Neurobehavioral and Neurophysiologic Methods in Diagnostic and Prognostic Assessment

1. Disorders of Consciousness Neurobehavioral and Neurophysiologic Methods in Diagnostic and Prognostic Assessment Joseph T. Giacino, Ph.D. JFK Johnson Rehabilitation Institute NJ Neuroscience Institute On the Boundaries of Consciousness: A Search for Contact Reggio Emilia, Italy March 23-25, 2006

2. Supporting Agencies • National Institute on Disability Rehabilitation and Research (H133A031713): “Investigating the utility of fMRI in assessing cognition, predicting outcome and planning treatment in persons diagnosed with minimally conscious state.” • National Institute of Health- NINDS (R21HD40987): “Multidisciplinary assessment of severe brain injury.”

3. Coma Vegetative State Minimally Conscious State Normal Consciousness AROUSAL AWARENESS AROUSAL AWARENESS AROUSAL AWARENESS AROUSAL AWARENESS Continuum of Consciousness S. Laureys Laureys et al, 2003

4. Incidence of Diagnostic Inaccuracy • 15% (Tresch et al, 1991) • 37% (Childs et al, 1993) • 43% (Andrews et al, 1996)

5. Implications of DiagnosticNon-Specificity and Inaccuracy • Inappropriate treatment decisions • Family adjustment complications • Misleading research findings

6. I. Definitions and Diagnostic Criteria Coma is a state of sustained pathologic unconsciousness in which the eyes remain closed and the patient cannot be aroused. (MSTF, 1994)

7. Coma: Course • Almost always resolves within 2-4 weeks • Resolution signaled by reemergence of eye opening • No evidence of awareness of self or environment: • No purposeful motor activity • No behavioral response to command • No evidence of language comprehension or expression • Usually transitions to vegetative or minimally conscious state

8. Vegetative State The vegetative state is a condition in which there is complete absence of behavioral evidence for awareness of self and environment, with preserved capacity for spontaneous or stimulus-induced arousal. (Aspen Workgroup, 2001)

9. Clinical Criteria for Diagnosis of theVegetative State Core Features: • No evidence of sustained or reproducible, purposeful or voluntary behavioral responses to visual, auditory, tactile or noxious stimuli • No evidence of language comprehension or expression • Intermittent wakefulness manifested by sleep-wake cycles (Multi-Society Task Force on PVS 1994)

10. Clinical Criteria for Diagnosis of theVegetative State (cont.) • Sufficient preservation of hypothalamic and brain stem autonomic functions for survival with medical and nursing care • Bowel and bladder incontinence • Variable preservation of cranial nerve function (pupillary, oculocephalic, corneal, vestibulo-ocular, gag, spinal reflexes) Ancillary Features:

11. Persistent Vegetative State A diagnostic term that denotes a vegetative state present 1 month after a traumatic or non-traumatic brain injury (AAN 1995)

12. PVS Use of the term persistent vegetative state (PVS) should be avoided. In place of PVS, the term vegetative state should be used, accompanied by a description of the cause of injury and the length of time since onset. (Aspen Workgroup 1997)

13. Permanent Vegetative State A prognostic term that denotes an irreversible state which can be applied 12 months after a traumatic injury and after 3 months following non-traumatic injury in adults and children (AAN 1995)

14. Probabilities for Recovery of Consciousness and Function at 12 Months After Traumatic and Non-Traumatic Brain Injury for Patients in the Vegetative State at 3 and 6 Months After Injury Outcome Probabilities for Adults in PVS 3 Months After Injury Outcome Traumatic PVS (n=434) Non-Traumatic PVS (n=169) Dead (%) 35 (27-43)% 46 (31-61)% PVS (%) 30 (22-38)% 47 (32-62)% Severe (%) 19 (12-26)% 6 (0-13)% Moderate/Good (%) 16 (10-22)% 1 (0-4)% Outcome Probabilities for Adults in PVS 6 Months After Injury Dead (%) 32 (21-43)% 28 (12-44)% PVS (%) 52 (40-64)% 72 (56-88)% Severe (%) 12 (4-20)% 0 Moderate/Good (%) 4 (0-9)% 0 ____________________________________________________________ Source: Rosenberg & Ashwal, Neurorehabilitation 1996;6(1)

15. Prognostic Guideline for Patients in the Vegetative State (AAN, 1995) Criteria for Permanence • After 12 monthsfollowing traumatic brain injury in adults and children • After 3 monthsfollowing non-traumatic brain injury in adults and children • After 1 to 3 monthsfollowing metabolic and degenerative diseases • At birthin infants with anencephaly and after 3 to 6 monthsfollowing congenital malformations of the brain

16. Minimally Conscious State (MCS) The minimally conscious state is a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated. (Giacino, et al., Neurology, 2002)

17. Minimally Conscious State: Course • Usually exists as transitional state reflecting improvement (as in coma/VS) or decline (as in neurodegenerative conditions) in consciousness • May represent permanent outcome • Natural history and long term outcome differ from VS

18. Diagnostic Criteria for MCS (Giacino, et al., 2002) • One or more of the following must be clearly discernible and occur on a reproducible or sustained basis: • Simple command-following • Gestural or verbal “yes/no” responses • Intelligible verbalization • Environmentally-contingent (non-reflexive) movements or emotional responses: • Smiling/crying • Vocalizations/gestures • Object reaching/manipulation • Visual pursuit

19. Comparison of Outcome: VS v. MCS • Increasing evidence that pts in MCS show: • More rapid rate of improvement • Longer course of recovery • Significantly better functional outcome by 12 months

20. Comparison of Outcome at 1 Year in Persons Diagnosed with VS and MCS (Giacino & Kalmar, JHTR, 1997)

21. Comparison of MCS TBI Outcome at 1 and 2-5 Years **Lammi et al, 2005 *Giacino & Kalmar, 1997 0-3 None-Partial 4-11 Mod-Mod/Sev 17-23 Ext Sev-VS DRS Score Range

22. How permanent is permanent?

23. Diagnostic Criteria for Emergence from MCS Reliable and consistent demonstration of one or both of the following: • Functional interactive communication • Verbalization • Yes/no signals • Spelling/symbol boards • Augmentative communication devices • Functional use of objects • Requires discrimination among items

24. II. Neurophysiologic Assessment of VS and MCS “The limits of consciousness are hard to define satisfactorily and we can only inferthe self-awareness of others by their appearance and their acts.” Plum and Posner, 1982 The Diagnosis of Stupor and Coma

25. Clues From Functional Neuroimaging Studies CornellColumbiaJFKMSKU. Liege Nicholas Schiff, MD Joy Hirsch, Ph.D. Joseph T. Giacino, Ph.D. Bradley Beattie Steven Laureys, MD, PhD Erik Kobylarz, MD, PhD Diana Rodriguez, PhD Kathleen Kalmar, Ph.D. Ron Blasberg, MD Melanie Boly, MD Fred Plum, MD Steve Dashaw Caroline McCagg, MD Cyclotron Research Ctr. Joseph Fins, MD Ray Cappiello Rodolfo Llinas, MD, Ph.D. Urs Ribary, Ph.D.

26. PET Studies of VS • Behavioral profiles of patients in VS highly variable • “Stereotypical fragments of organized behavior” have been observed in VS patients • Neurophysiologic substrate underlying these complex behaviors unknown • Prognostic relevance of neurophysiologic profiles unknown

27. Neurophysiologic heterogeneity in VS (CMRglu) 65% 31% Schiff et al, 2002

28. Sensory Processing in VS Visual Auditory Somatosensory Laureys, et al, 2005

29. Somatosensory regions active in controls but not in VS Laureys, et al., 2005

30. Discussion • VS essentially represents a global disconnection syndrome. • Isolated modular operations may survive in the absence of consciousness.

31. Passive Viewing Faces Emotionally salient Sensitive to FFA Landscapes Contrast v. faces Emotionally neutral Sensitive to PPA Hands Sensitive to FG (non-FFA) or Flashing Checkerboards Sensitive to V1 Forward narrative Familiar voice/event Normal content and prosody Backward (time-reversed) narrative Unintelligible speech Devoid of content and prosody Muffled narrative Unintelligible speech Retains prosody but not content fMRI Studies of VS and MCS Passive Listening Passive Viewing

32. Patient 1: 21 yo male (RH) 18m s/p L temporo-parietal intracranial hemorrhage w/ brain stem compression F/U MRI: Large area L T-P encephalomalacia Inconsistent one-step command-following, object identification, single word utterances Unable to communicate reliably Patient 2: 33 yo male (RH) 24m s/p b/l SDHs 2ndary to blunt head trauma F/U MRI: R frontal encephalomalacia + paramedian thalamic infarct Inconsistent complex command-following (go-no go, countermanding), occasional verbalization Unable to communicate reliably MCS Case Studies (Passive listening only)

33. MCS Case Studies: Patient 3 (w/ passive viewing) • 29 yo male (RH) • MVA v. pedestrian • 18m s/p L temporo-parietal intracranial hemorrhage w/ brain stem compression • F/U MRI: Large area L temporo-parietal encephalomalacia • Inconsistent one-step command-following • Unable to communicate

34. Healthy Volunteers • Unrelated/Unknown to patient • Demographically matched • Right-handed • Able to independently provide consent • No hx of major neurologic, developmental or psychiatric disorder • No implanted hardware above shoulders

35. FORWARD BACKWARD OVERLAP Subject 1 Subject 2 Subject 3 Subject 4 Subject 6 Subject 7 Subject 5 Listening to Narratives: Healthy Subjects

36. FORWARD BACKWARD OVERLAP GTs 22 GTt 41 GTm 21 Patient 1 Patient 2 Listening to Narratives

37. Language Activation Pattern by Condition Listening to narratives: Patient 3 Forward Speech Backward Speech Muffled Speech

38. Summary of Passive Listening Results in MCS • Activation pattern similar in MCS patients and controls • MCS patients retain functional connectivity • Language network foci preserved in MCS despite inability to follow commands or communicate reliably • In 2/3 MCS patients (but not controls), activation markedly reduced during backward condition

39. Viewing Pictures: Patient 3 L R R 0 L Faces Hands Landscapes

40. Summary of Passive Viewing Results in MCS • Selective activation of visual network foci noted despite complete absence of behavioral evidence for visual recognition

41. Discussion • MCS pts retain connected cortical networks underlying language and visual processing. • Loss of activation in MCS pts during backward narrative may be related to low emotional salience of these stimuli. • Recruitable cortical networks associated with language and visual processing may pre-sage further recovery.

42. Cognitive Processing in the Vegetative State? • 20 y/o college student (RH) • Drug overdose (opiates, cocaine, barbiturates) • Cardiac arrest (10 mins to resuscitation in ER) • CT: global ischemic changes on day 2 • Admitted to rehab at 3 mths post-injury • No discernible command-following, communication or visual response (vocalization??) • Spastic contractures all 4 extremities

43. Language: VS or MCS? L R R L Forward Speech Backward Speech Forward - Backward

44. Visuoperception: VS or MCS?? R R L L Checkerboard L Landscapes Faces

45. What do these findings mean? • “Functional” locked-in state? • Activation of cortical association areas not indicative of conscious processing? • More extensive hard-wiring than previously suspected? • Isolated surviving modular networks but insufficient to support consciousness • Other??

46. Pressing Questions • Is functional neuroimaging (FNI) an adequate proxy for neural activity? • Can FNI detect cognitive processing in the absence of behavioral evidence? • Can FNI improve prognostic accuracy? • Can FNI procedures identify patients likely to benefit from treatment when behavioral indicators are unfavorable? • Can FNI help determine which interventions are best for which patients?