Hal Blumenfeld, MD, PhD
Research & Publications
What is the relationship between brain activity and conscious thought? One of the most important unsolved questions in science, the basis of consciousness is worthy of empiric study. Our laboratory investigates brain mechanisms of normal consciousness, how consciousness is impaired in disorders like epilepsy, and how consciousness can be restored with neurostimulation.
Our work combines neuroimaging, electrophysiology and behavioral testing. We investigate cerebral cortical networks interacting with deeper brain structures such as the thalamus and brainstem. Current projects include single cell and larger-scale electrical recordings, neuroimaging with functional magnetic resonance imaging (fMRI) and other methods in animal models and human patients to understand changes in behavior during seizures.
Our goal is to understand and to prevent impaired consciousness. Other practical applications emerging from our research include: 1. Improved computational methods for neuroimaging data analysis; 2. Relating neuroimaging signals to underlying neurophysiology; and 3. Finding molecular mechanisms of epileptogenesis and strategies to prevent or cure epilepsy.
For more information visit: http://www.yale.edu/blumenfeld/
Specialized Terms: Impaired consciousness in epilepsy; Epilepsy neuroimaging and electrophysiology
Extensive Research Description
Expertise: Combined electrophysiology and neuroimaging Human functional neuroanatomy Epilepsy, human studies and animal models Cortical-subcortical mechanisms of consciousness.
For more information visit: http://www.yale.edu/blumenfeld/
Absence Epilepsy, EEG-fMRI and Attention
Absence seizures are brief episodes of staring and unresponsiveness. Seen most commonly in children, they can disrupt school and attention performance. The mechanisms for impaired attention in absence epilepsy are not known. To determine how brain networks are affected by absence seizures we perform simultaneous fMRI and EEG recordings in children during absence seizures. We also test attention both during seizures and under normal conditions. Our work has revealed abnormal activity in specific brain regions which may serve as new targets for treatment.
Neuronal Activity and Neuroimaging in Generalized Seizures
Are “generalized” seizures truly generalized? Our work using high field (9.4-11.7T)fMRI and electrophysiology recordings from animal models suggests that s ocalled generalized absence and tonic-clonic seizures are in fact localized to specific bilateral cortical-subcortical networks. These findings may help develop targeted therapies with better efficacy and fewer side effects. In addition our direct recordings of neuronal electrical activity improve the interpretation of indirect neuroimaging measurements of brain function.
Impaired Consciousness in Temporal Lobe Epilepsy
Temporal lobe seizures are the most common form of localized epilepsy. How do focal seizures impair consciousness? We propose a “network inhibition hypothesis” in which temporal lobe seizures inhibit subcortical arousal systems, causing depressed cortical function. In support of this hypothesis, we found sleep-like changes in the cortex with intracranial EEG and SPECT during temporal lobe seizures. We are now using high field (9.4 T, 11.7 T) fMRI,single neuron recordings, neurotransmitter studies, and optogenetic techniques in animal models to reveal the fundamental mechanisms of these changes, and to test novel treatment approaches.
Virtual Reality Driving Safety and other BedsideTesting in Epilepsy
One of the most devastating effects of altered consciousness in epilepsy is impaired driving safety. To determine how epileptic seizures affect performance, we use virtual-reality driving simulation during video/EEG monitoring while patients are in the hospital. In addition, we have developed a prospective bedside testing battery, the Responsiveness in Epilepsy Scale (RES). These testing methods provide better information to patients and physicians making decisions about driving, and may help identify brain areas crucial for impaired consciousness in epilepsy.
Technical Advances in Epilepsy Surgery Localization
Some patients have seizures that are so severe that they cannot be controlled by medicine. Many of these patients can be cured if we can identify a specific damaged region of the brain that can safely be removed and prevent the triggering of their seizures. We have recently developed novel approaches to target surgery to the correct location in the brain, including:(i) 3D color movies of the “brainwave” electroencephalogram (EEG) in patients with epilepsy show where the seizures start, making safe and effective surgery much more feasible; (ii) innovative methods using single photon emission computed tomography (SPECT) and positron emission tomography (PET) tracers can pinpoint the region of seizure onset for surgical planning.
One crucial goal is the prevention of epilepsy before it even begins. We found in a genetic form of epilepsy that if we treat rat pups with anti-seizure medication from a very early age (even before seizures started) we greatly reduce their tendency to have seizures as adults. In addition, we found in a recent review of human studies of the same form of epilepsy that early and effective treatment may improve long-term outcome. This is a paradigm shift from current treatment strategies which view seizure medications as suppressing the symptoms, not the underlying disease. The findings also raise the hope that as genes are identified and enable epilepsy to be predicted, beneficial treatments may be started even before symptoms begin.
Attention; Consciousness; Consciousness Disorders; Electrophysiology; Epilepsy; Magnetic Resonance Imaging; Neurobiology; Neurology; Neurosurgery; Behavioral Research; Neuroimaging
- Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizuresMcCafferty C, Gruenbaum B, Tung R, Li J, Zheng X, Salvino P, Vincent P, Kratochvil Z, Ryu J, Khalaf A, Swift K, Akbari R, Islam W, Antwi P, Johnson E, Vitkovskiy P, Sampognaro J, Freedman I, Kundishora A, Depaulis A, David F, Crunelli V, Sanganahalli B, Herman P, Hyder F, Blumenfeld H. Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures Nature Communications 2023, 14: 117. PMID: 36627270, PMCID: PMC9832004, DOI: 10.1038/s41467-022-35535-4.
- Human visual consciousness involves large scale cortical and subcortical networks independent of task report and eye movement activityKronemer S, Aksen M, Ding J, Ryu J, Xin Q, Ding Z, Prince J, Kwon H, Khalaf A, Forman S, Jin D, Wang K, Chen K, Hu C, Agarwal A, Saberski E, Wafa S, Morgan O, Wu J, Christison-Lagay K, Hasulak N, Morrell M, Urban A, Todd Constable R, Pitts M, Mark Richardson R, Crowley M, Blumenfeld H. Human visual consciousness involves large scale cortical and subcortical networks independent of task report and eye movement activity Nature Communications 2022, 13: 7342. PMID: 36446792, PMCID: PMC9707162, DOI: 10.1038/s41467-022-35117-4.
- Distinct signatures of loss of consciousness in focal impaired awareness versus tonic-clonic seizures.Juan E, Górska U, Kozma C, Papantonatos C, Bugnon T, Denis C, Kremen V, Worrell G, Struck A, Bateman L, Merricks E, Blumenfeld H, Tononi G, Schevon C, Boly M. Distinct signatures of loss of consciousness in focal impaired awareness versus tonic-clonic seizures. Brain 2022 PMID: 36383415, DOI: 10.1093/brain/awac291.
- EEG–fMRI in Animal ModelsGummadavelli A, Sanganahalli B, Herman P, Hyder F, Blumenfeld H. EEG–fMRI in Animal Models 2022, 663-694. DOI: 10.1007/978-3-031-07121-8_27.
- An epilepsy network derived from human brain lesions and deep brain stimulationSchaper F, Nordberg J, Cohen A, Hsu J, Lin C, Ferguson M, Siddiqi S, Blumenfeld H, Joutsa J, Fox M. An epilepsy network derived from human brain lesions and deep brain stimulation Brain Stimulation 2021, 14: 1643-1644. DOI: 10.1016/j.brs.2021.10.178.
- Thalamic Stimulation Improves Postictal Cortical Arousal and BehaviorXu J, Galardi MM, Pok B, Patel KK, Zhao CW, Andrews JP, Singla S, McCafferty CP, Feng L, Musonza ET, Kundishora AJ, Gummadavelli A, Gerrard JL, Laubach M, Schiff ND, Blumenfeld H. Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior Journal Of Neuroscience 2020, 40: 7343-7354. PMID: 32826310, PMCID: PMC7534908, DOI: 10.1523/jneurosci.1370-20.2020.
- Up and Down States of Cortical Neurons in Focal Limbic SeizuresYue Z, Freedman IG, Vincent P, Andrews JP, Micek C, Aksen M, Martin R, Zuckerman D, Perrenoud Q, Neske GT, Sieu LA, Bo X, Cardin JA, Blumenfeld H. Up and Down States of Cortical Neurons in Focal Limbic Seizures Cerebral Cortex 2019, 30: 3074-3086. PMID: 31800015, PMCID: PMC7197089, DOI: 10.1093/cercor/bhz295.
- Realistic driving simulation during generalized epileptiform discharges to identify electroencephalographic features related to motor vehicle safety: Feasibility and pilot studyCohen E, Antwi P, Banz BC, Vincent P, Saha R, Arencibia CA, Ryu JH, Atac E, Saleem N, Tomatsu S, Swift K, Hu C, Krestel H, Farooque P, Levy S, Wu J, Crowley M, Vaca FE, Blumenfeld H. Realistic driving simulation during generalized epileptiform discharges to identify electroencephalographic features related to motor vehicle safety: Feasibility and pilot study Epilepsia 2019, 61: 19-28. PMID: 31646628, PMCID: PMC7424790, DOI: 10.1111/epi.16356.
- Prevention of Epileptogenesis in Animal ModelsMishra A, Blumenfeld H. Prevention of Epileptogenesis in Animal Models 2019, 135-147. DOI: 10.1017/9781316257951.014.
- T148. Slow wave activity from bilateral subdural electrode contacts during awake, sleep, and postictal statesLundstrom B, Boly M, Duckrow R, Zaveri H, Blumenfeld H. T148. Slow wave activity from bilateral subdural electrode contacts during awake, sleep, and postictal states Clinical Neurophysiology 2018, 129: e59. DOI: 10.1016/j.clinph.2018.04.149.
- T02. Impairment of consciousness induced by electrical cortical stimulation: Under-reported phenomenon or a disease-specific condition?Quraishi I, Benjamin C, Spencer D, Blumenfeld H, Alkawadri R. T02. Impairment of consciousness induced by electrical cortical stimulation: Under-reported phenomenon or a disease-specific condition? Clinical Neurophysiology 2018, 129: e1-e2. DOI: 10.1016/j.clinph.2018.04.003.
- A Switch and Wave of Neuronal Activity in the Cerebral Cortex During the First Second of Conscious PerceptionHerman WX, Smith RE, Kronemer SI, Watsky RE, Chen WC, Gober LM, Touloumes GJ, Khosla M, Raja A, Horien CL, Morse EC, Botta KL, Hirsch LJ, Alkawadri R, Gerrard JL, Spencer DD, Blumenfeld H. A Switch and Wave of Neuronal Activity in the Cerebral Cortex During the First Second of Conscious Perception Cerebral Cortex 2017, 29: 461-474. PMID: 29194517, PMCID: PMC6319177, DOI: 10.1093/cercor/bhx327.
- Functional MRI in Basic Epilepsy Research☆Englot D, Blumenfeld H. Functional MRI in Basic Epilepsy Research☆ 2017 DOI: 10.1016/b978-0-12-809324-5.00092-4.
- Impaired consciousness in patients with absence seizures investigated by functional MRI, EEG, and behavioural measures: a cross-sectional studyGuo JN, Kim R, Chen Y, Negishi M, Jhun S, Weiss S, Ryu JH, Bai X, Xiao W, Feeney E, Rodriguez-Fernandez J, Mistry H, Crunelli V, Crowley MJ, Mayes LC, Constable RT, Blumenfeld H. Impaired consciousness in patients with absence seizures investigated by functional MRI, EEG, and behavioural measures: a cross-sectional study The Lancet Neurology 2016, 15: 1336-1345. PMID: 27839650, PMCID: PMC5504428, DOI: 10.1016/s1474-4422(16)30295-2.
- Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain StimulationKundishora AJ, Gummadavelli A, Ma C, Liu M, McCafferty C, Schiff ND, Willie JT, Gross RE, Gerrard J, Blumenfeld H. Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain Stimulation Cerebral Cortex 2016, 27: 1964-1975. PMID: 26941379, PMCID: PMC5964488, DOI: 10.1093/cercor/bhw035.
- Chapter 1 Neuroanatomical Basis of ConsciousnessBlumenfeld H. Chapter 1 Neuroanatomical Basis of Consciousness 2016, 3-29. DOI: 10.1016/b978-0-12-800948-2.00001-7.
- Chapter 16 Epilepsy and ConsciousnessBlumenfeld H. Chapter 16 Epilepsy and Consciousness 2016, 255-270. DOI: 10.1016/b978-0-12-800948-2.00016-9.
- Decreased Subcortical Cholinergic Arousal in Focal SeizuresMotelow JE, Li W, Zhan Q, Mishra AM, Sachdev RN, Liu G, Gummadavelli A, Zayyad Z, Lee HS, Chu V, Andrews JP, Englot DJ, Herman P, Sanganahalli BG, Hyder F, Blumenfeld H. Decreased Subcortical Cholinergic Arousal in Focal Seizures Neuron 2015, 85: 561-572. PMID: 25654258, PMCID: PMC4319118, DOI: 10.1016/j.neuron.2014.12.058.
- Physiological Basis of BOLD fMRI DecreasesKim R, Hyder F, Blumenfeld H. Physiological Basis of BOLD fMRI Decreases 2014, 88: 221-236. DOI: 10.1007/978-1-4939-0724-3_11.
- Chapter 33 Future Trends in Neuronal Networks—Selective and Combined Targeting of Network HubsFaingold C, Blumenfeld H. Chapter 33 Future Trends in Neuronal Networks—Selective and Combined Targeting of Network Hubs 2014, 467-485. DOI: 10.1016/b978-0-12-415804-7.00033-2.
- Chapter 6 Network ImagingGuo J, Blumenfeld H. Chapter 6 Network Imaging 2014, 77-89. DOI: 10.1016/b978-0-12-415804-7.00006-x.
- Chapter 21 Consciousness and Subcortical Arousal SystemsMotelow J, Blumenfeld H. Chapter 21 Consciousness and Subcortical Arousal Systems 2014, 277-298. DOI: 10.1016/b978-0-12-415804-7.00021-6.
- DedicationsFaingold C, Blumenfeld H. Dedications 2014, i. DOI: 10.1016/b978-0-12-415804-7.03001-x.
- Chapter 1 Introduction to Neuronal Networks of the BrainFaingold C, Blumenfeld H. Chapter 1 Introduction to Neuronal Networks of the Brain 2014, 1-10. DOI: 10.1016/b978-0-12-415804-7.00001-0.
- Temporal Lobe SeizuresFurman M, Blumenfeld H. Temporal Lobe Seizures 2013, 51-62. DOI: 10.1007/978-3-642-37580-4_4.
- Impaired consciousness in epilepsyBlumenfeld H. Impaired consciousness in epilepsy The Lancet Neurology 2012, 11: 814-826. PMID: 22898735, PMCID: PMC3732214, DOI: 10.1016/s1474-4422(12)70188-6.
- Where fMRI and Electrophysiology Agree to Disagree: Corticothalamic and Striatal Activity Patterns in the WAG/Rij RatMishra AM, Ellens DJ, Schridde U, Motelow JE, Purcaro MJ, DeSalvo MN, Enev M, Sanganahalli BG, Hyder F, Blumenfeld H. Where fMRI and Electrophysiology Agree to Disagree: Corticothalamic and Striatal Activity Patterns in the WAG/Rij Rat Journal Of Neuroscience 2011, 31: 15053-15064. PMID: 22016539, PMCID: PMC3432284, DOI: 10.1523/jneurosci.0101-11.2011.
- The Default Mode Network and Altered Consciousness in EpilepsyDanielson N, Guo J, Blumenfeld H. The Default Mode Network and Altered Consciousness in Epilepsy Behavioural Neurology 2011, 24: 55-65. DOI: 10.1155/2011/912720.
- Impaired consciousness in temporal lobe seizures: role of cortical slow activityEnglot DJ, Yang L, Hamid H, Danielson N, Bai X, Marfeo A, Yu L, Gordon A, Purcaro MJ, Motelow JE, Agarwal R, Ellens DJ, Golomb JD, Shamy MC, Zhang H, Carlson C, Doyle W, Devinsky O, Vives K, Spencer DD, Spencer SS, Schevon C, Zaveri HP, Blumenfeld H. Impaired consciousness in temporal lobe seizures: role of cortical slow activity Brain 2010, 133: 3764-3777. PMID: 21081551, PMCID: PMC2995886, DOI: 10.1093/brain/awq316.
- Dynamic Time Course of Typical Childhood Absence Seizures: EEG, Behavior, and Functional Magnetic Resonance ImagingBai X, Vestal M, Berman R, Negishi M, Spann M, Vega C, Desalvo M, Novotny EJ, Constable RT, Blumenfeld H. Dynamic Time Course of Typical Childhood Absence Seizures: EEG, Behavior, and Functional Magnetic Resonance Imaging Journal Of Neuroscience 2010, 30: 5884-5893. PMID: 20427649, PMCID: PMC2946206, DOI: 10.1523/jneurosci.5101-09.2010.
- Pathophysiology of Absence SeizuresVestal M, Blumenfeld H. Pathophysiology of Absence Seizures 2010, 225-234. DOI: 10.1007/978-1-84882-128-6_30.
- EEG–fMRI in Animal ModelsEllens D, Blumenfeld H. EEG–fMRI in Animal Models 2009, 485-509. DOI: 10.1007/978-3-540-87919-0_24.
- A Clinical Guide to Epileptic Syndromes and their Treatment, second ed., C.P. Panayiotopoulos, Springer, New York, 2007. 578 pp, US$90, Hard cover and colored. ISBN: 978-1-84628-643-8.Blumenfeld H. A Clinical Guide to Epileptic Syndromes and their Treatment, second ed., C.P. Panayiotopoulos, Springer, New York, 2007. 578 pp, US$90, Hard cover and colored. ISBN: 978-1-84628-643-8. Epilepsy & Behavior 2009, 15: 263. DOI: 10.1016/j.yebeh.2009.03.023.
- Brain imaging and electroconvulsive therapyPeng K, Blumenfeld H. Brain imaging and electroconvulsive therapy 2009, 94-108. DOI: 10.1017/cbo9780511576393.006.
- CHAPTER 19 Epilepsy and ConsciousnessBlumenfeld H. CHAPTER 19 Epilepsy and Consciousness 2009, 247-260. DOI: 10.1016/b978-0-12-374168-4.00019-8.
- IMAGING | SPECT in Epilepsy ResearchPurcaro M, Blumenfeld H. IMAGING | SPECT in Epilepsy Research 2009, 558-564. DOI: 10.1016/b978-012373961-2.00024-2.
- IMAGING | Functional MRI in Basic Epilepsy ResearchEnglot D, Blumenfeld H. IMAGING | Functional MRI in Basic Epilepsy Research 2009, 539-544. DOI: 10.1016/b978-012373961-2.00023-0.
- CHAPTER 2 The Neurological Examination of ConsciousnessBlumenfeld H. CHAPTER 2 The Neurological Examination of Consciousness 2009, 15-30. DOI: 10.1016/b978-0-12-374168-4.00002-2.
- Contributor's ListBerkovic S, Bilguvar K, Blackstone C, Bloch M, Blumenfeld H, Bredesen D, Bressman S, Brucal M, Burton E, Dalmau J, Dawson T, Dawson V, Depondt C, DiLuna M, DiMauro S, Ferrari M, Fink D, Flügel A, Frants R, Glorioso J, Goadsby P, Goldin A, Gunel M, Harel N, Helbig I, Hemmen T, Hisama F, Hyman B, Ingelsson M, Johnson D, Kamholz J, Kaul M, Kocsis J, Lammers G, Leckman J, Li J, Lipton S, Maragakis N, Mehlen P, Morimoto R, Orton K, Overeem S, Ozelius L, Pandolfo M, Pascual J, Paulson H, Peroutka S, Petroff O, Ransom C, Rao R, Rismanchi N, Rothstein J, Savitt J, Scheffer I, Schon E, Shy M, Strittmatter S, Tafti M, Tanriover G, Todi S, van den Maagdenberg A, Vance J, Vincent A, Voisine C, Waxman S, Wekerle H, Williams A, Wood J, Yang Y, Zivin J. Contributor's List 2007, vii-ix. DOI: 10.1016/b978-012369509-3.50001-9.
- 23 Acquired Epilepsy: Cellular and Molecular MechanismsRansom C, Blumenfeld H. 23 Acquired Epilepsy: Cellular and Molecular Mechanisms 2007, 347-370. DOI: 10.1016/b978-012369509-3.50025-1.
- CORRELATION OF MAGNETIC RESONANCE SPECTROSCOPIC IMAGING AND INTRACRANIAL EEG LOCALIZATION OF SEIZURESNovotny E, Scharff E, Zaveri H, Papademetris X, Blumenfeld H, Duckrow R, Hetherington H, Spencer S, Spencer D, Duncan J. CORRELATION OF MAGNETIC RESONANCE SPECTROSCOPIC IMAGING AND INTRACRANIAL EEG LOCALIZATION OF SEIZURES Neuropediatrics 2006, 37 DOI: 10.1055/s-2006-945791.
- Development of a Research Interface for Image Guided Intervention: Initial Application to Epilepsy NeurosurgeryPapademetris X, Vives K, DiStasio M, Staib L, Neff M, Flossman S, Frielinghaus N, Zaveri H, Novotny E, Blumenfeld H, Constable R, Hetherington H, Duckrow R, Spencer S, Spencer D, Duncan J. Development of a Research Interface for Image Guided Intervention: Initial Application to Epilepsy Neurosurgery 2006, 490-493. DOI: 10.1109/isbi.2006.1624960.
- Correlation of Magnetic Resonance Spectroscopic Imaging and Intracranial Eeg Localization of SeizuresScharff E, Papademetris X, Hetherington H, Pan J, Zaveri H, Blumenfeld H, Duckrow R, Spencer S, Spencer D, Duncan J, Novotny E. Correlation of Magnetic Resonance Spectroscopic Imaging and Intracranial Eeg Localization of Seizures 2006, 510-513. DOI: 10.1109/isbi.2006.1624965.
- Relationship between CMRO2 and Neuronal ActivityHyder F, Blumenfeld H. Relationship between CMRO2 and Neuronal Activity 2005, 173-194. DOI: 10.1002/0470020520.ch10.
- Neural basis of localized and delocalized fMRI patternsMaandag N, Smith A, Blumenfeld H, Shulman R, Hyder F. Neural basis of localized and delocalized fMRI patterns Cerebrovascular And Brain Metabolism Reviews 2005, 25: s383-s383. DOI: 10.1038/sj.jcbfm.9591524.0383.
- High resolution measurements of neuronal activity, cerebral blood flow, and fMRI during spike-wave seizures in WAG/Rij ratsBlumenfeld H, Nersesyan H, Khubchandani M, Schridde U, Berman R, Rothman D, Hyder F. High resolution measurements of neuronal activity, cerebral blood flow, and fMRI during spike-wave seizures in WAG/Rij rats Cerebrovascular And Brain Metabolism Reviews 2005, 25: s409-s409. DOI: 10.1038/sj.jcbfm.9591524.0409.
- Cellular Physiology of Status EpilepticusHope O, Blumenfeld H. Cellular Physiology of Status Epilepticus 2005, 159-180. DOI: 10.1385/1-59259-945-1:159.
- Quantitative fMRI of rat brain by multi-modal MRI and MRS measurementsHyder F, Kida I, Smith A, Blumenfeld H, Shulman R, Rothman D. Quantitative fMRI of rat brain by multi-modal MRI and MRS measurements International Congress Series 2002, 1235: 57-71. DOI: 10.1016/s0531-5131(02)00173-5.
- Corticothalamic Inputs Control the Pattern of Activity Generated in Thalamocortical NetworksBlumenfeld H, McCormick D. Corticothalamic Inputs Control the Pattern of Activity Generated in Thalamocortical Networks Journal Of Neuroscience 2000, 20: 5153-5162. PMID: 10864972, PMCID: PMC6772273, DOI: 10.1523/jneurosci.20-13-05153.2000.
- Facilitatory and inhibitory transmitters modulate calcium influx during action potentials in Aplysia sensory neuronsBlumenfeld H, Spiral M, Kandel E, Siegelbaum S. Facilitatory and inhibitory transmitters modulate calcium influx during action potentials in Aplysia sensory neurons Neuron 1990, 5: 487-499. PMID: 1976321, DOI: 10.1016/0896-6273(90)90088-w.
|Diseases of the Nervous System; Mental Health & Behavioral Research||Human Epilepsy Project 3: Newly Diagnosed Idiopathic Generalized Epilepsy|
|Diseases of the Cardiovascular System||Multimodal Outcome CHAracterization (MOCHA) in comatose cardiac arrest patients|