- Email: [email protected]
Capturing covert consciousness
Comment
AC is a member of the protocol team of the PROMISE study, which will investigate the research questions associated with Option B versus Option A. We declare that we have no conflicts of interest. 1
2
3
4 5
6
World Health Organization HIV/AIDS Programme. Use of antiretroviral drugs for treating pregnant women and preventing HIV infections in infants. Executive Summary. April, 2012. http://www.who.int/hiv/ PMTCT_update.pdf (accessed Oct 8, 2012). UNICEF. A business case for Options B and B+ to eliminate mother to child transmission of HIV by 2015. July, 2012. http://eptctasiapacific.org/ content/business-case-options-b-and-b-eliminate-mother-childtransmission-hiv-2015-model-methodology (accessed Oct 3, 2012). AIDS 2012. Washington DC. July, 2012. http://aids2012.org/WebContent/ File/AIDS2012_Plenary_Media_ Release_25_July_2012_EN.pdf (accessed Oct 8, 2012). Shapiro R, Hughes M, Oguwa A. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010; 362: 2282–94. The Kesho Bora Study Group. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis 2011; 11: 171–80. Hargrove J, Humphrey J, for the ZVITAMBO Study Group. Mortality among HIV-positive postpartum women with high CD4 cell counts in Zimbabwe. AIDS 2010; 24: 11–14.
7 8
9
10
11 12
13
14
Cohen M, Chen Y, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505. Chen JY, Ribaudo HJ, Souda S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012; 206: 1695–705. Struik GM, den Exter RA, Munthali C, et al. The prevalence of renal impairment among adults with early HIV disease in Blantyre, Malawi. Int J STD AIDS 2011; 22: 457–62. Siberry G, Williams P, Mendez H, et al, for the Pediatric HIV/AIDS Cohort Study (PHACS). Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012; 26: 1151–59. Rosen S, Fox M, Gill C. Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med 2007; 4: 1691–701. Unge C, Södergård B, Marrone G. Long-term adherence to antiretroviral treatment and program drop-out in a high-risk urban setting in sub-Saharan Africa: a prospective cohort study. PLoS Med 2010; 5: 1–12. Nachega J, Uthman O, Anderson J, et al. Adherence to antiretroviral therapy during and after pregnancy in low-, middle- and high-income countries: a systematic review and meta-analysis. AIDS 2012; 26: 2039–52. Wagner B, Blower S. Universal access to HIV treatment versus universal “test and treat”: transmission, drug resistance & treatment costs. PLoS One 2012; 7: e41212.
Capturing covert consciousness
www.thelancet.com Vol 381 January 26, 2013
were deemed to be neurophysiologically responsive to a command pertaining to motor imagery. But were they? In The Lancet, Andrew Goldfine and colleagues6 now challenge this investigation. First, they tested Cruse and coworkers’ assumptions and suggest that they were not valid for the data analysed. Second, Goldfine and colleagues reanalysed the data with a method that was independent of such assumptions and report no evidence for covert consciousness. Overall, Goldfine and colleagues present a compelling argument that this claim of neurophysiological responsiveness has a questionable statistical basis,6 potentially undermining the interpretation of two studies by Cruse and colleagues.5,7
See Correspondence page 289
Science Photo Library
In 1968, anaesthesiologist Henry Beecher published an article discussing the ethical problems created by the “hopelessly unconscious patient”.1 More than 40 years later, clinicians and investigators struggle with perhaps a more complex problem: the hopelessly conscious patient. The idea of so-called covert consciousness originated in a case report of ostensibly volitional neural activity in a patient presumed to be in a vegetative state.2 With functional MRI, investigators identified activity of the supplementary motor area after asking a patient to imagine playing tennis; and activity of the parahippocampal gyrus, posterior parietal lobe, and lateral premotor cortex after asking her to imagine walking through her home. Importantly, this pattern of activity was not significantly different from that recorded in healthy control individuals. Subsequent investigation of some patients with diagnoses of vegetative or minimally conscious states has confirmed neural activity consistent with volition,3 prompting a proposed nomenclature shift from vegetative state to unresponsive wakefulness syndrome.4 However, neuroimaging is not practical for bedside detection of covert consciousness. In 2011, Damian Cruse and colleagues5 described a comparison of electroencephalography in 16 patients with a diagnosis of vegetative state and 12 healthy control individuals. Despite behavioural unresponsiveness, three patients
271
Comment
Rather than focusing on the superiority of one method to another, we wish to comment on a challenge that is common to all investigations of covert consciousness. The reports by Cruse and colleagues5 and Goldfine and coworkers6 show that interpretation of states of consciousness exclusively on the basis of neurophysiological data is crucially dependent on the statistical model, which draws attention to the potential fragility of such an approach. With advanced techniques, Cruse and colleagues5 and Goldfine and coworkers6 report discrepant results that could lead to vastly different approaches to clinical condition and ethical care. As anaesthesiologists, we struggle with the occurrence of covert consciousness and explicit episodic recall in between one and two surgical patients per 1000 who are intended to be unconscious. Efforts to prevent awareness and memory with fairly rudimentary electroencephalographic techniques in surgical patients who are behaviourally unresponsive are similarly beset with uncertainties of probabilistic methods to detect consciousness.8,9 Experiences in the operating theatre suggest that presently available analytical approaches remain mere approximations. However, more controlled experimental settings in which anaesthetics are given allow for behavioural techniques to assess consciousness and memory, which could hold promise for investigation of patients with unresponsive wakefulness syndrome. Although adjudication between competing analytical techniques on the basis of statistical principles is certainly possible, any surrogate measure to detect covert consciousness will ultimately be controversial unless calibrated against a gold standard. Investigations of unresponsive wakefulness syndrome are unfortunately restricted to a between-patients design, in which inferences have to be made about unresponsive individuals on the basis of the neural activity of conscious and responsive patients. We believe that anaesthesiology offers the potential for a within-patients design that could help to validate statistical approaches for detection of covert consciousness in pathologically unresponsive patients. Potent drugs that are routinely used in the perioperative setting can be titrated to achieve different levels of responsiveness, allowing neuroscientists to test various analytical methods against either real-time or post-hoc assessments of consciousness in healthy individuals. Furthermore, 272
we suggest that neural activity postulated to reflect consciousness in the pathologically unresponsive patient should be attenuated by the effects of general anaesthetics. Importantly, anaesthetics do not seem to impair primary sensory processing,10 making them attractive instruments that could be used to probe higher-order events related to consciousness. Indeed, there are already commensurate findings between electroencephalographic investigations of recurrent processing in vegetative and anaesthetised states.11,12 Lastly, we wish to emphasise a point about scientific process. These two accomplished research groups— comprised of pioneers in the specialty—have chosen an open rather than a guarded attitude towards scientific inquiry. By sharing data and engaging in public dialogue, Cruse and coworkers and Goldfine and colleagues have given scientists and clinicians the opportunity to ponder these controversies and generate new ideas about patients who might be hopelessly conscious. *George A Mashour, Michael S Avidan Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109–5048, USA (GAM); and Department of Anesthesiology, Washington University, St Louis, MO, USA (MSA) [email protected] We declare that we have no conflicts of interest. 1 2 3 4
5 6
7
8
9
10
11 12
Beecher HK. Ethical problems created by the hopelessly unconscious patient. N Engl J Med 1968; 278: 1425–30. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness in the vegetative state. Science 2006; 313: 1402. Monti MM, Vanhaudenhuyse A, Coleman MR, et al. Willful modulation of brain activity in disorders of consciousness. N Engl J Med 2010; 362: 579–89. Laureys S, Celesia GG, Cohadon F, et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med 2010; 8: 68. Cruse D, Chennu S, Chatelle C, et al. Bedside detection of awareness in the vegetative state: a cohort study. Lancet 2011; 378: 2088–94. Goldfine AM, Bardin JC, Noirhomme Q, Fins JJ, Schiff ND, Victor JD. Reanalysis of “Bedside detection of awareness in the vegetative state: a cohort study”. Lancet 2013; 381: 289–91. Cruse D, Chennu S, Chatelle C, et al. Relationship between etiology and covert cognition in the minimally conscious state. Neurology 2012; 78: 816–22. Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk surgical population. N Engl J Med 2011; 365: 591–600. Mashour GA, Shanks A, Tremper KK, et al. Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial. Anesthesiology 2012; 117: 717–25. Boveroux P, Vanhaudenhuyse A, Bruno MA, et al. Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology 2010; 113: 1038–53. Boly M, Garrido MI, Gosseries O, et al. Preserved feedforward but impaired top-down processes in the vegetative state. Science 2011; 332: 858–62. Ku SW, Lee U, Noh GJ, Jun IG, Mashour GA. Preferential inhibition of frontal-to-parietal feedback connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PLoS One 2011; 6: e25155.
www.thelancet.com Vol 381 January 26, 2013
AC is a member of the protocol team of the PROMISE study, which will investigate the research questions associated with Option B versus Option A. We declare that we have no conflicts of interest. 1
2
3
4 5
6
World Health Organization HIV/AIDS Programme. Use of antiretroviral drugs for treating pregnant women and preventing HIV infections in infants. Executive Summary. April, 2012. http://www.who.int/hiv/ PMTCT_update.pdf (accessed Oct 8, 2012). UNICEF. A business case for Options B and B+ to eliminate mother to child transmission of HIV by 2015. July, 2012. http://eptctasiapacific.org/ content/business-case-options-b-and-b-eliminate-mother-childtransmission-hiv-2015-model-methodology (accessed Oct 3, 2012). AIDS 2012. Washington DC. July, 2012. http://aids2012.org/WebContent/ File/AIDS2012_Plenary_Media_ Release_25_July_2012_EN.pdf (accessed Oct 8, 2012). Shapiro R, Hughes M, Oguwa A. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010; 362: 2282–94. The Kesho Bora Study Group. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis 2011; 11: 171–80. Hargrove J, Humphrey J, for the ZVITAMBO Study Group. Mortality among HIV-positive postpartum women with high CD4 cell counts in Zimbabwe. AIDS 2010; 24: 11–14.
7 8
9
10
11 12
13
14
Cohen M, Chen Y, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505. Chen JY, Ribaudo HJ, Souda S, et al. Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana. J Infect Dis 2012; 206: 1695–705. Struik GM, den Exter RA, Munthali C, et al. The prevalence of renal impairment among adults with early HIV disease in Blantyre, Malawi. Int J STD AIDS 2011; 22: 457–62. Siberry G, Williams P, Mendez H, et al, for the Pediatric HIV/AIDS Cohort Study (PHACS). Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012; 26: 1151–59. Rosen S, Fox M, Gill C. Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med 2007; 4: 1691–701. Unge C, Södergård B, Marrone G. Long-term adherence to antiretroviral treatment and program drop-out in a high-risk urban setting in sub-Saharan Africa: a prospective cohort study. PLoS Med 2010; 5: 1–12. Nachega J, Uthman O, Anderson J, et al. Adherence to antiretroviral therapy during and after pregnancy in low-, middle- and high-income countries: a systematic review and meta-analysis. AIDS 2012; 26: 2039–52. Wagner B, Blower S. Universal access to HIV treatment versus universal “test and treat”: transmission, drug resistance & treatment costs. PLoS One 2012; 7: e41212.
Capturing covert consciousness
www.thelancet.com Vol 381 January 26, 2013
were deemed to be neurophysiologically responsive to a command pertaining to motor imagery. But were they? In The Lancet, Andrew Goldfine and colleagues6 now challenge this investigation. First, they tested Cruse and coworkers’ assumptions and suggest that they were not valid for the data analysed. Second, Goldfine and colleagues reanalysed the data with a method that was independent of such assumptions and report no evidence for covert consciousness. Overall, Goldfine and colleagues present a compelling argument that this claim of neurophysiological responsiveness has a questionable statistical basis,6 potentially undermining the interpretation of two studies by Cruse and colleagues.5,7
See Correspondence page 289
Science Photo Library
In 1968, anaesthesiologist Henry Beecher published an article discussing the ethical problems created by the “hopelessly unconscious patient”.1 More than 40 years later, clinicians and investigators struggle with perhaps a more complex problem: the hopelessly conscious patient. The idea of so-called covert consciousness originated in a case report of ostensibly volitional neural activity in a patient presumed to be in a vegetative state.2 With functional MRI, investigators identified activity of the supplementary motor area after asking a patient to imagine playing tennis; and activity of the parahippocampal gyrus, posterior parietal lobe, and lateral premotor cortex after asking her to imagine walking through her home. Importantly, this pattern of activity was not significantly different from that recorded in healthy control individuals. Subsequent investigation of some patients with diagnoses of vegetative or minimally conscious states has confirmed neural activity consistent with volition,3 prompting a proposed nomenclature shift from vegetative state to unresponsive wakefulness syndrome.4 However, neuroimaging is not practical for bedside detection of covert consciousness. In 2011, Damian Cruse and colleagues5 described a comparison of electroencephalography in 16 patients with a diagnosis of vegetative state and 12 healthy control individuals. Despite behavioural unresponsiveness, three patients
271
Comment
Rather than focusing on the superiority of one method to another, we wish to comment on a challenge that is common to all investigations of covert consciousness. The reports by Cruse and colleagues5 and Goldfine and coworkers6 show that interpretation of states of consciousness exclusively on the basis of neurophysiological data is crucially dependent on the statistical model, which draws attention to the potential fragility of such an approach. With advanced techniques, Cruse and colleagues5 and Goldfine and coworkers6 report discrepant results that could lead to vastly different approaches to clinical condition and ethical care. As anaesthesiologists, we struggle with the occurrence of covert consciousness and explicit episodic recall in between one and two surgical patients per 1000 who are intended to be unconscious. Efforts to prevent awareness and memory with fairly rudimentary electroencephalographic techniques in surgical patients who are behaviourally unresponsive are similarly beset with uncertainties of probabilistic methods to detect consciousness.8,9 Experiences in the operating theatre suggest that presently available analytical approaches remain mere approximations. However, more controlled experimental settings in which anaesthetics are given allow for behavioural techniques to assess consciousness and memory, which could hold promise for investigation of patients with unresponsive wakefulness syndrome. Although adjudication between competing analytical techniques on the basis of statistical principles is certainly possible, any surrogate measure to detect covert consciousness will ultimately be controversial unless calibrated against a gold standard. Investigations of unresponsive wakefulness syndrome are unfortunately restricted to a between-patients design, in which inferences have to be made about unresponsive individuals on the basis of the neural activity of conscious and responsive patients. We believe that anaesthesiology offers the potential for a within-patients design that could help to validate statistical approaches for detection of covert consciousness in pathologically unresponsive patients. Potent drugs that are routinely used in the perioperative setting can be titrated to achieve different levels of responsiveness, allowing neuroscientists to test various analytical methods against either real-time or post-hoc assessments of consciousness in healthy individuals. Furthermore, 272
we suggest that neural activity postulated to reflect consciousness in the pathologically unresponsive patient should be attenuated by the effects of general anaesthetics. Importantly, anaesthetics do not seem to impair primary sensory processing,10 making them attractive instruments that could be used to probe higher-order events related to consciousness. Indeed, there are already commensurate findings between electroencephalographic investigations of recurrent processing in vegetative and anaesthetised states.11,12 Lastly, we wish to emphasise a point about scientific process. These two accomplished research groups— comprised of pioneers in the specialty—have chosen an open rather than a guarded attitude towards scientific inquiry. By sharing data and engaging in public dialogue, Cruse and coworkers and Goldfine and colleagues have given scientists and clinicians the opportunity to ponder these controversies and generate new ideas about patients who might be hopelessly conscious. *George A Mashour, Michael S Avidan Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109–5048, USA (GAM); and Department of Anesthesiology, Washington University, St Louis, MO, USA (MSA) [email protected] We declare that we have no conflicts of interest. 1 2 3 4
5 6
7
8
9
10
11 12
Beecher HK. Ethical problems created by the hopelessly unconscious patient. N Engl J Med 1968; 278: 1425–30. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness in the vegetative state. Science 2006; 313: 1402. Monti MM, Vanhaudenhuyse A, Coleman MR, et al. Willful modulation of brain activity in disorders of consciousness. N Engl J Med 2010; 362: 579–89. Laureys S, Celesia GG, Cohadon F, et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med 2010; 8: 68. Cruse D, Chennu S, Chatelle C, et al. Bedside detection of awareness in the vegetative state: a cohort study. Lancet 2011; 378: 2088–94. Goldfine AM, Bardin JC, Noirhomme Q, Fins JJ, Schiff ND, Victor JD. Reanalysis of “Bedside detection of awareness in the vegetative state: a cohort study”. Lancet 2013; 381: 289–91. Cruse D, Chennu S, Chatelle C, et al. Relationship between etiology and covert cognition in the minimally conscious state. Neurology 2012; 78: 816–22. Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk surgical population. N Engl J Med 2011; 365: 591–600. Mashour GA, Shanks A, Tremper KK, et al. Prevention of intraoperative awareness with explicit recall in an unselected surgical population: a randomized comparative effectiveness trial. Anesthesiology 2012; 117: 717–25. Boveroux P, Vanhaudenhuyse A, Bruno MA, et al. Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology 2010; 113: 1038–53. Boly M, Garrido MI, Gosseries O, et al. Preserved feedforward but impaired top-down processes in the vegetative state. Science 2011; 332: 858–62. Ku SW, Lee U, Noh GJ, Jun IG, Mashour GA. Preferential inhibition of frontal-to-parietal feedback connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PLoS One 2011; 6: e25155.
www.thelancet.com Vol 381 January 26, 2013