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Autism
Altered social and emotional cognition in autism and in the related
disorder of Asperger’s Syndrome (AS) have received the most
attention in terms of neuroimaging. Hence, there is more information
available in this group about how activity in the social network
is disrupted. Consistent with behavioural studies showing that basic
face perception is abnormal in individuals with autism (37), activity
in the fusiform gyrus is reduced during face perception tasks involving
neutral faces (38,39). Interestingly, activity in the lateral temporal
cortex, which is thought to be more sensitive to nonface objects
(40,41), is increased in autism patients compared with control subjects
(39). Perception of emotion in faces is also impaired in autism
(42,43), and activity in the amygdala during presentation of emotional
faces is reduced (44). Autism patients, therefore, appear to have
significant problems with aspects of face perception that are crucial
to social cognition, along with deficits in activity of the brain
regions that mediate these functions.
TOM in children with autism has been examined in several studies
(45,46) and is generally impaired relative to normally developing
children. Neuroimaging has been used to study TOM in adults with
autism or AS in 2 experiments. Baron-Cohen and others (47) presented
pictures of individuals’ eyes and had subjects judge either
the sex of the person or the mental state expressed by the eyes
(for example, “concerned”). Both the persons with autism
and the control subjects had increased activity in the TOM task,
compared with the sex task, in the left DLPFC and the bilateral
STS. Control subjects had greater activity than did autism patients
in the left amygdala and the VLPFC, whereas activity in the STS
was greater in the patients. A second study by Happe and others
used a different task, consisting of stories that required TOM to
be interpreted correctly, contrasted with non-TOM stories (48).
Patients with AS were examined in this experiment and were impaired
on TOM performance and had reduced activity in a region of dorsomedial
PFC that showed increased activity during TOM tasks in previous
experiments (30,31). The patients did have activity in the medial
PFC, but it was located ventrally to the region seen in control
subjects, close to an area that has been found in at least 1 TOM
study in normal individuals (29). Activity in STS regions did not
differ between AS patients and control subjects. These experiments
indicate that the areas activated by TOM tasks appear to be somewhat
task-specific, but that prefrontal activity in autism and AS during
TOM tasks is reduced, both in ventrolateral and in dorsomedial regions.
In contrast, the areas of STS that are sensitive to gaze direction
may be activated normally.
Other experiments on individuals with autism have not addressed
social cognition directly but have provided information on some
of the brain areas in the proposed network. One experiment scanned
patients with autism and AS while they were performing a verbal
memory task (49) and found that they had reduced activation in both
the rostral and dorsal anterior cingulate regions, compared with
a control group. Another study used an embedded figures test (50),
in which the individuals with autism performed normally but, nevertheless,
showed reduced activity in the right DLPFC. Further, the patients
had greater activity in occipital areas, which is interesting in
light of abnormally activated occipital activity during face tasks,
mentioned above. Taken together, all these imaging experiments indicate
that individuals with autism have dysfunction in almost all regions
in the proposed social cognition network, mostly consisting of reduced
activity. Note that these abnormalities have been found in high-
functioning autism and AS patients, who clearly demonstrate these
widespread changes, despite being less disabled than autism patients
in general.
Schizophrenia
Despite the numerous studies describing impairments of social cognition
in persons with schizophrenia, very few imaging studies have addressed
any aspect of social cognition directly. TOM has been examined extensively
in schizophrenia and is generally found to be impaired (51,52–58).
Similarly, there is evidence that face processing is altered in
persons with schizophrenia, both the processing of neutral faces
(59) and the perception of emotional expressions on faces (60–62).
There have been 3 imaging experiments reported using faces as stimuli,
2 that examined emotional processing, and 1 that examined TOM. In
1 of these experiments, face stimuli that express basic emotions
were presented, and subjects carried out a sex-discrimination task
(63). Subjects with schizophrenia differed from control subjects
in several brain regions, depending on the emotion of the face.
They showed less activation in the left VLPFC for angry faces and
less activity in the amygdala for fearful faces. A second experiment
examining emotion in schizophrenia used happy and sad faces to induce
corresponding moods, with sex discrimination as the control task
(64). During the mood task, patients showed less activation of the
amygdala, as well as a reduced ability to recognize the face emotions,
compared with control subjects. The TOM experiment (65) used the
“eyes” task that was used for autistic patients (47).
Schizophrenia patients made more errors on the task and showed less
activation of the left VLPFC, compared with control subjects. Thus,
schizophrenia, like autism, associates with deficits in emotional
processing and TOM. In addition, it associates with reduced activity
in the amygdala and in the VLPFC on tests of emotion and TOM derived
from faces.
By far, most imaging studies of schizophrenia patients have focused
on impaired working memory and altered activity in DLPFC, and work
in this area has a long-standing history in the imaging field (66).
Recently, several fMRI studies have examined this issue, most using
a version of the n-back task, but sometimes with conflicting results.
The n-back task is one in which a stream of stimuli are presented,
and subjects are instructed to respond to a stimulus if it was presented
1 or 2 back in the sequence. In one such experiment, Callicott and
others used 0-, 1-, and 2-back tasks, with visually presented digits,
in both schizophrenia and control subjects (67). Both groups showed
an increase in prefrontal and parietal activity with increasing
task load, but this increase was larger in parietal cortex in the
control subjects and larger in the right DLPFC in schizophrenia
patients. In addition, this right PFC activity was correlated positively
with performance in control subjects but correlated negatively in
the patients, suggesting an inefficiency of cortical response in
this region. Perlstein and others reported a similar experiment
using 0-, 1-, and 2-back tasks with letters. In this study, however,
schizophrenia patients showed a smaller increase in right DLPFC
activity, with increasing task load compared with the control subjects.
Correlations with performance were not reported, but severity of
disorganization symptoms in the patients correlated with signal
change in the right DLPFC, such that more severe symptoms were associated
with smaller signal changes.
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Meyer-Lindenberg and colleagues (69) and Menon and others (70),
who used an auditory 2-back task, reported similar results of decreased
DLPFC activity during n-back tasks in schizophrenia. The study by
Menon also reported a negative correlation between severity-of-thought
disorder and activity in the right DLPFC, similar to that found
by Perlstein and others. Finally, Manoach and colleagues used a
different working memory paradigm, known as the Sternberg task,
in schizophrenia patients (71). This task involved presenting a
set of stimuli that, in this case, included sets of 2 or 5 digits
followed by a probe stimulus; the subject’s task was to decide
whether the probe was part of the presented set. The patients showed
more activation in the left DLPFC during the 5-digit task, and increases
in this region were correlated with better performance on the task,
unlike the finding of Callicott and others. The results of these
experiments make clear that activity in the DLPFC is altered in
individuals with schizophrenia and is related both to their memory
ability and to symptom severity, but the direction of change in
patients may be somewhat task-specific. Other factors are most likely
involved, as well, and these are discussed in the final section.
Two additional studies used an attentional function test in schizophrenia
patients, known as the continuous performance test (CPT). In 1 of
these, first-episode patients had reduced activity in the left DLPFC,
similar to that found in some of the working memory tasks discussed
above (72). However, unlike the typical working memory task where
schizophrenia patients show reduced performance, the patients in
this study did not show a behavioural deficit on the CPT. The second
attentional experiment degraded the letter stimuli in a CPT task
to increase the number of errors committed by the participants.
Control subjects showed increased activity in the dorsal cingulate
on error trials and slowed response times, indicating increased
demand on performance monitoring. Persons with schizophrenia had
significantly reduced activity in the cingulate and failed to show
the effect on reaction times, suggesting a failure of self-monitoring
in these patients. Thus, schizophrenia patients show altered activation
of several regions in the social cognition network—including
the amygdala, the dorsal cingulate, and the VLPFC—but the most
marked differences are found in the DLPFC.
Depression
Most neuroimaging depression studies have been carried out on patients
at rest. General findings have indicated abnormal blood flow and
glucose metabolism in several regions relevant to social cognition,
including the amygdala, the rostral anterior cingulate, the orbitofrontal
cortex, and the DLPFC (73). Typically, areas involved in higher
cognitive function (for example, the DLPFC) are deactivated, while
structures mediating emotional and stress responses (for example,
the amygdala) are abnormally activated. Drevets has suggested that
increased activity in the amygdala may reflect stimulation of cortical
structures involved in declarative memory, thus accounting for the
tendency of subjects with depression to “ruminate” about
particular emotionally negative memories (74). Ventromedial prefrontal
regions also have increased metabolic activity during rest in subjects
with depression, and subgenual cingulate metabolism is related both
to depression severity and autonomic changes (75). There is evidence
that the rostral cingulate may play a critical role in recovery
from depression. Patients responding to treatment are reported to
show higher activity in the rostral cingulate, compared with a control
group, whereas nonresponders were hypometabolic relative to control
subjects (76).
Depression, therefore, appears to associate with abnormal functioning
in both higher cognitive and limbic domains. This suggests that
the phenomenology of depression might not be the result of the functional
irregularity of isolated regions but a malfunction in the regulation
of an entire network of regions involved in emotional behaviour.
A limbic-cortical dysregulation model has been proposed to account
for the pathophysiology of depression (77). Increased blood flow
to ventral paralimbic regions is thought to reflect the vegetative-somatic
symptoms associated with the disorder, while decreased blood flow
in dorsal neocortical areas characterizes compromised cognitive
function and attention capacity. There is further evidence that
an imbalance between the subgenual cingulate and the DLPFC is critical
to the dysregulation of mood and cognition in depression (78).
Several studies have examined perception of emotional stimuli in
depression patients. Sheline and others presented masked emotional
and neutral faces to healthy control subjects and subjects with
depression during a fMRI study (79). Subjects with depression demonstrated
an exaggerated left amygdala response to all faces, which was significantly
greater for fearful faces, compared with healthy control subjects.
After treatment with sertraline (a selective serotonin reuptake
inhibitor), patients showed reduced activity in the amygdala bilaterally
to all faces, most notably fearful faces, whereas there was no difference
between scanning sessions for control subjects (who were drug-free
for both scans). Similar results were reported by Yurgelun-Todd
and colleagues (80), who found increased amygdalar response to fearful
faces in patients with bipolar affective disorder, and by Drevets
(74), who found greater amygdala activity during presentation of
sad faces in depression patients.
In addition, studies of mood induction have been fruitful in understanding
the neural mechanisms of depression. Mayberg and others examined
mood provocation techniques in healthy women to isolate specific
brain regions associated with sad-mood states (78). The mood-induction
paradigm required participants to prepare a script of a sad autobiographical
memory, and when the script was presented, subjects were instructed
to feel the sadness associated with that memory, but not to ruminate
or think about the event. During sadness, activity decreased in
the right DLPFC and in the dorsal anterior cingulate, but increased
in the subgenual anterior cingulate and the insula. Resting data
from depression patients who responded to treatment with fluoxetine
were compared with these changes associated with induced sadness
in the healthy subjects. The posttreatment scans in the patients,
compared with those obtained prior to treatment, showed changes
in the same regions as in healthy volunteers, when experiencing
transient sadness; however, the direction of change was reversed.
That is, remission of depression was associated with metabolic increases
in the DLPFC and dorsal anterior cingulate and decreases in the
subgenual cingulate and the insula. These results show that sad
mood associates with a specific pattern of changes in the limbic
and cortical regions—areas that are altered in depression—
and that resolution of negative mood symptoms in depressive illness
results in a normalization of this pattern.
A mood-induction study comparing remitted depression and acute
depression patients showed similar mood-related changes in the 2
groups, except for the rostral cingulate (81). Decreased activity
in this region in the remitted group, increased activity in the
acutely ill patients, and no changes in a control group suggests
that this region may play a unique role in mediating emotional health.
A final mood-induction fMRI study used a film clip to induce sad
mood in depression patients and found significantly greater activity
in the dorsomedial PFC and in the dorsal anterior cingulate gyrus
in depression patients vs control subjects, but no difference in
the average subjective ratings of sadness (82).
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