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Reappearance of event-related P3 potential in locked-in syndrome
COGNITIVE BRAIN RESEARCH ELSEVIER
Cognitive Brain Research 4 (1996) 95-97
Research report
Reappearance of event-related P3 potential in locked-in syndrome Marco Onofrj *, Donato Melchionda, Astrid Thomas, Tommaso Fulgente Department of Neurology, Institute of Neurological and Behavioral Sciences, Universityof Chieti, Chieti, Baly Accepted 7 February 1996
Abstract In a patient affected by locked-in syndrome, because of a lesion of the caudal-ventral pontine tegment, we recorded event-related potentials (ERPs) to an acoustic odd-ball paradigm. We did not record N2 and P3 components in the 50 days following the acute lesion although the patient was able to understand the task and communicate with blinking. 55 days after the acute lesion, N2 and P3 reappeared on scalp derivations. This findings suggest that brainstem structures are involved in P3 or N2-P3 generation. Keywords: Locked-in syndrome; P3-P300; Event-related potential (ERP); Basilar artery tromboembolism
1. Introduction Recent reports [11,1,5,6] showed that the P3 (or P300) component of event-related potentials (ERPs) arises almost simultaneously from multiple cortical areas. Several authors, in earlier studies, had suggested that brainstem structures or the thalamus were the trigger, or origin, of the P3 complex [3,2,14,12]. The necessary support to this hypothesis, i.e. the evidence that brainstem lesions induced P3 changes, has, however, been lacking: only in one of our previous studies [9], we showed P3 delays, but not disappearance of this potentials, in patients with lesions of thalamus and in one other paper we showed [10], again, a P3 delay in a single patient with an encephalitic lesion at the mesopontine level. With the present paper, we show that N2 and P3 ERPs were not recorded in a patient with a locked-in syndrome [13] due to basilar artery tromboembolism, when the patient was alert and collaborative and that the two ERP components reappeared about 2 months after the ischaemic lesion.
2. Case report The patient is a 32-year-old male, professional cook, normotype, 172 cm height, 68 kg weight, non-smoker,
* Corresponding author. Clinica Neurologica, Ospedale ex Pediatrico, via Martiri Lancianesi 6, 66100 Chieti, Italy. Fax: (39) (871) 63842. 0926-6410/96/$15.00 © 1996 Elsevier Science B.V. All fights reserved PH S 0 9 2 6 - 6 4 1 0 ( 9 6 ) 0 0 0 2 1 - 3
with a negative previous medical history. He arrived at the emergency unit of our hospital because of headache followed by 'abnormal vision' and numbness of the fight arm and leg. Blood pressure was at admission 200/120 mm Hg. Within 12 h, he became stuporous and tetraparetic with bilateral Babinski signs, anartric, he had two generalized tonic-clonic seizures, painful stimuli induced decerebrate posturing and lateral eyes movements. The first CT scan was reported as negative. He received 20 000 IU of heparin in 24 h. He developed central hyperventilation (frequency 40-50 min, pO 2 85-90 mm Hg, pCO 2 25-40 mm Hg), he was intubated and artificially ventilated, treated with tiopenthal 2 m g / k g / h . CSF was normal. Within 3 days, it was possible to interrupt artificial ventilation, he underwent tracheotomy. A new CT scan showed a caudal pontine ischaemic lesion, prominent on the fight side. The patient was then awake, painful stimuli induced blinking and decerebrate posturing, he could blink and move the eyes laterally and vertically spontaneously and on command. He understood verbal commands and spasmodic laughing or crying were elicited by appropriate stimuli. EEG showed posterior 9 - 1 0 Hz rhythms, disappearing to eyes closure and sporadic synchronous 5-6-Hz sequences lasting for 1-2 s. During sleep slow activity, K-complexes, spindles and vertex waves were recorded. Somatosensoryevoked potentials (SEPs), brainstem auditory-evoked potentials (BAEPs), event-related potentials (ERPs) were recorded for the first time 10 days after the acute ischaemic stroke. MRI showed a paramedian (right) area hypointense in Tl-weighted images, hyperintense in T2 images (Fig. 1). In the following 20 days, thoracic expan-
96
M. Onofrj et a L / Cognitive Brain Research 4 (1996) 95-97
A
B
C
Fig. 1. MRI obtained 14 days after the acute ischaemic lesion. Tl-weighted images extension of the pontine lesion in the sagittal (A) and axial plane (B). Notice prominenceof the lesion on the right. Axial T2-weightedimage (C) shows the extent of the surrounding oedema.
sion improved to the point that the tracheal cannula could be withdrawn. 30 days after the acute lesion, the patient could move the toes of the right foot; 15 days later, he could move the right leg and abduct the right arm. In 2 more months, he could swallow, utter small-word sentences, regained some movements of the right hand. He was than transferred to an intensive rehabilitation unit.
rately averaged and eventually reaveraged in a Grand Average program. The latencies and amplitudes of ERPs recorded in this patient were compared with results obtained in 15 age-matched controls (25-35 years old). SEP, BAEP and ERP recording sessions were repeated every 10-14 days for 3 months after the acute ischaemic event.
3. Materials and methods
4. Results
SEPs to median nerve (wrist) and tibial nerve (ankle) stimuli and BAEPs were recorded according to the guidelines of the International Federation of Clinical Neurophysiology [7,8]. ERPs were recorded, according to methods described elsewhere [9,11], from 21 scalp derivations (including Fp 1-Fp2-Fpz-F7-F3-F4-F8-Fz-T7-C3-C4-T8-Cz-P7-P3P4-P8-Pz-O1-O2-Oz), with Ag/AgC1 cups and 4 supplementary (out of the maps) derivations monitoring eye artifacts, all referenced to the linked earlobes with an interposite 10 KOhm resistance. Band-pass filters were 0.1-100 Hz, dwell time was 0.4 ms. Stimuli were presented in a binaural acoustic odd-ball paradigm: target (rare) stimuli were 500-Hz pure tones (plateau 100 ms, rise-fall time 150 ms, intensity 80 dB) non-target (frequent) stimuli were 2000-Hz pure tones (plateau 100 ms, rise-fall time 150 ms, intensity 80 dB). The frequent:rare probability ratio was 8:1. The patient was instructed to count mentally rare stimuli and to communicate with eye blinks whether he understood the commands. At the end of each recording session, he blinked for as many times as many target stimuli were delivered. During each recording session, 3 or 4 subsets of 19-20 responses to target stimuli (and 130-150 responses to non-target stimuli) were sepa-
The ischaemic lesion involving the caudal pontine area, prominent on the right, is shown in Fig. 1. BAEPs consisted in all recording session of normal sequences of I - V components with normal latency to stimuli of the right ear and of components I - I I I to stimuli of the left ear. ERPs consisted only of the N1, P2 components to target and non-target stimuli in recording sessions performed 10, 25 and 40 days after the ischaemic lesion (Fig. 2). The latency and amplitude of these components were inside normal limits. N2 and P3 were not recorded in these recording sessions although the patient understood the task, and blinked, at the end of each subset of stimuli for as many times as many target stimuli were delivered. Only in the 4th recording sessions (55 days after the ischaemic lesion) and in following sessions, N2 and P3 components were elicited by target stimuli (Fig. 2). The latency of these components was: N1 152 ms; P2 215 ms; N2 274 ms; P3 330 ms. The amplitude recorded in comparison with baseline was N2 12.3 pN; P3 18.4 pN. The distribution of these components was not different from normal distribution: significance probability mapping with Z transform evaluation was performed, in a comparison between age-matched maps vs. maps of this patient, and
M. Onofrj et al./ Cognitive Brain Research 4 (1996) 95-97
reorganization can lead to relocation of the generator (or trigger) of these components. The unprecedent demonstration that ERPs can be recorded in the locked-in s y n d r o m e is of interest as it m a y lead to further developments in the assessment of brainstem lesions or coma. Furthermore, an early study by Farwell and D o n c h i n [4] hypothesized that P3 ERPs could be recorded in locked-in s y n d r o m e and that P3 could be used to drive a c o m p u t e r program allowing simple c o m m u nications from the locked-in patient. A l t h o u g h lately, our report suggest that their project is feasible.
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Fig. 2. A: Grand Average of responses obtained in each recording session 10, 25 and 40 days after the acute lesion. Each trace of responses to target stimuli is the result of three subsets of 19-20 responses. Each non-target response is the result of 150 averages. B: responses obtained 55, 70 and 90 days after the acute lesion. Notice reappearance of N2 and P3.
did not evidence any Z value above or b e l o w 2 SDs in any of the scalp derivations. The m e a n values of N 1, P2, N2, P3 latency and amplitudes in controls are: latencies N1 98 +__ 13.3 ms; P2 1 5 7 . 8 _ 18.7 ms; N2 241.3 ___ 15.8 ms; 329.7 ___24.5 ms; amplitudes N2 9.8 ___2.2 ~V; P3 15.4 _ 4.1 txV.
5. Discussion N2 and P3 E R P c o m p o n e n t s were not recorded 10, 25 and 40 days after acute ischaemia of the basilar artery although the patient could perform adequately the task of the cognitive p a r a d i g m and the E E G was characterized by symmetric alpha activity during w a k i n g state and by normal sleep stages. A p p r o x i m a t e l y 2 m o n t h s after the ischaemic lesion, N2 and P3 to target stimuli could be recorded and the distribution of these potentials was not different from controls (Fig. 2). Our interpretation of these findings is that brainstem lesions can induce disappearance of the N 2 and P3 E R P c o m p o n e n t s and, therefore, that b r a i n s t e m structures are i n v o l v e d in the generation of these E R P components. The reappearance of N 2 - P 3 in about 2 m o n t h s after the acute ischemic lesion suggests furthermore that plastic
[1] Baudena, P., Halgren, E., Heit, G. and Clarke, J.M., Intracerebral potentials to rare target and distractor auditory and visual stimuli. III. Frontal cortex, Electroenceph. Clin. Neurophysiol., 94 (1995) 251-264. [2] Crick, F.H.C, The Astonishing Hypothesis, Charles Scribner (Ed.), Macmillan, New York, NY, 1994, pp. 141-144. [3] Desmedt, J.E., P300 in serial tasks: an essential post-decision closure mechanism, Prog. Brain Res., B 54 (1981) 682-686. [4] Farwell, A. and Donchin E., Talking off the top of the your head: toward a mental prosthesis utilizing event related brain potentials, Electroenceph. Clin. Neurophysiol., 70 (1988) 510-523. [5] Halgren, E., Baudena, P., Clark, J.M., Heit, G., Liegenois, C., Chauvel, P. and Musolino, A., Intracerebral potentials to rare target and distractor auditory and visual stimuli. I. Superior temporal plane and parietal lobe, Electroenceph. Clin. Neurophysiol., 94 (1995) 191-220. [6] Halgren, E., Baudena, P., Clark, J.F., Heir, G., Marinkovic, K., Devaux, B., Vignal, J.P. and Biraben A., Intracerebral potentials to rare target and distractor auditory and visual stimuli. II. Medial, lateral and posterior temporal lobe, Electroenceph. Clin. Neurophysiol., 94 (1995) 229-250. [7] Nuwer, M.R., Aminoff, M., Desmedt, J., Eisen, A.A., Goodin, D., Matsuoka, S., Mauguiere, F., Shibasaki, H., Sutherling, W. and Vibert J.F., IFCN recommended standards for short latency somatosensory evoked potentials. Report of an IFCN committee. International Federation of the Clinical Neurophysiology, Electroenceph. Clin. Neurophysiol., 91 (1994) 6-11. [8] Nuwer, M.R., Aminoff, M., Goodin, D., Matsuoka, S., Mauguiere, F., Starr, A. and Vibert, J.F., IFCN recommended standards for brainstem auditory evoked potentials. Report of an IFCN Commette. International Federation of Clinical Neurophysiology, Electroenceph. Clin. Neurophysiol., 91 (1994) 12-18. [9] Onofrj, M., Curatola, L., Malatesta, G., Colamartino, P., Bazzano, S., Fulgente, T. and Ferracci, F., Delayed P3 event related potential (ERPs) in thalamic hemorrhage, Electroenceph. Clin. Neurophysiol., 83 (1992) 52-61. [10] Onofrj, M., Fulgente, T., Nobilio, D., Malatesta, G., Bazzano, F., Colamartino P. and Gambi D., P3 recordings in patients with bilateral temporal lobe lesions, Neurology, 42 (1992) 1762-67. [11] Onofrj, M., Fulgente, T., Thomas, A., Locatelli, T. and Comi, G., P300 asymmetries in focal brain lesions are reference dependent, Electroenceph. Clin. Neurophysiol., 94 (1995) 432-439. [12] Picton, T.W., The P300 wave of human event-related potential, J. Clin. Neurophysiol., 9 (1992) 456-479. [13] Plum, F. and Posner, J.B., Diagnosis of Stupor and Coma, 3rd Ed., Davis, Philadelphia, 1980. [14] Yingling, C.D. and Hosobuchi, Y., A subcortical correlate of P300 in man. Electroenceph. Clin. Neurophysiol., 59 (1984) 72-76.
Cognitive Brain Research 4 (1996) 95-97
Research report
Reappearance of event-related P3 potential in locked-in syndrome Marco Onofrj *, Donato Melchionda, Astrid Thomas, Tommaso Fulgente Department of Neurology, Institute of Neurological and Behavioral Sciences, Universityof Chieti, Chieti, Baly Accepted 7 February 1996
Abstract In a patient affected by locked-in syndrome, because of a lesion of the caudal-ventral pontine tegment, we recorded event-related potentials (ERPs) to an acoustic odd-ball paradigm. We did not record N2 and P3 components in the 50 days following the acute lesion although the patient was able to understand the task and communicate with blinking. 55 days after the acute lesion, N2 and P3 reappeared on scalp derivations. This findings suggest that brainstem structures are involved in P3 or N2-P3 generation. Keywords: Locked-in syndrome; P3-P300; Event-related potential (ERP); Basilar artery tromboembolism
1. Introduction Recent reports [11,1,5,6] showed that the P3 (or P300) component of event-related potentials (ERPs) arises almost simultaneously from multiple cortical areas. Several authors, in earlier studies, had suggested that brainstem structures or the thalamus were the trigger, or origin, of the P3 complex [3,2,14,12]. The necessary support to this hypothesis, i.e. the evidence that brainstem lesions induced P3 changes, has, however, been lacking: only in one of our previous studies [9], we showed P3 delays, but not disappearance of this potentials, in patients with lesions of thalamus and in one other paper we showed [10], again, a P3 delay in a single patient with an encephalitic lesion at the mesopontine level. With the present paper, we show that N2 and P3 ERPs were not recorded in a patient with a locked-in syndrome [13] due to basilar artery tromboembolism, when the patient was alert and collaborative and that the two ERP components reappeared about 2 months after the ischaemic lesion.
2. Case report The patient is a 32-year-old male, professional cook, normotype, 172 cm height, 68 kg weight, non-smoker,
* Corresponding author. Clinica Neurologica, Ospedale ex Pediatrico, via Martiri Lancianesi 6, 66100 Chieti, Italy. Fax: (39) (871) 63842. 0926-6410/96/$15.00 © 1996 Elsevier Science B.V. All fights reserved PH S 0 9 2 6 - 6 4 1 0 ( 9 6 ) 0 0 0 2 1 - 3
with a negative previous medical history. He arrived at the emergency unit of our hospital because of headache followed by 'abnormal vision' and numbness of the fight arm and leg. Blood pressure was at admission 200/120 mm Hg. Within 12 h, he became stuporous and tetraparetic with bilateral Babinski signs, anartric, he had two generalized tonic-clonic seizures, painful stimuli induced decerebrate posturing and lateral eyes movements. The first CT scan was reported as negative. He received 20 000 IU of heparin in 24 h. He developed central hyperventilation (frequency 40-50 min, pO 2 85-90 mm Hg, pCO 2 25-40 mm Hg), he was intubated and artificially ventilated, treated with tiopenthal 2 m g / k g / h . CSF was normal. Within 3 days, it was possible to interrupt artificial ventilation, he underwent tracheotomy. A new CT scan showed a caudal pontine ischaemic lesion, prominent on the fight side. The patient was then awake, painful stimuli induced blinking and decerebrate posturing, he could blink and move the eyes laterally and vertically spontaneously and on command. He understood verbal commands and spasmodic laughing or crying were elicited by appropriate stimuli. EEG showed posterior 9 - 1 0 Hz rhythms, disappearing to eyes closure and sporadic synchronous 5-6-Hz sequences lasting for 1-2 s. During sleep slow activity, K-complexes, spindles and vertex waves were recorded. Somatosensoryevoked potentials (SEPs), brainstem auditory-evoked potentials (BAEPs), event-related potentials (ERPs) were recorded for the first time 10 days after the acute ischaemic stroke. MRI showed a paramedian (right) area hypointense in Tl-weighted images, hyperintense in T2 images (Fig. 1). In the following 20 days, thoracic expan-
96
M. Onofrj et a L / Cognitive Brain Research 4 (1996) 95-97
A
B
C
Fig. 1. MRI obtained 14 days after the acute ischaemic lesion. Tl-weighted images extension of the pontine lesion in the sagittal (A) and axial plane (B). Notice prominenceof the lesion on the right. Axial T2-weightedimage (C) shows the extent of the surrounding oedema.
sion improved to the point that the tracheal cannula could be withdrawn. 30 days after the acute lesion, the patient could move the toes of the right foot; 15 days later, he could move the right leg and abduct the right arm. In 2 more months, he could swallow, utter small-word sentences, regained some movements of the right hand. He was than transferred to an intensive rehabilitation unit.
rately averaged and eventually reaveraged in a Grand Average program. The latencies and amplitudes of ERPs recorded in this patient were compared with results obtained in 15 age-matched controls (25-35 years old). SEP, BAEP and ERP recording sessions were repeated every 10-14 days for 3 months after the acute ischaemic event.
3. Materials and methods
4. Results
SEPs to median nerve (wrist) and tibial nerve (ankle) stimuli and BAEPs were recorded according to the guidelines of the International Federation of Clinical Neurophysiology [7,8]. ERPs were recorded, according to methods described elsewhere [9,11], from 21 scalp derivations (including Fp 1-Fp2-Fpz-F7-F3-F4-F8-Fz-T7-C3-C4-T8-Cz-P7-P3P4-P8-Pz-O1-O2-Oz), with Ag/AgC1 cups and 4 supplementary (out of the maps) derivations monitoring eye artifacts, all referenced to the linked earlobes with an interposite 10 KOhm resistance. Band-pass filters were 0.1-100 Hz, dwell time was 0.4 ms. Stimuli were presented in a binaural acoustic odd-ball paradigm: target (rare) stimuli were 500-Hz pure tones (plateau 100 ms, rise-fall time 150 ms, intensity 80 dB) non-target (frequent) stimuli were 2000-Hz pure tones (plateau 100 ms, rise-fall time 150 ms, intensity 80 dB). The frequent:rare probability ratio was 8:1. The patient was instructed to count mentally rare stimuli and to communicate with eye blinks whether he understood the commands. At the end of each recording session, he blinked for as many times as many target stimuli were delivered. During each recording session, 3 or 4 subsets of 19-20 responses to target stimuli (and 130-150 responses to non-target stimuli) were sepa-
The ischaemic lesion involving the caudal pontine area, prominent on the right, is shown in Fig. 1. BAEPs consisted in all recording session of normal sequences of I - V components with normal latency to stimuli of the right ear and of components I - I I I to stimuli of the left ear. ERPs consisted only of the N1, P2 components to target and non-target stimuli in recording sessions performed 10, 25 and 40 days after the ischaemic lesion (Fig. 2). The latency and amplitude of these components were inside normal limits. N2 and P3 were not recorded in these recording sessions although the patient understood the task, and blinked, at the end of each subset of stimuli for as many times as many target stimuli were delivered. Only in the 4th recording sessions (55 days after the ischaemic lesion) and in following sessions, N2 and P3 components were elicited by target stimuli (Fig. 2). The latency of these components was: N1 152 ms; P2 215 ms; N2 274 ms; P3 330 ms. The amplitude recorded in comparison with baseline was N2 12.3 pN; P3 18.4 pN. The distribution of these components was not different from normal distribution: significance probability mapping with Z transform evaluation was performed, in a comparison between age-matched maps vs. maps of this patient, and
M. Onofrj et al./ Cognitive Brain Research 4 (1996) 95-97
reorganization can lead to relocation of the generator (or trigger) of these components. The unprecedent demonstration that ERPs can be recorded in the locked-in s y n d r o m e is of interest as it m a y lead to further developments in the assessment of brainstem lesions or coma. Furthermore, an early study by Farwell and D o n c h i n [4] hypothesized that P3 ERPs could be recorded in locked-in s y n d r o m e and that P3 could be used to drive a c o m p u t e r program allowing simple c o m m u nications from the locked-in patient. A l t h o u g h lately, our report suggest that their project is feasible.
........... 1 0 t h D a y - -
25th Day
- -
40th Day
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70th Day
- -
90lh Day
References
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Fig. 2. A: Grand Average of responses obtained in each recording session 10, 25 and 40 days after the acute lesion. Each trace of responses to target stimuli is the result of three subsets of 19-20 responses. Each non-target response is the result of 150 averages. B: responses obtained 55, 70 and 90 days after the acute lesion. Notice reappearance of N2 and P3.
did not evidence any Z value above or b e l o w 2 SDs in any of the scalp derivations. The m e a n values of N 1, P2, N2, P3 latency and amplitudes in controls are: latencies N1 98 +__ 13.3 ms; P2 1 5 7 . 8 _ 18.7 ms; N2 241.3 ___ 15.8 ms; 329.7 ___24.5 ms; amplitudes N2 9.8 ___2.2 ~V; P3 15.4 _ 4.1 txV.
5. Discussion N2 and P3 E R P c o m p o n e n t s were not recorded 10, 25 and 40 days after acute ischaemia of the basilar artery although the patient could perform adequately the task of the cognitive p a r a d i g m and the E E G was characterized by symmetric alpha activity during w a k i n g state and by normal sleep stages. A p p r o x i m a t e l y 2 m o n t h s after the ischaemic lesion, N2 and P3 to target stimuli could be recorded and the distribution of these potentials was not different from controls (Fig. 2). Our interpretation of these findings is that brainstem lesions can induce disappearance of the N 2 and P3 E R P c o m p o n e n t s and, therefore, that b r a i n s t e m structures are i n v o l v e d in the generation of these E R P components. The reappearance of N 2 - P 3 in about 2 m o n t h s after the acute ischemic lesion suggests furthermore that plastic
[1] Baudena, P., Halgren, E., Heit, G. and Clarke, J.M., Intracerebral potentials to rare target and distractor auditory and visual stimuli. III. Frontal cortex, Electroenceph. Clin. Neurophysiol., 94 (1995) 251-264. [2] Crick, F.H.C, The Astonishing Hypothesis, Charles Scribner (Ed.), Macmillan, New York, NY, 1994, pp. 141-144. [3] Desmedt, J.E., P300 in serial tasks: an essential post-decision closure mechanism, Prog. Brain Res., B 54 (1981) 682-686. [4] Farwell, A. and Donchin E., Talking off the top of the your head: toward a mental prosthesis utilizing event related brain potentials, Electroenceph. Clin. Neurophysiol., 70 (1988) 510-523. [5] Halgren, E., Baudena, P., Clark, J.M., Heit, G., Liegenois, C., Chauvel, P. and Musolino, A., Intracerebral potentials to rare target and distractor auditory and visual stimuli. I. Superior temporal plane and parietal lobe, Electroenceph. Clin. Neurophysiol., 94 (1995) 191-220. [6] Halgren, E., Baudena, P., Clark, J.F., Heir, G., Marinkovic, K., Devaux, B., Vignal, J.P. and Biraben A., Intracerebral potentials to rare target and distractor auditory and visual stimuli. II. Medial, lateral and posterior temporal lobe, Electroenceph. Clin. Neurophysiol., 94 (1995) 229-250. [7] Nuwer, M.R., Aminoff, M., Desmedt, J., Eisen, A.A., Goodin, D., Matsuoka, S., Mauguiere, F., Shibasaki, H., Sutherling, W. and Vibert J.F., IFCN recommended standards for short latency somatosensory evoked potentials. Report of an IFCN committee. International Federation of the Clinical Neurophysiology, Electroenceph. Clin. Neurophysiol., 91 (1994) 6-11. [8] Nuwer, M.R., Aminoff, M., Goodin, D., Matsuoka, S., Mauguiere, F., Starr, A. and Vibert, J.F., IFCN recommended standards for brainstem auditory evoked potentials. Report of an IFCN Commette. International Federation of Clinical Neurophysiology, Electroenceph. Clin. Neurophysiol., 91 (1994) 12-18. [9] Onofrj, M., Curatola, L., Malatesta, G., Colamartino, P., Bazzano, S., Fulgente, T. and Ferracci, F., Delayed P3 event related potential (ERPs) in thalamic hemorrhage, Electroenceph. Clin. Neurophysiol., 83 (1992) 52-61. [10] Onofrj, M., Fulgente, T., Nobilio, D., Malatesta, G., Bazzano, F., Colamartino P. and Gambi D., P3 recordings in patients with bilateral temporal lobe lesions, Neurology, 42 (1992) 1762-67. [11] Onofrj, M., Fulgente, T., Thomas, A., Locatelli, T. and Comi, G., P300 asymmetries in focal brain lesions are reference dependent, Electroenceph. Clin. Neurophysiol., 94 (1995) 432-439. [12] Picton, T.W., The P300 wave of human event-related potential, J. Clin. Neurophysiol., 9 (1992) 456-479. [13] Plum, F. and Posner, J.B., Diagnosis of Stupor and Coma, 3rd Ed., Davis, Philadelphia, 1980. [14] Yingling, C.D. and Hosobuchi, Y., A subcortical correlate of P300 in man. Electroenceph. Clin. Neurophysiol., 59 (1984) 72-76.