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The Journal of Neuroscience, February 1, 1998, 18(3):1085-1095
Cortical Networks Underlying Mechanisms of Time Perception
Deborah L.
Harrington1,
Kathleen Y.
Haaland1, and
Robert T.
Knight2
1 Research and Psychology Services, Veterans Affairs
Medical Center and the University of New Mexico, Albuquerque, New
Mexico 87108, and 2 Department of Neurology and Center for
Neuroscience, University of California, Davis, and Veterans Affairs
Medical Center, Martinez, California 94553
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ABSTRACT |
Precise timing of sensory information from multiple sensory streams
is essential for many aspects of human perception and action. Animal
and human research implicates the basal ganglia and cerebellar systems
in timekeeping operations, but investigations into the role of the
cerebral cortex have been limited. Individuals with focal left (LHD) or
right hemisphere (RHD) lesions and control subjects performed two time
perception tasks (duration perception, wherein the standard tone pair
interval was 300 or 600 msec) and a frequency perception task, which
controlled for deficits in time-independent processes shared by both
tasks. When frequency perception deficits were controlled, only
patients with RHD showed time perception deficits. Time perception
competency was correlated with an independent test of switching
nonspatial attention in the RHD but not the LHD patients, despite
attention deficits in both groups. Lesion overlays of patients with RHD
and impaired timing showed that 100% of the patients with anterior
damage had lesions in premotor and prefrontal cortex (Brodmann areas 6, 8, 9, and 46), and 100% with posterior damage had lesions in the inferior parietal cortex. All LHD patients with normal timing had
damage in these same regions, whereas few, if any, RHD patients with
normal timing had similar lesion distributions. These results implicate
a right hemisphere prefrontal-inferior parietal network in timing.
Time-dependent attention and working memory functions may contribute to
temporal perception deficits observed after damage to this network.
Key words:
timing; hemispheric asymmetry; prefrontal cortex; inferior parietal cortex; basal ganglia; cerebellum; frequency
perception; attention; working memory
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INTRODUCTION |
Current interest in neural systems
underlying timing processes emanates from studies of Parkinson's
disease or cerebellar damage in which motor timing abnormalities have
been reported (Ivry et al., 1988 ; O'Boyle et al., 1996; Harrington et
al., 1998), consistent with the traditional view of the basal ganglia
and cerebellum as motor systems. However, patient, animal, and
functional imaging studies (Ivry et al., 1988; Jueptner et al., 1995;
Meck, 1996; Harrington et al., 1998) also implicate both systems in perceptual timekeeping processes. The focus on the basal ganglia and
cerebellum contrasts with the limited attention paid to the role of the
cerebral hemispheres, although both systems have multiple cortical
connections that could play a direct role in time-dependent computations or an indirect role in nontemporal operations, such as
attention and working memory, which support timing (Gibbon et al.,
1984; Meck, 1984).
The present study investigated the role of the cerebral hemispheres in
time perception by studying individuals with focal left (LHD) or right
(RHD) hemisphere cortical lesions. A duration perception task measured
perceptual timing acuity, and a frequency perception task controlled
for impairments in processes common to both paradigms, to better
separate deficits specific to timing. Although frontal cortex damage
disrupts time discrimination in rats (Olton, 1989; Meck, 1996), the
findings in humans are discrepant (Ivry and Keele, 1989; Lacruz et al.,
1992; Nichelli et al., 1995) and have not delineated specific neural
networks that could advance explanations of the cognitive processes
underlying time perception. We hypothesized that cortical systems with
reciprocal pathways to the basal ganglia [e.g., supplementary motor
area (SMA), frontal eye fields (FEF), and dorsolateral prefrontal
(DLPF) cortex] (Alexander et al., 1986) would be candidates for
supporting time perception, given the role of the striatum in interval
timing. Similarly, the cerebellar dentate nucleus, which also has been
implicated in timing, projects to the DLPF and premotor cortex (Strick
et al., 1993; Middleton and Strick, 1994). Some of these cortical sites
may directly mediate interval timing (SMA) (Rao et al., 1997) or
support timing because of their putative role in working memory (DLPF)
and attention (Posner and Dehaene, 1994). The role of other cortical
areas has not been studied, but the inferior parietal cortex might
mediate time perception because it has strong, bilateral projections to
the putamen and caudate nucleus in monkeys (Cavada and Goldman-Rakic,
1991) and is typically damaged in patients with limb apraxia who show
disruptions in timing gestures (Poizner et al., 1995).
We also investigated whether there were hemispheric asymmetries in time
perception. One study using positron emission tomography (PET) did not
uncover a hemispheric bias for interval discriminations (Jueptner et
al., 1995), whereas another PET study found a right hemispheric bias
for interval, but also illumination intensity discriminations (Maquet
et al., 1996), possibly attributable to the emphasis on sustained
attention and working memory. Therefore, we correlated an independent
measure of switching attention with duration perception performance to
determine the relationship of attention and time perception in patients
with focal left or right hemisphere lesions.
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MATERIALS AND METHODS |
Subjects
Table 1 describes the four subject
groups. All subjects were right-handed, and t tests showed
that there were no significant differences among the patient groups and
their respective control groups in age, education, or gender. The
etiology of hemispheric damage was stroke, and patients were tested a
minimum of 3 months after onset. A Mann-Whitney U test
showed that the mean number of years after stroke did not differ
significantly between the LHD group (mean = 3.8; SD = 4.3)
and the RHD group (mean = 4.1; SD = 3.9). Lesion location was
assessed using magnetic resonance imaging (MRI) or computed tomography
(CT), which was conducted at least 3 months after onset. All lesions
were confined to one hemisphere and did not extend into the cerebellum
or brain stem. The right control and right hemisphere damaged (RHD)
stroke groups performed all tasks using their right hand, and the left
control and left hemisphere damaged (LHD) groups performed the tasks
using their left hand.
All subjects were administered a battery of neuropsychological tests to
document their language, visuospatial, motor, and somatosensory skills.
The Western Aphasia Battery (WAB) (Kertesz, 1982) was used to evaluate
the main clinical features of language function, including spontaneous
speech, auditory comprehension, and repetition. Spontaneous speech
(e.g., response to examiner questions, describing a picture) is
evaluated in terms of information content and fluency. Auditory
comprehension assesses the ability to follow one-, two-, and three-step
commands. Repetition assesses the ability to repeat high- and
low-probability words, phrases, or sentences of increasing difficulty
and has been used clinically to identify patients with conduction
aphasia. These three measures are used to derive an aphasia quotient
that reflects aphasia severity. Table 2
shows that, as anticipated, the LHD group was significantly impaired on
all measures of language function, whereas the RHD group was only
mildly impaired on the repetition test and had a slightly lower aphasia
quotient. Pearson correlations (one-tailed significance tests) showed
that severity of aphasia was not related to performance on the
experimental tasks. Visuospatial function was assessed using the Block
Design subtest from the Wechsler Adult Intelligence Scale-Revised
(WAIS-R) (Wechsler, 1981), which assesses the ability to construct
designs of increasing complexity using blocks that are colored red on
two sides, white on two sides, and red and white on the remaining two
sides. Both the RHD and the LHD groups were impaired on this test. Grip
strength, which is assessed using a hand dynamometer, was normal in
both stroke groups in the hand ipsilateral to the lesioned hemisphere
and impaired in the contralateral hand. The contralateral hand was hemiplegic in five RHD patients and was hemiparetic in four LHD patients. Somatosensory function (two-point discrimination) was evaluated using a two-point aesthesiometer, which has a single point on
one end and two points on the other end that can be adjusted to various
widths. A screen conceals the subject's hand, the examiner touches the
tip of the subject's index finger with either one or two points, and
the subject indicates whether one or two points were felt. The smallest
distance between the two points at which the subject made no more than
one error is scored. Somatosensory deficits were found in the
contralateral hand of both stroke groups, and the LHD group also showed
some mild somatosensory impairments in the ipsilateral hand. Visual
fields testing used the double simultaneous visual fields test and the
gross confrontation procedure (Lezak, 1995). Two RHD patients showed
contralateral visual field cuts, and two other patients showed neglect.
Visual fields were normal in all LHD patients, and none showed
neglect.
Procedures
Duration perception task. Subjects completed two
duration perception tasks in which they judged the relative duration of
two tone pairs. Tones were 75 dB and 50 msec in duration. A standard tone pair was presented and followed 1 sec later by a comparison tone
pair. Subjects indicated by pressing a key whether the interval between
the comparison tone pair was longer or shorter than the standard. In
one condition the interval between the two tones in the standard pair
was always 300 msec, and in the other condition it was 600 msec. There
were 30 possible longer and 30 possible shorter intervals that varied
in step sizes of 6 msec. The presentation order of the target intervals
was counterbalanced across subjects.
The Parameter Estimation by Sequential Testing (PEST) procedure was
used to derive a criterion threshold (Pentland, 1980; Lieberman and
Pentland, 1982). The PEST procedure is similar to staircase procedures
used in psychophysical experiments and has been shown to be a reliable
shortcut for assessing thresholds. The PEST procedure operates by
producing a maximum-likelihood estimate of the independent variable
that will result in the maximum amount of information about the
position of the threshold on each trial, based on all previous
responses (Lieberman and Pentland, 1982). The procedure establishes a
probability array based on a normal sigmoid-shaped psychophysical
function and then uses this to determine the next best current estimate
of a subject's upper (i.e., longer than the standard duration) or
lower (i.e., shorter than the standard duration) threshold point. This
is done for each trail, so that the selection of a stimulus value for a
particular trial represents the highest probability, given all previous
responses. Thus, a revised estimate of a subject's threshold point is
made after each response. The test threshold was set to equal 1 SD from
the point of subjective equality (PSE), which is the interval at which
subjects are equally likely to respond shorter or longer. The PEST
procedure does not produce data that can be averaged across individuals
within a group to systematically evaluate the relationship between
values of an independent variable (e.g., duration) and the probability
of classifying it as longer or shorter than the standard because each
subject receives a different subset of stimuli, and the number of
trials for a particular stimulus value also differs across subjects,
depending on their response distribution.
Ten practice trials were presented and followed by 50 experimental
trials consisting of 25 judgments each for the upper and lower
thresholds. A difference threshold was computed by taking the
difference between the upper and the lower duration thresholds and
dividing this value by 2.
Frequency perception task. A frequency perception task was
included as a control for the general auditory processing requirements of the duration perception task. Subjects judged the relative pitch of
two tone pairs, which were 75 dB and 50 msec in duration. The interval
between the two tones in the standard and comparison pairs was fixed at
550 msec, and the two tone pairs were separated by a 1 sec interval.
The frequency of the standard tones was 1000 Hz, and the comparison
tones consisted of higher or lower frequencies. Subjects indicated by
pressing a key whether the pitch of the comparison tone pair was higher
or lower than the standard pair. There were 30 possible higher and 30 lower frequencies that varied in step sizes of 1 Hz. Ten practice
trials were followed by 50 experimental trials, which consisted of 25 judgments each for the upper and lower thresholds. The PEST procedure
was used to derive a criterion threshold. As for the duration
perception data, a difference threshold was calculated by taking the
difference between the upper and lower frequency thresholds and
dividing this value by 2.
Attention task. A nonspatial attention task was used to
measure the subject's ability to disengage attention. Subjects made an
index or middle finger key press in response to a stimulus, which was a
circle or a triangle. The stimulus was preceded by either a neutral cue
(a cross), a valid cue (circle or triangle), or an invalid cue. At the
beginning of each trial, a 50 msec warning tone sounded, followed by
the cue, which appeared at the center of the monitor. After a random
delay of 200, 350, or 500 msec, the response stimulus appeared at the
center of the monitor, just below the cue, and subjects were instructed
to make a key press as quickly and accurately as possible. The
intertrial interval was 1 sec. Reaction time (RT) was measured from the
onset of the response stimulus to the completion of the key press. Two
blocks of experimental trials were given, each containing a random
presentation of 63 neutral cue trials (21 trials at each delay), 78 valid cue trials (26 at each delay), and 21 invalid cue trials (7 at
each delay). The experimental trials were preceded by 18 practice
trials. A measure of cost, which reflects disengagement of attention
(Posner et al., 1984), was calculated by subtracting the valid from the invalid RTs for a particular condition.
Lesion reconstruction. Computer reconstructions of lesion
size and location were derived from MRI scans in the majority of subjects. MRI scans were performed using a Siemens or a Picker 1.5 Tesla scanner, with a slice thickness of 5 mm. Reconstructions based on
CT scans (5 mm slice thickness) were performed in three LHD and four
RHD patients, who for medical reasons could not undergo an MRI scan
(e.g., pacemaker). All scans were obtained at least 3 months after
onset. Lesions were transcribed onto corresponding axial templates
derived from the atlas of DeArmond et al. (1989), using procedures
developed at the Veterans Affairs Medical Center (Martinez, CA) (Knight
et al., 1988; Singh and Knight, 1993). The software allowed for
reconstruction of the lesion volume, projections of the lesion onto the
lateral surface of the brain, and averaging of group lesions by
superimposing subjects' lesions on each horizontal slice. Figures
1 and 2 show the axial reconstructions for each subject in the LHD and RHD groups. A t test showed
that there was not a significant difference in lesion size between the
LHD group (mean = 35.7 cc; SD = 21.5; range, 13.3-89.9 cc) and the RHD group (mean = 39.3 cc; SD = 25.4; range,
7.1-102.2 cc). In some analyses, subjects were also separated into
those with primarily anterior damage or those with posterior damage (Figs. 1, 2). The anterior group included
patients whose lesions were mainly anterior to the central sulcus, but
also could involve damage to the sensorimotor cortex or temporal lobes,
and in three subjects (Fig. 1, cases 3 and 4;
Fig. 2, case 4), a lesion that extended slightly into
the supramarginal gyrus (SMG). The posterior group consisted of
patients whose lesions were mainly posterior to the central sulcus, but
also could involve damage to the primary motor cortex or temporal
lobes, and one subject had a small lesion in the prefrontal cortex
(Fig. 1, case 11). Figures 1 and 2 show that there were nine
RHD and six LHD patients in the anterior groups, and 10 RHD and 12 LHD
patients in the posterior groups. A t test showed that there
was no difference in lesion volume between the LHD (mean = 34.8 cc; SD = 21.2) and RHD (mean = 39.0 cc; SD = 34.3)
groups with anterior lesions. Similarly, lesion volume did not differ
significantly between the LHD (mean = 36.6 cc; SD = 22.9) and
RHD (mean = 39.4 cc; SD = 21.4) groups with posterior
lesions.
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Figure 1.
Axial sections showing the location of lesions in
19 individuals with left hemisphere damage. Case numbers are displayed
beneath each series of sections and are ordered according to whether
lesions were largely anterior or posterior to the central sulcus. The letter a refers to individuals with impaired frequency
perception, and the letter b refers to individuals with
impaired duration perception.
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Figure 2.
Axial sections showing the location of lesions in
18 individuals with right hemisphere damage. Case numbers are displayed beneath each series of sections and are ordered according to whether lesions were largely anterior or posterior to the central sulcus. The
letter a next to the case number refers to individuals
with impaired frequency perception, and the letter b
refers to individuals with impaired duration perception.
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RESULTS |
Frequency perception
The frequency perception data were analyzed using ANOVA, which
tested the between-subject effects of group (control, stroke) and hand
(left, right) and their interaction. The PSE data were first analyzed,
and the results showed that there were no significant effects of group,
indicating that the response criterion was similar across all groups.
However, frequency perception (difference threshold) was impaired in
the LHD (mean = 13.7; SD = 9.0) and the RHD groups (mean = 10.7; SD = 5.3) relative to the controls (mean = 8.3; SD = 6.5 for all control subjects)
[F(1,81) = 6.23; p < 0.025]. No other effects were significant. The results indicated that some
aspect of auditory processing (e.g., discrimination processes, sensory
processing, temporal ordering of stimulus events, pitch perception) was
deficient in both stroke groups. This raised the possibility that
deficits in duration perception might be attributable to more primary
problems in processing sequential auditory stimuli, because of the
similarity between the frequency and duration perception tasks in the
sequence of trial events. Therefore, analyses of the duration
perception data were conducted first by analyzing all subjects' data
and then by analyzing the data of only those whose performance was
within normal limits on the frequency perception task (i.e., within 1 SD of the control group). The latter procedure excluded four right
controls, three left controls, three RHD patients, and eight LHD
patients.
Figures 1 and 2 depict the lesions of all stroke patients, including
those with frequency perception deficits. The incidence of frequency
perception deficits was low for patients with left or right hemisphere
posterior lesions (i.e., two patients in each stroke groups) or with
right hemisphere anterior lesions (i.e., one patient). This contrasted
with the high incidence of frequency perception deficits associated
with left hemisphere anterior lesions (i.e., six patients), which could
not be explained by any particular lesion focus (Fig. 1) (see below) or
subject characteristic (e.g., age, neuropsychological test
performance). Additionally, temporal lobe lesions were not associated
with frequency perception deficits, which was consistent with a study
of patients with temporal lobe excisions (Zatorre and Samson, 1991) but
contrasts with functional imaging work showing activation of the left
and right superior temporal lobes during pitch discriminations of
linguistic or nonlinguistic stimuli (Zatorre et al., 1996; Rao et al.,
1997). Bilateral hemispheric activation of the middle and inferior
frontal gyri have also been associated with pitch discrimination,
putatively because of the role of short-term memory in linguistic
processing (Zatorre et al., 1994, 1996). Our frequency perception task
appears to have short-term memory requirements similar to those in the
latter studies, yet few patients with RHD showed pitch discrimination deficits. Rather, deficits were most associated with LHD to the frontal
cortex, which raises the possibility that our findings, and perhaps
those of others (Zatorre et al., 1994, 1996), may reflect left
hemispheric specialization for other processes ostensibly involved in
frequency discrimination, such as serial ordering (Von Steinbuchel,
1995).
Duration perception
The duration perception data were analyzed using a mixed-model
ANOVA with repeated measures, wherein the between-subject factors were
group and hand and the within-subject factors were target interval (300 msec, 600 msec) and order (testing order of the 300 and 600 msec
conditions). The PSE data were first analyzed, and no significant
effects of group or interactions with group were obtained. Figure
3a displays the duration
thresholds for all subjects on the duration perception task. The figure
shows that judgments of duration were less accurate when the interval between the standard tone pair was 600 msec than when it was 300 msec
[F(1,77) = 58.72; p < 0.0001]. Most importantly, judgments of duration were less accurate in
both stroke groups, especially in the RHD stroke group. This
observation was confirmed by the significant effects of group
[F(1,77) = 25.95; p < 0.001]
and the group × hand interaction [F(1,77) = 4.49; p < 0.05]. Simple effects analyses showed that
duration perception was significantly impaired in the RHD group
relative to their control group [F(1,38) = 28.70; p < 0.001], whereas there was only a trend for
difference thresholds to be elevated in the LHD group in comparison to
their controls [F(1,39) =4.05;
p = 0.051]. There was also a significant main effect
of order [F(1,77) = 4.76; p < 0.05], indicating that for all subjects duration perception was more
accurate when the 600 msec interval was tested first (mean = 39.9, SD = 30.6 for the 300 msec interval; mean = 69.2, SD = 33.7 for the 600 msec interval) than when the 300 msec interval was
tested first (mean = 54.56, SD = 35.6 for the 300 msec
interval; mean = 79.1, SD = 42.4 for the 600 msec interval).
No other significant effects were obtained.
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Figure 3.
Mean (SE) difference thresholds for the 300 msec
(black bars) and 600 msec (white bars)
conditions of the duration perception task. The top graph
(a) displays the data from all subjects, and the
bottom graph (b) includes data only from subjects
who performed within normal limits on the frequency perception
task.
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Next, the same analyses were conducted on the duration threshold data
after excluding subjects with difference thresholds on the frequency
perception task that were >1 SD of the control group mean (i.e.,
>15). These data are displayed in Figure 3b, which suggests
that judgments of duration were impaired only in the RHD group. This
observation was supported by the group × hand interaction
[F(1,59) = 12.61; p < 0.002],
in which difference thresholds were elevated in the RHD group in
comparison to their controls [F(1,31) = 18.14;
p < 0.001], but there was no difference between the
LHD group and their controls [F(1,28) < 1.0].
There was also an interaction of group × hand × order
[F(1,59) = 4.94; p < 0.05],
which was attributable to an order effect only in the RHD group. In
this group, duration thresholds were more accurate, albeit still
impaired, when patients performed the 600 msec condition first. As for
the previous analyses, duration thresholds were more accurate for the
300 than the 600 msec target interval [F(1,59) = 41.38; p < 0.0001]. No other significant effects
were found.
Although these results were similar to those obtained in the analyses
of all subjects, the analyses of the PSE data showed an interaction of
group × target interval [F(1,59) = 6.58;
p < 0.025], wherein the PSE was lower in the stroke
(mean = 313.0, SD = 25.6; mean = 589.9, SD = 43.7)
than in the control groups (mean = 309.5, SD = 38.3;
mean = 612.1, SD = 46.6), but only for the 600 msec target
interval. This effect was attributable to an asymmetry in the upper and
lower thresholds of the RHD group for the 600 msec target interval.
Specifically, the upper threshold (mean = 625) of the LHD group
was more accurate than that of the control group (mean = 672) or
the RHD group (mean = 706), whereas both stroke groups showed a
more accurate lower threshold (mean = 508) than the controls
(mean = 553). Consequently, the difference threshold data were
also analyzed by controlling for PSE (i.e., the difference threshold
was divided by the PSE and then multiplied by 100), and the analysis
produced similar findings. There was an interaction of group × hand [F(1,59) = 8.54; p < 0.01] wherein no difference in duration perception was found between
the LHD group (mean = 11, SD = 2, and mean = 10, SD = 2, for the 300 and 600 msec intervals, respectively) and their
controls (mean = 11, SD = 1, and mean = 10, SD = 1, for the 300 and 600 msec intervals, respectively), but the RHD group
(mean = 20, SD = 4, and mean = 17, SD = 2, for the
300 and 600 msec intervals, respectively) was impaired relative to
their controls (mean = 11, SD = 1, and mean = 10, SD = 1, for the 300 and 600 msec intervals, respectively) [F(1,31) = 13.09; p < 0.01].
We also conducted similar analyses, normalizing the data by dividing
the difference threshold by the standard interval to determine whether
accuracy was scalar across the two intervals (Gibbon et al., 1997). The
results from these analyses were similar to the ones above, showing an
interaction of group × hand [F(1,59) = 10.53; p < 0.01], such that in proportion to the
standard interval the RHD group still was less accurate (mean = 0.21, SD = 0.14, and mean = 0.17, SD = 0.06, for the 300 and 600 msec intervals, respectively) than their controls (mean = 0.11, SD = 0.07, and mean = 0.10, SD = 0.05, for the 300 and 600 msec intervals, respectively) [F(1,33) = 14.16; p < 0.01], but there were no differences
between the LHD group (mean = 0.12, SD = 0.06, and mean = 0.09, SD = 0.05, for the 300 and 600 msec intervals,
respectively) and their controls (mean = 0.12, SD = 0.06, and
mean = 0.09, SD = 0.05, for the 300 and 600 msec intervals,
respectively). However, the main effect of interval was significant
[F(1,59) = 5.22; p < 0.05],
showing that timing accuracy was nonscalar in all subjects. Most
importantly, the interaction of group × interval was not
significant, indicating that although accuracy was lower in proportion
to the standard interval in the RHD group, timing efficiency remained
the same across the two intervals.
Finally, we compared the two stroke groups to determine whether
duration thresholds differed in patients with anterior or posterior
lesions. Only patients with normal frequency thresholds were included
in the analyses, which were similar to the previous ones except that
the between-subject factors were stroke group (RHD, LHD) and lesion
location (anterior, posterior). The order effect was not tested because
of the limited cell size. Although duration thresholds were higher in
the RHD than in the LHD group [F(1,22) = 8.72;
p < 0.01] (Fig. 3b), thresholds did not
differ between patients with anterior (mean = 63.6, SD = 34.6, and mean = 93.0, SD = 33.2, for the 300 and 600 msec
intervals in the RHD group; mean = 30.0, SD = 16.7, and
mean = 42.0, SD = 13.7, for the 300 and 600 msec intervals in
the LHD group) or posterior lesions (mean = 62.7, SD = 46.7, and mean = 105.9, SD = 37.5, for the 300 and 600 msec
intervals in the RHD group; mean = 36.8, SD = 18.2, and
mean = 60.8, SD = 36.7, for the 300 and 600 msec intervals in
the LHD group), nor were there interactions of lesion location with
stroke group or interval.
Attention
The dependent measure, cost, was analyzed using a mixed-model
ANOVA with repeated measures, in which the between-subject factors were
group and hand and the within-subject factor was stimulus onset
asynchrony (SOA) (200, 350, and 500 msec). Only the tests involving the
group and hand factors are reported, because they were of main
interest. All subjects were included in the analyses to have sufficient
sample sizes for subsequent correlations with the main experimental
measures. There was a main effect of hand [F(1,80) = 6.69; p < 0.025)
showing that cost was greater for subjects performing with their left
than their right hand. Most importantly, both stroke groups showed
greater cost (mean = 122.6, SD = 52.8 for the RHD group;
mean = 284.6, SD = 352.1 for the LHD group) than the control
groups (mean = 92.5, SD = 30.7 for the right controls;
mean = 119.5, SD = 42.4 for the left controls). There were no
significant interactions of group, hand, or SOA. The results indicate
that both stroke groups showed similar deficits in disengaging
nonspatial attention. Moreover, a separate ANOVA focusing on the effect
of lesion location revealed no difference in cost between stroke
patients with anterior or posterior lesions, nor did lesion location
interact with stroke group.
Correlations among tasks
Pearson correlations (one-tailed significance tests) were
conducted to examine the interrelationships among the experimental tasks in all stroke patients, regardless of frequency perception performance. Duration perception was positively correlated with frequency perception, but the relationship was stronger for the LHD
group (r = 0.77; p < 0.001) than the
RHD group (r = 0.41; p < 0.05). This
suggests that the LHD group may have had greater deficits in
time-independent processes common to both tasks than the RHD group.
This speculation was also supported by the greater incidence of
frequency perception deficits in the LHD group (see above). Cost was
not related to frequency perception in either stroke group
(r = 0.16), whereas it was positively correlated with
duration perception, but only in the RHD group (r = 0.43; p < 0.05). These results suggest that the
attention demands of frequency perception were not as great or perhaps
different from those for duration perception, despite the similarity of
the paradigms. Additionally, competency in switching attention was
associated with perceptual timing processes only in the RHD group,
consistent with their greater incidence of timing deficits, which could
not be attributed to nontemporal processes shared with frequency
perception.
Analyses of lesion reconstruction data
Patients' lesions were next averaged by superimposing them on
each horizontal slice to determine whether there were regions within
the right hemisphere essential for duration perception. Patients were
separated into those with and those without duration perception
deficits (i.e., >1 SD above the control group mean at either or both
target intervals), and then averages were constructed for subjects with
lesions that were predominantly anterior or posterior to the central
sulcus. Lesion averages were constructed using only subjects with
normal frequency perception. Brodmann areas (BAs) corresponding to the
regions of 100% overlap were determined using the sulci landmarks from
the templates (DeArmond et al., 1989) and the projections of the lesion
overlays onto the lateral surface of the brain (Frey et al., 1987;
Knight et al., 1988).
Figure 4 contrasts the averages for
patients with anterior (Fig. 4a,b) or posterior lesions
(Fig. 4c,d) in the left and right hemispheres. Figure
4a shows that for the three patients with anterior RHD and
impaired duration perception, the one common area of infarction, in
which there was 100% lesion overlap (i.e., yellow), was the
lateral premotor area, including the FEF (BA 6; Section 9 and Section 10) and the middle and superior gyri of the DLPF
area (BA 9 and 46 on Section 9 and BA 8 on Section 9 and Section 10) (Rajkowska and Goldman-Rakic,
1995a,b). By comparison, Figure 4b shows that only two RHD
patients with anterior damage showed normal duration perception and the
location of their lesions was different. One of these patients (i.e.,
blue) had a lesion in the SMA (patient 1; Section
10 of Fig. 4b), and the other (patient 2) had damage to
the motor and caudal portion of the premotor cortex on Section 9 (Fig.
4b), as well as somatosensory cortex (Section 8).
Figure 4a,b also illustrates the hemispheric asymmetry in
duration perception for patients with anterior lesions. None of our LHD
patients with anterior lesions showed impaired duration perception
(Fig. 4a), and all three of the LHD patients with normal duration perception (Fig. 4b) had lesions in the same areas
as those that were associated with impaired duration perception in the
RHD group.
View larger version (52K):
[in this window]
[in a new window]
|
Figure 4.
Lesion overlap in individuals with damage
primarily anterior or posterior to the central sulcus. Axial sections
show overlap for left hemisphere (on the left of each
section) and right hemisphere (on the right of each
section) lesions in individuals with intact frequency perception. The
lines on the lateral view show the location of the
corresponding axial sections. The color scale indicates the percentage of patients within a particular group with damage in an
area. a, Overlapping lesions in patients with anterior
lesions and impaired performance on the duration
perception task. Only three patients with RHD were impaired on this
task, and the common areas of infarction (yellow)
were found on Section 9 (top row) and
Section 10 (bottom row). No individuals
with LHD were impaired on duration perception. b,
Overlapping lesions in patients with anterior lesions and normal
performance on the duration perception task. A region on
Section 9 shows 100% overlap in the three patients with
LHD. There were no common areas of infarction in the two RHD patients
(i.e., blue indicates a lesion from one patient). c, Overlapping lesions in patients with posterior
lesions and impaired performance on the duration
perception task. Seven patients with RHD were impaired on this task,
and the common area of infarction (yellow) was
found on Section 9 (top row). Only two
LHD patients were impaired on this task, and the common area of
infarction is seen on Section 8 (bottom
row). d, Overlapping lesions in patients with
posterior lesions and normal performance on the duration perception task. Section 9 shows 100% overlap in six
patients with LHD. There were no common areas of infarction in the
three RHD patients (i.e., green and red
signify lesions from one and two patients, respectively).
|
|
Recall, however, that six LHD patients with abnormal frequency
perception, five of whom also had abnormal duration thresholds (Fig.
1), were excluded from the analyses. To determine whether this
exclusion criterion biased the hemispheric findings, we constructed overlays of the LHD patients with anterior lesions who had both frequency and time perception deficits. The overlays showed that the
maximum percentage lesion overlap (66%) was in BA 9 of Section 9 and
in motor cortex of Section 10. By comparison, 100% of the LHD patients
with anterior lesions who showed normal frequency and time perception
also had damage to BA 9 on Section 9 (Fig. 4b). These
results indicate that, unlike time perception deficits after RHD,
frequency or time perception deficits after LHD were not strongly
associated with damage to a particular neuroanatomical region, although
there was clearly a left hemisphere asymmetry for pitch perception
processing. Nevertheless, it is still possible that time
discriminations are dependent on unspecified left hemisphere-dependent processes that are also common to frequency perception, because more
than half of our subjects with anterior LHD showed deficits on both
types of discriminations.
Figure 4c shows that the area of 100% lesion overlap in the
seven RHD patients with abnormal duration perception performance and
posterior damage involved the supramarginal gyrus (SMG; BA 40) on
Section 9 and rostral portions of the angular gyrus. In contrast,
Figure 4d shows that only three posterior RHD patients had
normal duration perception. The lesion of one patient (8) was occipital
and is not shown on these sections. The lesion of the other two (7 and
9) involved damage to BA 40 and 39 (i.e., red), as well as
other parietal regions. Duration perception performance was clearly
within normal limits for both target intervals in patients 7 and 8, whereas the performance of patient 9 was borderline normal in the 600 msec condition (i.e., 81 msec). Hence, damage in the region of the SMG
was associated with duration perception deficits in the large majority
of patients, but there were two exceptions, one of which could be
explained by borderline abnormal performance on this task. Figure
4c,d also illustrates the hemispheric asymmetry in duration
perception for patients with posterior lesions. Only two posterior LHD
patients (16 and 17) showed deficits on this task (Fig. 4c),
and although BA 40 was damaged in both patients, it was more ventral
(yellow area on slice 8). Moreover, 100% of the six
LHD patients who showed normal duration thresholds had damage in the
region of the SMG on slice 9 (Fig. 4d).
| |
DISCUSSION |
Hemispheric asymmetry in timing mechanisms
This is the first study to show directly that the right hemisphere
is essential for timekeeping mechanisms. Despite the similarity between
the stroke groups in lesion loci and size, only RHD was associated with
a disruption in time discriminations, when deficits in frequency
perception were controlled. In contrast, the left hemisphere does not
appear to play a role in these operations, at least in the analysis of
nonlinguistic acoustic stimuli. This is consistent with the finding
that aphasia severity was not correlated with duration perception. Our
lesion analyses of LHD patients with impaired frequency and duration
perception also failed to uncover evidence of a left hemisphere network
underlying timing, although it is still possible that the left
hemisphere supports nontemporal mechanisms used in time and frequency
discriminations that were not identified in this study.
What is the nature of the computations performed by the right
hemisphere? One interpretation is it regulates timekeeping operations. Although the duration perception paradigm did not separate timing from
other processes, the frequency perception paradigm controlled for
deficits in at least some nontemporal processes, so that duration thresholds could reasonably reflect right hemisphere deficits in a
central timekeeper, at least for the intervals studied here. Interestingly, right hemisphere activation of prefrontal and inferior parietal cortex has been found for rhythm discriminations, which have a
time-dependent component (Roland et al., 1981). This interpretation contrasts with animal research that favors the basal ganglia for a
timekeeper or clock (Gibbon et al., 1997). Although these studies use
different paradigms and longer intervals (typically 2 sec or more),
they have been more successful in isolating hypothetical timing
operations than most patient studies have. Still, human studies are
crucial for delineating specific neural networks and hemispheric biases
in timekeeping mechanisms, which the present study uncovered.
Although our study controlled for some extraneous variability in time
perception by partialing out deficits in unspecified processes,
nonspatial attention ability was correlated with duration thresholds
only in patients with RHD, suggesting another interpretation of the
results. Specifically, judgments of duration may engage attentional
operations that are asymmetrically represented in the cerebral cortex.
This proposal is consistent with the role of attention in interval
timing (Gibbon et al., 1997), although there have been few studies of
its neurobiology. Attention may also be required to operate a
timekeeper or clock, such that the clock is not continually activated
when attention is disrupted (Macar et al., 1994). Importantly, despite
attention deficits in both stroke groups, attention was not correlated
with frequency perception, suggesting that attentional abnormalities
were specific to time-dependent discriminations. This possibility
extends the prevailing view of the right hemisphere as biased for
switching and sustaining spatial attention (Knight et al., 1981; Posner et al., 1984; Heilman et al., 1985; Pardo et al., 1991; Corbetta et
al., 1993; Smith et al., 1996) to include the domain of time perception.
The prospect that the right hemisphere supports time-dependent
attentional mechanisms is compatible with findings in RHD individuals with and without neglect (Husain et al., 1997). Subjects were presented
a rapid, serial sequence of letters, and identified one (control task)
or two target letters (dual task) that varied in their temporal
proximity to one another. The dual task required shifts in nonspatial
attention between the two targets, and in healthy individuals
identification of a second target is impaired, relative to the control
task, if it appears within 400 msec of the first target. This
phenomenon is called the "attentional blink" and was increased (to
1440 msec) only in RHD patients with unilateral neglect. This
prolongation was not attributable to a disruption in sustaining
attention, because these same individuals showed normal performance on
the control task. Although hemispheric asymmetries and perceptual
acuity for time were not assessed directly, the findings of this study,
together with ours, raise the intriguing possibility that deficits in
attentional shifts after RHD have a significant temporal component.
Intrahemispheric networks in timing
Evidence for intrahemispheric specialization of timing was also
found that implicated the inferior parietal lobe and areas of the
prefrontal cortex, including the FEF (BA 6) and DLPF cortex (BA 8, 9, and 46). Few RHD patients with normal duration perception had damage to
these regions, and lesions in the same regions in LHD patients were
associated with normal timing. The results imply a role for anterior
and posterior regions of the right hemisphere in temporal computations,
which is compatible with the reciprocal connections between the
inferior parietal cortex and corresponding frontal cortical areas in
monkeys (Selemon and Goldman-Rakic, 1988).
Prefrontal cortex
Most investigations of frontal cortical mechanisms in timing have
been conducted in animals and suggest that the frontal cortex supports
working memory, which underlies timing (Gibbon et al., 1997).
Therefore, our findings associating time perception competency with the
prefrontal cortex could reflect the roles of one or more of these areas
in sustaining on-line representations of a standard interval for
comparison with an immediately after-target interval, a working memory
function. Duration perception deficits were associated with damage in
the middle and superior frontal gyri [some investigators designate
these areas 9 and 46 (Goldman-Rakic, 1987; Rajkowska and Goldman-Rakic,
1995b)], which are critical for working memory. These areas and the
FEF have direct access to an internal clock, assuming that the basal
ganglia regulate a timekeeper (Gibbon et al., 1997; Harrington et al.,
1998), through reciprocal connections with the caudate nucleus
(Alexander et al., 1986). However, different frontal areas have been
associated with working memory (Pardo et al., 1991; Paulesu et al.,
1993), and cytoarchitectonic maps of some areas (9 and 46) vary
considerably (Rajkowska and Goldman-Rakic, 1995a).
Our findings contrast with a PET study that reported right inferior
frontal gyrus (BA 45) activation for duration and intensity discriminations (Maquet et al., 1996). However, in both tasks subjects
had to remember a standard interval or illumination intensity for
several minutes to compare with target intervals during imaging trials.
In our task, the standard interval was presented on every trial,
placing minimal demands on retrieval or rehearsal processes. Hence, our
results are more compatible with a working memory interpretation of
prefrontal cortex function, although it is possible that one or more of
these areas might also support a central timekeeper.
We reported previously that the right inferior frontal gyrus (BA 44)
was activated in a motor timing task wherein a retained interval (300 or 600 msec) was reproduced continuously over an 18 sec trial (Rao et
al., 1997). This region appears to form a network involving the
superior temporal gyrus that is important for the retrieval and
rehearsal of nonlinguistic auditory images (Zatorre et al., 1996). In
the present study, damage to the inferior frontal gyrus was not
associated with time perception deficits, possibly because maintenance
of a standard interval was necessary for only a brief period (1 sec).
We also previously attributed activation of the basal ganglia-SMA
circuit to a timekeeper for movement (Rao et al., 1997). In the present
study, the one patient with a right hemisphere SMA lesion showed normal
duration perception, which may imply that different neural systems
support motor and perceptual timekeepers, although additional case
studies are clearly needed.
Parietal cortex
Our findings extend spatial attention theory (Posner and Dehaene,
1994) by suggesting that the parietal cortex is essential for covert
shifts of attention to temporal stimuli. Although impairments in
disengaging nonspatial attention were comparable between patients with
frontal and posterior lesions, attention is intricately linked to
working memory functions, possibly because of frontal-parietal interconnections (Selemon and Goldman-Rakic, 1988). Interestingly, neglect patients who showed prolonged attentional blink frequently had
right inferior parietal lesions (Husain et al., 1997), consistent with
the prospect that temporal aspects of stimuli are processed in this
area. Most importantly, the inferior parietal cortex has an avenue for
transmitting processing to a timekeeper through its bilateral
projections to the basal ganglia (Cavada and Goldman-Rakic, 1991). We
should mention that speculations of a time-specific mechanism supported
by the parietal cortex is inconsistent with the previously described
PET study (Maquet et al., 1996), in which duration and illumination
intensity discriminations both activated right inferior parietal cortex
(BA 40). Again, this study requires further verification using
paradigms that more clearly distinguish temporal from nontemporal
processes.
Concluding remarks
The present results extend existing knowledge of right hemisphere
function, designating an essential role in supporting time-dependent discriminations within specific areas of frontal and parietal cortex.
One intriguing speculation is that right hemisphere specialization for
timing might underlie the visuospatial functions of this hemisphere, because the ability to time switches between multiple sensory streams
could be crucial for the selection or binding of spatial features
(Husain et al., 1997). In contrast, attention to time-related information such as speed activates the left inferior parietal cortex
(Corbetta et al., 1991). This may illustrate the analog of the
time-dependent perceptual processes of the right hemisphere, reflecting
the dominance of the left hemisphere for the representation of movement
(Haaland and Harrington, 1996). In fact, damage to the left inferior
parietal cortex is commonly associated with limb apraxia, a disruption
in the spatiotemporal patterning of movements (Poizner et al., 1995;
Harrington and Haaland, 1997).
| |
FOOTNOTES |
Received Aug. 1, 1997; revised Nov. 17, 1997; accepted Nov. 18, 1997.
This research was funded by a grant from the Medical Merit Review,
Department of Veterans Affairs, to D.L.H. and K.Y.H., and National
Institute of Neurological Disorders and Stroke Grants NS21135 and PO
NS17778 to R.T.K. We thank Laura Anderson, Gabrielle Mallory, Lee
Stapp, and Nina Dronkers for technical assistance, and the Department
of Radiology at the Albuquerque Veterans Affairs Medical Center for
their support in providing magnetic resonance imaging and computed
tomography scans.
Correspondence should be addressed to Dr. Deborah L. Harrington,
Psychology Service 116B, Veterans Affairs Medical Center, 1501 San
Pedro SE, Albuquerque, NM 87108.
| |
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Top
Abstract
Introduction
