BACKGROUND: The clinical effects of deep brain stimulation for neurological conditions manifest across multiple timescales, spanning seconds to months, and involve direct electrical modulation, neuroplasticity, and network reorganization. In epilepsy, the delayed effects of deep brain stimulation on seizures limit optimization. Single pulse electrical stimulation and the resulting pulse evoked potentials offer a measure network effective connectivity and excitability. This study leverages single pulse and high frequency thalamic stimulation during stereotactic electroencephalography to assess seizure network engagement, modulate network activity, and track changes in excitability and epileptiform abnormalities. METHODS: Ten individuals with drug resistant epilepsy undergoing clinical stereotactic electroencephalography were enrolled in this retrospective cohort study. Each underwent a trial of high frequency (145 Hz) thalamic stimulation. Pulse evoked potentials were acquired before and after high frequency stimulation. Baseline evoked potential root-mean-square amplitude assessed seizure network engagement, and modulation of amplitude (post high frequency stimulation versus baseline; Cohen's d effect size) assessed change in network excitability. Interictal epileptiform discharge rates were measured by an automated classifier at baseline and during high frequency stimulation. Statistical significance was determined using paired-sample t-tests (p<0.05 significance level). This study was approved by the Mayo Clinic Institutional Review Board, with informed consent obtained from all participants. RESULTS: Thalamic stimulation delivered for >1.5 hours significantly reduced pulse evoked potential amplitudes in connected areas compared to baseline, with the degree of modulation correlated with baseline connectivity strength. Shorter stimulation durations did not induce reliable changes. High frequency stimulation immediately suppressed interictal epileptiform discharge rates in seizure networks with strong baseline thalamocortical connectivity. Pulse evoked potentials delineated the anatomical distribution of network engagement, revealing distinct patterns across thalamic subfields. CONCLUSION: Pulse evoked potentials and thalamic stimulation during stereotactic electroencephalography provide novel network biomarkers to evaluate target engagement and modulation of large-scale networks across acute and subacute timescales. This approach demonstrates potential for efficient, data-driven neuromodulation optimization, and a new paradigm for personalized deep brain stimulation in epilepsy.

Czech Institute of Informatics Robotics and Cybernetics Czech Technical University Prague Prague 160 00 Czech Republic

Department of Neurology Mayo Clinic Rochester MN 55905 USA

Department of Neurosurgery Mayo Clinic Rochester MN 55905 USA

Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN 55905 USA

Medical Scientist Training Program Mayo Clinic Rochester MN 55905 USA

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Schuepbach WM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610–622. PubMed

Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51(5):899–908. PubMed

Boccard SG, Pereira EA, Aziz TZ. Deep brain stimulation for chronic pain. J Clin Neurosci. 2015;22(10):1537–1543. PubMed

Tisch S, Rothwell JC, Bhatia KP, et al. Pallidal stimulation modifies after-effects of paired associative stimulation on motor cortex excitability in primary generalised dystonia. Exp Neurol. 2007;206(1):80–85. PubMed

Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dystonia. J Clin Neurophysiol. 2004;21(1):18–30. PubMed

Alagapan S, Choi KS, Heisig S, et al. Cingulate dynamics track depression recovery with deep brain stimulation. Nature. 2023;622(7981):130–138. PubMed PMC

Crowell AL, Garlow SJ, Riva-Posse P, Mayberg HS. Characterizing the therapeutic response to deep brain stimulation for treatment-resistant depression: a single center long-term perspective. Front Integr Neurosci. 2015;9:41. PubMed PMC

Ashkan K, Rogers P, Bergman H, Ughratdar I. Insights into the mechanisms of deep brain stimulation. Nat Rev Neurol. 2017;13(9):548–554. PubMed

Morgan RJ, Soltesz I. Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures. Proc Natl Acad Sci U S A. 2008;105(16):6179–6184. PubMed PMC

Wilke C, Worrell G, He B. Graph analysis of epileptogenic networks in human partial epilepsy. Epilepsia. 2011;52(1):84–93. PubMed PMC

Richardson MP. Large scale brain models of epilepsy: dynamics meets connectomics. J Neurol Neurosurg Psychiatry. 2012;83(12):1238–1248. PubMed

Piper RJ, Richardson RM, Worrell G, et al. Towards network-guided neuromodulation for epilepsy. Brain. 2022;145(10):3347–3362. PubMed PMC

Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475–482. PubMed

Karoly PJ, Rao VR, Gregg NM, et al. Cycles in epilepsy. Nature Reviews Neurology. 2021. PubMed

Keller CJ, Honey CJ, Megevand P, Entz L, Ulbert I, Mehta AD. Mapping human brain networks with cortico-cortical evoked potentials. Philos Trans R Soc Lond B Biol Sci. 2014;369(1653). PubMed PMC

van Blooijs D, van den Boom MA, van der Aar JF, et al. Developmental trajectory of transmission speed in the human brain. Nat Neurosci. 2023;26(4):537–541. PubMed PMC

Keller CJ, Huang Y, Herrero JL, et al. Induction and Quantification of Excitability Changes in Human Cortical Networks. J Neurosci. 2018;38(23):5384–5398. PubMed PMC

Valentin A, Alarcon G, Honavar M, et al. Single pulse electrical stimulation for identification of structural abnormalities and prediction of seizure outcome after epilepsy surgery: a prospective study. Lancet Neurol. 2005;4(11):718–726. PubMed

Matsumoto R, Kunieda T, Nair D. Single pulse electrical stimulation to probe functional and pathological connectivity in epilepsy. Seizure. 2017;44:27–36. PubMed PMC

Huang H, Ojeda Valencia G, Gregg NM, et al. CARLA: Adjusted common average referencing for cortico-cortical evoked potential data. J Neurosci Methods. 2024;407:110153. PubMed PMC

Janca R, Jezdik P, Cmejla R, et al. Detection of interictal epileptiform discharges using signal envelope distribution modelling: application to epileptic and non-epileptic intracranial recordings. Brain Topogr. 2015;28(1):172–183. PubMed

Sladky V, Nejedly P, Mivalt F, et al. Distributed brain co-processor for tracking spikes, seizures and behaviour during electrical brain stimulation. Brain Commun. 2022;4(3):fcac115. PubMed PMC

Dell KL, Payne DE, Kremen V, et al. Seizure likelihood varies with day-to-day variations in sleep duration in patients with refractory focal epilepsy: A longitudinal electroencephalography investigation. EClinicalMedicine. 2021:100934. PubMed PMC

Krauth A, Blanc R, Poveda A, Jeanmonod D, Morel A, Szekely G. A mean three-dimensional atlas of the human thalamus: generation from multiple histological data. Neuroimage. 2010;49(3):2053–2062. PubMed

Destrieux C, Fischl B, Dale A, Halgren E. Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. Neuroimage. 2010;53(1):1–15. PubMed PMC

Horn A, Li N, Dembek TA, et al. Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage. 2019;184:293–316. PubMed PMC

Amunts K, Lepage C, Borgeat L, et al. BigBrain: an ultrahigh-resolution 3D human brain model. Science. 2013;340(6139):1472–1475. PubMed

Pawley AD, Chowdhury FA, Tangwiriyasakul C, et al. Cortical excitability correlates with seizure control and epilepsy duration in chronic epilepsy. Ann Clin Transl Neurol. 2017;4(2):87–97. PubMed PMC

Arcot Desai S, Tcheng TK, Morrell MJ. Quantitative electrocorticographic biomarkers of clinical outcomes in mesial temporal lobe epileptic patients treated with the RNS(R) system. Clin Neurophysiol. 2019;130(8):1364–1374. PubMed

Turrigiano GG. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell. 2008;135(3):422–435. PubMed PMC

Chai Z, Ma C, Jin X. Homeostatic activity regulation as a mechanism underlying the effect of brain stimulation. Bioelectron Med. 2019;5:16. PubMed PMC

Turrigiano GG, Nelson SB. Homeostatic plasticity in the developing nervous system. Nat Rev Neurosci. 2004;5(2):97–107. PubMed

Marder E, Goaillard JM. Variability, compensation and homeostasis in neuron and network function. Nat Rev Neurosci. 2006;7(7):563–574. PubMed

Yu T, Wang X, Li Y, et al. High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans. Brain. 2018;141(9):2631–2643. PubMed

Grill WM, Snyder AN, Miocinovic S. Deep brain stimulation creates an informational lesion of the stimulated nucleus. Neuroreport. 2004;15(7):1137–1140. PubMed

Lozano AM, Lipsman N, Bergman H, et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol. 2019;15(3):148–160. PubMed PMC

Salanova V, Sperling MR, Gross RE, et al. The SANTE study at 10 years of follow-up: Effectiveness, safety, and sudden unexpected death in epilepsy. Epilepsia. 2021;62(6):1306–1317. PubMed

Horn A, Reich M, Vorwerk J, et al. Connectivity Predicts deep brain stimulation outcome in Parkinson disease. Ann Neurol. 2017;82(1):67–78. PubMed PMC

Johnson KA, Duffley G, Anderson DN, et al. Structural connectivity predicts clinical outcomes of deep brain stimulation for Tourette syndrome. Brain. 2020;143(8):26072623. PubMed PMC

Middlebrooks EH, Okromelidze L, Wong JK, et al. Connectivity correlates to predict essential tremor deep brain stimulation outcome: Evidence for a common treatment pathway. Neuroimage Clin. 2021;32:102846. PubMed PMC

Hollunder B, Ostrem JL, Sahin IA, et al. Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation. Nat Neurosci. 2024;27(3):573–586. PubMed PMC

Wu TQ, Kaboodvand N, McGinn RJ, et al. Multisite thalamic recordings to characterize seizure propagation in the human brain. Brain. 2023;146(7):2792–2802. PubMed PMC

Guye M, Regis J, Tamura M, et al. The role of corticothalamic coupling in human temporal lobe epilepsy. Brain. 2006;129(Pt 7):1917–1928. PubMed

Rosenberg DS, Mauguiere F, Catenoix H, Faillenot I, Magnin M. Reciprocal thalamocortical connectivity of the medial pulvinar: a depth stimulation and evoked potential study in human brain. Cereb Cortex. 2009;19(6):1462–1473. PubMed

Gross RE, Fisher RS, Sperling MR, Giftakis JE, Stypulkowski PH. Analysis of Deep Brain Stimulation Lead Targeting in the Stimulation of Anterior Nucleus of the Thalamus for Epilepsy Clinical Trial. Neurosurgery. 2021;89(3):406–412. PubMed PMC

Lehtimaki K, Mottonen T, Jarventausta K, et al. Outcome based definition of the anterior thalamic deep brain stimulation target in refractory epilepsy. Brain Stimul. 2016;9(2):268–275. PubMed

Schaper F, Plantinga BR, Colon AJ, et al. Deep Brain Stimulation in Epilepsy: A Role for Modulation of the Mammillothalamic Tract in Seizure Control? Neurosurgery. 2020;87(3):602–610. PubMed PMC

Jones EG. The Thalamus. Second ed. Cambridge: Cambridge University Press; 2007.

Wu D, Schaper F, Jin G, et al. Human anterior thalamic stimulation evoked cortical potentials align with intrinsic functional connectivity. Neuroimage. 2023;277:120243. PubMed

Oehrn CR, Cernera S, Hammer LH, et al. Chronic adaptive deep brain stimulation versus conventional stimulation in Parkinson’s disease: a blinded randomized feasibility trial. Nat Med. 2024. PubMed PMC

Stieve BJ, Richner TJ, Krook-Magnuson C, Netoff TI, Krook-Magnuson E. Optimization of closed-loop electrical stimulation enables robust cerebellar-directed seizure control. Brain. 2023;146(1):91–108. PubMed PMC