This study will evaluate emotional processing biases in the brain while viewing facial
expressions in adults with current or remitted major depressive disorder and healthy
The goal of this research is to elucidate the neurophysiological abnormalities associated
with processing emotionally valenced stimuli in MDD. Neuroimaging technology has led to the
identification of specific abnormalities in the amygdala, ventral striatum and medial
prefrontal cortex in response to affective pictures. Much of the knowledge involving these
structures in emotion processing has been elucidated through animal models including
classical fear conditioning and reversal-learning paradigms. Functional magnetic resonance
imaging (fMRI) studies have applied similar techniques in humans to study emotional
processing. The amygdala has been shown to play a role in the learning of fear (aversive)
conditioning to emotional stimuli, the ventral striatum has been shown to play a role in
appetitive conditioning, and areas of the prefrontal cortex are recruited for extinction of
conditioned responses. These areas have also been implicated as key structures in the
abnormal expression of emotion in MDD. Dysregulation of connections between the amygdala and
prefrontal cortex has been hypothesized to influence depressed subjects' tendency to
ruminate on emotional events and memories, which may be associated with an inability to
properly regulate emotional processing through habituation and extinction mechanisms.
Research suggests that depressed individuals have an impaired ability to disengage from or
habituate to emotional stimuli perceived as sad.
In addition to studying emotional processing at a conscious, cortical level, significant
evidence suggests that many aspects of emotional processing occur below conscious awareness,
at a preconscious level. The technique of backward masking assesses the automaticity of
emotional processing and responses to affective stimuli. In MDD, backward masking serves to
avoid confounding interpretation by the presence of other cognitive processing, which may
result from depressed subjects perseverating on emotional stimuli. The proposed study builds
on previous fMRI research to investigate neurophysiological differences in the processing of
aversively conditioned emotional stimuli in depressed compared to healthy individuals. Using
fMRI technology and a variation of the paradigm developed by Morris et al., subjects with
MDD will be classically conditioned to the presence of an unmasked specific target face
(angry or sad) and the subsequent neural responses to the stimuli will be assessed utilizing
the backward masking technique. The BOLD hemodynamic response and rates of habituation and
extinction to the faces will be compared between depressed subjects with MDD and healthy
controls, currently depressed versus currently remitted subjects with MDD, and MDD subjects
pre- and post-antidepressant therapy.
The present amendment proposes to include an additional paradigm in the testing battery.
This new paradigm has been extensively examined under different pharmacological
manipulations, and in healthy individuals undergoing fMRI but has yet to be examined in
patient populations. The task complements the paradigms presently included by extending the
research to encompass appetitive as well as aversive emotional processing.
This research will be used to evaluate neural processes involved in emotional dysregulation
in MDD and may direct future research to potential therapeutic approaches for the treatment
of mood and anxiety disorders with abnormalities in emotional processing.
- INCLUSION CRITERIA:
Healthy Volunteers (n=65)
Healthy Control Sample (n = 30, phase 1; n = 15, phase 3; n=20, phase 5): Right-handed
subjects (ages 18-55) will be selected who have not met criteria for any major psychiatric
disorder, have no known first-degree relatives with mood disorders, and have a current
score on the Hamilton Depression Rating Scale (HDRS; 17 item) in the not depressed range
(less than or equal to 7). Control subjects will be matched to depressed subjects for age,
gender, and education.
MDD Samples (n =80)
MDD Sample-Currently Depressed (n = 30, phase 1; n = 15, phase 3; n=20, phase 5):
Right-handed subjects (ages 18-55) will be selected with primary MDD currently depressed
by DSM-IV criteria for recurrent MDD and current HDRS score in the moderately-to-severely
depressed range (greater than or equal to 18).
MDD Sample-Remitted Depressed (n = 15, phase 2): Right-handed subjects (ages 18-50) will
be selected with a past history of MDD by DSM-IV criteria.
Healthy Relatives of MDD Subjects (n=45)
Right-handed subjects (ages 18-55) will be selected who have a first-degree relative with
MDD but do not themselves meet criteria for a psychiatric disorder. Subjects will be
matched to depressed and control subjects for age, gender, and education.
Subjects will be recruited who are drug-na ve or who have not received psychotropic drugs
for at least 3 weeks (8 weeks for fluoxetine) prior to scanning. Effective medications
will not be discontinued for the purposes of the study. Subjects will also be excluded if
they have a) serious suicidal ideation or behavior, b) psychosis to the extent that the
ability to provide informed consent is in doubt, c) medical conditions or concomitant
medications (see Appendix III) that are likely to influence cerebral blood flow or
neurological function including cardiovascular, respiratory, endocrine and neurological
diseases, d) a history of drug or alcohol abuse within 1 year or a lifetime history of
alcohol or drug dependence (DSM-IV criteria), e) current pregnancy (as documented by
pregnancy testing prior to scanning), f) general MRI exclusion criteria, g) history of
non-response to Zoloft or of intolerable or adverse side effects during Zoloft treatment.
Additional exclusion criteria applied to control subjects are: a) subjects with a current
or past history of other axis I psychiatric conditions, b) subjects with first-degree
family members with current or past history of mood disorder.
Subjects beyond age 55 are excluded to reduce the biological heterogeneity encompassed by
the MDD criteria, and to reduce the variability of the BOLD signal. Subjects whose first
major depressive episodes arose temporally after other major medical or psychiatric
conditions will also be excluded, since their functional imaging results generally differ
from those reported in primary MDD.