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Regional cerebral blood flow changes related to affective speech presentation in persistent vegetative state
Clinical Neurology and Neurosurgery ELSEVIER
Clinical Neurology and Neurosurgery 99 (1997) 213 216
Case report
Regional cerebral blood flow changes related to affective speech presentation in persistent vegetative state B.M. de Jong
a,*
A.T.M. Willemsen
b
A.M.J. Paans b
a Department of Neurology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands b Positron Emission Tomography Center, University Hospital Groningen, 9700 RB Groningen, The Netherlands
Received 11 April 1997; received in revised form 23 April 1997; accepted 23 April 1997
Abstract A story told by his mother was presented on tape to a trauma patient in persistent vegetative state (PVS). During auditory presentation, measuremelats of regional cerebral blood flow (rCBF) were performed by means of positron emission tomography (PET). Changes in rCBF related to this stimulus condition, as compared to presenting non-word sound, were evaluated by means of statistical parametric mapping (SPM). This analysis indicated activation of rostral anterior cingulate, right middle temporal and right premotor cortices, which may reflect appropriate cortical involvement in processing emotional attributes of sound or speech. © 1997 Elsevier Science B.V. Keywords: Positron emis,;ion tomography; Regional cerebral blood flow activation; Persistent vegetative state; Coma
1. Introduction Persistent vegetatiw,' state (PVS) is a neurological condition characterized by the absence of signs indicating awareness of self and surroundings, with preservation of vital vegetative functions, presence of sleep-wake cycles and occasional smiling or crying. There is no purposeful behaviour [1,2]. In contrast, the 'locked-in' syndrome includes body paralysis and inability to speak, but communication is still possible due to the patient's control of voluntary eye movements or blinks. This condition results from a lesion in the pons. If PVS, however, is accompanied by specific focal lesions on CT or MRI (e.g. mesencephalic or diencephalic), the question suggests itself whether some level of awareness might still be present of which expression is obstructed by complete paralysis. Measuring changes in regional cerebral blood flow (rCBF) related * Corresponding author. Tel.: +31 50 3612430; fax: +31 50 3611707. 0303-8467/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S0303-8467(97)000714-3
to cognitive stimulation [3,4] may provide insight in preserved cortical circuitry involved in (rudimentary) cognitive function. In the patient study presented we applied positron emission tomography (PET) in order to localize a possible cortical response induced by the voice of the patient's mother, as she was telling a domestic story. This experimental paradigm was designed along the question of the parents whether the patient would notice their voice. In order to maximize possible cerebral activation, mother was asked to present a story with familiar subjects.
2. Patient history and methods 2. I. P a t i e n t history
A 16 year old right-handed boy (JW) was a a car accident while riding his bicycle. On admission he had an isolated head injury with coma scale (GCS) E1-M2-V1, without motor
victim in hospital Glasgow response
214
B. de Jong et a l . / Clinical Neurology and Neurosurgery 99 (1997) 213 216
on the right side; pupils (5 mm) did not respond to light. Patient was intubated. CT scanning revealed a left epi-, subdural hematoma with mass effect. After neurosurgery pupils did respond to light again, GCS was 1-4-1. After 2 days the clinical picture was complicated by tentorial herniation which was treated with mannitol. CT revealed oedema, slight increase of ventricle and a right temporo-parietal sign of a haemorrhagic countercoup contusion. Ventricular drainage enabled the measurement of intracranial pressure while barbiturate sedation was given. CT after 3 weeks showed reduction of oedema, but also demarcation of hypodens regions particularly in the left hemisphere. On day 27 ventilation support could be stopped, GCS was 4-2-1 (bilateral extension response). The patient still remained in a vegetative state 2 months after injury. Conjugated eye-movements were induced by moving objects, no fixating saccades were made. Sudden noise might induce eyeblinks. Arms did not move spontaneously, the left knee was occasionally raised. Pain-stimuli given either left or right induced grimacing. Tendon reflexes right were more brisk than left, with bilateral Babinski signs and manual grasp reflexes. EEG registration 2 months after injury showed asymmetry with predominantly slow delta activity over the left hemisphere, 7 Hz activity over the right side and intermittent frontal rhythmic delta activity (FIRDA). Dubious suppression on light flashing was seen. At this time the PET study was performed. 2.2. P E T methods
Ordered in pairs AB or BA, 12 consecutive rCBF measurements were made, during which either nonword sound (condition A) or a domestic story told by the boy's mother (condition B) was presented on tape. Each measurement was performed in a Siemens CTI 951/31 PET scanner (10.8 cm axial field of view, fixed intercollimating septa). Scans lasted 90 s and started 20 s after intravenous injection of a 1.85 GBq bolus 15-O labelled H20. During scanning the patient was awake, as could be observed by his opened eyes. An interval of 20 min was kept between each scanning period. Statistical parametric mapping (SPM, version 1993), which includes both stereotaxic and global CBF normalization, was applied in order to evaluate the distribution of significant rCBF increases related to condition B [4-6].
(Fig. 1, upper row). Analysis of rCBF changes revealed that modulation of rCBF related to the presentation of mother's story, in comparison with non-words, was restricted to cortical areas of mainly the right hemisphere (Fig. 1, lower row). Radioactivity values were not thresholded in the SPM procedure. Therefore, modulation outside the most lesioned areas of the brain indicated that the observed changes were not introduced by statistical noise. The most significant increases (omnibus 0.001 threshold, Z-score above 3.5) were found in the right middle temporal gyrus (Brodmann Area 21), the rostral part of the anterior cingulate gyrus (BA 24) and inferiorly on the precentral gyrus (premotor cortex BA 6) (Table 1).
4. Discussion
The main finding of this study was that auditory presentation of language with an affective connotation regarding both intonation and content, induced rCBF changes in specific regions of the cerebral cortex. As sound was presented in both conditions tested, the observed distribution of rCBF changes, exceeding primary auditory areas, suggested the preservation of cortical neuronal responses related to complex stimulation in the here reported condition of PVS. In this case, the patient's left hemisphere was extensively lesioned. Therefore, language related activation of this hemisphere, which has been well documented in normal subjects, was unlikely to occur. However, the loci of activation on the right middle temporal gyrus and the rostral part of the anterior Table 1 Activated areas related to the presentation of mother's story Brodmann area
Talairach coordinates
z
x, y
Z-score
BA 21 BA 11 BA 21
-16 --12 --4
-50, 4 - 1 0 , 54 -56, -46
3.3 3.2 3.9
BA 24
4
- 6 , 34
3.6
BA45 BA 30 BA29 BA6
16 16 20 28
- 4 8 , 34 4, - 4 0 8, - 3 8 -54, -4
3.1 3.1 3.1 3.7
BA 8
40
- 3 4 , 26
3.3
Middle temporal gyrus Anterior cingulate gyrus
Precentral gyrus
3. Results
The mean rCBF distribution indicated lesioning of especially the left hemisphere. Cortical and ipsilateral basal ganglia rCBF was of the same order of magnitude
Localization of the areas with significant rCBF comparing the condition of presenting mother's sound (omnibus P<0.001). Positive x, y and z positions respectively left, anterior and superior anterior commissure.
change by SPM {t}, story with non-word coordinates indicate of the middle of the
B. de Jong et al./ Clinical Neurology and Neurosurgery 99 (1997) 213-216
215
Fig. 1. Upper row: Mean rCBF reflecting the distribution of gray matter, with lesioning of the left hemisphere. The plane with the anterior and posterior commissures (AC.PC) is positioned on level 0 by stereotaxic normalization. Lower row: SPM {t} loci of rCBF increases. Areas with Z-score > 3.5 are distributed over the right middle temporal gyrus (plane - 4), the anterior cingulate ( + 4) and the right premotor cortex ( + 28). Sections are transformed into Talairach coordinate space.
cingulate gyrus were highly similar to the regions Bottini et al. [7] have described to be related to the interpretation o f figurative aspects o f language. Indeed, the role o f the right hemisphere in nonlinguistic aspects o f language processing, such as comprehension o f the affective intonation o f speech, has been reported be,fore [8]. The right middle temporal gyrus and m e r e explicitly the right superior temporal gyrus m a y also be assumed to play a role in phonological processing [9]. We c a n n o t definitively answer the question whether indeed neutral words
would have activated the right temporal region as m u c h as the emotive story in our patient study. Activation localized rostrally in the anterior cingulate cortex, which was observed both in this study and in the afore q u o t e d study o f Bottini et al. [7], has also been reported to occur in relation to the verbal recall o f sad events in c o m b i n a t i o n with looking at sad faces [10]. In contrast, increases in r C B F related to nociception [11], attention and response selection [12,13,3,14] have been demonstrated to occur more caudally in the anterior cingulate cortex. The
216
B. de Jong et a l . / Clinical Neurology and Neurosurgery 99 (1997) 213-216
results from such PET studies are consistent with a general division of anterior cingulate cortex function into 'affect' and 'cognitive' components [15]. Based on these arguments, it seems to be legitimate to suggest that the right temporal and anterior cingulate cortex activation observed in our patient reflect a contribution to processing affective aspects of the presented story. Such affective aspects may either be carried by basic acoustic qualities of mother's voice, or be derived from fragments of the story's content. Whether rCBF increase of the right premotor cortex located anteriorly to the mouth representation on the primary motorstrip might reflect a responsive attempt to get access to executive control function [3] remains speculation. Notwithstanding care that has to be taken with regard to interpretation of the results from this study, they indicate that in some circumstances of PVS, elements of complex stimulation may be processed in appropriate cortical circuitry. Although the linkage between such cortical activity and awareness goes beyond the scope of scientific discussion, the here described findings suggest that the distinction between PVS and locked-in syndrome may be a gradual one.
References [1] Persistent vegetative state: Report of the American Neurological Association Committee on Ethical Affairs. Ann Neurol 1993;33:386-390. [2] Medical aspects of the persistent vegetative state. Multi-society task force on PVS. N Eng J Med 1994;330:1499-1508.
[3] Petersen SE, Fox PT, Posner MI, Mintum M, Raichle ME. PET studies of cortical anatomy of single-word processing. Nature 1988;331:585-9. [4] Friston K J, Frith CD, Liddle PF, Frackowiak RSJ. Comparing functional (PET) images: The assessment of significant change. J Cereb Blood Flow Metab 1991;11:690-9. [5] Friston K J, Frith CD, Liddle PF, Frackowiak RSJ. Plastic transformation of PET images. J Comput Assist Tomogr 1991;15:634-9. [6] Talairach J, Tournoux P. Co-Planar Stereotaxic Atlas of the Human Brain. Stuttgart: Thieme Verlag, 1988. [7] Bottini G, Corcoran R, Sterzi R, Paulesu E, Schenone P, Scarpa P, Frackowiak RSJ, Frith CD. The role of the right hemisphere in the interpretation of figurative aspects of language. A PET activation study. Brain 1994;117:1241 53. [8] Heilman KM, Scholes R, Watson RT. Auditory affective agnosia. J Neurol Neurosurg Psychiatry 1975;38:69-72. [9] Demonet JF, Chollet F, Ramsay S, Cardebat D, Nespoulos JL, Wise R, Rascol A, Frackowiak RSJ. The anatomy of phonological and semantic processing in normal subjects. Brain 1992;115:1753-68. [10] George MS, Ketter TA, Parekh PI, Horwitz B, Herscovitch P, Post RM. Brain activity during transient sadness and happiness in healthy women. Am J Psychiatry 1995;152:341-51. [11] Jones APK, Brown WD, Friston KJ, Qi LY, Frackowiak RSJ. Cortical and subcortical localization of response to pain in man using PET. Proc R Soc Lond 1991;B 224:39 44. [12] Corbetta M, Miezin FM, Shulman GL, Petersen SE. A PET study of visuospatial attention. J Neurosci 1993;13:1202-26. [13] Pardo JV, Pardo PJ, Janer KW, Raichle ME. The anterior cingulate mediates processing selection in the stroop attentional conflict paradigm. Proc Natl Acad Sci USA 1990;87:256-9. [14] Paus T, Petrides M, Evans AC, Meyer E. Role of the anterior cingulate cortex in the control of oculomotor, manual and speech responses: A PET study. J Neurophysiol 1993;70:453 69. [15] Devinsky O, Morrell M J, Vogt BA. Contributions of anterior cingulate cortex to behaviour [review]. Brain 1995;118:279- 306.
Clinical Neurology and Neurosurgery 99 (1997) 213 216
Case report
Regional cerebral blood flow changes related to affective speech presentation in persistent vegetative state B.M. de Jong
a,*
A.T.M. Willemsen
b
A.M.J. Paans b
a Department of Neurology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands b Positron Emission Tomography Center, University Hospital Groningen, 9700 RB Groningen, The Netherlands
Received 11 April 1997; received in revised form 23 April 1997; accepted 23 April 1997
Abstract A story told by his mother was presented on tape to a trauma patient in persistent vegetative state (PVS). During auditory presentation, measuremelats of regional cerebral blood flow (rCBF) were performed by means of positron emission tomography (PET). Changes in rCBF related to this stimulus condition, as compared to presenting non-word sound, were evaluated by means of statistical parametric mapping (SPM). This analysis indicated activation of rostral anterior cingulate, right middle temporal and right premotor cortices, which may reflect appropriate cortical involvement in processing emotional attributes of sound or speech. © 1997 Elsevier Science B.V. Keywords: Positron emis,;ion tomography; Regional cerebral blood flow activation; Persistent vegetative state; Coma
1. Introduction Persistent vegetatiw,' state (PVS) is a neurological condition characterized by the absence of signs indicating awareness of self and surroundings, with preservation of vital vegetative functions, presence of sleep-wake cycles and occasional smiling or crying. There is no purposeful behaviour [1,2]. In contrast, the 'locked-in' syndrome includes body paralysis and inability to speak, but communication is still possible due to the patient's control of voluntary eye movements or blinks. This condition results from a lesion in the pons. If PVS, however, is accompanied by specific focal lesions on CT or MRI (e.g. mesencephalic or diencephalic), the question suggests itself whether some level of awareness might still be present of which expression is obstructed by complete paralysis. Measuring changes in regional cerebral blood flow (rCBF) related * Corresponding author. Tel.: +31 50 3612430; fax: +31 50 3611707. 0303-8467/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S0303-8467(97)000714-3
to cognitive stimulation [3,4] may provide insight in preserved cortical circuitry involved in (rudimentary) cognitive function. In the patient study presented we applied positron emission tomography (PET) in order to localize a possible cortical response induced by the voice of the patient's mother, as she was telling a domestic story. This experimental paradigm was designed along the question of the parents whether the patient would notice their voice. In order to maximize possible cerebral activation, mother was asked to present a story with familiar subjects.
2. Patient history and methods 2. I. P a t i e n t history
A 16 year old right-handed boy (JW) was a a car accident while riding his bicycle. On admission he had an isolated head injury with coma scale (GCS) E1-M2-V1, without motor
victim in hospital Glasgow response
214
B. de Jong et a l . / Clinical Neurology and Neurosurgery 99 (1997) 213 216
on the right side; pupils (5 mm) did not respond to light. Patient was intubated. CT scanning revealed a left epi-, subdural hematoma with mass effect. After neurosurgery pupils did respond to light again, GCS was 1-4-1. After 2 days the clinical picture was complicated by tentorial herniation which was treated with mannitol. CT revealed oedema, slight increase of ventricle and a right temporo-parietal sign of a haemorrhagic countercoup contusion. Ventricular drainage enabled the measurement of intracranial pressure while barbiturate sedation was given. CT after 3 weeks showed reduction of oedema, but also demarcation of hypodens regions particularly in the left hemisphere. On day 27 ventilation support could be stopped, GCS was 4-2-1 (bilateral extension response). The patient still remained in a vegetative state 2 months after injury. Conjugated eye-movements were induced by moving objects, no fixating saccades were made. Sudden noise might induce eyeblinks. Arms did not move spontaneously, the left knee was occasionally raised. Pain-stimuli given either left or right induced grimacing. Tendon reflexes right were more brisk than left, with bilateral Babinski signs and manual grasp reflexes. EEG registration 2 months after injury showed asymmetry with predominantly slow delta activity over the left hemisphere, 7 Hz activity over the right side and intermittent frontal rhythmic delta activity (FIRDA). Dubious suppression on light flashing was seen. At this time the PET study was performed. 2.2. P E T methods
Ordered in pairs AB or BA, 12 consecutive rCBF measurements were made, during which either nonword sound (condition A) or a domestic story told by the boy's mother (condition B) was presented on tape. Each measurement was performed in a Siemens CTI 951/31 PET scanner (10.8 cm axial field of view, fixed intercollimating septa). Scans lasted 90 s and started 20 s after intravenous injection of a 1.85 GBq bolus 15-O labelled H20. During scanning the patient was awake, as could be observed by his opened eyes. An interval of 20 min was kept between each scanning period. Statistical parametric mapping (SPM, version 1993), which includes both stereotaxic and global CBF normalization, was applied in order to evaluate the distribution of significant rCBF increases related to condition B [4-6].
(Fig. 1, upper row). Analysis of rCBF changes revealed that modulation of rCBF related to the presentation of mother's story, in comparison with non-words, was restricted to cortical areas of mainly the right hemisphere (Fig. 1, lower row). Radioactivity values were not thresholded in the SPM procedure. Therefore, modulation outside the most lesioned areas of the brain indicated that the observed changes were not introduced by statistical noise. The most significant increases (omnibus 0.001 threshold, Z-score above 3.5) were found in the right middle temporal gyrus (Brodmann Area 21), the rostral part of the anterior cingulate gyrus (BA 24) and inferiorly on the precentral gyrus (premotor cortex BA 6) (Table 1).
4. Discussion
The main finding of this study was that auditory presentation of language with an affective connotation regarding both intonation and content, induced rCBF changes in specific regions of the cerebral cortex. As sound was presented in both conditions tested, the observed distribution of rCBF changes, exceeding primary auditory areas, suggested the preservation of cortical neuronal responses related to complex stimulation in the here reported condition of PVS. In this case, the patient's left hemisphere was extensively lesioned. Therefore, language related activation of this hemisphere, which has been well documented in normal subjects, was unlikely to occur. However, the loci of activation on the right middle temporal gyrus and the rostral part of the anterior Table 1 Activated areas related to the presentation of mother's story Brodmann area
Talairach coordinates
z
x, y
Z-score
BA 21 BA 11 BA 21
-16 --12 --4
-50, 4 - 1 0 , 54 -56, -46
3.3 3.2 3.9
BA 24
4
- 6 , 34
3.6
BA45 BA 30 BA29 BA6
16 16 20 28
- 4 8 , 34 4, - 4 0 8, - 3 8 -54, -4
3.1 3.1 3.1 3.7
BA 8
40
- 3 4 , 26
3.3
Middle temporal gyrus Anterior cingulate gyrus
Precentral gyrus
3. Results
The mean rCBF distribution indicated lesioning of especially the left hemisphere. Cortical and ipsilateral basal ganglia rCBF was of the same order of magnitude
Localization of the areas with significant rCBF comparing the condition of presenting mother's sound (omnibus P<0.001). Positive x, y and z positions respectively left, anterior and superior anterior commissure.
change by SPM {t}, story with non-word coordinates indicate of the middle of the
B. de Jong et al./ Clinical Neurology and Neurosurgery 99 (1997) 213-216
215
Fig. 1. Upper row: Mean rCBF reflecting the distribution of gray matter, with lesioning of the left hemisphere. The plane with the anterior and posterior commissures (AC.PC) is positioned on level 0 by stereotaxic normalization. Lower row: SPM {t} loci of rCBF increases. Areas with Z-score > 3.5 are distributed over the right middle temporal gyrus (plane - 4), the anterior cingulate ( + 4) and the right premotor cortex ( + 28). Sections are transformed into Talairach coordinate space.
cingulate gyrus were highly similar to the regions Bottini et al. [7] have described to be related to the interpretation o f figurative aspects o f language. Indeed, the role o f the right hemisphere in nonlinguistic aspects o f language processing, such as comprehension o f the affective intonation o f speech, has been reported be,fore [8]. The right middle temporal gyrus and m e r e explicitly the right superior temporal gyrus m a y also be assumed to play a role in phonological processing [9]. We c a n n o t definitively answer the question whether indeed neutral words
would have activated the right temporal region as m u c h as the emotive story in our patient study. Activation localized rostrally in the anterior cingulate cortex, which was observed both in this study and in the afore q u o t e d study o f Bottini et al. [7], has also been reported to occur in relation to the verbal recall o f sad events in c o m b i n a t i o n with looking at sad faces [10]. In contrast, increases in r C B F related to nociception [11], attention and response selection [12,13,3,14] have been demonstrated to occur more caudally in the anterior cingulate cortex. The
216
B. de Jong et a l . / Clinical Neurology and Neurosurgery 99 (1997) 213-216
results from such PET studies are consistent with a general division of anterior cingulate cortex function into 'affect' and 'cognitive' components [15]. Based on these arguments, it seems to be legitimate to suggest that the right temporal and anterior cingulate cortex activation observed in our patient reflect a contribution to processing affective aspects of the presented story. Such affective aspects may either be carried by basic acoustic qualities of mother's voice, or be derived from fragments of the story's content. Whether rCBF increase of the right premotor cortex located anteriorly to the mouth representation on the primary motorstrip might reflect a responsive attempt to get access to executive control function [3] remains speculation. Notwithstanding care that has to be taken with regard to interpretation of the results from this study, they indicate that in some circumstances of PVS, elements of complex stimulation may be processed in appropriate cortical circuitry. Although the linkage between such cortical activity and awareness goes beyond the scope of scientific discussion, the here described findings suggest that the distinction between PVS and locked-in syndrome may be a gradual one.
References [1] Persistent vegetative state: Report of the American Neurological Association Committee on Ethical Affairs. Ann Neurol 1993;33:386-390. [2] Medical aspects of the persistent vegetative state. Multi-society task force on PVS. N Eng J Med 1994;330:1499-1508.
[3] Petersen SE, Fox PT, Posner MI, Mintum M, Raichle ME. PET studies of cortical anatomy of single-word processing. Nature 1988;331:585-9. [4] Friston K J, Frith CD, Liddle PF, Frackowiak RSJ. Comparing functional (PET) images: The assessment of significant change. J Cereb Blood Flow Metab 1991;11:690-9. [5] Friston K J, Frith CD, Liddle PF, Frackowiak RSJ. Plastic transformation of PET images. J Comput Assist Tomogr 1991;15:634-9. [6] Talairach J, Tournoux P. Co-Planar Stereotaxic Atlas of the Human Brain. Stuttgart: Thieme Verlag, 1988. [7] Bottini G, Corcoran R, Sterzi R, Paulesu E, Schenone P, Scarpa P, Frackowiak RSJ, Frith CD. The role of the right hemisphere in the interpretation of figurative aspects of language. A PET activation study. Brain 1994;117:1241 53. [8] Heilman KM, Scholes R, Watson RT. Auditory affective agnosia. J Neurol Neurosurg Psychiatry 1975;38:69-72. [9] Demonet JF, Chollet F, Ramsay S, Cardebat D, Nespoulos JL, Wise R, Rascol A, Frackowiak RSJ. The anatomy of phonological and semantic processing in normal subjects. Brain 1992;115:1753-68. [10] George MS, Ketter TA, Parekh PI, Horwitz B, Herscovitch P, Post RM. Brain activity during transient sadness and happiness in healthy women. Am J Psychiatry 1995;152:341-51. [11] Jones APK, Brown WD, Friston KJ, Qi LY, Frackowiak RSJ. Cortical and subcortical localization of response to pain in man using PET. Proc R Soc Lond 1991;B 224:39 44. [12] Corbetta M, Miezin FM, Shulman GL, Petersen SE. A PET study of visuospatial attention. J Neurosci 1993;13:1202-26. [13] Pardo JV, Pardo PJ, Janer KW, Raichle ME. The anterior cingulate mediates processing selection in the stroop attentional conflict paradigm. Proc Natl Acad Sci USA 1990;87:256-9. [14] Paus T, Petrides M, Evans AC, Meyer E. Role of the anterior cingulate cortex in the control of oculomotor, manual and speech responses: A PET study. J Neurophysiol 1993;70:453 69. [15] Devinsky O, Morrell M J, Vogt BA. Contributions of anterior cingulate cortex to behaviour [review]. Brain 1995;118:279- 306.