Yuhao (Danny) Huang

All Publications

• Rates and Predictors of Pain Reduction With Intracranial Stimulation for Intractable Pain Disorders. Neurosurgery Huang, Y., Sadeghzadeh, S., Li, A. H., Schonfeld, E., Ramayya, A. G., Buch, V. P. 2024

  Abstract

  Intracranial modulation paradigms, namely deep brain stimulation (DBS) and motor cortex stimulation (MCS), have been used to treat intractable pain disorders. However, treatment efficacy remains heterogeneous, and factors associated with pain reduction are not completely understood.We performed an individual patient review of pain outcomes (visual analog scale, quality-of-life measures, complications, pulse generator implant rate, cessation of stimulation) after implantation of DBS or MCS devices. We evaluated 663 patients from 36 study groups and stratified outcomes by pain etiology and implantation targets.Included studies comprised primarily retrospective cohort studies. MCS patients had a similar externalized trial success rate compared with DBS patients (86% vs 81%; P = .16), whereas patients with peripheral pain had a higher trial success rate compared with patients with central pain (88% vs 79%; P = .004). Complication rates were similar for MCS and DBS patients (12% vs 15%; P = .79). Patients with peripheral pain had lower likelihood of device cessation compared with those with central pain (5.7% vs 10%; P = .03). Of all implanted patients, mean pain reduction at last follow-up was 45.8% (95% CI: 40.3-51.2) with a 31.2% (95% CI: 12.4-50.1) improvement in quality of life. No difference was seen between MCS patients (43.8%; 95% CI: 36.7-58.2) and DBS patients (48.6%; 95% CI: 39.2-58) or central (41.5%; 95% CI: 34.8-48.2) and peripheral (46.7%; 95% CI: 38.9-54.5) etiologies. Multivariate analysis identified the anterior cingulate cortex target to be associated with worse pain reduction, while postherpetic neuralgia was a positive prognostic factor.Both DBS and MCS have similar efficacy and complication rates in the treatment of intractable pain. Patients with central pain disorders tended to have lower trial success and higher rates of device cessation. Additional prognostic factors include anterior cingulate cortex targeting and postherpetic neuralgia diagnosis. These findings underscore intracranial neurostimulation as an important modality for treatment of intractable pain disorders.

  View details for DOI 10.1227/neu.0000000000003006

  View details for PubMedID 38836613

• Naturalistic acute pain states decoded from neural and facial dynamics. bioRxiv : the preprint server for biology Huang, Y., Gopal, J., Kakusa, B., Li, A. H., Huang, W., Wang, J. B., Persad, A., Ramayya, A., Parvizi, J., Buch, V. P., Keller, C. 2024

  Abstract

  Pain is a complex experience that remains largely unexplored in naturalistic contexts, hindering our understanding of its neurobehavioral representation in ecologically valid settings. To address this, we employed a multimodal, data-driven approach integrating intracranial electroencephalography, pain self-reports, and facial expression quantification to characterize the neural and behavioral correlates of naturalistic acute pain in twelve epilepsy patients undergoing continuous monitoring with neural and audiovisual recordings. High self-reported pain states were associated with elevated blood pressure, increased pain medication use, and distinct facial muscle activations. Using machine learning, we successfully decoded individual participants' high versus low self-reported pain states from distributed neural activity patterns (mean AUC = 0.70), involving mesolimbic regions, striatum, and temporoparietal cortex. High self-reported pain states exhibited increased low-frequency activity in temporoparietal areas and decreased high-frequency activity in mesolimbic regions (hippocampus, cingulate, and orbitofrontal cortex) compared to low pain states. This neural pain representation remained stable for hours and was modulated by pain onset and relief. Objective facial expression changes also classified self-reported pain states, with results concordant with electrophysiological predictions. Importantly, we identified transient periods of momentary pain as a distinct naturalistic acute pain measure, which could be reliably differentiated from affect-neutral periods using intracranial and facial features, albeit with neural and facial patterns distinct from self-reported pain. These findings reveal reliable neurobehavioral markers of naturalistic acute pain across contexts and timescales, underscoring the potential for developing personalized pain interventions in real-world settings.

  View details for DOI 10.1101/2024.05.10.593652

  View details for PubMedID 38766098

  View details for PubMedCentralID PMC11100805

• iSPAN: Explainable prediction of outcomes post thrombectomy with Machine Learning. European journal of radiology Kelly, B. S., Mathur, P., Vaca, S. D., Duignan, J., Power, S., Lee, E. H., Huang, Y., Prolo, L. M., Yeom, K. W., Lawlor, A., Killeen, R. P., Thornton, J. 2024; 173: 111357

  Abstract

  PURPOSE: This study aimed to develop and evaluate a machine learning model and a novel clinical score for predicting outcomes in stroke patients undergoing endovascular thrombectomy.MATERIALS AND METHODS: This retrospective study included all patients aged over 18years with an anterior circulation stroke treated at a thrombectomy centre from 2010 to 2020 with external validation. The primary outcome was day 90 mRS ≥3. Existing clinical scores (SPAN and PRE) and Machine Learning (ML) models were compared. A novel clinical score (iSPAN) was derived by adding an optimised weighting of the most important ML features to the SPAN.RESULTS: 812 patients were initially included (397 female, average age 73), 63 for external validation. The best performing clinical score and ML model were SPAN and XGB (sensitivity, specificity and accuracy 0.290, 0.967, 0.628 and 0.693, 0.783, 0.738 respectively). A significant difference was found overall and our XGB model was more accurate than SPAN (p<0.0018). The most important features were Age, mTICI and total number of passes. The addition of 11 points for mTICI of ≤2B and 3 points for ≥3 passes to the SPAN achieved the best accuracy and was used to create the iSPAN. iSPAN was not significantly less accurate than our XGB model (p>0.5). In the external validation set, iSPAN and SPAN achieved sensitivity, specificity, and accuracy of (0.735, 0.862, 0.79) and (0.471, 0.897, 0.67) respectively.CONCLUSION: iSPAN incorporates machine-derived features to achieve better predictions compared to existing clinical scores. It is not inferior to our XGB model and is externally generalisable.

  View details for DOI 10.1016/j.ejrad.2024.111357

  View details for PubMedID 38401408

• Direct cortical stimulation induces short-term plasticity of neural oscillations in humans. bioRxiv : the preprint server for biology Munot, S., Kim, N., Huang, Y., Keller, C. J. 2023

  Abstract

  Patterned brain stimulation is commonly employed as a tool for eliciting plasticity in brain circuits and treating neuropsychiatric disorders. Although widely used in clinical settings, there remains a limited understanding of how stimulation-induced plasticity influences neural oscillations and their interplay with the underlying baseline functional architecture. To address this question, we applied 15 minutes of 10Hz focal electrical simulation, a pattern identical to 'excitatory' repetitive transcranial magnetic stimulation (rTMS), to 14 medically-intractable epilepsy patients undergoing intracranial electroencephalographic (iEEG). We quantified the spectral features of the cortico-cortical evoked potential (CCEPs) in these patients before and after stimulation. We hypothesized that for a given region the temporal and spectral components of the CCEP predicted the location and degree of stimulation-induced plasticity. Across patients, low frequency power (alpha and beta) showed the broadest change, while the magnitude of change was stronger in high frequencies (beta and gamma). Next we demonstrated that regions with stronger baseline evoked spectral responses were more likely to undergo plasticity after stimulation. These findings were specific to a given frequency in a specific temporal window. Post-stimulation power changes were driven by the interaction between direction of change in baseline power and temporal window of change. Finally, regions exhibiting early increases and late decreases in evoked baseline power exhibited power changes after stimulation and were independent of stimulation location. Together, these findings that time-frequency baseline features predict post-stimulation plasticity effects demonstrate properties akin to Hebbian learning in humans and extend this theory to the temporal and spectral window of interest. These findings can help improve our understanding of human brain plasticity and lead to more effective brain stimulation techniques.

  View details for DOI 10.1101/2023.11.15.567302

  View details for PubMedID 38014071

  View details for PubMedCentralID PMC10680685

• An orexigenic subnetwork within the human hippocampus. Nature Barbosa, D. A., Gattas, S., Salgado, J. S., Kuijper, F. M., Wang, A. R., Huang, Y., Kakusa, B., Leuze, C., Luczak, A., Rapp, P., Malenka, R. C., Hermes, D., Miller, K. J., Heifets, B. D., Bohon, C., McNab, J. A., Halpern, C. H. 2023

  Abstract

  Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

  View details for DOI 10.1038/s41586-023-06459-w

  View details for PubMedID 37648849

  View details for PubMedCentralID 6468104

• An orexigenic subnetwork within the human hippocampus NATURE Barbosa, D. N., Gattas, S., Salgado, J. S., Kuijper, F., Wang, A. R., Huang, Y., Kakusa, B., Leuze, C., Luczak, A., Rapp, P., Malenka, R. C., Hermes, D., Miller, K. J., Heifets, B. D., Bohon, C., Mcnab, J. A., Halpern, C. H. 2023

  View details for DOI 10.1038/s41586-023-06459

  View details for Web of Science ID 001064862900002

• Spectro-spatial features in distributed human intracranial activity proactively encode peripheral metabolic activity. Nature communications Huang, Y., Wang, J. B., Parker, J. J., Shivacharan, R., Lal, R. A., Halpern, C. H. 2023; 14 (1): 2729

  Abstract

  Mounting evidence demonstrates that the central nervous system (CNS) orchestrates glucose homeostasis by sensing glucose and modulating peripheral metabolism. Glucose responsive neuronal populations have been identified in the hypothalamus and several corticolimbic regions. However, how these CNS gluco-regulatory regions modulate peripheral glucose levels is not well understood. To better understand this process, we simultaneously measured interstitial glucose concentrations and local field potentials in 3 human subjects from cortical and subcortical regions, including the hypothalamus in one subject. Correlations between high frequency activity (HFA, 70-170 Hz) and peripheral glucose levels are found across multiple brain regions, notably in the hypothalamus, with correlation magnitude modulated by sleep-wake cycles, circadian coupling, and hypothalamic connectivity. Correlations are further present between non-circadian (ultradian) HFA and glucose levels which are higher during awake periods. Spectro-spatial features of neural activity enable decoding of peripheral glucose levels both in the present and up to hours in the future. Our findings demonstrate proactive encoding of homeostatic glucose dynamics by the CNS.

  View details for DOI 10.1038/s41467-023-38253-7

  View details for PubMedID 37169738

  View details for PubMedCentralID PMC10174612

• The Hypothalamus, Nucleus Accumbens, and Hippocampus Demonstrate Increased Delta Band Power and Coherence During Reward Anticipation Seilheimer, R., Rolle, C., Vaz, A., Kakusa, B., Huang, Y., Barbosa, D. N., Halpern, C. ELSEVIER SCIENCE INC. 2023: S107-S108

  View details for Web of Science ID 000993018500256

• DEEP MOVEMENT: Deep learning of movie files for management of endovascular thrombectomy. European radiology Kelly, B., Martinez, M., Do, H., Hayden, J., Huang, Y., Yedavalli, V., Ho, C., Keane, P. A., Killeen, R., Lawlor, A., Moseley, M. E., Yeom, K. W., Lee, E. H. 2023

  Abstract

  OBJECTIVES: Treatment and outcomes of acute stroke have been revolutionised by mechanical thrombectomy. Deep learning has shown great promise in diagnostics but applications in video and interventional radiology lag behind. We aimed to develop a model that takes as input digital subtraction angiography (DSA) videos and classifies the video according to (1) the presence of large vessel occlusion (LVO), (2) the location of the occlusion, and (3) the efficacy of reperfusion.METHODS: All patients who underwent DSA for anterior circulation acute ischaemic stroke between 2012 and 2019 were included. Consecutive normal studies were included to balance classes. An external validation (EV) dataset was collected from another institution. The trained model was also used on DSA videos post mechanical thrombectomy to assess thrombectomy efficacy.RESULTS: In total, 1024 videos comprising 287 patients were included (44 for EV). Occlusion identification was achieved with 100% sensitivity and 91.67% specificity (EV 91.30% and 81.82%). Accuracy of location classification was 71% for ICA, 84% for M1, and 78% for M2 occlusions (EV 73, 25, and 50%). For post-thrombectomy DSA (n=194), the model identified successful reperfusion with 100%, 88%, and 35% for ICA, M1, and M2 occlusion (EV 89, 88, and 60%). The model could also perform classification of post-intervention videos as mTICI<3 with an AUC of 0.71.CONCLUSIONS: Our model can successfully identify normal DSA studies from those with LVO and classify thrombectomy outcome and solve a clinical radiology problem with two temporal elements (dynamic video and pre and post intervention).KEY POINTS: DEEP MOVEMENT represents a novel application of a model applied to acute stroke imaging to handle two types of temporal complexity, dynamic video and pre and post intervention. The model takes as an input digital subtraction angiograms of the anterior cerebral circulation and classifies according to (1) the presence or absence of large vessel occlusion, (2) the location of the occlusion, and (3) the efficacy of thrombectomy. Potential clinical utility lies in providing decision support via rapid interpretation (pre thrombectomy) and automated objective gradation of thrombectomy outcomes (post thrombectomy).

  View details for DOI 10.1007/s00330-023-09478-3

  View details for PubMedID 36847835

• Appetitive Mapping of the Human Nucleus Accumbens. Biological psychiatry Parker, J. J., Rolle, C. E., Shivacharan, R. S., Barbosa, D. A., Feng, A., Huang, Y., Kakusa, B. W., Prieto, T., Jaffe, R. A., Williams, N. R., Halpern, C. H. 2022

  View details for DOI 10.1016/j.biopsych.2022.09.016

  View details for PubMedID 36509559

• Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation. Molecular cell Janas, J. A., Zhang, L., Luu, J. H., Demeter, J., Meng, L., Marro, S. G., Mall, M., Mooney, N. A., Schaukowitch, K., Ng, Y. H., Yang, N., Huang, Y., Neumayer, G., Gozani, O., Elias, J. E., Jackson, P. K., Wernig, M. 2022

  Abstract

  Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce and maintain appropriate lineage-specific gene expression remain elusive. Here, we used an unbiased proteomics approach to characterize chromatin regulators that mediate the induction of neuronal cell fate. We found that Tip60 acetyltransferase is essential to establish neuronal cell identity partly via acetylation of the histone variant H2A.Z. Despite its tight correlation with gene expression and active chromatin, loss of H2A.Z acetylation had little effect on chromatin accessibility or transcription. Instead, loss of Tip60 and acetyl-H2A.Z interfered with H3K4me3 deposition and activation of a unique subset of silent, lineage-restricted genes characterized by a bivalent chromatin configuration at their promoters. Altogether, our results illuminate the mechanisms underlying bivalent chromatin activation and reveal that H2A.Z acetylation regulates neuronal fate specification by establishing epigenetic competence for bivalent gene activation and cell lineage transition.

  View details for DOI 10.1016/j.molcel.2022.11.002

  View details for PubMedID 36417913

• Anticipatory human subthalamic area beta-band power responses to dissociable tastes correlate with weight gain. Neurobiology of disease Kakusa, B., Huang, Y., Barbosa, D. A., Feng, A., Gattas, S., Shivacharan, R., Lee, E. B., Kuijper, F. M., Saluja, S., Parker, J. J., Miller, K. J., Keller, C., Bohon, C., Halpern, C. H. 2021: 105348

  Abstract

  The availability of enticing sweet, fatty tastes is prevalent in the modern diet and contribute to overeating and obesity. In animal models, the subthalamic area plays a role in mediating appetitive and consummatory feeding behaviors, however, its role in human feeding is unknown. We used intraoperative, subthalamic field potential recordings while participants (n = 5) engaged in a task designed to provoke responses of taste anticipation and receipt. Decreased subthalamic beta-band (15-30 Hz) power responses were observed for both sweet-fat and neutral tastes. Anticipatory responses to taste-neutral cues started with an immediate decrease in beta-band power from baseline followed by an early beta-band rebound above baseline. On the contrary, anticipatory responses to sweet-fat were characterized by a greater and sustained decrease in beta-band power. These activity patterns were topographically specific to the subthalamic nucleus and substantia nigra. Further, a neural network trained on this beta-band power signal accurately predicted (AUC ≥ 74%) single trials corresponding to either taste. Finally, the magnitude of the beta-band rebound for a neutral taste was associated with increased body mass index after starting deep brain stimulation therapy. We provide preliminary evidence of discriminatory taste encoding within the subthalamic area associated with control mechanisms that mediate appetitive and consummatory behaviors.

  View details for DOI 10.1016/j.nbd.2021.105348

  View details for PubMedID 33781923

• The insulo-opercular cortex encodes food-specific content under controlled and naturalistic conditions. Nature communications Huang, Y., Kakusa, B. W., Feng, A., Gattas, S., Shivacharan, R. S., Lee, E. B., Parker, J. J., Kuijper, F. M., Barbosa, D. A., Keller, C. J., Bohon, C., Mikhail, A., Halpern, C. H. 2021; 12 (1): 3609

  Abstract

  The insulo-opercular network functions critically not onlyin encoding taste, but also inguiding behavior based on anticipated food availability. However, there remains no direct measurement of insulo-opercular activity when humans anticipate taste. Here, we collect direct, intracranial recordings during a food task that elicits anticipatory and consummatory taste responses, and during ad libitum consumption of meals. While cue-specific high-frequency broadband (70-170Hz) activity predominant in the left posterior insula is selective for taste-neutral cues, sparse cue-specific regions in the anterior insulaare selective for palatable cues. Latency analysis reveals this insular activity is preceded by non-discriminatory activity in the frontal operculum. During ad libitum meal consumption, time-locked high-frequency broadband activity at the time of food intake discriminates food types and is associated with cue-specific activity during the task. These findings reveal spatiotemporally-specificactivity in the human insulo-opercular cortex that underlies anticipatory evaluation of food across both controlled and naturalistic settings.

  View details for DOI 10.1038/s41467-021-23885-4

  View details for PubMedID 34127675

• Multiparametric laryngeal assessment of the effect of thalamic deep brain stimulation on essential vocal tremor. Parkinsonism & related disorders Erickson-DiRenzo, E. n., Kuijper, F. M., Barbosa, D. A., Lim, E. A., Lin, P. T., Lising, M. A., Huang, Y. n., Sung, C. K., Halpern, C. H. 2020; 81: 106–12

  Abstract

  EVT is a refractory voice disorder that significantly affects quality of life. This work aims to conduct a multiparametric assessment of the effect of deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) on essential vocal tremor (EVT) and investigate the relation between DBS lead location and EVT outcomes.Nine participants underwent DBS for essential tremor and were diagnosed with co-occurring EVT in this prospective cohort study. Objective measurements including acoustic evaluation of vocal fundamental frequency (F0) and intensity modulation and subjective measurements including physiologic evaluation of the oscillatory movement of the laryngeal muscles and vocal tract and perceptual ratings of tremor severity were collected PRE and POST DBS. Finally, we investigated the relation between DBS lead location and EVT outcomes.Acoustic modulations of F0 and intensity were significantly improved POST DBS. Physiologic assessment showed a POST DBS reduction of oscillatory movement in the laryngeal muscles and vocal tract, but not significantly. Listener and participant perception, of EVT severity was also significantly reduced. Finally, our results indicate better EVT control with increased distance to midline of left VIM thalamic stimulation.By employing a battery of objective and subjective measures, our study supports the benefit of DBS for the treatment of EVT and specifies the acoustic and physiologic mechanisms that mediate its positive effect. We further provide preliminary results on the relation between lead location and EVT outcomes, laying the foundation for future studies to clarify the optimal DBS target for the treatment of EVT.

  View details for DOI 10.1016/j.parkreldis.2020.10.026

  View details for PubMedID 33120071

• Case Report on Deep Brain Stimulation Rescue After Suboptimal MR-Guided Focused Ultrasound Thalamotomy for Essential Tremor: A Tractography-Based Investigation. Frontiers in human neuroscience Saluja, S. n., Barbosa, D. A., Parker, J. J., Huang, Y. n., Jensen, M. R., Ngo, V. n., Santini, V. E., Pauly, K. B., Ghanouni, P. n., McNab, J. A., Halpern, C. H. 2020; 14: 191

  Abstract

  Essential tremor (ET) is the most prevalent movement disorder in adults, and can often be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound (MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for treating ET, optimal targeting during MRgFUS is essential for efficacy and durability. Various studies have reported cases of tremor recurrence following MRgFUS and long-term outcome data is limited to 3-4 years. We present a tractography-based investigation on a case of DBS rescue for medically refractory ET that was treated with MRgFUS that was interrupted due to the development of dysarthria during the procedure. After initial improvement, her hand tremor started to recur within 6 months after treatment, and bilateral DBS was performed targeting the VIM 24 months after MRgFUS. DBS induced long-term tremor control with monopolar stimulation. Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT) and corticothalmic (CTT) tracts being modulated by the procedures to understand the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines, it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for further investigation of targeting the CTT when using neuromodulatory procedures to treat refractory ET for more permanent tremor relief.

  View details for DOI 10.3389/fnhum.2020.00191

  View details for PubMedID 32676015

  View details for PubMedCentralID PMC7333679

• Simultaneous time of flight-MRA and T2* imaging for cerebrovascular MRI. Neuroradiology Lanzman, B. A., Huang, Y. n., Lee, E. H., Iv, M. n., Moseley, M. E., Holdsworth, S. J., Yeom, K. W. 2020

  Abstract

  3D multi-echo gradient-recalled echo (ME-GRE) can simultaneously generate time-of-flight magnetic resonance angiography (pTOF) in addition to T2*-based susceptibility-weighted images (SWI). We assessed the clinical performance of pTOF generated from a 3D ME-GRE acquisition compared with conventional TOF-MRA (cTOF).Eighty consecutive children were retrospectively identified who obtained 3D ME-GRE alongside cTOF. Two blinded readers independently assessed pTOF derived from 3D ME-GRE and compared them with cTOF. A 5-point Likert scale was used to rank lesion conspicuity and to assess for diagnostic confidence.Across 80 pediatric neurovascular pathologies, a similar number of lesions were reported on pTOF and cTOF (43-40%, respectively, p > 0.05). Rating of lesion conspicuity was higher with cTOF (4.5 ± 1.0) as compared with pTOF (4.0 ± 0.7), but this was not significantly different (p = 0.06). Diagnostic confidence was rated higher with cTOF (4.8 ± 0.5) than that of pTOF (3.7 ± 0.6; p < 0.001). Overall, the inter-rater agreement between two readers for lesion count on pTOF was classified as almost perfect (κ = 0.98, 96% CI 0.8-1.0).In this study, TOF-MRA simultaneously generated in addition to SWI from 3D MR-GRE can serve as a diagnostic adjunct, particularly for proximal vessel disease and when conventional TOF-MRA images are absent.

  View details for DOI 10.1007/s00234-020-02499-5

  View details for PubMedID 32945913

• Anatomic and Thermometric Analysis of Cranial Nerve Palsy after Laser Amygdalohippocampotomy for Mesial Temporal Lobe Epilepsy. Operative neurosurgery (Hagerstown, Md.) Huang, Y., Leung, S. A., Parker, J. J., Ho, A. L., Wintermark, M., Patel, S. H., Pauly, K. B., Kakusa, B. W., Beres, S. J., Henderson, J. M., Grant, G. A., Halpern, C. H. 2019

  Abstract

  BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive therapy for treating medication-resistant mesial temporal lobe epilepsy. Cranial nerve (CN) palsy has been reported as a procedural complication, but the mechanism of this complication is not understood.OBJECTIVE: To identify the cause of postoperative CN palsy after LITT.METHODS: Four medial temporal lobe epilepsy patients with CN palsy after LITT were identified for comparison with 22 consecutive patients with no palsy. We evaluated individual variation in the distance between CN III and the uncus, and CN IV and the parahippocampal gyrus using preoperative T1- and T2-weighted magnetic resonance (MR) images. Intraoperative MR thermometry was used to estimate temperature changes.RESULTS: CN III (n=2) and CN IV palsies (n=2) were reported. On preoperative imaging, the majority of identified CN III (54%) and CN IV (43%) were located within 1 to 2 mm of the uncus and parahippocampal gyrus tissue border, respectively. Affected CN III and CN IV were more likely to be found<1 mm of the tissue border (PCNIII=.03, PCNIV<.01; chi-squared test). Retrospective assessment of thermal profile during ablation showed higher temperature rise along the mesial temporal lobe tissue border in affected CNs than unaffected CNs after controlling for distance (12.9°C vs 5.8°C; P=.03; 2-sample t-test).CONCLUSION: CN palsy after LITT likely results from direct heating of the respective CN running at extreme proximity to the mesial temporal lobe. Low-temperature thresholds set at the border of the mesial temporal lobe in patients whose CNs are at close proximity may reduce this risk.

  View details for DOI 10.1093/ons/opz279

  View details for PubMedID 31555820

• Molecular correlates of cerebellar mutism syndrome in medulloblastoma. Neuro-oncology Jabarkheel, R., Amayiri, N., Yecies, D., Huang, Y., Toescu, S., Nobre, L., Mabbott, D. J., Sudhakar, S. V., Malik, P., Laughlin, S., Swaidan, M., Al Hussaini, M., Musharbash, A., Chacko, G., Mathew, L. G., Fisher, P. G., Hargrave, D., Bartels, U., Tabori, U., Pfister, S. M., Aquilina, K., Taylor, M. D., Grant, G. A., Bouffet, E., Mankad, K., Yeom, K. W., Ramaswamy, V. 2019

  Abstract

  BACKGROUND: Cerebellar Mutism Syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.METHODS: We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from five sites globally including Great Ormond Street Hospital, Christian Medical College and Hospital, Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumour volume, and CMS development were assessed in addition to molecular subgroup.RESULTS: Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P=0.0218) and had larger tumours (mean difference 10.25 cm3 ± 4.60, P=0.0010) that were more often midline (OR=5.72, P<0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumour volume, WNT (Wingless) (adjusted OR=4.91, p=0.0063), Group 3 (adjusted OR=5.56, p=0.0022) and Group 4 (adjusted OR=8.57 p=9.1x10-5) tumours were found to be independently associated with higher risk of CMS compared with SHH (Sonic Hedgehog) tumours.CONCLUSIONS: Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumour volume and midline location. These findings have significant implications for management of both the tumour and CMS.

  View details for DOI 10.1093/neuonc/noz158

  View details for PubMedID 31504816

• 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

  Abstract

  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

  View details for DOI 10.1016/j.biopsych.2019.03.148

  View details for Web of Science ID 000472661000135

• 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

  View details for DOI 10.1016/j.wneu.2019.01.112

  View details for Web of Science ID 000466491700065

• Intravenous and Intravascular Drug Delivery NERVOUS SYSTEM DRUG DELIVERY: PRINCIPLES AND PRACTICE Pan, J., Huang, Y., Grant, G., Lonser, R. R., Sarntinoranont, M., Bankiewicz, K. 2019: 165–91

  View details for DOI 10.1016/B978-0-12-813997-4.00009-8

  View details for Web of Science ID 000559759100010

• 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

  Abstract

  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

• 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

  Abstract

  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

• Induction and Quantification of Plasticity in Human Cortical Networks Keller, C., Huang, Y., Hajnal, B., Entz, L., Herrero, J., Mehta, A. NATURE PUBLISHING GROUP. 2018: S452

  View details for Web of Science ID 000509546600826

• 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

  Abstract

  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

  Abstract

  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

  Abstract

  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., Huang, Y., Edwards, R. A., Yang, S., Blackford, A. N., Niedzwiedz, W., Glover, J. N. 2017; 25 (10): 1582-1588.e3

  Abstract

  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

  Abstract

  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

  Abstract

  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