MSTP Publications: February 2023
The interictal suppression hypothesis in focal epilepsy: network-level supporting evidence.
Johnson GW, Doss DJ, Morgan VL, Paulo DL, Cai LY, Shless JS, Negi AS, Gummadavelli A, Kang H, Reddy SB, Naftel RP, Bick SK, Roberson SW, Dawant BM, Wallace MT, Englot DJ.
Brain. 2023 Feb 1:awad016. doi: 10.1093/brain/awad016. Online ahead of print.
Why are people with focal epilepsy not continuously having seizures? Previous neuronal signaling work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is a high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure onset zones have increased inward connectivity which could be associated with interictal suppression of seizure activity. Accordingly, we hypothesize that seizure onset zones are actively suppressed by the rest of the brain network during interictal states. Full testing of this hypothesis would require collaboration across multiple domains of neuroscience. We focused on partially testing this hypothesis at the electrographic network level within 81 individuals with drug resistant focal epilepsy undergoing presurgical evaluation. We utilized intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, early propagation, and non-involved zones. We then utilized diffusion imaging to acquire estimates of white matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, we generated a resting-state classification model to assist clinicians in detecting seizure onset and propagation zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and early propagation zones demonstrate markedly increased inward connectivity and decreased outward connectivity using both resting-state (one-way ANOVA, p-value=3.13e-13) and neurostimulation analyses to evaluate evoked responses (one-way ANOVA, p-value=2.5e-3). When controlling for the distance between regions, the difference between inward and outward connectivity remained stable up to 80 mm between brain connections (two-way repeated measures ANOVA, group effect p-value of 2.6e-12). Structure-function coupling analyses revealed that seizure onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue (two-way repeated measures ANOVA, interaction effect p-value of 9.76e-21). Using these observations, our support vector classification models achieved a maximum held-out testing set accuracy of 92.0±2.2% to classify early propagation and seizure onset zones. These results suggest that seizure onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure onset zones. These findings have implications for the identification of seizure onset zones using only brief electrographic recordings to reduce patient morbidity and augment the presurgical evaluation of drug resistant epilepsy. Further testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative, and neuromodulation approaches to improve surgical success rates in those suffering from drug resistant focal epilepsy.
Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies
O’Neill MJ, Sala L, Denjoy I, Wada Y, Kozek K, Crotti L, Dagradi F, Kotta MC, Spazzolini C, Leenhardt A, Salem JE, Kashiwa A, Ohno S, Tao R, Roden DM, Horie M, Extramiana F, Schwartz PJ, Kroncke BM.
Genet Med. 2022 Dec 7;25(3):100355. doi: 10.1016/j.gim.2022.12.002. Epub ahead of print.
Purpose: The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.
Methods: We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.
Results: Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among “hot spot” regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.
Conclusions: Bayesian penetrance estimates provide a continuous framework for variant interpretation.
Functional HIV-1/HCV cross-reactive antibodies isolated from a chronically co-infected donor.
Pilewski KA, Wall S, Richardson SI, Manamela NP, Clark K, Hermanus T, Binshtein E, Venkat R, Sautto GA, Kramer KJ, Shiakolas AR, Setliff I, Salas J, Mapengo RE, Suryadevara N, Brannon JR, Beebout CJ, Parks R, Raju N, Frumento N, Walker LM, Fechter EF, Qin JS, Murji AA, Janowska K, Thakur B, Lindenberger J, May AJ, Huang X, Sammour S, Acharya P, Carnahan RH, Ross TM, Haynes BF, Hadjifrangiskou M, Crowe JE Jr, Bailey JR, Kalams S, Morris L, Georgiev IS.
Cell Rep. 2023 Jan 27;42(2):112044. doi: 10.1016/j.celrep.2023.112044. Online ahead of print.
Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells.
Jacobse J, Brown RE, Li J, Pilat JM, Pham L, Short SP, Peek CT, Rolong A, Washington MK, Martinez-Barricarte R, Byndloss MX, Shelton C, Markle JG, Latour YL, Allaman MM, Cassat JE, Wilson KT, Choksi YA, Williams CS, Lau KS, Flynn CR, Casanova JL, Rings EHHM, Samsom JN, Goettel JA.
Cell Rep. 2023 Feb 17;42(2):112128. doi: 10.1016/j.celrep.2023.112128. Online ahead of print.
Short superficial white matter and aging: a longitudinal multi-site study of 1293 subjects and 2711 sessions.
Schilling KG, Archer D, Yeh FC, Rheault F, Cai LY, Shafer A, Resnick SM, Hohman T, Jefferson A, Anderson AW, Kang H, Landman BA.
Aging Brain. 2023;3:100067. doi: 10.1016/j.nbas.2023.100067. Epub 2023 Jan 16.
Association between preoperative hematologic markers and aggressive behavior in meningiomas.
Guidry BS, Chotai S, Tang AR, Le CH, Grisham CJ, McDermott JR, Kelly PD, Morone PJ, Thompson RC, Chambless LB.
Clin Neurol Neurosurg. 2023 Feb 16;226:107629. doi: 10.1016/j.clineuro.2023.107629. Online ahead of print.
Conditional Recurrence-Free Survival After Surgical Resection of Meningioma.
Tang AR, Chotai S, Guidry BS, Sun L, Ye F, Kelly PD, McDermott JR, Grisham CJ, Morone PJ, Thompson RC, Chambless LB.
Neurosurgery. 2023 Feb 23. doi: 10.1227/neu.0000000000002416. Online ahead of print.
Abnormal functional connectivity of the posterior hypothalamus and other arousal regions in surgical temporal lobe epilepsy.
Jiang JW, Narasimhan S, Johnson GW, González HFJ, Doss DJ, Shless JS, Paulo DL, Terry DP, Chang C, Morgan VL, Englot DJ.
J Neurosurg. 2023 Feb 17:1-11. doi: 10.3171/2023.1.JNS221452. Online ahead of print.
Establishing a Core Outcomes Set for Massive Transfusion: an EAST Modified Delphi Method Consensus Study.
Gelbard RB, Nahmias J, Byerly S, Ziesmann M, Stein D, Haut ER, Smith JW, Boltz M, Zarzaur B, Callum J, Cotton BA, Cripps M, Gunter OL, Holcomb JB, Kerby J, Kornblith LZ, Moore EE, Riojas CM, Schreiber M, Sperry JL, Yeh DD.
J Trauma Acute Care Surg. 2023 Jan 23. doi: 10.1097/TA.0000000000003884. Online ahead of print.
Sex and gender in neurodevelopmental conditions.
Bölte S, Neufeld J, Marschik PB, Williams ZJ, Gallagher L, Lai MC.
Nat Rev Neurol. 2023 Feb 6. doi: 10.1038/s41582-023-00774-6. Online ahead of print.