ELSEVIER SCIENCE INC. 2019: S56
  • Epidermal Growth Factor Receptor Mutation Status Confers Survival Benefit in Patients with Non-Small-Cell Lung Cancer Undergoing Surgical Resection of Brain Metastases: A Retrospective Cohort Study WORLD NEUROSURGERY Huang, Y., Chow, K. H., Aredo, J. V., Padda, S. K., Han, S. S., Kakusa, B. W., Gephart, M. 2019; 125: E487–E496
  • Ferumoxytol-enhanced MRI for surveillance of pediatric cerebral arteriovenous malformations. Journal of neurosurgery. Pediatrics Huang, Y. n., Singer, T. G., Iv, M. n., Lanzman, B. n., Nair, S. n., Stadler, J. A., Wang, J. n., Edwards, M. S., Grant, G. A., Cheshier, S. H., Yeom, K. W. 2019: 1–8


    Children with intracranial arteriovenous malformations (AVMs) undergo digital DSA for lesion surveillance following their initial diagnosis. However, DSA carries risks of radiation exposure, particularly for the growing pediatric brain and over lifetime. The authors evaluated whether MRI enhanced with a blood pool ferumoxytol (Fe) contrast agent (Fe-MRI) can be used for surveillance of residual or recurrent AVMs.A retrospective cohort was assembled of children with an established AVM diagnosis who underwent surveillance by both DSA and 3-T Fe-MRI from 2014 to 2016. Two neuroradiologists blinded to the DSA results independently assessed Fe-enhanced T1-weighted spoiled gradient recalled acquisition in steady state (Fe-SPGR) scans and, if available, arterial spin labeling (ASL) perfusion scans for residual or recurrent AVMs. Diagnostic confidence was examined using a Likert scale. Sensitivity, specificity, and intermodality reliability were determined using DSA studies as the gold standard. Radiation exposure related to DSA was calculated as total dose area product (TDAP) and effective dose.Fifteen patients were included in this study (mean age 10 years, range 3-15 years). The mean time between the first surveillance DSA and Fe-MRI studies was 17 days (SD 47). Intermodality agreement was excellent between Fe-SPGR and DSA (κ = 1.00) but poor between ASL and DSA (κ = 0.53; 95% CI 0.18-0.89). The sensitivity and specificity for detecting residual AVMs using Fe-SPGR were 100% and 100%, and using ASL they were 72% and 100%, respectively. Radiologists reported overall high diagnostic confidence using Fe-SPGR. On average, patients received two surveillance DSA studies over the study period, which on average equated to a TDAP of 117.2 Gy×cm2 (95% CI 77.2-157.4 Gy×cm2) and an effective dose of 7.8 mSv (95% CI 4.4-8.8 mSv).Fe-MRI performed similarly to DSA for the surveillance of residual AVMs. Future multicenter studies could further investigate the efficacy of Fe-MRI as a noninvasive alternative to DSA for monitoring AVMs in children.

    View details for DOI 10.3171/2019.5.PEDS1957

    View details for PubMedID 31323627

  • Stereotactic laser ablation for completion corpus callosotomy. Journal of neurosurgery. Pediatrics Huang, Y. n., Yecies, D. n., Bruckert, L. n., Parker, J. J., Ho, A. L., Kim, L. H., Fornoff, L. n., Wintermark, M. n., Porter, B. n., Yeom, K. W., Halpern, C. H., Grant, G. A. 2019: 1–9


    Completion corpus callosotomy can offer further remission from disabling seizures when a prior partial corpus callosotomy has failed and residual callosal tissue is identified on imaging. Traditional microsurgical approaches to section residual fibers carry risks associated with multiple craniotomies and the proximity to the medially oriented motor cortices. Laser interstitial thermal therapy (LITT) represents a minimally invasive approach for the ablation of residual fibers following a prior partial corpus callosotomy. Here, the authors report clinical outcomes of 6 patients undergoing LITT for completion corpus callosotomy and characterize the radiological effects of ablation.A retrospective clinical review was performed on a series of 6 patients who underwent LITT completion corpus callosotomy for medically intractable epilepsy at Stanford University Medical Center and Lucile Packard Children's Hospital at Stanford between January 2015 and January 2018. Detailed structural and diffusion-weighted MR images were obtained prior to and at multiple time points after LITT. In 4 patients who underwent diffusion tensor imaging (DTI), streamline tractography was used to reconstruct and evaluate tract projections crossing the anterior (genu and rostrum) and posterior (splenium) parts of the corpus callosum. Multiple diffusion parameters were evaluated at baseline and at each follow-up.Three pediatric (age 8-18 years) and 3 adult patients (age 30-40 years) who underwent completion corpus callosotomy by LITT were identified. Mean length of follow-up postoperatively was 21.2 (range 12-34) months. Two patients had residual splenium, rostrum, and genu of the corpus callosum, while 4 patients had residual splenium only. Postoperative complications included asymptomatic extension of ablation into the left thalamus and transient disconnection syndrome. Ablation of the targeted area was confirmed on immediate postoperative diffusion-weighted MRI in all patients. Engel class I-II outcomes were achieved in 3 adult patients, whereas all 3 pediatric patients had Engel class III-IV outcomes. Tractography in 2 adult and 2 pediatric patients revealed time-dependent reduction of fractional anisotropy after LITT.LITT is a safe, minimally invasive approach for completion corpus callosotomy. Engel outcomes for completion corpus callosotomy by LITT were similar to reported outcomes of open completion callosotomy, with seizure reduction primarily observed in adult patients. Serial DTI can be used to assess the presence of tract projections over time but does not classify treatment responders or nonresponders.

    View details for DOI 10.3171/2019.5.PEDS19117

    View details for PubMedID 31374542

  • Induction and Quantification of Excitability Changes in Human Cortical Networks JOURNAL OF NEUROSCIENCE Keller, C. J., Huang, Y., Herrero, J. L., Fini, M. E., Du, V., Lado, F. A., Honey, C. J., Mehta, A. D. 2018; 38 (23): S384–S398


    How does human brain stimulation result in lasting changes in cortical excitability? Uncertainty on this question hinders the development of personalized brain stimulation therapies. To characterize how cortical excitability is altered by stimulation, we applied repetitive direct electrical stimulation in eight human subjects (male and female) undergoing intracranial monitoring. We evaluated single-pulse corticocortical-evoked potentials (CCEPs) before and after repetitive stimulation across prefrontal (n = 4), temporal (n = 1), and motor (n = 3) cortices. We asked whether a single session of repetitive stimulation was sufficient to induce excitability changes across distributed cortical sites. We found a subset of regions at which 10 Hz prefrontal repetitive stimulation resulted in both potentiation and suppression of excitability that persisted for at least 10 min. We then asked whether these dynamics could be modeled by the prestimulation connectivity profile of each subject. We found that cortical regions (1) anatomically close to the stimulated site and (2) exhibiting high-amplitude CCEPs underwent changes in excitability following repetitive stimulation. We demonstrate high accuracy (72-95%) and discriminability (81-99%) in predicting regions exhibiting changes using individual subjects' prestimulation connectivity profile, and show that adding prestimulation connectivity features significantly improved model performance. The same features predicted regions of modulation following motor and temporal cortices stimulation in an independent dataset. Together, baseline connectivity profile can be used to predict regions susceptible to brain changes and provides a basis for personalizing brain stimulation.SIGNIFICANCE STATEMENT Brain stimulation is increasingly used to treat neuropsychiatric disorders by inducing excitability changes at specific brain regions. However, our understanding of how, when, and where these changes are induced is critically lacking. We inferred plasticity in the human brain after applying electrical stimulation to the brain's surface and measuring changes in excitability. We observed excitability changes in regions anatomically and functionally closer to the stimulation site. Those in responsive regions were accurately predicted using a classifier trained on baseline brain network characteristics. Finally, we showed that the excitability changes can potentially be monitored in real-time. These results begin to fill basic gaps in our understanding of stimulation-induced brain dynamics in humans and offer pathways to optimize stimulation protocols.

    View details for PubMedID 29875229

  • Stereotactic radiosurgery for central nervous system hemangioblastoma: systematic review and meta-analysis JOURNAL OF NEURO-ONCOLOGY Pan, J., Jabarkheel, R., Huang, Y., Ho, A., Chang, S. D. 2018; 137 (1): 11–22


    Hemangioblastomas are rare, benign, vascular tumors of the central nervous system (CNS), often associated with von-hippel lindau (VHL) disease. Current therapeutic options include microsurgical resection or stereotactic radiosurgery (SRS). With no randomized controlled studies and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. We completed a Pubmed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year progression free survival (PFS). The pooled 5-year PFS across all eligible studies was 88.4%. No difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease. Adverse events were associated with increasing marginal dose, independent of tumor volume. VHL status, sex, radiosurgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. Multiple studies show excellent tumor control at 5-year follow up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.

    View details for PubMedID 29204841

  • Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis. Journal of neurosurgery. Pediatrics Azad, T. D., Pendharkar, A. V., Pan, J. n., Huang, Y. n., Li, A. n., Esparza, R. n., Mehta, S. n., Connolly, I. D., Veeravagu, A. n., Campen, C. J., Cheshier, S. H., Edwards, M. S., Fisher, P. G., Grant, G. A. 2018: 1–7


    OBJECTIVE Pediatric spinal astrocytomas are rare spinal lesions that pose unique management challenges. Therapeutic options include gross-total resection (GTR), subtotal resection (STR), and adjuvant chemotherapy or radiation therapy. With no randomized controlled trials, the optimal management approach for children with spinal astrocytomas remains unclear. The aim of this study was to conduct a systematic review and meta-analysis on pediatric spinal astrocytomas. METHODS The authors performed a systematic review of the PubMed/MEDLINE electronic database to investigate the impact of histological grade and extent of resection on overall survival among patients with spinal cord astrocytomas. They retained publications in which the majority of reported cases included astrocytoma histology. RESULTS Twenty-nine previously published studies met the eligibility criteria, totaling 578 patients with spinal cord astrocytomas. The spinal level of intramedullary spinal cord tumors was predominantly cervical (53.8%), followed by thoracic (40.8%). Overall, resection was more common than biopsy, and GTR was slightly more commonly achieved than STR (39.7% vs 37.0%). The reported rates of GTR and STR rose markedly from 1984 to 2015. Patients with high-grade astrocytomas had markedly worse 5-year overall survival than patients with low-grade tumors. Patients receiving GTR may have better 5-year overall survival than those receiving STR. CONCLUSIONS The authors describe trends in the management of pediatric spinal cord astrocytomas and suggest a benefit of GTR over STR for 5-year overall survival.

    View details for PubMedID 30028275

  • Structural Insight into BLM Recognition by TopBP1. Structure (London, England : 1993) Sun, L. n., Huang, Y. n., Edwards, R. A., Yang, S. n., Blackford, A. N., Niedzwiedz, W. n., Glover, J. N. 2017; 25 (10): 1582–88.e3


    Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1.

    View details for DOI 10.1016/j.str.2017.08.005

    View details for PubMedID 28919440

    View details for PubMedCentralID PMC6044410

  • Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study JOURNAL OF DIABETES AND ITS COMPLICATIONS Huang, Y., Abdelmoneim, A. S., Light, P., Qiu, W., Simpson, S. H. 2015; 29 (2): 196-202


    To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD).Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use.Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78-1.05) or repaglinide use (aHR 0.80; 95% CI 0.63-1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome.In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae.

    View details for DOI 10.1016/j.jdiacomp.2014.11.012

    View details for Web of Science ID 000350531600008

    View details for PubMedID 25534984

  • beta-Catenin is O-GlcNAc glycosylated at Serine 23: Implications for beta-catenin's subcellular localization and transactivator function EXPERIMENTAL CELL RESEARCH Ha, J. R., Hao, L., Venkateswaran, G., Huang, Y. H., Garcia, E., Persad, S. 2014; 321 (2): 153-166


    We have previously reported that β-catenin is post-translationally modified with a single O-linked attachment of β-N-acetyl-glucosamine (O-GlcNAc). We showed that O-GlcNAc regulated β-catenin's subcellular localization and transcriptional activity.The objectives of this investigation were to identify the putative O-GlcNAc sites of β-catenin and the relevance of identified sites in the regulation of β-catenin's localization and transcriptional activity.Missense mutations were introduced to potential O-GlcNAc sites of pEGFP-C2-N-Terminal- or pEGFP-C2-Wild Type-β-catenin by site-directed mutagenesis. We determined the levels of O-GlcNAc-β-catenin, subcellular localization, interaction with binding partners and transcriptional activity of the various constructs.Serine 23 of β-catenin was determined as a site for O-GlcNAc modification which regulated its subcellular distribution, its interactions with cellular partners and consequently its transcriptional activity.O-GlcNAcylation of Serine 23 is a novel regulatory modification for β-catenin's subcellular localization and transcriptional activity. This study is the first report to characterize site specific regulation of β-catenin by the O-GlcNAc modification.

    View details for DOI 10.1016/j.yexcr.2013.11.021

    View details for Web of Science ID 000331419300006

    View details for PubMedID 24342833

  • Prostate Cancer Progression to Androgen Independent Disease: The Role of the PI3K/AKT Pathway Advances in Prostate Cancer Ha, J. R., et al 2013
  • Prostate Cancer Progression to Androgen Independent Disease: The Role of the PI3K/AKT Pathway Advances in Prostate Cancer Ha, J. R., Huang, Y., Persad, A., Persad, S. 2013

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