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Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study

S. Abrahams , L. H. Goldstein , A. Simmons , M. Brammer , S. C. R. Williams , V. Giampietro , P. N. Leigh
DOI: http://dx.doi.org/10.1093/brain/awh170 1507-1517 First published online: 26 May 2004

Summary

The cognitive impairment revealed in some non‐ demented amyotrophic lateral sclerosis (ALS) patients is characterized by executive dysfunction with widely repeated deficits on tests of verbal (letter) fluency. However, conflicting evidence exists of an impairment on other word retrieval tasks, such as confrontation naming, which do not place heavy demands on executive processes. Previous research has demonstrated intact confrontation naming in the presence of verbal fluency deficits, although naming deficits have been described in other studies. In this investigation, functional MRI (fMRI) techniques were employed to explore whether word retrieval deficits and underlying cerebral abnormalities were specific to letter fluency, which are more likely to indicate executive dysfunction, or were also present in confrontation naming, indicating language dysfunction. Twenty‐eight non‐demented ALS patients were compared with 18 healthy controls. The two groups were matched for age, intelligence quotient, years of education, and anxiety and depression scores. Two compressed‐sequence overt fMRI activation paradigms were employed, letter fluency and confrontation naming, which were developed for use with an older and potentially impaired population. In ALS patients relative to controls, the letter fluency fMRI task revealed significantly impaired activation in the middle and inferior frontal gyri and anterior cingulate gyrus, in addition to regions of the parietal and temporal lobes. The confrontation naming fMRI task also revealed impaired activation in less extensive prefrontal regions, including the inferior frontal gyrus and regions of the temporal, parietal and occipital lobes. These changes were present despite matched performance between patients and controls during each activation paradigm. The pattern of dysfunction corresponded to the presence of cognitive deficits on both letter fluency and confrontation naming in the ALS group. This study provides evidence of cerebral abnormalities in ALS in the network of regions involved in language and executive functions. Moreover, the findings further illustrate the heterogeneity of cognitive and cerebral change in ALS.

  • Keywords: motor neuron disease; language functions; executive functions; verbal fluency; naming
  • Abbreviations: ALS = amyotrophic lateral sclerosis; PASAT = Paced Auditory Serial Addition Test; SPM = Standard Progressive Matrices; SSQratio = ratio of model/residual sum of squares

Introduction

The traditional view of amyotrophic lateral sclerosis (ALS) as a disease exclusively of the motor system has been brought into question by the repeated demonstration of cognitive change in these patients. It is well known that in ∼3–5% of ALS patients a frontotemporal dementia occurs, characterized by behavioural and cognitive impairments reflecting gross frontal lobe dysfunction with relative preservation of functions of the posterior association cortices (Kew and Leigh, 1992; Peavy et al., 1992; Neary and Snowden, 1996; Vercelletto et al., 1999). The underlying pathology in these cases has been shown to consist of spongiform neuronal degeneration in the prefrontal and temporal cortices (Hudson, 1981; Wikstrom et al., 1982; Neary et al., 1990; Wightman et al., 1992), with additional involvement of regions in the limbic system (Okamoto et al., 1991; Wightman et al., 1992; Kato et al., 1993; Anderson et al., 1995).

However, it is now recognized that cognitive change can occur in some ALS patients who are not suffering from dementia, and a profile of selective cognitive impairment, with predominant executive dysfunction, has been repeatedly demonstrated across studies (Abrahams and Goldstein, 2002). Deficits have been found across a range of measures of executive functions (Hartikainen et al., 1993; Talbot et al., 1995; Abrahams et al., 1997; Frank et al., 1997), although evidence of memory deficits has been less consistently reproduced (David and Gillham, 1986; Gallassi et al., 1989; Iwasaki et al., 1990; Ludolph et al., 1992; Kew et al., 1993; Massman et al., 1996).

With respect to language functions, it has remained unclear which processes are affected in ALS. The most striking and consistently reported deficit has been found using a test of word retrieval, namely verbal (predominantly letter) fluency (Gallassi et al., 1989; Ludolph et al., 1992; Kew et al., 1993; Abrahams et al., 1996, 1997, 2000; Massman et al., 1996; Abe et al., 1997; Frank et al., 1997; Lomen‐Hoerth et al., 2003). Here the participant is required to say or write as many words as they can beginning with a given letter of the alphabet in a limited time period [e.g. Controlled Oral Word Association (Benton and Hamsher, 1976); Thurstone’s Word Fluency Test (Thurstone and Thurstone, 1962)]. The test is characterized by rapid intrinsic word generation, in which responses are minimally specified by external cues (Frith et al., 1991a, b). Successful performance on letter fluency requires the initiation and use of effective retrieval strategies and the switching between strategies to produce continued generation (Estes, 1974; Laine, 1988; Troyer et al., 1997). Hence, in addition to the linguistic processes of word retrieval the task strongly engages executive resources and has been typically employed to measure executive dysfunction within clinical populations (Baddeley and Wilson, 1988).

Letter fluency deficits in ALS have been shown to be independent of motor disability using a written version which incorporates a motor control condition and corrects for motor speed (Abrahams et al., 1996, 1997, 2000). Previous findings have indicated that the primary impairment in ALS appears to lie in executive functions rather than in short‐term working memory or in basic linguistic abilities, other processes involved in verbal fluency (Abrahams et al., 2000). ALS patients with a letter fluency deficit were shown to have intact phonological loop processes of working memory, as assessed by the phonological similarities and word‐length effects, and moreover intact word retrieval abilities, as assessed by a sentence completion test and confrontation naming. The latter involves the presentation of pictures of objects to be named, e.g. the Boston Naming Test (Kaplan et al., 1983) and the Graded Naming Test (McKenna and Warrington, 1983). Confrontation naming differs from fluency procedures in that the responses (words to be retrieved) are more fully determined by external stimuli (pictures of objects). Hence there is less reliance on executive resources. The finding of intact confrontation naming was consistent with our previous results (Kew et al., 1993). However, some cases of a naming deficit in ALS, indicating an underlying language dysfunction in basic word‐finding processes, have been reported (Massman et al., 1996; Rakowicz and Hodges, 1998; Strong et al., 1999).

The cerebral basis for this pattern of cognitive impairment in ALS has been investigated using functional imaging techniques. These have revealed dysfunction predominantly in the prefrontal cortex and a corresponding profile of executive dysfunction seen on neuropsychological testing (Ludolph et al., 1992; Kew et al., 1993; Talbot et al., 1995; Abrahams et al., 1996; Abe et al., 1997). Kew and colleagues demonstrated that ALS patients performing a random movement joystick PET activation task, who were impaired on a letter fluency test, showed marked activation abnormalities along a limbo‐thalamo‐cortical pathway (Kew et al., 1993). Furthermore, non‐demented ALS patients with deficits on the Written Verbal Fluency Test were found to have reduced activation in extensive prefrontal regions when performing a letter fluency PET paradigm (Abrahams et al., 1996). These abnormalities were present when patients with letter fluency impairments were compared with healthy controls and with ALS patients who were unimpaired on the verbal fluency test (Abrahams et al., 1996).

The aim of this study was to determine whether word retrieval deficits and underlying cerebral abnormalities were specific to letter fluency and hence more likely to be executive in nature, or whether they were also present in other word retrieval processes, such as confrontation naming, which do not rely on executive resources to the same extent and hence are more likely to represent language dysfunction. The profile of cognitive impairment and underlying cerebral substrate in ALS was investigated using functional MRI (fMRI), which is non‐invasive and provides better spatial resolution compared with PET. The letter fluency and confrontation naming activation paradigms were specifically developed for this study and were designed for an older and potentially impaired patient group (Abrahams et al., 2003).

Material and methods

Subjects

ALS patients

Patients with sporadic ALS (21 male, 7 female) with clinical and electrophysiological evidence of combined upper and lower motor neuron involvement in at least one region (Revised El Escorial Criteria for clinically probable or definite ALS; Brooks et al., 2000) were recruited from the MND Care and Research Centre, King’s College Hospital, London. All patients were right‐handed and none had a history of cerebrovascular disease (including ischaemia), hypertension or diabetes, and none were taking psychoactive medication. Patients were excluded if the severity of bulbar symptoms made it uncomfortable for them to speak whilst lying supine in the MRI scanner. Patients with significant respiratory symptoms (forced vital capacity below 70) were also excluded; hence cognitive deficits and cerebral changes could not be attributed to respiratory failure or nocturnal hypoventilation (Newsom‐Davis et al., 2001). All patients in this study can be described as non‐demented, as patients were excluded if their cognitive performance indicated a dementing illness, as determined by the discrepancy between the actual and predicted score on Raven’s Standard Progressive Matrices (SPM; see below).

Healthy controls

Healthy age‐matched controls (13 men, 5 women) were recruited from local voluntary organizations or were friends or spouses of patients with ALS recruited through the local branch of the Motor Neurone Disease Association. All participants were right‐handed and none were taking medication or had a history of psychiatric or neurological disorder or previous significant head injury.

Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki and the study was approved by the Institute of Psychiatry and King’s College London ethics committees.

Participant characteristics

Participant characteristics are presented in Table 1. The ALS and control groups were matched for age, years of education and anxiety and depression using an adaptation of the Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983; Abrahams et al., 1996). There were no significant differences between the two groups in intellectual ability as assessed by the National Adult Reading Test (2nd edition), which estimates premorbid full‐scale intelligence quotient (Nelson and Willison, 1991) and Raven’s SPM (Raven, 1958) which estimates current intellectual functioning. Using the National Adult Reading Test (2nd edition), an estimated premorbid Raven’s score was also calculated and subsequently compared with the actual Raven’s score to determine whether there had been a significant deterioration in function (Davis et al., 2000). There was no significant difference between the two groups in this discrepancy score. Physical disability was measured using the ALS Severity Scale (Hillel et al., 1989), which provides a score for both spinal and bulbar function from a maximum of 20 (low scores represent functional impairment) (Bulbar Function, mean 17.5, SD. 2.7; Spinal Function, mean 15.3, SD 2.8). This measure also produces separate scores for speech and swallowing function and hence provides more detailed information on the extent of bulbar symptoms, which was useful in determining whether participants would have had difficulty in lying supine whilst speaking during the imaging procedure. The average time between onset of symptoms and date of testing was 21 months.

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Table 1

Participant characteristics

ALSControlsSignificant
(n = 28)(n = 18)(P < 0.05)
Age (years)57.3 (11.1)55.0 (12.8)No
Education (years)12.7 (2.5)13.6 (2.6)No
HAD anxietya5.0 (3.0)4.7 (2.8)No
HAD depressionb1.4 (1.8)1.9 (2.3)No
NART premorbid full‐scale intelligence quotient108.5 (10.7)112.9 (8.4)No
Raven’s SPM score45.3 (7.9)48.1 (9.3)No
Estimated premorbid Raven’s SPM score40.1 (5.4)42.5 (5.3)No
Raven’s SPM discrepancyc0.80 (0.9)0.88 (1.2)No

Data are mean (SD) and analyses are between groups. NART = National Adult Reading Test (2nd edition); HAD = Hospital Anxiety and Depression scale. aMaximum score 21; bmaximum score 18; cRaven’s SPM discrepancy is actual Raven’s SPM score minus estimated premorbid Raven’s SPM score.

Neuropsychological assessment

The ALS and control groups underwent a battery of neuropsychological tests which focused on tests of executive and memory function, adapted to accommodate motor impairment, and previously reported to be sensitive to deficits in ALS patients (Abrahams et al., 1997, 2000).

Executive functions

The Written Verbal Fluency Test and the Spoken Verbal Fluency Test, two measures of phonemic (letter) verbal fluency, the Category Fluency Test, a measure of semantic word generation, and the Design Fluency Test, a measure of non‐verbal fluency, were administered. The fluency measures were designed to control for individual variations in motor speed with the production of a fluency index (fi), representing the average time taken to think of each item (Abrahams et al., 2000) (Table 2). The Wisconsin Card Sorting Test (Grant and Berg, 1990) was also employed. In addition a variation of the Paced Auditory Serial Addition Test (PASAT; Gronwall, 1977) was administered, which assesses speed of information processing. The participant is instructed to add pairs of numbers, with each number added to the one immediately preceding it (second to first, third to second, etc.). Two rates of presentation were administered (2.4 s and 2.8 s). Patients with bulbar symptoms were excluded from this measure.

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Table 2

Neuropsychological assessment

ALSControlsSignificant
(n = 28)(n = 18)(P < 0.05)
Executive functions
Written Verbal Fluency (fi)9.77 (4.3)5.92 (2.3)P < 0.001
Spoken Verbal Fluency (fi)4.42 (1.2)3.16 (0.6)P < 0.001
Category Fluency (fi)2.98 (1.7) 2.50 (1.3)n.s.
Design Fluency(n = 23)
fi7.42 (4.4)7.62 (3.2)n.s.
 Perseverative responses (%)1.48 (3.3)1.62 (2.5)n.s.
 Unacceptable responses (%)1.89 (3.6)1.58 (2.3)n.s.
Wisconsin Card Sorting Test
 Categories (max. 6)3.29 (2.3)3.78 (2.4)n.s.
 Total errors51.53 (25.4)49.0 (23.4)n.s.
 Trials to first criterion41.32 (45.6)32.94 (39.1)n.s.
 Perseverative errors (%)24.13 (13.3)20.56 (12.5)n.s.
PASAT(n = 16)
 2.8 sa no. correct (max. 60)48.38 (10.2)47.94 (9.6)n.s.
 2.4 sa no. correct (max. 60)43.80 (13.0)43.24 (10.6)n.s.
Memory functions
Paired Associate Learning
 Easy (max. 18)16.39 (2.3)17.28 (1.0)P = 0.081
 Hard (max. 12)5.25 (3.5)7.28 (3.1)P = 0.058
 Score (max. 21)13.66 (4.6)15.92 (3.4) P = 0.079
Recognition Memory Test (words)
 Age‐scaled score11.57 (2.1)12.50 (2.9)n.s.
Kendrick Object Learning Test
 Total (raw scores) (max. 70)46.14 (7.8)49.83 (6.4)n.s.
Letter Span
 Sequences (max. 21)15.29 (2.1)16.50 (1.8)P = 0.046
 Items (max. 84)65.57 (7.4)70.89 (6.4)P = 0.016
Language functions
Graded Naming Test (max. 30)23.21 (2.9)25.17 (2.1)P = 0.018
Computerised Sentence Completion Test
Sentence Completion RTlnb–0.858 (0.44)–0.813 (0.34)n.s.
Word Repetition RTln–2.183 (0.70)–2.289 (0.82)n.s.
Visuoperceptual functions
Benton Line Orientation Test
 Score (max. 30)27.21 (3.6)26.11 (4.2)n.s.
 Object Decisionc (max. 20)17.71 (1.8)17.89 (1.4)n.s.

Data are mean (SD) and analyses are between groups. fi = fluency index; all fluency tests consisted of a generation condition (during which the participant was required to generate as many items as possible) and a control condition (in which they were timed as they copied/repeated the items they had previously generated). From this a fluency index fi was produced which represented the average time taken to think of each item, i.e. fi = (time for generation condition – time of control condition)/total number of items generated. Higher scores represent longer thinking times and greater impairment. aPresentation rates for the PASAT; bRTln = log linear reaction time; csubtest of the Visual Object and Space Perception Battery.

Memory

Memory tests included Paired Associate Learning (Wechsler, 1987), the Recognition Memory Test (Warrington, 1984) using words only and the Kendrick Object Learning Test (Kendrick, 1985). A Letter Span test was also administered, which consisted of the Phonologically Dissimilar Letters condition of the Phonological Similarities Effect reported in our earlier investigation (Abrahams et al., 2000). Performance was measured in terms of the total number of correct sequences (maximum of 21) and number of items recalled in the correct serial position (maximum of 84).

Language functions

Two tests of simple word retrieval were administered. The Computerised Sentence Completion Test involves the presentation of 15 sentences, each with the last word missing. Following the presentation of each sentence, the participant was required to say a word to complete the sentence as fast as they could. Performance is measured in reaction times. Slowed response times due to bulbar dysfunction and speech difficulties were accommodated by the incorporation of a speech motor (Word Repetition) control condition (for more details see Abrahams et al., 2000). The Graded Naming Test (McKenna and Warrington, 1983) was used to provide an estimate of object confrontation naming.

Visuoperceptual functions

The Benton Line Orientation Test (Benton et al., 1978) was used to provide a measure of visuoperception, whereas object perception was tested using Object Decision from the Visual Object and Space Perception Battery (Warrington and James, 1991).

fMRI

Data acquisition

Data were acquired using a 1.5 Tesla GE Signa Neuro‐optimized MR System (GE, Milwaukee, WI, USA) at the Maudsley Hospital, London. Daily quality assurance was carried out to ensure a high signal‐to‐ghost ratio, a high signal‐to‐noise ratio and temporal stability using automated quality control procedures (Simmons et al., 1999). A quadrature birdcage head coil was used for RF transmission and reception. One hundred T2*‐weighted gradient echo planar images depicting blood oxygenation level‐dependent contrast were acquired from 14 non‐contiguous planes parallel to the anterior commissure–posterior commissure plane [slice thickness 7 mm, slice gap 0.7 m, repetition time (TR) 6000 ms, echo time (TE) 40 ms, θ = 90°]. A compressed pulse sequence was used where the data acquisition took place within the last 2 s of each TR, with 4 s during which the participant provided an overt response when there was no sound of the MR gradients. A high‐resolution inversion recovery echo‐planar image of the whole brain was also obtained [TE = 73ms, inversion time (TI) = 180 ms, TR = 16 000 ms] for subsequent registration to the standard stereotaxic space of Talairach and Tournoux (Talairach and Tournoux, 1998).

Experimental design

The two activation paradigms were specifically designed for an older, potentially impaired patient population and are detailed elsewhere (Abrahams et al., 2003). In brief, each task consisted of a periodic block design with alternating periods of baseline and experimental conditions (60 s each), which were repeated five times across a 10‐min scanning schedule. During the tasks the participant was presented with a stimulus cue every 6 s and responded overtly with a single word in a 4 s quiet period. This was followed by 2 s of compressed sequence acquisition.

Letter fluency. The experimental condition consisted of letter‐based word generation, in which the participant heard an auditory cue consisting of a letter and responded overtly with a word beginning with that letter. On failure to generate an appropriate word the participant was required to say the word ‘pass’ during the quiet, 4 s response time. At the start of each block, to ensure that the participant heard the cue correctly, the first presentation consisted of the letter followed by the corresponding word from the phonetic alphabet (e.g. ‘a for alpha’), during which they remained silent. There then followed nine successive presentations of the same letter cue, after each of which the participant responded with a word beginning with that letter. A different letter (T, A, B, G, F) was presented for each 60 s block, producing a total of 45 possible responses. During the baseline condition the participant was cued by auditory presentation of the word ‘rest’ which they were required to repeat in the 4 s period.

Confrontation naming. In the experimental condition the participant was presented with a visual line drawing of an object for 4 s and was required to say the correct name of the object during the response period. Ten drawings were presented in each 60 s block. On failure to say an appropriate name the participant was required to say the word ‘pass’ during the 4 s response time. In the baseline condition the participant was presented with a meaningless fragmented picture and was required to say the word ‘rest’. The line drawings were selected from the Boston Naming Test (Kaplan et al., 1983) and were supplemented with pictures from the Snodgrass and Vanderwart (Snodgrass and Vanderwart, 1980) series.

Prior to the scanning session the participant was familiarized with the scanning procedure using a similar letter fluency and confrontation naming task with different stimuli and with simulated sound of the MR gradients. This ensured that they were able to undertake the task with few passes and would only respond during the quiet periods.

Image analysis

Movement estimation and correction procedures as described by Friston and colleagues (Friston et al., 1996) were first applied to the data. The data were then analysed by convolving the experimental design with two Poisson functions parameterizing the haemodynamic delays of 4 and 8 s (Friston et al., 1998). The weighted sum of the two convolutions giving the best (least squares) fit to the time series at each voxel was computed and the sums of squares due to the fitted model and the residuals were evaluated. The ratio of model/residual sum of squares (SSQratio) computed at each voxel was then evaluated for significance by comparison with the null distribution of the same statistic computed by repeating the fitting procedure 10 times at each voxel after wavelet‐based random permutation of the time series and combining data across all voxels. This non‐parametric procedure has been reliably validated for use with fMRI time series analyses and shown to give excellent type I error control (Bullmore et al., 2001). Statistical testing at group level was carried out after transformation of the SSQratio maps obtained from the observed and randomized data into standard space (Brammer et al., 1997). Median activation maps were computed across subjects and thresholded at a voxel‐wise probability of a false activation of P < 0.005 using the spatially transformed randomized data maps to construct the distribution of median SSQratios under the null hypothesis of no significant response. Between‐group comparisons were then carried out using cluster‐level statistics (Bullmore et al., 1999) and random permutation of group membership to obtain the distribution of SSQratio differences between groups under the null hypothesis of no group difference in level of response. A conservative significance level was adopted for all between group comparisons in which P values were set to ensure less than one false positive cluster per image.

Results

Neuropsychological tests

The results are presented in Table 2. The ALS patients displayed a selective deficit in letter fluency, with impairments on both written and spoken versions of this test, ALS patients displaying longer thinking times than controls. However, executive dysfunction did not generalize across other measures and the two groups did not differ significantly on a measure of Category Fluency, Design Fluency, the Wisconsin Card Sorting Test or on the Paced Serial Addition Test. On tests of memory the ALS patients were impaired on a test of Letter Span, recalling significantly fewer total sequences and items than the control group. However, there were no significant differences between the two groups on word recognition (Recognition Memory Test), object recall (Kendrick Object Learning Test) and the learning of word pairs (Paired Associate Learning Test), although the latter tended towards significance. In terms of language functions, performance on the Graded Naming Test revealed a significant impairment in the ALS patients relative to the control group on the total score, the ALS patients naming correctly significantly fewer objects than controls. Of note, although the ALS group named fewer objects correctly than controls, no individual patients’ score (range 18–28) could be described as clinically impaired (Warrington, 1997). There was no significant difference between groups in performance on the Computerised Sentence Completion Test. Finally, there were no significant differences between the two groups in visuoperceptual functions.

Task performance during scanning

In the letter fluency paradigm, the number of different words produced (excluding passes) was recorded as a measure of task performance during scanning. All participants were clearly capable of performing the word generation task successfully and on average produced 42 different words from a total of 45 possible responses (ALS, mean 41.82, SD 2.60; controls, mean 42.39, SD 1.85). A comparison of the scores between the two groups revealed no significant difference (P > 0.05). In the confrontation naming task the number of correct names was recorded and participants produced on average 45 correct responses from a possible maximum of 50 (ALS, mean 45.41, SD 2.7; controls, mean 45.39, SD 3.8). A comparison between the two groups again revealed no significant difference (P > 0.05). These findings demonstrate that the two groups were matched in terms of performance during the scanning tasks and excludes the possibility that differences in blood oxygenation level‐dependent response between the groups can be associated with performance variables.

Comparison of blood oxygenation level‐dependent changes between groups

Letter fluency

The ALS group displayed reduced activation in comparison with the control group in extensive regions of the prefrontal cortex. This included the left middle frontal gyrus (areas 10/46), left inferior frontal gyrus (area 44), right middle frontal gyrus (areas 9/46) and right anterior cingulate gyrus (area 32). In addition, impaired activation was also revealed in regions of the left temporal (area 21) and left parietal lobes (area 31 and 40). These regions are displayed in Fig. 1 and details of the centroids of each cluster presented in Table 3. The analysis also revealed that the ALS group displayed increased activation relative to the control group in a number of small clusters in the right middle temporal gyrus, left superior frontal gyrus and right inferior frontal gyrus, details of which are presented in Table 3.

Figure

Fig. 1 Reduced fMRI activation in ALS patients relative to the control group during the letter fluency task. Axial slices parallel to the anterior commissure–posterior commissure plane are displayed for Talairach Z coordinates +6 mm, +11 mm, +16 mm, +21 mm (above) and +26 mm, +31 mm, +36 mm, +41 mm (below). Corresponding regions and coordinates are displayed in Table 3.

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Table 3

Regions of significant difference in activation in the comparison between control and ALS groups during the letter fluency task

Cortical region of centroid (Brodmann area)No. of voxelsTalairach coordinates
x y z
ALS < controls
 Left middle temporal gyrus (area 21)69–45–576
 Left precuneus (area 31)120–3–6621
 Left inferior frontal gyrus (area 44)142–42725
 Right middle frontal gyrus (area 9/46)150284323
 Left middle frontal gyrus (area 10/46)151–294122
 Left inferior parietal lobe (area 40)166–39–3537
 Right anterior cingulate gyrus (area 32)17232329
ALS > controls
 Right middle temporal gyrus (area 21)3539–4–12
 Left superior frontal gyrus (area 10)11–7600
 Right inferior frontal gyrus (area 45)3847184
 Right inferior frontal gyrus (area 44)1750633

The centroids of the significant clusters are displayed.

Confrontation naming

The ALS group exhibited impaired activation in comparison with the control group in regions of the prefrontal cortex, including the left inferior frontal gyrus (area 44) and right inferior frontal gyrus (area 46). In addition, impaired activation was also revealed in the right cingulate gyrus (area 24), left temporal lobes (areas 37 and 22), left and right parietal lobes (area 18) and left occipital lobes (area 19). These regions are displayed in Fig. 2 and details of the centroids of each cluster are presented in Table 4. The analysis also revealed increased activation in the ALS group relative to the control group in one small cluster, details of which are presented in Table 4.

Figure

Fig. 2 Reduced fMRI activation in ALS patients relative to the control group during confrontation naming. Axial slices parallel to the anterior commissure–posterior commissure plane are displayed for Talairach Z coordinates –4 mm, +6 mm, +16 mm (above) and +26 mm, +36 mm, +46 mm (below). Corresponding regions and coordinates are displayed in Table 4.

View this table:
Table 4

Regions of significant difference in activation in the comparison between control and ALS groups during confrontation naming

Cortical region of centroid (Brodmann area)No. of voxelsTalairach coordinates
x y z
ALS < controls
 Left middle temporal gyrus (area 37)61–52–50–3
 Left middle occipital gyrus (area 19)105–40–735
 Left superior temporal gyrus (area 22)123–55–3115
 Right inferior frontal gyrus (area 46)126452812
 Right cuneus (area 18)1405–7516
 Left inferior frontal gyrus (area 44)149–44197
 Left cuneus (area 18)151–7–7129
 Right cingulate gyrus (area 24)1783–146
ALS > controls
 Right fusiform gyrus (area 19)4028–62–8

The centroids of the significant clusters are displayed.

The significance threshold for the analysis of both tasks was set to give less than one false positive cluster over the whole brain. The finding of small regions of increased activation in the patient group relative to the controls demonstrates that the pattern of impaired activation reported on both activation paradigms cannot be the result of a global reduction in activation in the patient group.

Discussion

This study demonstrates that cognitive deficits associated with word retrieval processes and corresponding extra‐motor cerebral activation abnormalities in ALS were not specific to letter fluency, but were also present in confrontation naming. The ALS patients displayed impaired activation in extensive prefrontal regions during letter fluency task, including dorsolateral regions of the prefrontal cortex (the middle and inferior frontal gyri) and the anterior cingulate gyrus. Additional abnormalities were revealed in the middle temporal gyrus, precuneus and inferior parietal lobes. In the confrontation naming procedure the ALS group also displayed an abnormal pattern of activation, with impairments in the inferior frontal gyrus in addition to regions of the middle and superior temporal gyri, middle occipital lobes and cuneus. These between‐group differences were found despite matched performance output between ALS patients and controls during both scanning tasks, and hence differences cannot be attributed to this factor. Additionally, the finding of small regions of increased activation in the ALS patient group relative to the controls indicates that these abnormalities cannot be the result of a global reduction in activation in ALS patients.

The ALS group demonstrated impaired activation along the network of regions involved in confrontation naming (Smith et al., 1996; Zelkowicz et al., 1998; Murtha et al., 1999; Abrahams et al., 2003). Activation abnormalities were found in the inferior frontal gyrus (Broca’s area), associated with language production and word retrieval (Paulesu et al., 1997) and regions of the occipitotemporal pathway, involved in the semantic processing of visual information. The latter corresponds to the ventral pathway involved in object recognition (Ungerleider and Mishkin, 1982). The ALS group also displayed significant impairment on a test of confrontation naming, the Graded Naming Test. However the group was unimpaired on the second test of word retrieval, the Computerised Sentence Completion Test, consistent with our previous study (Abrahams et al., 2000). Although a naming deficit was not observed in our previous investigations, this result is in accord with the findings of three other studies of ALS (Massman et al., 1996; Rakowicz and Hodges, 1998; Strong et al., 1999). Rakowicz and Hodges reported that five of 18 ALS patients displayed a naming deficit (although three were also suffering from the ALS–dementia syndrome), whereas Massman and colleagues demonstrated that 11.7% of a large cohort of 146 ALS patients performed at or below the 5th percentile on the Boston Naming Test. In the present study no individual patient demonstrated clinical levels of a naming impairment, although the group as a whole was impaired relative to controls. Together, these findings suggest the presence of underlying language dysfunction in some ALS patients, with subclinical levels of language impairment in others.

The ALS group demonstrated impaired activation along the network of regions which has been shown to be involved in letter fluency (Friston et al., 1991; Frith et al., 1991a, b; Abrahams et al., 2003). This included the dorsolateral prefrontal cortex (areas 46 and 9), associated with the executive component of the task, the anterior cingulate gyrus, which is thought to be involved in the attentional aspects of the task, in addition to the inferior frontal gyrus. Impaired activation was also revealed in the supramarginal gyrus (inferior parietal lobe area 40), which has been related to the phonological store component of working memory (Paulesu et al., 1993) and the auditory association areas of the temporal lobe, related to phonological and lexical processing. The demonstration of predominant frontal lobe dysfunction is in accord with our previous PET study in which similar impaired activation was demonstrated during letter fluency in a small group of non‐demented ALS patients who were specifically impaired on the Written Verbal Fluency Test. These patients demonstrated cerebral blood flow abnormalities in regions of the dorsolateral prefrontal cortex, anterior cingulate gyrus, lateral and medial premotor cortices, primary motor cortex insular cortex, precuneus and anterior thalamus when conducting the letter fluency activation task (Abrahams et al., 1996). In the present study, although the ALS patients were not selected on the basis of cognitive ability and hence were more representative of the scope of disease presentation (although those with a dementia profile were excluded), the group as a whole was also impaired on the Written Verbal Fluency Test and a spoken version of this test.

The use of language paradigms in the present study focuses the investigation on predominantly dominant hemispheric functions, and the pattern of decreased activation in both confrontation naming and letter fluency was mainly left‐sided, as expected. However, there was also evidence of bilateral dysfunction, particularly in frontal regions, with right‐sided reductions in the middle frontal gyrus and anterior cingulate gyrus (letter fluency) and inferior frontal gyrus (confrontation naming). The pattern of bilateral changes in letter fluency is similar to that previously reported in ALS patients using PET (Abrahams et al., 1996).

We have previously demonstrated that verbal fluency deficits in ALS can occur with intact working memory and basic language skills, including intact confrontation naming (Abrahams et al., 2000). This finding indicates that such fluency deficits in many ALS patients most likely result from higher‐order executive dysfunction and is consistent with the presence of abnormalities in dorsolateral prefrontal regions. Verbal (letter) fluency deficits are the most commonly reported impairment in ALS and hence executive dysfunction appears to be a fundamental component of the cognitive profile in this disease. However, the results from the present study demonstrate that in some non‐demented ALS patients there is clearly broader cerebral and cognitive involvement. In both letter fluency and confrontation naming paradigms, the ALS patients demonstrated abnormalities in the inferior frontal gyrus (Broca’s area, 44). Dysfunction in Broca’s area may result in difficulties with word finding and speech production, with underlying language rather than executive dysfunction. Similarly, involvement of the temporal regions may cause semantic and phonological processing deficits, while parietal lobe involvement (supramarginal gyrus) may result in impairments in the phonological store. It is possible that all of these abnormalities may not only serve to exaggerate letter fluency deficits but also underlie other cognitive impairments, such as a deficit in confrontation naming or in measures of working memory (the Letter Span Test), which was found in the present study. The present letter fluency activation task revealed a more widespread pattern of cerebral involvement in ALS than was found using PET (Abrahams et al., 1996), with involvement of Broca’s area, the supramarginal gyrus and temporal lobe association areas. However, the present study included a much larger group of ALS patients (28 relatively unselected patients compared with six patients with impaired letter fluency scores and six with normal letter fluency scores). Hence, it is possible that this cohort included a more cognitively heterogeneous sample of patients, which may be more representative of the spectrum of disease presentation. It is also noteworthy that patients with more severe bulbar involvement, which would make it uncomfortable to speak whilst lying supine, were excluded from this study. There are numerous reports of an association between cognitive impairment and bulbar involvement (e.g. Abrahams et al., 1997; Strong et al., 1999). Hence, the current findings demonstrated abnormal activation patterns in less severely affected ALS patients.

An alternative explanation for the profile of reduced activation in the confrontation naming procedure may be that this pattern of posterior dysfunction is a secondary consequence of executive factors, such as the degree of mental effort exerted in processing the meaning of the picture and/or retrieving the appropriate word. However, this interpretation is unlikely for a number of reasons. Previous studies have demonstrated that increased mental effort or attentional demand associated with, for example, difficulty level, novel procedures, new learning and the working memory load, results in increased frontal activation, particularly in the anterior cingulate gyrus (e.g. Jueptner et al., 1997; Paus et al., 1998; Jansma et al., 2000). In the present study the ALS patients performed at a similar level to controls on the confrontation naming scanning paradigm. If activation differences were the result of the degree of mental effort exerted, then we would expect to see increased activity in the anterior cingulate gyrus in the ALS patients, which was not found. Conversely the reduction in activation in the ALS patients may be explained by the possibility that patients may have a general reduction in drive and initiative and hence do not expend more effort than is absolutely necessary to complete the task sufficiently. Patients will therefore not engage in the additional cognitive processing that controls may undertake spontaneously when performing the tasks. Although this is a plausible explanation for the pattern of activation changes in ALS, such explanations based on differences in drive and mental effort are not consistent with the pattern of selective neuropsychological deficits displayed by this group, as no impairments were found across tests which exert high attentional demands and require considerable mental effort, including Category Fluency, Design Fluency, the Wisconsin Card Sorting Test, the Paced Serial Addition Test, and object recall. A deficit was found in the confrontation naming test, in which responses are strongly cued by the stimulus and which places minimal demands on attention and executive functions. The latter is supported by the lack of activation in the anterior cingulate during task performance in healthy controls (Abrahams et al., 2003).

The word retrieval deficit and underlying cerebral abnormalities reported here suggest similarity with the non‐fluent aphasia described in some ALS cases (ALS–aphasia) (Caselli et al., 1993; Doran et al., 1995; Bak and Hodges, 2001). These cases are reported to display severe aphasia in both spoken and written language in addition to frequent comprehension deficits. Many patients also display behavioural abnormalities typical of the frontal lobe dementia syndrome associated with ALS and can be described as having the ALS–dementia syndrome. It has also been suggested that ALS–aphasia may represent a separate subtype of ALS–dementia (Bak and Hodges, 2001) as there is clear overlap between the groups. In the study reported by Rakowicz and Hodges (Rakowicz and Hodges, 1998), three patients displayed an aphasic syndrome in association with dementia, whereas two displayed an aphasic syndrome with word‐finding and naming deficits in the absence of a generalized dementia. Bak and colleagues describe six cases of ALS–dementia and or aphasia (Bak et al., 2001). All patients displayed a progressive, severe, non‐fluent aphasia with impairments on confrontation naming. Four cases also displayed marked personality changes, consistent with the dementia syndrome. Post‐mortem examination was undertaken in four cases, all of which showed mild to moderate frontal lobe atrophy with consistent pathology in Brodmann areas 44 and 45. The present findings of subclinical levels of language impairment in addition to the demonstration of activation abnormalities in Broca’s area (area 44) suggests the involvement of similar regions within a large non‐demented ALS group. Together, these studies suggest that language dysfunction in ALS may be more common than was originally assumed, with a spectrum of severity from subclinical levels of impairment to the ALS–aphasia syndrome. Importantly, in Rakowicz and Hodges’ study the remaining 13 patients performed normally on other cognitive measures apart from having decreased verbal fluency output. This finding demonstrates the predominance of this cognitive deficit in ALS and suggests that executive dysfunction is the most common neuropsychological abnormality in this disorder.

This study focused on word retrieval abilities and did not explore other areas of language functions. However there have been some reports of impairments in ALS patients on tests of comprehension including; the Test of Reception of Grammar (TROG), the Pyramids and Palm Trees Test, a test of semantic associations (Rakowicz and Hodges, 1998), the Token Test, a test of comprehension of commands (Talbot et al., 1995) and the Peabody Picture Vocabulary Test—III, a test of vocabulary comprehension (Strong et al., 1999). In addition word retrieval abilities could also be further explored in terms of the type of word to be retrieved. The present study demonstrates a deficit with picture–object/noun associations in the confrontation naming test. However, Bak and colleagues demonstrated greater impairment in the generation and processing of actions/verbs than in objects/nouns in patients with ALS–dementia, some of whom were shown to have pathology in Brodmann areas 44 and 45 (Bak et al., 2001). As similar regions were found to be impaired in the present sample (particularly area 44), further investigation of verb processing is warranted.

The reports of differing patterns and degrees of cognitive and extra‐motor change in ALS across studies highlights the variability of cerebral involvement within the disorder. Imaging and pathological investigations support a similar network of frontal and temporal involvement in both non‐demented ALS patients and ALS–dementia (Hudson, 1981; Neary et al., 1990; Okamoto et al., 1991, 1992; Wightman et al., 1992; Kato et al., 1994; Anderson et al., 1995; Talbot et al., 1995). The findings of the present study demonstrate a link between non‐demented ALS and ALS–aphasia. This strongly supports the hypothesis that within the disorder there exists a continuum of cerebral change and suggests that such additional cerebral involvement may not be restricted to a small subgroup of patients (Kew and Leigh, 1992; Leigh et al., 1994).

In conclusion, the findings of our research to date demonstrate that the cognitive profile in non‐demented ALS patients is characterized by letter fluency deficits, resulting from executive dysfunction and associated frontal lobe abnormalities. However, naming deficits indicating an underlying language dysfunction and corresponding cerebral abnormalities are also found. The presence of abnormalities within the network of cerebral regions involved in both word retrieval processes provides further evidence of the heterogeneity of the presentation of the disorder and supports the notion that within ALS there exists a spectrum of cerebral involvement.

Acknowledgements

This project was funded by the Wellcome Trust and S. A. was funded by a Wellcome Trust Fellowship throughout the period of research. The King’s MND Care and Research Centre is funded by the Motor Neurone Disease Association, UK.

References

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