Machine learning models improve prediction of large vessel occlusion and mechanical thrombectomy candidacy in acute ischemic stroke

Background and PurposeEarly identification of large vessel occlusions (LVO) and timely recanalization are paramount to improved clinical outcomes in acute ischemic stroke. A stroke assessment that maximizes sensitivity and specificity for LVOs is needed to identify these cases and not overburden the health system with unnecessary transfers. Machine learning techniques are being used for predictive modeling in many aspects of stroke care and may have potential in predicting LVO presence and mechanical thrombectomy (MT) candidacy.MethodsIschemic stroke patients treated at Loyola University Medical Center from July 2018 to June 2019 (N = 286) were included. Thirty-five clinical and demographic variables were analyzed using machine learning algorithms, including logistic regression, extreme gradient boosting, random forest (RF), and decision trees to build models predictive of LVO presence and MT candidacy by area of the curve (AUC) analysis. The best performing model was compared with prior stroke scales.ResultsWhen using all 35 variables, RF best predicted LVO presence (AUC = 0.907 ± 0.856–0.957) while logistic regression best predicted MT candidacy (AUC = 0.930 ± 0.886–0.974). When compact models were evaluated, a 10-feature RF model best predicted LVO (AUC = 0.841 ± 0.778–0.904) and an 8-feature RF model best predicted MT candidacy (AUC = 0.862 ± 0.782–0.942). The compact RF models had sensitivity, specificity, negative predictive value and positive predictive value of 0.81, 0.87, 0.92, 0.72 for LVO and 0.87, 0.97, 0.97, 0.86 for MT, respectively. The 10-feature RF model was superior at predicting LVO to all previous stroke scales (AUC 0.944 vs 0.759–0.878) and the 8-feature RF model was superior at predicting MT (AUC 0.970 vs 0.746–0.834).ConclusionRandom forest machine learning models utilizing clinical and demographic variables predicts LVO presence and MT candidacy with a high degree of accuracy in an ischemic stroke cohort. Further validation of this strategy for triage of stroke patients requires prospective and external validation.     

Cerebral foreign body granulomas after mechanical thrombectomy: Two case reports and a review of the literature

ObjectivesA foreign body granuloma after an endovascular intervention is a rare complication. Some cases of foreign body granulomas, especially after coil embolization, have been reported. However, only four cases of foreign body granulomas after mechanical thrombectomy (MT) have previously been reported. The current study reports two cases of post-MT foreign body granulomas, including a biopsy-proven case.Material and MethodsCase 1: A 73-year-old woman presented with complete occlusion of the right middle cerebral artery. Cerebral angiography and MT were successfully performed with improvement in clinical symptoms. Left hemiparesis and a disturbance in attention appeared after discharge and progressed slowly. She was re-admitted to our hospital 120 days after cerebral infarction owing to foreign body granulomas diagnosed on biopsy. Case 2: A 78-year-old man presented with occlusion of the left cervical internal carotid artery and the left middle cerebral artery. Cerebral angiography, percutaneous transluminal angioplasty, and MT were successfully performed. On the 34th day, he experienced progressive consciousness disorder because of foreign body granulomas. Both cases were successfully treated with steroid therapy.ResultsMRI after steroid treatment showed the disappearance of most nodular lesions and improvement of the encephalopathy.ConclusionsThe cause of the granuloma may be an allergic reaction to the hydrophilic polymers that peel from endovascular devices. Steroid therapy is an effective treatment; therefore, neurologists should consider this complication when neurological symptoms or signs on image appears or worsens. A reliable diagnosis is important for prompt treatment.     

Clinical features and prognostic factors in patients with cancer-associated multiple ischemic stroke: A retrospective observational study

ObjectivesTo investigate the patient demographics, survival after diagnosis, and prognostic factors among patients with multiple-territory cerebral infarctions due to cancer-associated ischemic stroke (multiple CAIS).Materials and methodsWe performed a retrospective review of the medical records from a 10-year period of consecutive patients with multiple CAIS, defined as (1) newly developed multiple cerebral infarctions involving two or more cerebrovascular territories, (2) association with active cancer diagnosed or treated <6 months before or after stroke, and (3) exclusion of obvious etiologies other than cancer-associated coagulopathy in routine screening. We extracted demographic features, stroke severity and characteristics, cancer characteristics, comorbidities, and laboratory data. Univariable Cox proportional hazards regression was used to idenify the prognostic factors.ResultsThe median age was 74 years (interquartile range, 68.3–80.5), and the median survival after diagnosis was 44.5 (27.3–76.8) days in 26 patients with complete follow-up. The median National Institutes of Health Stroke Scale was 5.5 (2.0–9.0). Twenty (76.9%) patients had received a cancer diagnosis prior to the diagnosis of multiple CAIS, and most patients (25 patients, 96.2%) had stage IV cancer. Univariate analysis showed that high serum albumin (hazard ratio, 0.31; 95% confidence interval, 0.11–0.88) was significantly associated with prolonged survival, whereas stroke severity and comorbidities were not associated with survival.ConclusionMultiple CAIS predominantly occurred in elderly patients with advanced cancer, and their survival was short. Serum albumin levels were significantly associated with prognosis, indicating the poor general condition associated with cancers may affect prognosis.     

The impact of the approval of prothrombin complex concentrates for vitamin K antagonist-related intracerebral hemorrhage: A retrospective study

ObjectivesThis study aimed to determine the impact of the approval of prothrombin complex concentrates on the treatment of vitamin K antagonist-related intracerebral hemorrhage.Materials and MethodsWe retrospectively studied all patients with vitamin K antagonist-related intracerebral hemorrhage treated with prothrombin complex concentrate at our institutes between January 2010 and June 2021. Before approval, prothrombin complex concentrate was administered as either 500 or 1000 IU at the physician's discretion (previous dose group). After approval, we adopted the manufacturer's recommended regimen (recommended dose group). The primary outcome was post-administration international normalized ratio. Secondary outcomes were the amount of prothrombin complex concentrate administered and proportion of post-administration international normalized ratio <1.5, hematoma expansion, thrombotic events within 30 days, modified Rankin scale 0–3 at discharge, and in-hospital mortality.ResultsThirty-two and 19 patients in the previous and recommended dose groups, respectively, were included. The post-administration international normalized ratio significantly differed between groups. The prothrombin complex concentrate dose and proportion of patients achieving post-administration international normalized ratio <1.5 were significantly higher in the recommended dose group than in the previous dose group (1500 IU vs. 500 IU, p<0.001 and 100% vs. 68%, p = 0.008). The proportions of hematoma expansion, thromboembolic events, modified Rankin scale 0-3, and mortality did not differ between groups.ConclusionAfter prothrombin complex concentrate approval, prothrombin time-international normalized ratio correction was more effective with a significant increase in the prothrombin complex concentrates dose for vitamin K antagonist-associated intracerebral hemorrhage; however, there was no apparent difference in clinical outcomes.     

Leukoaraiosis and earlier neurological outcome after mechanical thrombectomy in acute ischemic stroke

Background and purposeThe aim of the study was to evaluate whether leukoaraiosis (LA) severity is associated with earlier neurological outcome in acute stroke patients undergoing mechanical thrombectomy.Materials and methodsIn this retrospective multicenter study, we evaluated 273 acute stroke patients treated with mechanical thrombectomy. LA severity was graded as 0–2 (absent-to-moderate) versus 3–4 (severe) according to the van Swieten scale. The main clinical outcome was the proportion of early neurological improvement and early neurological deterioration. Early neurological improvement was defined as a decrease of ≥ 4 points on the NIHSS, or an NIHSS score of zero 24 hours after baseline assessment. Early neurological deterioration was defined as an increase of ≥ 4 points on the NIHSS 24 hours after baseline assessment.ResultsThere was a significantly lower early neurological improvement rate (17.1% versus 39.2%; P = 0.006) and non-significantly higher early neurological deterioration rate (29.3% versus 17.7%; P = 0.084) in patients with severe LA (sLA) compared with patients with absent-to-moderate LA. In multivariable analysis, sLA was inversely associated with early neurological improvement (OR, 0.31; 95% CI, 0.13–0.78; P = 0.012). There was no significant association of sLA with early neurological deterioration. However, in patients without symptomatic intracranial hemorrhage, sLA was an independent predictor of early neurological deterioration (OR, 2.65; 95% CI, 1.09–6.45; P = 0.032).ConclusionssLA is a significant negative predictor of early neurological improvement and is an independent predictor of early neurological deterioration in patients without symptomatic intracranial hemorrhage.     

Early mobilisation is associated with lower subacute blood pressure and variability in ICH: A retrospective cohort study✰

BackgroundVery early rehabilitation after stroke appears to worsen outcome, particularly in intracerebral haemorrhage (ICH). Plausible mechanisms include increased mean blood pressure (BP) and BP variability.AimsTo test associations between early mobilisation, subacute BP and survival, in observational data of ICH patients during routine clinical care.MethodsWe collected demographic, clinical and imaging data from 1372 consecutive spontaneous ICH patients admitted between 2 June 2013 and 28 September 2018. Time to first mobilisation (defined as walking, standing, or sitting out-of-bed) was extracted from electronic records. We evaluated associations between early mobilisation (within 24 h of onset) and both subacute BP and death by 30 days using multifactorial linear and logistic regression analyses respectively.ResultsMobilisation at 24 h was not associated with increased odds of death by 30 days when adjusting for key prognostic factors (OR 0.4, 95% CI 0.2 to 1.1, p = 0.07). Mobilisation at 24 h was independently associated with both lower mean systolic BP (−4.5 mmHg, 95% CI −7.5 to −1.5 mmHg, p = 0.003) and lower diastolic BP variability (−1.3 mmHg, 95% CI −2.4 to −0.2 mg, p = 0.02) during the first 72 h after admission.ConclusionsAdjusted analysis in this observational dataset did not find an association between early mobilisation and death by 30 days. We found early mobilisation at 24 h to be independently associated with lower mean systolic BP and lower diastolic BP variability over 72 h. Further work is needed to establish mechanisms for the possible detrimental effect of early mobilisation in ICH.     

Nusinersen treatment in adults with severe spinal muscular atrophy: A real-life retrospective observational cohort study

Background and objectivesSpinal muscular atrophy (SMA) is a progressive neurodegenerative disease due to homozygous loss-of-function of the survival motor neuron gene SMN 1 with absence of the functional SMN protein. Nusinersen, a costly intrathecally administered drug approved in 2017 in Europe, induces alternative splicing of the SMN2 gene, which then produces functional SMN protein, whose amount generally increases with the number of SMN2 gene copies.MethodsWe retrospectively collected data from consecutive wheelchair-bound adults with SMA managed at a single center in 2018–2020. The following were collected at each injection, on days 1, 14, 28, 63, 183, and 303: 32-item Motor Function Measurement (MFM) total score and D2 and D3 subscores; the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores; and lung function tests. The patients were divided into two groups based on whether their MFM total score was < or ≥ the mean (15.6%). Adverse events were recorded.ResultsWe identified 18 patients who received 4 to 8 Nusinersen injections. No significant improvements occurred over time in any of the MFM scores or lung function test results, which did not differ between groups. The COPM performance score improved significantly from day 0 to day 303 in the high-MFM group and the COPM satisfaction score in the overall population from D0 to D183. Half the patients achieved the minimal clinically important difference for both COPM scores.DiscussionThe overall stability of conventional motor assessment in this population with advanced disabilities is encouraging to use more sensitive tools based on self-perception and autonomy in daily life activities, such as COPM. Our finding of a significant COPM performance score improvement from days 0 to 303 only in the patients with initial MFM-32 scores above the mean in the population suggests that the severity of the baseline disabilities may affect treatment efficacy.Classification of evidence levelIV, retrospective observational cohort study.     

Association of distal hyperintense vessel sign and recurrent stroke in patients with symptomatic intracranial stenosis

ObjectiveThe distal hyperintense vessel sign (DHV) on fluid-attenuated inversion recovery magnetic resonance image (MRI) is an imaging biomarker of slow leptomeningeal collateral flow in the presence of large artery stenosis or occlusion reflecting impaired cerebral hemodynamics. In this study, we aim to investigate the significance of the DHV sign in patients with symptomatic ≥ 70% intracranial atherosclerotic stenosis.MethodsWe retrospectively reviewed patients with ischemic stroke or transient ischemic attack admitted to a single center from January 2010 to December 2017. Patients were included if they had symptomatic ≥ 70% atherosclerotic stenosis of the intracranial internal carotid artery or middle cerebral artery. The presence of the DHV sign was evaluated by blinded neuroradiologist and vascular neurologists. Recurrent ischemic stroke in the vascular territory of symptomatic intracranial artery was defined as new neurological deficits with associated neuroimaging findings during the follow up period.ResultsA total of 109 patients were included in the study, of which 55 had DHV sign. Average duration of follow up was 297 ± 326 days. Four patients were lost during follow up. Patients with the DHV sign had a higher rate of recurrent ischemic stroke (38%), compared to patients without the DHV sign (17%; p=0.018). In multivariate regression analysis, the presence of DHV sign was an independent predictor of recurrent ischemic stroke. A DHV score of ≥ 2 had a 63% sensitivity and 69% specificity for recurrent ischemic stroke.InterpretationIn patients with severe symptomatic intracranial atherosclerotic stenosis, those with a DHV sign on MRI are at higher risk of recurrent ischemic stroke.     

Functional organization of the human primary somatosensory cortex: A stereo-electroencephalography study

ObjectiveThe classical homunculus of the human primary somatosensory cortex (S1) established by Penfield has mainly portrayed the functional organization of convexial cortex, namely Brodmann area (BA) 1. However, little is known about the functions in fissural cortex including BA2 and BA3. We aim at drawing a refined and detailed somatosensory homunculus of the entire S1.MethodsWe recruited 20 patients with drug-resistant focal epilepsy who underwent stereo-electroencephalography for preoperative assessments. Direct electrical stimulation was performed for functional mapping. Montreal Neurological Institute coordinates of the stimulation sites lying in S1 were acquired.ResultsStimulation of 177 sites in S1 yielded 149 positive sites (84%), most of which were located in the sulcal cortex. The spatial distribution of different body-part representations across the S1 surface revealed that the gross medial-to-lateral sequence of body representations within the entire S1 was consistent with the classical “homunculus”. And we identified several unreported body-part representations from the sulcal cortex, such as forehead, deep elbow and wrist joints, and some dorsal body regions.ConclusionsOur results reveal general somatotopical characteristics of the entire S1 cortex and differences with the previous works of Penfield.SignificanceThe classical S1 homunculus was extended by providing further refinement and additional detail.     

Associations of carotid artery flow parameters with MRI markers of cerebral small vessel disease and patterns of brain atrophy

ObjectivesA growing body of evidence links age related brain pathologies to systemic vascular processes. We aimed to study the prevalence and interrelations between magnetic resonance imaging (MRI) markers of cerebral small vessel disease and patterns of brain atrophy, and their association to carotid duplex ultrasound flow parameters.Materials and methodsWe investigated a population based randomised cohort of older adults (n=391) aged 70-87, part of the Swedish Good Aging in Skåne Study. Peak systolic and end diastolic velocities of the carotid arteries were measured by ultrasound, and resistivity- and pulsatility indexes were calculated. Subjects with increased peak systolic velocity indicating carotid stenosis were excluded from analysis. Nine MRI findings were rated by visual scales: white matter changes, pontine white matter changes, microbleeds, lacunar infarctions, medial temporal lobe atrophy, global cortical atrophy, parietal atrophy, precuneus atrophy and central atrophy.ResultsMRI pathologies were found in 80% of subjects. Mean end diastolic velocity in common carotid arteries was inversely associated with white matter hyperintensities (OR=0.92; p=0.004), parietal lobe atrophy (OR=0.94; p=0.039), global cortical atrophy (OR=0.90; p=0.013), precuneus atrophy (OR=0.94; p=0.022), “number of CSV pathologies” (β=-0.07; p<0.001) and “MRI-burden score” (β=-0.11; p<0.001), after adjustment for age and sex. The latter three were also associated with pulsatility and resistivity indexes.ConclusionsLow carotid end diastolic velocity, as well as increased carotid resistivity and pulsatility, were associated with signs of cerebral small vessel disease and patterns of brain atrophy, indicating a vascular component in the process of brain aging.     

Sleep modulates effective connectivity: A study using intracranial stimulation and recording

ObjectiveSleep is an active process with an important role in memory. Epilepsy patients often display a disturbed sleep architecture, with consequences on cognition. We aimed to investigate the effect of sleep on cortical networks’ organization.MethodsWe analyzed cortico-cortical evoked responses elicited by single pulse electrical stimulation (SPES) using intracranial depth electrodes in 25 patients with drug-resistant focal epilepsy explored using stereo-EEG. We applied the SPES protocol during wakefulness and NREM – N2 sleep. We analyzed 31,710 significant responses elicited by 799 stimulations covering most brain structures, epileptogenic or non-epileptogenic. We analyzed effective connectivity between structures using a graph-theory approach.ResultsSleep increases excitability in the brain, regardless of epileptogenicity. Local and distant connections are differently modulated by sleep, depending on the tissue epileptogenicity.In non-epileptogenic areas, frontal lobe connectivity is enhanced during sleep. There is increased connectivity between the hippocampus and temporal neocortex, while perisylvian structures are disconnected from the temporal lobe. In epileptogenic areas, we found a clear interhemispheric difference, with decreased connectivity in the right hemisphere during sleep.ConclusionsSleep modulates brain excitability and reconfigures functional brain networks, depending on tissue epileptogenicity.SignificanceWe found specific patterns of information flow during sleep in physiologic and pathologic structures, with possible implications for cognition.     

Quantitative evaluation of WEB shape modification: A five-year follow-up study

Background and purposeWeb shape modification (WSM) has previously been associated with aneurysm recurrence. We report here our five-year experience of WEB device use with a quantitative approach of the WSM phenomenon.MethodsFrom July 2012 to July 2017, 50 patients with 51 unruptured aneurysms treated with the WEB device have been prospectively enrolled in our data base and retrospectively analyzed. An independent “core lab” evaluated anatomical results and potential WSM in DSA follow-up. We defined the WSM ratio (WSMr) as a relative index between the height and the width of the device in working projections which gave an evaluation of the device deformation over the time.ResultsDuring the total follow-up period, WSM was observed in 35/48 aneurysms (72.9%). Adequate occlusion rates were 87.0% and 92.6% with and without WSM respectively (P = 0.65). 30 out the 35 (85.7%) shape modifications were already noticed at short-term follow-up (6-month DSA). 33 patients had 2 DSA controls and WSMr measurements were available in 24 patients: 18 (75%) with WSM and 6 (25%) without WSM. In the group with WSM, WSMr values were 0.80 in post-embolization, 0.52 at the first DSA angiogram and 0.42 at the second DSA angiogram.ConclusionWEB shape modification was observed in more than half of cases but with no influence regarding adequate occlusion rate. This quantitative approach of WSM highlights that this phenomenon appears to be early and progressive over time. This supports the hypothesis that WSM could be more probably related to aneurysm healing rather than external compression.     

Subthalamic nucleus deep brain stimulation improves sleep in Parkinson's disease patients: a retrospective study and a meta-analysis

BackgroundMost Parkinson's patients suffered from sleep problems. There is increasing evidence that Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has a positive effect on several sleep parameters, improving overall sleep quality in patients with PD. However, the results are controversial.MethodsWe performed a retrospective study and meta-analysis to assess the Parkinson's disease sleep scale (PDSS) in Parkinson's patients.ResultsWe reviewed our data of patients who underwent STN-DBS, and then extracted five other trials to perform a meta-analysis. The pooled results showed an advantage on post-operative PDSS in both our medical center and pooled results (MD = 20.41, 95% CI = [13.03, 27.79], I² = 61%, P < 0.001). There was a significant difference in Unified Parkinson's Disease Rating Scale (UPDRS)-Ⅲ score between pre and post-operation (MD = −12.59, 95% CI = [−14.70, −10.49], I² = 90%, P < 0.001). What's more, Parkinsonian medication was significantly lower in the post-operative groups after DBS (MD = −314.71, 95% CI = [−468.13, −161.28], I² = 53%, P < 0.001).ConclusionIn the retrospective study and meta-analysis of 6 trials, we found that DBS can significantly increase sleep quality. Furthermore, motor function improved and Parkinsonian medication was significantly decreased postoperatively. The sample size was enough and no further investigations would change the conclusion.     

A modality-specific somatosensory evoked potential test protocol for clinical evaluation: A feasibility study

ObjectiveWe aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system.MethodsIn order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference.ResultsWe found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aβ-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aβ-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings.ConclusionIn this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application.SignificanceEstablished and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.     

The mucormycosis and stroke: The learning curve during the second COVID-19 pandemic

BackgroundThe Angio-invasive Rhino-orbito-cerebral mucormycosis (ROCM) producing strokes is a less explored entity. Our hospital, a stroke-ready one, had an opportunity to manage mucormycosis when it was identified as the nodal center for mucormycosis management. We are sharing our experiences and mistakes in managing the cerebrovascular manifestations of ROCM.MethodsWe conducted a prospective observational study during the second wave of the COVID-19 pandemic from 1st May 2021 to 30th September 2021, where consecutive patients aged more than 18 years with microbiologically confirmed cases of ROCM were included. Clinical details (timing of stroke onset after ROCM symptoms, GCS, NIHSS), imaging findings (ASPECTS, the territory of stroke, the pattern of infarct, hemorrhagic transformation, cavernous sinus thrombosis), angiogram findings, management details (IV thrombolysis), and outcomes (mRS at discharge and duration of hospital stay) were documented. We also compared the demographics, clinical features (NIHSS), radiological findings, treatment details, duration of hospital stay, and functional outcome at the discharge of the ROCM stroke patients with stroke patients without ROCM.ResultsStroke developed in 42% of patients with ROCM, predominantly anterior circulation border zone ischemic infarcts. Strokes occurred after a median of five days from the onset of ROCM symptoms. The most common vessel involved was the ophthalmic artery, followed by the cavernous ICA. We could not thrombolyse ROCM stroke patients. ROCM patients who developed stroke compared with patients without stroke had a more infiltrative fungal infection and higher inflammatory markers. Mucormycosis associated stroke patients had higher in-hospital mortality and poor functional outcomes.TConclusionDue to delayed recognition of stroke symptoms, none received reperfusion strategies, leading to poor functional outcomes. For early stroke detection, ROCM cases need frequent monitoring and education of patients and their relatives about the ALS acronym (loss of ambulation, limb weakness, and loss of speech).     

Evidence of state-dependence in the effectiveness of responsive neurostimulation for seizure modulation

BackgroundAn implanted device for brain-responsive neurostimulation (RNS® System) is approved as an effective treatment to reduce seizures in adults with medically-refractory focal epilepsy. Clinical trials of the RNS System demonstrate population-level reduction in average seizure frequency, but therapeutic response is highly variable.HypothesisRecent evidence links seizures to cyclical fluctuations in underlying risk. We tested the hypothesis that effectiveness of responsive neurostimulation varies based on current state within cyclical risk fluctuations.MethodsWe analyzed retrospective data from 25 adults with medically-refractory focal epilepsy implanted with the RNS System. Chronic electrocorticography was used to record electrographic seizures, and hidden Markov models decoded seizures into fluctuations in underlying risk. State-dependent associations of RNS System stimulation parameters with changes in risk were estimated.ResultsHigher charge density was associated with improved outcomes, both for remaining in a low seizure risk state and for transitioning from a high to a low seizure risk state. The effect of stimulation frequency depended on initial seizure risk state: when starting in a low risk state, higher stimulation frequencies were associated with remaining in a low risk state, but when starting in a high risk state, lower stimulation frequencies were associated with transition to a low risk state. Findings were consistent across bipolar and monopolar stimulation configurations.ConclusionThe impact of RNS on seizure frequency exhibits state-dependence, such that stimulation parameters which are effective in one seizure risk state may not be effective in another. These findings represent conceptual advances in understanding the therapeutic mechanism of RNS, and directly inform current practices of RNS tuning and the development of next-generation neurostimulation systems.