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University of Oxford, Department of Experimental Psychology, Oxford OX1 3UD, United Kingdom
Submitted 6 September 2002; accepted in final form 24 February 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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; Carmichael and
Price 1995,
1996;
Ongur and Price 2000;
Van Hoesen et al. 1993;
Vogt et al. 1987;
Vogt and Pandya 1987). Area 25
has descending connections in the rat to autonomic effector regions—such
as the nucleus of the solitary tract, dorsal vagal nucleus, magnocellular
neurosecretory cell groups in the hypothalamus, ventrolateral medulla, or
intermediolateral column of the spinal cord (Gabbott and Busby
1997,
2000;
Hurley et al. 1991). In the
monkey, descending projections from area 25 do reach structures with strategic
roles in autonomic function, such as the bed nucleus of the stria terminalis,
perifornical, and anterior hypothalamus, periaqueductal gray, dorsal raphe,
and lateral parabrachial nucleus (Freedman
et al. 2000). The anterior cingulate cortex (which includes also
areas 24a and 24b) has output projections to the periaqueductal gray in the
midbrain (which is implicated in pain processing), to the nucleus of the
solitary tract and dorsal motor nucleus of the vagus (through which autonomic
effects can be elicited), and to the ventral striatum and caudate nucleus
(through which behavioral responses could be produced).
The subgenual cingulate cortex has been implicated in depression in humans
in that the recovery of depression associated with fluoxetine treatment is
associated with a decrease of glucose metabolism [as indicated by
fluorodeoxyglucose positron emission tomography (PET)] in the ventral
(subgenual) cingulate area 25, while the induction of a mood of sadness in
normal subjects increased glucose metabolism in the same area (see
Mayberg 1997;
Mayberg et al. 1997). On the
other hand, Drevets et al.
(1997) showed that PET
measures of regional blood flow and glucose metabolism and magnetic resonance
imaging (MRI) based measures of gray matter volume are abnormally reduced in
the "subgenual prefrontal cortex" in depressed subjects with
familial major depressive disorder ("unipolar depression") and
bipolar disorder ("manic-depressive illness").
Raichle (1998) has noted
that when humans become engaged in tasks such as word reading and verb
generation, the activity observed in neuroimaging studies along the midline in
the orbitofrontal cortex decreases, whereas when the humans are not actively
involved in such tasks, but merely passively viewing the words, the activity
increases.
Given that the subgenual cingulate cortex has been implicated in
depression, we performed the single neuron recording investigation described
here to provide fundamental evidence on the types of input it might receive
that would activate neurons in it. Because the subgenual cingulate cortex has
connections with areas such as the amygdala and orbitofrontal cortex in which
the stimuli that activate neurons have been analyzed (Rolls
1999,
2000a,b),
we performed the experiments described here using similar stimuli and testing
methods. In particular, we investigated whether neurons in the pregenual
cingulate cortex are activated by taste, olfactory, oral somatosensory, or
visual stimuli. The visual stimuli were given during a visual discrimination
reversal task, as this has been shown to activate orbitofrontal cortex neurons
(Rolls et al. 1996a;
Thorpe et al. 1983), and
included faces, as these activate a small proportion of orbitofrontal cortex
neurons (Rolls et al. 2003). We were also able to measure whether the neurons
had activity related to movements, in that during the Go/NoGo visual and
olfactory discrimination tasks, the monkeys had to initiate the response of
licking a tube to obtain fruit juice when some olfactory or visual stimuli
were shown, and to with-hold licking when other visual or olfactory stimuli
were shown to avoid the taste of aversive saline
(Rolls et al. 1996a).
These are the first recordings we know from the primate subgenual cingulate cortex.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Recordings were made from single neurons in the subgenual cingulate cortex,
area 25. The subjects were two rhesus macaques (Macaca mulatta)
weighing 2.5–3.5 kg. Neurophysiological methods were the same as
described previously (Rolls et al.
1990; Rolls and Baylis
1994; Scott et al.
1986a,b;
Yaxley et al. 1990). All
procedures, including preparative and subsequent ones, were carried out in
accordance with the "Policy on the use of animals in neuroscience
research" of the Society for Neuroscience and were licensed under the UK
Animals (Scientific Procedures) Act 1986. The monkey was fed during the
experiments and on return to its home cage was allowed ad libitum access to
water. Glass-coated tungsten microelectrodes were constructed in the manner of
Merrill and Ainsworth (1972)
without the platinum plating. A computer (Pentium) with real-time digital and
analogue data acquisition collected spike arrival times and displayed on-line
summary statistics or a peristimulus time histogram and rastergram. To ensure
that the recordings were made from single cells, the interspike interval was
continuously monitored to make sure that intervals of <2 ms were not seen,
and also the waveform of the recorded action potentials was continuously
monitored using an analogue delay line.
Localization of recordings
X-radiography was used to determine the position of the microelectrode
after each recording track relative to permanent reference electrodes and to
the anterior sphenoidal process. This is a bony landmark whose position is
relatively invariant with respect to deep brain structures
(Aggleton and Passingham 1981).
Microlesions made through the tip of the recording electrode during the final
tracks were used to mark the location of typical units. These microlesions
together with the associated X-radiographs allowed the position of all cells
to be reconstructed in the 50-µm brain sections with the methods described
in Feigenbaum and Rolls
(1991). The subgenual
cingulate cortex was as defined in the studies of Carmichael and Price
(1994,
1995); Freedman et al.
(2000); Van Hoesen et al.
(1993); Vogt et al.
(1987); Vogt and Pandya
(1987); and where these
sources differ, we used the borders shown in the standard laboratory atlas for
macaques of Paxinos et al.
(2000), which uses Nissl and
other histochemical staining techniques to define cortical areas.
Screening of neurons
TASTE. The testing methods used were those described by Rolls et
al. (1990,
1996b) and shown to activate
orbitofrontal cortex neurons. The gustatory stimuli included 1.0 M glucose
(G), 0.1 M NaCl (N), 0.01 M HCl (H), 0.001 M QHCl (Q), and 0.1 M monosodium
glutamate (M). The concentrations of most of the tastants were chosen because
of their comparability with our previous studies, and because they are in a
sensitive part of the dose-response curve. The monkey's mouth was rinsed with
distilled water during the inter-trial interval (which lasted ≥30 s, or
until neuronal activity returned to baseline levels) between taste stimuli.
The stimuli within a set were delivered in random sequence. The stimuli were
delivered orally in quantities of 0.2 ml with a hand-held 1 ml syringe. For
chronic recording in monkeys, this manual method for stimulus delivery is used
because it allows for repeated stimulation of a large receptive surface
despite different mouth and tongue positions adopted by the monkeys (Scott et
al.
1986a,b).
The firing rates were measured in a 3-s poststimulus delivery period, as this
is the period in which taste neurons, and the neurons described here, were
found to have their main responses. For additional comparisons, the neuronal
responses were also tested to a range of foods including banana, orange, apple
juice, milk, and 20% blackcurrant juice.
ORAL SOMATOSENSORY STIMULI INCLUDING FAT. The testing methods
used were those described by Rolls et al.
(1999) and shown to activate
orbitofrontal cortex neurons. To test for the oral effects of fat on neuronal
activity, a set of fat and fat-related stimuli was delivered in the same way
with a pseudorandom sequence. The fat stimuli included "single"
cream (cream) (18% fat), "double" cream (47.5% fat), triolein,
groundnut oil, and half-fat milk (milk) (1.8% fat). Triolein (glyceryl
trioleate) was used as a pure fat. Vegetable oil (59.5% monounsaturates, 34%
polyunsaturates, and 6.5% saturates) and groundnut oil were used as other
natural high-fat stimuli. To investigate whether the neurons responsive to
cream were in some way responding to the somatosensory sensations elicited by
the fat, stimuli with a similar mouth feel but nonfat chemical composition
were used. These stimuli included paraffin oil (pure hydrocarbon) and silicone
oil [Si(CH3)2O)n]. To control for
specificity of the somatosensory input which could activate these neurons,
other nonfat-related, oral somatosensory or motor responsiveness of neurons
was screened for by allowing the monkey to chew on a short length of plastic
tubing. Due to the tenacious nature of the oral coating resulting from the
delivery of cream or oil, the interstimulus interval was prolonged (usually
more than 2 min) and repeated rinses with water were given during this
period.
OLFACTORY STIMULI. Responses to odorants were determined using
either a perfumer strip method or an olfactory discrimination task (see
Critchley and Rolls
1996a,b;
Rolls et al. 1996a). The
criteria for olfactory responsiveness were a significant elevation of cellular
firing above the spontaneous firing rate to an odorant (measured during a 5-s
period of presentation in front of the monkey's nose of a cotton bud/perfumer
strip saturated in odor vapor), and no response to an odorless cotton bud was
used as a control. The olfactory discrimination task involved the randomized
delivery of odorant-saturated air via a computer-driven olfactometer
(Critchley and Rolls 1996a). A
cue tone preceded the delivery, following which the monkey was required to
sample each odor to identify odors as part of a Go/NoGo task. A lick response
to a rewarded odorant was rewarded with the delivery of a sweet aspartame
solution from the lick tube; a lick response on the NoGo trials was associated
with the delivery of a mildly aversive saline solution. On-line rastergrams
and statistics enabled the determination of olfactory responsiveness. An air
extraction apparatus was located above the monkey's head to remove odor (see
Critchley and Rolls 1996a).
VISUAL STIMULI. Responses to visual stimuli were determined
using a visual discrimination task to present images, views of objects, and
faces on a video monitor (see Rolls et al.
1996a, 2003;
Rolls and Deco 2002), and by
presenting real objects and faces through a large aperture (5 cm) shutter
(Thorpe et al. 1983). The
visual discrimination task involved the randomized presentation on a video
monitor of one stimulus per trial in a Go/NoGo paradigm. A 500-ms cue tone
preceded the visual stimulus. A lick response to a rewarded visual stimulus
was rewarded with the delivery of a fruit juice solution from the lick tube; a
lick response on the NoGo trials was associated with the delivery of a mildly
aversive saline solution. The task was typically run with two visual stimuli,
one of which was rewarded and the other was not, or with six visual stimuli,
three of which were rewarded and three of which were not. The actual stimuli
being used could easily be changed, so that a comparison of the effects of
novel and already familiar stimuli could be compared. The stimuli could
include faces (cf. Rolls and Tovee
1995). On-line rastergrams and statistics enabled the
determination of visual responsiveness.
SLEEP. If the monkey was not being delivered stimuli, he sometimes fell asleep. Because some of the subgenual cingulate neurons altered their activity when this occurred, we now define the criteria used to judge that the monkey was asleep. The criteria included the onset of smooth (in contrast to saccadic) eye movements, closing of the eyes, and being behaviorally less responsive, in that sometimes a loud noise or a touch was required to awaken the monkey. When the monkey was awakened, it typically took a few seconds for the monkey to become fully alert, as judged by the eyes being fully open, the monkey opening his mouth to receive fruit juice offered, and starting to perform a visual discrimination task if this was available. To confirm that these behavioral criteria were adequate to define sleep, the electrocorticogram (ECG) was measured on a number of occasions. The recordings were made between a large electrode touching the dorsal parietal cortex and a large reference ground wire attached to the head. The potentials were low-pass-filtered to include the frequency range 0–50 Hz and sampled at 100 Hz. When the monkey was awake by the behavioral criteria, the ECG showed low-voltage fast activity. When the monkey was asleep by the behavioral criteria, large-voltage slow waves appeared in the ECG. Analysis of the power spectrum as described in the results indicated that when the monkey was judged to be asleep by the behavioral criteria (described further below), the ECG showed slow waves (low-frequency activity), indicating that the type of sleep was slow-wave sleep.
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RESULTS |
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The activity of a neuron that had a baseline firing rate of 0 spikes/s when
the monkey was awake and performing a visual discrimination task, or being
tested with taste and olfactory stimuli, is shown in
Fig. 1. Each point represents
the firing rate measured over a 2-s period. At the start of the period of
recording shown, the monkey was awake, having just been tested with taste,
olfactory, and visual stimuli. After a period without testing and interaction
with the experimenter, the monkey fell asleep at 26 s after the start of the
recording period shown. Sleep was assessed by the experimenter by the monkey
adopting a relaxed position in which the arms and legs remained still, the
eyes closed, and only a loud noise from the experimenter would arouse the
monkey to perform the task if it was re-enabled. In this period the eyes
showed the typical slow drift typical of drowsiness and slow-wave sleep. Rapid
eye movements were not observed, and indeed in the relatively short periods of
sleep that took place during the recordings, given that the monkey was
squatting in a chair, and given that the monkeys were not sleep deprived, it
is very unlikely that the monkeys entered paradoxical sleep from slow-wave
sleep. At the time when the monkey became drowsy and fell asleep at 26 s in
Fig. 1, the subgenual cingulate
neuron increased its firing rate to approximately 4 spikes/s. As the neuron
had previously been so silent, this was a major change in its activity. The
neuron continued to fire for approximately 110 s, and then it stopped firing
and the monkey woke up. The increase of firing rate when the monkey was asleep
was thus repeatable and highly statistically significant (t-test,
awake versus asleep, P = 7 x
10–17). No other stimuli or event was found that
altered the firing rate of the neuron, including performance of the visual
discrimination task. The decrease of firing rate as the sleep period
progressed was found for this particular neuron, but was not characteristic of
the population as a whole. Most of the neurons did not show a trend of firing
rate during the period while the monkey was asleep. The 10-s decrease in the
firing rate of the neuron during the second sleep epoch shown in
Fig. 1 (around time 230 s) was
probably related to a short epoch of ECG activation, which often occurs during
slow-wave sleep (Steriade
1996a,b,
2000).
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The behavioral criteria for sleep were complemented by ECG recordings as
described in the Methods. The changes in the ECG from the low-voltage fast
activity when the monkey was behaviorally awake to the large-voltage slow
waves found when the monkey was asleep were measured quantitatively by
calculating the power spectra of the ECG when awake and asleep, using 40
samples each 1 s long to provide low errors in the spectral calculation
performed by fast fourier transform (FFT) methods
(Press et al. 1992). These
power spectra are shown in Fig.
2. It is clear that when asleep, there was much more power in the
low-frequency range (5–15 Hz) than when awake. This is the typical
signature of slow-wave sleep and shows that in the periods when the monkey was
behaviorally identified as in sleep, then the ECG signs confirmed this and
showed that the sleep was slow-wave sleep. The power spectra shown in
Fig. 2 show that, although low
frequencies (<15 Hz) are drastically reduced during waking, fast
frequencies (from approximately 18 to 50 Hz) survive during sleep and are
almost similar to fast activities during waking. This is due to the fact that
the depolarizing phase of the slow sleep oscillation is crowned by fast
activities, which are not only evident in anesthetized animals
(Steriade et al. 1996) but
also by using intracellular recordings of neocortical neurons in naturally
sleeping animals (Steriade et al.
2001).
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Twelve of the sample of 93 neurons (12%) recorded in the subgenual
cingulate cortex had responses that were similar to those of the neuron shown
in Fig. 1 (apart from the trend
to gradually decrease toward the end of the sleep period). Although typically
the neurons recorded in the subgenual cingulate cortex with sleep-related
activity increased their firing rate when the monkey fell asleep, one neuron
had a decrease from 7.5 to 5 spikes/s when the monkey fell asleep. The
spontaneous firing rates of this population of 12 neurons, and the changes
they showed when the monkeys fell asleep, are shown in
Table 1. The changes were
highly statistically significant, as shown. The very low firing peak rates of
these neurons were very notable, as shown in
Table 1. The firing pattern of
the neurons was quite regular when they were firing, and the interspike
intervals of a typical neuron are shown in
Fig. 3. It is of interest that
these subgenual cortex neurons not only increase their activity during
slow-wave sleep, but also do not show bursting patterns (which would be
reflected in the interspike interval histogram by many intervals shorter than
100 ms) during sleep. Both of these properties are different from those of the
majority of neurons in other cortical areas (Steriade
1996a,b,
2000).
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To investigate whether disengagement from the task that the monkeys performed was sufficient to activate these neurons, their firing rate was measured in the inter-trial interval, which was normally 8 s. This was not sufficient for any of the neurons with sleep-related activity to increase their firing rate. However, to increase the disengagement from the task much more in the inter-trial interval, the inter-trial interval was lengthened to periods of ≤60 s. No sleep-related neurons increased their firing rate with these long inter-trial intervals if the monkey remained awake. For two other neurons, not classified as sleep-related, the neuronal response was generally fast during the inter-trial interval and decreased only during the trial. An example of one such neuron is shown in Fig. 4. The visual stimulus was shown at time 0 and was preceded by a 500-ms warning tone cue. The neuron decreased its firing rate approximately 100 ms after the visual stimulus was shown and remained low until approximately the time when the trial ended (which occurred 0.5 s after the 2-s discriminative visual stimulus was turned off). The other neuron (bk036) which fired when the monkey was disengaged in this way from the task had activity that was similar to that illustrated for neuron bk022 in Fig. 4. These two neurons did not alter their activity further when the monkey became drowsy and fell asleep.
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It was found that some subgenual cingulate neurons increased their firing rates only when novel visual stimuli were shown. An example is provided in Fig. 5. The neuron had no responses to familiar visual stimuli, including three faces associated with fruit juice reward and three faces associated with saline in the visual discrimination task. However, when a completely novel visual stimulus was shown on the screen (in the visual discrimination task), the neuron increased its firing rate (to 4 spikes/s). Figure 5 shows that over subsequent presentations of these novel visual stimuli (interleaved with others), the neuronal response decreased, reaching half-maximum over three to four trials. For the other neuron (bk063), the mean firing rate to novel stimuli was 3.6 spikes/s, and the mean firing rate to familiar stimuli was 3.0 spikes/s, with no further decrease found with increasing familiarity.
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The recording sites of the neurons described here are shown in Fig. 6. A summary of the proportions of each neuron type is shown in Table 2.
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In addition, we explored beyond the subgenual cingulate cortex to investigate whether any neurons in nearby areas had activity related to sleep. We found a population of 4 neurons of 177 neurons tested in the orbitofrontal cortex that increased their activity during sleep. Data on these neurons are shown in Table 3. The recording sites of these four cells in the orbitofrontal cortex are shown in Fig. 7.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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It is of interest to compare the responses of subgenual cortex neurons with
those of neurons in the head of the caudate nucleus, for the comparison
underscores that fact that whereas the head of caudate nucleus neurons become
engaged in firing on a trial-by-trial basis, the subgenual neurons have a
tonic change which lasts throughout the period in which the monkey is asleep
and do not generally switch on tonically just while the monkey waits between
trials for the next trial to start a few seconds later. In this sense the
subgenual cingulate neurons are not just the converse of the large population
of neurons in the head of the primate caudate nucleus, which are very closely
related to the monkey being involved in each trial of a task. These
head-of-caudate neurons start to respond when a 500-ms warning cue such as a
tone or a light, which indicates that a trial of the visual discrimination
task used here is starting. They continue to respond throughout the trial;
that is, they stop firing on reward trials when the reward-related
discriminative visual stimulus disappears and fruit juice is no longer
available and stop responding on saline trials within approximately 200 of the
onset of the visual stimulus which informs the monkey that licks should not be
made; otherwise aversive saline will be obtained
(Rolls et al. 1983;
Rolls and Treves 1998; Chapter
9; Rolls 1999; Chapter 6).
Some neurons in this population respond to environmental cues such as the door
opening, or the experimenter reaching toward the place where food that may be
given to the monkey during testing is located. This population of neurons in
the head of the caudate thus respond between them to a wide range of stimuli
which have in common the property that they engage the monkey in the testing
situation by indicating that an event such as a reward stimulus which will
require an action or a nonreward stimulus is shown. In contrast, the primate
subgenual cingulate neurons described here do not respond in a clear
time-locked way to the engagement in a trial and the stimuli that initiate
this, but instead are much more closely related to actually sleeping.
It was surprising in view of the connections between the orbitofrontal cortex and the subgenual cingulate cortex that subgenual cingulate neurons did not in some cases have responses to taste, olfactory, and most visual stimuli, even though the testing methods, including the tasks used, were the same for both areas. One type of response found in the subgenual cingulate cortex was, however, similar to those of a population of neurons in the anterior orbitofrontal cortex that responds to novel visual stimuli (in preparation).
The subgenual cingulate cortex neurons recorded were probably pyramidal cells and not interneurons in that the spikes of these neurons were large and wide, which is typical of cortical pyramidal cells.
The findings on the subgenual cingulate cortex indicate that the most
frequent correlate of neuronal firing was the state of sleep, with high firing
rates during slow-wave sleep. Neurons that show large increases in their
firing rates during sleep are unusual, and indeed, are not characteristic of
any other cortical area we know apart from callosal neurons linking precentral
motor areas (see Steriade 2000
and Steriade et al. 1974). To
obtain further evidence on whether there is any similar set of neurons in
nearby, and connected, brain areas, we also recorded from orbitofrontal cortex
neurons in one of the same monkeys with the same protocol. Of quite a large
sample of orbitofrontal cortex neurons (177), we found four that did increase
their firing rates during slow-wave sleep. This shows that such neurons are
not found only in the subgenual cingulate cortex. However, the orbitofrontal
cortex neurons were different from those in the subgenual cingulate cortex, in
that the increases of rate were small, from a mean of 0.1 spikes/s when awake
to a mean of 1.0 spikes/s when asleep. Moreover, in contrast to the subgenual
cingulate neurons, the orbitofrontal cortex sleep-related neurons were
intermixed with neurons that had responses to many other types of stimuli and
events, including taste, olfactory, and visual reward-related stimuli (see
Rolls 1999,
2000a,b).
The finding that the most frequent type of neuron found in the subgenual
cingulate cortex increased the firing rate during sleep is of interest for a
number of reasons. First, there are few brain regions known where the neurons
show an overall increase in their firing rates very markedly during sleep. In
the midbrain reticular-activating system, for example, neurons have low firing
rates during sleep and increase their firing rates during wakefulness, being
stimulated into activity by arousing stimuli such as somatosensory inputs, and
once firing, by maintaining the evoked increase of firing rates for periods of
often several minutes (Rolls
1971; Steriade
1996a,b).
Second, the neurophysiological findings reported here suggest that it would
be interesting to extend the human neuroimaging observations described by
Raichle (1998). He summarized
a number of findings which indicated that in neuroimaging studies the
activation of medial frontal lobe areas is increased when humans are not
performing a task. The possibility that this activation reflected some
disengagement from the tasks was discussed. In view of the findings described
here, and to help understand these brain areas better in humans, we suggest
that it would be of interest to investigate whether a better correlate of the
activation of these medial frontal areas might be sleep. Indeed, some of the
subjects in the investigations described by Raichle
(1998) may have become drowsy
when they were not required to perform a task, and it would be of interest to
investigate whether it is the drowsiness or sleep that accounts for the
activation here, rather than not actually being engaged in performing a
task.
Third, the subgenual cingulate cortex may play a role as a strategic
cortical portal for regulation of the autonomic nervous system (e.g.,
Owens and Verberne 2001). This
role is indicated by, for example, its descending connections in rats to brain
stem autonomic effector regions such as the dorsal motor nucleus of the vagus
(related to parasympathetic function) and the ventrolateral medulla (related
to sympathetic function) (Gabbott and Busby
1997,
2000;
Hurley et al. 1991). The
connections in primates are to regions that may have similar functions and are
in addition to the periaqueductal gray, dorsal raphe, parabrachial nucleus,
and hypothalamus, as noted above. In this context, the increased activity in
sleep in the subgenual cingulate cortex might be hypothesized to be involved
in the altered control of gut and cardiopulmonary function that occurs during
sleep.
Fourth, the findings reported here are of interest in relation to findings
on the brain states related to depression
(Drevets and Raichle 1992;
Dolan 1997;
Dolan et al. 1992). Mayberg
and colleagues reported that the recovery of depression in humans associated
with fluoxetine treatment is associated with a decrease of glucose metabolism
(as indicated by fluorodeoxyglucose PET) in the ventral (subgenual) cingulate
area 25, while the induction of a mood of sadness in normal subjects increased
glucose metabolism in the same area (see
Mayberg 1997;
Mayberg et al. 1997). Now it
might be expected that depressed patients would interact much less with their
environment, while after recovery they would be much more alert and engaged in
their environment. Inducing sadness might similarly produce less alertness and
responsiveness to environmental activating stimuli. It would thus be of
considerable interest to know whether simply reducing arousal and allowing
sleep in humans would result in an increase in activation found by
neuroimaging in the subgenual cingulate region. If so, the findings in this
region in depressed patients might just reflect their altered state of
alertness. Of course, it might also be the case that the activity in this
region is a contributing causal factor to depression, one manifestation only
of which might be altered alertness and engagement with the environment. In
either case, it would help to interpret the findings in this brain region (and
the reciprocal changes in more dorsal parts of the frontal cortex) of
depressed patients if it were known whether this area did increase its
activation in humans simply when they become less alert or fall asleep. Given
the suggestions of a relation between depression and paradoxical sleep
(Liscombe et al. 2002;
Wichniak et al. 2000), it
would also be of interest in future investigations to perform single-neuron
recordings in monkeys from the subgenual cingulate cortex and to study this
region using functional magnetic resonance imaging (fMRI) in humans, during
paradoxical sleep.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Present addresses: K. Inoue, University of Kyoto, Graduate School of Agriculture, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan; A. Browning, Monash University, Department of Physiology, 3800 Victoria, Australia.
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FOOTNOTES |
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Address reprint requests to E. T. Rolls (E-mail: Edmund.Rolls{at}psy.ox.ac.uk; URL: http://www.cns.ox.ac.uk).
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REFERENCES |
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