r
Human Brain Mapping 5:84–92(1997)
r
Regional Cerebral Blood Flow During Word and
Nonword Reading
A.N. Herbster,1* M.A. Mintun,1,2 R.D. Nebes,1 and J.T. Becker1,3
1Department of Psychiatry, Neuropsychology Research Program,
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
2Department of Radiology, Functional Imaging Research Program,
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
3Department of Neurology, Neuropsychology Research Program,
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
r
r
Abstract: The purpose of this study was to examine changes in regional cerebral blood flow (rCBF) using
positron emission tomography (PET) during overt word and nonword reading tasks to determine
structures involved in semantic processing. Ten young, healthy, right-handed subjects were scanned 12
times, twice in each of six specific conditions. Blood flow was measured by 15O-water using standard PET
imaging technology. The rCBFs during different cognitive conditions were compared by using analysis of
covariance (SPM94), which resulted in three-dimensional maps of those brain regions more active in one
condition relative to another. When the subjects read aloud words with difficult or unusual graphemephoneme translations (i.e., third-order approximation to English or irregularly spelled real words),
increases in activation were seen in the inferior frontal cortex. When subjects were reading aloud regular
and irregular words (which had important semantic components relative to nonwords), activation of the
fusiform gyrus was seen. These data are broadly consistent with brain regions generally associated with
reading based on other neuropsychological paradigms, and they emphasize the multicomponent aspects
of this complex cognitive process. Hum. Brain Mapping 5:84–92, 1997. r 1997 Wiley-Liss, Inc.
Key words: cognition; positron emission tomography; frontal cortex; fusiform gyrus
r
r
INTRODUCTION
Current techniques in neuroimaging permit studies
of the functional organization of the human brain in
vivo, which allows for the identification of specific
Contract grant sponsor: National Institute of Mental Health; Contract grant number MH49815; Contract grant sponsor: National
Institute on Aging; Contract grant number AG13669; Contract grant
sponsor: Research Scientist Development Award—Level II; Contract
grant number K02-MH0177
*Correspondence to: Amy N. Herbster, B.S., Neuropsychology Research Program, 502 Iroquois Building, 3600 Forbes Avenue, Pittsburgh, PA 15213.
Received 6 September 1996; accepted 11 February 1997
r 1997 Wiley-Liss, Inc.
changes in focal regions in response to cognitive
demands such as reading [Fox et al., 1985; Mintun et
al., 1989]. Reading is a complex cognitive skill involving, at the very least, visual analysis of letters, analysis
of letter strings and word forms, conversion of the
graphemic representation of word forms into phonological representations (for oral reading), and activation of the lexical/semantic representation of the word.
However, in spite of a variety of neurobehavioral data
concerning the functional localization of the processors essential for successful reading (see, for example,
Damasio and Damasio [1983] and Henderson and
colleagues [1985]), the results from functional imaging
studies, particularly positron emission tomography
r
rCBF During Word and Nonword Reading r
system of three laser lines the face was marked with
washable ink in five places to allow checks for movement of the subject during the study and positioning of
the subject’s head if necessary. Transmission scanning
was done in all PET studies prior to radiopharmaceutical injection using three rotating rod sources of 68Ge/
68Ga. Following this scan, the septa were retracted to
permit three-dimensional acquisition of data.
Measurements of relative cerebral blood flow were
made after an intravenous bolus injection of 5–7 mCi
of 15O-water in 5–7 ml of saline. Beginning approximately 5 seconds after the point when activity began to
enter the brain (to allow for partial clearance of the
15O-water from vascular structures), we began a 60
second sampling frame, which was used as the qualitative map of CBF [Fox and Mintun, 1989]. Data were
acquired and reconstructed in full three-dimensional
mode [Townsend et al., 1991].
The collected PET images from each patient were
centered (left-right), vertically aligned to correct for
movement in the transverse and coronal planes, and
coregistered to one another to correct for slight head
movement during the scan [Miroshima et al., 1992;
Woods et al., 1992]. The rest of the PET scans collected
on the subject were mathematically registered to the
first scan by PET-to-PET alignment [Woods et al.,
1992]. These processes centered the images and oriented them in the same coordinate system for later
processing.
Statistical analysis of the data was carried out using
the Statistical Parametric Mapping program (SPM94)
[Friston et al., 1991] in PRO MATLAB (Mathworks,
Sherborn, MA). The scans were spatially normalized
using linear transformation, which removed individual subject variability and transformed each brain
into the Talairach and Tournoux [1988] atlas reference
space. We used the linear transformation to avoid loss
of information at the top- and bottom-most images,
which can occur with the SPM default nonlinear
transformation. The scans were then smoothed with a
three-dimensional gaussian filter with 16 mm fullwidth half-maximum (inplane) to suppress noise and
minimize effects of normalization errors by increasing
the sensitivity of the signal.
Differences in global activity within and between
subjects were removed by analysis of covariance (ANCOVA) on a voxel-by-voxel basis with global counts as
covariate and regional activity across subjects for each
task as treatment. The ANCOVA is used for the
comparison of tasks, with each subject being studied in
all conditions. Comparisons of the means across selected conditions were made on a voxel-by-voxel basis
using the t-statistic. The resulting values constituted a
(PET), are less clear (see, for example, work by Petersen and colleagues [1989, 1990], Howard and Patterson [1992], and Fiez et al. [1993]). Given the importance
of between-center replication in functional imaging
studies [e.g., Becker et al., 1994], the present study was
an attempt to determine those brain regions whose
activity covaried with specific aspects of oral reading.
We were further interested in learning how these
patterns of activation might change as a function of the
spelling-sound regularity of the written words. Thus,
words that have a straightforward grapheme-phoneme correspondence appear to use different cognitive
processes (or are biased to use certain processes preferentially) relative to words whose spelling does not
directly reveal the correct pronunciation [Patterson
and Hodges, 1992; Plaut et al., 1996]. Thus, the purpose
of this study was to develop a protocol to examine the
neuroanatomical correlates of oral reading, with particular reference to the similarities and differences
arising from reading words with regular and irregular
spelling.
MATERIALS AND METHODS
Subjects
There were ten young subjects (five males, five
females), 28.4 years of age (range, 18–38 years) with
14.6 years of education (range, 12–18 years). All were
healthy (no history of neurological or psychiatric
disorders) and right-handed, and English was their
native language. Informed consent was obtained prior
to the start of the scanning session. All of the women
had a negative pregnancy test on the day of, and prior
to, the scanning session.
PET procedures
Each subject was scanned 12 times measuring regional cerebral blood flow (rCBF) using 15O-water with
standard laboratory procedures [Becker et al., 1994].
The subjects were placed in the supine position on the
Siemens 951R/31 PET scanning table. The scanner
collects 31 parallel planes over a 10.8 cm axial field of
view. An antecubital intravenous catheter was placed
in the left arm for radiopharmaceutical injection. The
head was positioned within the head holder and a
softened thermoplastic mask fitted over the face,
molded to the patient’s facial contours (with cutouts
for the eyes, ears, and mouth), and fastened to the head
holder [Fox et al., 1985]. The PET gantry was rotated
and tilted such that the lowest imaging plane was
parallel to, and at the canthomeatal line. Using a
r
85
r
r
Herbster et al. r
statistical parametric map (SPM) [Friston et al., 1991].
The critical level of alpha was set at 0.001 for all
comparisons.
Processes involved in this task include visual processing and motor aspects of speech production.
Nonword reading
Reading task procedures
The subject was shown a series of pronounceable
letter strings conforming to English rules with thirdorder approximation to English (e.g., ‘‘CHOURN’’)
[Hirata and Bryden, 1971]. The subject was instructed
to read the words aloud, as they were presented.
Processes involved in this task include visual processing and motor aspects of speech production, as well as
conversion of visual input (graphemes) into oral output (phonemes); however, there are no semantic representations of these letter strings.
Test materials were presented using PsyScope [Cohen et al., 1993] via a Macintosh computer with a video
monitor above the subject’s head in the PET scanner.
PsyScope was set up to sample randomly from two
sets of word lists without replacement. In all conditions, the subject was shown the letter string/word for
200 msec at the rate of one every 2 seconds, with 48
trials during each scan (i.e., 96 seconds). There were
two blocks of six scans; scan order was randomized
within blocks. All words and letter strings appeared in
upper case print. To be consistent with another semantic memory study currently under way, the regular
words used in this study were generally the names of
the objects in the Snodgrass and Vanderwart [1980]
corpus. Irregular words were taken from the National
Adult Reading Test [Nelson and O’Connell, 1978] and
the Psycholinguistic Assessments of Language Processing in Aphasia [Kay et al., Lesser & Coltheart, 1992].
The mean frequency for the regular words was 51.69/
1,000,000 (SD 5 24.7) and 27.60/1,000,000 (SD 5 25.5)
for the irregular words [Carroll et al., 1971]. The
pronounceable nonwords were matched to the real
words for length (in letters).
Six conditions were used in this study, with two
separate scans made for each of the conditions: fixation, and five different reading-related tasks. During
the Fixation condition, the subject was instructed to
fixate on a cross-hair target for the duration of the scan;
this serves as a baseline condition. The five cognitive
tasks were: zero-order view, zero-order speak, nonword reading, regular word reading, and irregular
word reading.
Regular word reading
The subject was shown a series of words that were
pronounced following the standard rules of English
(e.g., ‘‘KITE’’) and was instructed to read the words
aloud. Processes involved in this task include visual
processing, motor aspects of speech production, grapheme-to-phoneme conversion, and (automatic) activation of the semantic representation of the word.
Irregular word reading
The subject was shown a series of words pronounced in a manner that does not conform to standard English rules (e.g., ‘‘DEBT’’) and was instructed
to read the words aloud as shown. Processes involved
in this task include visual processing and motor
aspects of speech production. Because these words did
not conform to standard rules, pronunciation is thought
to rely more heavily on the mediating connection with
semantics [e.g., Patterson and Hodges, 1992; Plaut et
al., 1996].
Zero-order view
RESULTS
The subject was shown a series of letter strings with
zero-order approximation to English (e.g., ‘‘ZBJXD’’)
[Hirata and Bryden, 1971]. The letter strings were
matched for length to the words in the regular and
irregular conditions. Processes involved in this task
include initial visual processing and perhaps letter
identification, but no word form analysis.
Tasks used in this study were easily accomplished
by the subjects. Further, they produced activations that
were highly significant and also consistent with previously published data. There were two principal regional activations: first, reading aloud real words, with
both regular and irregular spelling, consistently activated the left fusiform gyrus; second, reading aloud
real words with irregular spelling, or reading pronounceable nonwords, activated a region of the left
inferior frontal cortex.
We first contrasted real word reading (regular and
irregular) with the zero-order speak condition. The
Zero-order speak
The same as above except that the subject repeated
the word ‘‘Hiya’’ as each letter string was presented.
r
86
r
r
rCBF During Word and Nonword Reading r
TABLE I. Regions of peak activity (P F 0.001) for four conditions compared with the zero-order speak condition
Location
Left/
right
Irregular 1 regular
X
Y
Z
(Z)
Regular
X
Y
Z
Irregular
(Z)
X
Y
Z
Nonwords
(Z)
X
Y
Z
(Z)
L
238 240 224 (4.63) 234 238 224 (4.13) 238 240 224 (4.26)
—
—
252
0
0 (3.39)
—
260 222
4 (4.00)
230
18 224 (3.78)
260 218
0 (3.78)
—
260 218
0 (3.54)
L
246
0
L
L
L
212
2
Fusiform gyrus
Superior temporal
gyrus
Middle temporal
gyrus
Inferior frontal
gyrus
Globus pallidus
Cingulate (4.41)
Cerebellum
L
L
Cerebellum
R
24 (3.88)
24 (3.69)
—
28 266
28 (3.47)
38 274 224 (3.42)
—
240
12
212
0
24 (4.16) 248
6
0 (5.09)
0 (4.11)
—
26
28 264 212 (3.65) 232 290 216
216 234 212 (3.51) 226 254 228
38 276 224 (3.42)
—
42 272 224
16 258 220
—
—
zero-order speak) projected onto a rendering of the left
cortical surface.
We then directly contrasted the word reading conditions with one another to see if the significant activations in the left fusiform gyrus and left inferior frontal
gyrus (IFG) were as expected. Subtracting regular from
irregular word reading reveals significant activation in
the left IFG (Table II); in the reverse contrast, there are
no significant differences in activation in either the
frontal or temporal cortical regions. The contrast between irregular and nonword reading also shows a
significant difference in activation (P , 0.01) in the left
fusiform cortex. The reverse contrast shows no significant differences in activation in either of the two
regions. Most important, the direct contrast between
regular and nonword reading shows significantly
greater activation in the left fusiform cortex during
regular word reading, as well as significantly greater
activation in the left IFG during nonword reading.
latter condition, like the word reading condition,
involves visual stimulation, speech, audition (i.e., hearing the repeatedly spoken word ‘‘Hiya’’), and any
automatic processes related to letter recognition. The
tasks differ, at the very least, in that the real word
reading conditions involve word analysis and recognition, as well as automatic processes related to word
semantics and phonology. The results of this contrast
are presented in Table I and Figure 1.
There were two large areas of activation. The largest
region (312 contiguous voxels, P (nmax . k) 5 0.009)
was centered in the fusiform cortex on the left; the
second region (142 voxels, P 5 0.077) involved the
inferior frontal gyrus. The activation in the left fusiform cortex not only appeared when both real word
conditions were contrasted with zero-order speak, but
also when the individual conditions were so evaluated
(Fig. 1, bottom row). The same cannot be said for the
activation of the inferior frontal cortex, which was only
seen during irregular word reading.
Consistent with these findings were the results of the
contrast between nonword reading and zero-order
speak (Fig. 1, top right). That contrast shows no
significant activation of the fusiform cortex but does
have a large (862 voxels, P , 0.001) contiguous region
of activation over the inferior frontal cortex, including
(at least) BA47 (lateral sulcus) and BA44.
Finally, Figure 2 (left) shows the region of activation
in the fusiform cortex superimposed in the MRC
standard magnetic resonance image. This coronal view
is taken at the focus of the left temporal activity in
response to real words relative to zero-speak. The right
side shows the focus of the left inferior frontal activity
while reading aloud irregular real words (relative to
r
4 40
(4.00)
(3.65)
(4.16)
(4.01)
DISCUSSION
The purpose of this study was to design and implement a scanning protocol to identify those brain
regions involved in word and nonword reading in
healthy, young, normal subjects. The cognitive tasks
produced robust activations of discrete brain regions
consistent with previously published data [Bookheimer et al., 1995]. Furthermore, they produced activations that were highly significant, and the tasks used in
this study were easily accomplished by the subjects.
Word presentation was at a speed in which subjects
were able to respond in the allotted time as well as
correctly. Although mean reaction time and length of
87
r
Figure 1.
r
Herbster et al. r
Figure 2.
Projection of the left fusiform activation onto the MRC standard magnetic resonance images in
coronal section taken at the level of the regional maximum (left image). On the right is the frontal and
temporal activation seen during irregular word reading projected onto the nearest point of the
cortical surface (left hemisphere).
fusiform in word meaning. In this study, however, only
one region of activation was seen in the fusiform
cortex, and this was somewhat between the regions
identified by Luders and colleagues. Furthermore,
distinct regions within the fusiform cortex may respond differentially to word and word-like stimuli
[Nobre et al., 1994], although in the present study we
were not able to make such distinctions. Pathology in
this area is also associated with word selection anomia—a severe impairment of word-finding abilities
[Benson, 1979].
The finding that relative to the zero-speak condition
both irregular and nonword reading activated the IFG
may be related to the process by which sound is
generated from the written word form. This pattern of
activation appears similar to that reported by Fiez and
colleagues [1993]. They found that in the deep frontal/
insular cortex there was significant activation when
reading low frequency exception (i.e., irregular) words,
but no activation while reading regular words (relative
to a fixation control condition). This activity seen in the
present study cannot be related to word form generation for speech since similar activation is not seen in
regular word reading. The activity in the left IFG may
be related to word frequency (as the irregular words
were lower in frequency than the regular words). Low
frequency words may activate phonological processing centers in the IFG, while more frequent words
could be processed through a direct route. This explanation would predict a graded effect of activation in
the IFG, however, and the activation due to nonwords,
utterance was not measured in these normal subjects,
these variables may be relevant in later studies.
Upon subtracting the rCBF seen while reading meaningless words from that seen while reading meaningful words, the only statistically significant region was
the fusiform gyrus. This finding is similar to a previous
report in which this region was implicated in semantic
processing during word and object naming tasks that
required retrieval from the semantic lexicon [Bookheimer et al., 1995]. In another study, the left and right
fusiform were both active during a word identification
task that was designed to require retrieval of semantic
information, but only the left fusiform gyrus was
active in a word identification task designed to require
word retrieval [Madden et al., 1996]. Howard [1992]
also found left fusiform activation, but it was substantially above (i.e., dorsal to) the focus seen here. Electrical stimulation studies have also shown the fusiform
gyrus of the language dominant hemisphere to be
important in language functions [Luders et al., 1986,
1991]. Some data suggest that the posterior fusiform
may be involved in word formation and the anterior
Figure 1.
Statistical parametric maps (SPMt) of the reading tasks compared
with the control condition zero-order speak. The regions of
significant activation (P , 0.001) are projected onto sagittal, coronal, and transverse outlines of a brain in these ‘‘look through’’
images. All the contrasts are expressed relative to the zero
order-speak condition.
r
89
r
r
Herbster et al. r
TABLE II. Regions of peak activity (P F 0.001) in the left fusiform gyrus and left inferior frontal gyrus
during direct comparisons
Location
Fusiform gyrus (left)
Inferior frontal
gyrus (left)
Irregular 2 regular
Irregular 2 nonwords*
Regular 2 nonwords
Nonwords 2 regular
X
Y
Z
(Z)
X
Y
X
X
Y
Z
234
6
—
16
234
246
(4.19)
244
4
—
16
Z
(Z)
224
—
(3.07)
Y
Z
(Z)
236 230 224 (3.50)
—
(Z)
(4.87)
* P , 0.01.
surely the least frequent of all, did not differ from that
of the irregular words.
The third possibility, and the one favored here, is
derived from current behavioral and computational
models of reading [e.g., Patterson and Hodges, 1992;
Plaut et al., 1996]. In dual-path models, reading is
supported by two processes, one related to the direct
translation from orthography to phonology, and the
other mediated through the meaning, or semantics of
the written word. One recent model [Plaut et al., 1996]
may be somewhat more consistent with the present
data than other computational systems. According to
this model, the phonological pathway directly transforms orthography into phonology. The semantic pathway performs two tasks—the transformation of orthography into semantics and the transformation of
semantics into phonology. As we gain reading experience, and as the semantic system becomes more
competent, the phonological system becomes more
specialized, so that reading regular words is rapid and
accurate, while reading irregular words suffers. In the
case of irregular words there is competition between
the different ‘‘correct’’ pronunciation form (i.e., one via
phonology and one via semantics). The phonological
output is thus delayed as the system decides which
pronunciation to use. Similarly, the reading of nonwords is affected by the fact that there is no semantic
bias to the phonological system to aid in the pronunciation of these nonwords. Thus we conclude that we are
seeing in the activation of the inferior frontal cortex the
manifestation of increased processing in the phonological system—in one case (irregular words) due to the
competition between the phonological and semantic
reading pathways, and in the other (nonwords) because the phonological pathway has never had experience with these particular strings of letters or phonemes.
Resolution of these issues will help to clarify PET
study design issues and (perhaps) advance theories of
reading. At present, our data do not directly support
any particular model of the nature of the information
r
processing associated with reading aloud. There is also
nothing in these data to exclude specifically other
dual-path models that permit multiple routes to phonology from orthography, and indeed data may be
relevant to the predictions of such models.
There has been a recent debate in the PET neuroimaging literature concerning which central nervous
system regions are active in the intact brain during
reading tasks. In early studies, activation of the left
medial extrastriate cortex was observed in response to
the silent processing of words and nonwords and
activation of the left frontal cortex in response to real
words [Petersen et al., 1989, 1990]. Later work has
failed to replicate this finding. For example, activation
of the left temporal cortex in response to word reading
has been observed, but without increases in activity in
the frontal or extrastriate regions [Howard et al., 1992].
In another study, activity was observed in the left
middle temporal lobe in response to word reading, as
well as activation of the left inferior/middle occipital
gyri [Price, 1994]. Activation of the IFG was observed
during silent reading and activation of the superior
temporal lobes (bilaterally), left supramarginal gyrus,
cerebellum, and supplementary motor area when reading out loud [Bookheimer et al., 1995]. Our data are
basically consistent with these later studies, confirming the importance of both the left fusiform and left
inferior frontal cortex.
Our interest in understanding the neuroanatomical
bases of oral reading arises mainly from our research
focus on patients with Alzheimer’s disease (AD)
[Becker et al., 1996; Herbster et al., 1996]. The clinical
characteristics of AD patients suggest that reading
abilities are relatively spared until late in the course of
the dementia. However, careful examination of the
reading performance of AD patients suggests that they
do have difficulty with reading, arising secondary to
deficiencies in semantic memory [Patterson et al.,
1994]. Thus, not only is reading comprehension impaired [Cummings et al., 1986], but reading irregular
words aloud is affected as well [Fromm et al., 1991;
90
r
r
rCBF During Word and Nonword Reading r
Patterson et al., 1994]. Consequently, studying the
rCBF correlates of oral reading of a variety of different
types of word and word-like stimuli provides an
important clue toward understanding the breakdown
of semantics in AD.
Before such a PET study can be attempted, however,
a protocol must be developed in healthy, young subjects, and that protocol must be within the capability of
demented elderly patients. An additional purpose of
the present study was to evaluate the power of the
present protocol in terms of its applicability to patients
with AD. With regard to the extension of this study
into AD patients, three changes most likely will need
to be made. First, the mean frequency of both the
regular and irregular words will need to exceed, on
average, 100/1,000,000, based on pilot data from our
laboratory. Second, the exposure time of the stimuli
will need to be extended, and this must be determined
by examination of elderly control subjects. Third, and
perhaps most important, response latency and perhaps
length of utterance will need to be recorded for
correlation with mean rCBF.
After examining the present results, some predictions may be made concerning reading and rCBF with
Alzheimer patients. Performance on the real word
reading tasks may reveal a decrease in activity of the
fusiform gyrus (compared with normal elderly subjects). This would be consistent with other PET studies
showing a decrease in rCBF of the temporal lobes of
AD patients [Duara et al., 1986; Foster et al., 1984;
Haxby et al., 1986] and the neurodegenerative changes
that occur in this region [Khachaturian, 1985]. However, to the extent that a breakdown of a semantic
network might result in a less well-defined pattern of
central nervous system activity [Tippett and Farah,
1994], we might predict a significant increase in the
extent of fusiform activation in AD patients [Becker et
al., 1996].
The irregular word and nonword reading tasks may
produce an even greater increase in activity in the
inferior frontal lobes of the Alzheimer patients. It is
likely the AD patients will find these word reading
tasks slightly more challenging than did the normal
subjects, causing a greater increase in rCBF in the
regions used to complete the task. However, AD
patients may attempt to regularize these word forms
[Patterson et al., 1994], which could result in lower
activation in the frontal cortex.
The results of this study support the observations
that the fusiform gyrus on the inferior temporal lobe is
important for processing the meaning of stimuli, in
this case words. Furthermore, our data are also consistent with observations suggesting that the inferior
r
frontal cortex plays a role in the processing of sound
streams prior to the production of speech, in this case
determining which of two competing pronunciations
will be used. Finally, the results of the study suggest
that with a few minor modifications, this protocol can
be adapted for use in patients with degenerative
dementias and will thus afford us the opportunity to
investigate the nature of the semantic breakdown in
these complex neuropsychiatric disorders.
ACKNOWLEDGMENTS
This research was supported in part by funds from
the National Institute of Mental Health (MH49815) and
the National Institute on Aging (AG13669). J.T.B. was
supported by a Research Scientist Development AwardLevel II (K02-MH0177). We are grateful to Dr. K.
Patterson for kindly commenting on an earlier draft of
this paper.
REFERENCES
Becker JT, Mintun MA, Diehl DJ, Dobkin J, Martidis A, Madoff DC,
DeKosky ST (1994): Functional neuroanatomy of verbal free
recall: A replication study. Hum Brain Mapping 1:284–292.
Becker JT, Mintun MA, Aleva K, Wiseman MB, Nichols T, DeKosky
ST (1996): Compensatory reallocation of brain resources supporting verbal episodic memory in Alzheimer’s disease. Neurology
46:692–700.
Benson DF (1979): Aphasia, Alexia, and Agraphia. New York:
Churchill Livingstone.
Bookheimer SY, Zeffiro TA, Blaxton T, Gaillard W, Theodore W
(1995): Regional cerebral blood flow during object naming and
word reading. Hum Brain Mapping 3:93–106.
Carroll JB, Davies P, Richman B (1971): The American Heritage Word
Frequency Book. Boston: Houghton Mifflin.
Cohen JD, MacWhinney B, Flatt M, Provost J (1993): Psyscope: A
new graphic interactive environment for designing psychology
experiments. Behav Res Methods Instrume Comput 25:257–271.
Cummings JL, Houlihan JP, Hill MA (1986): The pattern of reading
deterioration in dementia of the Alheimer type: Observations
and implications. Brain Lang 29:315–323.
Damasio AR, Damasio H (1983): The anatomic basis of pure alexia.
Neurology 33:1573–1583.
Duara R, Grady C, Haxby J, Sundaram BES, Cutler NR, Heston L,
Moore A, Schlageter N, Larson S, Rapoport SI (1986): Positron
emission tomography in Alzheimer’s disease. Neurology 37:879–
887.
Fiez JA, Balota DA, Raichle ME, Petersen SE (1993): The effects of
word frequency and spelling-to-sound regularity on the functional anatomy of reading. Presented at the Society for Neuroscience 23rd Annual Meeting, Washington, DC.
Foster NL, Chase TN, Mansi L, Brooks R, Fedio P, Patronas NJ,
DiChiro G (1984): Cortical abnormalities in Alzheimer’s disease.
Ann Neurol 16:649–654.
Fox PT, Mintun MA (1989): Noninvasive functional brain mapping
by change-distribution analysis of averaged PET images of H15
2 O
tissue activity. J Nucl Med 30:141–149.
91
r
r
Herbster et al. r
Fox PT, Perlmutter JS, Raichle ME (1985): A stereotactic method of
anatomical localization for positron emission tomography. J
Comput Assist Tomogr 9:141–153.
Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ (1991): Comparing
functional (PET) images: The assessment of significant change. J
Cereb Blood Flow Metab 10:458–466.
Fromm D, Holland AL, Nebes RD, Oakley MA (1991): A longitudinal
study of word reading ability in Alzheimer’s disease: Evidence
from the National Adult Reading Test. Cortex 27:367–376.
Haxby JV, Grady CL, Duara R, Schlageter N, Berg G, Rapoport SI
(1986): Neocortical metabolic abnormalities precede nonmemory
cognitive deficits in early Alzheimer’s-type dementia. Arch
Neurol 43:882–885.
Henderson VW, Friedman RB, Teng EL, Weiner JM (1985): Left
hemisphere pathways in reading: Inferences from pure alexia
without hemianopia. Neurology 35:962–968.
Herbster AN, Nichols T, Wiseman MB, Mintun MA, DeKosky ST,
Becker JT (1996): Functional connectivity in auditory verbal
short-term memory in Alzheimer’s disease. NeuroImage 4:67–77.
Hirata K, Bryden MP (1971): Tables of letter sequences varying in
order of approximation to English. Psychon Sci 25:322–324.
Howard D, Patterson K (1992): The Pyramid and Palm Trees Test: A
Test of Semantic Access From Words and Pictures. Bury St.
Edmunds: Thames Valley Test Company.
Howard D, Patterson K, Wise R, Brown WD, Friston K, Weiller C,
Frackowiak R (1992): The cortical localization of the lexicons:
Positron emission tomography evidence. Brain 115:1769–1782.
Kay J, Lesser R, Coltheart M (1992): PALPA: Psycholinguistic
Assessments of Language Processing in Aphasia. East Sussex,
England: Lawrence Erlbaum Associates.
Khachaturian Z (1985): Diagnosis of Alzheimer’s disease. Arch
Neurol 42:1097–1105.
Luders H, Lesser RP, Hahn J, Dinner DS, Morris H, Resor S (1986):
Basal temporal language area demonstrated by electrical simulation. Neurology 36:505–510.
Luders H, Lesser RP, Hahn J, Dinner DS, Morris HH, Wyllie E,
Godoy J (1991): Basal temporal language area. Brain 114:743–754.
Madden DJ, Turkington TG, Coleman RE, Provenzale JM, DeGrado
TR, Hoffman JM (1996): Adult age differences in regional cerebral
blood flow during visual word identification: Evidence from
H15
2 O PET. Neuroimage 3:127–142.
Mintun MA, Fox PT, Raichle ME (1989): A highly accurate method of
localizing regions of neuronal activation in the human brain with
r
positron emission tomography. J Cereb Blood Flow Metab 9:96–
103.
Miroshima S, Berger KL, Lee KS, Mintun MA (1992): An automated
method for rotational correction and centering of three-dimensional functional brain images. J Nucl Med 33:1579–1585.
Nelson E, O’Connell A (1978): Dementia: The estimation of premorbid intelligence levels using the new adult reading test. Cortex
14:234–244.
Nobre AC, Allison T, McCarthy G (1994): Word recognition in the
human inferior temporal lobe. Nature 372:260–263.
Patterson K, Hodges JR (1992): Deterioration of word meaning:
Implications for reading. Neuropsychologia 30:1025–1040.
Patterson K, Graham N, Hodges JR (1994): Reading in dementia of
the Alzheimer type: A preserved ability. Neuropsychology 8:395–
407.
Petersen SE, Fox PT, Posner MI, Mintun MA, Raichle ME (1989):
Positron emission tomographic studies of the processing of
single words. J Cogn Neurosci 1:153–170.
Petersen SE, Fox PT, Snyder AZ, Raichle ME (1990): Activation of
extrastriate and frontal cortical areas by visual words and
word-like stimuli. Science 249:1041–1044.
Plaut DC, McClelland JL, Seidenberg MS, Patterson K (1996):
Understanding normal and impaired word reading: Computational principles in quasi-regular domains. Psychol Review
103:56–115.
Price CJ (1994): Brain activity during reading: The effects of exposure
duration and task. Brain 117:1255–1269.
Snodgrass JG, Vanderwart M (1980): A standardized set of 260
pictures: Norms for name agreement, image agreement, familiarity, and visual complexity. J Exp Psychol [Hum Learn Memory]
6:174–215.
Talairach J, Tournoux P (1988): Co-Planar Stereotactic Atlas of the
Human Brain: 3-Dimensional Proportional System: An Approach
to Cerebral Imaging. New York: Thieme Medical Publishers.
Tippett LJ, Farah MJ (1994): A computation model of naming in
Alzheimer’s disease: Unitary or multiple impairments? Neuropsychology 8:3–13.
Townsend DW, Geissbuhler A, Defrise M, Hoffman EJ, Spinks TJ,
Bailey DL, Gilardi M-C, Jones T (1991): Fully three-dimensional
reconstruction for a PET camera with retractable septa. IEEE
Trans Med Imaging 10(4):505–512.
Woods RP, Cherry SR, Mazziotta JC (1992): Rapid automated
algorithm for aligning and reslicing PET images. J Comput Assist
Tomogr 16:620–633.
92
r