Gustav Klimt. Portrait of Adele Bloch-Bauer

The Neuronal Mechanisms of Consciousness

What consciousness is and how it works has been intensely debated for millennia but is now accessible to modern tools of neuroscience. We are contributing to this exciting new field of research using a set of visual and auditory perceptual behavioral tasks coupled with a series of recording techniques, including pupillometry, fMRI, intracranial EEG and high-density surface EEG. These experimental methods offer insights to where and when the human brain is active during conscious perception. This work has important clinical implications particularly for the diagnosis and treatment of patients that experience abnormal conscious states, including epilepsy, vegetative/minimally conscious states, and psychiatric disorders.

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Impaired Consciousness in Childhood 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.

Increased resting functional connectivity in spike-wave epilepsy in WAG/Rij rats.
Mishra AM, Bai X, Motelow JE, Desalvo MN, Danielson N, Sanganahalli BG, Hyder F, Blumenfeld H.
Epilepsia. 2013 Jul;54(7):1214-22.

Resting functional connectivity between the hemispheres in childhood absence epilepsy.
Bai X, Guo J, Killory B, Vestal M, Berman R, Negishi M, Danielson N, Novotny EJ, Constable RT, Blumenfeld H.
Neurology. 2011 Jun 7;76(23):1960-7.

Symptoms of anxiety and depression in childhood absence epilepsy.
Vega C, Guo J, Killory B, Danielson N, Vestal M, Berman R, Martin L, Gonzalez JL,
Blumenfeld H, Spann MN.
Epilepsia. 2011 Aug;52(8):e70-4.

The default mode network and altered consciousness in epilepsy.
Danielson NB, Guo JN, Blumenfeld H.
Behav Neurol. 2011 Jan 1;24(1):55-65.

Impaired attention and network connectivity in childhood absence epilepsy.
Killory BD, Bai X, Negishi M, Vega C, Spann MN, Vestal M, Guo J, Berman R, Danielson N, Trejo J, Shisler D, Novotny EJ Jr, Constable RT, Blumenfeld H.
Neuroimage. 2011 Jun 15;56(4):2209-17.

Differentiation of attention-related problems in childhood absence epilepsy.
Vega C, Vestal M, DeSalvo M, Berman R, Chung M, Blumenfeld H, Spann MN.
Epilepsy Behav. 2010 Sep;19(1):82-5.

Simultaneous EEG, fMRI, and behavior in typical childhood absence seizures.
Berman R, Negishi M, Vestal M, Spann M, Chung MH, Bai X, Purcaro M, Motelow JE, Danielson N, Dix-Cooper L, Enev M, Novotny EJ, Constable RT, Blumenfeld H.
Epilepsia. 2010 Oct;51(10):2011-22.

Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging.
Bai X, Vestal M, Berman R, Negishi M, Spann M, Vega C, Desalvo M, Novotny EJ, Constable RT, Blumenfeld H.
J Neurosci. 2010 Apr 28;30(17):5884-93.

Consciousness and epilepsy: why are patients with absence seizures absent?
Blumenfeld H.
Prog Brain Res. 2005;150:271-86.

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.

Restoring Conscious Arousal During Focal Limbic Seizure with Deep Brain Stimulation.
Kundishora AJ, Gummadavelli A, Ma C, Liu M, McCafferty C, Schiff D, Gerrard J, Blumenfeld, H.
Cereb Cortex. 2017 Mar 1;27(3):1964-1975.

Impaired Serotonergic Brainstem Function during and after Seizures.
Zhan Q, Buchanan GF, Motelow JE, Andrews J, Vitkovskiy P, Chen WC, Serout F, Gummadavelli A, Kundishora A, Furman M, Li W, Bo X, Richerson GB, Blumenfeld H.
J Neurosci. 2016 Mar 2;36(9):2711-22.

Decreased subcortical cholinergic arousal in focal seizures.
Motelow 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.
Neuron. 2015 Feb 4;85(3):561-72.

Thalamic stimulation to improve level of consciousness after seizures: evaluation of electrophysiology and behavior.
Gummadavelli A, Motelow JE, Smith N, Zhan Q, Schiff ND, Blumenfeld H.
Epilepsia. 2015 Jan;56(1):114-24

Impaired consciousness in temporal lobe seizures: role of cortical slow activity.
Englot 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.
Brain. 2010 Dec;133(Pt 12):3764-77.

Cortical deactivation induced by subcortical network dysfunction in limbic seizures.
Englot DJ, Modi B, Mishra AM, DeSalvo M, Hyder F, Blumenfeld H.
J Neurosci. 2009 Oct 14;29(41):13006-18.

Consciousness and epilepsy: why are complex-partial seizures complex?
Englot DJ, Blumenfeld H.
Prog Brain Res. 2009;177:147-70.

Theories of impaired consciousness in epilepsy.
Yu L, Blumenfeld H.
Ann N Y Acad Sci. 2009 Mar;1157:48-60.

Remote effects of focal hippocampal seizures on the rat neocortex.
Englot DJ, Mishra AM, Mansuripur PK, Herman P, Hyder F, Blumenfeld H.
J Neurosci. 2008 Sep 3;28(36):9066-81. Erratum in: J Neurosci. 2009 Mar 25;29(12):3969.

Ictal neocortical slowing in temporal lobe epilepsy.
Blumenfeld H, Rivera M, McNally KA, Davis K, Spencer DD, Spencer SS.
Neurology. 2004 Sep 28;63(6):1015-21.

Positive and negative network correlations in temporal lobe epilepsy.
Blumenfeld H, McNally KA, Vanderhill SD, Paige AL, Chung R, Davis K, Norden AD, Stokking R, Studholme C, Novotny EJ Jr, Zubal IG, Spencer SS.
Cereb Cortex. 2004 Aug;14(8):892-902.

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 so called 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.

Where fMRI and Electrophysiology Agree to Disagree: Corticothalamic and Striatal Activity Patterns in the WAG/Rij Rat.
Mishra AM, Ellens DJ, Schridde U, Motelow JE, Purcaro MJ, Desalvo MN, Enev M, Sanganahalli BG, Hyder F, Blumenfeld H.
J Neurosci. 2011 Oct 19;31(42):15053-64.

Neurovascular and Neurometabolic Couplings in Dynamic Calibrated fMRI: Transient Oxidative Neuroenergetics for Block-Design and Event-Related Paradigms.
Hyder F, Sanganahalli BG, Herman P, Coman D, Maandag NJ, Behar KL, Blumenfeld H, Rothman DL.
Front Neuroenergetics. 2010 Aug 19;2. pii: 18.

Focal BOLD fMRI changes in bicuculline-induced tonic-clonic seizures in the rat.
DeSalvo MN, Schridde U, Mishra AM, Motelow JE, Purcaro MJ, Danielson N, Bai X, Hyder F, Blumenfeld H.
Neuroimage. 2010 Apr 15;50(3):902-9.

Cerebral oxygen demand for short-lived and steady-state events.
Herman P, Sanganahalli BG, Blumenfeld H, Hyder F.
J Neurochem. 2009 May;109 Suppl 1:73-9.

Cortical and subcortical networks in human secondarily generalized tonic-clonic seizures.
Blumenfeld H, Varghese GI, Purcaro MJ, Motelow JE, Enev M, McNally KA, Levin AR, Hirsch LJ, Tikofsky R, Zubal IG, Paige AL, Spencer SS.
Brain. 2009 Apr;132(Pt 4):666-1012.

Oxidative neuroenergetics in event-related paradigms.
Sanganahalli BG, Herman P, Blumenfeld H, Hyder F.
J Neurosci. 2009 Feb 11;29(6):1707-18.

Functional neuroimaging of spike-wave seizures.
Motelow JE, Blumenfeld H.
Methods Mol Biol. 2009;489:189-209.

Energetics of neuronal signaling and fMRI activity.
Maandag NJ, Coman D, Sanganahalli BG, Herman P, Smith AJ, Blumenfeld H, Shulman RG, Hyder F.
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20546-51.

Negative BOLD with large increases in neuronal activity.
Schridde U, Khubchandani M, Motelow JE, Sanganahalli BG, Hyder F, Blumenfeld H.
Cereb Cortex. 2008 Aug;18(8):1814-27.

Functional MRI studies of animal models in epilepsy.
Blumenfeld H.
Epilepsia. 2007;48 Suppl 4:18-26.

Imaging onset and propagation of ECT-induced seizures.
Enev M, McNally KA, Varghese G, Zubal IG, Ostroff RB, Blumenfeld H.
Epilepsia. 2007 Feb;48(2):238-44.

Cellular and network mechanisms of spike-wave seizures.
Blumenfeld H.
Epilepsia. 2005;46 Suppl 9:21-33.

Lamotrigine suppresses neurophysiological responses to somatosensory stimulation in the rodent.
Kida I, Smith AJ, Blumenfeld H, Behar KL, Hyder F.
Neuroimage. 2006 Jan 1;29(1):216-24.

Relative changes in cerebral blood flow and neuronal activity in local microdomains during generalized seizures.
Nersesyan H, Herman P, Erdogan E, Hyder F, Blumenfeld H.
J Cereb Blood Flow Metab. 2004 Sep;24(9):1057-68.

Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats.
Nersesyan H, Hyder F, Rothman DL, Blumenfeld H.
J Cereb Blood Flow Metab. 2004 Jun;24(6):589-99.

Focal network involvement in generalized seizures: new insights from electroconvulsive therapy.
McNally KA, Blumenfeld H.
Epilepsy Behav. 2004 Feb;5(1):3-12.

Why do seizures cause loss of consciousness?
Blumenfeld H, Taylor J.
Neuroscientist. 2003 Oct;9(5):301-10.

Selective frontal, parietal, and temporal networks in generalized seizures.
Blumenfeld H, Westerveld M, Ostroff RB, Vanderhill SD, Freeman J, Necochea A, Uranga P, Tanhehco T, Smith A, Seibyl JP, Stokking R, Studholme C, Spencer SS, Zubal IG.
Neuroimage. 2003 Aug;19(4):1556-66.

Targeted prefrontal cortical activation with bifrontal ECT.
Blumenfeld H, McNally KA, Ostroff RB, Zubal IG.
Psychiatry Res. 2003 Jul 30;123(3):165-70.

From molecules to networks: cortical/subcortical interactions in the pathophysiology of idiopathic generalized epilepsy.
Blumenfeld H.
Epilepsia. 2003;44 Suppl 2:7-15.

The role of subcortical structures in human epilepsy.
Norden AD, Blumenfeld H.
Epilepsy Behav. 2002 Jun;3(3):219-231.

Cerebral energetics and spiking frequency: the neurophysiological basis of fMRI.
Smith AJ, Blumenfeld H, Behar KL, Rothman DL, Shulman RG, Hyder F.
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10765-70.

Virtual Reality Driving and other Bedside Testing 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.

Human bedside evaluation versus automatic responsiveness in epilepsy (ARTiE).
Touloumes G, Morse E, Chen WC, Dente J, Lilenbaum R, Katzenstein E, Pacelli A, Johnson E, Si Y, Sivaraju A, Grover E, Khozein R, Cunningham C, Hirsch LJ, Blumenfeld H. 
Bauerschmidt A, Koshkelashvili N, Ezeani CC, Yoo JY, Zhang Y, Manganas LN, Kapadia K, Palenzuela D, Schmidt CC, Lief R, Kiely BT, Choezom T, McClurkin M, Shorten A, Detyniecki K, Hirsch LJ, Giacino JT, Blumenfeld H.
Epilepsy Behav. 2013 Jan;26(1):25-8. 

Testing for minimal consciousness in complex partial and generalized tonic-clonic seizures.
McPherson A, Rojas L, Bauerschmidt A, Ezeani CC, Yang L, Motelow JE, Farooque P, Detyniecki K, Giacino JT, Blumenfeld H.
Epilepsia. 2012 Oct;53(10):e180-3.

Impaired consciousness in epilepsy investigated by a prospective responsiveness in epilepsy scale (RES).
Yang L, Shklyar I, Lee HW, Ezeani CC, Anaya J, Balakirsky S, Han X, Enamandram S, Men C, Cheng JY, Nunn A, Mayer T, Francois C, Albrecht M, Hutchison AL, Yap EL, Ing K, Didebulidze G, Xiao B, Hamid H, Farooque P, Detyniecki K, Giacino JT, Blumenfeld H.
Epilepsia. 2012 Mar;53(3):437-47.

A prospective study of loss of consciousness in epilepsy using virtual reality driving simulation and other video games.
Yang L, Morland TB, Schmits K, Rawson E, Narasimhan P, Motelow JE, Purcaro MJ, Peng K, Raouf S, Desalvo MN, Oh T, Wilkerson J, Bod J, Srinivasan A, Kurashvili P, Anaya J, Manza P, Danielson N, Ransom CB, Huh L, Elrich S, Padin-Rosado J, Naidu Y, Detyniecki K, Hamid H, Farooque P, Astur R, Xiao B, Duckrow RB, Blumenfeld H.
Epilepsy Behav. 2010 Jul;18(3):238-46.

Technical Advances in Epilepsy Surgery Localization

In some patients, seizures are so severe that they cannot be controlled by medicines. Many of these patients can be cured if we identify a damaged brain region to remove safely and prevent the triggering of their seizures. We have recently developed two novel approaches to target surgery to the correct location in the brain: 

  • 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. 
  • Innovative methods using single photon emission computed tomography (SPECT) and positron emission tomography (PET) tracers can pinpoint the region for surgical planning.

Seizure localization using three-dimensional surface projections of intracranial EEG power.
Lee HW, Youngblood MW, Farooque P, Han X, Jhun S, Chen WC, Goncharova I, Vives K, Spencer DD, Zaveri H, Hirsch LJ, Blumenfeld H.
Neuroimage. 2013 Dec;83:616-26.

Intracranial EEG surface renderings: new insights into normal and abnormal brain function.
Youngblood MW, Han X, Farooque P, Jhun S, Bai X, Yoo JY, Lee HW, Blumenfeld H.
Neuroscientist. 2013 Jun;19(3):238-47.

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empty empty empty New open-source ictal SPECT analysis method implemented in BioImage Suite.
Scheinost D, Teisseyre TZ, Distasio M, DeSalvo MN, Papademetris X, Blumenfeld H.
Epilepsia. 2010 Apr;51(4):703-7.

An improved unbiased method for diffSPECT quantification in epilepsy.
Scheinost D, Blumenfeld H, Papademetris X.
Proc IEEE Int Symp Biomed Imaging. 2009 Jun 1;2009:927-930.

Clinical use of ictal SPECT in secondarily generalized tonic-clonic seizures.
Varghese GI, Purcaro MJ, Motelow JE, Enev M, McNally KA, Levin AR, Hirsch LJ, Tikofsky R, Paige AL, Zubal IG, Spencer SS, Blumenfeld H.
Brain. 2009 Aug;132(Pt 8):2102-13.

Evaluating the accuracy of perfusion/metabolism (SPET/PET) ratio in seizure localization.
Buch K, Blumenfeld H, Spencer S, Novotny E, Zubal IG.
Eur J Nucl Med Mol Imaging. 2008 Mar;35(3):579-88.

Localizing value of ictal-interictal SPECT analyzed by SPM (ISAS).
McNally KA, Paige AL, Varghese G, Zhang H, Novotny EJ Jr, Spencer SS, Zubal IG, Blumenfeld H.
Epilepsia. 2005 Sep;46(9):1450-64.

Comparison of statistical parametric mapping and SPECT difference imaging in patients with temporal lobe epilepsy.
Chang DJ, Zubal IG, Gottschalk C, Necochea A, Stokking R, Studholme C, Corsi M, Slawski J, Spencer SS, Blumenfeld H.
Epilepsia. 2002 Jan;43(1):68-74.

Preventing Epilepsy

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.

Anti-epileptogenesis: Electrophysiology, diffusion tensor imaging and behavior in a genetic absence model.
van Luijtelaar G, Mishra AM, Edelbroek P, Coman D, Frankenmolen N, Schaapsmeerders P, Covolato G, Danielson N, Niermann H, Janeczko K, Kiemeneij A, Burinov J, Bashyal C, Coquillette M, Lüttjohann A, Hyder F, Blumenfeld H, van Rijn CM.
Neurobiol Dis. 2013 Dec;60:126-38.

Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy.
Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O'Brien TJ, Jones NC.
Epilepsia. 2013 Apr;54(4):635-43.

New strategies for preventing epileptogenesis: perspective and overview.
Blumenfeld H.
Neurosci Lett. 2011 Jun 27;497(3):153-4.

Neuroimaging biomarkers of epileptogenesis.
Mishra AM, Bai H, Gribizis A, Blumenfeld H.
Neurosci Lett. 2011 Jun 27;497(3):194-204.

Is epilepsy a preventable disorder? New evidence from animal models.
Giblin KA, Blumenfeld H.
Neuroscientist. 2010 Jun;16(3):253-75.

Increased seizure severity and seizure-related death in mice lacking HCN1 channels.
Santoro B, Lee JY, Englot DJ, Gildersleeve S, Piskorowski RA, Siegelbaum SA, Winawer MR, Blumenfeld H.
Epilepsia. 2010 Aug;51(8):1624-7.

LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology.
Owuor K, Harel NY, Englot DJ, Hisama F, Blumenfeld H, Strittmatter SM.
Mol Cell Neurosci. 2009 Dec;42(4):448-57.

Separating kindling and LTP: lessons from studies of PKM zeta in developing and adult rats.
Heida JG, Englot DJ, Sacktor TC, Blumenfeld H, Moshé SL.
Neurosci Lett. 2009 Apr 10;453(3):229-32.

Development of spike-wave seizures in C3H/HeJ mice.
Ellens DJ, Hong E, Giblin K, Singleton MJ, Bashyal C, Englot DJ, Mishra AM, Blumenfeld H.
Epilepsy Res. 2009 Jul;85(1):53-9.

DTI abnormalities in anterior corpus callosum of rats with spike-wave epilepsy.
Chahboune H, Mishra AM, DeSalvo MN, Staib LH, Purcaro M, Scheinost D, Papademetris X, Fyson SJ, Lorincz ML, Crunelli V, Hyder F, Blumenfeld H.
Neuroimage. 2009 Aug 15;47(2):459-66.

Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis.
Blumenfeld H, Lampert A, Klein JP, Mission J, Chen MC, Rivera M, Dib-Hajj S, Brennan AR, Hains BC, Waxman SG.
Epilepsia. 2009 Jan;50(1):44-55.

Early treatment suppresses the development of spike-wave epilepsy in a rat model.
Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS, Bashyal C, Giblin K, Paul-Laughinghouse C, Wang F, Phadke A, Mission J, Agarwal RK, Englot DJ, Motelow J, Nersesyan H, Waxman SG, Levin AR.
Epilepsia. 2008 Mar;49(3):400-9.

Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy.
Klein JP, Khera DS, Nersesyan H, Kimchi EY, Waxman SG, Blumenfeld H.
Brain Res. 2004 Mar 12;1000(1-2):102-9.