Download Frontal lobe dysfunction in amyotrophic lateral sclerosis

Brain (1996), 119, 2105-2120
Frontal lobe dysfunction in amyotrophic lateral
sclerosis
A PET study
S. Abrahams,1 L. H. Goldstein,1 J. J. M. Kew,3 D. J. Brooks,3 C. M. Lloyd,2 C. D. Frith 34 and
P. N. Leigh2
1
Department of Psychology, Institute of Psychiatry, the
Department of Clinical Neurosciences, Institute of
Psychiatry and King's College Hospital Medical School,
the 3MRC Cyclotron Unit, Hammersmith Hospital and the
^Wellcome Department of Cognitive Neurology, Institute of
Neurology, London, UK
2
Correspondence to: Dr Sharon Abrahams, Department of
Psychology, Institute of Psychiatry, De Crespigny Park,
London SE5 8AF, UK
Summary
PET measurements of regional cerebral blood flow (rCBF)
were used to explore frontal lobe dysfunction in amyotrophic
lateral sclerosis (ALS). An activation paradigm of executive
frontal lobe function (verbal fluency), which contrasted rCBF
during word generation and word repetition, was used. Two
groups of ALS patients, defined by the presence or
absence of cognitive impairment (ALSi) (impaired, n = 6;
ALSu, unimpaired, n = 6) were compared with healthy
age-matched controls (n = 6). Patient selection was based
on prior performance on a written test of verbal fluency.
Additional neuropsychological assessment of the patients
revealed evidence of executive and memory dysfunction
in the ALSi group only, with marked deficits in tests of
intrinsic generation. The ALSi patients displayed significantly
(P < 0.001) impaired activation in cortical and subcortical
regions including the dorsolateral prefrontal cortex (DLPFC;
areas 46 and 9), lateral premotor cortex (areas 8 and 6),
medial prefrontal and premotor cortices (areas 8 and 9),
insular cortex bilaterally and the anterior thalamic nuclear
complex. Although the three groups showed matched word
generation performance on the scanning paradigm, the ALSu
group displayed a relatively unimpaired pattern of activation.
These results support the presence of extra-motor neuronal
involvement, particularly along a thalamo-frontal association
pathway, in some non-demented ALS patients. In addition,
this study suggests dysfunction of DLPFC in some ALS
patients with associated cognitive impairments.
Keywords: frontal lobes; cognitive impairment; ALS; PET; verbal fluency
Abbreviations: ALS = amyotrophic lateral sclerosis; ALSi = cognitively impaired ALS patients; ALSu, = cognitively
unimpaired ALS patients; DLPFC = dorsolateral prefrontal cortex; rCBF = regional cerebral blood flow; RMJT = random
movement joystick task; SPM = statistical parametric mapping; VFI = Verbal Fluency Index; WCST = Wisconsin Card
Sorting Test
Introduction
Amyotrophic lateral sclerosis is a progressive disorder
characterized by degeneration of the corticospinal tract and
lower motor neurons of the brainstem and spinal cord. Hence
most research on the mechanisms of neurodegeneration in
ALS has focused on the motor system. There is, however,
increasing evidence that ALS should be regarded as a
multisystem disorder and that cortical involvement extends
beyond the confines of the primary motor areas (Smith, 1960;
Kew et al., 1993a, b; Leigh et al., 1994; Talbot et al., 1995).
© Oxford University Press 1996
Dementia occurs in - 3 % of patients with sporadic ALS
(Kew and Leigh, 1992, 1994), and such patients display
cognitive and behavioural changes characteristic of frontal
lobe dysfunction (Neary et al., 1990; Peavy et al., 1992). The
underlying pathology in these cases consists of spongiform
neuronal degeneration in layers 2 and 3 of the prefrontal and
temporal cortex (Hudson, 1981; Wikstrom etal., 1982; Morita
et al., 1987; Neary et al., 1990; Wightman et al, 1992) with
additional involvement of regions within the limbic system
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S. Abrahams et al.
(the hippocampal formation, subiculum and amygdala)
(Okamoto et al., 1991; Wightman et al., 1992; Kato et al.,
1994).
In non-demented patients with sporadic ALS cognitive
changes have been reported in a number of neuropsychological investigations (Gallassi et al., 1985, 1989; David and
Gillham, 1986; Ludolph et al., 1992; Kew et al., 1993b).
These studies have revealed a pattern of frontal lobe (executive) and memory deficits, clearly suggestive of cortical
involvement extending beyond the motor system. Executive
dysfunction has been demonstrated using tests of verbal
reasoning, visual attention, picture sequencing and category
formation on the Wisconsin Card Sorting Test (WCST)
(Gallassi et al., 1985, 1989; David and Gillham, 1986; Talbot
et al., 1995). However, the most striking and consistent
impairment is found using tests of verbal fluency, which
require rapid word generation, typically involving orthographic or category-based procedures (Gallassi et al., 1985,
1989; Ludolph et al., 1992; Kew et al., 1993*). Memory and
learning impairments have also been reported using tests of
prose recall, word list and verbal paired associate learning,
and picture recall (Gallassi et al., 1985, 1989; David and
Gillham, 1986; Iwasaki et al., 1990; Kew et al., \993b).
ALS patients with cognitive impairment, and also
demonstrated that verbal fluency appears to be a sensitive
indicator of such cortical dysfunction.
In the present investigation, we used PET to further explore
frontal lobe functions in ALS using a verbal fluency activation
paradigm. The task was based closely on a study by Frith
et al. (1991a) and contrasts rCBF increases during two
conditions, orthographically based word generation and word
repetition. Word generation is known to produce relative
activation of the DLPFC (Frith et al., 1991a). The purpose
of this study was to identify the neural basis of the marked
abnormalities of verbal fluency detected in some ALS subjects
and to test the hypothesis that such subjects show impaired
activation of prefrontal and subcortical areas, previously
shown to be implicated in ALS (Kew et al., 1993a).
Material and methods
Amyotrophic lateral sclerosis patients
Twelve patients with sporadic ALS, recruited from the
Maudsley/King's College Hospital, London MND Care and
Research Centre, were studied. All patients had clinical and
electrophysiological evidence of combined upper and lower
motor neuron involvement and were classified as 'definite'
or 'probable' ALS according to the El Escorial criteria
(Swash and Leigh, 1992; World Federation of Neurology
Research Group, 1994). The clinical characteristics of the
patients are presented in Table 1. No patient had a history
of cerebrovascular disease, hypertension or diabetes, and
none was taking psychoactive drugs or any medication that
might influence CBF. All patients were right handed. Patients
were excluded if severity of speech, swallowing or respiratory
symptoms would have hindered their task performance
(speaking whilst lying supine in the PET scanner). Prior to
the investigation, the patients underwent a pilot of the test
Further insight into the neural basis of the cognitive
changes in ALS has been provided by a PET study (Kew
et al., 1993a, b). This was conducted using a motor paradigm
which compared paced joystick movements in a freely chosen
(random) direction to movements only in a forward direction
(stereotyped). The study showed impaired activation of
medial prefrontal cortex (Brodmann areas 10 and 32), anterior
cingulate gyrus, parahippocampal gyrus and anterior thalamic
nuclear complex, in ALS subjects selected on the basis of
abnormal verbal fluency scores (Kew et al., 1993£>). Such
dysfunction was less marked in patients with unimpaired
verbal fluency. This study therefore revealed clear evidence
of medial prefrontal cortex dysfunction, in non-demented
Table 1 Clinical characteristics of 12 ALS patients
Patient
(group)
Pseudobulbar
Palsy
(UMN)
Bulbar
involvement
(LMN)
Wasting
UL
Wasting
LL
Fasciculations
(UL and LL)
Spasticity
UL
Spasticity
LL
Hyperreflexia
Babinski
sign
1 (ALSu)
2 (ALSu)
3 (ALSu)
4 (ALSu)
5 (ALSu)
6 (ALSu)
7 (ALSi)
8 (ALSi)
9 (ALSi)
10 (ALSi)
11 (ALSi)
12 (ALSi)
—
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
—
+
+
+
+
+
—
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
—
+
+
+
+
+
+
+
+
-
Pseudobulbar palsy evidence: brisk jaw jerk, spasticity of factila and or tongue muscles, spastic dysarthria. Bulbar involvement evidence
nasal speech, fasciculations, wasting of tongue and weak cough. UMN = upper motor neuron; LMN = lower motor neuron.
UL = upper limb; LL = Lower Limb. + = present/positive; - = absent/negative; ALSu = ALS unimpaired; ALSi = ALS impaired.
Frontal lobe activation in ALS
Table 2 Subject characteristics
Age (years)
Gender
VFI
Duration (months)
Bulbar function
Spinal function
Total disability
HAD anxiety
HAD depression
ALSu
(n = 6)
ALSi
(» = 6)
Controls
(« = 6)
57.3 (10.3)
6M , OF
4.2 (10)
25.7 (17.0)
19.8 (0.4)
15.2 (1.7)
35.0 (1.9)
6.2 (3.0)
4.2 (2.1)
57.3 (13.2)
5M , IF
14.1 (10.8)
22.7 (15.0)
17.5 (3.3)
14.7 (2.9)
32.2 (2.7)
6.8 (2.8)
3.5 (1.9)
57.7 (9.7)
4M , 2F
4.8 (2.0)
NA
NA
NA
NA
5.5 (4.1)
3.3 (2.7)
Means (and standard deviations). Disability scores (bulbar and
spinal functions and total disability) are taken from the ALS
severity scale (Hillel et al., 1989; see text). Low scores
represent functional impairment. Duration = illness time (months)
between onset of symptoms and testing. NA = not applicable;
HAD = Hospital Anxiety and Depression Scale.
procedure to establish whether they could comfortably speak
whilst lying supine. The patients' severity of bulbar symptoms
(particularly swallowing) did not significantly affect their
dietary state and none had a percutaneous endoscopic
gastrostomy.
The patients were selected on the basis of prior performance
on a test of written verbal fluency, based on the Thurstone
Word Fluency Task (Thurstone and Thurstone, 1962). The
task involved the written generation of as many words as
possible beginning with a given letter, in a limited time
period: Subjects were required to write (i) words beginning
with the letter S in 5 min and (ii) four-letter words beginning
with the letter C in 4 min. We adapted the task to control
for speed of writing by using a copy condition where,
following the fluency tests (i) and (ii), the subject was timed
as they copied the words they had written previously. This
writing control condition enabled the calculation of the Verbal
Fluency Index (VFI), which consisted of the average time
(s) taken to think of each word, i.e. (total time allowed for
test, 9 min - time to copy all words generated)/(total number
of words generated). Higher scores represent longer thinking
times and greater impairment. Six patients displayed
unimpaired VFI scores [ALSu (unimpaired performance)],
with scores comparable to the control group (see Table 2 for
means and standard deviations). Six were selected for their
poor VFI scores [ALSi (impaired performance)]. The scores
between the two ALS subgroups were separated by more
than 2 SDs.
Healthy controls
Six age-matched right-handed control subjects were studied.
Three of the controls were either friends or spouses of ALS
patients, recruited through the local Motor Neuron Disease
Association and three were recruited independently and did
not know of any friend or relative with ALS. The subjects
were asked whether they had any neurological symptoms,
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but were not examined in detail neurologically. None had
any neurological symptoms or a history of any neurological
disease. Details (age and gender) are presented in Table 2.
Written informed consent was given by all subjects. The
study was approved by the Hammersmith Hospital and
Maudsley Hospital ethics committees, and permission to
administer radioactive H2I5O was obtained from ARSAC
(UK).
Design for analysis of subject characteristics
and neuropsychological assessment
A one-way ANOVA, with one between-subjects factor of
group, was used to compare the two patient groups (ALSu
and ALSi) or all three subject groups (controls, ALSi,
ALSu). In the latter, two specified independent contrasts
were employed: (i) comparing all ALS patients with controls
(ALSu + ALSi versus controls), (ii) comparing the two
patient groups (ALSu versus ALSi). An additional contrast
was also employed to determine whether one patient group
was significantly different from controls (controls versus
ALSi). Only those contrasts with significant findings are
quoted below (for values of P > 0.05, n.s. denotes nonsignificant). For subject characteristics, a 95% confidence
interval for the difference in means between groups is also
quoted, where a value of 0 contained within the interval
demonstrates a non-significant difference.
Subject characteristics (see Table 2 for means
and standard deviations)
All three subject groups were matched for age and the
analysis revealed no significant differences between groups.
The 95% confidence intervals for the difference in mean
age between ALSu and ALSi (-1.6, 3.0), controls and
ALSu (-3.6, 1.8), controls and ALS (-2.8, 2.4), demonstrates
that the differences were not significant. In the analysis
of VFI scores, the one-way ANOVA revealed a significant
effect of group [F(2,15) = 4.50, P < 0.05] with a
significant difference between the ALSi and the ALSu
patients [F(l,15) = 7.17, P < 0.025] and between the
ALSi group and controls [F(l,15) = 6.29, P < 0.025).
The 95% confidence intervals for the difference in mean
VFI scores between ALSu and ALSi (-18.6, -1.2), controls
and ALSi (-18.0, -0.5), controls and ALSu (-1.2, 2.4),
are consistent with the results of the ANOVA. This
demonstrates that the ALSi group were clearly impaired
on the measure of fluency relative to controls and to
ALSu patients, which is consistent with selection criteria.
The two patient groups did not differ significantly in
length of disease duration, with a 95% confidence interval
for the difference in means between groups (-15.1, 21.1)
revealing no significant difference. Degree of disability
was measured using the ALS Severity Scale (Hillel et al.,
1989), which provides separate measures for bulbar and
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S. Abrahams et al.
spinal function (see Table 2, lower scores represent greater
functional impairment). There was no significant difference
between the two patient groups in the separate bulbar and
spinal function disability scores, although a non-significant
trend emerged for the comparison of total disability scores
[F(l,lO) =4.39, P = 0.06] which was significant using a
95% confidence interval (0.2, 5.4), with the ALSi group
tending to show greater disability than the ALSu patients.
This difference was more apparent on mean scores of
bulbar function; however, the scores are computed from a
maximum of 20, demonstrating that the ALSi group
displayed some slight bulbar functional impairment, while
the ALSu group was virtually unimpaired.
A measurement of anxiety and depression was also
obtained in order to exclude the possibility that abnormalities
in blood flow may be associated with such psychological
factors. This was obtained using the Hospital Anxiety and
Depression Scale (Zigmond and Snaith, 1983), which we
adapted for use with both patients and controls. This alteration
consisted of the removal of one statement ('I feel as if I am
slowed down'), used to calculate depression scores, and
which we felt would falsely exaggerate the measure of
depression in ALS patients.
The analysis of the Hospital Anxiety and Depression Scale
questionnaire scores (see Table 2) demonstrated no significant
differences between the three groups on anxiety (P > 0.05),
with a 95% confidence interval for the difference in means
between ALSu and ALSi (-3.9, 2.7), controls and ALSu
(-4.8, 3.4) and controls and ALSi (-5.3, 2.7). This was
also the case for the modified depression scores (P >
0.05), with a 95% confidence interval for the difference
in means between ALSu and ALSi (-1.6, 3.0), controls
and ALSu (-3.6, 1.8), and controls and ALSi (-2.8, 2.4).
This demonstrates that the three groups were matched in
terms of anxiety and depression.
Neuropsychological assessment
A neuropsychological assessment was conducted on both
patients and controls to determine whether the three groups
differed in terms of neuropsychological profile. The
assessment consisted of standard and experimental tests of
frontal lobe and memory function. The tests included the
National Adult Reading Test—Revised, to estimate premorbid
full scale IQ (Nelson and Willison, 1991). In addition to the
written verbal fluency procedure (see above), frontal lobe
tests measuring executive functions included a computerized
Wisconsin Card Sorting Test (Grant and Berg, 1990) and a
random movement joystick task (RMJT) (Deiber et al., 1991)
where subjects have to generate random sequences of 50
movements with a four-way directional joystick. Memory
tests included verbal Paired Associate Learning (Wechsler,
1987), the Recognition Memory Test (Warrington, 1984)
using both words and faces, and the Kendrick Object Learning
Test (Kendrick, 1985), in which a subject has to remember
pictorial representations of common objects, printed on a
card and presented to the subject for a limited time period.
Structural imaging
Wherever possible, patients underwent either an MRI scan,
or a CT scan of the brain to exclude any significant cerebral
atrophy or ventricular dilation, which may have affected the
stereotactic normalization of the PET scans (see below). MRI
images were acquired using a Picker 1.0 Tesla HPQ Vista
MRI system. The scans consisted of a T r weighted 3D RF
spoiled scan (TR = 21, TE = 6, flip angle 35%). The CT
scans consisted of a series of axial images with a 10 mm
inter-plane distance using a CT9800 whole body scanner
(IGE Medical Systems Ltd, Slough, UK). Four of the patients
studied underwent MRI and one CT, none of which showed
any evidence of atrophy. In addition, an autopsy on a further
patient was found to be normal. Of these six patients, four
were from the ALSi cognitively impaired group.
An MRI scan was performed on one control subject for
the purposes of co-registration with his PET image. This was
conducted in order to identify clearly and display optimally
the regions of significant rCBF change produced by this
word generation paradigm in a healthy individual. Coregistration of the PET and MRI was conducted using
methods described previously (Watson et al., 1993; Woods
et al, 1993).
PET imaging
Experimental design
The PET activation paradigm was based on that developed
by Frith et al. (1991a) and contrasted rCBF during two
conditions: word generation and word repetition. In the
present study, modifications to the procedure were required
to accommodate an older patient group with possible speech
impairment. The subjects had eight PET measurements of
rCBF during a scanning session. Four measurements were
made during each condition using an ABAB design. The
rCBF measurements were performed with the subjects' eyes
closed in a darkened room. During the word generation
condition the subject was required to say aloud any word
beginning with a given letter in response to the word 'next'
presented aurally every 5 s. (The optimum rate of presentation
was established prior to the scanning investigation in a
rigorous pilot study of paced verbal fluency in a separate
group of ALS patients, some with bulbar symptoms.) The
subject was given a different letter (S, C, F, T) for each of
the four word generation scans. On failure to generate an
appropriate word, the subject was required to respond with
the word 'pass', within the 5 s response time. This enabled
the amount of speech output to be matched between the two
conditions. During the four word repetition scans, random
words (see Frith et al., 1991a) were presented verbally to
the subject every 5 s and the subject was required to respond
Frontal lobe activation in ALS
by repeating the words aloud. Prior to the scanning session,
all subjects underwent up to five practice word generation
trials (with different letters), to familiarize them with the
protocol.
Data acquisition
PET scans were performed using a Siemens 935b PET
Scanner allowing 31 planes of data acquisition (CTI,
Knoxville, Tenn., USA), whose physical characteristics have
been described previously (Spinks et al., 1988). Scanning is
performed in 3D mode with the septa retracted. At the start
of each scanning session, a transmission scan was performed
with an external ^Ge/^Ga ring source to correct for tissue
attenuation of "/-irradiation. Regional cerebral blood flow
measurements were obtained by recording regional levels of
cerebral 15O activity following repeated infusions 15 mCi of
H215O, administered through an antecubital vein, at a flow
rate of 10 ml min~'. Prior to each rCBF measurement, a
background scan lasting 30 s was performed. The rCBF scan
lasted 165 s and followed the background scan. Five seconds
before the start of the rCBF scan the subjects began
performing the activating task, the entry of the radioactive
water into the brain coinciding with performance of the
activating task. A 10-min interscan interval was used to allow
15
O activity to decay to background levels. Each image was
reconstructed in 31 axial planes, using a Hanning filter with
a cut-off frequency of 0.5, giving an image resolution of
8.5X8.5X4 mm, full width at half maximum.
Data analysis
Data analysis was performed on a SUN Sparc2 workstation
(Sun Microsystems Europe Inc., Surrey, UK) using display
software (ANALYZE 6.0: Robb and Hanson, 1991). Image
matrix calculations were performed using PRO MATLAB
(Mathworks Inc., Sherborn, Mass., USA), and images were
analysed using Statistical Parametric Mapping (SPM)
software (MRC Cyclotron Unit, London, UK). The 31 planes
in each image were initially interpolated to 43 planes to
produce images with ~2 mm3 voxels. Correction for head
movement between scans was conducted using a automated
realignment program (Woods et al., 1992). The images were
then standardized by resizing into stereotactic space, using
the intercommissural line (AC-PC) as a reference plane for
reslicing and reorientation (Friston et al., 1989). The images
were smoothed using a Gaussian filter (10X10x6 mm, full
width half maximum), to improve signal to noise ratio and
accommodate variability in functional anatomy. This process
generated a normalized set of 26 image planes, parallel to
the AC-PC line, with an interplane distance of 4 mm
corresponding to the axial brain sections of the atlas of
Talairach and Tournoux (1988).
Statistical image analysis
Variations in global CBF between subjects and conditions were
removed using a voxel based ANCOVA with global blood flow
2109
as the covariate (Friston et al, 1990). This process normalized
global CBF to a value of 50 ml/100 g/min and produced a mean
rCBF value and adjusted error variance for each voxel for
each condition (word repetition and word generation). The
normalized mean rCBF values for the two conditions in
normals and patients were then compared with a within-group
analysis using the t statistic for each voxel, and significant
differences were displayed in three orthogonal projections as
a statistical parametric map (SPM{f}; Friston et al., 1991a).
The between-group analysis differences in mean rCBF
distribution were first assessed with y} statistic using an
omnibus threshold of P < 0.001 to avoid false positives due
to multiple comparisons. Normalized mean rCBF differences
were then again compared with the t statistic.
Results
Verbal fluency during scanning
The number of different words produced (excluding passes)
during each word generation scan was recorded as a measure
of task performance. All subjects were clearly capable of
conducting the word generation task successfully, following
up to five practice trials, and, on average, produced five
passes in 35 responses during scanning. A comparison of the
scores between subject groups (ALSu, ALSi and controls)
revealed no significant differences (group, P > 0.35; contrasts
P > 0.15). The 95% confidence intervals for the difference
in means between ALSu and ALSi (-5.3, 7.3), controls and
ALSu (-1.4, 7.2) and controls and ALSi (-1.4, 9.3) are
consistent with the results of the ANOVA revealing no
significant differences between groups. This analysis
demonstrates that the three subject groups were matched in
terms of performance during scanning, and excludes the
possibility that differences in rCBF between groups can be
associated with this factor.
rCBF changes in verbal fluency in healthy
controls
The regions of relative significant rCBF increase in healthy
controls {n — 6), comparing word generation with word
repetition, are represented in a within-group SPM, where
only voxels with a t value corresponding to P < 0.001 are
displayed (see Fig. 1). The areas of significant rCBF increase
include extensive regions of the left prefrontal cortex,
particularly of the DLPFC areas 46 and 9 with evidence of
bilateral prefrontal and premotor activation. Regional cerebral
blood flow increases were also found in the anterior cingulate
gyrus and parietal lobes. The location of the regions of
significant rCBF increase (including Brodmann areas) and
the co-ordinates of voxels of peak activation within each
region are displayed in Table 3. The PET-MRI co-registration
of a single subject verifies the precise locations of the regions
of rCBF activation produced by this verbal fluency paradigm,
within a healthy individual (see Fig. 2).
2110
S. Abrahams et al.
sogitfbl
I
V
-10*
1H
1
coronal
\
n
V J L VAC
68
VPC VAC
0
P I PL
}
SPM
projections
transverse
Fig. 1 Statistical parametric map (SPM) representing increases in rCBF produced in the comparison of word repetition and word
generation in healthy controls (n = 6). Cortical and subcortical regions of significant (P < 0.001) rCBF increase are displayed in black.
Left: sagittal, coronal and transverse projections of SPM displayed on a grid representing the stereotactic co-ordinate system of Talairach
and Tournoux (1988). VAC and VPC are orientation lines transecting the anterior and posterior commissures. Right: medial and lateral
view of left hemisphere (above); medial and lateral views of right hemisphere (below). The location of regions of significant change are
displayed in Table 3.
Table 3 Cortical regions of significant rCBF increase (P < 0.001) in controls, produced in the comparison of word
generation with word repetition
Region
Region (mm
above AC-PC)
Coordinates
Z score
z)
Left dorsal prefrontal cortex (areas 9 and 46)
Right dorsal prefrontal cortex (area 9)
Left inferior frontal gyms (areas 44 and 45)
Left anterior prefrontal cortex (area 10)
Right lateral premotor cortex (areas 6 and 8)
Left lateral premotor cortex (areas 6 and 8)
Left medial premotor cortex (area 6)
Left anterior cingulate gyms (areas 32 and 24)
Left insular cortex
Right insular cortex
Left inferior and superior parietal lobe (areas 40 and 7)
Right inferior and superior parietal lobe (areas 40 and 7)
Left precuneus (area 7)
Right precuneus (area 7)
Left cuneus (area 19)
Left supramarginal gyms (area 40)
Left superior occipital gyms (area 19)
Left anterior thalamus (na and dm)
Left posterior thalamus
Right anterior thalamus (va)
16-36
24-36
20-28
20-24
40-64
40-64
44-60
24-44
8-12
4-20
40-48
36-48
44-52
36-44
36
36
28-32
18
8
8
-38
30
-40
-28
18
-24
0
-6
-30
28
-46
32
-14
6
-6
-34
-24
-6
0
12
24
32
12
44
0
2
16
14
20
12
-42
-64
-68
-74
-78
-46
-66
-14
-30
-6
28
32
24
24
60
52
44
40
12
8
44
44
48
40
36
36
32
16
8
8
5.67
5.93
4.62
5.73
4.82
5.50
5.30
6.12
5.40
4.43
4.62
4.38
4.22
3.64
3.96
4.45
3.79
3.12
3.40
4.03
Talairach and Tournoux coordinates of the most significant voxel within each region are displayed. AC-PC refers to the intercommissural
line; 'area' refers to the cytoarchitectonic (Brodmann) area in which significant voxels were located. Z score refers to the specified
coordinate, va = ventral anterior nucleus; na = anterior nucleus; dm = dorsal medial nucleus; p = pulvinar.
The comparison of verbal fluency with repetition also
showed relative decreases in rCBF in healthy controls. These
regions of significant (P < 0.001) rCBF reduction (from
word repetition to word generation) were found in posterior
cingulate gyrus (areas 31, 23 and 30) and temporal lobes
bilaterally; the left and right middle and inferior temporal
gyri (areas 39, 21 and 37), and the left and right superior
temporal gyri (areas 22 and 38). This is consistent with
findings reported by Frith et al. (1991a).
Comparison of rCBF activation between groups
The ALSi group versus controls
The ALSi group displayed significantly (P < 0.001) impaired
activation in the DLPFC (areas 46 and 9), premotor cortex
Frontal lobe activation in ALS
2111
"Fig. 2 Increases in rCBF in a single healthy control subject. Co-registered PET and MRI images. Left: transverse section 4 mm above
AC-PC line, areas of rCBF increase include left dorsolateral prefrontal cortex (DLPFC; areas 46 and 45) Middle: transverse section
38 mm above AC-PC line, areas of rCBF increase include left and right DLPFC (area 9) anterior cingulate (area 32), left inferior
parietal lobe (areas 40 and 19). Right: transverse section 55 mm above AC-PC line, areas of rCBF increase include left premotor cortex
(areas 8 and 6) and right premotor cortex (area 8).
sagittal
i
coronal
A
n
=•
^v -"C VAC
-10*
VPCVAC
6B
SPM
projections
transverse
Fig. 3 Between-group SPM comparing the pattern of activation in ALSi and control groups. Cortical and subcortical regions showing
significantly (P < 0.001) impaired activation in the ALSi group compared with controls, are displayed in black. Left: sagittal, coronal
and transverse projections. Right: medial and lateral views of left hemisphere (above): medial and lateral views of right hemisphere
{below). The location of the regions displayed are described in Table 4.
(8 and 6), insular cortex (see Fig. 3.) and thalamus (see Table
4). Differences in activation arose as a result of increases in
rCBF in controls relative to ALSi patients comparing word
generation with word repetition.
40) and the left middle and superior temporal gyri (areas 39
and 22).
The ALSi group versus the ALSu group
The ALSu group versus controls
A comparison of the ALSu group with controls at an omnibus
significance level of P < 0.001 revealed minor differences
in rCBF activation between the two groups (see Fig. 4).
Areas of impaired activation included right dorsal prefrontal
cortex (area 9), the left and right inferior parietal lobule (area
The comparison of the two patient groups (ALSi versus
ALSu) produced a similar pattern of rCBF activation
differences as found in the comparison of the ALSi group
with controls (see Fig. 5). The regions of significant (P
< 0.001) difference included prefrontal cortex, lateral and
medial premotor cortex, bilateral insular cortex, and
thalamus (see Table 5). In general, these differences were
S. Abrahams et al.
2112
Table 4 Regions of significant difference (P < 0.001) in activation in the comparison between the control and the ALSi
(ALS impaired) groups
Region
Region
(mm above
AC-PC)
Left dorsal prefrontal cortex (areas 46 and 9)
Left anterior prefrontal cortex (area 10)
Right medial prefrontal cortex (area 9)
Right lateral prefrontal cortex (area 9)
Right anterior medial prefrontal cortex (area 10)
Left medial premotor cortex (area8)
Left lateral premotor cortex (areas 6 and 8)
Right lateral premotor cortex (area 8)
Right primary motor cortex (area 4)
Left primary motor cortex (area 4)
Left anterior cingulate gyrus (area 24)
Left posterior cingulate gyrus (area 23)
Left insular cortex
Right insular cortex
Left precuneus (area 7)
Left cuneus (area 19)
Right cuneus (area 18)
Left anterior thalamus (na and dm)
Right anterior thalamus (va)
Left posterior thalamus
24-32
24
36-44
28-36
20
36—44
44-52
40-48
52-56
44
24
28
16
8-16
48-52
32-36
24
12-16
16
8-12
Coordinates
—
(x
-34
-22
4
28
12
-10
-36
26
36
-44
-8
-10
-6
30
-8
-12
10
-26
10
-4
38
52
48
32
50
44
2
30
12
-2
16
34
14
4
66
80
•82
10
-4
32
Z score
z)
% Changes
in rCBF
controls/ALSi
28
24
36
36
20
36
52
40
52
44
24
28
16
8
52
32
24
16
8
8
+3.4/-3.5
+2.11-2.1
—1.1/—6.6
+5.0/-0.4
+0.5/-2.6
+2.27-5.6
+2.8/-4.5
+4.3/-0.2
+ 1.9/-3.0
+2.2/-3.3
+5.1/-0.5
+2.4/-3.5
+ 1.9/-4.2
+2.3/-2.1
+3.1/-3.4
+2.9/-2.5
+ 1.9/-2.8
+ 1.7/-2.1
+ 3.3/-2.8
+3.2/-2.2
3.83
3.18
3.33
4.17
3.18
3.25
4.35
3.25
3.30
3.70
3.21
3.17
3.12
3.76
3.75
3.46
3.11
3.38
4.03
3.31
% Changes in rCBF denotes the change in rCBF from word repetition to word generation (a positive sign denotes a relative activation
and a negative sign a relative deactivation). Talairach and Tournoux coordinates (and corresponding Z score) of the most significant
voxel within the region are displayed. See Table 3 legend for abbreviations.
BO grtt d
/
a an al
\
72
V
i
1 i— \
-•-
1 '
\
n
32JLil
66
-104
f
r 1
VPC VAC
*
\
\
\
0
projections
\
s
64
SPM
f
Jy
iransvans
Fig. 4 Between-group SPM comparing the pattern of activation in ALSu and control groups. Cortical and subcortical regions showing
significantly (P < 0.001) impaired activation in the ALSu group in comparison with controls are displayed in black. Left: sagittal,
coronal and transverse projections. Right: medial and lateral views of left hemisphere {above); medial and lateral views of right
hemisphere {below).
due to increases in rCBF in the ALSu group relative to
the ALSi group comparing word generation with word
repetition {see Table 5).
Neuropsychological tests
The mean scores (and standard deviations) for the
neuropsychological tests are reported in Table 6. The analysis
of variance on National Adult Reading Test—Revised, IQ
scores revealed no significant differences between the groups
{P > 0.05). The 95% confidence intervals for the difference
in means between ALSu and ALSi (-8.2, 20.8), controls and
ALSu (-8.1, 12.5), controls and ALSi (-5.4, 21.7) are
consistent with the results of the ANOVA, demonstrating
that the three groups were matched in premorbid IQ.
The WCST was measured in terms of four scores: number
of categories achieved (maximum of six), total number of
errors, trials to first criterion (number of trials taken to
Frontal lobe activation in ALS
*
—<
1
sn
\
i
f
-4
-T
1
-f
i-*
T
V•L V J.
-t(M
If
2113
VPCVAC
SPM
/
*
projections
*
\
y
j
fi4
transverse
Fig. 5 Between-group SPM comparing the pattern of activation in ALSi and ALSu. Cortical and subcortical regions of significantly
(P < 0.001) impaired activation in the ALSi group in comparison with the ALSu group are displayed in black. Left: sagittal, coronal and
transverse projections. Right: left hemisphere (above); right hemisphere (below). The locations of the regions displayed are described in
Table 5.
Table 5 Regions of significant difference (P < 0.001) in activation in the comparison between the ALSu (ALS unimpaired)
and ALSi (ALS impaired) groups
Region
Left DPFC (area 46)
Left DPFC (area 46)
Right DPFC (areas 44 and 45)
Right medial prefrontal cortex (area 9)
Right lateral prefrontal cortex (area9)
Right premotor cortex (area 8)
Left medial premotor cortex (area 8)
Left lateral premotor cortex (area 8)
Left anterior medial premotor cortex (area 8)
Right medial premotor cortex (area 8)
Left paracentral lobule
Left SMA (paracentral lobule)
Right primary motor cortex (area 4)
Left primary motor cortex (area 4)
Left primary motor cortex (area 4)
Right cingulate gyms (area 24)
Left anterior cingulate gyrus (area 24)
Right insular cortex
Left insular cortex
Left anterior thalamus (na and dm)
Right posterior thaJamus (p)
Region
(mm above
AC-PC)
Coordinates
24-28
16
16-20
28
24-28
52-56
52
44-48
40
36-44
48
44-48
52
44-48
32-36
-36
-34
44
24
15
36^40
12
16-20
16
16
12
v)
12
-8
-46
-8
12
-16
-12
34
-46
-50
-10
-8
26
-22
-4
12
36
46
14
6
50
26
32
-6
44
40
•34
14
-4
-6
-8
12
32
16
8
14
•26
Z score
•r)
% Changes
inrCBF
ALSu/ALS
28
16
20
28
28
56
52
44
40
40
48
44
52
44
32
40
12
20
16
16
12
+2.6/-4.I
+5.5/-1.1
+0.1/—3.9
+0.2/-4.0
+ 1.0/-3.1
-0.4/-6.7
-2.0/-7.9
-0.1/-4.8
-2.0/-7.3
-0.5/-4.9
+ I.3/-3.5
+ 3Z7/-2.6
+ 1.1/-4.0
+ 3.7/-2.7
+3.0/-1.6
+3.0/-4.1
+2.5/-2.5
+ 1.4/-4.0
+ 1.9/-3.I
+ 1.5/-4.7
+ 2.6/-3.0
3.52
3.44
3.22
3.13
3.20
3.29
3.10
3.45
3.23
3.26
3.18
3.18
3.17
3.74
3.18
4.02
3.10
3.10
3.11
3.07
3.10
SMA = supplementary motor area; DPFC = dorsal prefrontal cortex. See Table 3 legend for abbreviations.
complete the first category) and perseverative errors (where
the subject continues to use a previous and irrelevant rule).
No significant differences emerged between groups on the
category scores or on the total number of errors. The analysis
of perseverative errors revealed a trend towards a significant
difference in the comparison of the two patient groups
[F(1,I3) = 3.84, P = 0.07], with the ALSi patients
showing greater perseveration than the ALSu group.
However, there was no overall difference between the
three groups and the ALSi group were not significantly
impaired relative to controls. In the analysis of the number
of trials taken to reach the first criterion, a significant
difference emerged between the three groups, [F(2,14) =
9.09, P < 0.005], with a clearly significant impairment in
the ALSi patients as compared with the ALSu group
[F( 1,14) = 14.04, P < 0.005] and controls [ALSi versus
controls, F( 1,14) = 14.04, P < 0.005]. This result
demonstrated a deficit in the ALSi group in the speed at
which they learned to sort the cards and deduce the first rule.
Performance on the RMJT was measured in terms of
2114
S. Abrahams et al.
Table 6 Neuropsychological test scores
Test
Controls
ALSu
ALSi (/> < 0.05)
Significant
NART predicted full scale IQ
Wisconsin Card Sorting Test
Categories
Total errors
Trials to first criterion
Perseverative errors (%)
Random Movement Joystick Task
Three string information statistic
Decision time (s)
Paired Associate Learning
Easy
Hard
Total
Recognition memory
Words: raw score
Words: age scaled score
Faces: raw score
Faces: age scaled score
Kendrick object learning test total
U5.5(7.5)/i = 6
111.3 (10.5)/i = 6
107.0 (14.7) n = 6
No
5.2 (1.0) n = 6
29.5 (10.4) n =6
14.0 (6.4) n = 6
12.9 (2.6) n = 6
4.2(1.8)/i = 6
33.3 (20.1)/i = 6
14.0 (3.7) n = 6
9.5 (3.4) n = 6
4.2 (2.2) n = 6
48.6(21.8)/! = 6
40.0(19.8)/! = 6
15.3 (7.1)/i = 6
No
No
Yes
No
1.10(0.04)/i = 6
0.13 (0.14) n = 6
1.08 (0.12)/i = 4
0.16(0.18)/! = 4
0.95 (0.06) /i = 4
0.50(0.10)/! = 4
11.3(1.2) n = 6
7.2 (2.5) n = 6
18.5 (3.4) n = 6
11.2(1.3)/! = 6
6.5 (3.2) n = 6
17.7 (4.2)/i = 6
10.3 (1.2)/i = 6
2.5 (1.6)/i = 6
12.8 (2.4)/i = 6
47.5(1.6)
12.5(1.8)
40.8 (5.0)
8.0 (4.9)
50.3 (5.4)
47.0 (3.5) n
12.4(1.8)/i
43.8 (4.7) n
11.0 (4.1) n
52.2 (7.7) n
43.5
9.7
43.3
9.8
38.7
n
n
n
n
n
=
=
=
=
=
6
6
6
6
6
=
=
=
=
=
5
5
5
5
6
(4.6)
(3.5)
(3.9)
(4.2)
(9.8)
/i
/i
/i
/i
n
=
=
=
=
=
6
6
6
6
6
Yes
Yes
No
Yes
Yes
No
No
No
No
Yes
Means (and standard deviations). NART = National Adult Reading test.
'randomness coefficients'. This was estimated by observing
the sequence of 50 moves produced by each subject and
comparing their frequency of occurrence with that predicted
in a completely random set. The resulting measure of
randomness was expressed as an 'information statistic' for
strings of one, two, three and four movements (Frith and
Done, 1983). The analysis of variance was conducted on
each of the four information statistics. The results revealed
a significant difference between the three groups on strings of
three movements only [F(2,ll) = 6.51, P < 0.O25], with all
three contrasts on this measure revealing a significant effect
[ALSu + ALSi versus controls F(l,ll) = 5.45, P < 0.05;
ALSu versus ALSi F(l,ll) = 7.57, P < 0.025; ALSi versus
controls F(l,ll) = 11.97, P < 0.01]. Inspection of the
information statistic for strings of three movements (Table
6) demonstrated that the ALSi group was clearly impaired
on this measure of frontal lobe function in comparison with
the ALSu group and the control group. The ALSu group
and controls had comparable scores, despite the significant
difference in the comparison of all ALS patients (ALSu +
ALSi) and controls. Analysis of the RMJT decision items
(time taken to decide in which direction to move the joystick)
was also undertaken. This was calculated by comparing
response times on the free selection task and a 'control' task,
in which the direction of movement was specified by the
computer. Analysis of this measure revealed a significant
difference between the three groups [F(2,ll) = 9.07,
P < 0.005], with all three contrasts demonstrating
significant effects [ALSu + ALSi versus controls / r (l,ll) =
7.00, P < 0.025; ALSu versus ALSi F(l,ll) = 11.15, P <
0.01; ALSi versus controls F(l,ll) = 16.34, P < 0.005].
Inspection of the means (Table 6) showed that the ALSi
group were impaired in comparison with both the ALSu and
control groups. However, for the RMJT results the data were
obtained from only eight patients.
Overall, these tests of frontal lobe function demonstrated
a pattern of deficits in the ALSi group alone, across tasks
which included both verbal (VFI) and non-verbal (RMJT)
procedures. The deficit found in the WCST was less
striking than that on the verbal fluency task, since a
significant impairment was revealed only in the number
of trials to first criterion. However, when examining the
mean scores for all of the WCST measures (Table 6), it
was apparent that the patients in the ALSi group did not
perform as well controls, despite differences being nonsignificant.
With respect to measures of memory, the verbal Paired
Associate Learning test revealed no significant differences
between groups on the learning of the four 'easy' (semantically
related) pairs. However, a significant difference was apparent
between groups in learning the four 'hard' (semantically
unrelated) pairs [F(2,15) = 5.98, P < 0.025]. The ALSi group
showed a significant impairment relative to the ALSu group
[F(l,15) =7.51, P < 0.025] and to controls [F(l,15) = 10.23,
P < 0.01]. A similar pattern emerged for the total learning
scores [F(2,15) = 4.80, P < 0.05], with the ALSi group
displaying a significant deficit in comparison with the two other
groups [ALSu versus ALSi F(l,15) = 5.98, P < 0.05; controls
versus ALSi F(l, 15) = 8.23, P < 0.025].
In the Recognition Memory Test, no differences were
found between groups for face recognition using raw or agescaled scores. In the word recognition test, the analysis of
the raw scores revealed no significant differences between
the three groups (P > 0.1), but a trend towards a
significant difference emerged in the comparison of the
ALSi group and controls [F(l,14) = 4.02, P = 0.06],
Frontal lobe activation in ALS
with the ALSi group displaying lower scores. For age
scaled scores, a similar pattern was revealed with no
evidence of an effect of group although contrasts
demonstrated a trend towards a significant difference
between the ALSi group and controls [F(l,14) = 3.74,
P = 0.07].
The analysis of performance on the Kendrick object
learning test was conducted on total scores, as the three
groups were closely age-matched. The ANOVA revealed a
significant group effect 17(2,15) = 5.21, P < 0.025] with
the contrasts demonstrating a significant difference
between ALSu and ALSi groups [F(l,15) = 8.86, P < 0.01]
and between ALSi patients and controls [F(l,15) = 6.62,
P < 0.025], in each case, with poorer performance by the
ALSi group. Therefore the above tests revealed evidence of
memory impairments in the ALSi group only, with significant
deficits on the Kendrick object learning test and Paired
Associate Learning Task.
Overall, the findings of the neuropsychological assessment
revealed a profile of cognitive dysfunction in the ALSi
group, with deficits on frontal lobe and memory tasks, while
cognitive functions in the ALSu patients appeared to be
relatively unaffected.
Discussion
The findings of this study clearly illustrate that regional brain
activation abnormalities, particularly in the frontal association
areas, can be detected in a subgroup of ALS subjects, using
a paced verbal fluency PET paradigm. Cognitively impaired
ALS patients showed impaired activation in DLPFC (left
areas 46, 9 and 10; right area 9), lateral and medial premotor
cortex (areas 6 and 8) and frontal cortex (areas 8 and 9).
They also displayed bilateral impaired activation of the
insulae and anterior thalamic nuclei. In contrast, rCBF
activation in ALS patients who performed normally on the
written verbal fluency task (ALSu) was similar to healthy
controls. This pattern of results was revealed despite matched
performance between the three groups on the scanning
paradigm, hence differences in rCBF activation cannot be
associated with verbal output during scanning.
Cerebral regions activated by verbal fluency
paradigm
The task, adapted from Frith et al. (1991a), activated regions
of the frontal cortex, particularly the left DLPFC; areas 46
and 9, in a group of healthy subjects. The location of this
region of activation was verified in a control subject, through
the direct co-registration of rCBF increases onto the MRI
scan. Activation of the left DLPFC is consistent with rCBF
increases reported in previous studies of internal word
generation (Friston et al., 1991; Frith etal., 1991a, b; CantorGraae et al., 1993). In contrast to the study by Frith et al.
(1991a), the regions of cerebral activation revealed in the
2115
current task extended beyond the left DLPFC, as bilateral
prefrontal rCBF increases were revealed. Such bilateral
prefrontal activity has also been demonstrated in other tasks
requiring volitional output such as internal generation of
paced joystick movements, in freely chosen directions
(Deiber et al., 1991) and freely chosen finger movements
(Frith et al., 1991a). These nonverbal procedures are similar
to verbal fluency in that responses are not wholly specified
by the immediate situation and so decision making is central
to the tasks. Our current study also revealed rCBF increases
in the anterior cingulate gyms (areas 32 and 24) during word
generation consistent with previous reports. This region is
probably concerned with processes of response selection and
attention (Petersen et al, 1988; Frith et al, 1991a).
The regions of rCBF increase seen in healthy controls
during word generation also encompassed areas known to be
involved in language production, including regions of Broca's
area (areas 44 and 45 and lateral premotor cortex 6; see
Mesulam, 1990). The task was designed to ensure that die
speech components of the word repetition and word
generation conditions were matched, using a paced procedure
in which the subject responded to every stimulus. However,
differences may have occurred in the amount of subvocal
speech each condition generated. Verbal fluency not only
involves intrinsic generation, but also working memory.
Letter-based fluency paradigms encourage the processing
and manipulation of phonological information, which (in
Baddeley's working memory model), is rehearsed through
subvocalization within the articulatory loop (Baddeley, 1986).
Functional studies have associated subvocal rehearsal and
the covert retrieval of words with regions involved in the
production of speech sounds, i.e. Broca's area (Wise et al,
1991; Demonet et al, 1992; Hinke et al, 1993; Paulesu
et al, 1993). In the word repetition condition, fewer demands
are placed on working memory and subvocalization is
unnecessary, as the response is fully specified by the stimulus
and generated immediately after the stimulus presentation.
The paced verbal fluency paradigm employed also
produced activation within the superior, inferior and medial
aspects of the parietal lobes (areas 7 and 40). Connections
between the prefrontal cortex (area 46) and superior parietal
lobe have been described by Pandya and Barnes (1987). In
addition, activation of the inferior parietal lobe was reported
in covert word retrieval paradigms using verb generation
(Warburton et al, 1996). Reports have also associated such
regions of the parietal cortex to the processing of phonological
information (Demonet et al, 1992, 1994; Zatorre et al,
1992). In neuropsychological investigations of brain-damaged
patients (Shallice and Vallar, 1990), the left inferior parietal
lobule was shown to be associated with the short-term
phonological store. This was recently supported by the
demonstartion of activation of the supramarginal gyms in a
phonological short-term memory task (Paulesu et al. 1993)
and is consistent with the intensive connectivity which is
found between parietotemporal cortex and Broca's area
(Mesulam, 1990). Paulesu et al, (1993) also showed
2116
S. Abrahams et al.
association of bilateral increases in the insulae with such
phonological processes. A similar pattern of activation was
found in the current study.
Hence, in the current paradigm, the pattern of rCBF change
in healthy controls (in regions other than the DLPFC) may
be related to demands on working memory. In orthographic
verbal fluency, subvocal rehearsal and the short-term memory
of phonological information is required to help cue wordretrieval and keep track of recent responses to avoid repetition
(Jones-Gotman and Milner, 1977; Miller, 1984). The present
paradigm may more reliably detect such areas of activation
associated with verbal fluency, as a greater number of rCBF
measurements were acquired (four measurements of each
condition, in six subjects) than in previous studies.
Cortical and subcortical dysfunction in ALS
The results of the current investigation revealed frontal
association area dysfunction in those ALS patients with
cognitive impairment. Dysfunction of the DLPFC in
ALS is consistent with reports from neuropsychological
investigations of frontal lobe (executive) type cognitive
deficits (Gallassi et al., 1985, 1989; David and Gillham,
1986; Ludolph et al., 1992; Kew et al, 1993ft). Verbal
fluency deficits have been frequently related to lesions of the
left prefrontal cortex (Benton, 1968; Miceli et al., 1981;
Pendleton et al., 1982; Miller, 1984; Bornstein, 1986) and
such impairments are repeatedly found in ALS using verbal
and non-verbal tasks of the fluency-type (Gallassi et al.,
1985, 1989; Ludolph et al., 1992; Kew et al., 1993ft). In
addition, the results of our neuropsychological assessment of
ALSi patients revealed evidence of executive dysfunction on
verbal and nonverbal frontal lobe tests, with deficits on the
RMJT and one measure of WCST, i.e. trials to first criterion.
The RMJT was based on an activation paradigm reported by
Deiber et al. (1991) which was associated with bilaterally
increased rCBF in the DLPFC (as described above). The
task involves the production of freely chosen sequences
of movements and is similar to verbal fluency in terms of
intrinsic generation; the ALSi subgroup was impaired in
terms of its ability to generate a random string of movements.
The neuropsychological profile displayed by the ALSi patients
is therefore characterized by deficits in tests of verbal and
non-verbal willed actions. Several studies have also reported
an association between deficits on the WCST and damage
of the DLPFC (Milner, 1963, 1971). The WCST has been
employed as a functionally activating task and is also
associated with rCBF increases in this region of the prefrontal
cortex (Weinberger et al., 1986). Hence, the results of this
neuropsychological investigation are in accordance with the
pattern of rCBF abnormalities, in that ALS patients with
frontal lobe executive-type deficits display corresponding
dysfunction of the DLPFC.
Cortical abnormalities in non-demented ALS patients have,
until recently, not been well documented. However, the
finding of frontal lobe involvement is supported by some brain
imaging investigations. Ludolph et al. (1992) demonstrated
reduced cortical glucose utilization in a group of 18 ALS
patients. Neuropsychological assessment, conducted on some
of these patients, revealed deficits in verbal and non-verbal
fluency tests; however, no impairment was found on the
WCST. Talbot et al. (1995) demonstrated pronounced
reductions in rCBF in frontal and anterior temporal cortices
in non-demented patients with classical ALS using single
photon emission computed tomography. These patients
showed evidence of subtle frontal lobe dysfunction with a
significant deficit on a picture sequencing task, and trends
towards reduced verbal fluency and category formation on
the WCST. Structural imaging studies have typically shown
atrophy restricted to the motor cortex and cortico-spinal tracts
in non-demented ALS patients, using CT (Poloni et al., 1986;
Gallassi et al., 1989) and MRI (Goodin et al., 1988; Luis
et al., 1990; Abe et al., 1993; Ishikawa et al., 1993), with
frontal lobe atrophy limited to ALS patients with dementia
(Abe et al., 1993). Recently more sensitive analysis
techniques using volumetric measurements have revealed
atrophy of the underlying subcortical white matter in the
anterior frontal cortex, but with no significant frontal cortical
atrophy. In addition, in a longitudinal investigation of ALS
patients, progressive atrophy of the frontal and temporal
regions with serial CT and MRI was reported (Kato et al.,
1993). This study demonstrated atrophy involving initially
the frontal and anterior temporal lobes and progressing to
pre- and then post-central gyrus, anterior cingulate and corpus
callosum. Three of the patients studied were also demented;
however, the fronto-temporal degeneration was not restricted
to these patients. Unfortunately in neither of these structural
imaging investigations were the findings related to
neuropsychological status.
The findings of our current investigation suggest that the
deficit in verbal fluency revealed in several neuropsychological investigations is predominantly a result of
dysfunction of the DLPFC. The pattern of impaired activation
in the ALSi group did not include other regions which may
be associated with the working memory component of the
task (Broca's area and area 40 of the parietal cortex; see
Paulesu et al., 1993). Bilateral abnormalities in rCBF were
also revealed in lateral and medial premotor areas when
comparing ALSi patients with controls. These regions, however, were located dorsal to those associated with Broca's
area. In addition, the comparison of the two patient groups
revealed a significant impairment of activation of the supplementary motor area in ALSi patients. In the study of shortterm memory and phonological processing conducted by
Paulesu et al. (1993), activation of the supplementary motor
area was demonstrated, even though the task was conducted
using covert speech. This region may be involved in the
motor aspect of vocal or subvocal speech preparation and
execution, hence dysfunction could exaggerate the verbal
fluency deficit. This pattern of rCBF abnormalities is supported by our previous findings of reduced rCBF in the lateral
premotor cortex (area 6) bilaterally and in the supplementary
Frontal lobe activation in ALS
motor area in resting state scans of ALS patients (Kew
et al, 1993a).
The comparison of ALSi patients with controls also
revealed impaired activation bilaterally in the anterior insular
cortex. Unilateral dysfunction in this region has been reported
previously in ALS patients, with reduced rCBF at rest,
but increased activation during upper limb movement, as
compared with healthy controls (Kew et al., 1993a). In the
working memory task conducted by Paulesu et al. (1993),
the insular cortex was bilaterally activated in control subjects,
suggesting that this region is involved in phonological
processing. In addition, the insulae also possess specific
connections to areas 45 and 46 of the prefrontal cortex
(Mesulam and Mufson, 1985). Hence dysfunction of the
insular cortex could also contribute to the production of
fluency-type deficits in ALS.
The results of this investigation also support our previous
findings of subcortical involvement in ALS patients with
cognitive impairment. In our earlier investigations,
impaired activation was revealed in some ALS patients,
involving the medial prefrontal cortex, anterior cingulate
gyrus, parahippocampal gyrus and anterior thalamic nuclear
complex (Kew et al., 1993a, b). Attenuation of rCBF along
this pathway was associated with the presence of impaired
written verbal fluency. This is supported by the present
comparison of ALSi patients and controls which revealed
reduced rCBF bilaterally in predominantly anterior, but
also posterior thalamus. Fibres running through the anterior
thalamic nuclei project to the medial prefrontal areas and to
the lateral premotor cortices (Aggleton et al., 1986;
Bachevalier and Mishkin, 1986; Walsh, 1994). Our findings
also suggest impairment of activation of the dorsomedial
thalamic nucleus which projects to the prefrontal cortex
(Walsh, 1994). However, resolution using PET is not sufficient
to determine involvement of specific nuclei.
Thalamic degeneration has been shown to be associated
with motor neuron disease in a number of investigations.
Brownell et al. (1970) reported thalamic gliosis in 53% of
36 cases of non-demented patients with ALS. In addition,
subcortical involvement in ALS is corroborated by Ludolph
et al. (1992), who noted reduced resting glucose metabolism
in the thalamus, although this reduction was not significant.
Ludolph et al. (1992) suggested that the findings of cognitive
deficits in ALS may be related to degeneration of subcortical
structures. Thalamic abnormalities have been associated with
severe cognitive changes resulting in dementia in a number
of studies (Cambier and Graveleau, 1985; Moossy et al.,
1987). Unilateral thalamic damage has been associated with
memory loss and frontal signs (Speedie and Heilman, 1982,
1983). Thalamic dysphasia has also been observed with an
accompanying verbal adynamia (see Walsh, 1994). This is
characterized by a lack of spontaneous speech and is clearly
associated with processes of intrinsic generation related to
the DLPFC. The reduced thalamic activation and glucose
metabolism currently seen may, however, simply reflect
reduced afferent input and not intrinsic degeneration of this
2117
nucleus. Indeed, in view of the evidence for extra-motor
cortical damage in ALS (Smith, 1960; Okamoto et al, 1992;
Kato et al, 1993; Kiernan and Hudson, 1994; Leigh et al,
1994), subcortical degeneration is unlikely to be the dominant
cause of neuropsychological impairments, although it is
almost certainly contributory.
Involvement of the hippocampal system in ALS reported
in our previous investigation could not be verified in this
study, since the verbal fluency paradigm employed does
not activate this region in healthy controls. However, the
neuropsychological profile of the ALSi patients also revealed
evidence of memory impairments, which is consistent with
dysfunction of the limbic system. Deficits were found on the
Kendrick Object Learning Test and Paired Associate Learning
test, supporting previous reports of impairments on visual
recall (Gallassi et al, 1985, 1989; Kew et al, 1993/?) and
verbal memory (Gallasi et al, 1985; David and Gillham,
1986; Iwasaki et al, 1990a, b). Pathological changes in
limbic structures consisting of ubiquitin immunoreactive
inclusions in the dentate gyrus of the hippocampus and
associated entorhinal cortex and in the amygdala are present
in some non-demented ALS subjects (Okamoto et al, 1991;
Wightman et al, 1992; Leigh et al, 1994; Anderson et al,
1996).
Altered function in extra-motor cortex in non-demented
patients with cognitive impairment, closely parallels the
regions most affected in patients with ALS with dementia
(Neary et al, 1990; Kew and Leigh, 1992; Wightman et al,
1992; Talbot et al, 1995). The neuropsychological profile
of ALS patients with dementia is also characterized by
behavioural and cognitive problems reflecting gross frontal
lobe dysfunction, with relative preservation of functions
of the posterior association cortices (Neary et al, 1990).
Behavioural features include disinhibition, apathy, and personality changes (Kew and Leigh, 1992). Neuropsychological test results are difficult to obtain. However,
some studies have demonstrated gross deficits in verbal
fluency, attention, and tests requiring the ability to shift from
one line of thinking to another, similar to the WCST (Peavy
et al, 1992; Kato et al, 1994; Talbot et al, 1995). Hence
the findings of the current and earlier investigations demonstrates that some non-demented ALS patients display a lesser
degree of the cognitive dysfunction found in ALS-dementia
patients. This has led to the suggestion that a spectrum of
extra-motor cortical and subcortical involvement exists in
ALS (Leigh et al, 1994), although an alternative hypothesis
is that an ALS subgroup exists, characterized by cognitive
impairment. Interestingly ALS-related dementia frequently
occurs in conjunction with bulbar pathology, which may be
present in up to 85% of cases (Wikstrom et al, 1982;
Mitsuyama, 1984; Kew and Leigh, 1992; Talbot et al, 1995).
In this study, clinical features were similar in cognitively
impaired and unimpaired groups, but there was a tendency
for the ALSi group to show greater bulbar involvement than
the ALSu patients. In addition there was a slightly higher
incidence of pseudobulbar involvement in patients with
2118
S. Abrahams et al.
cognitive impairment, suggesting the possibility of a subtle
association. Only longitudinal studies will indicate whether
the two groups are dissimilar from the outset, or whether
subjects in the ALSu group progress to show the same
cognitive impairments identified in the ALSi patients.
In summary, this investigation has demonstrated that PET
activation studies are an effective technique for detecting
frontal lobe dysfunction in ALS subjects and has revealed
evidence of impaired function in the prefrontal cortex in
some non-demented patients with ALS, associated with
selective cognitive deficits. It has also provided evidence that
dorsolateral and not just medial prefrontal cortex may be
impaired in some ALS patients. The PET findings are
consistent with dysfunction of thalamo-cortical pathways, as
suggested in our previous studies using a motor paradigm
(Kew et al., 1993&). Future studies will need to define the
temporal sequence of cognitive changes and the pathological
correlates of frontal lobe involvement in ALS subjects.
These observations will help to identify important phenotypic
variations in ALS.
Acknowledgements
This project was supported by the Medical Research Council
of Great Britain, and additional assistance was provided by
the Tregaskis Bequest (University of London), the Wellcome
Trust and the Guarantors of Brain.
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Received August 14, 1996. Revised June 24, 1996.
Accepted July 24, 1996