Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:759–764

759

Event related potentials recorded in patients with
locked-in syndrome
Marco Onofrj, Astrid Thomas, Cristina Paci, Michele Scesi, Renato Tombari

Department of
Neurology, University
of Chieti, Italy
M Onofrj
A Thomas
C Paci
Intensive Care Unit,
University of Chieti,
Italy
M Scesi
R Tombari
Correspondence to:
Professor Marco Onofrj,
Clinica Neurologica,
Ospedale clinicizzato “SS
Annunziata”, Dipartimento
di Oncologia e Neuroscienze,
Via dei Vestini, 66100 Chieti,
Italy. Telephone 0039 871
358527; fax 0039 871
562019; E-Mail:
Onofrj@phobos.unich.it or
Onofrj@phobos.ibmpe.it
Received 9 April 1997 and in
revised form 19 June 1997
Accepted 30 June 1997

Abstract
Objective—To determine the possibility of
recording “cognitive” event related potentials (ERPs) in locked-in patients and
therefore to determine whether ERPs can
have a role in diVerential diagnosis of
coma.
Methods—ERPs to classic auditory or
visual “odd ball paradigms” were recorded three to four days, seven to eight
days, and 30 to 60 days after admission to
the intensive care unit, in four patients
aVected by basilar artery thrombembolism resulting in locked-in syndrome. Two
patients (one 32 year old man, one 31 year
old woman) could move the eyes laterally
and vertically spontaneously and on command. One patient (a 39 year old man)
had a “one and half syndrome”, one
patient (a 40 year old woman) could only
elevate the left eyelid and eye. Results
were compared with data from 30 age
matched controls. In the last recording
session a letter recognition paradigm was
applied, in which ERPs were produced by
the identification of letters forming a
word. Results were compared with five age
matched controls. Brainstem lesions extending to the pontomesencephalic junction were found on MRI and CT.
Results—ERPs to the oddball paradigms
were recorded in three patients in the first
recording session, in all patients in the
second recording session. Latency, amplitude, and topographic distribution of ERP
components were inside normal limits.
With the letter recognition paradigm the
patients could emit a P3 component to
correspond with target letters, with the
same margin of error as controls.
Conclusion—It is possible to record ERPs
in patients with locked-in syndrome
shortly after the acute ischaemic lesion,
and therefore to assess objectively cognitive activities. Furthermore the letter recognition paradigm could be implemented
to facilitate linguistic communication
with patients with locked-in syndrome.
(J Neurol Neurosurg Psychiatry 1997;63:759–764)
Keywords: locked-in syndrome; P3-P300; event related
potentials; basilar artery thromboembolism

P3 (or P300) event related potentials (ERPs)
are electric signals from the brain recorded during the performance of cognitive tasks. Several
diVerent paradigms have been devised to elicit

the P3-ERP. These include active1 and passive2
discrimination between frequent or infrequent
(rare) targets, recognition of known versus
unknown faces,3 mental rotation task,4 preparation for a motor task,5 and recognition of a
missing stimulus inside a rhythmic sequence.6
P3 was described as an activity reflecting
attention,7 context updating,8 decisional
closure,9 or as a subcortical reaVerence subserving the build up of conscious perception.10
As P3 was recorded in patients with severe
lesions of the temporal lobe and amnesia,11–14
the hypotheses suggesting that its origin is in
the medial temporal lobe15 16 have been reconsidered: recent reports show that P3 arises
almost simultaneously from multiple cortical
areas,17–19 in agreement with the studies concluding that brainstem structures or the thalamus could be the trigger of P3.20–22 The studies
quoted above suggest that P3 recordings could
be applied in diVerential diagnosis of coma,
such as catatonic stupor, locked-in syndrome,
or diencephalic lesions: published papers on P3
ERPs and coma are, however, surprisingly
few,23–25 and only one methodological study,
performed in normal controls, hypothesised
that P3 could be recorded in locked-in
patients, and used to drive a computer based
communication system.26
The present paper shows actual recordings
of P3 ERPs in four patients with locked-in syndrome: P3-ERPs were recorded with classic
oddball paradigms in the visual and the
auditory modality (the patient had to recognise
target stimuli). Furthermore, patients were
presented a letter recognition task. The patients produced P3-ERPs to target letters, and
a template was devised to identify P3 and
therefore the selected letter.
Case reports
PATIENT 1

Patient 1 was a 32 year old man, a professional
cook, 172 cm in height, 68 kg weight, a
non-smoker, with a negative medical history.
He arrived at the emergency unit of our hospital because of headache followed by “abnormal
vision” and numbness of the right arm and leg.
Blood pressure was 200/120 mm Hg at admission. Within 12 hours he became stuporous,
anartric, and tetraparetic with bilateral Babinski signs, he had two generalised tonic-clonic
seizures, painful stimuli induced decerebrate
posturing, and lateral eye movements. The first
CT was reported as negative. He received
20 000 units of heparin in 24 hours. He developed central hyperventilation (frequency 40-50/
min, PO2 85-90 mm Hg, PCO2 25-40 mm Hg).

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Onofrj, Thomas, Paci, Scesi, Tombari

He was intubated and artificially ventilated and
treated with 2 mg/kg/h thiopental. His CSF was
normal. Within three days it was possible to
interrupt artificial ventilation and he underwent
tracheotomy. A new CT showed a caudal
pontine ischaemic lesion, prominent on the right
side. The patient was then awake. Painful stimuli
induced blinking and decerebrate posturing and
he could blink and move the eyes laterally and
vertically spontaneously and on command. He
understood verbal commands and spasmodic
laughing or crying was elicited by appropriate
stimuli. An EEG showed posterior 9-10 Hz
rhythms, disappearing on eye closure, and
sporadic synchronous 5-6 Hz sequences lasting
for one to two seconds. During sleep, slow activity, K complexes, spindles, and vertex waves
were recorded. MRI showed a paramedian
(right) area hypointense in T1 weighted images
and hyperintense in T2 images (fig 1).
PATIENT 2

Patient 2 was a 39 year old man, a library clerk,
175 cm in height, 81 kg weight, previously
aVected by “basilar artery migraine”. He
arrived at the emergency unit of our hospital
because of headache and right brachiocrural
hemiparesis. Within six hours he became
dysartric (nasal and scanned speech), the right
hemiparesis subsided, and left faciobrachial
paresis was seen. The first CT was reported as

normal. The first EEG showed posterior á
rhythms unresponsive to stimuli. He was
treated with 20 000 units of heparin intravenously, but he became tetraparetic and stuporous, with ataxic breathing. He was intubated
and artificially ventilated; within five days it was
possible to interrupt artificial ventilation and
he underwent tracheotomy. The patient was
then awake. Painful stimuli elicited blinking
and decerebrate posturing, he could move his
eyes spontaneously and on command vertically
and to the left with a contralateral “one and a
half” syndrome. He laughed and cried spasmodically. A second CT showed a caudalpontine ischaemic lesion. An EEG showed
posterior 10-11 Hz rhythms, disappearing
when his eyes were closed. Slow activity, K
complex, spindles, vertex V waves, and REM
desynchronisation were seen during sleep.
Brain MRI confirmed the paramedian area,
which was hypointense in T1 weighted images
and hyperintense in T2 images (fig 1).
PATIENT 3

Patient 3 was a 40 year old woman, a
housewife, obese (163 cm in height, 91 kg
weight), with a negative medical history. She
was admitted to the surgery of our hospital
because of acute abdominal pain, ileus, and
suspected mesenteric artery thrombosis. She
became stuporous and tetraparetic, with ataxic

Figure 1 MRI (patients 1, 2, and 3) and CT (patient 4) showing brain stem lesions in four patients with locked-in syndrome. (1) MRI, T1 time echo
(sagittal and first axial), T2 time echo (last axial) of patient 1. (2) MRI, T2 time echo (sagittal and axial) of patient 2. (3) Sagittal MRI, T1 time echo
of patient 3. (4) CT showing pontine hypointensities in patient 4. Arrows point to lesions.

Event related potentials recorded in patients with locked-in syndrome

breathing, and underwent tracheotomy and
artificial ventilation. An EEG showed posterior
á rhythms, unmodified by stimuli. The first CT
showed hypointensity in pontine structures;
haematological studies showed platelet decrement and increment of fibrinogen degradation
products. She was treated with 20 000 units
heparin daily.
Within three days she was awake. She could
elevate the left eyelid and the left eye spontaneously and on command and EEG showed
10-11 Hz á rhythms and normal sleep patterns
during sleep. Painful stimuli elicited spasmodic
crying and decerebrate posturing. She developed left femoral vein thrombosis. A new CT
showed the hypointense lesions of the pons,
and repeated MRI (fig 1) confirmed earlier
findings. She was found positive for antiphospholipid antibodies.
PATIENT 4

Patient 4 was a 31 year old housewife, normotype (166 cm in height, 56 kg weight). She
underwent a caesarean section due to initial
gestosis, with delivery of a normal baby. She
was somnolent-stuporous for three days and
she was then transferred from the obstetric
division of a nearby hospital to our department. At the first neurological examination she
was found to be tetraplegic, but in a waking
state. She was able to blink and move her eyes
vertically, spontaneously and on command.
Brain CT showed hypointensity of the caudal
pons, left hypointensity of the rostral pons, and
bilateral hypointensities of the cerebral peduncles (fig 1). The first EEG showed 9-11 Hz á
rhythmic activity, disappearing when her eyes
closed, and normal sleep patterns. She was
intubated and artificially ventilated for six days.
Thoracic expansion than returned to normal.
Ten days after admission to our department
she had left hemiplegia, right hemiparesis (she
could lift her left arm), facial diplegia, and
tongue protrusion. Three months after rehabilitation therapy she could walk with the aid of
a frame.
Methods
ERPs to the auditory and visual oddball paradigms were recorded three to four days after
admission to the intensive care unit of our
University, when the patients were artificially
ventilated, seven to eight days later, when artificial ventilation could be discontinued and
patients could be transferred to our neurology
department, and 30 to 60 days later when
patients were transferred to a rehabilitation
unit. The letter recognition paradigm was used
only in the last recording session. The ERPs
were recorded according to methods described
in detail elsewhere12 19 22 27 from 21 scalp leads
(comprising Fp, Fp2, Fpz, F7, F3, F4, F8, Fz,
T7, C3, C4, T8, Cz, P7, P3, P4, P8, Pz, O1,
O2, Oz) with Ag/AgCl cups, and four supplementary leads monitoring eye artefacts, all referenced to the linked earlobes with an
interposite 10 kohm resistance. Band pass
filters were 0.1-100 Hz, and dwell time was 0.4
ms. In the binaural tones (plateau 100 ms, risefall time 150 ms, intensity 80 dB) non-target

761

(frequent) stimuli were 2000 Hz pure tones
(plateau 100 ms, rise-fall time 150 ms,
intensity 80 dB) delivered with a random
sequence and a minimum intersimulus interval
of 1010 ms. The frequent/rare probability ratio
was 8/1. The patients were instructed to count
mentally rare stimuli and to communicate with
eye blinks whether they understood the commands. In the visual odd ball paradigm,
patients were asked whether they could identify
vertical and horizontal bars subtending 30’ of
visual arc, 75% contrast presented on a pattern
generator for 80 ms, followed by an isoluminance screen (75 cd/m2). The pattern generator
subtended 25° of visual angle and was placed at
1 m from the patient’s head. The scleral reflection of the patterned stimuli was centred on the
pupil. During the visual oddball paradigm
patients had to recognise only horizontal target
stimuli and communicated with eyeblinks
whether they understood the task. Target and
non-target stimuli were presented in a random
sequence with a minimum interstimulus interval of 2010 ms and with a probability ratio of
1/8. At the end of each recording session the
patients blinked for as many times as many target stimuli were delivered. The latencies and
amplitudes of ERPs recorded in these patients
were compared with results obtained in two
groups of 15 age matched controls (25 and 35
years old).
The letter recognition paradigm was developed as a simplification of the “mental
prosthesis” paradigm introduced by Farwell
and Donchin.26 Stimuli were grey letters
subtending 5° visual angles, presented on the
same pattern generator screen used for the orientation “odd ball paradigm”. Luminance of
the blank screen and the screen surrounding
the letters was 75 cd/m2, luminance of the letters was 32 cd/m2. Letters of the alphabet were
presented randomly for one second on the
screen. In the first recording session (template
definition) five healthy controls, 30-43 years
old, were asked to discriminate between letters
forming the word “video” and other letters; the
target letters were to be recognised only when
presented in the appropriated sequence. The
EEG was recorded from 15 scalp derivations
(Fp1-2, F7-8, and T3-4 were excluded, one
EOG channel was included), with 0.5-70 Hz
band pass filtered and at a 1000 Hz sampling
rate. Data were stored on the computer hard
disk. Responses to target and non-target
stimuli were averaged oV line. The averaged
response to target stimuli was used to define
“template” characteristics, with the ESAOTE
shape detection program, based on a time window (290-500 ms), slope of the descending
(0.15-0.4 mV/ms) and ascending limb (0.1-0.3
mV/ms), and minimum duration of
descending-ascending positive deflection (70110 ms).
In the second recording session each control
was asked to select letters forming a word from
the letter sequence presented on the screen, in
five sets of six minutes each. The P3 template
obtained in the first recording session in each
control was used to compute the covariance of
single responses to letter presentation with this

762

Onofrj, Thomas, Paci, Scesi, Tombari

Latencies and amplitudes of ERP components to the auditory and visual odd ball paradigm
in patients and controls: measurements from Pz derivations
N1

P2

N2

P3

Auditory ERPS
Latency (ms):
Controls
Patients:
1
2
3
4
Amplitude (µV):
Controls
Patients:
1
2
3
4
Latency (ms):
Controls
Patients:
1
2
3
4
Amplitude (µV):
Controls
Patients:
1
2
3
4

130.2 (10.8)

181.8 (16.4)

258.4 (14.2)

330.4 (18.4)

121
148
152
132

190
202
207
188

254
265
270
260

315
335
330
325

11.1 (2.8)
18.1
15.5
14.2
11.0

8.7 (2.1)
5.6
7.2
7.8
6.5
Visual ERPS

2.5 (1.9)

10.5 (2.8)

2.5
4.1
3.6
7.3

9.0
10.8
6.8
11.2

142.1 (10.8)

196.1 (15.8)

264.6 (16.7)

355.8 (19.1)

147
132
150
145

200
188
196
202

290
274
278
269

370
338
340
330

10.6 (3.1)

7.8 (2.4)

6.1 (2.7)

10.6 (2.7)

7.6
6.8
11.5
9.3

5.8
4.8
7.5
9.9

5.6
6.7
7.5
4.8

9.5
11.3
8.6
12.8

The mean values of controls included both age matched groups. Values in parentheses are SD.

template. The values obtained from this analysis were then used to determine the letter on
which the subject was focusing attention. This
same letter recognition paradigm was used in
the last recording session. All four patients
were initially asked to blink or elevate the eyelid when they understood the task. The letter
sequences with the predefined target (“video”)
were then presented for 15 minutes and the
template was obtained for each patient. In the
second part of the paradigm 370-600 acquisitions were stored on the hard disk in 30
minutes and compared with the template.
Attended letters were 45-72.
Results
Figure 1 shows the ischaemic lesion involving
the caudal pontine area, prominent on the
right.
The ERPs to the auditory and visual oddball
paradigms were recorded in the first session in
patients 2, 3, and 4 and only in the second and
third session in patient 1. They consisted of a
“normal” N1-P1 sequence to frequent nontarget stimuli, and N, P1, N2, and P3 components to target stimuli (fig 2). Latencies, amplitudes, and scalp distributions of ERP
components were within normal limits. The
table reports mean values of age matched controls and results obtained in each patient. Significance probability mapping with Z transform evaluation28 was performed as a
comparison between age matched maps and
maps of each patient, and did not show any Z
value above or below 2 SD in any of the scalp
derivations. Paired Wilcoxon tests of N2 and
P3 amplitude or latencies did not show any
significant increment or decrement in the three
recording sessions for patients 2, 3, and 4 and
in the two recording sessions for patient 1.

Figure 2 Visual oddball ERPs of patient 1, auditory
oddball ERPs of patients 2 and 3. Arrows point to P3 ERP
component. In patient 1 thick lines correspond to target
stimuli ERPs, thin lines correspond to frequent (non-target)
stimuli. In patients 2 and 3 the overlapping sets of traces
show responses obtained in the three diVerent recording
sessions.

Test-retest reliability of P3 in patients with
locked-in syndrome was 0.81-0.88, not diVerent from controls (0.81-0.91). Figure 2 shows
ERPs recorded with the visual or auditory
oddball paradigm in the first three patients.
The letter recognition task elicited positive
P3 components to attended letters in all
patients and controls. The averaged responses
obtained during the template definition task
consisted of N1 components recorded from
Cz, Pz, P3, P4, O1, O2, and Oz leads to
attended and unattended letters. N1 peaked at
120-185 ms, the amplitude (measured from
Pz) was 12.2 (SD 3.6) mV in patients and controls. A following peak, P2 was recorded also
from central and frontal derivations, latency
was from 182 to 260 ms. Only attended letters
elicited N2 (272-336 ms, amplitude 4.2 (SD
2.8) mV from Pz) and P3 on Cz, C3, C4, P3,
Pz, P4, O1, Oz, and O2 leads (348-452 ms).
The mean P3 latency was 408 (SD 18.5) ms in
controls , 411 (SD 17.2) ms in the four
patients. The mean amplitude from baseline,
recorded from Pz, was 7.7 (SD 2.1) mV in
controls and 8.1 (SD 3.00) mV in patients. A
Student’s t test comparison with the five
controls was not significant. The template
(shape detection program) obtained from

Event related potentials recorded in patients with locked-in syndrome

Figure 3 ERPs to the letter recognition paradigm in patient 4. The sequence of traces from
top to bottom show responses to single stimuli recorded from Pz derivation. The shaded
frames represent the template identifying the corresponding P3 component. Attended letters
are represented as dark; bright letters are unattended. The patient was emitting P3 ERPs to
a sequence of four letters meaning “I see” in italian (VEDO).

averaged responses to attended letters could
detect 67%-100% of P3 to attended letters in
the rerun of the 30 minute acquisition during
the second part of the paradigm. False positives
were 10%-28% of detected P3s. Sequences of
letters forming words could be detected with a
9%-43% margin of error (false positives, false
negatives), single words (“hunger”, “tired”,
“stupid” in italian) could be identified every
1.5-3.5 min. A ÷2 comparison of detection
errors did not show diVerences between
patients and controls. Figure 3 shows a
sequence of single responses obtained in
patient 4 during the second part of the letter
recognition paradigm.
Discussion
Although many studies29–31 have been published
on the electrophysiological assessment of the
locked-in syndrome, ERP recordings have
never been described before. In our paper we
show that ERP components could be detected
in all four locked-in patients, with three diVerent cognitive paradigms. In patient 1, ERPs
could not be recorded in the first recording
session, probably because the initial reversible
ischaemic lesion was extending rostrally to the
pons.
As ERPs were recorded also during artificial
ventilation in at least three patients, we suggest
that the recording of ERP to the simple classic
auditory oddball paradigm could become a
useful tool in the evaluation of locked-in
syndrome. Compared with the heterogeneity of

763

findings with other electrophysiological
techniques29–31 that could only show normal or
abnormal aVerence of sensory pathways, ERPs
can evidence an ongoing cognitive activity, and
thus confirm the integrity of some brain functions. The utility of ERP recording might seem
overstated if only classic descriptions of
locked-in syndrome are considered32—that is,
with integrity of ocular movements—thus
implying that patients can communicate with
eye movements. As we report in our description, however, eye movements can be severely
altered in patients who are otherwise capable of
complex cognitive activities (patient 2 had a
one and half syndrome, patient 3 could only
elevate one eye and one eyelid), and previous
literature already described cases of complete
(“mesencephalic”) locked-in syndrome33 in
patients incapable of eye movements. The
involvement of eye and lid movements in our
patients prompted the second part of our
study, based on the letter recognition paradigm. In two of our patients the “augmentive
communication systems” such as the ETRAN
board or the words + infrared switch, that were
developed for patients with amyotrophic lateral
sclerosis34 could not be used because of impairment of eye movement. We therefore tested the
feasibility of the mental prosthesis project proposed by Farwell and Donchin.26 We showed
that ERPs to a letter recognition paradigm can
be recorded in patients with locked-in syndrome; and therefore that the mental prosthesis
project might be feasible. Obviously the
method used in our patients cannot have any
practical application, because attended letters
can be related to ERPs only after the acquired
EEG activity is analysed oV line with the template shape detection program, but further
developments of on line EEG analysis systems
might be able to overcome the technical problems.
A final comment relates to some of the current hypotheses on P3 generators. As reported
in the introduction, some authors think that a
trigger of P3 activity might be located in the
thalamus or in brain stem structures.9 10 20–22
One of the generators might correspond to the
cholinergic neurons of the tegmentopontine
area that constitute the trigger of widespread
electrocortical activities.35 In our patients we
showed, however, that ischaemic lesions were
extended to the tegmental pons (fig 1): as P3
had normal latencies and amplitudes in these
patients, we suggest that a P3 generator located
in tegmentopontine areas is unlikely and,
therefore, that any P3 generator must be
located more rostrally.
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