Tracking The Life Course. The Emotional Brain Across The Life Course

Wisconsin Longitudinal Study: Tracking the Life Course
The Emotional Brain Across the Life Course
a. Specific Aims
This project will use magnetic resonance imaging (MRI) to obtain high resolution information
about the morphometry of particular brain regions
implicated in emotion and emotion regulation and
their levels of functional activation in a highly
stratified biological subsample of 500 high school
graduates in the Wisconsin Longitudinal Survey
(WLS). The WLS has followed the lives of sample members from their senior year (1957) to the
present with very little attrition, and it has supplemented adolescent socioeconomic and psychological measures with rich longitudinal data on
education, careers, economic status, family, social
activ ities, and health.
Respondents will undergo functional and structural MR imaging, along with brain electrical activity measures. The circuitry that will be featured will include the amygdala, hippocampus
and different territories of the prefrontal cortex
(PFC). Each of these structures has been implicated in different aspects of emotion and emotion
regulation and is part of the central circuitry that
is likely crucial for understanding how cumulative psychosocial burden can have deleterious effects upon health. For example, the hippocampus
plays a crucial role in the regulation of the hypothalamic -pituitary-adrenal axis. The hippocampus is a site that contains a very high density of
glucocorticoid receptors and in animal studies, it
has been found that chronically high levels of
glucocorticoids will produce hippocampal cell
death (see McEwen, 1998 for review). In humans, MRI studies have revealed hippocampal atrophy in patients with specific psychiatric disorders that involve chronic stressboth depression
and post-traumatic stress disorder. For the former, it has been reported that the cumulative
number of days depressed is in versely associated
with hippocampal volume (see Sapolosky, 2000,
for review). The hippocampus plays an important
role in context-dependent emotional responding
(see Davidson, Jackson & Kalin, 2000). An important consequence of hippocampal dysfunction
is the display of normal emotion in inappropriate contexts. The prototypic example of this is in
post-traumatic stress disorder where high levels
of fear and anxiety that might be appropriate for
Principal Investigator: Hauser, Robert M.

Project 8 Leader: Davidson, Richard J.
the original traumatic context are displayed repeatedly in safe environments. The failure to
modulate emotion in a context-appropriate fashion is likely a consequence of hippocampal dysfunction (Davidson et al., 2000). It should be
noted that in primates, in contrast to rodents, there
appears to be relatively few glucocorticoid receptors (GR) in the hippocampus (Sanchez et al.,
2000) and thus, whatever impact chronic exposure to high levels of cortisol might have in the
hippocampus, such effects may not operate
through GRs. Moreover, Sanchez et al. (2000)
have reported relatively dense GR distributions in
several neocortical areas including temporal, prefrontal and anterior cingulate cortices. The volume and shape of these regions will be extracted
in this project through voxel-wise deformationbased morphometry.
In addition to the hippocampus, the amygdala
and prefrontal cortices are other key structures in
the circuitry of emotion regulation and also play
an important role in regulating peripheral biology
that may be consequential for health (see Davidson & Irwin, 1999; Davidson, Putnam & Larson,
2000). The amygdala plays an important role in
the detection of cues of threat as well as in the
coordination of the beha vioral, autonomic and
hormonal responses that accompany responding
to aversive stimuli. The dorsolateral prefrontal
and orbitofrontal cortices play crucial roles in different aspects of emotion regulation. These areas
of the brain enable us to maintain emotion in the
absence of immediate cues for its elicitation (e.g.,
maintaining positive affect while pursuing distant
goals) and also facilitate the rapid recovery of
negative affect following exposure to a stressful
event.
For each of the brain regions identified above,
both structural and functional abnormalities have
been observed. The proposed work will include
both structural and functional assessments of cortical and subcortical territories of the brain.
In light of the fact that both age and gender have
been found to be critically important variables in
the determination of hippocampal volume,
Pruessner et al., (2001) have recently noted that
such findings underscore the need to include sociodemographic variables in functional and anatomical MRI designs (p. 194). This project in-

deed will be one of the first, and certainly, the

most systematic effort of this sort ever undertaken
and it will provide a comprehensive assessment of
the association of life-course trajectories, including gender and socioeconomic status, on the morphometric measures we propose to obtain. With
the functional data we will acquire, the nature of
the dataset will be unparalleled and will enable us
for the first time to examine relations that go from
social and demographic factors across the life
course, e.g., cumulative exposure to adversity or
advanta ge, to brain structure and function.Finally,
we will also obtain physical exam and laboratory
measures of health status to examine in relation to
the psychosocial and imaging measures.
Aim 1: To assess with structural MRI the volume
and shape of the hippocampus, amygdala and several territories of the prefrontal cortex in a WLS
subsample. We predict that the volume of the
amygdala (De Bellis et al., 2000) will be positively correlated with anxiety symptoms and other
indices of negative affect. We predic t that the
volume of the hippocampus (Sapolsky, 2000) will
be reduced in individuals with a greater cumulative exposure to adversity. Moreover, hippocampal volume in particular will be inversely correlated with cortisol.
Aim 2: To assess with functional MRI and a specific emotion regulation task designed to probe
the circuitry described above the functional status
of the amygdala, hippocampus and prefrontal cortex. We predict that greater cumulative exposure
to adversity will be associated with accentuated
activation of the amygdala following the offset of
a negative stimulus and with inability to voluntarily suppress amygdala activation through controlled efforts to attenuate negative emotion. The
requirement to regulate negative emotion will
also be associated with less activation of the certain regions of the prefrontal cortex in subjects
with greater exposure to adversity. In addition,
on a task requiring emotional memory, we predict
less activation of the hippocampus in more vulnerable subjects exposed to adversity.
Aim 3: To examine relations between electrophysiological measures of prefrontal activation

asymmetry and morphometric and functional

brain imaging measures as well as measures of
dispositional affect, well being, exposure to adversity and cortisol.
Aim 4: To obtain data on physical health using
both physical exam and laboratory indices. These
measures will be used to examine relations among
psychosocial, neuroimaging and health variables.
b. Background and significance
The results of a number of studies using
diverse methodologies assessing normal and
clinical populations are consistent with the hypothesis that specific anterior cortical regions in
the left hemisphere are relatively more activated
during the experience or expression of certain
positive emotions while other cortical regions of
the right hemisphere are relatively more activated
during the experience or expression of certain
negative emotions (see Davidson & Tomarken,
1989; Davidson, 1995; Davidson & Irwin, 1999,
for reviews). Following from the analysis by
Schnierla (1959) of the importance of approach
and withdrawal over the course of phylogeny and
the speculations by Kinsbourne (1978; see also
Kinsbourne & Bemporad, 1984), we have interpreted the findings on asymmetry and affect to reflect differences in anterior systems mediating
approach and withdrawal (e.g., Davidson et al.,
1990; Davidson & Tomarken, 1989; Davidson,
1998) with certain regions of the left prefrontal
cortex playing a role in an approach system and
other regions of the right anterior cortical zone
playing a role in a withdrawal system. These cortical regions are undoubtedly part of larger systems that colle ctively constitute approach and
withdrawal systems. I have recently reviewed
(Davidson, 1994; Davidson & Sutton, 1995;
Davidson, 1998; Davidson & Irwin, 1999) relevant animal and human data and proposed on the
basis of these reviews that the approach system
facilitates appetitive behavior and generates certain types of positive affect that are approachrelated. This form of positive affect arises in the
context of moving toward a desired goal (see
Carver & Scheier, 1990; Lazarus, 1991; Stein &
Trabasso, 1992). The representation of the appeti-

tive goal state is hypothesized to be implemented

in dorsolateral prefrontal cortex (PFC), partic ularly on the left side. The medial and orbital zones
of the PFC appear to play an important role in
maintaining representations of behavioralreinforcement contingencies in working memory
(Thorpe et al., 1983). In addition, output from the
medial PFC to the nucleus accumbens, partic ularly the caudomedial shell region has been implicated in the expression of goals in action plans
and in the anticipation of reward (Schultz et al.,
1995; see Davidson & Sutton, 1995; Davidson,
1998, for reviews). We have recently found that
subjects with greater left prefrontal activation also
show less activation in the amygdala (Abercrombie et al., 1996). This finding is consistent with
animal data (Morgan et al., 1993). Thus, the pattern of activation assoc iated with positive affect
and approach includes both cortical activation and
subcortical inhibition consistent with models that
have emphasized the inhibitory role of prefrontal
cortex in emotion regulation (e.g., Tucker, 1981;
Liotti & Tucker, 1995). Note that strong reciprocal connections exist between the amygdala and
medial prefrontal cortex (Amaral et al., 1992) that
provide the requisite anatomical substrate for this
inhibitory relation.
The withdrawal system facilitates the wit hdrawal of an individual from sources of aversive
stimulation and generates certain forms of negative affect that are withdrawal-related, such as
fear and disgust. The right prefrontal cortex activates during such withdrawal-related emotional
states and may be associated with the heightened
vigilance, particularly to threat-related cues, that
is apparent during such emotions (e.g., MacLeod
et al., 1986). It appears that the amygdala is critically involved in this system (LeDoux, 1987;
1992). In addition, the anterior temporal cortex
also appears to be activated during withdrawalrelated negative emotion as does the anterior cingulate and insular cortex (e.g., Rauch et al. ,1995)
and the hypothalamus (Smith et al., 1990). We
published one of the first studies to demonstrate
in humans activation of the amygdala using fMRI
in response to aversive pictures (Irwin et al.,
1996). In addition, we performed an FDG-PET
study using an extended picture presentation
paradigm that we developed and validated (Sutton

et al., 1997) in which we demonstrated reliable

changes in regional glucose metabolism during
objectively verified (with startle) appetitive and
aversive affect. Appetitive emotion was associated with activation in the left inferior and medial
prefrontal cortex, left nucleus accumbens and left
superior lateral prefrontal cortex and premotor region. Aversive emotion was associated with activation in the right lateral prefrontal cortex and the
right amygdala (the latter was demonstrated with
MR-PET coregistration) (Sutton et al., 1997).
Over the past 10 years, my laboratory has been
engaged in a program of research on individual
differences in electrophysiological measures of
tonic asymmetric anterior activation in normal
adults, patients with affective disorders, children
who differ in their temperamental style and in
rhesus monkeys (with Kalin). We have established that individual differences in EEG measures of prefrontal activation asymmetry are reliable (Tomarken et al., 1992a). They are both stable over time and show excellent internal consistency reliability. We have now demonstrated this
repeatedly in adults, children and rhesus monkeys
(see Davidson, 1995, 1998 for reviews). We have
also established the validity of these individual
differences by showing that they predict dispos itional mood (Tomarken et al., 1992b), reactivity
to experimental emotion elicitors (Wheeler et al.,
1993), temperament in children (Davidson, 1992),
temperament in rhesus monkeys (Davidson et al.,
1993), immune function (Kang et al., 1991;
Davidson et al., 1999) and affective disorders
(Henriques & Davidson, 1990; 1991). We have
also used FDG-PET to examine individual differences in patterns of regional glucose metabolism
in a manner similar to that we have developed for
EEG (Schaefer et al., 2000). Using MRIcoregistration procedures to extract metabolic rate
in the amygdala and other discrete subcortical
structures, we have demonstrated that such measures of metabolic rate are stable over time and
that depressed patients with higher levels of
amygdala metabolism report more intense dispositional negative affect (Abercrombie et al.,
1998). We have also begun to mechanistically
characterize the time course of emotional reactivity and examine relations between measures of
the kinetics of affective responding and individual

differences in both electrophysiological measures

of prefrontal asymmetry and hemodynamic measures of regional prefrontal activation (see Davidson, Putnam & Larson, 2000).
Over the past six years we have performed a
number of pilot studies directly relevant to the
major aims of this Project. Findings from these
studies will be briefly reviewed in the next section. Several general themes will be highlighted
here. We have begun a major collaboration with
the Hausers, Carol Ryff and Burt Singer using a
small sample of respondents from the Wisconsin
Longitudinal Study (WLS). For the first time in
the history of this study, which began as a strictly
socio-demographic study, we brought subjects to
campus for laboratory evaluation. We studied
them in the psychophysiology laboratory in addition to conducting a physical examination and obtaining measures that reflect allostatic load and
immunocompetence. The latter measure consisted of antibody titers to influenza vaccine.
Among the psychophysiological measures we obtained were brain electrical activity and cardiovascular measures. The ele ctrophysiological and
cardiovascular data were obtained under both
baseline and challenge conditions. These measures were obtained from subjects who were classified as resilient (lives of adversity accompanied
by reports of high levels of psychological wellbeing) and several comparison groups. The sample size for the biological data ranged from
approximately 70 to 100 depending upon the
measure.
Our initial analyses focused on
examining specific questions that were based
upon a priori data and/or theory. One of our
major hypotheses concerned relations between
individual differences in asymmetric prefrontal
activation and immune function. In earlier work
we found that subjects with greater relative left
prefrontal activation had higher baseline levels of
natural killer cell (NK) function (Kang et al.,
1991). In more recent studies (Davidson et al.,
1999) we replicated this earlier finding with a
larger sample of subjects and demonstrated that
the relation is present throughout the continuum
of prefrontal activation asymmetry, not just in a
comparison of extreme groups.
We also
established that subjects with greater relative leftsided prefrontal activation at baseline show a
smaller decrease in NK function in response to

function in response to both a naturally occurring

and an experimentally-induced stressor. These
data were based exclusively upon relatively crude
electrophysiological measures and used an in vitro measure of immune function. In the WLS pilot study, we found consistent relations between
baseline left-sided prefrontal activation and
higher antibody titers in response to influenza
vaccine. This finding was present for most of the
prefrontal electrode sites but was not present in
the posterior scalp region, underscoring the specificity of the effect. We also found that subjects
with greater left-sided prefrontal activation at
baseline consistently reported fewer symptoms of
dispositional negative affect, depression, anxiety
and perceived stress.
Another issue that we have pursued in the WLS
data is the question of emotion regulation (see
Davidson, Putnam & Larson, 2000; Davidson,
Jackson & Kalin, 2000; Jackson et al., 2000a).
We have distinguished between automatic and
voluntary forms of emotion regulation though
there is little evidence on the relations between
these forms of regulation. For example, we do
not know if individuals who are good at voluntary
regulation of negative affect are also adept at
automatic regulation of negative emotion (see
Davidson, Jackson & Kalin, 2000, for discussion). In the WLS pilot study, we presented unpleasant, pleasant and neutral pictures during
which we exposed subjects to startle probes that
occurred either during picture presentation or 1.5
seconds following picture presentation. The latter
probe time was used to capture automatic regulation. Subjects who recover quickly from negative
challenges should show decreased startle magnitude during this post picture period while those
less facile in recovering from negative challenge
should show greater startle magnitude at this
time. In these analyses, we use the probe during
the picture presentation as the first predictor in a
regression equation to equate for differences in
reactivity to the emotional stimulus tiself. We
then examined, in a second step in the regression
model, the amount of variance accounted for in
the post-picture startle response by electrophysiological measures of asymmetric prefrontal activation. In this analysis, we found that the prefrontal
asymmetry indices accounted for a large percent-

age of the variance (65%) in the magnitude of the

post-negative picture startle response after the
variance accounted for by the startle magnitude
during the picture was removed. The direction of
the effect was that subjects with greater left-sided
prefrontal activation showed a diminished startle
magnitude during the post-picture period suggesting that these individuals were better able to regulate their negative affect and return to baseline
more quickly. A specific example from these
data will be presented below in the Preliminary
Studies section.
In another task we administered to the WLS respondents, we had them write about the most extreme positive and most extreme negative experiences in their lives. In the three-minute period after a five-minute writing epoch, subjects were instructed to sit quietly and think about the material
they had just written. We collected both brain
electrical activity measures and startle measures
during this period. Those subjects who showed
the most extreme negative affect as ni dexed by
the highest magnitude startle following the negative compared with the positive writing period
had the smallest rise in antibody titers following
vaccine (r=.42).
What we were not able to examine in the WLS
data was the detailed neurocircuitry of emotion
and affective style since we did not collect neuroimaging data and relied solely on measures of
brain electrical activity to make inferences about
regional brain function. These measures of brain
electrical activity are only sensitive to cortical
function and thus, activity in subcortical regions
critically important for emotion was not assessed.
Moreover, we did not obtain any morphometric
data in the WLS data collection to date. Recent
findings have suggested that changes in the volume of the hippocampus, amygdala and select
neocortical areas may be associated with chronic
exposure to stress (Sapolsky, 2000), and the WLS
data will provide ample evidence of such exposure across the life course. Moreover, the opportunity to relate such measures to both fMRI
measures of regional brain activation in response
to emotional challenges and also to measures of
cortisol that have been hypothesized to play a
causal role in the production of tissue atrophy is
unprecedented. In short, we will collect a large

corpus of imaging data as well as objective ni formation on health status on subjects for whom
extensive history of sociodemographic information is available.
c. Preliminary Studies
In this section, I first review data from my laboratory using electrophysiological measures of activation that provided the early evidence on the differential role of the left and right prefrontal cortex
in various aspects of emotion and affective style.
I then turn to neuroimaging data.
A. Electrophysiological measures of anterior
asymmetry as a trait-like index: Psychometric
evidence: A critical initial question that required
an answer was the extent to which electrophysiological measures of activation asymmetries in anterior scalp regions were stable over time and exhibited other psychometric characteristics desirable for a trait-like index. Investigators who use
physiological measures as dependent variables
rarely examine the psychometric characteristics of
these measures, yet if they are to be used in individual differences and psychopathology research,
it is imperative to examine them in this way. Accordingly, we (Tomarken, Davidson, Wheeler &
Kinney, 1992) performed the first psychometric
evaluation of this kind for electrophysiological
measures of frontal and anterior temporal alpha
power asymmetry measures.
We focused on alpha power as a dependent
measure for several reasons. First, some electrophysiologists have argued that in the waking
adult, power in the alpha band (8-13 Hz) is inversely related to activation (e.g., Shagass, 1972;
Lindsely & Wicke, 1974). Second, we have systematically examined power in other bands in
many published articles (e.g., Davidson et al.,
1990a, b; Davidson et al., 1995). We have repeatedly found that individual differences in alpha
power asymmetry are more consistently related to
theoretically-predicted psychological measures
than asymmetry measures derived from other
bands. Third, in experiments where we have manipulated either cognitive or affective task variables to induce a change in asymmetry, we have
repeatedly found that the most consistent task-

dependent changes are found in the alpha band,

with decreased alpha power observed in the hemisphere hypothesized to be most activated by the
task and/or increased alpha power in the opposite
hemisphere (see Davidson et al., 1990 for a detailed consideration of this issue). It should be
noted that we still examine power across the entire spectrum to ascertain whether asymmetries in
other frequency bands also account for variance
in mood or other emotion-related variables. We
have specifically been interested in evaluating
power in the gamma band (centered around 40
Hz) to evaluate claims that power in this band is a
direct measure of activation (Spydell & Sheer,
1982; Miltner et al., 1999), in contrast to alpha
power which is indirectly related to activation.
Although other studies had examined the stability of spectral power per se (e.g., Fein et al., 1984;
Gasser et al., 1985), it was critical to examine
asymmetry of power since a determinant of absolute power is skull thickness (e.g., Leissner et al.,
1970), which will be largely responsible for high
test-retest reliability of power. However, measures of asymmetry are not particularly influenced
by skull thickness, since substantial asymmetries
in skull thickness are not present (see discussion
in Tomarken et al., 1992b). 90 right-handed subjects were tested on two occasions separated by
approximately three weeks. EEG was recorded
from left and right mid-frontal and anterior te mporal scalp sites referenced to both Cz and computer-derived ears [for the derivation of an ears
reference, we now always use a computer-derived
average, rather than physical linking since slight
impedance differences between the ears can cause
substantial variations in measured asymmetry.
This problem does not arise if each ear is separately recorded to a common reference, since the
high input impedance of the amplifiers effectively
eliminates the impact of any variation within the
normal range of ele ctrode impedance]. At each of
the two sessions, 8 one-minute trials of resting
brain activity were acquired. These one minute
trials were divided into 4 eyes-open and 4 eyesclosed trials that were presented in counterbalanced order. A fast Fourier transform was performed on 2 second chunks of artifact-free EEG
and extracted with overlapping Hamming windows (see Tomarken et al., 1992b in Appendix

for additional details). Power in the delta (1-4

Hz), theta (4-7 Hz), alpha (8-13 Hz), beta 1 (1320 Hz) and beta 2 (20-30 Hz) bands was extracted
and converted to power density (V/Hz). Power
values were log-transformed to normalize their
distribution. For the purpose of analyses assessing
the stability of EEG asymmetry, weighted means
across each of the eight baselines within a session
were computed. Asymmetry values were obtained
by subtracting the power density in the left hemisphere ele ctrode from the power density in the
homologous right hemisphere lead. We pooled
over eyes-open and eyes-closed measures because
the correlation of asymmetry between eyes-open
and eyes-closed trials was uniformly high and the
aggregated measure led to greater stability compared with separate eyes-open or eyes-closed
measures for most bands. In the article presenting
these data (Tomarken et al., 1992a), we also present the results separately by eyes condition for
archival purposes.
The findings of most importance from this study
were that measures of frontal (F3/F4) and anterior
temporal (T3/T4) alpha power asymmetry were
stable over time. The intraclass correlation for the
frontal sites was .66 and for the anterior temporal
sites it was .72. We also computed coefficient alpha, a measure of internal consistency reliability
within each session across the 8 baseline trials, as
well as across the 2 sessions (16 trials). The internal consistency reliability for the midfrontal region (across the 16 baseline trials) was .90 and for
the anterior temporal region it was .94. These
findings were the first to show that EEG measures
of anterior asymmetry were psychometrically reliable. We focused on alpha power because of a
wealth of data that indicate an inverse relation between alpha power and activation in the awake,
behaving adult (see Pivik et al., 1993 for a general
review; Davidson, Chapman et al., 1990 for an
empirical demonstration; Michel et al., 1999 for
another empirical demonstration and extension to
magnetoencephalography; and Oakes et al., 2001,
from my lab where we developed a method to examine on a voxel-wise basis the relation between
hemodynamic imaging methods and the intensity
of brain electrical sources located in a coregistered brain volume).

Since this first study, we have had the opportunity to examine the test-retest stability of EEG
measures of activation asymmetry from multiple
scalp sites in a much larger sample of subjects.
We pooled the data across several cohorts tested
over the past three years where the interval between assessments was six weeks. Subjects were
tested at the same time of day on each testing occasion. We tested a total of 175 subjects (N=88
females), all of whom were right-handed. The
procedure for the assessment of baseline EEG
was identical to that described for the initial study
above. EEG was recorded from 29 scalp sites
(FP1/2, AF3/4, F3/4, F7/8, FC3/4, FT7/8, T3/4,
T5/6, C3/4, CP3/4. CP5/6, P3/4, PO3/4, FZ, PZ
and Cz) and re-derived off-line to an average reference and an derived-ears reference. For the average ears reference, the mean ICC for alpha
power (8-13 Hz) asymmetry scores across site
was .53. For the average reference, the mean ICC
for asymmetry scores across site was .66. The
correlations for mid-frontal asymmetry (F3/4) are
.55 for the AA reference and .74 for the average
reference; for anterior temporal asymmetry the
same correlations were .54 and .70 (all ps
<.0001). These values are generally consistent
with the effects we previously reported using a
smaller sample size, only females and a shorter
interval between test occasions. We had the opportunity to examine longer-term stability by
computing the ICCs based upon the means of
Assessment 1 and 2 (held 6 weeks apart) and the
session during which the startle task was presented (see below), which took place an average
of 273 days following the second assessment
(N=55 for these analyses). The mean ICC for
asymmetry scores across region for the average
ears reference was .58. The ICC for the midfrontal asymmetry score was .62 and the ICC for
the anterior temporal asymmetry score was .61.
These data indicate that when aggregation can be
performed, good test-retest stability over a relatively long period is observed. Comparisons of
stability estimates separately for males (N=87)
and females (N=88) revealed no gender differences. There were also no significant gender differences in measures of asymmetry from any of
the anterior scalp regions, though males did have

slightly greater relative left-sided activation (e.g.,

for F8-F7, M for males=.034; M for females=.01).
Tomarken (who was a post-doc in my lab at the
time the first set of studies in my lab on this topic
were completed and who is now at Vanderbilt)
showed that if multiple assessments are obtained
in each year (i.e., 2 or 3 assessments), the testretest reliability over a one year period is very
high (>.80; Tomarken et al., 1994).
Another important parameter of reliability is internal consistency reliability that is measured by
coefficient alpha. By extracting measures of each
of the 8 one-minute baselines at each session we
can compute coefficient alpha, which reflects the
extent to which each individual baseline trial is
representative of the aggregate index across trials.
The mean coefficient alpha across site based upon
8 trials was .90 for the ears reference (range=.86
to .94) and .88 for the average reference
(range=.77 to .94). These data indicate that these
electrophysiological measures of asymmetry have
excellent internal consistency reliability.
We also examined the test-retest stability of
residualized alpha power measures using intraclass correlations. As we have explained in detail
elsewhere (Wheeler et al., 1993; Pivik et al.,
1993; Davidson, Jackson & Larson, 2000), if one
wishes to examine power at a single individual
site (rather than compute an asymmetry score) it
is necessary to residualize alpha power by whole
head power since a major contributor to overall
differences in alpha power across individuals is
skull thickness. Residualizing in this way effectively eliminates skull thickness contributions.
The sample size was again the 175 subject data
set described above. We found that the intraclass
correlations for this measure were excellent, ranging from .70 to .89, with a mean across site and
reference of .83.
B. Relation of EEG asymmetry to dispositional
mood and reactivity to emotion elicitors: Having
established that measures of anterior brain electrical asymmetries were stable over time and exhibited excelle nt internal consistency reliability, we
were now in a position to examine how such
measures predicted features of emotional reactivity and how they were associated with affective
and anxiety disorders. One of the first questions

we asked was whether subjects selected on the

basis of stable and extreme electrophysiological
asymmetry differed in ratings of dispositional
mood (Tomarken, Davidson, Wheeler & Doss,
1992a). We administered the Positive and Negative Affect Scale (Watson et al., 1988), a factoranalytically-derived and relatively pure measure
of dispositional positive and negative affect. Subjects simply rate the degree to which a series of
adjectives characterizes how they generally feel.
Examples of the positive adjectives include interested, strong, enthusiastic, proud and alert; negative adjectives include distressed, upset, nervous,
jittery and afraid. We examined whether those
subjects in the top and bottom 25% of the asymmetry score distribution on both assessment occasions differed in their ratings of dispos itional
positive and negative affect. We found that subjects in the left frontal group (i.e., those with less
alpha on the left side and more alpha power on
the right side) reported significantly more positive
and less negative affect than their right frontallyactivated counterparts. A similar pattern was observed for subjects classified on the basis of stable and extreme anterior temporal activation
asymmetry. When we examined the data correlationally using the entire range of the distribution
on asymmetry scores, we generally found that
electrophysiological measures were significant
predictors of PANAS measures for those subjects
who exhibited stable asymmetry across time. The
findings from this study indicated that classifying
subjects exclusively on the basis of electrophysiological measures of anterior asymmetry, we could
predict their self-reported dispositional affect.
Our findings with the PANAS have been independently replicated by Jacobs and Snyder
(1996).
More recently, we (Sutton & Davidson, 1997)
have administered several additional self-report
instruments that we predicted should be associated with anterior activation asymmetry. In one
study (N=57), we administered the scales that
were designed to assess individual differences in
Grays (1994) Behavioral Activation (BAS) and
Behavioral Inhibition (BIS) systems (Carver &
White, 1994). Examples of items from the BAS
scale include: When Im doing well at something, I love to keep at it and When I want

something, I usually go all out to get it. Items

from the BIS scale include: Criticism or scolding hurts me quite a bit and I worry about making mistakes. Items are answered on a 1 to 4
scale that ranges from very true for me to very
false for me. The BAS scale consists of three
separate sub-scales--Reward Sensitivity, Drive
and Fun-Seeking. Carver and White (1994) have
demonstrated good reliability for these sub-scales.
Using the derived-ears reference and our standard
alpha power band (8-13 Hz), we found that subjects with greater relative left-sided prefrontal activation in both mid-frontal (F3/4) and la teral
frontal (F7/8) regions had higher scores on the
overall BAS (for F3/4, r=.28, p=.07; for F7/8,
r=.35, p<.01) as well as on the Drive subscale in
particular (for F3/4, r=.28, p=.03; for F7/8, r=.38,
p<.005). Subjects with greater relative right-sided
prefrontal activation reported more behavioral inhibition (for F3/4, r=-.41, p<.002; for F7/8, r=.47, p<.0005). We also computed a within subject
difference score that reflected the relative strength
of the BAS over the BIS by standardizing the
scores on these scales and then taking a difference
score within subjects. Subjects with greater relative left-sided prefrontal activation had higher
BAS relative to BIS scores (for F3/4, r=.43,
p<.001; for F7/8, r=.53, p<.0001). Relations between activation asymmetry and scores on this
index are specific to anterior scalp regions. Measures derived on the basis of the average reference
data showed the same pattern of effects, though
were less robust. Analyses based upon residualized power measures at separate left and right
hemisphere scalp sites indicates that the effects
described above are indeed due to a relative difference in activation between the hemispheres
since the correlations with asymmetry scores are
consistently much higher than the correlations
with individual hemisphere residualized power
values. In most cases, the latter indices by themselves were not significantly related to the BAS
and BIS measures, while the asymmetry score did
significantly predict these scores. Thus, contrary
to what might have been expected, BAS scores
were not related primarily to activation differences in the left prefrontal region and BIS scores
were not related primarily to activation differences in the right prefrontal region. Scores on

these scales were best predicted by the asymmetry

metric, implying that the balance of activation in
these systems is the most important determinent
of at least self-reports of these behavioral tende ncies.
We next wished to examine whether such measures of asymmetry might predict reactivity to
standardized emotion elicitors. In three studies
(reported in two articles: Tomarken, Davidson &
Henriques, 1990; Wheeler, Davidson &
Tomarken, 1993) we obtained support for the hypothesis that baseline measures of prefrontal
asymmetry predict reactivity to emotion elicitors.
In particular, those subjects with greater baseline
right-sided prefrontal activation reported more intense negative affect in response to the negative
emotional film clips while those with greater
baseline left-sided prefrontal activation reported
more intense positive affect in response to positive film clips (see Wheeler et al., 1993 in Appendix). An aggregate (across two sessions)
measure of prefrontal asymmetry correlated .45
with an index of positive affect and -.49 with
negative affect. We also computed a measure of
generalized affective reactivity that represented
the sum of positive affect in response to the positive film clips and negative affect in response to
the negative film clips. Frontal asymmetry was
unrelated to this measure of generalized affective
reactivity (r=-.01). In this study, we also obtained
baseline mood ratings at the time the EEG assessment was obtained. The baseline measures of
frontal asymmetry were unrelated to subjects current mood, but did predict their reactivity to the
emotional film clips, even when baseline mood
was statistically partialled in a hierarchical regression. In the published article that presents these
data, we examine relations between reactivity
measures and residualized power values at individual left and right hemisphere sites, as noted
above.
Collectively, the studies reviewed above on
baseline asymmetries, mood, and emotional reactivity in normals indicate that baseline measures
of anterior asymmetry predict self -reports of dispositional mood but are unrelated to the current
mood or emotion that a subject reports at the time
of EEG assessment (perhaps because of the low
base rates and consequently low variability of re-

portable emotion while sitting and resting). The

electrophysiological measures do predict reactivity to emotion elicitors. In particular, those subjects with greater left-sided frontal activation
(both absolute and relative; this issue was specif ically examined in the Wheeler et al. study) report
more intense pos itive affect to positive elicitors
while subjects with greater right-sided anterior
activation report more intense negative affect in
response to negative elicitors. These findings
support the diathesis/stress conception of individual differences in prefrontal asymmetry that I
have advanced (see in particular, Davidson, 1993
and Davidson, 1998 where this position is explicitly articulated). On this view, individual differences in anterior activation act as diatheses that
alter an individuals vulnerability to positive and
negative elicitors, provided the requisite elic itor is
presented.
C. Anterior activation asymmetry and immune
function: A growing corpus of evidence suggests
that certain parameters of immune function are
responsive to psychological events that elicit
emotion. In particular, it is by now a common observation that stress, such as final exams, bereavement and divorce, can cause a decrease in
the cellular immune response (see review by Kiecolt-Glaser & Glaser, 1991). These are all events
that have a strong affective component. A notable
fact about these studies is the pronounced individual variability in both baseline measures as
well as in the magnitude of change of the immune
measures. In light of the observation that individual differences in anterior asymmetry predict important features of affective responsivity, we were
interested in examining the extent to which baseline measures of anterior asymmetry might account for some of the variability across individuals in immune function.
A second body of literature also points toward
possible relations between asymmetric brain function and immunity. The pioneering work of
Geschwind argued for an association between
hemispheric specialization as reflected in handedness and autoimmune disorders (Geschwind &
Galaburda, 1985). Handedness, and hemispheric
specialization more generally, capture only a
small component of the variance across individu-

als in hemispheric function. A number of investigators (e.g., Levy, 1983) have highlighted the
distinction between hemispheric specialization
and hemispheric activation and have noted that
variations in the latter are superimposed upon the
former. More direct evidence for the existence of
a connection between cerebral asymmetry and
immune function has been provided by animal
studies in which the effects of unilateral cortical
lesions on immune function were evaluated (Barneoud et al., 1987; Neveu, 1988; Neveu et al.,
1986; Renoux et al., 1983). Renoux et al. (1983)
and Neveu et al. (1986) showed that ablation of
the left fronto-parietal cortex of mice, which
would result in a pattern of relative right-sided activation, decreased immune responses, whereas
comparable lesions of the right cortex either had
no effect or increased immune responses.
By comparing subjects with extreme and stable
patterns of left and right-sided prefrontal activation, we could examine whether naturally occurring (in contrast to lesion-induced) asymmetries
accounted for variance across individuals in baseline measures of immune function (see Kang,
Davidson et al., 1991 in Appendix). We selected
20 subjects from a cohort that was tested on two
occasions on EEG measures. 10 subjects showed
extreme and stable left-frontal activation and 10
showed extreme and stable right-frontal activation. These subjects were brought to the laboratory where blood samples were taken and several
self-report measures were administered. The experimenters and lab techs were all blind to group
status. We examined natural killer (NK) cell activity, lymphocyte proliferation to mitogen stimulation (concanavalin A (Con A), phytohemmagglutinin (PHA) and pokeweed (PWM)), with each
mitogen presented at three different concentrations. In addition, the helper/suppressor T-cell ratio was determined and plasma cortisol was also
obtained. Our results indicated that the right frontal subjects had significantly lower NK activity
compared with their left-frontal counterparts. This
difference was apparent at the two lower effector:target cell ratios. No group differences in
lymphocyte proliferation or in T-cell subsets were
found. In addition, no difference in plasma cortisol was found, nor was cortisol correlated with
any of the immune measures. Self-report meas-

ures of trait anxiety and depression did not differentiate between groups nor did these measures
correlate with immune function. This was the first
study in normal humans to demonstrate a relation
between a parameter of immune function and individual differences in asymmetric hemispheric
activation.
More recently, we attempted to conceptually
replicate our finding of NK differences between
subjects who differ on electrophysiological measures of frontal asymmetry. Rather than select extreme groups, we wished to determine whether
individual differences in prefrontal asymmetry
were associated with immune function in a group
of unselected subjects. In this study, we (Davidson et al., 1999) assessed baseline measures of
brain electrical activity on two occasions separated by 6 weeks in our standard paradigm in 24
subjects. In a third session, we brought subjects
back to the laboratory for a blood sample, from
which measures of NK activity were obtained.
We found that the aggregate measure of frontal
asymmetry from the initial two sessions was significantly correlated with NK activity at the two
effector:target cell ratios that were associated with
frontal asymmetry in our first study (for 11:1,
r=.46, p=.02; for 33:1, r=.51, p=.01). This indicates that subjects with lower asymmetry scores
(more relative right-sided frontal activation) had
lower levels of NK activity, thus replicating our
initial finding on an unselected group.
In this more recent study, in addition to examining relations between asymmetry and baseline
NK activity, we were also interested in whether
our asymmetry measures would predict change in
NK activity in response to negative elicitors. We
predicted that subjects with more right-sided anterior activation would show a larger decrease in
NK activity to the negative event. We studied this
question in two ways. The first strategy involved
the use of academic stress as a naturally occurring
negative event. We obtained blood samples from
subjects at a point in the semester during which
no exams were being taken and at a second point
24 hours prior to the subjects most important final exam (based upon their own report). We
found a large and significant decrease in NK activity during the final exam period compared to
the earlier time point (p<.02 for both 33:1 and

100:1 ratios), replicating Kiecolt-Glaser et al.

(1984; Glaser et al., 1986). Most critical to our
hypothesis was whether the baseline measures of
prefrontal activation asymmetry predicted the
change in NK activity from the first to the second
assessment. To answer this question we focused
on the 100:1 effector:target cell ratio since the
greatest variability was observed at this ratio. We
computed a hierarchical regression where the
variable to be predicted was NK activity at the final exam period. The first step in the model was
NK activity at the pretest (i.e., the mid-semester
blood draw at a time of little academic stress).
The second step in the model was the frontal EEG
asymmetry variable. We found that the pretest
NK measure accounted for a non-significant 6%
of the variance in the final exam NK measure
(F(1,22)=1.40, p=n.s.). The frontal asymmetry
variable entered as Step 2 in the model accounted
for an additional 21% of the variance beyond that
accounted for by the pretest NK measure
(F(1,22)=6.06, p=.02). The sign of the beta
weight indicated that subjects with greater relative right-sided prefrontal activation had a larger
decline in NK function at the final exam period
compared to the baseline period. Our single
measure of frontal asymmetry accounted for 21%
of the unique variance in the decline in NK function from the baseline to the final exam period.
Since many aspects of a students life change
during final exam period (e.g., diet, sleep), we
also wished to obtain a more well-controlled
measure of this relation. In addition, we were interested in assessing possible immune changes in
response to both negative and positive challenges.
Accordingly, we brought subjects back to the
laboratory later in the year during a period they
judged to be relatively non-stressful and exposed
them to two 30 minute film clips. One was designed to elicit sadness. The clip, from the movie
Beaches, depicted a mother dying of cardiomyopathy and her interactions with her 10 yearold child. More than one third of the subjects
cried in response to this clip. The happy clip was
a medley of segments from the Lady and the
Tramp, the Olympics and Parenthood. Clips
were selected based upon normative ratings from
144 subjects. The or der of clips was randomized
across subjects. Blood samples were obtained

prior to film exposure (baseline) and then after

each clip. Overall, there was no significant pre-topost film change in NK activity. However, we
found that the magnitude of change in response to
the film clips was significantly predicted by our
measures of anterior asymmetry. We examined
the data in a manner identical to that described
above for the final exam analyses. Hierarchical
regressions were computed where the variable to
be predicted was the NK activity following the
film clip. Step one in the model was always the
NK activity at baseline and Step two was the EEG
asymmetry measure. In response to the happy
film clip, we found that subjects with greater relative left-sided prefrontal activation (F4-F3) had
significantly higher NK activity at the 100:1 ratio
after removing the variance associated with baseline NK activity (F(1,19)=4.19, p=.05), though
this effect accounted for only 3.5% of the variance. Prefrontal asymmetry from the F8-F7 leads
significantly predicted NK activity following the
happy film clip at the 11:1 and 33:1 ratios
(F(1,19)=6.07, p=.02; F(1,19)=4.27, p=.05, respectively), accounting for 6.2% and 5.2% of the
variance respectively, after removing the variance
accounted for by baseline NK activity. A marginal effect was found at the 100:1 ratio
(F(1,19)=3.90, p=.06). These findings indicate
that subjects with greater relative left-sided activation show higher levels of NK activity following the happy film clip after the variance in the
pre-film baseline NK is removed. Similar effects
were found for the anterior te mporal region,
though they failed to reach significance. In response to the negative film clips, we found that
subjects with greater relative right-sided anterior
temporal activation had less NK activity (for the
33:1 ratio) after the negative film clip, following
removal of the variance accounted for by prefilm
baseline NK activity (F(1,19)=4.38, p=.05). Similar though marginally significant effects were
found for other effector:target ratios and with the
prefrontal scalp sites. Collectively, these data indicate that although main effects for the 30 min.
film clips on NK activity are not present, some of
the variability in NK response to the film clips is
significantly predicted by individual differences
in anterior activition asymmetry, after removing
the variance accounted for by baseline NK activ-

ity. Subjects with greater relative left-sided anterior activation show a larger increase in NK activity in response to the positive film clip, while
those with greater right-sided anterior te mporal
activation show a larger decrease in NK activity
in response to the negative film clip.
D. Preliminary data from the Wisconsin Longitudinal Study: As noted in the Background and
Significance section above, we have been col-
Mean asymmetry (+ = greater left active)
Baseline asymmetry (FC3/4) and

self-acceptance
.6
.4
.2
-.0
r =.352
p <.001
n = 97
-.2
-.4
In general, higher levels of distress and depression were associated with lower antibody titer
levels to influenza vaccine, as was increased
right-sided activation and greater startle magnitude following the negative compared with the
positive writing period. Figure 2 presents data
from this study showing relations between startle
magnitude and immune function. These data indicate that subjects with larger magnitude startle
responses following the negative compared with
the positive writing period show lower levels of
antibody rise (r=-.50).
We also presented standardized positive, negative and neutral pictures in this study and examined
the magnitude of startle to acoustic probes that
were presented both during the stimulus and 1.5 sec
following the stimulus, the latter of which was used
to assess recovery. We found that subjects with
greater left-sided prefrontal activation showed a
greater diminution of startle magnitude in the interStartle Response during Negative - Positive
Thinking Task and Immune Response
-.6
20

30
40
50
60
70
80
90
Well-being: Self-acceptance
Figure 1: Relations between baseline prefrontal asymmetry

and Self-Acceptance. Higher numbers on the ordinate denote
greater relative left-sided prefrontal activation
laborating with Hauser, Ryff and Singer on the

laboratory component of the WLS study for the
past four years. This effort has involved the
testing of approximately 120 respondents from
the WLS sample (though not all were available
for each measure). These individuals came to
campus for a 1.5 day visit during which they
partic ipated in an extensive protocol in my laboratory that included recording of brain electrical
activity, cardiovascular activity and startle. Preliminary data from this study were presented
above in the Background and Significance section. What we wish to emphasize here is the coherent network of associations that we observed
when we examined relations among prefrontal activation, startle, immune function and self-report
measures of well-being, distress, depression and
perceived stress. We found systematic relations
between left prefrontal activation and various
well-being subscales including Self-Acceptance,
Purpose in Life, and Positive Relations with others. This is illustrated in Figure 1.
1.5
1
0.5
0
-0.5
-1
-1.5
-2
r = -.501
p = .0056
n = 29
-4
-2
L o g 2 transformed antibody titer fold-rise
Figure 2: Higher numbers on the ordinate denote greater relative startle magnitude during the negative versus positive thinking periods.
Abscissa reflects antibody rise to influenza vaccine
val after the negative picture. Figure 3 below illustrates this finding. We have not yet collected any
imaging data in this study and so conclusions about
the functional neuroanatomical bases of these effects remains speculative. This is something we
intend to pursue over the next two years with the
fresh WLS sample proposed here.
E. Functional magnetic resonance imaging of the
human amygdala and prefrontal cortices in response to affective stimuli: Valence effects and
individual differences: We have conducted sev
eral studies over the past five years to interrogate


Frontal Pole EEG Asymmetry and Late Startle Reactivity Following Picture Offset
0.4
0.3
0.2
0.1
0
-0.1
-0.2
r = -.41
-0.3
p < .03
n = 32
-0.4
-1.5
-1
-0.5
0.5
1.5
2.5
Late Startle Reactivity (Negative - Neutral)
Figure 3: Higher numbers on the ordinate reflect greater relative left -sided prefrontal activation. Positive numbers on the abscissa
denote greater startle magnitude 1.5 s following the offset of a negative versus neutral picture
the functioning of the human amygdala with fMRI.

As noted above, the amygdala is a key site in the
circuitry underlying emotion and both functional
and structural differences have been associated
with psychopathology and stress. We published
one of the first studies to document the capacity of
fMRI to detect signal in the amygdala in response
to negative emotional stimuli (Irwin et al., 1996).
For this study, we used unpleasant, pleasant and
neutral pictures and found that the amygdala was
significantly activated in response to negative versus neutral stimuli. We did not find this pattern in
response to positive versus ne utral stimuli.
More recently, we sought to examine relations
between individual differences in the magnitude of
amygdala activation and dispositional negative and
positive affect. In this study (Irwin et al., 2001) 14
subjects were presented with unpleasant and neutral pictures in a block design. We quantified the
magnitude of MR signal change for each subject in
the amygdala in response to the unpleasant versus
neutral pictures. We describe our imaging parameters and analytic strategy in detail below since our
proposed research will use a similar though not
identical sequence since our proposed work will be
conducted at 3T. P
The image acquisition protocol consisted of 10

scans, the details of which are provided only for
those scans relevant to the description below: 1)
an axial 3D spoiled gradient-recalled echo scan
[SPGR; echo time (TE)/repetition time (TR) =
8/35 ms, field of view (FOV) = 24 x 24 cm, flip
angle () = 30, number of excitations (NEX) = 1,
matrix 256 x 128, reconstructed to 256 x 256, 124
slices, slice thic kness = 0.9 - 1.2 mm, scan time =
937] graphically prescribed to cover the entire
brain volume; 2) a coronal 3D SPGR scan
(TE/TR = 10/35 ms, = 30, NEX = 1, FOV = 24
x 24 cm, matrix = 256 x 128, reconstructed to 256
x 256, 28 slices, slice thic kness = 1.0 mm, scan
time = 227) covering a 28 mm region beginning
at approximately the middle of the pons, posteriorly, which provided the image data for localization of the amygdalae; 3) a coronal T1-weighted
spin-echo scan (TE/TR = 20/500, = 90, NEX =
1, FOV = 24 x 24 cm, matrix = 256 x 128,
reconstructed to 256 x 256, 23 slices, slice
thickness = 7 mm, interslice spacing = 1 mm,
scan time = 224) which provided the slice locations from which functional image data would be
acquired. This scan was manually prescribed such
that one slice was centered on the amygdalae.
This was defined such that the posterior edge of
this slice was positioned 1 mm anterior to the lo-

was positioned 1 mm anterior to the location

where the hippocampus could first be identified in
the image data acquired in scan 2; 4) a coronal
T2*-weighted gradient-echo echo-planar scan
(TE/TR = 50/3000 ms, = 90, NEX = 1, FOV =
24 x 24 cm, matrix = 64 x 64, same interleaved
slice parameters as scan 3, 1 image per slice, scan
time = 0:03) based on the Mansfield (1977) and
the blood oxygen level dependent contrast
(Ogawa, 1992) methods, was used to acquire
functional image data. The pulse sequence used
for this scan was customized to use a ShinnarLeRoux slice-selective pulse (Pauly, 1991) to
minimize slice cross-talk and increase the signalto-noise ratio (Mock, 1997). The final scan pr ovided the functional image data using the same
imaging parameters as scan 4 except that 191 images were acquired from each slice location (scan
time = 933).
Image data were acquired on a General Electric
(Waukesha, WI) EchoSpeed 1.5 Tesla scanner
equipped with high-speed, whole -body gradients
(2.2 g/cm, 100 ms rise time) and a standard clinical whole -head transmit-receive quadrature bir dcage headcoil.
The functional image data were reconstructed
off-line running on a Sun SPARC Ultra 1 (Sun
Microsystems, Mountain View, CA) without the
application of any filters to the k-space data (cf.,
Lowe, 1997) and with a band-pass filter to correct
for asymmetries in the analog-to-digital signal
conversion (King, 1995) All other image data
were reconstructed on-line.
All individual subject timeseries datasets
were adjusted to correct for any possible head
movement (Cox, 1996). To identify paradigmcorrelated MR signal increases, the time series
from each voxel were fitted to a hemodynamically -delayed box-car reference function which
modeled the alternating stimulus blocks using a
three-parameter (amplitude, mean, slope) leastsquares method (Lowe, 1999). The hemodynamic
delay was estimated to be 6 sec (i.e., 2 functional
images) by examining MR signal changes in the
amygdalae. The first 5 images from each trial acquired while the subject viewed the work Begin
were discarded. Thus, for each trial, for each subject, 184 images (i.e., 191 acquired images - 5
discarded images - 2 images to account for hemo-

dynamic delay) were included in the fitting procedure. The fitting procedure yielded a statistical
parametric map where the voxel values were the
Students t statistic.
Using Analysis of Functional NeuroImages (AFNI, Version 2.00, Cox, 1996; Cox,
1997) each subjects anatomical data were transformed into the Talairach and Tournoux (1988)
stereotaxic coordinate system. Then, the statistical
maps were coregistered to the transformed anatomical mage data using nearest-neighbor interpolation and resampled to 1 mm isotropic voxels to
create new statistical maps. These new statistical
maps were combined across subjects using inhouse code by summing the square of the (unthresholded) voxel values to create a group-wise
t map. The distribution of t is approximated by
the distribution (Hotelling, 1931; Worsley,
1995).
Using a maximal estimation of the search
volume for the region of the amygdalae (Pruessner, 2000), the group-wise map was thresholded
to visualize contiguous clusters of activation = 10
mm3, corresponding to a corrected false-positive
rate of p = 0.05 per cluster, as estimated using the
simultaneous inference tool within AFNI. Using
in-house code (TRO) written in Interactive Data
Language (Version 5.2, Research Systems, Inc.,
Boulder, CO), image masks based on the groupwise clusters in the amygdalae were applied to
each subjects image data to identify the subjectwise Students t values for each cluster. Millimetric coordinates reported below are in reference
to the Talairach and Tournoux stereotaxic coordinate system. The term activation is used to describe greater mean MR signal during the viewing
of the negative compared to neutral stimuli.
False-color ROIs are shown coregistered to a
mean anatomical image derived from the 14 subjects. We then examined the correlation between
the subject-wise Student t- values and scores on
the PANAS positive and negative affect scales
(see appendix for manuscript).
Figure 4 illustrates the activation in the amygdala we detected with fMRI in response to unpleasant versus pleasant pictures (left side of the
image is the right side of the brain) while the figure on the right presents a scatter plot depicting
the strong positive correlation between dispos i-


patients we examined the extent to which the prefrontal

activation elicited by unpleasant pictures was significantly
more right-sided and whether
this differed between patients
and controls. Figure 6 illustrates the data from this study
(Davidson et al., 2001).
We found greater right-sided
prefrontal activation in the
middle and superior prefrontal
gyri and this pattern of activaFigure 4: Left: activation of the right amygdala in response to negative versus neutral pictures
tion was present in both nor(N=14); Right: relation between magnitude of MR signal change in the right amygdala and
dispositional negative affect
mal controls and in patients in
an acute depressive episode.
tional negative affect and the magnitude of rightThese fin dings are consistent with our data using
sided amygdala activation elicited in response to
considerably more crude electrophysiological
the unpleasant compared with the neutral stimuli
techniques (e.g., Davidson, Ekman et al., 1990).
(see Irwin et al., 2001 for details).
Unfortunately, our acquisition sequence using
We also had the opportunity to examine changes
whole brain imaging with 7 mm slices in this
in activation in other brain regions in response to
study resulted in significant susceptibility artifact
the unpleasant versus neutral stimuli since we acin the region of the orbital prefrontal cortex
quired data from the entire brain volume. View(OFC) and we were thus unable to obtain adeing unpleasant pictures consistently activated difquate signal from this region to examine. Recent
ferent sectors of the prefrontal cortex. Figure 5 ilwork using a somewhat different echoplanar
lustrates the pattern of prefrontal activation in repulse sequence with a higher field strength and
sponse to the unpleasant (compared with the neuspecifically shimming to obtain good signal qua ltral) pictures (right side of the brain is on the left
ity from the OFC has found significant asymmetside of image). The sagittal image at the left indiric activations in response to monetary reward
cates the slice locations for the coronal slices on
and loss in the direction predicted on the basis of
the right.
our prior data and theory (ODoherty et al., 2001).
Recently, in a sample of normal and depressed
Figure 5: Saggital image at left denotes

the slice locations for the coronal images
displayed to the right. Activations represent the contrast between viewing negative versus neutral pictures. Left side of
the image is right side of the brain.


0.15
0.10
Right
0.05
Left
0.00
Controls
Patients
Figure 6: Left: MR signal change in response to negative versus neutral pictures in the regions of the left and right prefrontal cortex
identified by the cross-hairs in the image on the right in normal controls (N=14) and depressed patients off medication (N=16).
Right: location of maximal activation in the prefrontal cortex across groups.
One important aspect of the functional imaging paradigm proposed in the present application
involves voluntary regulation of emotion using a
paradigm that we have deve loped and extensively
validated using psychophysiological measures including facial EMG and emotion-modulated startle (Jackson et al., 2000b). We recently completed our first fMRI study using a variant of this
paradigm that requires subjects to either passively
view emotional pictures or to voluntarily maintain the emotion during a delay period following
the presentation of the picture. We were specifically interested in the MR signal change during
an 8 second delay period that occurred immediately following a 6 second exposure of an emotional (or neutral) picture. Following the 8 second delay period during which subjects were requested to either maintain the emotion or not, a
signal to RELAX was presented that cued subjects to cease whatever regulatory strategy in
which they were enga ged. Using event-related
fMRI we were specifically interested in interrogating brain activity during the delay period.
Figure 7 presents data from this study (Schaefer
et al., 2001) illustrating voxels in the amygdala
that were significantly more active during the
maintain versus passive conditions in the delay
period.
G. Hippocampal morphometry and its association
with depression and anxiety: We recently exa mined the relation between hippocampal volume
and mood and anxiety in a group of 40 subje cts
(25 patients with major depressive disorder and
15 healthy controls screened for an absence of
lifetime history of psychopathology in themselves
and their first degree relatives).
We present here the details of
our procedures for drawing
ROIs for the hippocampus
since they will serve as a basis
for the work we propose
Figure 7: Voxels within the

amygdala that are significantly more activated during
voluntary emotion regulation
(MAINTAIN) compared
with passive viewing (Schaefer et al., 2001)

in this application. Using the same basic MR

methods, we have also established reliable criteria
for drawing ROIs for the amygdala (see Schaefer
et al., 2000).
The MRI image data underwent the following
preprocessing steps: (1) reformatting into a single
3-dimensional volume (ANALYZE [R.Robb,
Mayo Clinic] format); (2) psuedo-histogram rebinning to set the highest 0.1% of values to the
99.9 percentile level, enhancing the apparent contrast in the brain regions of interest; and (3)
smoothing using a 3-dimensional anisotropic annealing algorithm (Perona & Malik 1990; Gerig et
al. 1992), which preserves edges and small features while smoothing large homogeneous areas.
The criterion for smoothing was that similar pixel
clusters smaller than 2-4 pixels should be removed, but pixel clusters larger than 4 pixelsshould remain.
In-house software (SPAMALIZE) was used to
define regions of interest. This software displays
axial, coronal, and sagittal views simultaneously,
and allows the user to draw in any of the views to
quickly construct a 3-dimensional Volume-ofInterest (VOI) with pixel- level precision. Volumes for the whole brain and the cerebellum were
determined using automated segmentation techniques (Oakes et al. 1999) followed by manual
corrections if needed. The hippocampal VOIs
were rapidly defined manually with the aid of
software that limited the VOI to grey matter, and
were then refined without the grey-matter limitation.
Hippocampus VOIs were traced and edited on
both sagittal and coronal slices. Sagittal criteria
follow: On the lateral- most slices, the hippocampus borders were defined superiorly by the fimbria, anteriorly by the alveus, posteriorly by the
CSF of the lateral ventricle, and inferiorly by the
white matter of the temporal lobe. On more medial slices, a white matter tract appearing posterior to the hippocampus was excluded. For most
subjects, the amygdala could be readily distinguished from the hippocampus on sagittal slices
by defining the alveus (a white matter tract) as the
anterior border of the hippocampus. On the medial-most slices, the head and tail of the hippocampus are separated by thalamic nuclei. At this
point, the tail was no longer traced sagittally be-

cause of an inability to exclude the gyrus fasciolaris and the fasciola cinera.
Coronal criteria follow: The posterior portion of
the hippocampus was defined as being bordered
laterally by the white matter of the fornix (or the
CSF of the lateral ventricle in places where the
fornix was indistinguishable), medially by CSF,
inferiorly by white matter, and superiorly by the
splenium of the corpus callosum (moving anteriorly, the superior border is defined by the gyrus
fasciolaris and the fasciola cinera, and then by the
fimbria). For the most anterior portions of the
hippocampus, the amygdala delineates the superior edge of the hippocampus, while the inferior
border was defined by white matter resulting in
the subiculum being included in the hippocampal
volume.
To account for individual differences in overall
brain size, total cerebral volume is used as a regressor in the analyses. Because not all scans included the entire cerebellum, the cerebellum was
excluded from whole brain measurements.
The group of subjects we tested in this study
consisted of relatively young community volunteers. The mean ages were 33.2 years for the depressed sample and 37.4 years for the controls.
This is a potentially important factor since most
of the prior data on hippocampal atrophy in depression were derived from older samples (see review in our article, Rusch et al., 2001; in appendix). We first wished to determine if our methods
for drawing hippocampal volumes were reliable.
Accordingly, we had two raters draw volumes independently on 5 subjects and computed the intraclass correlations between them. Intra-class
correlations indicated reliable tracing of both the
left (IC = .97, p = .007) and right (IC = .80, p =
.10) hippocampi.. Consiste nt with other recent
reports (Pruessner et al. 2000; Mervaala et al.
2000), we found that right corrected hippocampal
volumes were be significantly larger than left corrected hippocampal volumes.
In our sample, the volumes of the hippocampus
did not differ between the depressed and control
subjects using measures of either absolute volume
or of corrected volume (corrected for whole brain
volume) for either the left, right or total hippocampus. Half of our depressed sample met criteria for melancholic depression and when we ex-


amined this group separately compared with the

other depressed patients and controls, no group
differences were found. Power calculations indicated that this was not an artifact of the study being underpowered.
Interestingly, for the both the depressed patients
and the controls, right hippocampal volume and
total volume were correlated with trait anxiety.
Figure 8 illustrates this finding. The failure to
find group differences between depressed patients
activity may be a potential cause of generalized

anxiety (McNaughton 1997). Again, we intend to
follow-up these data in the current project with a
much larger sample size and a much more complete battery of mood and affect measures in the
respondents.
Anxiety Correlation (Depressives)
Anxiety Score
80
70
60
r=.75
p=.00
3
d. Research Design And Methods

The central goal of the work proposed in this
project is to interrogate brain mechanisms that
might underlie vulnerability and
resilience in a moderately large,
representative and highly stratified
sample of WLS participants. We
propose to test 500 subjects over
the course of this five year project
period.
The major hypotheses pursued in
this project are:
50
Brain electrical activity measures of prefrontal activation

asymmetry will be assoc iated
Right Corrected Volume
with measures of dispositional
negative affect, anxiety and psyFigure 8: Relation between trait anxiety and hippocampal volume in depressed
chological well-being. Specif ipatients (N=25).
cally, subjects with greater right
and controls in this study may, as noted earlier, be
prefrontal activation will report more negative afa product of the relatively young age at which
fect and anxiety and show higher levels of cortithese patients were tested. Given findings that
sol compared with their more less anxious and
indicate a relation between number of cumulative
more positive counterparts. Subjects with greater
days depressed and hippocampal volume in such
left-sided prefrontal activation are predicted to repatients (Sheline et al., 1996), it may well be that
port higher levels of psychological well-being and
examining an older group of patients will yield
to show a more resilient profile on both selfmore consistent findings. In the proposed rereport and other biological measures.
search, we will be able to take advantage of the
2.
The volume of the hippocampus will be inextensive corpus of psychosocial and demoversely
correlated with measures of cumulative
graphic data on these respondents to examine
stress
and
depression. However, in light of our
which factors are most strongly associated with
new data indicating that hippocampal volume corvolume reductions in the hippocampus.
relates pos itively with trait anxiety (Rusch et al. ,
The discovery of a positive correlation between
2001), we will also examine the role of anxiety in
trait anxiety and right and total corrected hippomoderating this relation. We also predict that
campal volumes was novel. Animal studies have
hippocampal volume will be correlated with
suggested a role for the hippocampus as part of a
measures of cortisol available from these subjects.
coping system for stressful and anxiety-rich situaWe will also examine possible gender differences
tions, with the dentate gyrus (Henke 1990; Belsince recent data indicate a decline in hippocamzung 1992) and ventral subiculum (Herman et al.
pal volume for men but not for women (Pruessner
1998) being specifically implicated. Furthermore,
40
0.001
1.
0.00125
0.0015
0.00175
0.002
it has been hypothesized that hippocampal hyper-
0.00225
0.0025

3.
4.
5.
6.
et al., 2001). Gender will be examined in all of

our analyses.
The volume of the amygdala will also be positively correlated with anxiety symptoms (De Bellis et al., 2000). We have established procedures
for accurately drawing the amygdala on MR in
my laboratory (see Schaefer et al., 2000) and will
use these in the current work.
Using fMRI to measure the BOLD signal in
response to a task designed to elicit emotion and
to assess the voluntary regulation of emotion, we
predict that greater cumulative exposure to adversity will be associated with larger magnitude
amygdala signal in response to aversive compared
with neutral stimuli. In addition, we predict
greater activation of the amgydala during a delay
period immediately following the presentation of
the emotional stimulus. We also predict that respondents with more cumulative adversity will be
less able to voluntarily regulate negative affect
and will show a larger amygdala signal in a condition that requires them to voluntarily attenuate
their negative affect.
In the task designed to assess reactivity and
regulation of emotion, a series of novel emotional
pictures will be presented. We will examine the
magnitude of hippocampal signal in response to
the presentation of these novel pictures. We predict that subjects exposed to more cumulative adversity will show less hippocampal activation
than their more advantaged counterparts. We also
predict that hippocampal activation will be correlated with recognition memory and with levels of
basal cortisol.
We will examine relations between the anatomical and functional data, specifically for the amygdala and hippocampus. These, as well as other
analyses involving the anatomical data will use
new voxel-wise deformation-based morphometric
measures that have been pioneered by our new
colleague at UW, Moo Chung, who is a CoInvestigator on this proposal. We will conduct
exploratory analyses examining the relation between individual differences in electrophysiological measures of prefrontal activation asymmetry
and the morphometric and functional MRI data.

Subjects:
The subjects will consist of 500, randomly selected WLS participants. Because the examinations will take place over a 4 -year period, at the
time of testing, subjects will be between the ages
of 63 and 67. The random sample will be representative of the graduate cohort, but highly stratified by gender, adolescent cognitive ability, educational attainment, marital status, and employment history. 1 There are numerous questions that
will be addressed in this project and separate
power calculations were performed for all of the
major classes of variables. For every neural variable, the effect size ranges from moderate to
large. For example, in research examining differences in hippocampal volume between depressed
patients and controls, the effect size is large. In
the Bremner et al. (2000) study, the effect size is
d=.99; in the Sheline et al. (1999) study, the effect
size is d=.80. Sheline et al. (1999) also report a
correlation of r=.60 between hippocampal volume
and total number of days depressed over the
course of the lifetime. This latter correlation results in a power of .80 to detect this relation using
a .05 two-tailed alpha level with a sample size of
19. In our studies of relations between electrophysiological measures of prefrontal activation
asymmetry, well-being and emotion-modulated
startle, the magnitude of most correlations ranges
between r=.3 and r=.5 (see Preliminary Studies
above). A power of .8 to detect a relation at the
.05 (2-tailed) level between our electrophysiological measure of asymmetric prefrontal activation and these other variables would require a
sample size of 84 subjects for a correlation of .3.
The rationale for a sample size of 500 is so that
we can maximize our range on the variables of interest and could then form smaller subgroups that
are still sufficiently large to provide adequate
power to test our hypotheses.
Aside from its much smaller size, the sample used in my

earlier work with Ryff and Singer was stratified by psychological characteristics and was not fully representative of the
WLS cohort. The new sample will also be 5 to 10 years older
at the time of examination, and I will have the benefit of a
new wave of life-history data.

Procedures:
Subjects will begin their assessment procedures
in the morning by checking into the General
Clinical Research Center (GCRC). During their
stay at the GCRC, a Registered Nurse (under Dr.
Muller's supervision) will conduct comprehensive
physical examinations (see protocol in Appendix). These data will complement and corroborate self-report data. In our pilot studies, we have
found that subjects do not always report findings
that may be of significance for predicting future
health and daily functioning. Examples include
carotid arterial bruits, abnormal heart sounds (S3,
S4), lower extremity edema, anosmia, osteoarthritis of the hands, lower extremity varicosities, and
fibromyalgia and other regional pain syndromes
such as bursitis or tendenitis. The physical exam
reveals vessel changes in the eye, usually due to
hypertension, that may be predictive of future
brain, kidney, or heart damage. Vibration loss in
the lower extremities may indicate nerve damage
in subclinical diabetes; subc linical diabetes is also
tested by measuring glycosylated hemoglobin
(HbA1c, laboratory test). Forgotten injuries and
surgeries are found by asking about scars. Notations on teeth alignment, repair, and false teeth
may reflect both behavioral and economic factors.
Cardiac findings in the physical exam may be reflected in the cardiovascular measures of emotional reactivity and allostatic load (cortisol, epinephrine). Other physical findings such as ni tegument scars, sun exposure skin lesions, striae,
arcus senilis, nail lesions, skin and mucus membrane moisture, heart murmurs, ear crease, subclinical sinusitis, grip strength, peak flow (lung
function) may be predictive of future health. We
view these examinations as a valuable opportunity to identify potential predictive markers of
physical health with possible linkage to social and
demographic factors and other biological assessments of allostatic load, immune function, and
cerebral activation asymmetry.
Standard laboratory blood tests will be performed in the GCRC and can be used a general
markers of health. The complete blood count
may indicate anemia. Abnormalities in electrolytes (sodium, potassium, bicarbonate) indicate
abnormal regulation in the kidney and cardiovas-

cular systems. Elevations in liver enzymes can

indicate occult alcohol abuse (GGT) or intrinsic
liver disease (GGT, AST, bilirubin). Mild elevations in creatinine can indicate early kidney insufficiency. Modestly low serum albumin can be a
marker for inflammation or malnutrition, and the
sedimentation rate is a sensitive marker of inflammation. Other abnormalities in routine laboratory tests such as total protein, calcium, lactate
dehydrogenase, and alkaline phosphatase can indicate a myriad of diseases. Glycosylated hemoglobin is an excellent marker for occult diabetes
mellitus. Chole sterol and HDL cholesterol are
good markers for future risk of cardiac disease.
Our preliminary analyses of a simple variable
such as total numbers of abnormalities on physical examination or total numbers of abnormalities
on standard laboratory blood tests show correlation with social relationship variables. Further
analyses will examine variables ranked as to possible risk for future morbidity and mortality.
Less routine laboratory blood tests such as Creactive protein and homecysteine have clear
links to increased risk of coronary artery disease
(Ridker et al. 2000). Dihydroepiandrosteronesulfate (DHEA-S) and interleukin-6 are markers
of aging and immune-dysregulation, with decreases in DHEA-S with age and decreased
health, inversely related to increases in interleukin-6 (Daynes et al, 1993; Papanicolaou et al,
1998). Three cytokine markers are strongly associated with links between psychosocial factors
and the immune system: interleukin-6, tumor necrosis factor and interleukin-2 receptor. Tumor
necrosis factor is closely linked with interleukin-6
as a proinflammatory cytokine, but interleukin-6
has separate links to psychosocial factors such as
depression (Dentino et al, 1999). A third cytokine marker, interleukin-2 receptor, has independent links to schizophrenia and major depression (Maes et al, 1995). The use of three cytokines in combination with other tests of infla mmation such as the sedimentation rate, using multivariate analyses increases our potential to assign
the cytokine to simple underlying occult infla mmation versus a more subtle and complex relationships to psychological and physical health.
After spending the morning in the GCRC, subjects will have lunch. Following lunch they will


be taken to an MR simulator that consists of the

tion of the self-report and interview measures,
shell of an MR scanner, along with the bed and a
subjects will be taken into the scanner.
The
mock head coil of the precise diameter used in the
scanning sequence will consist of anatomical
actual scanner. We use this apparatus to accliscans following by functional scans. The anamate subjects to the MR environment and to fatomical scans will be obtained with a 3D whole
miliarize them with the behavioral tasks that will
brain T1-weighted SPGR, 30 flip angle, 1mm
be presented in the scanner. In addition, we have
axial slices with 0mm skip. The functional data
digitized the sounds of the actual scanner and
will be collected in a time series using T2*play them to the subjects so that they will know
weighted gradient echo EPI sequences on our 3T
ahead of time exactly what to expect during the
GE scanner. Data will be acquired in the sagittal
actual scanning session. We have found the
orientation, TE=30 ms, TR=3000 ms, slice thic ksimulator session to be important in reducing subness=4mm, with a .5mm skip. These are scanjects anxiety about the upcoming scan and to faning parameters that we are currently using on the
cilitate the acquis ition of higher quality data.
3T and they are providing high quality data.
At the simulator session, subjects will also comThe anatomical acquisition protocol will permit
plete a number of standardize d self-report instrudeformation-based morphometric analyses to be
ments including an assessment of handedness
performed on a voxel-wise basis by Moo Chung
(Chapman & Chapman, 1987), along with a group
(see Chung, 2001). An example of volumetric
of instruments that assess mood and dispositional
measurement using Chungs deformation-based
affect that we have found to be related to individalgorithms is presented in Figure 9 below. This
ual differences in prefrontal activation. These infigure illustrates changes over time in a longitudiclude the Positive and Negative Affect Scales
nal study and highlights in red areas that increase
(Watson et al., 1988); the Behavioral Inhibition
in volume, in blue areas that decrease in volume
and Activation Scales (Carver & White, 1994);
and in yellow areas that display displacement in
the
Spielberger
State-Trait Anxiety Scale (Spie lberger
et
al.,
1983), the Mood
Affect Symptom
Questionnaire
(MASQ; Watson
et al., 1995) and
the Daily Retrospective Questio nnaire (Kahneman,
2001; see appendix). In addition,
all subjects will be
given a SCID interview to assess
current and past
history of psychopathology according to the DSM-IV
(First et al., 1995).
Following
the
simulation session
Figure 9: Deformation-based morphometry illustrating longitudinal changes in volume and displaceand the complement (Chung et al., 2001)

location over time.

The task will be based upon recent event-related
studies with emotional stimuli that have been conducted in my laboratory (e.g., Putnam et al., 2001).
A total of five runs will be presented. Each run
will consist of 75 different picture presentations.
All presentations will be unique. Pictures are selected from the International Affective Pictures Series (Lang et al., 1998). Each picture will be presented for 3 s, with an ISI of 12 Ss. An equal number of positive, negative and neutral pictures will
be presented. The first two runs will be passive
viewing though subjects will be told that they will
be tested for their memory of the pictures after the
scan. The final three runs will consist of a regulation task.
Immediately after the presentation of
each picture, subjects will be presented with either
an arrow up, an arrow down or a circle. The circle
denotes that they are to maintain the emotion that
they are experiencing; the up arrow denotes that
they should accentuate the emotion they are experiencing and the down arrow indicates that they
should attenuate the emotion they are experiencing.
We have performed extensively initial research
with this task and know that both emotionmodulated startle (Jackson et al., 2000b) and MR
signal change in the amygdala (Schaefer et al.,
2000) are modified in response to emotion regulation instructions. At six seconds post picture offset, the word RELAX will appear on the screen
for one second informing the subjects to cease the
emotion regulation strategy that they have invoked.
To assess the impact of the instructed regulation
strategy on MR signal change, we will specifically
interrogate the activity in the six-second postpicture period prior to the instruction to RELAX.
Following the scanning session, subjects will be
presented with a recognition memory test to probe
for memory of the pictures presented. A subset of
150 of the pictures that were presented, with an
equal number selected across the different conditions (passive viewing, accentuate, attenuate and
maintain) of each valence, along with an equal
number of recognition foils will be presented.
Each picture will be presented for 2 seconds with
a 2 second ISI and subjects will simply have to
press one of two buttons following each picture to
indicate whether it was a new or old picture.

We will pilot this task to insure that activation in

the hippocampus can be detected. If we do not
see reliable signal in the hippocampus in middle
aged adults during this task, we will modify it to
include a basis set of pictures that the subjects
will have been familiarized on prior to the scanning session (see Constable et al., 2000). These
familiar pictures would then be interspersed with
the novel pictures during the picture presentation
paradigm. This might be required to elicit hippocampal activation based upon recent imaging data
(Constable et al., 2000).
Finally, following the recognition task, subjects
will be escorted to the electrophysiology testing
room at Keck where baseline EEG will be recorded with the geodesic sensor net system according to our standard protocol (Tomarken et al.,
1992). We will acquire eight 1-minute trials of
EEG, half during eyes open and half during eyes
closed, presented in counterbalanced order.
Data reduction, analyses and hypotheses: The
electrophysiological data will be analyzed as previously described in a long series of publications
(see Davidson, Jackson & Larson, 2000 for extensive description). Measures of prefrontal activation will be computed from spectral measures of
alpha power from a composite of the prefrontal
scalp sites. In addition, source localization methods will be used to compute the sources of signals
in theta, alpha, beta and gamma bands and relate
them to the key variables of interest (see Pizzagalli et al., 2001, from our lab). The source localization method we have been extensively using
for spectral EEG data is Low Resolution Electromagnetic Tomography (LORETA; PascualMarqui, 1999). LORETA computes the threedimensional intracerebral distributions of current
density for specified EEG frequency bands. In
simulations comparing five source localization
techniques using linear solutions for the EEG inverse problem, only LORETA reliably localized
sources in three-dimensional space (PascualMarqui, 1999). One important difference between the LORETA algorithm and previously
published source localization methods (e.g.,
BESA; Scherg & Von Cramon, 1986) is that
LORETA does not assume a specific number of
sources for solving the inverse problem. The only

assumption implemented is that neighbor neurona l sources are likely to be similarly active (i.e.,
have similar orientations and strengths). This assumption is well supported by animal single unit
recordings (e.g., Llinas, 1988). Mathematically,
the assumption of simultaneous and synchronous
activation of neighboring neurons is implemented
by computing the smoothest of all possible activity distributions. A recent study (Worrell et al.,
2000) provided direct cross modality validation
by showing that LORETA generators of ictal discharge were remarkably close to the locations of
MRI-identified epileptic foci.
The LORETA version we have implemented in
our laboratory uses a three-shell spherical head
model registered to the Talaraich brain atlas (Talaraich & Tournoux, 1988) , as well as EEG ele ctrode coordinates derived from cross-registrations
between spherical and realistic head geometry
(Towle et al., 1993). Computations will be restricted to cortical gray matter and hippocampus
using the digitized Talaraich and probability atlases of the Brain Imaging Centre, Montreal Neurologic Institute. If a voxels probability of being
gray matter is higher than 33% and higher than
the probability of being white matter or cerebrospinal fluid, that voxel is labeled as gray matter.
The solution space contains 2394 voxe ls, and the
spatial resolution is 7 mm.
The LORETA analyses consist of three steps:
First, for every subject, all available artifact-free
2048-ms EEG epochs derived from average reference data are subjected to cross-spectrum analysis. Second, LORETA computes current density
as the linear, weighted sum of the scalp electrical
potentials and then squares this value for each
voxel to yield power of current density. Finally,
for every subject and every band, the LORETA
solution is normalized to a total power of 1 and
log-transformed. LORETA units are proportional
to square amperes per square meter. A MonteCarlo procedure is used to estimate the false positive rate in testing the null-hypothesis of no relation between the chosen experimental variable or
group identification and the LORETA signal (see
Pizzagalli et al., 2001 for an example of this approach from our lab).
The structural MR data will be analyzed as described in the Preliminary Studies section to ob-

tain measures of hippocampal volume (see Rusch

et al., 2001, in appendix). The volume of amygdala core nuclei and the non-core amygdala
(Sheline et al., 1999) will be separately obtained
since the former has been found to be positively
correlated with hippocampal volume (r=.68) and
to be associated with number of days depressed
voer the course of a lifetime in patients with recurrent major depression (Sheline et al., 1999).
The core nuclei of the amygdala will be defined
by the white matter tracts surrounding them. Included will be the basal nucleus, accessory basal
nucleus and the lateral nucleus (medial portion).
Excluded are the periamygdaloid areas, the medial nucleus and the central nucleus. The noncore amydala is defined by measuring the total
amygdala and subtracting the core amygdala.
The anterior boundary of the amygdala will be
visualized in coronal section and is the first slice
in which the temporal stalk connects to the white
matter of the insula. Dorsally, visualized in coronal section, the border is defined in anterior sections by the endorhinal sulcus between the basal
forebrain and temporal lobe, and posteriorly in
sagittal sections by a horizontal to the poste roin ferior edge of the temporal stem with the temporal
horn of the lateral ventricle. Ventrally, visualized
in sagittal section, the amygdala is bounded by a
horizontal line connecting to the ventral/anterior
edge of the hippocampus. Posteriorly, observed
in sagittal section, the amygdala is bounded by its
border with the hippocampus. Medially, seen in
coronal section, the amygdala is bounded by the
subarachnoid space. Laterally, seen in coronal
section, the amygdala is bounded by white matter.
Corrected volumes, corrected for overall differences in cerebral volume will be calculated. Deformation-based morphometric measures will be
utilized to perform voxel-wise searches for morphometric relations with select variables and
group definitions (Chung et al., 2001).
Event-related functional MRI data will be analyzed as we have described in recent reports (Putnam et al., 2001). Briefly the following steps will
be performed on the data: volume registration,
linear detrending and then non-linear fitting using
a gamma-variate function to model the hemodynamic response. The primary dependent measure
from this data reduction process will be percent

signal change though other indices such as area

under the curve will also be computed and examined on an exploratory basis.
The data from the physical exam will be quantitated by summing the number of abnormalities
detected. The specific laboratory tests on the
blood samples will be examined by first determining the pattern of intercorrelation among the
measures and reducing the variable set by aggregating across measures. These aggregate measures will then be used in regression models where
key psychosocial and socioeconomic variables are
entered as predictors. In addition, they will be
used in analyses that examine relations between
the brain imaging variables and peripheral biology and physical health.
Using the four primary corpora of data (phys ical
health and peripheral biomarkers; EEG; structural
MR measures; functional MR measures), relations with aggregate summary variables from the
WLS data set will be examined to test the following major hypotheses:
1. We predict that we will replicate previous findings and observe that subjects with increased
left-sided prefrontal activation on the electrophysiological measures will report greater levels
of well-being, partic ularly on the subscales of
Self-acceptance, Positive Relations with Others,
Purpose in Life and Environmental Mastery.
We also predict that individuals with greater
left-sided prefrontal activation will have fewer
phys ical health problems as revealed in the
physical exam and a healthier profile of peripheral biomarkers, particularly IL-6 (i.e., lower
levels).
2. A major addition to the new WLS data collection will be the inclusion of Kahnemans Daily
Retrospective Questionnaire that is derived from
experience-sampling studies and is more closely
associated with momentary affect measures
compared with memory-based retrospective
measures. For each of our key measures of
brain function, we will systemically compare the
traditional memory based measures with Kahnemans new measure and predict that relations
will be systemically more robust with the new
Kahneman measure.
3. Examine relations between stressful life events,
coping styles and functional and structural

measures. We predict that increased exposure to

adversity and stressors will be associated with
smaller hippocampal volumes. While we did
find smaller hippocampal volumes in our recent
study with depressed patients (Rusch et al.,
2001), this study was performed with relatively
young individuals (average age=35 years). Cumulative exposure to adversity over a considerably longer period of time is predicted to have
consequences for the hippocampus. Exposure to
adversity is also predicted to be associated with
smaller amygdala core nuclei since it was this
measure of amygdala anatomy that was most
strongly correlated with hippocampal volume in
Sheline et al.s (1999) recent data. We also predict thatanxiety will be positively associated
with noncore amygdala volume, so trait levels of
anxiety will be included as a predictor in all of
these analyses. In the analyses of stressful life
events, we will take advantage of the detailed
and differentiated information available in the
WLS corpus of data to examine for possible differences in types of stressors, including subjective economic strains. The moderating effects
of coping strategies and styles will be included
in these analyses using regression-based analytic
approaches. In light of the recent data from the
Montreal group, we predict hippocampal volume reductions with age in men, but not in
women (Pruessner et al., 2001). These hypotheses will be examined with both region-ofinterest analyses as well as voxel-wise whole
brain searches using deformation morphometry
methods (Chung et al., 2001) that will allow us
to examine measures of shape in addition to
volume.
4. Examine relations between the cognitive measures and the structural and functional measures
of the brain. We predict that hippocampal volume will be associated with variations in verbal
memory. Individual differences in verbal fluency and in working memory are predicted to be
associated with structural and functional variations in prefrontal cortex. These hypotheses will
again be examined using both voxel-wise whole
brain searches as well as region-of-interest
(ROI) analyses using a probabilistic atlas
(Chung et al., 2001).

5. On the fMRI measures, we predict that increased exposure to adversity and greater exposure to stressors will be associated with be associated with greater magnitude activation of the
amygdala in response to unpleasant pictures and
followin g the presentation of the unpleasant pictures. In our previous fMRI studies with emotional pictures, we have not found many group
differences in response to the positive pictures
but we will test for relations between our key
subject variables (well-being, anxiety and dispositional negative and positive affect) and wholebrain reactivity to positive pictures. In the regulation task, we predict that instructions to attenuate negative affect will be associated with
less facility at modulating amygdala reactivity to
negative pictures in the post-picture period in
subjects with increased exposure to adversity.
This is conceptually analogous to the findings
using emotion-modulated startle that were presented in the Preliminary Studies section. All
fMRI analyses will be performed on data corrected for overall amount of gray matter, was
well as the uncorrected data.
6. Examine relations between the peripheral biomarkers and the structural and functional measures of the brain. We predict that decreased
hippocampa l volume, increased amygdala activation both during the following negative picture presentation and possibly decreased volume
in certain regions of the PFC (detected with
deformation-based morphometric methods) will
be associated with a profile of biomarkers in the
less healthy direction. These include higher
body mass index, greater waist-hip ratio, lower
levels of DHEA, higher levels of total cholesterol and HDL cholesterol. and higher levels of
IL-6.


e. Human Subjects
1. The subjects for this study will consist of 500
respondents from the WLS sample. Half the subjects will be female. Subjects will range in age
from 63 to 67 years.
All subjects will be carefully screened for possible presence of metal implants and/or cardiac
pacemakers and will be excluded if any such implants are suspected (because of MR imaging).
2. The sources of the research material will be
data collected in the laboratory strictly for research purposes. The principal types of data will
be blood samples, brain electrical activity measures, and MR measures of brain structure and
functional brain activity.
3. The sample will be recruited from the ongoing
WLS study. Prospective subjects will be given a
short statement describing the research and provided with an oral description of the project. Any
questions a prospective subject might have about
the nature of the research will be answered by a
staff member associated with the project. Following this, subjects will give signed consent to the
experimental procedure.
4. The risks associated with all procedures are
very minimal. There is essentially no risk to the
electrophysiological recording procedures other
than possible slight irritation at the site of electrode application. The risk associated with the
MR procedure is minimal. Subjects with metal
implants or cardiac pacemakers will be excluded
from participation. Individuals with claustrophobia may experience some anxiety in the small
bore of the magnet. There may be slight discomfort in having to lie still during the scanning pr ocedure. The emotional pictures used in the MR
study may be slightly disturbing, though they are
culled from readily available media to which citizens in this age range are exposed daily.
5. Every effort will be made to provide information to subjects to reduce their anxiety about the
MR procedures and the electrophysiological recordings. Confidentiality will be maintained

throughout the project period. Names will not be

kept on data records and standardized codes will
be used at each site. Subjects will be identified
only by a code number.
If any adverse effects occur during the imaging
protocols, appropriate medical intervention is provided.
6. The risks to the subjects in this research are
minimal. The research proposed offers considerable promise in furthering our understanding of
the biological bases of vulnerability and resilience
and their relation to health and disease. The potential benefits of this research far outweigh the
risks involved.

e.1. Gender and Minority Inclusion

Table 1. Gender and Minority Inclusion
Grads
sibs

NOTE: This table includes all of the original members of the graduate sample (N=10,317), and the
selected siblings who responded to the 1977 and/or
1994 surveys (N=5,812), and their living spouses
(N=10,148).
American
& Indian or Asian or Black, not of
Pacific
Hispanic
Hispanic
Alaskan
Islander Origin
Native
Female
17
Male
Total
12
29
White, not of
Other or
Hispanic
Total
Unknown
Origin
1
2
3
20
12
32
7
11
18
8,254
7,793
16,047
8,299
7,830
16,129
1
1
2
8
13
20
7
4
11
4,903
5,193
10,096
4,926
5,222
10,148
2
3
5
28
25
52
Spouses
Wives
Husb
Total
8
11
18
Full-sample
Female
25
Male
TOTAL
23
47
Among Americans aged 60 to 64 in March 2000,

66.7% are non-Hispanic white women and men
who completed at least 12 years of schooling (U.S.
Bureau of the Census 2000: Table 1a) and thus resemble the WLS cohort. The WLS is unusually
valuable in its representation of women as well as
men. The WLS cohort, mainly born in 1939, precedes by about a decade the bulk of the baby boom
generation that continues to tax social institutions
and resources at each stage of life. For this reason,
the study can provide early indications of trends
and problems that will become important as the
larger group passes through its sixties. In addition,
the WLS is the first of the large, longitudinal studies of American adolescents, and it thus provides
the first large-scale opportunity to study the life
course from late adolescence through the mid-60s
in the context of a full record of ability, aspiration,
14
13,157
13,225
15
12,986
13,052
29
26,143
26,277
and achievement. 2 The WLS overlaps the youngest
cohorts that entered the HRS, and this provides
opportunities to check the scope of our findings
(and those of the HRS). Unlike the WLS, the HRS
is nationally representative, but it does not cover
the lives of respondents from adolescence forward
to midlife.
The WLS data also have obvious limitations.
Some strata of American society are not represented. Everyone in the primary sample graduated
from high school. (Sewell and Hauser 1975:20715) estimated that about 75% of Wisconsin youth
graduated from high schools in the late 1950s;
There have, of course, been important and influential longer-term studies of the life-course in the
U.S. These reflect careful and insightful work, but
they are based on small, local, or highly selected
samples (Holahan and Sears 1995; Elder 1974;
Clausen 1993).

about 7% of siblings in the WLS did not graduate.

There are only a handful of African American,
Hispanic, or Asian persons in the WLS. Given the
minuscule share of minorities in Wisconsin when
the WLS began, there is no way to remedy this
omission. About 19% of the WLS sample is of
farm origin; this is consistent with national estimates in cohorts of the late 1930s. In 1964, in
1975, and again in 1992, 70% of the sample lived
in Wisconsin, but 30% lived elsewhere in the U.S.
or abroad. Fifty-seven percent of the graduates
have always lived in Wisconsin, and 17% have
lived outside Wisconsin at every contact since
1957. The WLS graduates are homogeneous in age,
but their siblings are not, and their ages cover a
broad range, mainly within 8 to 10 years of the age
of graduates.
In summary, the WLS samples consist of
women (5323) and men (4994) who graduated
from Wisconsin high schools in 1957 and a random
sample of approximately 5800 of their sisters and
brothers. Because of differences in longevity and
willingness to respond, there are yet more women
than men currently active in the study. While there
are no restrictions on the ethnic compositions of the
samples, because of the population composition
and schooling outcomes in Wisconsin in the late
1950s, the sample contains a very small share of
racial or ethnic minorities, and there is now no way
in which this problem in sample coverage can be
corrected.
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Tracking The Life Course. The Emotional Brain Across The Life Course

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Wisconsin Longitudinal Study: Tracking the Life Course

The Emotional Brain Across the Life Course

Principal Investigator: Hauser, Robert M.

Wisconsin Longitudinal Study: Tracking the Life Course

deed will be one of the first, and certainly, the

Principal Investigator: Hauser, Robert M.

asymmetry and morphometric and functional

Wisconsin Longitudinal Study: Tracking the Life Course

tive goal state is hypothesized to be implemented

Principal Investigator: Hauser, Robert M.

et al., 1997) in which we demonstrated reliable

Wisconsin Longitudinal Study: Tracking the Life Course

differences in both electrophysiological measures

Principal Investigator: Hauser, Robert M.

function in response to both a naturally occurring

Wisconsin Longitudinal Study: Tracking the Life Course

age of the variance (65%) in the magnitude of the

Principal Investigator: Hauser, Robert M.

Wisconsin Longitudinal Study: Tracking the Life Course

dependent changes are found in the alpha band,

Principal Investigator: Hauser, Robert M.

for additional details). Power in the delta (1-4

Wisconsin Longitudinal Study: Tracking the Life Course

Principal Investigator: Hauser, Robert M.

slightly greater relative left-sided activation (e.g.,

Wisconsin Longitudinal Study: Tracking the Life Course

we asked was whether subjects selected on the

Principal Investigator: Hauser, Robert M.

something, I usually go all out to get it. Items

Wisconsin Longitudinal Study: Tracking the Life Course

these scales were best predicted by the asymmetry

Principal Investigator: Hauser, Robert M.

portable emotion while sitting and resting). The

Wisconsin Longitudinal Study: Tracking the Life Course

Principal Investigator: Hauser, Robert M.

Wisconsin Longitudinal Study: Tracking the Life Course

100:1 ratios), replicating Kiecolt-Glaser et al.

Principal Investigator: Hauser, Robert M.

prior to film exposure (baseline) and then after

Wisconsin Longitudinal Study: Tracking the Life Course

Mean asymmetry (+ = greater left active)

Baseline asymmetry (FC3/4) and

Principal Investigator: Hauser, Robert M.

Figure 1: Relations between baseline prefrontal asymmetry

laborating with Hauser, Ryff and Singer on the

L o g 2 transformed antibody titer fold-rise

Wisconsin Longitudinal Study: Tracking the Life Course

Principal Investigator: Hauser, Robert M.

Late Startle Reactivity (Negative - Neutral)

the functioning of the human amygdala with fMRI.

The image acquisition protocol consisted of 10

Wisconsin Longitudinal Study: Tracking the Life Course

was positioned 1 mm anterior to the location

Principal Investigator: Hauser, Robert M.

Wisconsin Longitudinal Study: Tracking the Life Course

Principal Investigator: Hauser, Robert M.

patients we examined the extent to which the prefrontal

Figure 5: Saggital image at left denotes

Wisconsin Longitudinal Study: Tracking the Life Course

Principal Investigator: Hauser, Robert M.

Figure 7: Voxels within the

Wisconsin Longitudinal Study: Tracking the Life Course

in this application. Using the same basic MR