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. Author manuscript; available in PMC: 2013 Jun 6.
Published in final edited form as: Curr Opin Neurol. 2011 Dec;24(6):564–569. doi: 10.1097/WCO.0b013e32834cd4f5

What is the role of brain mechanisms underlying arousal in recovery of motor function after structural brain injuries?

Andrew M Goldfine 1,✉, Nicholas D Schiff 1
PMCID: PMC3675222  NIHMSID: NIHMS474749  PMID: 22002078

Abstract

Purpose of review

Standard neurorehabilitation approaches have limited impact on motor recovery in patients with severe injuries. Consideration of the contributions of impaired arousal offers a novel approach to understand and enhance recovery.

Recent findings

Animal and human neuroimaging studies are elucidating the neuroanatomical bases of arousal and of arousal regulation, the process by which the cerebrum mobilizes resources. Studies of patients with disorders of consciousness have revealed that recovery of these processes is associated with marked improvements in motor performance. Recent studies have also demonstrated that patients with less severe brain injuries also have impaired arousal, manifesting as diminished sustained attention, fatigue and apathy. In these less severely injured patients it is difficult to connect disorders of arousal with motor recovery due to a lack of measures of arousal independent of motor function.

Summary

Arousal impairment is common after brain injury and likely plays a significant role in recovery of motor function. A more detailed understanding of this connection will help to develop new therapeutic strategies applicable for a wide range of patients. This requires new tools that continuously and objectively measure arousal in patients with brain injury, to correlate with detailed measures of motor performance and recovery.

Keywords: arousal regulation, sustained attention, post-stroke fatigue, post-stroke apathy, goal-directed behavior

Introduction

Only a small percentage of the variance of motor recovery from stroke, and likely traumatic brain injury (TBI), is explainable by rehabilitation interventions; the remainder falls under the category of “spontaneous” recovery (1,2). In the setting of focal stroke, animal model and human imaging studies provide evidence that recovery of movement is associated with peri-lesional brain regions taking over for lost functions (3,4). On the other hand, in the setting of larger injuries produced by large-vessel strokes or TBI, this local neuroplasticity may play less of a role. In these situations, we propose that a major driver of motor recovery is restitution of brain networks supporting arousal and production of goal-directed behavior.

Below we briefly review the neuroanatomical basis of level of arousal and the initiation and maintenance of goal-directed behavior. We then review evidence from a variety of brain injury types for the connection of functioning of these networks and recovery of motor function and learning. This connection is strongest in cases of severe brain injury with disorders of consciousness, but there is also evidence for patients with milder diffuse or focal injuries. Finally we discuss steps that can be taken in future work to clarify the role of arousal in recovery of motor function in patients without disorders of consciousness to support the development of appropriate interventions.

Background

Goal-directed movements require, in addition to the typically discussed sensory and motor systems, an adequate level of generalized arousal and a mobilization of distributed neural networks to initiate and sustain the behavior. Generalized arousal refers to an overall state function of brain activity, and in the intact brain, ranges from stage three non-REM sleep, where strong stimuli are required to elicit a response, to states of high vigilance within wakefulness, where subtle stimuli can be detected and acted upon(5,6). Within the awake state, level of arousal is often termed alertness, and can be measured by speed of response to stimuli, and ability to continue responding over a period of time (i.e. vigilance or sustained attention) (7). Initiation and maintenance of goal-directed behavior involves enhancement of arousal with a focus on activation of corticothalamic networks involved in task performance. This mobilization of resources (8) is one of the brain’s “executive functions” and is termed arousal regulation (9).

Arousal level and regulation of arousal are supported by a collection of highly interactive cortical, subcortical and brainstem areas. The core areas for generalized arousal appear to be glutamatergic and cholinergic neurons in the dorsal tegmentum of the midbrain and pons (10,11). In humans, these neuronal populations broadly activate the cerebrum predominantly via the basal forebrain and central thalamus (primarily intralaminar nuclei). The basal forebrain and central thalamus subsequently activate the cortex through cholinergic and glutamatergic projections, respectively. The brainstem norepinephrine system also enhances arousal via modulation of the cortex, basal forebrain, and thalamic intralaminar nuclei. (12,13). Other arousal system components include brainstem dopaminergic, and hypothalamic histaminergic and orexin/hypocretin producing neurons (14–17).

Arousal regulation is primarily implicated in healthy subjects during tasks requiring enhancement of alertness or sustained attention. It is primarily supported by activity in the medial frontal and anterior cingulate cortices, though also relies on the broadly activating neurons of the intralaminar thalamus (18–21). Further organization of goal-directed behaviors is by broadly distributed activity across frontal and parietal systems (22). Loop connections between the frontal and parietal cortices, basal ganglia and thalamus (both specific and non-specific) are also important to focus and support both arousal regulation and organization of behavior (23–25).

In healthy subjects, arousal and arousal regulation play a major role in motor performance and motor learning. Low arousal states, such as those often produced by sleep deprivation, are well known to impair motor performance and learning (26). Sleep deprivation is associated with decreased metabolism on FDG PET (fluorodeoxyglucose positron emission tomography) across the frontal lobe, basal ganglia and thalamic regions that support goal-directed behavior (27,28). This is consistent with other studies showing that activation of these regions is the first to reduce with sleep onset (29), and the last to recover after awakening, associated with an impairment of motor responsiveness known as ‘sleep inertia’ (30). A recent study using local-field potential recording in rats supports that the hypometabolism during sleep deprivation represents intermittent pauses in firing of cortical neurons (31). The authors suggested that these cortical areas are entering a local sleep state despite an overall appearance of wakefulness, and that this local sleep state can impair motor performance.

Increasing arousal through processes including motivation, reward, pain, stimulant medications and anxiety, improves motor performance and learning to a point, though too high levels of stimulation impair behavior and learning (32,33). Arousal-promoting stimuli likely improve behavior by enhancing signal to noise ratios; but too high levels of arousal can enhance response to all stimuli, preventing detection of salient ones (34).

The effect of brain injury on arousal and production of goal-directed behavior

Diffuse and focal brain injuries can impair goal-directed behavior by directly injuring or disconnecting the networks of brain areas involved in arousal and arousal regulation. The connection between these injuries and recovery of motor performance and learning is clearest in patients with global impairments in brain function, known as disorders of consciousness. For patients with less severe diffuse injuries or focal injuries, there is evidence of deficits in arousal and arousal regulation, but less so for a connection with motor recovery.

The disorders of consciousness arising from structural brain injury include coma, vegetative state, and the minimally conscious state (35). Three canonical pathophysiologies are: widespread neuronal death and/or disconnection from global hypoxia; diffuse axonal injury (DAI) from TBI; and focal destruction of the upper brainstem and thalamus often from top of the basilar stroke. These anatomic pathologies all involve dysfunction of corticothalamic activity from either direct loss of neurons or overwhelming impairment of arousal system activation. In these conditions, recovery of voluntary movement is by definition associated with recovery of arousal (36), though the inverse is not true, due to deficits of corticospinal (37) or higher order motor systems (38–40). Evidence for the causal link of improved arousal and motor recovery include patients with rapid improvements in arousal due to zolpidem (41) and central thalamic deep brain stimulation (DBS) (42), who had marked improvements in movement ability. Recovery of consciousness is also associated with return of motor learning. One extreme example is a patient who recovered consciousness after 19 years in the minimally conscious state, and over the subsequent year transitioned from no lower extremity movement, to being able to use his lower extremities to elevate his lower back to help in personal care (43).

A relevant, but less common disorder of consciousness is akinetic mutism (44,45). Here the behavioral appearance is that of low-level minimally conscious state, but the injury is restricted to areas involved in arousal regulation (medial frontal cortices or connected subcortical nuclei), without loss or disconnection of typical brainstem or basal forebrain arousal centers (46). One of the hallmarks of the syndrome of akinetic mutism is the occasional appearance of high-level organized behaviors in response to specific stimuli (47); these marked variations in goal-directed behavior may provide a model of the role of arousal regulation in motor system function. The pathophysiology of akinetic mutism thus could provide clues for ways to recruit the arousal regulation networks towards recovery of goal-directed behavior in patients with disorders of consciousness. A recently proposed model (48) suggests that specific variations in the activation of different cell types within this network can alter widespread corticothalamic activity, and thereby explain fluctuations in goal-directed behavior in akinetic mutism and similar syndromes. This model accounts for the role of dopaminergic agents (49–51), zolpidem (41,52), central thalamic DBS (42), and other potential agents that would act on these neuronal subsystems.

In patients with less severe diffuse brain injuries, deficits in arousal and arousal regulation are common. Even six months post-injury, subjective and objective evidence of excessive daytime sleepiness is relatively common in patients with TBI (53), and affects ability to sustain attention (54). Daily fluctuations in arousal can lead to significant variations in behavior (55,56). Theories for mechanisms of impaired arousal and arousal regulation include loss of cholinergic neurons (57) and impaired cortical connectivity (58), possibly produced from residual axonal injury (59). The connection between recovery of arousal and of motor function in this population is not well understood, though is important, as motor recovery can be prolonged and incomplete (60).

In patients with focal brain injury from stroke, the clearest cases of impaired arousal are in those with focal injuries to the upper brainstem and thalamus, who may either have a disorder of consciousness (discussed above), or may appear alert, but demonstrate impaired attention and slowed responsiveness (61). Strokes of the medial frontal lobe or basal ganglia, areas involved in arousal regulation, may result in a milder form of akinetic mutism called abulia (47). There is also evidence that the syndrome of left-sided neglect can be due to damage to areas involved in arousal regulation, resulting in loss of right greater than left arousal tone, rather than a specific loss of attentional network functioning (62). These syndromes are clearly relevant to overall function after stroke, but their role in motor recovery still needs to be determined.

In patients with focal stroke but without damage to arousal systems or regions involved in arousal regulation, there is still a significant prevalence of disorders of arousal and production of goal directed behavior, presenting as fatigue and apathy. Both fatigue and apathy are defined by patient description of a lack of drive to perform goal-directed behaviors, with motivation retained in fatigue, but lost in apathy. Both syndromes have been documented post-stroke independent of depression (63,64) and correlate with prolonged disability (65,66). The connection between fatigue and apathy and the patterns of underlying brain injuries is still poorly defined (67), though one study did find a higher prevalence with brainstem strokes (68). The lack of a clear pathophysiologic basis is likely due to a combination of small sample sizes in observational studies, multiple other contributing factors (e.g. pre-morbid depression, infection, medications, sleep disorders, medical comorbidities), and definition of conditions by use of questionnaires rather than physiological biomarkers. Going forward, it is important to develop objective markers of apathy and fatigue to determine their role in motor recovery and to develop treatment approaches aimed at underlying mechanisms.

There is also evidence that exogenous factors that act on arousal pathways may affect motor performance and recovery from brain injury. Medications that correlate with slower recovery and inhibit generalized arousal include: alpha-2 adrenergic agonists (generally inhibit norepinephrine release); GABA enhancers (benzodiazepines and barbiturates); and antiepileptics including phenytoin (69–71). Benzodiazepines have even been shown to transiently reinstate motor deficits in patients in the chronic stage post-stroke (72). Anti-dopaminergic agents such as haloperidol also slow recovery from brain injury (69), with potential mechanisms including inhibition of an implicit form of arousal regulation (73) and of skill learning (74). Conversely, medications that enhance noradrenergic (75) and dopaminergic (74) neurotransmitter levels have been shown in animal studies to improve motor learning and recovery, though human trials have been inconsistent (76). Sleep disorders are another common factor after stroke and TBI (77,78) and affect recovery. As with direct effects of brain injury on arousal and initiation, most of the studies on exogenous factors are observational and use non-physiological outcome measures. An approach focused on mechanism could reveal which patients’ recoveries are being impaired by these factors, and which ones would most benefit from interventions to enhance arousal.

An approach to determine the role of arousal in recovery of motor function after structural brain injury

The above review highlighted some of the anatomy of highly interconnected brain networks supporting arousal and production of goal-directed behavior. We reviewed clinical evidence linking specific patterns of brain injuries, as well as common exogenous arousal-inhibiting factors, that affect the functioning of these networks. However, with the exception of patients with disorders of consciousness, the demonstrated connection between improved arousal and motor recovery is weak. One reason is that the behavioral definitions of arousal and arousal regulation are either based on subjective patient reports, or on neuropsychological measures (e.g. vigilance tests) that require movement as the output. By requiring patients to move to respond, deficits in arousal and motor control are confounded. Furthermore, most trials are retrospective, limiting interpretation. To address these limitations to allow for development of new therapeutic strategies, we now offer a framework for future studies to allow for a more direct association between these phenomena.

To better define arousal and arousal regulation, behavioral measures should be based on objective evidence of a patients’ overall level of responsiveness, as well as performance of goal-directed behavior. Wireless wearable devices now offer a solution to monitor patient behavior continuously and without need for direct interaction with research staff. Triaxial accelerometers have been used in the home and rehabilitation setting for patients with stroke and brain injury and can demonstrate overall level of activity (79), as well as more specific actions such as walking speed (80). Machine-learning algorithms allow for detection of more complex behaviors such as reaching and grasping (81). Once level of goal-directed behavior can be defined, it can be correlated with other measures of arousal that don’t require voluntary movement including eye closures and EEG (electroencephalography)(82–85).

Once objective markers of arousal and goal-directed behavior are available, they should be incorporated into observational and clinical trials focused on motor recovery from brain injury. Motor outcome measures in these trials should include both impairment and disability measures, as it is important to determine whether arousal and measures of arousal regulation correlate with true recovery at a kinematic level, or with compensation behaviors. If such information can be included in clinical trials, it may help reveal some of the unexplained variance in recovery (2), so causative factors can be discovered. Further, it also may help to explain the varied responsiveness to adrenergic agents (75), as these drugs may benefit those who have loss of movement from impaired arousal, rather than loss of motor systems.

Conclusion

Sufficient arousal level and ability to regulate arousal to mobilize neuronal resources are basic requirements for all higher-level behaviors. This is shown in our daily lives with sleep-wake cycling and in states of sleep deprivation, and is also revealed by the global impairments in behavior in patients with disorders of consciousness. Above we review evidence that the systems that support goal-directed behavior are dysfunctional in a wide range of brain-injured patients. Experience with patients with disorders of consciousness has revealed that enhancement of activity in systems underlying arousal and arousal regulation can lead to marked improvements in motor recovery. We suggest that a deeper study of the presence and influence of arousal disorders in patients with less severe brain injuries will reveal underlying sources of delayed recovery, as well as identify new targets and approaches to enhance recovery.

Key points.

  • Goal-directed behavior requires an adequate arousal level as well as ability to mobilize neuronal resources, termed arousal regulation.

  • Recovery of arousal and arousal regulation in patients with disorders of consciousness can be associated with marked recovery of motor performance.

  • Disorders of arousal and production of goal-directed behavior are common in patients with traumatic brain injury and stroke.

  • New approaches are needed to document disorders of arousal and goal-directed behavior after brain injury independent of motor dysfunction.

Acknowledgments

AMG and NDS are both funded by the National Institutes of Health.

AMG has done consulting work with Johnson and Johnson pharmaceuticals. AMG is supported by grant KL2RR024997 of the Clinical & Translational Science Center at Weill Cornell Medical College. NDS is supported by NIH grants NS067249, HD51912, and the James S. McDonnell Foundation.

Footnotes

NDS has no conflicts of interest.

References

  • 1.Kwakkel G, Kollen B, Lindeman E. Understanding the pattern of functional recovery after stroke: facts and theories. Restor Neurol Neurosci. 2004;22(3–5):281–99. [PubMed] [Google Scholar]
  • 2.Prabhakaran S, Zarahn E, Riley C, Speizer A, Chong JY, Lazar RM, et al. Inter-individual variability in the capacity for motor recovery after ischemic stroke. Neurorehabil Neural Repair. 2008 Feb;22(1):64–71. doi: 10.1177/1545968307305302. [DOI] [PubMed] [Google Scholar]
  • 3.Dancause N, Nudo RJ. Shaping plasticity to enhance recovery after injury. Prog Brain Res. 2011;192:273–95. doi: 10.1016/B978-0-444-53355-5.00015-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Buma FE, Lindeman E, Ramsey NF, Kwakkel G. Review: Functional Neuroimaging Studies of Early Upper Limb Recovery After Stroke: A Systematic Review of the Literature. Neurorehabilitation and Neural Repair. 2010;24(7):589–608. doi: 10.1177/1545968310364058. [DOI] [PubMed] [Google Scholar]
  • 5.Steriade M, McCarley RW. Brain control of wakefulness and sleep. Springer; 2005. p. 768. [Google Scholar]
  • 6.Pfaff D. Brain Arousal and Information Theory: Neural and Genetic Mechanisms. 1. Harvard University Press; 2005. [Google Scholar]
  • 7.Oken BS, Salinsky MC, Elsas SM. Vigilance, alertness, or sustained attention: physiological basis and measurement. Clin Neurophysiol. 2006 Sep;117(9):1885–901. doi: 10.1016/j.clinph.2006.01.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Kahneman D. Attention and Effort. Prentice Hall; 1973. p. 240. [Google Scholar]
  • 9.Schiff ND. Central Thalamic Contributions to Arousal Regulation and Neurological Disorders of Consciousness. Annals of the New York Academy of Sciences. 2008 May 1;1129(1):105–18. doi: 10.1196/annals.1417.029. [DOI] [PubMed] [Google Scholar]
  • 10.Steriade M, Glenn LL. Neocortical and caudate projections of intralaminar thalamic neurons and their synaptic excitation from midbrain reticular core. J Neurophysiol. 1982 Aug;48(2):352–71. doi: 10.1152/jn.1982.48.2.352. [DOI] [PubMed] [Google Scholar]
  • 11.Parvizi J, Damasio A. Consciousness and the brainstem. Cognition. 2001 Apr;79(1–2):135–60. doi: 10.1016/s0010-0277(00)00127-x. [DOI] [PubMed] [Google Scholar]
  • 12.Berridge CW. Noradrenergic modulation of arousal. Brain Res Rev. 2008 Jun;58(1):1–17. doi: 10.1016/j.brainresrev.2007.10.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Vogt BA, Hof PR, Friedman DP, Sikes RW, Vogt LJ. Norepinephrinergic afferents and cytology of the macaque monkey midline, mediodorsal, and intralaminar thalamic nuclei. Brain Struct Funct. 2008 Aug;212(6):465–79. doi: 10.1007/s00429-008-0178-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci. 2002 Nov;5( Suppl):1071–5. doi: 10.1038/nn944. [DOI] [PubMed] [Google Scholar]
  • 15.Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep State Switching. Neuron. 2010 Dec 22;68(6):1023–42. doi: 10.1016/j.neuron.2010.11.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Bayer L, Eggermann E, Saint-Mleux B, Machard D, Jones BE, Mühlethaler M, et al. Selective Action of Orexin (Hypocretin) on Nonspecific Thalamocortical Projection Neurons. The Journal of Neuroscience. 2002;22(18):7835–9. doi: 10.1523/JNEUROSCI.22-18-07835.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Parmentier R, Anaclet C, Guhennec C, Brousseau E, Bricout D, Giboulot T, et al. The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochemical Pharmacology. 2007 Apr 15;73(8):1157–71. doi: 10.1016/j.bcp.2007.01.002. [DOI] [PubMed] [Google Scholar]
  • 18.Nagai Y, Critchley HD, Featherstone E, Fenwick PBC, Trimble MR, Dolan RJ. Brain activity relating to the contingent negative variation: an fMRI investigation. NeuroImage. 2004 Apr;21(4):1232–41. doi: 10.1016/j.neuroimage.2003.10.036. [DOI] [PubMed] [Google Scholar]
  • 19.Paus T, Koski L, Caramanos Z, Westbury C. Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies. Neuroreport. 1998 Jun 22;9(9):R37–47. doi: 10.1097/00001756-199806220-00001. [DOI] [PubMed] [Google Scholar]
  • 20.Paus T, Zatorre RJ, Hofle N, Caramanos Z, Gotman J, Petrides M, et al. Time-Related Changes in Neural Systems Underlying Attention and Arousal During the Performance of an Auditory Vigilance Task. Journal of Cognitive Neuroscience. 1997;9(3):392–408. doi: 10.1162/jocn.1997.9.3.392. [DOI] [PubMed] [Google Scholar]
  • 21.Kinomura S, Larsson J, Gulyás B, Roland PE. Activation by Attention of the Human Reticular Formation and Thalamic Intralaminar Nuclei. Science. 1996 Jan 26;271(5248):512–5. doi: 10.1126/science.271.5248.512. [DOI] [PubMed] [Google Scholar]
  • 22.Andersen RA, Cui H. Intention, Action Planning, and Decision Making in Parietal-Frontal Circuits. Neuron. 2009 Sep 10;63(5):568–83. doi: 10.1016/j.neuron.2009.08.028. [DOI] [PubMed] [Google Scholar]
  • 23.McFarland NR, Haber SN. Convergent Inputs from Thalamic Motor Nuclei and Frontal Cortical Areas to the Dorsal Striatum in the Primate. The Journal of Neuroscience. 2000 May 15;20(10):3798–813. doi: 10.1523/JNEUROSCI.20-10-03798.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Zikopoulos B, Barbas H. Parallel Driving and Modulatory Pathways Link the Prefrontal Cortex and Thalamus. PLoS ONE. 2007;2(9):e848. doi: 10.1371/journal.pone.0000848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Grillner S, Hellgren J, Menard A, Saitoh K, Wikstrom M. Mechanisms for selection of basic motor programs roles for the striatum and pallidum. Trends in Neurosciences. 2005 Jul;28(7):364–70. doi: 10.1016/j.tins.2005.05.004. [DOI] [PubMed] [Google Scholar]
  • 26.Killgore WDS. Effects of sleep deprivation on cognition. Prog Brain Res. 2010;185:105–29. doi: 10.1016/B978-0-444-53702-7.00007-5. [DOI] [PubMed] [Google Scholar]
  • 27.Thomas M, Sing H, Belenky G, Holcomb H, Mayberg H, Dannals R, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res. 2000 Dec;9(4):335–52. doi: 10.1046/j.1365-2869.2000.00225.x. [DOI] [PubMed] [Google Scholar]
  • 28.Wu JC, Gillin JC, Buchsbaum MS, Chen P, Keator DB, Khosla Wu N, et al. Frontal Lobe Metabolic Decreases with Sleep Deprivation not Totally Reversed by Recovery Sleep. Neuropsychopharmacology. 2006 Jul;31(12):2783–92. doi: 10.1038/sj.npp.1301166. [DOI] [PubMed] [Google Scholar]
  • 29.Braun AR, Balkin TJ, Wesenten NJ, Carson RE, Varga M, Baldwin P, et al. Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study. Brain. 1997 Jul 1;120(7):1173–97. doi: 10.1093/brain/120.7.1173. [DOI] [PubMed] [Google Scholar]
  • 30.Balkin TJ, Braun AR, Wesensten NJ, Jeffries K, Varga M, Baldwin P, et al. The process of awakening: a PET study of regional brain activity patterns mediating the re-establishment of alertness and consciousness. Brain. 2002 Oct 1;125(10):2308–19. doi: 10.1093/brain/awf228. [DOI] [PubMed] [Google Scholar]
  • 31**.Vyazovskiy VV, Olcese U, Hanlon EC, Nir Y, Cirelli C, Tononi G. Local sleep in awake rats. Nature. 2011 Apr;472(7344):443–7. doi: 10.1038/nature10009. This study reveals that a potential mechanism for impaired performance with sleep deprivation is brief periods of localized cortical sleep. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Yerkes RM, Dodson JD. The relation of strength of stimulus to rapidity of habit-formation. Journal of Comparative Neurology and Psychology. 1908;18(5):459–82. [Google Scholar]
  • 33.Arent SM, Landers DM. Arousal, anxiety, and performance: a reexamination of the Inverted-U hypothesis. Res Q Exerc Sport. 2003 Dec;74(4):436–44. doi: 10.1080/02701367.2003.10609113. [DOI] [PubMed] [Google Scholar]
  • 34.Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AFT. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007 Mar;10(3):376–84. doi: 10.1038/nn1846. [DOI] [PubMed] [Google Scholar]
  • 35.Goldfine AM, Schiff ND. Consciousness: Its Neurobiology and the Major Classes of Impairment. Neurologic Clinics. 2011 doi: 10.1016/j.ncl.2011.08.001. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, et al. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002 Feb 12;58(3):349–53. doi: 10.1212/wnl.58.3.349. [DOI] [PubMed] [Google Scholar]
  • 37.Smart CM, Giacino JT, Cullen T, Moreno DR, Hirsch J, Schiff ND, et al. A case of locked-in syndrome complicated by central deafness. Nat Clin Pract Neurol. 2008 Aug;4(8):448–53. doi: 10.1038/ncpneuro0823. [DOI] [PubMed] [Google Scholar]
  • 38.Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting Awareness in the Vegetative State. Science. 2006 Sep 8;313(5792):1402. doi: 10.1126/science.1130197. [DOI] [PubMed] [Google Scholar]
  • 39**.Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, Tshibanda L, et al. Willful Modulation of Brain Activity in Disorders of Consciousness. N Engl J Med. 2010 Feb;362(7):579–89. doi: 10.1056/NEJMoa0905370. This study describes patients who appear to be in vegetative or minimally conscious states, yet can demonstrate high-level cognitive behaviors via fMRI. Its relevance here is in demonstrating that return of movement requires both recovery of high level goal directed behavior and functional motor systems. [DOI] [PubMed] [Google Scholar]
  • 40**.Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA, Tabelow K, et al. Dissociations between behavioural and functional magnetic resonance imaging-based evaluations of cognitive function after brain injury. Brain. 2011 Mar;134(Pt 3):769–82. doi: 10.1093/brain/awr005. This study complements the study by Monti and colleagues by revealing that the imagery tasks performed by some patients behaviorally in vegetative or minimally conscious state, are cognitively demanding enough that they cannot be performed by some patients who are behaviorally fully conscious. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Brefel-Courbon C, Payoux P, Ory F, Sommet A, Slaoui T, Raboyeau G, et al. Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy. Ann Neurol. 2007 Jul;62(1):102–5. doi: 10.1002/ana.21110. [DOI] [PubMed] [Google Scholar]
  • 42.Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber M, et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature. 2007;448(7153):600–3. doi: 10.1038/nature06041. [DOI] [PubMed] [Google Scholar]
  • 43.Voss HU, Uluç AM, Dyke JP, Watts R, Kobylarz EJ, McCandliss BD, et al. Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest. 2006 Jul 3;116(7):2005–11. doi: 10.1172/JCI27021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Cairns H, Oldfield RC, Pennybacker JB, Whitteridge D. Akinetic mutism with an epidermoid cyst of the 3rd ventricle. Brain. 1941 Dec 1;64(4):273–90. [Google Scholar]
  • 45.Segarra JM. Cerebral Vascular Disease and Behavior: The Syndrome of the Mesencephalic Artery (Basilar Artery Bifurcation) Arch Neurol. 1970 May 1;22(5):408–18. doi: 10.1001/archneur.1970.00480230026003. [DOI] [PubMed] [Google Scholar]
  • 46.Schiff ND, Plum F. The role of arousal and “gating” systems in the neurology of impaired consciousness. J Clin Neurophysiol. 2000 Sep;17(5):438–52. doi: 10.1097/00004691-200009000-00002. [DOI] [PubMed] [Google Scholar]
  • 47.Fisher CM. Honored guest presentation: abulia minor vs. agitated behavior. Clin Neurosurg. 1983;31:9–31. doi: 10.1093/neurosurgery/31.cn_suppl_1.9. [DOI] [PubMed] [Google Scholar]
  • 48.Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends in Neurosciences. 2010 Jan;33(1):1–9. doi: 10.1016/j.tins.2009.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Kraus MF, Smith GS, Butters M, Donnell AJ, Dixon E, Yilong C, et al. Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET) Brain Inj. 2005 Jul;19(7):471–9. doi: 10.1080/02699050400025059. [DOI] [PubMed] [Google Scholar]
  • 50.Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil. 2002 Aug;17(4):300–13. doi: 10.1097/00001199-200208000-00004. [DOI] [PubMed] [Google Scholar]
  • 51.Fridman EA, Krimchansky BZ, Bonetto M, Galperin T, Gamzu ER, Leiguarda RC, et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj. 2010;24(4):636–41. doi: 10.3109/02699051003610433. [DOI] [PubMed] [Google Scholar]
  • 52.Schiff ND, Posner JB. Another “Awakenings. Ann Neurol. 2007 Jul;62(1):5–7. doi: 10.1002/ana.21158. [DOI] [PubMed] [Google Scholar]
  • 53.Baumann CR, Werth E, Stocker R, Ludwig S, Bassetti CL. Sleep wake disturbances 6 months after traumatic brain injury: a prospective study. Brain. 2007 Jul 1;130(7):1873–83. doi: 10.1093/brain/awm109. [DOI] [PubMed] [Google Scholar]
  • 54.Whyte J, Polansky M, Fleming M, Coslett HB, Cavallucci C. Sustained arousal and attention after traumatic brain injury. Neuropsychologia. 1995 Jul;33(7):797–813. doi: 10.1016/0028-3932(95)00029-3. [DOI] [PubMed] [Google Scholar]
  • 55.Hart T, Whyte J, Millis S, Bode R, Malec J, Richardson RN, et al. Dimensions of Disordered Attention in Traumatic Brain Injury: Further Validation of the Moss Attention Rating Scale. Archives of Physical Medicine and Rehabilitation. 2006 May;87(5):647–55. doi: 10.1016/j.apmr.2006.01.016. [DOI] [PubMed] [Google Scholar]
  • 56.Sherer M, Yablon SA, Nakase-Richardson R. Patterns of recovery of posttraumatic confusional state in neurorehabilitation admissions after traumatic brain injury. Arch Phys Med Rehabil. 2009 Oct;90(10):1749–54. doi: 10.1016/j.apmr.2009.05.011. [DOI] [PubMed] [Google Scholar]
  • 57.Salmond CH, Chatfield DA, Menon DK, Pickard JD, Sahakian BJ. Cognitive sequelae of head injury: involvement of basal forebrain and associated structures. Brain. 2005 Jan 1;128(1):189–200. doi: 10.1093/brain/awh352. [DOI] [PubMed] [Google Scholar]
  • 58**.Castellanos NP, Paúl N, Ordóñez VE, Demuynck O, Bajo R, Campo P, et al. Reorganization of functional connectivity as a correlate of cognitive recovery in acquired brain injury. Brain. 2010;133(8):2365–81. doi: 10.1093/brain/awq174. This MEG study of patients with severe brain injury demonstrates normalization of cerebral synchrony occurring along with cognitive recovery. It supports the concept that patients with diffuse brain injury retain potential for marked recovery with the support of increased arousal tone or reconnection of networks of goal-directed behavior. [DOI] [PubMed] [Google Scholar]
  • 59*.Kinnunen KM, Greenwood R, Powell JH, Leech R, Hawkins PC, Bonnelle V, et al. White matter damage and cognitive impairment after traumatic brain injury. Brain. 2011 Feb;134(Pt 2):449–63. doi: 10.1093/brain/awq347. This diffusion tensor MRI study of patients with varied degrees of traumatic brain injury supports the idea that disruption of white matter tracks leads to specific cognitive deficits. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Katz DI, Alexander MP, Klein RB. Recovery of arm function in patients with paresis after traumatic brain injury. Arch Phys Med Rehabil. 1998 May;79(5):488–93. doi: 10.1016/s0003-9993(98)90060-0. [DOI] [PubMed] [Google Scholar]
  • 61.Katz DI, Alexander MP, Mandell AM. Dementia Following Strokes in the Mesencephalon and Diencephalon. Arch Neurol. 1987 Nov 1;44(11):1127–33. doi: 10.1001/archneur.1987.00520230017007. [DOI] [PubMed] [Google Scholar]
  • 62.Corbetta M, Shulman GL. Spatial Neglect and Attention Networks. Annual Review of Neuroscience. 2011 Jul 21;34:569–99. doi: 10.1146/annurev-neuro-061010-113731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Starkstein SE, Fedoroff JP, Price TR, Leiguarda R, Robinson RG. Apathy following cerebrovascular lesions. Stroke. 1993 Nov;24(11):1625–30. doi: 10.1161/01.str.24.11.1625. [DOI] [PubMed] [Google Scholar]
  • 64.Ingles JL, Eskes GA, Phillips SJ. Fatigue after stroke. Archives of Physical Medicine and Rehabilitation. 1999 Feb;80(2):173–8. doi: 10.1016/s0003-9993(99)90116-8. [DOI] [PubMed] [Google Scholar]
  • 65.Andersen G, Christensen D, Kirkevold M, Johnsen SP. Post-stroke fatigue and return to work: a 2-year follow-up. Acta Neurol Scand [Internet] 2011 Jun 21; doi: 10.1111/j.1600-0404.2011.01557.x. [cited 2011 Jul 28]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/21692753. [DOI] [PubMed]
  • 66.Hama S, Yamashita H, Shigenobu M, Watanabe A, Hiramoto K, Kurisu K, et al. Depression or apathy and functional recovery after stroke. Int J Geriat Psychiatry. 2007 Oct;22(10):1046–51. doi: 10.1002/gps.1866. [DOI] [PubMed] [Google Scholar]
  • 67.Choi-Kwon S, Kim JS. Poststroke fatigue: an emerging, critical issue in stroke medicine. Int J Stroke. 2011 Aug;6(4):328–36. doi: 10.1111/j.1747-4949.2011.00624.x. [DOI] [PubMed] [Google Scholar]
  • 68.Staub F, Bogousslavsky J. Fatigue after Stroke: A Major but Neglected Issue. Cerebrovascular Diseases. 2001;12(2):75–81. doi: 10.1159/000047685. [DOI] [PubMed] [Google Scholar]
  • 69.Goldstein LB. Common drugs may influence motor recovery after stroke. The Sygen In Acute Stroke Study Investigators. Neurology. 1995 May;45(5):865–71. doi: 10.1212/wnl.45.5.865. [DOI] [PubMed] [Google Scholar]
  • 70.Taylor S, Heinrichs RJ, Janzen JM, Ehtisham A. Levetiracetam is Associated with Improved Cognitive Outcome for Patients with Intracranial Hemorrhage. Neurocritical Care. 2010 Oct 2;15:80–4. doi: 10.1007/s12028-010-9341-6. [DOI] [PubMed] [Google Scholar]
  • 71.Cunningham MO, Dhillon A, Wood SJ, Jones RSG. Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin. Neuroscience. 1999 Dec;95(2):343–51. doi: 10.1016/s0306-4522(99)00468-6. [DOI] [PubMed] [Google Scholar]
  • 72.Lazar RM, Berman MF, Festa JR, Geller AE, Matejovsky TG, Marshall RS. GABAergic but not anti-cholinergic agents re-induce clinical deficits after stroke. J Neurol Sci. 2010 May 15;292(1–2):72–6. doi: 10.1016/j.jns.2010.01.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Mazzoni P, Hristova A, Krakauer JW. Why Don’t We Move Faster? Parkinson’s Disease, Movement Vigor, and Implicit Motivation. The Journal of Neuroscience. 2007 Jul 4;27(27):7105–16. doi: 10.1523/JNEUROSCI.0264-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Hosp JA, Pekanovic A, Rioult-Pedotti MS, Luft AR. Dopaminergic Projections from Midbrain to Primary Motor Cortex Mediate Motor Skill Learning. The Journal of Neuroscience. 2011 Feb 16;31(7):2481–7. doi: 10.1523/JNEUROSCI.5411-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Barbay S, Nudo RJ. The effects of amphetamine on recovery of function in animal models of cerebral injury: a critical appraisal. NeuroRehabilitation. 2009;25(1):5–17. doi: 10.3233/NRE-2009-0495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Martinsson L, Hårdemark H, Eksborg S. Amphetamines for improving recovery after stroke. Cochrane Database Syst Rev. 2007;(1):CD002090. doi: 10.1002/14651858.CD002090.pub2. [DOI] [PubMed] [Google Scholar]
  • 77.Hermann DM, Bassetti CL. Sleep-related breathing and sleep-wake disturbances in ischemic stroke. Neurology. 2009 Oct 20;73(16):1313–22. doi: 10.1212/WNL.0b013e3181bd137c. [DOI] [PubMed] [Google Scholar]
  • 78.Rao V, Rollings P. Sleep disturbances following traumatic brain injury. Curr Treat Options Neurol. 2002 Feb;4(1):77–87. doi: 10.1007/s11940-002-0006-4. [DOI] [PubMed] [Google Scholar]
  • 79.Schnakers C, Hustinx R, Vandewalle G, Majerus S, Moonen G, Boly M, et al. Measuring the effect of amantadine in chronic anoxic minimally conscious state. Journal of Neurology, Neurosurgery & Psychiatry. 2008 Feb 1;79(2):225–7. doi: 10.1136/jnnp.2007.124099. [DOI] [PubMed] [Google Scholar]
  • 80*.Dobkin BH, Xu X, Batalin M, Thomas S, Kaiser W. Reliability and Validity of Bilateral Ankle Accelerometer Algorithms for Activity Recognition and Walking Speed After Stroke. Stroke. 2011;42(8):2246–50. doi: 10.1161/STROKEAHA.110.611095. This study shows that inexpensive, noninvasive devices (accelerometers) can give information about motor behavior more ecologically valid than, and often unobtainable by, standard laboratory approaches. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81*.Patel S, Hughes R, Hester T, Stein J, Akay M, Dy J, et al. Tracking motor recovery in stroke survivors undergoing rehabilitation using wearable technology. Conf Proc IEEE Eng Med Biol Soc. 2010:6858–61. doi: 10.1109/IEMBS.2010.5626446. This preliminary study shows that wireless accelerometers will soon be able to give detailed assessments of quality of reaching movements in the home setting. [DOI] [PubMed] [Google Scholar]
  • 82.Dockree PM, Kelly SP, Foxe JJ, Reilly RB, Robertson IH. Optimal sustained attention is linked to the spectral content of background EEG activity: greater ongoing tonic alpha (10 Hz) power supports successful phasic goal activation. European Journal of Neuroscience. 2007 Feb 1;25(3):900–7. doi: 10.1111/j.1460-9568.2007.05324.x. [DOI] [PubMed] [Google Scholar]
  • 83.Makeig S, Inlow M. Lapse in alertness: coherence of fluctuations in performance and EEG spectrum. Electroencephalography and Clinical Neurophysiology. 1993 Jan;86(1):23–35. doi: 10.1016/0013-4694(93)90064-3. [DOI] [PubMed] [Google Scholar]
  • 84**.Sadaghiani S, Scheeringa R, Lehongre K, Morillon B, Giraud A-L, Kleinschmidt A. Intrinsic Connectivity Networks, Alpha Oscillations, and Tonic Alertness: A Simultaneous Electroencephalography/Functional Magnetic Resonance Imaging Study. The Journal of Neuroscience. 2010 Jul 28;30(30):10243–50. doi: 10.1523/JNEUROSCI.1004-10.2010. This study measured fluctuations in spontaneous “resting state” brain activity to reveal the connection between the brain regions most involved in arousal regulation and an EEG-measurement of alertness. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Jung Tzyy-Ping, Makeig S, Stensmo M, Sejnowski TJ. Estimating alertness from the EEG power spectrum. IEEE Transactions on Biomedical Engineering. 1997 Jan;44(1):60–9. doi: 10.1109/10.553713. [DOI] [PubMed] [Google Scholar]

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