Delineating Necessary and Sufªcient Neural Systems with Functional Imaging Studies of Neuropsychological Patients
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Delineating Necessary and Sufªcient Neural
Systems with Functional Imaging Studies of
Neuropsychological Patients
C. J. Price, C. J. Mummery, C. J. Moore, R. S. J. Frackowiak, and
K. J. Friston
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Institute of Neurology, London
Abstract
■ This paper demonstrates how functional imaging studies of is peri-infarct activity around the damaged left-hemisphere tis-
neuropsychological patients can provide a way of determining sue. Functional imaging of the patient is required to discount
which areas in a cognitive network are jointly necessary and these possibilities. We investigated a patient (SW), who was
sufªcient. The approach is illustrated with an investigation of able to associate words and pictures on the basis of semantic
the neural system underlying semantic similarity judgments. relationships despite extensive damage to the left frontal, infe-
Functional neuroimaging demonstrates that normal subjects rior parietal, and superior temporal cortices. Although SW
activate left temporal, parietal, and inferior frontal cortices showed peri-infarct activation in left extrasylvian temporal cor-
during this task relative to physical size judgments. Neuropsy- tices, no activity was observed in either left or right inferior
chology demonstrates that damage to the temporal and parietal frontal cortices. These ªndings demonstrate that activity in
regions results in semantic deªcits, indicating that these areas extrasylvian temporo-parietal and medial superior frontal re-
are necessary for task performance. In contrast, damage to the gions is sufªcient to perform semantic similarity judgments. In
inferior frontal cortex does not impair task performance, indi- contrast, the left inferior frontal activations detected in each
cating that the inferior frontal cortex might not be necessary. control subject appear not to be necessary for task perfor-
However, there are two other possible accounts of intact per- mance. In conclusion, necessary and sufªcient brain systems
formance following frontal lobe damage: (1) there is functional can be delineated by functional imaging of brain-damaged
reorganization involving the right frontal cortex and (2) there patients who are not functionally impaired. ■
INTRODUCTION component brain areas in one of three ways. The
ªrst, more conventional, approach involves identify-
Functional neuroimaging in normal subjects reveals dis- ing the lesion site associated with a functional deªcit;
tributed brain systems that can be considered sufªcient by implication, this region was necessary for the
to perform a task but does not distinguish the relative speciªed function. The second approach involves the
contributions of the subcomponents involved. Some reverse, that is, identifying the functional deªcit associ-
activated regions may be superºuous (not necessary) to ated with a lesion in an area identiªed by neuro-
the task requirements (Price, Wise, & Frackowiak, 1996). imaging (e.g., Fiez, Petersen, Cheney, & Raichle,
In contrast, lesion-deªcit models (neuropsychological 1992). The third approach, described in this paper,
studies) identify regions that are necessary to perform involves inferences from patients who are not function-
a task but do not establish the premorbid sufªciency ally impaired on a speciªed task but nevertheless have
of the damaged regions. For instance, a cognitive func- damage to parts of the system deªned by neuroimaging.
tion can be impaired if the connections between two Here the damaged regions can be construed as not
vital cortical areas are damaged; the connections are necessary. By designating each region in the sufªcient
necessary but not sufªcient to execute a particular func- system as necessary or not necessary, the critical system
tion. could be identiªed. However, the caveat is that some
The joint complementary use of neuroimaging and patients may be able to perform a task by activating
neuropsychology offers a fundamental advantage over peri-infarct tissue that appears damaged with rou-
either technique in isolation. Neuroimaging in nor- tine structural imaging (Warburton, Price, Swinburn, &
mal subjects deªnes the set of regions (the neural sys- Wise, 1999). Another possibility is that functionality
tem) involved in performing one task relative to is preserved due to functional reorganisation (e.g.,
another. Neuropsychology establishes the necessity of involving the homologue region in the contralateral
© 1999 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 11:4, pp. 371–382
Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/089892999563481 by guest on 15 September 2021hemisphere, Weiller et al., 1995; Buckner, Corbetta, RESULTS
Schatz, Raichle, & Petersen, 1996). To discount these
SW was investigated in three ways. First, a neuropsy-
possibilities, functional imaging of the patient is a pre-
chological proªle of his language abilities was con-
requisite.
ducted. Second, a structural magnetic resonance image
This approach of functional imaging studies of
(MRI) of his brain was contrasted to that of neurologi-
neuropsychological patients who are not impaired on a
cally normal controls to reveal the extent of his cerebral
task is illustrated in this paper with an investigation of
lesion. Third, functional neuroimaging was used to inves-
the functional anatomy required to make semantic
tigate how he managed to perform semantic tasks by
similarity judgments. During this task, subjects associate
comparing his activation pattern with six normal control
words and pictures on the basis of semantic relation-
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subjects. See Methods for details.
ships. The speciªc aim of the experiment was to con-
sider a contentious issue: the necessity of left inferior
frontal activity for the performance of semantic similar-
Language Assessment
ity judgments relative to physical size similarity judg-
ments. Functional neuroimaging of normal subjects has Although SW has not recovered any residual speech
demonstrated that the associated system of regions output, he was able to comprehend task requirements
involves the left inferior frontal and extensive ex- and make decisions to respond appropriately. The results
trasylvian temporo-parietal regions (Vandenberghe, of a language assessment performed at the time of the
Price, Wise, Josephs, & Frackowiak, 1996). Other neuroi- neuroimaging experiment (July 1997) are shown in
maging studies have also demonstrated left inferior fron- Table 1.
tal activity during a variety of tasks emphasizing On the lexical decision task, SW performed quickly
semantic processing (Petersen, Fox, Posner, Mintun, & and easily with 155/160 correct. This was within the
Raichle, 1988, 1989; Petersen, Fox, Snyder, & Raichle, normal range for both high and low imageable words.
1990; Kapur et al., 1994; Demb et al., 1995; Gabrielli On the pyramids and palm trees test, SW scored 49/52,
et al., 1996), yet damage to the frontal lobes is not which is within the normal range of accuracy. On syno-
classically associated with semantic deªcits. One cur- nym judgments, SW scored well above chance for both
rently held view for this discrepancy is that the left high (35/38) and low (29/38) imagability words, but his
inferior frontal lobe plays an executive role in semantic performance falls just below the normal cutoff (36/38
tasks, perhaps controlling the retrieval of semantic infor- and 33/38, respectively). On the sentence comprehen-
mation (Kapur et al., 1994; Buckner et al., 1995; Fiez, sion tasks, SW scored 46/60 for the written versions and
1997) or acting as a working memory system for seman- 41/60 on the auditory version. This was well above
tic processing (Gabrielli, Poldrack, & Desmond, 1998). chance (20/60) but fell below the normal cutoff (55/60);
Thompson-Schill, D’Esposito, Aguirre, & Farah (1997) see Table 1 for details.
have also proposed that the inferior frontal cortex is On the spoken word to picture matching and spoken
required for semantic tasks that require “high selection,” word rhyming tasks, SW scored 35/40 and 28/30, respec-
such as when there are many competing and possible tively. Although he made occasional errors, his perfor-
responses. mance on the rhyming task (28/30) was markedly
In this study, the semantic similarity task was an adap- superior to the same task with visually presented words
tation of the pyramids and palm trees test (Howard & (17/30) where performance was at chance (15/30). A
Patterson, 1992) for which the subject has to decide further indication of a severe impairment making
which of two semantically similar words is closest in phonological decisions from visually presented words
meaning to a third semantically related word (e.g., is was the complete inability to make homophone judg-
PALM TREE or DECIDUOUS TREE closest in meaning to ments from written words—SW scored at chance
PYRAMID). Relative to physical size judgments, the se- (52/100).
mantic similarity task has been associated with inferior On orthographic output tests, SW was unable to use
frontal and extrasylvian temporal activity (Vandenberghe his right hand due to a right-sided hemiplegia. With his
et al., 1996). Nevertheless, patients with frontal lobe left hand, SW’s ability to copy words (10/10) indicated
damage do not show marked impairment. By imaging he was not suffering from apraxia. Nevertheless, he was
activation in a patient (SW), who retained the ability to severely impaired writing high-frequency familiar words
perform the task in the context of extensive left frontal, to dictation (4/10) or from visually presented pictures
temporal, and parietal lobe damage, we considered (5/10).
three possible explanations for his good performance: In summary, SW has a severe expressive aphasia
(1) There is residual functional integrity in tissue sur- reºected in his impaired orthographic output and inabil-
rounding the lesion; (2) there is functional reorganiza- ity to make any verbal utterances. He was also unable to
tion involving the right inferior frontal cortex; and (3) generate phonology from visually presented words to
inferior frontal activity is not necessary to perform the perform phonological judgments that were possible
task. with auditory presented words. With synonym judg-
372 Journal of Cognitive Neuroscience Volume 11, Number 4
Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/089892999563481 by guest on 15 September 2021Table 1. Results of the Language Assessment on SW at the Time of the Imaging Experiment.
Normal
Semantics SW Chance cutoff
Visual word to pictures (pyramids and palm trees) 49/52 26/52 48/52
Visual word pairs (synonym judgments) high 35/38 19/38 36/38
imageable
Visual word pairs (synonym judgments) low 29/38 19/38 33/38
imageable
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Lexical decision on visual words and pseudowords 155/160 80/160 158/160
Visual sentence to picture matching 46/60 20/60 55/60
Auditory sentence to picture matching 41/60 20/60 55/60
Phonology from auditory words
Spoken word to picture matching 35/40 8/40 39/40
Auditory word rhyme judgments 28/30 15/30 29/30
Phonology from visual words
Visual word rhyme judgments: 17/30 15/30
Homophone judgments 52/100 50/100
Orthographic output
Orthographic output to dictation 4/10 10/10
Orthographic output to pictures 5/10 10/10
Copying words 10/10 15/15
ments, performance was not severely impaired but just gion that is most associated with semantic processing
below normal expectations. Sentence comprehension (Fiez, 1997).
was also below normal. Nevertheless, he was able to
make lexical decisions even when the nonwords were
very wordlike, and he was able to make difªcult seman- Results of Functional Imaging Study
tic similarity judgments. It was his ability with the latter Task Performance during Scanning Acquisition
task that motivated the functional imaging experiment,
because it indicates intact memory for knowledge about 1. The word semantic task required subjects to
decide which of a pair of items was most semantically
objects.
similar to a target item. Although each triad of stimuli had
a most likely response (according to the choices of
previous subjects), there was individual variation in how
Results of Analysis of Structural MRI
subjects associated items because all three items were
The analysis of structural images revealed that SW had a from the same semantic category. Hence, none of the
large left-hemisphere lesion incorporating the left infe- normal subjects performed at 100%. The mean accuracy
rior frontal, anterior superior temporal, and anterior pa- was 87.5% (range, 78.1 to 93.7%). SW performed within
rietal cortices. The delineation of this left middle cerebral the normal range (81%), signiªcantly above chance
infarct is rendered on a 3-D model of the normal brain (X2 = 4.2, p < 0.01, two tailed) and less than one
(see Figure 1). The technique also revealed reduced gray standard deviation below the mean. Examples of his
matter in the right cerebellum, consistent with the oc- responses recorded as errors are (1) selecting SKIRT
currence of crossed cerebellar atrophy (Dow & Moruzzi, rather than TROUSERS in response to SHIRT and (2)
1958). See Figure 1A. Interestingly, there appeared to be selecting ORANGE rather than PEAR in response to
some preservation of tissue in the left inferior frontal APPLE. Together with SW’s normal accuracy on
cortex around Brodmann’s area (BA) 47, the frontal re- performing the pyramids and palm trees test outside the
Price et al. 373
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Figure 1. The extent of the cerebral infarct in the left hemisphere. In section A, regions of reduced gray matter (relative to neurologically nor-
mal controls) are shown on models of the left and right hemispheres of the brain. In addition to the classic left middle cerebral artery infarct,
SW showed reduced gray matter in the right cerebellum. In section B, the lesion is illustrated conventionally on horizontal slices of a structural
MRI scan, normalized to a template brain from the Montreal Neurological Institute. The slices are at 10-mm intervals centered on the anterior
posterior commissure line.
scanner, we conclude that SW was fully engaged in the subjects to respond within that time. The mean normal
semantic task. response was 3.38 sec on the semantic task and 2.45 sec
2. The actual size task required subjects to decide on the visual task. SW was slower to respond than the
which of a pair of orthographically identical items normal subjects on both the semantic task (5.13 sec) and
sustained the most similar visual angle to the target. To the visual task (3.57 sec). A two-way analysis of variance
equate the actual size decision to the semantic decision (ANOVA) conªrmed that SW’s reaction times (RTs) were
for subjectivity and difªculty, none of the stimuli within signiªcantly slower than normal (F(1, 427) = 39.2, p <
a triad had identical size. The range of normal responses 0.0001). There was also a signiªcant main effect of task
was 83 to 100% (mean, 91%), SW fell just below this (F(1, 427) = 29.3, p < 0.0001) because responses to the
range (81%), but his performance did not differ semantic task were slower than to those for the visual
signiªcantly from the normals. task. However, the interaction between task and subject
3. Analysis of reaction time. The interstimulus group (SW vs. normals) was not signiªcant (F(1, 427) =
interval for both tasks was 6 sec, thereby encouraging 1.9, p = 0.16).
374 Journal of Cognitive Neuroscience Volume 11, Number 4
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trol subjects during the scanning session, the difference controls. The minimum number of voxels activated per
in the reaction times was on the order of 1 to 2 sec (50% normal subject was 99 (at p < 0.05), but SW showed no
slower than normals). During routine neuropsychologi- signiªcant voxels at p = 0.05 (or below). In the absence
cal assessment, where RTs to these tasks are not meas- of a neurological deªcit, the likelihood of detecting
ured, SW’s slower responses would not be identiªable. activation in SW is identical to that of detecting activity
SW’s slower responses could be for a number of in the normal subjects; the paradigm, degrees of freedom,
reasons. One possibility is that they result directly from and error variance are identical. We conclude that the
neurological damage to regions involved in semantic failure to detect activation in the left inferior frontal lobe
tasks (e.g., the left inferior frontal lobe). However, this and right cerebellum was a direct consequence of SW’s
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would not explain why he was also slower with visual neurological deªcit.
decisions. Another possibility is that they result from 3. Other areas activated by SW. At a signiªcance level
differences in motor control either generally or because of p < 0.001, SW also showed activations in the right
SW was only able to use his nondominant (left) hand anterior middle temporal cortex (x = +56, y = −10, z =
(his right hand was disabled due to hemiplegia). A third −16, Z = 3.4), the medial superior frontal cortex (BA 10;
option is that the slower responses result from SW x = 0, y = +70, z = +22, Z = 3.6), and the left inferior
having reduced vision in one visual ªeld due to ophthal- parietal cortex (BA 40; × = −52, y = −34, z = +50, Z =
mological problems. Differentiating between these ex- 3.2). These activations were not unique to SW because
planations would require extensive investigation. For the in each of these regions between one and four of the
present study, the critical question relates to how SW normal control subjects showed equivalent activation.
performed the tasks, albeit slower than the control sub- Therefore, we can not be certain that they reºect
jects. compensatory changes following neurological damage.
This would require an investigation of how patients
recover following inferior frontal damage. In summary,
Activation Associated with the Semantic Task
functional imaging of SW revealed no evidence of
1. Conjunction of normal and patient activations functional reorganization involving the right prefrontal
(see Table 2A; Figure 2B). Areas that were activated by cortex and no evidence of peri-infarct activation in left
the normal controls and SW in the absence of subject by inferior frontal cortex.
task interactions revealed common activation in several
regions of the ventral extrasylvian temporal cortex (BA
DISCUSSION
21, 22, 28, 37), the dorsal posterior middle temporal
gyrus (BA 39), the parieto-occipital junction (BA 19/39), In this study, we asked whether a patient with an exten-
and the cuneus/precuneus (BA 19). The threshold for sive frontal lobe infarct accomplished semantic similarity
these group activations was set at p < 0.001. The judgments with (1) peri-infarct activity in his left frontal
subject-speciªc responses for SW within this system lobe, (2) compensatory activity due to functional reor-
reached a threshold of (1) p < 0.001 in the left anterior ganization in his right frontal lobe, or (3) activation in a
middle temporal (BA 21), posterior basal temporal (BA subset of the normal regions. We discuss, respectively,
37), and posterior middle temporal/parietal (BA 39) the structural damage incurred by SW, the effect that this
cortices (2) p < 0.01 in left anterior superior temporal damage had on his language skills, the results of the
(BA 22), and superior occipital (BA 19) cortices and the functional neuroimaging experiment, and the implica-
cuneus/ precuneus, and (3) p < 0.05 in the left anterior tion that these results have for the interpretation of
medial temporal cortex (BA 28). See Table 2. As can be frontal lobe responses during semantic tasks.
seen from Figure 3, some of the temporal and parietal The structural T1-weighted MRI scan of SW’s brain
activation observed in SW lay close to lesioned regions. revealed that areas known to be crucial for language
This is consistent with peri-infarct functionality that production (i.e., Broca’s area, the left anterior superior
might not be predicted from routine structural imaging. temporal lobe, and the left supramarginal gyrus) had
2. Areas activated by normals but not SW (see Table been severely damaged. The effect of this lesion was to
2B and 2C and Figure 2C). Each normal subject render SW literally speechless. He is unable to articulate
activated the left inferior frontal gyrus (BA 47) and right any speech sounds and is also severely impaired in his
cerebellum during the semantic task relative to the visual attempt to write even single words. His performance is
task. SW failed to activate any voxels in these areas. at chance on neuropsychological tests designed to evalu-
Differences between SW and the control subjects were ate whether he is able to access phonology from seen
conªrmed by highly signiªcant subject by task words. These results, in terms of a lesion-deªcit model,
interactions in these regions (see Table 2B). The location indicate that premorbidly SW’s ability to retrieve phonol-
of the peak activation and its extent in the left inferior ogy and generate speech depends on at least a subset of
frontal cortex is given for each control subject in Table the brain regions damaged by his stroke. In terms of
2C. Activation reached signiªcance at a p < 0.001 level preserved language abilities, SW’s performance with se-
Price et al. 375
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SW, and C: the individual normal control subjects in the left inferior frontal cortex. Coordinates are given in the order x, y, z
according to the atlas of Talairach and Tournoux (1988). The z score follows in bold. Part C also reports the number of voxels
activated.
A. Common Activations for Controls and SW
Main Effect Control Group SW
Left anterior superior temporal (BA 22) −60 2 −8 4.1 −58 4 −6 3.8 −60 2 −8 2.4
Left anterior middle temporal (BA 21) −68 −28 −2 3.7 −68 −28 −2 3.2 −70 −36 −6 3.0
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Left anterior medial temporal (BA 28) −14 −6 −24 3.9 −14 −6 −26 3.6 −12 −4 −24 2.0
Left inferior temporal (BA 37) −60 −48 −10 3.5 −58 −50 −10 3.6 −70 −42 −14 2.7
−70 −70 −6 4.3 −68 −66 −4 3.7 −72 −70 −10 3.3
−72 −66 6 3.8 −68 −66 4 3.3 −72 −68 8 2.6
Left posterior middle temporal/ (BA 39) −66 −72 22 4.0 −66 −60 16 4.1 −64 −76 22 3.2
angular gyrus
−70 −64 28 3.6 −66 −72 22 3.2 −66 −76 32 3.2
Left angular gyrus (BA 19) −52 −78 40 3.6 −44 −74 38 3.8 −54 −76 44 2.6
Left cuneus/precuneus (BA 19) −24 −90 38 3.8 −22 −92 38 3.5 −18 −82 38 2.7
B. All Control Subjects but Not SW
Controls > SW Control Group SW
Left inferior frontal (BA 45/47) −48 28 −6 5.7 −48 28 0 5.5 NS
(BA 47) −48 36 −12 4.4 −50 34 −6 3.9 NS
(BA 47) −40 36 −22 4.2 −40 36 −20 4.1 NS
Right cerebellum 20 −64 −32 4.4 16 −64 −30 4.5 NS
42 −60 −36 4.5 34 −64 −44 4.1 NS
Left cerebellum −58 −60 −46 4.0 −60 −58 −42 3.8 NS
C. Activations for Each Control Subject in Left Inferior Frontal Cortex (BA 47)
Subject 1 2 3 4 5 6
Peak location −40 28 −4 4.6 −42 28 0 3.0 −44 28 −2 2.6 −44 26 4 2.6 −42 22 −10 3.2 −44 32 −10 3.0
and Z
Voxels at p < 668/441 182/32 99/12 284/9 443/215 254/95
0.05/0.01
mantic similarity judgments indicates an ability to main- sue in the left inferior frontal lobe. To address this ques-
tain and control access to semantic information to make tion, functional imaging of the patient was required.
high-level decisions. Fiez (1997) and others have sug- The functional imaging experiment measured brain
gested that the brain region responsible for the control activity while SW was performing semantic similarity
of semantic information during the execution of seman- judgments. Activation was detected in several left ex-
tic tasks is the left inferior frontal cortex (BA 47). Inter- trasylvian temporal regions, in particular, the posterior
estingly, examination of the structural MRI indicated that basal temporal (BA 37), posterior inferior parietal (BA
there was some preservation of tissue in this region (see 39), and anterior middle temporal (BA 21) cortices. As
Figure 1). One possibility then was that SW managed to can be seen from Figure 3, some of this activity lay
perform the semantic tasks by activating peri-infarct tis- around the areas that appeared damaged on the struc-
376 Journal of Cognitive Neuroscience Volume 11, Number 4
Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/089892999563481 by guest on 15 September 2021Figure 2. The areas activated
(p < 0.05) during the seman-
tic decision task on models of
the left and right side of the
brain. The corresponding loca-
tions and z scores are given
in Table 2. The top row illus-
trates the normal system. The
second row illustrates the ar-
eas where SW activates nor-
mally, and the third row
illustrates the areas that SW
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fails to activate.
tural MRI scan, indicating peri-infarct activity in temporal These studies indicate that the extrasylvian temporal
and parietal regions. There was also signiªcant activation regions are necessary for semantic processing. In con-
in right anterior middle temporal and medial superior trast to these patients, structural imaging demonstrates
frontal cortices. This pattern of activation during seman- that SW, who is good at semantic tasks, had viable tissue
tic decisions has been discussed previously by Vanden- in both the left inferior temporal and posterior, inferior
berghe et al. (1996) and Price, Moore, Humphreys, and parietal cortices. The neuropsychological interpretation
Wise (1997). Within the system activated by SW, we can then is a double dissociation in function and lesion sites
make hypotheses as to which regions are necessary (or for SW and semantically impaired aphasics, verifying the
not) by reference to previous neuropsychological importance of the extrasylvian temporal regions for se-
ªndings. For example, patients with transcortical sensory mantics. The functional imaging component of the study
aphasia have a severe deªcit in comprehension, and takes the conclusions a stage further by demonstrating
lesions are distributed in the left inferior temporal lobe, that activity in the extrasylvian temporal and medial
the posterior, inferior parietal lobe (the junction of BA superior frontal cortices is sufªcient to perform seman-
39 and 19), the left thalamus and the white matter tic similarity judgments relative to physical size judg-
connecting these regions (Alexander, Hiltbrunner, & Fis- ments.
cher, 1989). Hart and Gordon (1990) have also linked We turn now to activity in the left inferior frontal
damage to the posterior inferior parietal lobe with com- cortex—BA 47. Functional imaging studies of normal
prehension deªcits, and Hodges et al. (1992) report that subjects have demonstrated repeatedly that this region
patients with semantic dementia have damage that com- is more active during semantic tasks on words. For in-
mences in the anterior temporal cortex and extends stance, it is activated signiªcantly by each of the normal
back along the ventral surface of the temporal lobe. subjects in this study and in the study reported by
Price et al. 377
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tion of the semantically re-
lated activation coregistered
onto a structural MRI of SW’s
brain. Section A shows areas
that SW was activating nor-
mally. Section B illustrates re-
gions that the normal controls
activated where there was no
activation for SW. As can be
seen, the functional deªcit cor-
responds to regions where
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there is reduced gray matter.
Vandenberghe et al. (1996). Nevertheless, as discussed in though BA 47 normally becomes more active during the
the Introduction, although functional imaging experi- semantic task than the control task, it does not play a
ments with normal subjects reveal distributed brain sys- crucial role in performance accuracy. SW’s manual re-
tems that are sufªcient to perform a task, they do not sponses were generally slower than normal, but this
establish the necessity of the subcomponents involved. effect was not speciªc for semantic tasks (see Results).
By combining functional imaging and neuropsychology, To distinguish whether the slower response times reºect
we have demonstrated that the inferior frontal cortex is slowing of semantically related neural dynamics, an
not necessary for the types of semantic decision that SW electrophysiological investigation would be required. In
is able to perform (see Table 1). Either (1) inferior frontal the absence of such, we cannot discount the possibility
activation seen in normal subjects is incidental to the that normal function in BA 47 contributes to the
semantic component of task requirements or (2) the efªciency of the semantic decisions. Indeed, one possi-
semantic system can adapt to emulate the same cogni- bility is that the activity normally seen in BA 47 repre-
tive functionality in the absence of a viable frontal activ- sents a preparation for more effortful semantic tasks.
ity (for instance, in SW, the function of BA 47 may be For instance, frontal lobe activity does appear to be
executed by the medial superior frontal cortex). In necessary for tasks such as word generation or stem
either case inferior frontal activity is not necessary to completion where performance is impaired following
complete the task. left frontal damage. Recently, Buckner et al. (1996) used
Implicit and redundant language processing that is functional neuroimaging to demonstrate that a patient
incidental to the demands of a task has been demon- with left frontal lobe damage retained the ability to
strated previously when subjects were required only to perform the stem completion task by activating the right
detect visual features in letter strings (Price et al., 1996). inferior frontal cortex. Stem completion involves the
In the present study, we have demonstrated that al- production of words beginning with a particular letter
378 Journal of Cognitive Neuroscience Volume 11, Number 4
Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/089892999563481 by guest on 15 September 2021combination (e.g., TRO . . .). This contrasts to the seman- essary for a task is generally uninteresting. However, the
tic similarity judgments described in this paper that rely constraints provided by neuroimaging (that the region
on intact knowledge of objects but do not require word was part of a sufªcient system) renders this information
retrieval. much more powerful. We conclude that functional brain
One other area of the semantically activated system— architectures can be delineated by using neuroimaging
the right cerebellar cortex—also showed consistent ac- data from (1) normal subjects to guide neuropsychologi-
tivation in all normal controls but an absence of cal investigations and (2) patients who are not function-
activation in SW. Remarkably, the functional deªcit re- ally impaired but have damage to regions hypothesized
vealed by the analysis of the positron emission tomogra- to be important from normal data. The inferences drawn
phy (PET) images mirrored the structural deªcit revealed from one group are only complete in the light of the
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by independent analysis of the MRI images. The reduced other.
gray matter in the right cerebellar cortex is presumed to
result from atrophy following crossed cerebellar di-
aschisis (Dow & Moruzzi, 1958; Lenzi, Frackowiak, &
METHODS
Jones, 1982; Feeney & Baron, 1986). Fiez et al. (1992) The Patient
have reported a neuropsychological case study of a pa-
SW, a right-handed male (date of birth 5/1/37), suffered
tient with a right cerebellar infarct. On nonmotor tasks,
an extensive left middle cerebral artery infarct on May
the patient showed deªcits completing and learning the
16, 1993. He was assessed at Charing Cross Hospital,
verb generation task but had normal or above normal
London, and agreed to participate in a research project
behavior when performing standardized language tasks.
that would monitor his language abilities both behavior-
In this instance, the behavioral investigation was moti-
ally and with functional neuroimaging. The behavioral
vated by functional imaging studies showing activity in
assessments investigated SW’s comprehension and
the right cerebellum during verbal ºuency. The behav-
phonological skills in April 1994, August 1995, and July
ioral study then identiªed the role of the lesioned region.
1997. At the time of the neuroimaging experiment (July
In the present study, we demonstrate that SW performed
1997), SW was 50.5 years old.
the semantic similarity task without activating the right
lateralized cerebellar region as normals do. This might
indicate that the right cerebellum is not necessary for Control Subjects
semantic similarity judgments. However, SW did activate
a more medial and more posterior cerebellar region (see The six control subjects were all right-handed volunteers
Table 2), which may have taken over the function of the with a mean age of 57 (ranging from 52 to 64). They had
right lateralized cerebellum. Therefore we do not at- no history of neurological or psychiatric illness and gave
tempt to interpret these ªndings further. informed consent to participate in the project.
In summary, functional imaging data from our neuro-
psychological case has demonstrated that activity in the
Language Assessment
left extrasylvian temporal, left posterior parietal, and me-
dial superior frontal cortices is sufªcient to make seman- Single-word recognition and comprehension were as-
tic similarity judgments. Although the left inferior frontal sessed with (1) lexical decision, (2) the pyramids and
cortex was activated for semantic similarity judgments palm trees test (Howard & Patterson, 1992), and (3)
on words for each of the six subjects in this study and synonym judgments from the PALPA test battery (Kay,
each of the six subjects reported by Vandenberghe et al. Lesser, & Coltheart, 1992). The lexical decision task in-
(1996), the same paradigm did not reveal any inferior volved deciding whether visually presented letter strings
frontal activity in SW. The inferior frontal activity de- were known words (e.g., Century) or not (e.g., Cen-
tected in all the normal subjects therefore appears not mury); nonwords were pseudowords that differed from
to be necessary for the requirements of this speciªc the words by only one letter. For the pyramids and palm
semantic task. Further investigations are needed to de- trees test, a word is given (e.g., PYRAMID) and one of
termine whether there are patients who maintain the two pictures (e.g., PALM TREE and DECIDUOUS TREE)
ability to perform semantic tasks in the context of left must be selected on the basis of semantic association.
extrasylvian temporal, left posterior parietal, or medial For synonym judgments, pairs of words are classiªed as
superior frontal damage. Such cases will enable us to having similar meaning (e.g., IRONY and SARCASM) or
characterize in a more reªned way the subset of regions different meaning (e.g., MOCKERY and NOTION).
that constitute a necessary and sufªcient semantic sys- The sentence comprehension tasks from the PALPA
tem. test were used (Kay, Lesser, & Coltheart, 1992). This
Investigations of brain-damaged patients who are not requires the patient to listen to or read a short sentence
functionally impaired on a task could facilitate a new (e.g., “The man kicked the horse”), to look at three
avenue of neuropsychological enquiry. Without neuro- pictures, and to point to the picture that accurately
imaging, the observation that a brain region is not nec- depicts the scene described by the sentence.
Price et al. 379
Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/089892999563481 by guest on 15 September 2021Phonological processing was assessed with spoken expect the response to affect semantically related activ-
word to picture matching, rhyming tasks, and homo- ity (but differences may be seen in the reaction times to
phone judgments. Tasks were from the PALPA test (Kay, both tasks). In all other respects, the conditions for SW
Lesser, & Coltheart, 1992). In the rhyming task, SW either were identical to those of the normal controls. The target
listened to two words or read two words and then stimuli were displayed 6.7° above the center of a screen
decided if they rhymed or not. During homophone judg- at a distance of 45 cm, and the two choices were dis-
ments, two written words were presented and SW de- played 5.6° below the center of the screen. For each run
cided if they were associated with the same sound or (scan), there were 12 triads of stimuli from one of the
not (e.g., decide if BLUE sounds like BLEW). four conditions. A new stimulus was presented every 5
Orthographic output processing was assessed with to 8 sec. Conditions were presented in randomized and
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word copying, dictation to heard words, and dictation to counterbalanced order.
seen pictures. In the Results section, we focus on the word semantic
task, which evoked reliable prefrontal activation in each
of the normal controls. We do not discuss the results of
Structural MRI
the picture semantic task in this paper because consis-
Structural magnetic resonance (MR) images were ob- tent activation for the normal subjects was limited to
tained with a 2 T Magnetom VISION scanner (Siemens, posterior structures (bilateral posterior parietal cortices,
Erlangen, Germany). The extent of the lesion was inves- BA 39/19, and posterior temporal cortices, BA 37/21).
tigated by contrasting the gray/white matter density Activation in the left inferior frontal activity for picture
with that of the six control subjects following stereotac- semantics only reached signiªcance in half the normal
tic normalization of each brain and smoothing with a subjects. Furthermore, for the picture semantic task
12-mm ªlter. The technique used (voxel-based morphol- there were no areas that were activated by all the normal
ogy) was implemented with Statistical Parametric Map- controls but not SW.
ping (SPM97) as previously described (Wright et al.,
1995).
Data Acquisition
Functional Neuroimaging with PET SW and each control subject underwent 12 PET scans
indexing regional cerebral blood ºow (rCBF) over a 2-h
Tasks period with three scans per condition. Scans were ob-
The aim of the functional neuroimaging experiment was tained using a Siemens/CPS ECAT EXACT HR+ (model
to identify regional activation associated with semantic 962) PET scanner (Siemens/CTI, Knoxville, TN) with
processing. Stimuli were objects from the Snodgrass and collimating septa retracted. A 20-sec intravenous bolus of
Vanderwart stimulus set (1980). The four conditions H215O at a concentration of 55 Mbq•ml-1 and a ºow rate
were chosen from a previous study by Vandenberghe et of 10 ml•min-1 was injected through a forearm cannula.
al. (1996). The design was factorial with two factors (1) The data were analyzed with statistical parametric
stimulus modality (either words or pictures) and (2) task mapping (using SPM97 software from the Wellcome
(either semantic decisions or visual decisions). In each Department of Cognitive Neurology, London,
task, triads of stimuli were presented with a target above http//www.ªl.ion.ucl.ac.uk/spm) implemented in Mat-
and two choices below. For the semantic decision, stim- lab (Mathworks Inc. Sherborn, MA) using standardized
uli within a triad were different but all from the same procedures (Friston et al., 1995a, 1995b). Following
category. The task was to select a choice item that had realignment to correct for head movement, the images
the strongest semantic association with a target. Exam- were coregistered into the same space as the MRI
ples of the stimuli are Target = TABLE, choices = SOFA scan discussed above. For stereotactic normalization, pa-
and CHAIR. The correct answer is chair because you sit rameters were determined from the more detailed struc-
at a table with a chair. For the visual decision, the stimuli ture in the T1-weighted MRI scans and then applied to
within each triad were identical except that they varied the PET images. The normalized images were smoothed
in their actual size (i.e., the visual angle subtended on with a 16-mm Gaussian ªlter resulting in an effective
the screen). The task was to select the choice item that resolution of 9.5 mm in the statistical parametric map
sustained the most similar visual angle to the target. (SPM).
Subjects were instructed to press the right key if the The statistical analysis aimed to identify the regions
right stimulus was most related to the target and the left where SW showed (1) normal activation, (2) reduced
key if the left stimulus was most related to the target. activation relative to normals, and (3) increased activa-
For the control subjects, the keys were in different tion relative to normals. This was achieved in a multi-
hands; SW used two ªngers from his unaffected left hand study design with replications and 49 degrees of
(his right hand was disabled due to hemiplegia). Because freedom. Condition-speciªc effects were estimated in a
there were an equal number of right and left responses subject-speciªc fashion for the six normal controls and
in the activation and baseline conditions, we would not SW. This approach allowed us to distinguish areas that
380 Journal of Cognitive Neuroscience Volume 11, Number 4
Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/089892999563481 by guest on 15 September 2021were activated by every subject from those where there Acknowledgments
was intersubject variability, in particular where SW’s The study was funded by the Wellcome Trust. We would also
activation pattern differed from that of each control like to thank the radiographers for their help in the process of
subject. Condition and subject effects were estimated at data acquisition and Richard Wise for referring the patient.
each voxel according to the general linear model, and
linear contrasts were used to test hypotheses about Reprint requests should be sent to Cathy J. Price, Wellcome
regionally speciªc condition effects and subject by con- Department of Cognitive Neurology, Institute of Neurology,
dition interactions (Friston et al., 1995b). The resulting Queen Square, London WC1N 3BG, UK.
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