Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520
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ABSTRACT |
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Chafee, Matthew V. and Patricia S. Goldman-Rakic. Inactivation of Parietal and Prefrontal Cortex Reveals Interdependence of Neural Activity During Memory-Guided Saccades. J. Neurophysiol. 83: 1550-1566, 2000. Dorsolateral prefrontal and posterior parietal cortex share reciprocal projections. They also share nearly identical patterns of neuronal activation during performance of memory-guided saccades. To test the hypothesis that the reciprocal projections between parietal and prefrontal neurons may entrain their parallel activation, the present experiments have combined cortical cooling in one cortical area with single-unit recording in the other to more precisely determine the physiological interactions between the two during working memory performance. The activity of 105 cortical neurons during the performance of an oculomotor delayed response (ODR) task (43 parietal neurons during prefrontal cooling, 62 prefrontal neurons during parietal cooling) was compared across two blocks of trials collected while the distant cortical area either was maintained at normal body temperature or cooled. The mean firing rates of 71% of the prefrontal neurons during ODR performance changed significantly when parietal cortex was cooled. Prefrontal neurons the activity of which was modulated during the cue, delay, or saccade periods of the task were equally vulnerable to parietal inactivation. Further, both lower and higher firing rates relative to the precool period were seen with comparable frequency. Similar results were obtained from the converse experiment, in which the mean firing rates of 76% of the parietal neurons were significantly different while prefrontal cortex was cooled, specifically in those task epochs when the activity of each neuron was modulated during ODR performance. These effects again were seen equally in all epochs of the ODR task in the form of augmented or suppressed activity. Significant effects on the latency of neuronal activation during cue and saccade periods of the task were absent irrespective of the area cooled. Cooling was associated in some cases with a shift in the best direction of Gaussian tuning functions fit to neuronal activity, and these shifts were on average larger during parietal than prefrontal cooling. In view of the parallel between the similarity in activity patterns previously reported and the largely symmetrical cooling effects presently obtained, the data suggest that prefrontal and parietal neurons achieve matched activation during ODR performance through a symmetrical exchange of neuronal signals between them; in both cortical areas, neurons activated during the cue, delay, and also saccade epochs of the ODR task participate in reciprocal neurotransmission; and the output of each cortical area produces a mixture of excitatory and inhibitory drives within its target.
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INTRODUCTION |
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Our recent interest (Chafee and Goldman-Rakic 1998)
has been a comparison of patterns of activity evoked in parietal area 7ip and prefrontal area 8a neurons during an oculomotor
delayed-response (ODR) task. The motivating hypothesis has been that
neurons in parietal and prefrontal cortex interact during the ODR task,
and as such this task may serve as a model for parietal-prefrontal interaction whenever a spatial datum derived from visual input is
loaded into working memory. The interaction between prefrontal and
posterior parietal neurons is predictable on several grounds. First,
numerous investigators have described the large and reciprocal corticocortical projection extending between prefrontal and posterior parietal cortex (Andersen et al. 1985a
, 1990a
;
Barbas 1988
; Barbas and Mesulam 1981
;
Cavada and Goldman-Rakic 1989
; Petrides and Pandya 1984
; Schall et al. 1995
; Schwartz
and Goldman-Rakic 1984
; Stanton et al. 1995
).
Second, their output is tightly linked, efferent projections from the
two cortical areas travel in parallel to target the same
15 cortical
and subcortical targets, where they terminate either in interdigitating
columns or alternating cortical lamina (Selemon and
Goldman-Rakic 1988
). Finally, distinct but related functions
have been ascribed to both regions. Posterior parietal cortex is
believed to combine both retinal and extraretinal signals to build a
three-dimensional representation of visual space (Andersen and
Mountcastle 1983
; Andersen et al. 1985b
, 1987
, 1990b
; Brotchie et al. 1995
). In addition,
parietal cortex is believed to contribute to motor command signals
moving the eyes (Andersen et al. 1987
; Barash et
al. 1991a
,b
; Gnadt and Mays 1995
; Mazzoni
et al. 1996
; Mountcastle et al. 1975
) and hands
(Johnson et al. 1996
; Mountcastle et al.
1975
; Snyder et al. 1997
, 1998
) to points
defined in this space. The dorsolateral prefrontal cortex also has been
associated with the spatial guidance of both eye and arm
(Butters and Pandya 1969
; Niki 1974a
,b
;
Niki and Watanabe 1976
) movements, but has been
associated particularly with spatial working memory
(Goldman-Rakic 1987
, 1988
, 1995
); in this context, the
internal representation of a spatial coordinate to direct these
movements when none is specified by a currently available stimulus
(Funahashi et al. 1989
, 1993
; Sawaguchi and
Goldman-Rakic 1991
particularly). It would be advantageous to
know what principles might govern the physiological interaction between
parietal and prefrontal neurons suggested by these facts, in that these
subsequently may indicate how distributed representations in the
visuospatial domain emerge and are stored by the concerted action of
groups of interacting cortical areas.
Interestingly, it does not appear to be the case that parietal and
prefrontal neurons exhibit categorically different patterns of activity
during such a process (Chafee and Goldman-Rakic 1998; Quintana and Fuster 1992
) in spite of the prediction to
the contrary that lesion studies would seem to support. For example,
the effects of lesions of parietal and prefrontal cortex have been
considered to exemplify a "double dissociation" because damage to
parietal cortex rarely has been associated with memory problems
(Butters and Pandya 1969
; Jacobsen 1936
;
Pu et al. 1993
; although see Quintana and Fuster
1993
), and perceptual difficulties are uncommon after prefrontal lesions (Goldman et al. 1971
; Jacobsen
1936
; Pohl 1973
; Ungerleider and Brody
1977
). However, a direct comparison of activity within neuronal
populations in parietal area 7ip and prefrontal area 8a has indicated
that the two cortical areas contain the same heterogeneity of defined
neuronal types while monkeys performed the ODR task (Chafee and
Goldman-Rakic 1998
). The patterns of activation characteristic
of each of these subpopulations were matched to a greater extent
(Chafee and Goldman-Rakic 1998
) than could be gleaned
from independent studies of the two populations using similar, but not
identical, tasks (Andersen et al. 1990b
; Bruce
and Goldberg 1985
; Funahashi et al. 1989
-1991
;
Gnadt and Andersen 1988
). This would suggest that
whatever physiological principles drive the interaction between neurons
in these two cortical areas, the net result appears to be that changes
in neuronal activity within them are virtually coincident during at
least some behaviors. Contributions made by either prefrontal or
parietal neurons to their aggregate activity might only become evident when the normally integrated system is perturbed. Thus a more direct
examination of physiological interaction between prefrontal and
parietal cortices at a neuronal level seems warranted to address the
contribution made to the activation of neurons in each cortical area by
the operation of the network in which both are embedded.
Toward this end, single-unit recording and reversible cryogenic
inactivation are combined in the present experiments to determine whether changes in the activity of parietal neurons during ODR performance depend on the normal function of prefrontal cortex and vice
versa. This approach has been adopted previously in two studies using
cryoinactivation to address interactions between prefrontal and
parietal (Quintana et al. 1989) and inferotemporal (Fuster et al. 1985
) cortex during the performance of a
task in which the color rather than the spatial location of a cue
stimulus was stored in working memory. The present experiments sought
to extend these data by addressing the operation of the
parietal-prefrontal system when the visuospatial dimensions of a
stimulus were critical to task performance. Parietal and prefrontal
neurons are nearly identical in their activation during ODR performance
(Chafee and Goldman-Rakic 1998
). It remains a
possibility that the activities of these distant neuronal populations
are brought into register by the operation of corticocortical
projections between them as a result of the exchange of neuronal
signals throughout distributed systems in the cortex
(Mountcastle 1978
, 1995
, 1998
). The present experiments
are intended to reveal whether such an exchange between parietal and
prefrontal cortex might take place and what patterns of activity it
might include during ODR performance.
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METHODS |
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The neurons presently described represent a subset of
those the activity of which during the ODR task was the subject of a previous report: the effects of cortical cooling on the activation of
these neurons are addressed here. Additional detail regarding the
surgical and single-unit recording methods can be found in that earlier
study (Chafee and Goldman-Rakic 1998). All procedures conformed to the Guiding Principles for Research Involving Animals and
Human Beings of the American Physiological Society. Briefly, using
aseptic surgical procedures, two male rhesus macaque monkeys (7 and 9 kg) were implanted (in stages) with a head-restraint device, a scleral
search coil (Judge et al. 1980
), and recording chambers
positioned over parietal and prefrontal cortex in the right cerebral
hemisphere. A Peltier cryothermode (see following text) or a
microelectrode (glass-coated Elgiloy or varnish-coated tungsten: FHC,
part 120-110-1, Brunswick, ME) could be introduced into either
recording chamber to cool the underlying cortex or to record
single-unit activity from within it. The microelectrode signal was
amplified (BAK MDA-4, BAK Electronics, Germantown, MD) and filtered
(Khrone-Hite 3700, Khrone-Hite, Avon, MA) before being input to a
PC-based waveform discrimination system (8701 waveform discriminator,
Signal Processing Systems, Prospect, South Australia). A PDP 11/73
computer ran a program (generously made available by C. J. Bruce)
controlling the experiment. This program generated visual stimuli via a
Graph-11 graphics card (Pacific Binary Systems) that were presented on
a video monitor (NEC DM3000P, NEC Technologies, Itasca, IL) 57 cm in
front of the monkey. The program also collected digitized samples
(ADAC, Woburn, MA: 0.1° resolution) of the horizontal and vertical
eye position outputs of the eye coil system at a frequency of 500 Hz.
Saccades were recognized on-line, and the time as well as horizontal
and vertical positions of each saccade start and end point were saved
to the data file. The occurrence of the discriminated action potentials of up to two simultaneously recorded units also were sampled at 500 Hz.
ODR task
Two visual stimuli were presented on each trial: a small
(0.1°) stimulus always appearing at the center of the monitor (the fixation target) and a larger (0.5°) stimulus (the cue) presented in
the visual periphery. Both stimuli were square and solid white in
color. The trial began with the presentation of the fixation target
(Fig. 1A1). The monkey was
required to fixate this target for an initial period of 500 ms (Fig.
1A2), after which the peripheral cue was presented for an
additional 500 ms (Fig. 1A3) at one of eight possible
locations, equally spaced on a circle 13° in radius centered on the
fixation target (Fig. 1B). The location of the cue among
these eight possible locations was chosen pseudorandomly each trial and
was therefore unpredictable. After cue offset, the fixation target
remained visible for a fixed 3-s delay period (Fig. 1A4).
Continual fixation of the fixation target (within a central 4-6° eye
position window) was required during both cue presentation and the
subsequent delay period, a break in fixation terminated the trial.
After the end of the delay period, signaled by the offset of the
fixation target, the monkey was allowed 500 ms to complete a
memory-guided saccade in the dark (Fig. 1A5). If that
saccade brought the eyes to within 4-6° of the x-y
location where the peripheral stimulus appeared before the delay (Fig. 1A3), the response was rewarded with a drop of juice.
Relatively large eye position windows were made necessary by systematic
errors in memory-guided saccades; nonetheless the average saccade of monkeys JK and AR began within 2° of the
fixation target and ended within 3° of the actual cue location
(Chafee and Goldman-Rakic 1998
).
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Unit recording and cortical cooling
A cryoprobe (described below) that could be mounted temporarily within either the prefrontal or parietal recording chambers was used to cool the brain. The cryoprobe was mounted firmly against the tissue at the bottom of each recording chamber and fixed in place with set screws in the walls of the chamber. This was necessary for cold to penetrate the volume of thickened dura and granulation tissue present in both monkeys at the bottom of the recording chamber. As one cortical area was cooled, single-unit activity was collected from the other. Locations of recording and cooling were switched between parietal and prefrontal cortex on subsequent days. A search for neuronal activity was conducted by lowering the electrode into the chosen brain area while the cryoprobe mounted in the other chamber was maintained at normal body temperature (37°C). Once the activity of a unit was isolated, its activity was recorded for ~8-10 ODR trials per cue location. In general, cooling was reserved for units showing clear changes in activity during one or more epochs of the ODR task. If isolations were stable and the activity clearly task-related, the temperature of the cryoprobe was then lowered from 37°C to between 2 and 5°C in ~1 min and held at this temperature (±0.5°C). During the cooling procedure, care was taken to assure the stability of the unit isolations by comparison of incoming wave forms against samples stored at the beginning of the run. Once the cold temperature had been achieved, data collection resumed after a 5-min waiting period, allowing some time for brain temperature to stabilize and the physiological response to cold to develop. The monkeys performed the ODR task throughout the transition from warm to cold temperatures without interruption and did not show any overt signs of discomfort during this interval. The activity of the neuron then was recorded for a second set of between 8 and 10 ODR trials per cue location. Some isolations lasted long enough to enable collection of additional trials after the temperature of the brain had been returned to normal, and a few allowed for multiple cooling cycles.
Cryoprobe and brain temperature
The cryoprobe (Fig. 2A) consisted of a lower cylindrical piece of gold-plated copper made to fit within the recording chamber (16 or 20 mm ID) to which a vertical rectangular piece of copper was soldered to provide a mounting surface for two Peltier thermoelectric cooling devices (CP Series, Melcor, Trenton, NJ) connected in series and mounted on either side of the vertical copper piece. A ±4 A DC power supply used in conjunction with a control circuit adjusted both the amount and polarity of the current delivered to the Peltier devices so that the cryoprobe could be either cooled or warmed (by reversing the direction of current) and small adjustments in current could maintain any desired set temperature. This circuit employed the difference between a desired set temperature and the temperature of the cryoprobe measured by a small (0.010 in) copper-constantan thermocouple (Omega 5TC-TT-T-30-36, Omega Engineering, Stamford, CT) cemented to its under surface, at the interface between the cryoprobe and underlying tissue within the chamber. Excess heat accumulating at the outer face of each Peltier device during the cooling of the cryoprobe was removed by water circulating within copper heat sinks (Fig. 2A). To serve as a secondary temperature measurement device, a bead thermistor (YSI 44033, YSI, Yellow Springs, OH) was connected to a telethermometer (YSI) and cemented close to the dura at the bottom of a hole drilled through the long axis of the cryoprobe.
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At the end of these experiments, the temperature within the brain underneath the cryoprobe was measured in one animal. To make these measurements, the bead thermistor in the central hole within the cryoprobe was removed. While the cryoprobe was mounted within the chamber and maintained at 2°C, a needle temperature probe (Physitemp, Clifton, NJ) attached to the telethermometer was lowered through the hole along the central axis of the cryoprobe into the brain and the temperature within the tissue directly measured at 1-mm intervals. This relationship was essentially linear at depths between 3 and 10 mm, temperature increasing on average an additional 2.8°C/mm beneath the cryoprobe (Fig. 3A). Below a depth of 10 mm, the temperature gradient was less steep, warming 1.3°C/mm. Measurements within prefrontal cortex were on average within 0.8°C of parietal measurements at each depth (the largest discrepancy between the 2 being 1.7°C, data not shown). Temperature measurements obtained with this technique were likely to underestimate actual brain temperature because the temperature of the tip of the probe would reflect both the ambient temperature of the brain and also the temperature of the shaft of the needle probe cooled directly along its course through the cryoprobe. To establish an approximate measure of this inaccuracy, the needle probe was lowered by 1-mm increments through the cold (2°C) cryoprobe into either a cold (2°C) or warm (37°C) oil bath. Errors in the warm bath (considered a boundary condition reflecting maximal error) fell off with greater probe depth (Fig. 3B). Below a depth of 5 mm, the error was <3°C.
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Statistical analysis of cooling effects on neuronal activity
Trials were segregated according to cue direction and cryoprobe
temperature. Then within each group of trials, neuronal firing rates
were measured in five time windows, within the cue, delay, early-saccade, late-saccade, and intertrial periods. The cue and delay
windows were coextensive with the corresponding 500 and 3,000 ms
periods in the ODR trial. The boundaries of early (100-400 ms after
fixation target offset)- and late (400-700 ms after fixation target
offset)-saccade period windows were adjusted to coincide with the
average timing and duration of pre- and postsaccadic neuronal activity
(Chafee and Goldman-Rakic 1998). These windows in the
saccade period were not defined relative to saccade initiation because
variability in the on-line recognition of saccades could vary the
number of trials recognized in a minority number of cases, and the
ANOVA we employed required a constant number of trials across each of
the repeated measures (trial periods). The window in the intertrial
period was the last 2,000 ms of the 2,500-ms intertrial interval (in a
minority of the data, a shorter 2,000-ms intertrial interval
occasionally was included, and the window spanned the entire period).
The monkey was free to make eye movements during the intertrial period,
and this occasionally may have included the centering saccade the
monkey made after reward delivery (typically this saccade was completed
within 500 ms of reward and so would not be included in the bulk of the
data with the longer intertrial interval).
Thus three factors described each neuronal firing rate measurement;
these were task period (5 levels), cue direction (8 levels), and
cryoprobe temperature (2 levels, this analysis was limited to the
firing rates observed while the brain was at normal temperature before
cooling was initiated, and firing rates observed during the subsequent
set of trials administered while cooling was in effect). A three-way
repeated measure ANOVA (as implemented in the SYSTAT computer
statistics package) was used to analyze the data. Task period was
treated as a repeated measure. If the F statistic for the
main effect of trial period in the overall analysis was significant,
the neuron was defined as task-related. In these cases, additional
tests isolated which trial periods contained significantly modulated
activity. Four planned comparisons contrasted the mean firing rates in
cue, delay, and early- and late-saccade periods each to the intertrial
interval. Depending on which of these yielded significance, neurons
were assigned a combination of C (cue), D (delay), or S (either early
or late saccade) designations. If the F statistic for the
main effect of temperature in the overall analysis was significant, the
significance of this effect for each of the repeated measures was
examined to determine whether cryoprobe temperature impacted firing
rates in each trial period. An alpha level of P 0.05 was
employed throughout. The analysis was limited further only to those
trial periods in which neurons exhibited significantly modulated
activity. Thus cooling effects were identified as cases where two
conditions were met; neuronal firing rates within a given trial period
were significantly different from the intertrial interval and the main
effect of temperature was significant on firing rates within the same
trial period. In this way, the analysis was focused on cooling induced
changes in task-related activity. The significance of the main effect of temperature on activity within the intertrial period assessed whether cooling had an overall effect on background activity. This was
determined for each neuron. The magnitude of cooling effects was
defined as the ratio of the mean firing rate during a given task epoch
when the brain was cold, to the mean firing rate during the same epoch
when the brain was warm (after Sandell and Schiller
1982
). This ratio was <1 when cooling lowered firing rates and
>1 when cooling elevated firing rates. Recovery of cooling effects was
assessed in a separate three-way repeated measures ANOVA directly
analogous to the analysis described in the preceding text, with the
exception that neuronal firing rates during cooling were compared with
firing rates after the brain had been returned to normal temperature.
Latencies of neuronal activation were defined with the method of
MacPherson and Aldridge (1979) based on confidence
intervals established around a spike density function of each neuron's
activity. We employed Gaussian curves to measure the spatial tuning of
neuronal activity. Within each trial period containing significantly
modulated activity, the mean neuronal firing rate was measured across
the eight cue/saccade directions tested. Then a reiterative
curve-fitting algorithm determined the parameters defining the Gaussian
curve that best fit these eight mean firing rates (separate fits were made to data collected during warm and cold conditions). Only cases in
which the curve fitting procedure provided an F-statistic significant at the P
0.05 level were included in
subsequent analyses. Further details of both latency and spatial tuning
analyses were described previously (Chafee and Goldman-Rakic
1998
). Changes in the spatial tuning of neuronal activity were
defined as the difference in the best direction or width parameters of
the Gaussian tuning functions fit to warm and cold data sets for a
given neuron. Two separate two-way analyses of variance then were
conducted on the populations of these difference measures each using
trial period and cortical area as factors. This addressed whether the mean shift in either spatial tuning parameter varied depending on which
cortical area was cooled (main effect of area), and which task period
was considered (main effect of trial period).
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RESULTS |
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Database
A total of 105 neurons were isolated and their activity recorded within one cortical area as the monkeys completed two full sets of ODR trials, one conducted while the other cortical region remained at normal body temperature and a second set while the temperature of that region was lowered. Forty three of these neurons were located in parietal cortex (Fig. 2, B and C), and their activity collected while prefrontal cortex was subjected to cold. The majority of these (31 neurons) were located in parietal area 7ip (LIP) in the lateral bank of the intraparietal sulcus (Fig. 4, A and C), but a few also were located in area 7a (7 neurons) in the inferior parietal gyrus and also in area DP in the dorsal prelunate gyrus (5 neurons). Conversely, 62 of the neurons in the database were located in prefrontal cortex (Fig. 2, B and C), the majority of which (52 neurons) was located in area 8a in the anterior bank of the arcuate sulcus (Fig. 4, B and D), in the approximate location of the FEF, whereas the remainder (10 neurons) was located in the principal sulcus, in area 46.
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The results of the repeated-measure ANOVA indicated that 90% of neurons within the database were task responsive and directionally selective. (i.e., the main effects of trial epoch and cue direction, or their interaction, were significant in the analysis, see Table 1). Using a set of planned comparisons (METHODS), the present analysis recognized seven types of neuron on the basis of whether significant activity modulation occurred during the cue, delay, and/or saccade periods or in combinations of these periods. Neurons tested during cooling in both parietal and prefrontal cortex included examples from most of these types (Fig. 5, A and B).
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Extent of cryoinactivation
Cortical cooling involved a group of areas in parietal and
prefrontal cortex (Fig. 2, B and C), with the
coldest temperatures existing within the more superficial cortex
immediately beneath the cryoprobes (Figs. 3A and 4,
A-D). Progressively warmer brain temperatures occurred at
greater depths. At a cryoprobe temperature of 2°C, cortical
temperatures at depths of 3, 6, and 9 mm beneath the surface of the
brain were 14, 23, and 29°C, respectively (Figs. 3A and 4,
A-D). The lateral spread of cooling was not measured in the
present experiments but was likely to extend beyond the boundaries of
the cryoprobe (Fuster and Bauer 1974). Thus cooling established a gradient of subnormal temperature and functional inactivation across considerable portions of parietal and prefrontal cortex. Changes in the activity of area 7ip neurons resulted therefore not only from the cooling of area 8a, but of an expanse of prefrontal cortex which included it. Similarly, changes in the activity of area 8a
neurons resulted from the cooling of a portion of parietal cortex that
included area 7ip but was not limited to this cortical area. The degree
to which the volume of cooled cortex involved areas 7ip and 8a can be
estimated from the depths of neurons in these areas the activity of
which was significantly modulated during ODR performance (Chafee
and Goldman-Rakic 1998
) and from the temperature measurements
made at these depths (Fig. 3A). Most ODR task-related
neurons in monkeys JK and AR sampled in area 7ip
(Fig. 3C) and nearly all of those sampled in area 8a (Fig. 3D) were located at cortical depths <6 mm (lightly shaded
region, Fig. 3, C and D), where the temperature
of the cortex was <23°C (Fig. 3A). It has been shown that
whereas colder temperatures are required to block neuronal
responsiveness entirely, the response of V1 neurons to an optimal
visual stimulus is reduced by ~80% at a temperature of 20°C
(Girard and Bullier 1989
). Thus cooling in the present
experiments would be expected to substantially reduce the activity and
output of a large portion of the neurons in parietal area 7ip and
prefrontal area 8a. Because neurons in area 8a that were driven during
ODR performance were more superficially located, the degree of
functional inactivation achieved in area 8a was likely to exceed that
in area 7ip.
In parietal cortex, cooling involved a group of cortical areas, which included, in addition to area 7ip in the lateral bank of the intraparietal sulcus, portions of area 5 in monkey AR (Fig. 2B), as well as the dorsal prelunate gyrus (including area DP) and parts of striate cortex in monkey JK (Fig. 2C). Parts of area 7a were cooled in both animals. In prefrontal cortex, cooling included not only area 8a in the anterior bank of the arcuate sulcus but also portions of area 46 in the posterior principal sulcus, posterior portions of the dorsolateral and inferior prefrontal convexities, and area 6 (Fig. 2, B and C).
Effect of cold on ODR performance
Cooling prefrontal cortex produced an impairment in memory-guided saccade performance (Fig. 1C). In a two-way ANOVA on the mean error distance between the endpoint of memory-guided saccades and their respective visual cues (with cue direction and cortical temperature as factors), error distance increased during cryogenic depression of prefrontal cortex-both the main effect of temperature (Ftemp =149.47, df = 1, P < 0.001) and the interaction between temperature and direction (Ftemp*dir = 15.01, df = 10, P < 0.001) were significant in this analysis. This behavioral deficit was confined largely to saccades toward targets appearing contralateral to the cooled prefrontal hemisphere (Fig. 1C). During cooling, monkeys would maintain fixation of the central target until its disappearance but then frequently make inaccurate saccades (sometimes into the visual hemifield opposite the target). These trials were interspersed with others in which comparatively accurate saccades were made. Cooling parietal cortex produced a much smaller impact on the accuracy of memory-guided saccades (Fig. 1D), failing to significantly effect the mean error between memory-guided saccade endpoints and their targets (Ftemp = 3.41, df = 1, P = 0.065; Ftemp*dir = 1.50, df = 10, P = 0.131).
Effect of cold on neuronal firing rate
Cooling affected the intensity of activation of neurons in various ODR trial epochs in both parietal and prefrontal cortex. The parietal area 7ip neuron illustrated in Fig. 6A exhibited sustained delay period activation when the cue appeared in the upper (90°) and upper left (135°) locations before the prefrontal cortex was cooled. When the activity of the same neuron was recorded with the prefrontal cortex cooled, delay period activity was attenuated sharply in the 135° direction (Fig. 6B; Ftemp = 45.99, df = 1, P < 0.001), and early-saccade period activity also was suppressed significantly (Ftemp = 25.69, df = 1, P < 0.001). The activity in the cue period also was affected but less strongly and not significantly (Ftemp = 0.357, df = 1, P = 0.551). The delay period activity of nine additional parietal area 7ip neurons significantly changed during prefrontal cooling (4 neurons suppressed, 5 augmented; Fig. 9C).
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Comparable effects were observed among prefrontal neurons while cooling parietal cortex. Figure 7A illustrates a neuron in the principal sulcus (area 46) recorded during cryogenic inactivation of the parietal cortex. Like the parietal neuron described in the preceding text, the activity of this prefrontal neuron was reduced significantly by cooling (Fig. 7B), in this instance during the cue period (Ftemp = 99.29, df = 1, P < 0.001). There was also a general suppression of the level of activity during the intertrial interval in this case (Ftemp = 108.60, df = 1, P < 0.001). Six additional prefrontal neurons (1 in area 46 and 5 in area 8a) similarly exhibited reduced cue period activation when parietal cortex was cooled, whereas augmented cue period activation was observed in 11 prefrontal area 8a neurons (Fig. 9B). Thus whereas the illustrated cooling effects fit well those that prefrontal mnemonic and parietal visuospatial functions would predict (namely the reduction of cue period activity in prefrontal neurons and delay period activity in parietal neurons), counter examples were equally numerous. For example, delay period activity of several prefrontal area 8a neurons was altered by parietal cooling (9 neurons, Figs. 9D and 11, E-H), and prefrontal cooling altered the activation of parietal 7ip neurons in response to the visual stimulus (9 neurons, Fig. 9A). Neurons whose primary activation during ODR performance occurred during the saccade period also were impacted by cooling either area (17 parietal 7ip neurons, 25 prefrontal 8a neurons, Fig. 9, E and F). Thus prefrontal cooling could reduce the presaccadic activation of neurons in area 7ip (Fig. 8, A and B; Ftemp = 34.54, df = 1, P < 0.001), and cooling parietal cortex could augment the presaccadic activation of neurons in prefrontal area 8a (Fig. 8, C and D; Ftemp = 34.89, df = 1, P < 0.001). In general, both enhanced and suppressed levels of activation were observed in all task periods after the transient inactivation of either cortical area (Fig. 9, A-H).
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MAGNITUDE AND FREQUENCY OF EFFECTS. In the case of significant suppressive cooling effects, the mean cooling index was quite constant both across trial period and cortical area (Fig. 10A). In this population of neurons, firing rates were reduced by ~40% of their level of activation seen at normal brain temperature. It was not the case that cooling one area produced stronger suppressive effects than cooling the other or that stronger suppressive effects were seen in some trial periods. In a two-way ANOVA of the cooling indices of suppressed neurons (cortical area by trial period), neither the main effects of area or trial period nor the interaction between them were significant (Farea = 0.10, df = 1, P = 0.75; Fperiod = 0.37, df = 4, P = 0.83; Farea*period = 0.19, df = 4, P = 0.94). Similarly, in the case of enhancing effects, neither the main effects of area (Farea = 0.89, df = 1, P = 0.35) or trial period (Fperiod = 1.47, df = 4, P = 0.22) were significant, although the interaction term was (Farea×period = 2.72, df = 4, P = 0.03). Both early- and late-saccade period activities were more strongly augmented in parietal units under prefrontal cooling than the converse (Fig. 10B).
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REVERSIBILITY OF EFFECTS. The activity of 52 neurons was recorded after the brain had been returned to normal temperature. A repeated-measures ANOVA similar to the original analysis (METHODS) was performed on these neurons to determine whether changes seen under cooling reversed on warming the brain. Nine of the 33 neurons (27%) whose activity was augmented by cooling, and 9 of the 19 neurons (47%) whose activity was suppressed by cooling, exhibited significant changes in activity in the opposite direction when the brain was returned to normal temperature. Thus significant recovery was more common among those neurons suppressed by cooling. In other neurons, changes in activity seen on cooling did not immediately reverse on warming the brain within the period of time over which that activity was sampled. In some neurons, changes in activity were consistently observed across multiple cooling cycles. For example, cooling prefrontal cortex had a reversible and repeatable impact on the activity of the neuron located in parietal area 7ip (Fig. 11, A-D, same neuron as in Fig. 6). Before cooling, the firing rate of this neuron was elevated during the delay period (Fig. 11A). During the first cooling of prefrontal cortex, the delay period activation was reduced (Fig. 11B) and then after the brain was warmed back to normal temperature, rebounded to a level greater than that originally seen before cooling was initiated (compare Fig. 11, C and A). Delay period firing rates were again suppressed a second time when prefrontal cortex was again cooled (Fig. 11D). The neuron in prefrontal area 8a exhibited a tonic excitation during the delay period (Fig. 11E) that was attenuated when parietal cortex was cooled (Fig. 11F), regained its original strength when parietal cortex was warmed (Fig. 11G), and was attenuated again when parietal cortex was cooled a second time (Fig. 11H).
Cooling effects on spatial tuning
The technique employed to quantify the spatial tuning of neuronal activity (METHODS) provided for each neuron the parameters of the Gaussian curve representing the best fit to the mean firing rates observed in each of the eight cue/saccade directions tested. Significant Gaussian fits were obtained to the activity of 19 parietal neurons and 32 prefrontal neurons in at least one ODR task period in both warm and cold conditions. Comparison of tuning curves fit with the activity of these 51 neurons within a given trial period across temperature indicated whether cooling affected the breadth of tuning (Td parameter of the Gaussian equation) or the best direction (D parameter) of that activity. The best directions of fits to cue, delay, and saccade period activities shifted <10° in the large majority of neurons (Fig. 12A, neurons contributed multiple shift values to this distribution if they were activated in >1 ODR task epoch). However, larger shifts occasionally were seen. For example, after cooling prefrontal cortex, the best direction of the saccade period activity of an area 7ip parietal neuron shifted counterclockwise (leftward) by 28° due largely to opposite changes in mean firing rate observed at off-peak 45 and 135° directions (Fig. 13A). In a neuron in prefrontal area 8a, a 26° clockwise (rightward) shift in the preferred direction of saccade period activity was seen (Fig. 13C). Comparing the size of the shifts in best direction across parietal and prefrontal cooling in a two-way ANOVA with cortical area and task epoch as factors, the main effect of cortical area was significant (Farea = 5.08, df = 1, P = 0.027), indicating that larger shifts in best directions were associated with cooling parietal than prefrontal cortex (Fig. 12A). The size of the shift in best direction did not vary with task period (Fepoch = 1.89, df = 2, P = 0.157). Cooling also could affect the width of tuning (Td parameter; Fig. 12B), and a minority of neurons exhibited considerable shifts. The best direction of the saccade period activity of the illustrated area 8a neuron remained constant as the width of tuning changed markedly (Fig. 13B). Cooling parietal and prefrontal cortex did not differentially impact this measure (Farea = 0.64, df = 1, P = 0.424), which was comparable across task epoch (Fepoch = 0.32, df = 1, P = 0.724).
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Cooling effects on neuronal latency
Cooling neither prefrontal nor parietal cortex had an appreciable
impact on delaying the activation of neurons during the cue and saccade
periods. Recruitment curves illustrating the percentage of the
populations of neurons activated during cue and saccade periods as a
function of time relative to cue onset (Fig.
14, A and B) or
saccade initiation (Fig. 14, C and D) largely
overlap, indicating that on average the activation of these populations followed a similar time course whether the brain was cold or at normal
temperature. In both parietal (Fig. 14A) and prefrontal (Fig. 14B) cortex, there is a tendency for neuronal
activation late in the cue period to be delayed during cooling, such
that recruitment curves diverge ~100 ms after cue onset; however,
neither the mean onset time of cue (parietal: paired t = 1.43, df = 18, P = 0.169; prefrontal: paired
t =
0.55, df = 24, P = 0.585) or saccade period activation (parietal: paired t = 0.91, df = 14, P = 0.38; prefrontal: paired
t = 0.38, df = 36, P = 0.943)
differed significantly as a function of cortical temperature in either cortical area.
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DISCUSSION |
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Neuronal activity in both prefrontal and parietal cortex increases
during the primary ODR trial epochs that separate sensory stimulation,
working memory operation, and response execution in time. The
population of neurons activated in both cortical areas can be divided
into several distinct groups on the basis of which combination of these
task epochs include elevated activity (Fig. 5), and the large majority
of neuronal types so defined were found to exist simultaneously in both
parietal and prefrontal cortex (Chafee and Goldman-Rakic
1998). Thus several subpopulations of neurons in parietal and
prefrontal cortex appear to be physiologically synchronized in the
sense that the levels of their activity rise and fall together
throughout the ODR trial. The present experiments were intended in part
to address the mechanisms through which this parallel activation might
come about, specifically whether reciprocal neurotransmission between
these cortical areas may be involved. The known projection between
parietal neurons in area 7ip and prefrontal neurons in area 8a
(Andersen et al. 1990a
; Cavada and Goldman-Rakic
1989
; Schall et al. 1995
; Stanton et al.
1995
) implies that activity is exchanged between these neuronal populations during ODR performance but not whether this exchange is
symmetrical or asymmetrical nor whether it equally includes neuronal
activation during the cue, delay, and saccade epochs of the task. As
some of these signals (specifically neuronal activity sustained
throughout the delay period) appear to effect the retention of a
spatial datum defined by the location of a visual stimulus in working
memory, the question is of interest as to how prefrontal cortex may
engage, and in turn be engaged by, other cortical areas as working
memory operates. Our results included the following observations:
1) neurons the activation of which occurred during periods
of sensory input, working memory operation, or saccade execution were
equally vulnerable to the effects of cooling. 2) The effects
of cooling parietal versus prefrontal cortex were largely equivalent
(with a few exceptions discussed in the following text). 3)
The average change in neuronal activity associated with cooling was on
the order of 40% of the firing rate observed in each trial epoch at
normal temperature and tended to be equally strong across all
cue/saccade directions tested. And 4) both the suppression
and enhancement of activation were observed. How these findings might
bear on the nature of the interaction between prefrontal and posterior
parietal neurons during the ODR task will be considered in turn. It
should be noted that using the current technique it is not possible to
conclude whether cooling effects were mediated by direct monosynaptic
projections between parietal and prefrontal neurons or via
multisynaptic pathways involving other cortical or subcortical areas.
Neuronal activity in all ODR task epochs was affected
The similarity that parietal and prefrontal neuronal activities
achieve during ODR performance might arise through any one of several
different mechanisms. One possibility is that this similarity is the
consequence of a redundancy of oculomotor function between parietal and
prefrontal cortex, which generate similar patterns of neuronal activity
in physiological isolation without requiring or involving the exchange
of neuronal signals between them. As this would predict that cooling
one cortical area ought to have negligible effect on the other, the
present data indicate that a physiological interaction between parietal
and prefrontal neurons takes place during ODR performance and that this
interaction contributes to the modulation of activity that neurons in
both areas exhibit. In this manner, the physiological operations
performed by the two cortical areas appear to be linked. It was
observed further that the reduction of output that could be assumed to accompany cooling of one of the two cortical areas produced equal effects on neuronal activation during cue, delay, and saccade epochs
concurrently recorded in the remaining cortical area (Figs. 9 and 10).
This was evidence that the cortical output suppressed by cooling was
normally active during each of these ODR task epochs to contribute to
the modulation of neuronal activity taking place in the other cortical
area during those same times in the ODR trial. Thus the present data
favor the hypothesis that neural signals associated with sensory input,
working memory operation, and saccade execution in both parietal and
prefrontal cortex all participate in cortical output. The heterogeneity
of output signals suggested by these data are consistent with the
results of Paré and Wurtz (1997), who have
combined antidromic activation and unit recording to demonstrate that
two physiologically distinct classes of 7ip neuron, one active during
the cue period, and another the activity of which extended into the
delay and saccade periods of a memory-guided saccade task, both give
rise to axons projecting to the superior colliculus.
The present results are in agreement with the data presented by
Quintana and colleagues (1989) in their study of the
effects of parietal cooling on prefrontal unit activity during delayed match to sample and conditional position discrimination tasks, both of
which employed the color of a cue stimulus to direct a delayed arm
movement. These authors found that cooling parietal cortex
significantly altered the level of activity of some prefrontal neurons
in each of the cue, delay, choice, and response epochs comprising these
tasks. Further, cooling produced a mixture of increased and decreased
levels of activation. Our results extend these by examining the impact
of prefrontal inactivation on parietal unit activity and the use of a
task employing a visuospatial cue and an oculomotor response to
investigate this system. In their study of interactions between
prefrontal and inferotemporal cortex, Fuster and colleagues
(1985)
observed that in either cortical area, remote cortical
inactivation had a significant impact on the neuronal activity observed
during cue, delay, and choice epochs of the same delayed color match to
sample task. The agreement between these data suggests a general
pattern of intracortical communication existing between prefrontal
cortex and areas providing its input during a variety of working
memory-dependent behaviors.
Parietal and prefrontal cooling were equivalent
Parietal and prefrontal cooling were largely equivalent in their
impact on neuronal activity. Cooling had a significant impact on cue,
delay, and saccade class neurons with comparable frequency irrespective
of which cortical area was cooled (Fig. 9). Furthermore suppressive
effects were of comparable magnitude (Fig. 10A), although saccade responses were enhanced to a larger degree after prefrontal cooling (Fig. 10B) than the converse. Thus it did not appear
to be the case that the symmetrical patterning of neuronal activity patterns previously described (Chafee and Goldman-Rakic
1998) was achieved through an asymmetrical exchange of signals
between parietal and prefrontal neurons. For example, it is possible
that activation elicited by the visual stimulus during the cue period originates in parietal cortex and then is transmitted to prefrontal cortex in a strictly feedforward direction. Along similar lines, prefrontal neurons might employ this input to generate locally a neural
signal that is sustained throughout the delay period that once
initiated drives parietal neurons in a strictly feedback manner. This
exchange of different neural signals in feedforward and feedback
components of the reciprocal projection between parietal and prefrontal
neurons would have the effect of mixing activity patterns between the
two populations that were initially unique to one or the other.
However, the present data do not support the possibility that
activation during any individual period of the ODR task is transmitted
in only one direction between parietal and prefrontal neurons. Instead,
they argue that all neuronal signals in this system are concurrently
feedforward and feedback signals and consequently that the input
prefrontal cortex provides to parietal neurons conveys the same signals
as the input from parietal cortex to prefrontal neurons. This is
supported by the symmetry of the effects of cooling parietal and
prefrontal cortex on their shared activity. That the suppression of
function of prefrontal cortex was able to modify the sustained
modulation of neuronal activity during a working memory interval in a
distant cortical area (Figs. 6, 9C, and 10, A and
B) indicates that the role of prefrontal cortex in working
memory may be partly carried out through its output projections to
other cortical areas. It is of further interest that prefrontal cooling
was effective in altering the response of posterior parietal neurons to
the presentation of a visual stimulus in the present experiment. This
argues for a prefrontal modulation of even early sensory processing
taking place in posterior sensory association cortex, where neurons
appear to be driven from two sides in effect, from earlier extrastriate areas on the one hand and prefrontal cortex on the other. Similar feedback influences on neuronal activation evoked by a visual stimulus
have been described for V1 neurons, the responses of which can be
suppressed by cryoinactivation of V2 (Sandell and Schiller
1982
), and also for IT neurons, whose differential activation to the color of a cue stimulus diminishes under conditions of prefrontal inactivation (Fuster et al. 1985
).
Furthermore, in split-brain monkeys, prefrontal feedback can drive
pattern-selective visual activity in inferotemporal neurons that have
been otherwise deprived of feedforward visual input from ipsilateral
extrastriate cortex (Tomita et al. 1999
). Such a dynamic opens a
possibility that dysfunction of prefrontal cortex also might impact
sensory processing in disease states, contributing to pathology
observed in schizophrenia, for example, that is associated with
abnormalities in both anatomic and functional characteristics of
prefrontal cortex (Goldman-Rakic and Selemon 1997
) and
also is characterized by sensory hallucinations.
Both enhancement and suppression were observed
In the present experiments, cooling was associated both with
enhancement and suppression of the response magnitude observed before
cooling, depending on the neuron under study. A similar mixture of
enhanced and suppressed unit responses after cryoinactivation has been
reported in several studies of corticocortical interaction between
striate and extrastriate cortex (Girard et al. 1992;
Rodman et al. 1989
; Sandell and Schiller
1982
), between prefrontal and inferotemporal cortex
(Fuster et al. 1985
), and between prefrontal and
posterior parietal cortex (Quintana et al. 1989
).
Corticocortical projections target both pyramidal neurons and also
GABAergic interneurons within the target area (Somogyi et al.
1998
). As such, cooling the neurons that give rise to a
corticocortical projection would be expected to produce a mixture of
effects on target pyramidal neurons, a direct suppression of their
activity as the level of excitatory input they received was reduced and
an indirect augmentation of activity, as excitatory drive to
interneurons was reduced and pyramidal neurons in their vicinity were
released from inhibition. Although GABAergic interneurons are less
numerous than pyramidal cells by ~5 to 1, in the case of basket and
chandelier cells, the output of each targets ~300 surrounding
pyramidal neurons (Salin and Bullier 1995
). Reduced
drive to a small number of interneurons could impact a much larger
number of pyramidal cells. There is also supporting evidence that
activation of corticocortical inputs can produce an exclusively
inhibitory influence in some target neurons. Intracellular recording of
motor cortical pyramidal neurons demonstrated that in a minority of
cases, stimulation of corticocortical inputs from premotor and
somatosensory cortex produced inhibitory postsynaptic potentials
without a preceding excitatory postsynaptic potential (Ghosh and
Porter 1988
). In the present data, perhaps the clearest
difference between prefrontal and parietal cooling related to the
augmentation of saccade period activities during cooling. The degree of
augmentation was stronger in this task period when prefrontal cortex
was cooled and parietal neurons recorded from than the converse (Fig.
10B).
It is also possible that cooling directly enhanced the activity of some
neurons within the cooled cortical region and so increased their
output. Cooling depolarizes the resting membrane potential and if
cooling is slight (5° below normal temperature), higher firing rates
result (Adey 1974). Neurons have been observed to discharge repetitively at somewhat colder temperatures (9° below normal temperature) before entering a state of electrical silence (Moseley et al. 1972
). Thus neurons cooled to
intermediate temperatures may have exhibited an increased level of
activity, contributing to the augmentation of neuronal activity we
observed in the target cortical region.
Both the enhancing and depressing effects of cooling observed in the
present experiments support the view that corticocortical projections
within the same hemisphere, perhaps in addition to influencing the
temporal structure of spike trains, can and do directly influence the
total number of spikes emitted by target neurons during a given
behavioral epoch, contributing therefore to changes in average firing
rate over time, or rate coding, as this feature of neuronal physiology
has been termed (Shadlen and Newsome 1994).
COOLING COMMONLY MODULATED BUT DID NOT BLOCK NEURONAL ACTIVATION.
Cooling effects were common in the present results; firing rates of the
majority of the current sample of task-related neurons were
significantly different at cold temperatures. Some of these significant
effects were nonetheless subtle, and the general pattern of activity
across the ODR trial typically persisted through cryoinactivation. The
effects of cooling were on average ±40% of the activity level in a
given task epoch measured before cooling began (Fig. 10). In the monkey
visual system, cryoinactivation of area V1 completely silences neurons
in areas V2-V4 the receptive fields of which overlap those represented
in the inactivated portion of V1 (Salin and Bullier
1995). However, in cases where projections exist to circumnavigate the blocked projection (such as the cat where LGN projections target V2), the effects of cooling V1 are commonly less
complete (Salin and Bullier 1995
). In the present
experiments, two structures in association cortex were examined that
share reciprocal projections with 15 cortical structures
(Selemon and Goldman-Rakic 1988
). Thus the network of
input projections that could convey activity potentially relevant to
ODR performance into parietal and prefrontal cortex is broadly
distributed. Among the cortical projections alone, this network
includes inputs from area STP in the upper bank of the superior
temporal sulcus (Seltzer and Pandya 1984
,1989
) and from
other extrastriate cortical areas (Barbas and Mesulam
1981
; Cavada and Goldman-Rakic 1989
;
Huerta et al. 1987
) as well as from area 7m located on
the medial wall of the cerebral hemisphere (Cavada and
Goldman-Rakic 1989
), all of which are potential conduits for
parallel visual input to prefrontal and parietal cortices initiating
the chain of events producing delay and ultimately saccade-related
neuronal responses within them.
Direct interaction between areas 7ip and 8a
The experimental technique presently employed did not limit
inactivation to parietal area 7ip and prefrontal area 8a nor was inactivation of these areas (particularly area 7ip) complete. However,
the volumes of cooled cortex included substantial portions of both
areas 7ip and 8a (Figs. 3 and 4). Projections between parietal area 7ip
and prefrontal area 8a are strong and selective (Andersen et al.
1985a, 1990a
; Barbas 1988
; Cavada and
Goldman-Rakic 1989
; Schall et al. 1995
).
Granting the technological limitations of the cooling method employed,
the preferential interconnection of areas 8a and 7ip suggest that
changes in neuronal activation we observed in each cortical area were
mediated at least in part by changes that cooling imposed on the direct
interaction between the two. Thus the cooling effects observed in
prefrontal area 8a, for example, were much more likely to be due to
partial cooling of area 7ip with which it is directly and reciprocally
connected (Cavada and Goldman-Rakic 1989
) than to
partial cooling of areas surrounding 7ip (such as area 5) that are
indirectly or not at all connected to area 8a. However, cooling of some
parietal areas, such as areas 7a and DP, were more likely to contribute
to the observed effects as these areas both contain neurons that are modulated during ODR performance (Chafee and Goldman-Rakic
1998
) and project to prefrontal area 8a (Andersen et al.
1990a
). Similarly area 46 in the principal sulcus contains
neurons that are driven during ODR performance (Chafee and
Goldman-Rakic 1998
; Funahashi et al. 1989
), and
the posterior principal sulcus projects to area 7ip (Cavada and
Goldman-Rakic 1989
). The present results can be characterized
therefore as the effect on the neuronal activity specifically within
parietal area 7ip and prefrontal 8a of cooling groups of neighboring
areas in each cortical region including but not limited to these two areas.
We estimate, on the basis of the depth of the recorded neurons, the
measured temperature-depth relationship (Fig. 3), and a study of the
direct effects of cooling in the striate cortex (Girard and
Bullier 1989), that cooling suppressed neuronal activation by
80% in the majority of neurons in parietal area 7ip and prefrontal area 8a. This represents a substantial if incomplete reduction in
output. There is further evidence in a number of systems that the
physiological response to cold at this level and beyond is graded and
progressive (Gahwiler et al. 1972
; Girard and
Bullier 1989
; Jasper et al. 1970
; Moseley
et al. 1972
). Deeper inactivation of parietal area 7ip or
prefrontal area 8a therefore might be expected to produce stronger
effects in more neurons but may not be expected to yield substantively
different results from those presently obtained. The possibility cannot
be excluded at present, however, that an asymmetry in the physiological
effects of inactivating areas 7ip and 8a might not emerge if total
inactivation of each area was achieved. Finally, changes in neuronal
activity we observed may have been secondary to changes in oculomotor
behavior that cooling produced. Arguing against this interpretation of
the results was the finding that cooling parietal and prefrontal cortex
produced largely equivalent effects on neuronal physiology but had
differential effects on ODR performance.
The results of the present experiment agree with work in other
distributed cortical networks in the visual (Bressler
1995,1996
; Payne et al. 1996
; Salin and
Bullier 1995
) and motor systems (Alexander and Crutcher
1990a
,b
; Ashe and Georgopoulos 1994
;
Caminiti et al. 1996
; Crutcher and Alexander
1990
; Johnson et al. 1996
) to indicate that
patterns of neuronal activity recorded within a single cortical area
are likely to reflect concurrent processing in many others. Taken in
conjunction with anatomic data indicating the prevalence of projections
between cortical areas (Felleman and Van Essen 1991
),
the present data support a dynamic view in which the patterns of
neuronal activity modulation associated with behavioral events are
generated by the concerted action of groups of interacting cortical
areas. This interaction appears to involve the flux across cortical
areas of a group of shared signals exchanged between neurons with
similar patterns of activity modulation. The present data favor the
inclusion of working memory in such a process through which prefrontal
cortex and other cortical areas interact to drive the sustained
neuronal discharge associated with the formation and maintenance of
internal representations.
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ACKNOWLEDGMENTS |
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The authors thank S. Funahashi for important assistance during early phases of this research. We thank J. Fuster for generously providing a prototype cryoprobe on which the current design was based, S. Ó Scalaidhe for insightful discussions regarding this work and for assistance regarding the method of analysis of the data, and C. Bruce for the computer program that controlled the experiments. We also thank G. Leydon for the development of data analysis programs, T. Beattie, P. Pivirotto, and M. Papero for assistance with animal care, and J. Coburn and M. Pappy for assistance in histological processing.
This work was supported by National Institute of Mental Health Grants MH-38546 and MH-44866.
Present address of M. V. Chafee: Brain Sciences Center, Dept. of Veterans Affairs Medical Center, Minneapolis, MN 55417.
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FOOTNOTES |
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Address reprint requests to P. S. Goldman-Rakic.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 May 1999; accepted in final form 29 November 1999.
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REFERENCES |
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