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Auditory Processing in Severely Brain Injured Patients
Differences Between the Minimally Conscious State and the Persistent Vegetative State
Mélanie Boly, BS;
Marie-Elisabeth Faymonville, MD, PhD;
Philippe Peigneux, PhD;
Bernard Lambermont, MD, PhD;
Pierre Damas, MD, PhD;
Guy Del Fiore, PhD;
Christian Degueldre, PhD;
Georges Franck, MD, PhD;
André Luxen, PhD;
Maurice Lamy, MD, PhD;
Gustave Moonen, MD, PhD;
Pierre Maquet, MD, PhD;
Steven Laureys, MD, PhD
Arch Neurol. 2004;61:233-238.
ABSTRACT
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Background The minimally conscious state (MCS) is a recently defined clinical condition; it differs from the persistent vegetative state (PVS) by the presence of inconsistent, but clearly discernible, behavioral evidence of consciousness.
Objective To study auditory processing among patients who are in an MCS, patients who are in a PVS, and healthy control subjects.
Methods By means of 15O-radiolabeled water–positron emission tomography, we measured changes in regional cerebral blood flow induced by auditory click stimuli in 5 patients in an MCS, 15 patients in a PVS, and 18 healthy controls.
Results In both patients in an MCS and the healthy controls, auditory stimulation activated bilateral superior temporal gyri (Brodmann areas 41, 42, and 22). In patients in a PVS, the activation was restricted to Brodmann areas 41 and 42 bilaterally. We also showed that, compared with patients in a PVS, patients in an MCS demonstrated a stronger functional connectivity between the secondary auditory cortex and temporal and prefrontal association cortices.
Conclusions Although assumptions about the level of consciousness in severely brain injured patients are difficult to make, our findings suggest that the cerebral activity observed in patients in an MCS is more likely to lead to higher-order integrative processes, thought to be necessary for the gain of conscious auditory perception.
INTRODUCTION
The minimally conscious state (MCS) has recently been defined as "a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated".1(pp350-351) Bedside evaluation of residual cognitive function in patients in an MCS is difficult because they are rapidly exhausted and may show fluctuating levels of arousal, attention, and motor responsiveness. We used 15O-radiolabeled water–positron emission tomography (PET) to objectively measure cerebral activation patterns in response to auditory stimuli in patients in an MCS and compared it with that observed in healthy control subjects and in patients in a persistent vegetative state (PVS). Given that our previous studies have stressed the role of functional cerebral integration deficits in unconscious patients in a PVS,2-3 we also looked for differences in cortico-cortical functional connectivity4 during auditory processing in patients in an MCS compared with patients in a PVS.
METHODS
SUBJECTS
We prospectively studied 5 patients in an MCS (2 females and 3 males; age range, 46-74 years), 15 patients in a PVS (3 females and 12 males; age range, 19-75 years), and 18 healthy volunteers (10 females and 8 males; age range, 19-64 years). Patients' conditions were diagnosed according to internationally established criteria for MCS1 and PVS.5 Demographic data of patients in an MCS are summarized in Table 1. Demographic data of patients in a PVS have been reported previously2; causes were cardiorespiratory arrest (n = 5), diffuse axonal injury (n = 3), drug overdose (n = 2), prolonged respiratory insufficiency (n = 2), encephalitis with diffuse white matter lesions (n = 2), and carbon monoxide intoxication (n = 1). All patients had preserved pupillary, corneal, and vestibuloocular reflexes.
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Table 1. Clinical, Electrophysiological, and Structural Imaging Data of Patients in the Minimally Conscious State
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After admission to the hospital and while in awake periods (as demonstrated by simultaneous polygraphic recordings) patients underwent scanning a mean (SD) of 33 (11) days for those in an MCS and 36 (9) days for those in a PVS. Informed consent was obtained from the persons having legal responsibility for the patients and from all controls. The study was approved by the ethics committee of the University of Liège, Liège, Belgium.
DATA ACQUISITION
Changes in regional cerebral blood flow were measured using 15O-radiolabeled water–PET as described elsewhere.3 Scanning was performed during rest and left-sided and right-sided auditory stimulation (5.1-Hz, 95-dB monaural clicks with contralateral 55-dB white noise). The remaining scans were performed with median nerve stimulation (14 patients in a PVS and 4 patients in an MCS) or presentation of human voices (1 patient in a PVS and 1 patient in an MCS). Results regarding the other acquisitions will be reported elsewhere once a larger cohort of patients is included. Each condition was repeated 3 times and the presentation order was pseudorandomized. Patients' vital parameters and brainstem auditory evoked potentials were recorded throughout the procedure. Stimulation intensity was identical for all subjects. A high-resolution, T1-weighted, magnetic resonance image was obtained for coregistration to the PET data.
DATA ANALYSIS
Positron emission tomographic data were realigned, spatially normalized,6 smoothed (16 mm), and analyzed using statistical parametric mapping (SPM99).7 Data obtained during left-sided auditory stimulation and rest were flipped as reported previously.3 A random effect8 analysis identified brain areas that activated during auditory stimulation. We calculated 1 contrast (stimulation-rest) per subject (accounting for the within-subject component of the variance) and used these contrast images in a second design matrix (accounting for the between-subject component of the variance) separating the data into 3 groups (controls, patients in an MCS, and patients in a PVS). We then performed 2 conjunction analyses looking for activation (1) common to controls and those in a PVS and (2) common to controls and those in an MCS. We also looked for the groups (MCS-PVS) x condition (stimulation-rest) interaction, searching for areas less activated in patients in a PVS than in patients in an MCS. Given our a priori3 activation in superior temporal areas, results were thresholded at small-volume–corrected P<.05 (20-mm-diameter sphere centered on peak voxels).
Finally, a psychophysiological interaction analysis2-4 looked for differences in functional connectivity between MCS and PVS. Our hypothesis was that patients in an MCS and patients in a PVS would differ in their degree of functional integration of auditory stimuli. We identified areas in which activity was modulated by secondary auditory cortex (ie, peak activation in controls; Brodmann area 42) differently in those in an MCS vs those in a PVS. As we expected a large diversity of areas9 and no a priori areas could be suggested; results were thresholded at cluster- or voxel-level–corrected P<.05.
RESULTS
Brainstem auditory evoked potentials were normal, showing preserved function of the auditory periphery to the inferior colliculus in all patients. In controls, auditory stimulation activated auditory cortex contralateral and ipsilateral to the side of stimulation (mean volumes of activation were 6.4 and 1.6 mL, respectively; Figure 1A). The activated areas encompassed bilateral transverse temporal gyri (TTG) (Brodmann area 41) and superior temporal gyrus (STG) (Brodmann areas 42 and 22) (Table 2). In patients in an MCS, auditory stimulation activated bilateral auditory cortex (mean volumes were 2.8 mL contralateral and 1.6 mL ipsilateral to the side of stimulation; Figure 1B). Peak voxels were located in bilateral TTG (Brodmann area 41) and STG (Brodmann areas 42 and 22) (Table 2). In patients in a PVS, auditory stimuli also activated the bilateral auditory cortex, but the extent of this activation was much smaller (mean volumes were 0.4 mL contralateral and 0.7 mL ipsilateral; Figure 1C). The peak voxels were located in bilateral TTG (Brodmann area 41) and STG (Brodmann area 42) (Table 2). In controls, patients in a PVS, or patients in an MCS, activation patterns were not significantly different for left- or right-sided auditory stimulation. The group (those in an MCS vs those in a PVS) x task (stimulation vs rest) interaction did not reveal significant differences in cerebral activation between our 2 patient groups.
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Figure 1. Brain regions showing activation during auditory stimulation in healthy control subjects (A), patients in a minimally conscious state (B), and patients in a persistent vegetative state (C). Coronal section 28 mm behind the anterior commissural line.
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Table 2. Areas That Became Activated During Auditory Stimulation in Healthy Control Subjects and in Patients in an MCS
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Finally, we observed a significantly tighter functional connectivity2-4 in patients in an MCS than in patients in a PVS between Brodmann area 42 contralateral to the stimulation and a network of brain areas including contralateral posterior temporal areas (Brodmann areas 21 and 22) and several prefrontal regions: bilateral middle frontal gyri (Brodmann areas 9 and 46), contralateral inferior frontal gyrus (Brodmann area 44-45), and contralateral frontal pole (Brodmann area 10) (Table 3 and Figure 2).
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Table 3. Areas Where Functional Connectivity With Secondary Auditory Cortex Was Different in Patients in MCS Compared With Patients in PVS
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Figure 2. Cross-correlation of neural activity in auditory cortex (coordinates -44, -31, and 7) and prefrontal cortex (coordinates -42, 35, and 4) in patients in a minimally conscious state (MCS) vs patients in a persistent vegetative state (PVS). Inset, View of the the brain areas that remain functionally connected with auditory cortex in patients in an MCS but not in patients in a PVS. BA indicates Brodmann area; rCBF, regional cerebral blood flow.
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COMMENT
In response to auditory stimulation, patients in an MCS activated spatially larger areas of auditory cortex than did patients in a PVS. Functional connectivity2-4 between the secondary auditory cortex and the posterior temporal and prefrontal areas, involved in higher levels of auditory processing, was significantly more effective in patients in an MCS than in patients in a PVS. In agreement with our previous results,3 controls activated bilateral temporal Brodmann areas 41, 42, and 22. Patients in a PVS activated bilateral Brodmann areas 41 and 42, but not higher-order associative Brodmann area 22. These results extend to a larger population of patients then our previous work about auditory processing in a PVS.3 Moreover, using a random effect analysis, we identified the common denominator of cortical activation in response to these auditory stimuli in the patient in a canonical PVS.
In patients in an MCS, the activation pattern was spatially more extended than in patients in a PVS and encompassed not only Brodmann auditory areas 41 and 42 but also higher-order Brodmann area 22. A direct comparison between MCS and PVS, however, showed no significant difference in activation. This might be due to (1) an intermediate level of activation in patients in an MCS compared with controls and patients in a PVS, (2) power limitations of the design (large variance in patient populations), or (3) lack of emotional valence of the auditory stimuli. Indeed, clinical experience shows that patients in an MCS are often more responsive to stimuli with high emotional content. Nevertheless, the activation of higher-order associative temporal cortices found in patients in an MCS probably corresponds to a more elaborate auditory processing, allowing further cognitive integration of the stimuli.
Whereas the aforementioned analyses of cerebral segregation related to simple auditory processing did not show significant differences between patients in an MCS and patients in a PVS, the study of functional connectivity2-4 showed significant differences in cortical integration of the stimuli between patients in an MCS and patients in a PVS. Indeed, only patients in an MCS showed preserved functional connections between Brodmann area 42 and posterior temporal and prefrontal associative areas. Posterior temporal cortices (Brodmann area 22-21) have been involved in high-order auditory perception.11-12 The unimodal part of this auditory associative area (Brodmann area 22) is thought to be involved in the analysis of temporal acoustic features of speech and other highly modulated sounds.13 Whereas its temporoparietal junction area is known to receive inputs from caudal parabelt areas,14 many of its neurons are heteromodal and participate in cognitive aspects of auditory processing.15 Functional imaging studies have reported activation of this area during auditory attention and perception.16-18 Lesions in this region lead to contralateral hemi-inattention, neglect, or extinction of auditory stimuli in both monkeys19 and humans.20 The posterior part of the middle temporal gyrus (Brodmann area 21) is a multimodal associative area. Its neurons do not code for specific acoustic features (eg, do not exhibit frequency tuning), but are thought to be closely related to auditory selective attention16 and aware perception.17 Therefore, the observed preservation in cortico-cortical connectivity within different regions of the auditory associative Brodmann areas in the MCS compared with the PVS could be related to differences in attentional state and conscious perception.
Our findings also showed preserved functional connections in patients in an MCS between Brodmann area 42 and dorsolateral prefrontal (Brodmann areas 9 and 46), posterior inferior frontal (Brodmann areas 44 and 45), and frontopolar (Brodmann area 10) cortices. The role of the frontal lobe in auditory processing and its connections with auditory association cortices are not yet as precisely determined as for the visual domain. However, studies in primates demonstrate connections between the temporal and prefrontal cortex.12 Recent work also suggests the involvement of frontal processing in successful normal auditory perception.21 Prefrontal cortex is also known to be involved in auditory attention16, 22 and conscious perception of auditory stimuli.17
Apart from their clinical interest, our findings also contribute to the study of the neural correlates of consciousness. It is, however, of major importance to stress that our results should be used with appropriate caution regarding clinical decisions in individuals in a PVS or an MCS. Our data describe canonical PVS and MCS but do not rule out that some individuals might have cortical activation above the identified common denominator of cortical activation. For instance, some patients in a PVS may show a relatively preserved isolated cortical activity,23-24 which may express itself through isolated nonpurposeful behavior.24 Also, the present 15O-radiolabled water–PET studies are only snapshot assessments of residual brain function, even if they were acquired during continuous electroencephalographic monitoring to assure the highest possible level of vigilance in each patient. It is well known from clinical experience that repetitive evaluations are mandatory in the evaluation and categorization of severely brain injured patients.
CONCLUSIONS
We showed preserved activation in bilateral auditory cortices (Brodmann areas 41 and 42) in patients in a PVS during simple auditory click stimuli, which probably reflects a residual neural encoding of basic sound attributes without further high-order processing or functional integration.3 In patients in an MCS, a more widespread activation was observed, encompassing bilateral auditory associative areas (Brodmann area 22), suggesting a more elaborate level of processing. Moreover, we identified differences in cortico-cortical functional connectivity between auditory cortex and a large network of temporal and prefrontal cortices in patients in an MCS compared with patients in a PVS. These findings encourage ongoing developments of neuromodulatory and cognitive revalidation therapeutic strategies in patients in an MCS.10 As a next step, more complex auditory stimuli should be used to better characterize the residual cognitive faculties of patients in an MCS.
AUTHOR INFORMATION
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Corresponding author: Steven Laureys, MD, PhD, Cyclotron Research Center and Department of Neurology, University of Liège, Sart Tilman B35, 4000 Liège, Belgium (e-mail: steven.laureys{at}ulg.ac.be).
Accepted for publication September 25, 2003.
Author contributions: Study concept and design (Drs Maquet and Laureys); acquisition of data (Drs Faymonville, Lambermont, Damas, Del Fiore, Degueldre, and Laureys); analysis and interpretation of data (Ms Boly and Drs Peigneux, Franck, Luxen, Lamy, Moonen, and Laureys); drafting of the manuscript (Ms Boly and Dr Laureys); critical revision of the manuscript for important intellectual content (Drs Faymonville, Peigneux, Lambermont, Damas, Del Fiore, Degueldre, Franck, Luxen, Lamy, Moonen, and Maquet); statistical expertise (Ms Boly and Drs Peigneux, Maquet, and Laureys); obtaining funding (Drs Franck, Luxen, Lamy, Moonen, and Maquet); administrative, technical, or material support (Drs Lambermont, Del Fiore, Damas, and Degueldre); study supervision (Dr Faymonville, Maquet and Laureys).
This study was supported by grant 3.4536.99 from Fonds National de la Recherche Scientifique, Brussels, Belgium; Reine Elisabeth Medical Foundation, Brussels; research grants from the University of Liège; and Pôle D'Attraction Interuniversitaire Projet de recherche PAI/IAP P5/04, Brussels (Dr Peigneux).
We thank Patrick Hawotte, Jean-Luc Génon, Christianne Mesters, George Hodiaumont, and Jeannine Hodiaumont for their technical assistance.
We thank Timothy Griffiths, MD, PhD, Newcastle University Medical School, Newcastle upon Tyne, England, for having kindly reviewed the first version of the manuscript.
From the Cyclotron Research Center (Ms Boly and Drs Peigneux, Del Fiore, Degueldre, Maquet, Luxen, and Laureys), and the Departments of Neurology (Drs Franck, Moonen, Maquet, and Laureys), Anesthesiology and Reanimation (Drs Faymonville, Damas, and Lamy), Intensive Care Medicine (Drs Faymonville, Lambermont, Damas, and Lamy), Neuropsychology (Dr Peigneux), and Internal Medicine (Dr Lambermont), University of Liège, Liège, Belgium.
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