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l id i l b i i j d h bj tzolpidem in a severely brain injured human subjectzolpidem in a severely brain-injured human subjectzolpidem in a severely brain injured human subjectp y j jS 1 C 1 1 2 1 S ff1S T Williams1 M M Conte1 E J Kobylarz1 J E Hersh2 J D Victor1 N D Schiff1S T Williams1 M M Conte1 E J Kobylarz1 J E Hersh2 J D Victor1 N D Schiff1S. T. Williams , M. M. Conte , E. J. Kobylarz , J. E. Hersh , J. D. Victor , N. D. Schiff, , y , , ,

1D t t f N l d N i d 2D t t f P bli H lth W ill C ll M di l C ll N Y k NY1Department of Neurology and Neuroscience and 2Department of Public Health Weill Cornell Medical College New York NYDepartment of Neurology and Neuroscience and Department of Public Health, Weill Cornell Medical College, New York, NYp gy p , g , ,

PURPOSE Pl h ldMETHODSPURPOSE PlaceholderMETHODSPURPOSE PlaceholderMETHODS• 24 hr continuous video EEGData Collection & AnalysisTo explore the spectral and coherence characteristics of the Subject• 24 hr continuous video EEGData Collection & AnalysisTo explore the spectral and coherence characteristics of the Subject

• 200Hz sampling rate

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paradoxical arousal response to zolpidem after severe brain injury

j32 ld l d i 9 i• 200Hz sampling rate• Single subject, unblinded studyparadoxical arousal response to zolpidem after severe brain injury. • 32 year old male, near drowning 9 years prior

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S h i b i i j MCS f 2• Longitudinal bipolar montage (International 10-20 system)• Subject admitted to inpatient neurology unit • Severe hypoxic brain injury; MCS for >2 years• XLTEK data acquisition system (XLTEK Ontario)

Subject admitted to inpatient neurology unit Severe hypoxic brain injury; MCS for 2 yearsXLTEK data acquisition system (XLTEK, Ontario)

• Maintained home zolpidem doseBACKGROUND • MRI: Left thalamic lesion• Two- and three-second EEG segments with minimal artifact

Maintained home zolpidem doseBACKGROUND MRI: Left thalamic lesion

Overview:• Two- and three-second EEG segments with minimal artifact

• 10mg crushed in solution by mouth via syringeBACKGROUND

• Arousal response to zolpidem discovered incidentally by motherOverview:identified

10mg crushed, in solution by mouth via syringe • Arousal response to zolpidem discovered incidentally by mother

Zolpidem is commonly used to induce sleep in healthy adultsidentified• Every 3-5 hours during day• Zolpidem is commonly used to induce sleep in healthy adults.

• Power & coherence spectra estimated using five SlepianEvery 3 5 hours during day

18FDG PET OFF d ON l idp y p y

P d i l l b d i b i i j d• Power & coherence spectra estimated using five Slepian• 18FDG-PET OFF and ON zolpidem• Paradoxical arousal response observed in some brain-injured

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f ti t 7FDG PET OFF and ON zolpidem

Sample EEG Segments Selected for Analysis. Observed BehaviorObserved BehaviorZolpidem 10mg dosesParadoxical arousal response observed in some brain injured

ti t th h i l i l b i f hi h i kfunctions as tapers7Sample EEG Segments Selected for Analysis.

Red = Hour before dose Blue = Hour after dose Observed BehaviorObserved BehaviorZolpidem 10mg dosesD f hi h ltpatients the physiological basis for which is unknown

functions as tapersRed = Hour before dose, Blue = Hour after dose.

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Observed BehaviorObserved BehaviorDoses for which results

t di l dpatients, the physiological basis for which is unknown. ONOFFOFF Z l id ON Z l id

are not displayed

• Prior study in akinetic mute patient shows increased metabolism in TimelineOFF

OFF Zolpidem ON Zolpidem• Prior study in akinetic mute patient shows increased metabolism in Timeline OFF ZolpidemAO 2 ( lf l ti )

ON ZolpidemI d b l fl & i l imedial frontal cortex thalami and postrolandic regions after Ad t EEG di B f d

AOx2 (self, location) Improved verbal fluency & articulation08:10 08:29medial frontal cortex, thalami and postrolandic regions after Adequate EEG recordings Before andAOx2 (self, location)

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Video EEG Recordingsp g

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After olpidem administration ereDysarthria Shortened latency of motor responses10:00 16:24

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Video EEG Recordings

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• No study to date compares EEG & PET characteristics of the available for Days 2,3 and 5y p g

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arousal response to zolpidem in severe brain injury in humansy

LUE: flexor posturingp y

Smooth goal directed movementsDay 1 Day 2 Day 3 Day 4 Day 5 Day 6arousal response to zolpidem in severe brain injury in humans. LUE: flexor posturing Smooth, goal-directed movementsDay 1 Day 2 Day 3 Day 4 Day 5 Day 6

Ab t B i I j RUE: 1-1 5Hz resting tremor Elimination of resting tremorAbout Brain Injury: RUE: 1-1.5Hz resting tremor Elimination of resting tremor00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00About Brain Injury:

2 LLE & RLE: extensor posturing Object manipulation00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00 08:00 16:00 00:00

• Over 1 4 million cases annually 2 LLE & RLE: extensor posturing Object manipulation Over 1.4 million cases annually.

RESULTS (pen spoon baseball)• Etiologies: head trauma cerebrovascular events seizure RESULTS (pen, spoon, baseball)• Etiologies: head trauma, cerebrovascular events, seizure, RESULTS

cardiopulmonary insufficiency intracranial masses infectious orcardiopulmonary insufficiency, intracranial masses, infectious or p y y, ,

inflammatory diseases metabolic disorders toxic ingestionsinflammatory diseases, metabolic disorders, toxic ingestions. Power Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidem Power Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidem Power Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemy , , g

R f i ti ft i j i t l 3 Power Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidem Power Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidem Power Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & AfterPower Spectra: Before & After ZolpidemZolpidem• Recovery of communication years after injury is extremely rare.3

Power Spectra: Before & After Power Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & After Power Spectra: Before & After ZolpidemZolpidem Power Spectra: Before & After Power Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & After Power Spectra: Before & After ZolpidemZolpidem Power Spectra: Before & After Power Spectra: Before & After ZolpidemZolpidemPower Spectra: Before & After Power Spectra: Before & After ZolpidemZolpidemRecovery of communication years after injury is extremely rare.

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H lf lif 2 4 h (i h lth bj t )5• Half life = 2 4 hours (in healthy subjects)5 Average % PowerAverage % PowerHalf life 2.4 hours (in healthy subjects) Average % Power Average % Power

Ab t EEG P & C h S t DISCUSSION Decrease at 7 67HzDecrease at 7 67HzAbout EEG Power & Coherence Spectra: DISCUSSION Decrease at 7.67HzDecrease at 7.67HzAbout EEG Power & Coherence Spectra:

C hC hDISCUSSION

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• Power spectra used to estimate the relative contributions of each CoherenceCoherence Findings Possible Mechanisms100%

Power spectra used to estimate the relative contributions of each CoherenceCoherence Findings Possible Mechanisms cortex 71%80%

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OFF Z l id A ibl h i l i l b i f th h i EEGcortex 71%

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• May be used to establish prognosis after severe brain injury6• Narrow aberrant EEG spectral peaks in 7 11Hz of thalamocortical outflow

striatumMay be used to establish prognosis after severe brain injury • Narrow, aberrant EEG spectral peaks in 7-11Hz of thalamocortical outflow. 0%

range globally ti tiglobus F3-C3 T5-O1 Fz-Cz Cz-Pz F4-C4 T6-O2range globally As a GABA-A1 agonist zolpidem may inhibit theactivationglobus F3 C3 T5 O1 Fz Cz Cz Pz F4 C4 T6 O2

PET I OFF d ONPET I OFF d ON Z l idZ l idg g y

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PET Images OFF and ONPET Images OFF and ON ZolpidemZolpidem • Intermittent spectral peaks at 70-80Hz GABA sensitive neurons of the globus pallidus interna zolpidemzolpidem??pallidus

internaThe bars represent the mean percent decrease in

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Global metabolism increased ~2 fold The OFF state low frequency peak (at 7-11Hz) may and upregulating cortico-striato-pallido-thalamo-corticalGlobal metabolism increased 2 fold. The OFF state low frequency peak (at 7 11Hz) may

l h l i di i h i i h i

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k ( fi ) 8 10 A di ff i l REFERENCEScorrelate to pathologic conditions: hypoxic-ischemic networks (see figure) 8-10 A direct effect on cortical REFERENCES% Change in correlate to pathologic conditions: hypoxic ischemic networks (see figure). A direct effect on cortical

1 Brefel-Courbon C Payoux P Ory F Sommet A Slaoui T Raboyeau G Lemesle B Puel M Montastruc JL Demonet JF Cardebat D Clinical and Imaging Evidence of Zolpidem Effect in% Change in encephalopathy alpha coma thalamic deafferentation inhibitory interneuronal networks likely also contributes

1. Brefel Courbon C, Payoux P, Ory F, Sommet A, Slaoui T, Raboyeau G, Lemesle B, Puel M, Montastruc JL, Demonet JF, Cardebat D. Clinical and Imaging Evidence of Zolpidem Effect in

Hypoxic Encephalopathy Ann Neurol 2007; 62: 102-105

% g

M SUV* encephalopathy, alpha coma, thalamic deafferentation. inhibitory interneuronal networks likely also contributes Hypoxic Encephalopathy. Ann Neurol 2007; 62: 102-105.

2 Langlois JA Rutland Brown W Thomas KE Traumatic brain injury in the United States: emergency department visits hospitalizations and deaths Atlanta (GA): Centers for DiseaseMean SUV*OFF to the observed effects 11

2. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta (GA): Centers for Disease

Control and Prevention Nation Center for Injury Prevention and Control; 2006

Mean SUVOFF ON Zolpidem: to the observed effects.11 Control and Prevention, Nation Center for Injury Prevention and Control; 2006.

3 S hiff ND M d li th i i ll i t t t f b i f ti d th ti ibiliti P i B i R h 2005 150 477 497Region Left RightOFF ON Zolpidem: 3. Schiff ND. Modeling the minimally conscious state: measurements of brain function and therapeutic possibilities. Progress in Brain Research 2005;150:477-497.

4 S hiff ND Th l f i i d i h ll f iti i I G i MS d Th C iti N i 3 d d B t MIT P 2004

Region Left Right

Improved communication and motor control with: This model predicts increased metabolism in the4. Schiff ND. The neurology of impaired consciousness: challenges for cognitive neuroscience. In: Gazzaniga MS ed. The Cognitive Neurosciences, 3rd ed. Boston: MIT Press; 2004.

Mesial frontal 139% 146% Improved communication and motor control, with: This model predicts increased metabolism in the 5. Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs. 2000;59:865-889.Mesial frontal 139% 146%

• Increases in regional & global metabolism thalamus striatum and frontal cortex and decreased6. Davey MP, Victor JD, Schiff ND. Power spectra and coherence in the EEG of a vegetative patient with severe asymmetric brain damage. Clin Neurophys 2000;111:1949-1954.

Lateral frontal 166% 183% • Increases in regional & global metabolism thalamus, striatum and frontal cortex and decreased y p g p y g p y

7. Mitra PP, Pesaren B. Analysis of dynamic brain imaging data. Biophysical Journal 1999; 76: 691-708.Lateral frontal 166% 183% g g

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8. Schiff, ND, Ribary, U, Moreno, D, Beattie, B, Kronberg, E, Blasberg, R, Giacino, J, McCagg, C, Fins, JJ, Llinas, R and Plum, F. Residual cerebral activity and behavioral fragments in the

C l i 145% 153% • Loss of aberrant spectral peaks in 7-11Hz range metabolism in the GPi and suggests other potential 8. Schiff, ND, Ribary, U, Moreno, D, Beattie, B, Kronberg, E, Blasberg, R, Giacino, J, McCagg, C, Fins, JJ, Llinas, R and Plum, F. Residual cerebral activity and behavioral fragments in the

persistent vegetative state Brain 2002;125 1210-1234Calcarine 145% 153% oss o abe a t spect a pea s a ge

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t t f th ti i t ti hi h h h dpersistent vegetative state. Brain 2002;125, 1210 1234.

9 Schiff ND Rodriguez-Moreno D Kamal A Petrovich N Giacino J Plum F and Hirsch J fMRI reveals large-scale network activation in minimally conscious patients Neurology

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S % % • Downward shifting of 70-80Hz peaks targets for therapeutic intervention which have had9. Schiff ND, Rodriguez-Moreno D, Kamal A, Petrovich N, Giacino J, Plum F and Hirsch J. fMRI reveals large-scale network activation in minimally conscious patients. Neurology

2005;64:514 523Striatum 156% 156% Downward shifting of 70 80Hz peaks targets for therapeutic intervention, which have had 2005;64:514-523.

10 Schiff ND Posner JB Another “Awakenings” Ann Neurol 2007;62:5 7Striatum 156% 156%

ON • Reduction in local coherence in 5-15Hz range empiric success:10. Schiff ND, Posner JB. Another Awakenings . Ann Neurol. 2007;62:5-7.

11 McCarth MM Bro n EN Kopell N Potential net ork mechanisms mediating electroencephalographic beta rh thm changes d ring propofol ind ced parado ical e citation JThalamus 148% 127%ON Reduction in local coherence in 5 15Hz range empiric success: 11. McCarthy MM, Brown EN, Kopell N. Potential network mechanisms mediating electroencephalographic beta rhythm changes during propofol –induced paradoxical excitation. J

N i 2008 28 13488 13504Thalamus 148% 127%

• Dopaminergic agents support the function of striatalNeurosci. 2008;28:13488-13504.

The ON state behaviors reflected normalization of • Dopaminergic agents support the function of striatal 12. Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber M, Fritz B, Eisenberg B, Biondi T, O'Connor J, Kobylarz EJ, Farris S, Machado A, McCagg C, Plum F, Fins JJ, Rezai AR.Peaks in short-range coherence noted in The ON state behaviors reflected normalization of medium spiny neurons

Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 2007; 448: 600-603.Peaks in short range coherence noted in

5 15Hz frequency range which are*SUV S d di d U k V l integrative function that is dependent on circuit-level medium spiny neurons. 13. Schiff ND. An integrative research paradigm for the cognitive neuroscience of consciousness. In: Gazzaniga MS ed. The Cognitive Neurosciences, 4th ed. Boston: MIT Press; 2009.5-15Hz frequency range, which are *SUV = Standardized Uptake Value integrative function that is dependent on circuit-level p y

Thalamic DBS directly activates thalamostriatal and Support: The Rockefeller University Clinical and Translational Science Center Clinical Scholars Program (STW) The Charles A Dana Foundation (NDS) The

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reduced after zolpidem administration.SUV Standardized Uptake Value

mechanisms • Thalamic DBS directly activates thalamostriatal and Support: The Rockefeller University Clinical and Translational Science Center, Clinical Scholars Program (STW), The Charles A. Dana Foundation (NDS), The

J S M D ll F d ti (NDS) d NIH HD 91512 (NDS) W th k B dl B tti f tit ti l i f th PET i Pl di t

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th l ti l tfl 12James S. McDonnell Foundation (NDS), and NIH HD 91512 (NDS). We thank Bradley Beattie for quantitative analysis of the PET images. Please direct

thalamocortical outflow.12 correspondence to shawniqua.williams@gmail.com.thalamocortical outflow. p q @g