sign in sign up
<<
Home , Neurointensive care, Spontaneous recovery

Neurosurg Focus 29 (2):E14, 2010

Deep brain stimulation in the management of disorders of : a review of physiology, previous reports, and ethical considerations

An i s h N. Se n , B.S.,1 Pe t e r G. Ca m pb e l l , M.D.,2 Sa n j a y Yad l a , M.D.,2 Jac k Ja l l o , M.D., Ph.D., 2 a n d As h w i n i D. Sh a r a n , M.D.2 1Jefferson Medical College, Thomas Jefferson University, and 2Department of , Thomas Jefferson University Hospital, Philadelphia, Pennsylvania

Patients suffering from disorders of consciousness constitute a population that exists largely outside of the daily practice patterns of neurosurgeons. Historically, treatment has focused on nursing and custodial issues with limited neurosurgical intervention. Recently, however, deep brain stimulation has been explored to restore cognitive and physical function to patients in minimally conscious states. In this article, the authors characterize the physiological mechanisms for the use of deep brain stimulation in persistently vegetative and minimally conscious patients, review published cases and associated ethical concerns, and discuss future directions of this technology. (DOI: 10.3171/2010.4.FOCUS1096)

Ke y Wo r d s • deep brain stimulation • minimally conscious state • persistent vegetative state • thalamus • disorder of consciousness • ethics

h e application of deep brain stimulation (DBS) has .3,27 The patients who fall into this category of grown to include a wide variety of clinical situa- consciousness have a functional brainstem and various tions. A fairly novel and sparsely studied applica- dispersed “islands” of dysfunctional cortex.22 In contrast, Ttion involves the use of DBS in improving the clinical an MCS represents a more advanced stage of conscious- condition of patients in a persistent vegetative state (PVS) ness in which a patient demonstrates an increased aware- or minimally conscious state (MCS) following traumatic ness of his or her environment via observed, cognitively brain injury. Beginning in the 1950s, infrequent reports of mediated behaviors but remains inconsistent in his or her the use of DBS for disorders of consciousness had been communication abilities.3,16,27 On functional brain im- described. More recently, a widely publicized case of aging tests, these patients may have organized cortical dramatic improvement in a patient in an MCS who was functioning despite appearing grossly unconscious.26,28 treated with DBS rejuvenated interest in this therapeutic While either state may result from a traumatic brain in- intervention.33 Still, many factors may ultimately contrib- jury and both have profound functional consequences, ute to or confound the possible success of this treatment, differentiating between the two states may be important including spontaneous recovery, incorrect diagnosis, and in determining the possible benefit of DBS . the fluctuating baseline consciousness of the patient. This review characterizes the physiological mecha- While it is known that a spectrum of conscious- nisms for the use of DBS in disorders of consciousness, ness exists from comatose to fully conscious, not until reviews published cases of its use in the literature, the recently has a distinction between a PVS and an MCS associated ethical concerns, and provides a discussion of been established.16 A PVS is defined as a degree of con- the possible future for this application of DBS. sciousness after severe brain injury whereby a patient has developed wakefulness with some degree of -wake cycling but without any demonstration of environmental Physiological Basis for DBS in PVS or MCS Initial theories regarding stimulation of the reticular Abbreviations used in this paper: DBS = deep brain stimulation; formation and thalamus as a means of stimulating wake- MCS = minimally conscious state; PVS = persistent vegetative fulness date to early basic science studies conducted in state. the 1960s elucidating these activating centers.6,29 Further

Neurosurg Focus / Volume 29 / August 2010 1

Unauthenticated | Downloaded 09/24/21 01:37 PM UTC A. N. Sen et al. work revealed the role of the intralaminar nuclei in main- tients would be the most likely to benefit. Unfortunately, taining and based upon their anatomi- this conclusion may be confounded by growing evidence cal neural connections and physiological characteristics.23 of a bias to classify patients as in a PVS, when they may The subsequent discovery of widespread thalamocortical truly be in an MCS.2 projections then contributed to the of the importance of the central lateral nuclei of the intralami- nar nuclei of the thalamus in promoting arousal.30,39 Review of Reported Cases Many thalamic nuclei share important roles in the re- The earliest published cases of electrical stimulation lay of sensory and motor functions. Biochemical advances as a therapy for patients with decreased arousal were con- have revealed a specific type of thalamic neuron ducted in the late 1960s and 1970s. Hassler et al.19 were to be involved in the more basic function of activating the first to report nonspecific behavioral and electroen- cortical networks.20,21 These calbindin-positive staining cephalographic arousal after stimulating an unspecified neurons differ from the standard thalamic relay neurons projection system (possibly the rostral ventral thalamic in that they maintain axonal projections to more diffuse nucleus or intralaminar thalamic nucleus) in a posttrau- areas of cortex, including portions of the frontal lobe and matic persistently vegetative patient. Although Hassler other areas not traditionally involved in sensory or mo- was unaware of the exact neurophysiological underpin- tor function. Moreover, these neurons synapse in layers nings of the projection system at the time, it has since of the cortex where relay neurons are typically absent.20,21 been suggested that they likely involved the recently dis- These special characteristics, combined with the finding covered calbindin-positive thalamocortical pathway from that a significant portion of the intralaminar nuclei (nu- the intralaminar nucleus.35 In 1979, Sturm et al.36 reported clei previously believed to be important in the activating that bipolar stimulation of the nucleus reticulatus polaris system) were composed of such calbindin-positive neu- thalami in a patient with a medial midbrain infarct re- rons, helped establish the importance of specific thalamic sulted in improvement in following commands, wakeful- nuclei in arousal. More recent research has demonstrated ness, verbal communication, and an increased oral intake. that such neural connections between the central lateral The patient initially was described as having “some kind nuclei and the cortex are reciprocal and that these nuclei of unconsciousness which was neither manifest are densely innervated by brainstem arousal systems as nor a typical apallic [PVS] syndrome.” The patient died well.31 2 months after the implantation of electrodes. Unfortu- Multiple cases have been reported whereby a lesion nately, these early cases were confounded by a limited restricted to these nuclei resulted primarily in disturbanc- understanding of the differences in the states of impaired es of consciousness and behavior, further confirming the consciousness, which have since been shown to alter the importance of intralaminar nuclei in cognitive arousal prognosis for recovery and outcome. The fact that stimu- and particularly attention and concentration.4,38 Patients lation was performed within the spontaneous recovery with specific ischemic infarctions of these nuclei primar- period further limits the conclusions that can be drawn ily demonstrated disturbances in attention. Subsequent from these early studies. A more recent study suggests SPECT imaging performed in these patients revealed de- that spontaneous recovery in MCS patients can occur up creased blood flow to the frontal cortices.38 to 1 year following the initial insult.25 As basic research demonstrated the im- More recent reported cases of the use of DBS in PVS or portance of these thalamic nuclei for wakefulness, theo- MCS patients include reports by Tsubokawa et al.37 These ries regarding the possibility of stimulating such nuclei authors performed therapeutic DBS targeting the mesen- to possibly induce an awake state in unconscious patients cephalic reticular formation and nonspecific thalamic nu- became increasingly popular. The initial trials involving clei and followed 8 patients in a PVS as a result of severe artificial stimulation of these areas were correspondingly brain injury (closed head injury, cerebrovascular accident, designed and performed in patients with disorders of con- or anoxia) over 6 months. Improvement in vocal communi- sciousness. However, a major distinction in the conscious cation and arousal was noted in 4 of the 8 patients. Over the state of the patient was not discovered until much later following decade, the same group increased their cohort to in the process—namely, the difference between PVS and a total of 21 patients (including the heavily publicized case MCS patients. Schiff et al.33 suggested that patients most of Terri Schiavo), 8 of whom showed improvement in abil- likely to show improvement with DBS therapy are those ity to obey verbal commands.42 Despite the large number with relatively preserved areas of essential cortical func- of patients in the more recent trials, this study was limited tioning with damage primarily involving the arousal cen- by the timing of DBS therapy within the accepted 1-year ters (that is MCS patients rather than PVS patients). These time frame of spontaneous recovery. The decision to at- authors reported on a carefully selected study subject in tempt DBS in patients whose condition was initially diag- an MCS who showed dramatic improvement with DBS. nosed as a PVS, a cohort that is less likely to benefit from The positive outcome in this case was hypothesized to such stimulation than patients in an MCS, may have also relate to the patient’s having had an underlying primary limited their findings.32 defect in the arousal system while overall cortical func- The most recent and widely publicized published tion had been preserved.33 The authors suggested that the case of DBS-based improvement in PVS or MCS patients central lateral thalamic nuclei of the intralaminar nucleus was reported by Schiff et al. in 2007.33 In this case, DBS would be the highest yield targets for stimulation based therapy was attempted in a 38-year-old man whose condi- upon neurophysiological calculation and that MCS pa- tion was diagnosed as an MCS 6 years after a traumatic

2 Neurosurg Focus / Volume 29 / August 2010 Unauthenticated | Downloaded 09/24/21 01:37 PM UTC Deep brain stimulation for minimally conscious states brain injury. Prior to DBS stimulation, the patient demon- families whose loved ones are comatose, stating, “the at- strated visual pursuit and intermittently followed simple tending of a patient with a devastating neuro- commands.32 Following implantation and therapy, the re- logic illness will have to come to terms with the futility searchers reported improvements in level of arousal (sus- of care.” Often, clinicians evaluate brain-injured patients tained eye opening, head turning to voices), functional relatively early in the course of injury and are unaware limb movements, ability to feed orally, and improvement of any longitudinal recovery.11 Clinicians are trained to in the JFK Coma Recovery Scale-Revised score despite a respect patient preferences at the end of life and often 6-year history of minimal consciousness. The patient was believe they are advocating on behalf of the patient by soon able to name objects, move objects with his hands, steering families toward less-aggressive treatment. Pal- and feed himself. liative measures are often advocated based on an ethical A major difference between this case and previous at- sense that nothing can or should be done for patients with tempts to evaluate DBS in PVS or MCS patients was the pa- catastrophic brain dysfunction.9 While this approach is tient selection criteria. This patient was in a clearly defined generally appropriate in the neurointensive care unit, it MCS and demonstrated preservation of cortical structure is essential that acute-care clinicians avoid prognostic er- and language function but suffered primarily from incon- rors about outcome based solely on decreased conscious- sistency and loss of arousal. Additionally, he demonstrated ness in the setting of brain injury. This reduced level of improvement outside of the 1-year window whereby the consciousness may be a precursor to brain death or the likelihood of spontaneous improvement is low, unlike pa- beginning of a variable recovery process depending upon tients in previous studies.33 This is an important consid- the underlying anatomical severity.11 eration given that the window of spontaneous recovery, Over the past several years, counseling families with which strongly confounded prior studies, has only recently regard to the decision to withdraw life-sustaining therapy been described.25 Moreover, this study was the first to use from patients with severe brain injuries has become more a widely accepted outcome measure, the JFK Coma Re- complex. Since the 1968 creation of brain death criteria, covery Scale-Revised, to determine the clinical benefit of the description of brain states has been refined.10 Patients periods when DBS was turned on.17 While most previous who are brain-dead and those in a PVS are often believed studies reported subjective outcome improvements such as to be hopelessly damaged and permanently unconscious. verbalization, behavioral changes, or limb motion improve- A vegetative state is generally considered permanent 3 ments, this was the first to document objective clinical im- months after anoxic injury and 12 months after trauma.13 provement. This report also demonstrated that the bulk of However, shortly after injury, PVS patients may progress improvement occurred when stimulation was turned on to an MCS, of which the natural history is not yet known. outside of a 50-day postoperative window to minimize Unlike patients in a vegetative state, the minimally con- any possible residual surgical source of improvement. Ad- scious may demonstrate inconsistent evidence of self- and ditionally, Schiff et al.33 demonstrated carry-over improve- environmental awareness.15 Patients in an MCS may show ment from prior DBS stimulation periods even after DBS a spectrum of behavior ranging from responding to en- stimulation was turned off. vironmental stimuli to following simple commands or Despite being based upon only one case, the Schiff possibly the production of incongruous verbal communi- et al.33 report provided much less biased information in cation.15 Unfortunately, the diagnostic timeline introduces the study of DBS for MCS patients. The applicability of a piquant paradox. To fully determine whether recovery this single case however remains difficult to determine. from the vegetative state is possible, a patient with a trau- Moreover, the patient chosen for this study was among matic brain injury might have to be observed for as many the higher functioning patients in the MCS state prior to as 12 months. Currently, decisions about withholding DBS therapy. While the rationale for this decision was life-sustaining therapy are typically made within days to that a patient with largely preserved cortical function weeks of presentation for patients with disorders of con- would be the most likely to recover meaningful function, sciousness because options for withdrawal diminish as the gains demonstrated in the case may not be as signifi- the patient moves from the acute to the chronic stage of cant as initially believed given the patient’s high baseline illness.9 level of functioning. Arriving at an accurate diagnosis in a patient with a decreased level of consciousness is challenging. Diag- Ethical Considerations in the Treatment of nostic error rates of roughly 40% have been reported in Disorders of Consciousness nursing home patients in an MCS who were labeled as vegetative.1,5,41 The most famous example of such cases Since being first described approximately 4500 years is that of Terry Wallis, a minimally conscious Arkansas ago in the Edwin Smith Papyrus, damage to the adult CNS man who was erroneously diagnosed as vegetative 19 in humans has been regarded as an “ailment which can- years previously; he began to speak fluently in 2003 and not be treated.”7 This view still seems to be the prevailing it was subsequently learned that he likely experienced one with respect to disorders of consciousness. Despite episodic consciousness.8 Two goals should be achieved recent developments in , pharmacology, in the evaluation of patients in PVS and MCS.28 First, it and , the functional utility of these im- should be ascertained whether the patient retains the ca- provements in the setting of disorders of consciousness pacity for a purposeful response to stimulation, even if it remains largely untapped.11 In a recent editorial, Wijdicks is inconsistently manifested. Such an aptitude implies at and Rabinstein40 presented guidelines for meeting with least partial awareness (MCS), which has ramifications

Neurosurg Focus / Volume 29 / August 2010 3 Unauthenticated | Downloaded 09/24/21 01:37 PM UTC A. N. Sen et al. for subsequent care, level of rehabilitation, and ethical vere brain injury, what would be the appropriate ethical decision making. Second, clinical assessment should also response to a patient who received DBS only to awaken focus upon reproducible communication, as consistent from a minimally conscious state to express the consis- communication is the upper boundary of MCS.15 Monti tent desire for termination of care? These issues are not et al.28 used functional MR imaging to evaluate preserved isolated to this debate; this “self-awareness paradox” of awareness in a series of 54 patients in PVS and MCS. In recovery is frequently encountered after initial injury by this series, 3 MCS and 2 PVS patients were determined severely brain-injured patients who must come to terms to able to modulate their brain activity by generating vol- with the comprehension of a “new self.”9,32 untary, reliable, and repeatable neuroimaging responses In cases of disorders of consciousness, evaluating a in predefined neuroanatomical regions when prompted to patient with residual cortical activity and the potential perform imagery tasks.28 to recover neurological functions for stimulation therapy Neurostimulation for MCS is still an area of inves- raises the ethical questions of beneficence and nonmalefi- tigation and not yet a widely accepted therapy.18 While cence. Ostensibly, any procedure resulting in an improve- advances in neuromodulation have the ability to offer ment in could be considered a benefit to the pa- new therapeutic interventions for patients with disorders tient. However, the crux of this ethical argument hinges of consciousness, these interventions have not been tested upon the degree to which cognitive and physical func- in large clinical trials and have been performed in only a tions are restored in patients with severe brain injury.18 If small number of patients. Moreover, conducting clinical a procedure were to completely restore consciousness as research trials in patients with PVS and MCS is difficult well as cognitive and physical functioning, the procedure as a result of regulatory complexity. These patients are would be considered of unequivocal benefit. However, deemed a vulnerable population and thus are subject to it is conceivable that some patients may experience ad- special protections with regard to enrollment in clinical verse psychological effects of DBS that would outweigh trials.9 Although the patient’s surrogate may consent to the benefits of the restorative effects.18 Furthermore, the therapeutic procedures with demonstrated benefit, the difficulty in risk-benefit analysis is complicated by the -as surrogate’s ability to authorize enrollment in a research sertion that restoration of consciousness following brain trial is curtailed when the medical benefit of the treatment injury will likely vary along a spectrum.18 To create a is yet to be demonstrated.10 Ultimately, these restrictions responsible research ethic, current clinical investigators may result in counteracting advances in neuromodula- must attempt to balance the principles of respect, benefi- tion that could aid the population that the United States cence, nonmaleficence, and surrogate consent within an National Bioethics Advisory Commission has sought to ethical framework. protect from exploitation.10 These issues severely limit the potential for Phase I surgical trials in individuals who are Conclusions unable provide consent for the very procedure that may restore some of their decision making capacity. Accord- While the application of DBS for patients in vegeta- ingly, some bioethicists have argued that clinical trials tive and minimally conscious states is relatively novel, to reestablish consciousness would be ethically appro- great promise exists for this neurosurgical intervention in priate, even with the challenges posed by surrogate con- cases in which limited therapeutic options currently ex- sent, when these distinctions and the burdens imposed on ist. Current strategies for the medical management of pa- these patients and families are taken into consideration.12 tients in PVS or MCS are largely guided by principles of Overcoming these barriers is essential if translational re- sustaining life rather than improving a patient’s clinical search is to be accomplished in this population, which has situation, primarily because of the very limited interven- historically been sequestered from clinical research and tional options for such patients. The emerging prospect would otherwise remain in a hopeless clinical situation.14 that DBS may be able to restore function to patients in an With improvements in consciousness also comes the otherwise hopeless situation may bolster the future use of possibility of unexpected burdens.12 In some cases, af- this technology as both clinicians and patients may begin ter stimulation, an individual may become more aware to view DBS as a practicable treatment.11 of cognitive and physical disabilities that he or she was However, before DBS can be viewed as a clinically previously unable to perceive. Cognitive improvements sound therapeutic intervention for patients in MCS or resulting from stimulation would need to be evaluated to even PVS, significant additional research is necessary. determine if the increased awareness of self, others, and Given the absence of a good translational animal model, the environment is, in fact, a “patient-centered benefit.”32 short and long-term results and complications remain In this sense, the harm associated with conscious aware- predominately unknown and untested. Over the past 5 ness of one’s cognitive and physical impairments might decades, only a handful of studies have been conducted be enough to abolish any benefits.18 An appraisal should on a wide variety of patients, with only one most recent not only be restricted to third-person interpretation, but study of a single patient without confounding factors like also a first-person affirmation by the individual who will spontaneous recovery. By report, the US Food and Drug be summarily required to function with these deficits.18 Administration approved use of this therapy in 11 addi- Furthermore, several studies have determined the preva- tional patients to provide more clinical results.24 Current lence of suicidal ideation in people with traumatic brain research is extremely limited both in the number of pa- injuries as varying between 3% and 33%.34 In light of the tients studied, as well as the clinical situations in which increased prevalence of suicidality among people with se- to best consider the application of DBS therapy. Hence,

4 Neurosurg Focus / Volume 29 / August 2010 Unauthenticated | Downloaded 09/24/21 01:37 PM UTC Deep brain stimulation for minimally conscious states no definitive conclusions can be made based on current 11. Fins JJ: The ethics of measuring and modulating conscious- data regarding whether to attempt DBS therapy, or even ness: the imperative of minding time. Prog Brain Res 177: in which patients it would be most beneficial. 371–382, 2009 12. Fins JJ: A proposed ethical framework for interventional cog- While a better understanding of these clinical issues nitive neuroscience: a consideration of deep brain stimulation will invariably emerge following additional trials, the re- in impaired consciousness. Neurol Res 22:273–278, 2000 sultant ethical complexity that will almost certainly en- 13. Fins JJ: Rethinking disorders of consciousness: new research sue will likely need to be thoughtfully deliberated on an and its implications. Hastings Cent Rep 35:22–24, 2005 individual basis. Given the abuses of psychosurgery in the 14. Fins JJ, Schiff ND, Foley KM: Late recovery from the mini- previous century, the use of DBS in the minimally con- mally conscious state: ethical and policy implications. Neu- scious should be supported by strong scientific evidence, rology 68:304–307, 2007 stringent oversight, and the full interdisciplinary sup- 15. Giacino JT: The vegetative and minimally conscious states: port of neurosurgeons, , psychiatrists, and consensus-based criteria for establishing diagnosis and prog- nosis. 19:293–298, 2004 physiatrists who can help assess a patient’s suitability for 16. Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DBS and provide continuous follow-up over time. Never- DI, et al: The minimally conscious state: definition and diag- theless, a significant hope for the future of this technology nostic criteria. 58:349–353, 2002 exists. We are only beginning to discover the full impli- 17. Giacino JT, Kalmar K, Whyte J: The JFK Coma Recovery cations of this application of DBS, and an exciting future Scale-Revised: measurement characteristics and diagnostic may await both patients and providers in a once hopeless utility. Arch Phys Med Rehabil 85:2020–2029, 2004 clinical situation. 18. Glannon W: Neurostimulation and the minimally conscious state. Bioethics 22:337–345, 2008 19. Hassler R, Ore GD, Dieckmann G, Bricolo A, Dolce G: Be- Disclosure havioural and EEG arousal induced by stimulation of un- Dr. Sharan is a consultant for St. Jude, Covidian, and Medtronic; specific projection systems in a patient with post-traumatic and received study support from St. Jude, honoraria from St. Jude apallic syndrome. Electroencephalogr Clin Neurophysiol and Integra, and other financial support from Zimmer Spine. The 27:306–310, 1969 other authors report no conflict of interest concerning the materials 20. Jones EG: The thalamic matrix and thalamocortical synchro- or methods used in this study or the findings specified in this paper. ny. Trends Neurosci 24:595–601, 2001 Author contributions to the study and manuscript preparation 21. Jones EG, Hendry SH: Differential calcium binding protein include the following. Conception and design: Campbell, Yadla, immunoreactivity distinguishes classes of relay neurons in Sharan. Acquisition of data: Campbell, Sen. Analysis and interpre- monkey thalamic nuclei. Eur J Neurosci 1:222–246, 1989 tation of data: Campbell, Sen, Yadla, Sharan. Drafting the article: 22. Kinney HC, Samuels MA: of the persistent Campbell, Sen. Critically revising the article: all authors. Reviewed vegetative state. A review. J Neuropathol Exp Neurol 53: final version of the manuscript and approved it for submission: 548–558, 1994 all authors. Administrative/technical/material support: Campbell, 23. Kinomura S, Larsson J, Gulyás B, Roland PE: Activation by Sharan. Study supervision: Campbell. attention of the human reticular formation and thalamic intra- laminar nuclei. Science 271:512–515, 1996 24. Kuehn BM: Scientists probe deep brain stimulation: some References promise for brain injury, psychiatric illness. JAMA 298:2249– 1. Andrews K, Murphy L, Munday R, Littlewood C: Misdiagno- 2251, 2007 sis of the vegetative state: retrospective study in a rehabilita- 25. Lammi MH, Smith VH, Tate RL, Taylor CM: The minimally tion unit. BMJ 313:13–16, 1996 conscious state and recovery potential: a follow-up study 2 to 2. Bernat JL: Questions remaining about the minimally con- 5 years after . Arch Phys Med Rehabil scious state. Neurology 58:337–338, 2002 86:746–754, 2005 3. Boly M, Faymonville ME, Peigneux P, Lambermont B, Damas 26. Laureys S, Owen AM, Schiff ND: Brain function in coma, P, Del Fiore G, et al: Auditory processing in severely brain vegetative state, and related disorders. Lancet Neurol 3:537– injured patients: differences between the minimally conscious 546, 2004 state and the persistent vegetative state. Arch Neurol 61:233– 27. Machado C, Korein J: Persistent vegetative and minimally 238, 2004 conscious states. Rev Neurosci 20:203–220, 2009 4. Castaigne P, Lhermitte F, Buge A, Escourolle R, Hauw JJ, Ly- 28. Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pick- on-Caen O: Paramedian thalamic and midbrain infarct: clinical ard JD, Tshibanda L, et al: Willful modulation of brain activi- and neuropathological study. Ann Neurol 10:127–148, 1981 ty in disorders of consciousness. N Engl J Med 362:579–589, 5. Childs NL, Mercer WN, Childs HW: Accuracy of diagnosis of 2010 persistent vegetative state. Neurology 43:1465–1467, 1993 29. Moruzzi G, Magoun HW: Brain stem reticular formation and 6. Dieckmann G: Cortical synchronized and desynchronized re- activation of the EEG. 1949. J Clin Neuro- sponses evoked by stimulation of the putamen and pallidum in sci 7:251–267, 1995 cats. J Neurol Sci 7:385–391, 1968 30. Purpura KP, Schiff ND: The thalamic intralaminar nuclei: a 7. Donovan WH: Donald Munro Lecture. —past, role in visual awareness. 3:8–15, 1997 present, and future. J Spinal Cord Med 30:85–100, 2007 31. Schiff N, Purpura K: Towards a neurophysiological founda- 8. Fins JJ: Being conscious of their burden: severe brain injury tion for cognitive neuromodulation. Thalamus Relat Syst 2: and the two cultures challenge. Ann N Y Acad Sci 1157:131– 55–69, 2002 147, 2009 32. Schiff ND, Giacino JT, Fins JJ: Deep brain stimulation, neu- 9. Fins JJ: Clinical pragmatism and the care of brain damaged roethics, and the minimally conscious state: moving beyond patients: toward a palliative for disorders of con- proof of principle. Arch Neurol 66:697–702, 2009 sciousness. Prog Brain Res 150:565–582, 2005 33. Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber 10. Fins JJ: Constructing an ethical stereotaxy for severe brain in- M, et al: Behavioural improvements with thalamic stimula- jury: balancing risks, benefits and access. Nat Rev Neurosci tion after severe traumatic brain injury. Nature 448:600–603, 4:323–327, 2003 2007 (Erratum in Nature 452:120, 2008)

Neurosurg Focus / Volume 29 / August 2010 5 Unauthenticated | Downloaded 09/24/21 01:37 PM UTC A. N. Sen et al.

34. Simpson G, Tate R: Suicidality in people surviving a traumat- functional evidence for participation in processes of arousal ic brain injury: prevalence, risk factors and implications for and awareness. Brain Res Brain Res Rev 39:107–140, 2002 clinical management. Brain Inj 21:1335–1351, 2007 40. Wijdicks EF, Rabinstein AA: The family conference: end-of- 35. Staunton H: Arousal by stimulation of deep-brain nuclei. Na- life guidelines at work for comatose patients. Neurology 68: ture 452:E1–E2, 2008 1092–1094, 2007 36. Sturm V, Kühner A, Schmitt HP, Assmus H, Stock G: Chronic 41. Wilson FC, Harpur J, Watson T, Morrow JI: Vegetative state electrical stimulation of the thalamic unspecific activating and minimally responsive patients—regional survey, long- system in a patient with coma due to midbrain and upper brain term case outcomes and service recommendations. NeuroRe- stem infarction. Acta Neurochir (Wien) 47:235–244, 1979 habilitation 17:231–236, 2002 37. Tsubokawa T, Yamamoto T, Katayama Y, Hirayama T, Mae- 42. Yamamoto T, Katayama Y: Deep brain stimulation therapy jima S, Moriya T: Deep-brain stimulation in a persistent veg- for the vegetative state. Neuropsychol Rehabil 15:406–413, etative state: follow-up results and criteria for selection of can- 2005 didates. Brain Inj 4:315–327, 1990 38. Van Der Werf YD, Weerts JG, Jolles J, Witter MP, Lindeboom J, Scheltens P: Neuropsychological correlates of a right uni- Manuscript submitted April 14, 2010. lateral lacunar thalamic infarction. J Neurol Neurosurg Psy- Accepted April 21, 2010. chiatry 66:36–42, 1999 Address correspondence to: Peter G. Campbell, M.D., 909 Wal­ 39. Van der Werf YD, Witter MP, Groenewegen HJ: The intra- nut Street, 3rd Floor, Philadelphia, Pennsylvania 19107. email: peter. laminar and midline nuclei of the thalamus. Anatomical and [email protected].

6 Neurosurg Focus / Volume 29 / August 2010 Unauthenticated | Downloaded 09/24/21 01:37 PM UTC