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The precise role of the cortex in human anxiety is not well characterised. Previous imaging research among healthy controls has reported alterations in regional cerebral blood flow (rCBF) within the prefrontal and temporal cortices during periods of anxious anticipation; however, the temporal dynamics of this activity has yet to be examined in detail. The present study examined cortical Steady State Probe Topography (SSPT) changes associated with anticipatory anxiety (AA), allowing examination of the temporal continuity and the excitatory or inhibitory nature of AA activations. We recorded Steady State Visually Evoked Potentials (SSVEPs) at 64 scalp locations, skin conductance, and self reported anxiety among 26 right-handed males while relaxed and during the anticipation of an electric shock. Relative to the baseline condition, the AA condition was associated with significantly higher levels of self-reported anxiety and increased phasic skin conductance levels. Across the seven second imaging window, AA was associated with increased SSVEP latency within medial anterior frontal, left dorsolateral prefrontal and bilateral temporal regions. In contrast, increased SSVEP amplitude and decreased SSVEP latency were observed within occipital regions. The observed SSVEP latency increases within frontal and temporal cortical regions are suggestive of increased localised inhibitory processes within regions reciprocally connected to subcortical limbic structures. Occipital SSVEP latency decreases are suggestive of increased excitatory activity. SSVEP amplitude increases within occipital regions may be associated with an attentional shift from external to internal environment. The current findings provide further support for the involvement of frontal, anterior temporal, and occipital cortical regions during anticipatory anxiety, and suggest that both excitatory and inhibitory processes are associated with AA alterations.
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Cortical neurophysiology of anticipatory anxiety: an investigation
utilizing steady state probe topography (SSPT)
M. Gray, A.H. Kemp, R.B. Silberstein, and P.J. Nathan*
Neuropsychopharmacology Laboratory, Brain Sciences Institute, Swinburne University of Technology,
400 Burwood Road Hawthorn 3122, Victoria, Australia
Received 31 March 2003; revised 23 June 2003; accepted 30 June 2003
Abstract
The precise role of the cortex in human anxiety is not well characterised. Previous imaging research among healthy controls has reported
alterations in regional cerebral blood flow (rCBF) within the prefrontal and temporal cortices during periods of anxious anticipation;
however, the temporal dynamics of this activity has yet to be examined in detail. The present study examined cortical Steady State Probe
Topography (SSPT) changes associated with anticipatory anxiety (AA), allowing examination of the temporal continuity and the excitatory
or inhibitory nature of AA activations. We recorded Steady State Visually Evoked Potentials (SSVEPs) at 64 scalp locations, skin
conductance, and self reported anxiety among 26 right-handed males while relaxed and during the anticipation of an electric shock. Relative
to the baseline condition, the AA condition was associated with significantly higher levels of self-reported anxiety and increased phasic skin
conductance levels. Across the seven second imaging window, AA was associated with increased SSVEP latency within medial anterior
frontal, left dorsolateral prefrontal and bilateral temporal regions. In contrast, increased SSVEP amplitude and decreased SSVEP latency
were observed within occipital regions. The observed SSVEP latency increases within frontal and temporal cortical regions are suggestive
of increased localised inhibitory processes within regions reciprocally connected to subcortical limbic structures. Occipital SSVEP latency
decreases are suggestive of increased excitatory activity. SSVEP amplitude increases within occipital regions may be associated with an
attentional shift from external to internal environment. The current findings provide further support for the involvement of frontal, anterior
temporal, and occipital cortical regions during anticipatory anxiety, and suggest that both excitatory and inhibitory processes are associated
with AA alterations.
© 2003 Elsevier Inc. All rights reserved.
Keywords: Anticipatory anxiety; Steady state probe topography; SSPT; BOLD; Electrophysiology; Electric shock; Healthy human participants
Introduction
Human anxiety consists of a complex pattern of cogni-
tive, affective, physiological and behavioural changes in
response to threat, loss, or perceived negative outcome
(Beck and Clark, 1997). Anxiety reactions cross into the
spectrum of clinical disorders when they are situationally
inappropriate or excessive in duration or degree. Within any
one-year period, 5.7% of the Australian population meet the
DSM-IV criteria for an anxiety disorder, a level closely
matched in both UK and US samples (Andrews et al., 2001),
highlighting the importance of gaining a better understand-
ing of the neural underpinnings of anxious symptomatology.
Research within a range of anxiety disorders employing
symptom provocation, pharmacological or behavioural
challenges, and resting state comparison methodologies has
highlighted the fact that in addition to the activity of limbic
and brain stem structures, higher cortical areas are function-
ally significant to the pathophysiology of anxiety. The most
consistently reported cortical brain regions with functional
significance to anxiety are found within the prefrontal cor-
tex, the temporal cortex (particularly anteriorly) and insula,
and within the occipital lobes. Alterations in activity within
the prefrontal cortex have been observed amongst a range of
patient populations including social phobia (Davidson et al.,
* Corresponding author. Neuropsychopharmacology Laboratory, Brain
Sciences Institute, Swinburne University of Technology, 400 Burwood
Road Hawthorn 3122, Victoria, Australia. Fax: 61-3-92145525.
E-mail address: pnathan@bsi.swin.edu.au (P.J. Nathan).
NeuroImage 20 (2003) 975–986 www.elsevier.com/locate/ynimg
1053-8119/$ – see front matter © 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S1053-8119(03)00401-4
2000), simple phobia (SP) (Paquette et al., 2003; Johanson
et al., 1998; Fredrickson et al., 1995; Wik et al., 1993),
panic disorder (PD) (Boshuisen et al., 2002; Bremner et al.,
2000; Meyer et al., 2000; Malizia et al., 1998; Nordahl et
al., 1998, 1990; De Cristofaro et al., 1993), post traumatic
stress disorder (PTSD) (Shaw et al., 2002; Osuch et al.,
2001; Mirzaei et al., 2001; Semple et al., 2000, 1993;
Liberzon et al., 1999; Shin et al., 1999; Zubieta et al., 1999),
and obsessive compulsive disorder (OCD) (Rauch et al.,
2002; Lucey et al., 1997; Schwartz et al., 1996; Rubin et al.,
1992; Zohar et al., 1989; Baxter et al., 1987). The results of
the above studies are consistent with the hypothesis that
prefrontal cortical regions (particularly within the right
hemisphere) are involved with the regulation and control of
anxiety by regulating the activity of subcortical limbic areas
including the anterior cingulate and amygdala (Davidson,
2002; Davidson and Irwin, 1999).
Alterations in temporal lobe function associated with
anxious symptomatology have also been frequently re-
ported. Increased temporal lobe rCBF activity was reported
among patients with generalised anxiety disorder (GAD)
(Johanson et al., 1992; Wu et al., 1991), OCD (Breiter et al.,
1996), SP (Rauch et al., 1995; Davidson et al., 2000), PD
(Boshuisen et al., 2002) and PTSD (Shin et al., 1999).
Increased rCBF was observed within the right insula of SP
(Rauch et al., 1995) and OCD patients (Breiter et al., 1996)
and among SP, OCD and PTSD patients (Osuch et al., 2001;
Shin et al., 1999; Rauch et al., 1997). Decreased rCBF has
been reported within the parietotemporal cortex (Meyer et
al., 2000; Bisaga et al., 1998) and anterior insula (Boshuisen
et al., 2002) of PD patients, and within the temporal polar
cortices of SP patients (Fredrickson et al., 1995). Anxious
symptomatology has also been associated with alterations in
occipital lobe activity. Reduced rCBF within primary and
secondary visual cortical areas has been reported among SP
patients (Wik et al., 1996, 1993) and PTSD patients (Mir-
zaei et al., 2001). Increases in occipital rCBF have also been
reported among subjects with PTSD (Rauch et al., 1996), SP
(Paquette et al., 2003; Fredrikson et al., 1993 1997), GAD
(Wu et al., 1991) which were attenuated after benzodiaz-
epine treatment (Buchsbaum et al., 1987), and subjects with
OCD (Zohar, 1989).
Pharmacological challenges, whilst providing another
avenue for investigation of the neural basis of anxious
symptomatology, are somewhat difcult to synthesize be-
cause of the use of various panicogens (CCK-4, pentagas-
trin, yohimbine, lactate, and CO
2
inhalation) in both clinical
and normal groups. Although each of these agents may be
used to induce anxious symptomatology to varying degrees
within patients and controls, each has a differing inuence
on the adrenergic and vascular functioning of the central
nervous system. As a result, the specic results appear
somewhat contradictory, however regional cortical alter-
ations within PFC, temporal lobes and insula, and occipital
cortex are commonly reported (Boshuisen et al., 2002;
Cameron et al., 2000; Javanmand et al., 1999; Bremner et
al., 1997; Benkelfat et al., 1995; De Cristofaro et al., 1993;
Stewart et al., 1988; Gur et al., 1987), highlighting the
involvement of these cortical regions during periods of
anxiety.
While clinical anxiety represents an excessive or inap-
propriate response to perceived threat, the underlying neural
circuitry associated with the basic components of anxiety
reactions may be common to both healthy and pathological
anxiety. Research within healthy adults aims at delineating
the specic neural circuitry involved in the normal emo-
tional self regulation associated with the various aspects of
anxiety reactions, providing a baseline for comparison with
the disordered and excessive reactions observed within clin-
ical populations. Evidence suggests that although disorder
specic abnormalities are observed within unique systems,
there is a core system comprised of elements of the para-
limbic belt which is common to anxiety states within both a
range of clinical anxiety populations, and within physiolog-
ical or normal anxiety (Rauch et al., 1997). Cortical activa-
tions associated with anxiety within healthy control subjects
are generally consistent to those observed amongst clinical
populations. Experimentally induced anxiety has also been
associated with activity within the prefrontal cortex (Simp-
son et al., 2001; Liotti et al., 2000; Critchley et al., 2001;
Chua et al., 1999). The results of Simpson et al. (2001)
suggests a dynamic interrelationship between decreased
rCBF within the PFC, attentional focus and subjective lev-
els of anxiety. These authors propose that the ability to
remain relaxed during anxiety provocation was associated
with successful suppression of prefrontal cortical activity in
the face of threatening aversive environmental stimuli. Ac-
tivations within the temporal poles and within the right
superior temporal sulcus and bilateral insula have also been
reported within healthy anxious subjects, as have activa-
tions within occipital cortical regions (Paquette et al., 2003;
Liotti et al., 2000; Kimbrell et al., 1999; Reiman et al.,
1989).
Anticipatory Anxiety (AA) is one of the most basic
forms of anxiety, and while being experienced by normal
individuals, also occurs within a number of clinical anxiety
disorders such as PD and phobias. AA refers to human
anxiety that is focused on an imminent threat or danger and
is typically associated with sympathetic arousal and ght or
ight reactions. AA can be differentiated from the more
long term and distally focused anxiety, such as worry,
which may largely constitute disorders such as GAD in a
similar fashion to Heller et al.s (1997) differentiation of
Anxious Arousal from the more generalised Anxious Ap-
prehension. AA has previously been induced within healthy
male controls via the expectation of an unpleasant electric
shock (Simpson et al., 2001; Chua et al., 1999; Reiman et
al., 1989). AA is also associated with arousal of the central
autonomic nervous system, previously gauged by examina-
tion of electrodermal activity (Chua et al., 1999; Kopacz
and Smith, 1971). These previous investigations amongst
healthy controls have employed Positron Emission Tomog-
raphy (PET) to investigate the alterations in cerebral meta-
bolic function associated with AA. Whilst providing data
976 M. Gray et al. / NeuroImage 20 (2003) 975–986
with an exceptional spatial resolution, PET data is less able
to provide ne-grained information on when these changes
occur and insight into the temporal continuity of AA acti-
vations.
In the current study, we aimed to examine electrical brain
activity associated with AA using an electrophysiological
technique called Steady State Probe Topography (SSPT).
SSPT is a variant of EEG which allows the examination of
cortical electrical activity on a millisecond timescale. Pre-
vious studies also have indicated that SSVEP is relatively
insensitive to noise contamination from sources including
Electrocculargraphic (EOG), eye blink, 50 Hz mains, and
electromyographic (EMG) noise (Silberstein et al., 1998;
Regan 1989). Furthermore, studies within our laboratory
suggest that SSVEPs are sensitive to cognitive (Silberstein
et al., 1998, 1996) and emotional alterations (Kemp et al.,
2003, 2002, in press). In addition, the differing neural basis
of PET and SSVEP data may provide complementary in-
formation the metabolic demands and excitatory or inhibi-
tory nature of localized cortical activity.
Methods
Subjects
Twenty-six healthy males (age 23.4 yrs, 4.0) par-
ticipated in the present study. Prior to inclusion in the study,
all subjects underwent a medical examination, screening for
physical illness, and past or present neuropsychiatric disor-
ders. Subjects were non-smokers and were free of psycho-
tropic or prescribed medications. All subjects were strongly
right handed as assessed by the Edinburgh Handedness
Inventory (Oldeld et al., 1971). Subjects were recruited via
university notice board advertisements, and were generally
well educated (education 15.2 years, 2.0 yrs). All
subjects gave written informed consent to take part in the
study, which was approved by the Swinburne University
Human Research Ethics Committee.
Behavioural measures
Upon arrival subjects completed the Stait Trait Anxiety
Inventory (STAI) State and Trait versions (Spielberger et
al., 1970), and the Beck Depression Inventory (BDI) to
assess levels of anxious and depressive symptomatology
(Beck et al., 1961). Subjects also completed a Visual Ana-
logue Scale (VAS) measure of anxiety prior to scanning,
after the baseline scan and again after the anxiety-inducing
scan. The VAS consisted of three 100 mm lines anchored at
each end with the words relaxed/anxious, calm/nervous, and
tense/peaceful.
Experimental tasks
Subjects completed a simple computer based Continuous
Performance Task, the CPT-AX under two conditions; a
relaxed followed by an anticipatory anxiety condition. The
CPT-AX task, previously described in Silberstein et al.
(2000, 1998, 1996), was included in order to ensure a basic
level of cognitive activity which was consistent between
task conditions. Subjects were instructed to view a computer
monitor upon which a random letter appeared every 1.5 sec,
remaining on the screen for 1.2 sec after which it was
replaced by a central xation cross. Subjects held a button
box and were required to make a button press on the un-
predictable appearance of the letter X, only when this was
preceded by the letter A. The ratio of targets to non-targets
was set at 1:4. The letters subtended a vertical and horizon-
tal angle of approximately 1.2 degrees when viewed at the
xed distance of 2.3 meters. During the relaxed task con-
dition, a 1.2 cm blue border framed the stimulus presenta-
tion screen. Subjects were assured that they would not
receive any electric shocks during the baseline task. During
the anticipatory anxiety condition, SS performed the same
CPT-AX task. As in the control condition, this task began
with a blue-bordered screen. Every 25 sec, this border
changed from blue to red, for a period of 11 sec. This
occurred 11 times throughout the task. SS were informed
that during this task they may receive electric shocks at any
time during the red border display. Five shocks were ad-
ministered at varying latencies after red border onset, en-
suring that subjects could not predict the exact timing of
electrical stimulation.
Procedureexperimental design
Subjects sat in a quiet recording room 2.3 meters from the
task computer monitor. Brain electrical activity was recorded
through an electrode cap containing 64 electrodes (1020
international location system and other midpoint electrodes),
with linked ear electrodes as a reference and a nose electrode
as ground. Half-mirrored goggles were tted which emitted a
ickering mild white light (13 Hz) while allowing subjects to
see the computer monitor before them. Subjects completed the
baseline task while SSPT data was collected. An isolated
stimulator CMS1-200 (Dogwood scientic equipment) was
used to deliver electrical stimulation via electrodes applied to
the dorsal aspect of the subjectsright hand immediately prior
to completion of the AA condition. Shocks were set at a
predetermined level of 30 mA, 115 v (maximum).
SSPT signal processing
The key features of the SSPT signal processing em-
ployed is described in Silberstein et al. (1995, 1990). Brain
electrical activity was amplied and ltered with a 0.74 Hz
high pass lter and a 74 Hz low pass lter prior to digiti-
zation (16 bit accuracy). Electrical activity was recorded at
a sampling rate of 500 Hz. SSVEPs, induced via a spatially
uniform 13 Hz visual icker were extracted from the brain
electrical activity by calculating the sine and cosine Fourier
Transform (FT) coefcients at each stimulus cycle during
each task recording. FT coefcients were smoothed to re-
977M. Gray et al. / NeuroImage 20 (2003) 975986
duce noise by averaging overlapping blocks of 10 stimulus
cycles. All data were checked for artifact within each elec-
trode as described in Silberstein et al. (1995).
SSVEP data analysis
The SSVEP was rst epoched to provide measures of
cortical activity within the relaxed and AA conditions. Dur-
ing the relaxed condition, nine seven-second periods were
randomly selected and averaged to form an epoch of relaxed
task SSVEPs for each subject. Similarly, nine seven-second
epochs were selected during the AA condition. These ep-
ochs were chosen so that they began upon the presentation
of the red-bordered screen and ended before shock delivery.
Electrical stimulation was delivered within the rst 1.5 sec
of the red border presentation during the remaining AA
periods, and as a result these were not included as AA
SSVEP epochs. The task characteristics during the relaxed
and AA epochs were matched, so that each contained the
same number of A and X targets as well as the same number
of AX responses required. SSVEP data is comprised of both
amplitude; the size of the SSVEP signal recorded at each
electrode site, and phase components; alterations in the time
between sinusoidal steady state visual stimuli presentation,
and their expression as SSVEP within the cortex. SSVEP
amplitude was normalized by subtracting the average am-
plitude for all electrodes from each electrode time series
(discrete waveform) data, for each subject. SSVEP phase
was normalized by subtracting the mean phase for each
electrode from its time series for each subject. Cross subject
averages were then constructed for each task condition,
providing averaged SSVEP maps for each of the 91 data
cycles (13 Hz 7 sec) within both the relaxed baseline and
AA conditions.
Topographic mapping of SSVEP data
Difference maps, subtracting the relaxed condition SS-
VEP from the SSVEP obtained during the AA condition,
were generated to provide a measure of electro-cortical
activity observed during periods of anticipatory anxiety.
SSVEP phase variations are presented in millisecond (msec)
latencies; (change in phase/2
)(1000/13). Hotellings
T statistics indicating the statistical strength of differences
in amplitude and phase combined were also calculated.
Previous spatial component analysis of SSVEP data sug-
gests that 5 independent factors are represented in SSVEP
data (Silberstein et al., 1995). As a result, Hotellings T p
values (2-tailed) have been divided by 5 before being re-
ported. Hotellings T statistics are presented as topographic
maps illustrating the statistical signicance of differences in
amplitude and latency at each electrode. Contour lines il-
lustrate areas of statistical signicant at 0.05 and 0.01 and
0.001 alpha levels.
Statistical cluster plot & component mapping
A statistical cluster plot displaying Hotellings T data
across all electrodes (y-axis) and time-points (x-axis) was
generated to investigate the location and time course of
signicant SSVEP differences. One benet of statistical
cluster plots is their ability to display data at each time point
across all electrodes, providing a clear summary of temporal
patterns of signicance. While datasets comprised of nu-
merous point wise t-tests will contain randomly distributed
type 1 error, clusters of statistical signicance are likely to
reect real effects, and may provide a useful guide for
further examination (Murray et al., 2002; Guthrie and Buch-
wald, 1991). Electrodes are approximately separated into
frontal (electrodes 020, including Fp1, Fp2, F7, F3, Fz, F4,
and F8), parieto-temporal (electrodes 2152, including T3,
C3, Cz, C4, T4, T5, P3, Pz, P4, and T6) and occipital
(electrodes 5363, including O1, Oz, and O2) locations.
The two clusters of signicant differences within frontal/
temporal electrodes clearly evident in the statistical cluster
plot were further examined by generating early and late
epochs (each 1 sec at 13 Hz), applying the original normal-
isation routine, and averaging the resulting data sets to form
topographic maps.
Electrodermal data analysis
Electrodermal measures of skin conductance (SC) were
recorded throughout the baseline and AA conditions for 14
of the 26 subjects using the Psylab SC5-SA skin conduc-
tance and temperature coupler. Electrodes were located on
the distal phalanx of index and middle ngers, and a hy-
poallergenic gel ensured contact between the skin and elec-
trode. Skin conductance was recorded at 40 Hz and digitized
to 24-bit accuracy at the electrode site, producing SC data
with an absolute accuracy of 0.1 micro siemens. Mean Skin
Conductance Level (SCL) was chosen as an electrodermal
index of sympathetic nervous system arousal, as this mea-
sure is able to reect differences in both the amplitude and
the frequency of non-specic skin conductance responses,
as well as general phasic increases in galvanic SC. In order
to ensure SCLs were not articially inated by shock de-
livery, we selected the four red-bordered epochs during
which no shocks were actually delivered. These were aver-
aged together to provide a measure of AA SC for each
subject. Relaxed SC was constructed from the average of
the entire baseline condition.
EMG artifact investigation
In order to ensure the results from our study were not
contaminated by electromyographic (EMG) noise, we ex-
amined the inuence of EMG activity on SSVEP proles. A
subset of 15 subjects were quasi-randomly selected to com-
plete an EMG artifact condition immediately following the
recording of the baseline AX condition. Subjects instructed
to complete the baseline AX task a second time while
978 M. Gray et al. / NeuroImage 20 (2003) 975986
clenching their jaw every 2 to 3 sec. Apart from this, the
task instructions were identical, as were data analysis pro-
cedures.
Results
The BDI scores (M5.3, SD 5.7) indicated that no
subjects suffered from depressive symptomatology to any
discernable extent. These scores are within the normal BDI
range for male college students. Likewise the trait STAI
scores (M36.4, SD 7.6) also indicated that all subjects
were within the normal ranges (Spielberger et al., 1970).
State STAI scores (M32.3, SD 6.8) indicated that
subjects were reasonably relaxed before testing com-
menced. VAS scores indicated that subjects were signi-
cantly more anxious during the anxiety induction task t(21)
8.194, p0.001, see Fig. 1.
EMG artefact results
Mann-Whitney Unon-parametric tests for independent
samples indicated that the 15 subjects included in the EMG
control study were not signicantly different from the re-
maining 11 subjects in terms of STAI (state or trait mea-
sures), BDI scores, or VAS levels during either the relaxed
or anticipatory conditions. Hotellings T analysis failed to
reveal any signicant differences at any electrode site be-
tween SSPTs recorded during the baseline and the EMG
artifact condition.
Behavioural self-report measures and SCL
Again, Mann-Whitney Uanalysis indicated that the 14
subjects for which SCL data was recorded were not signif-
icantly different from the remaining subjects in terms of
STAI (state or trait measures), BDI scores, or VAS levels
during either the relaxed or anticipatory conditions. Analy-
sis of SC data revealed signicant increases in sympathetic
nervous system arousal during the AA condition, relative to
the baseline t(13) 3.256, p0.006, see Fig. 1.
SSVEP data
We rst examined the SSVEP difference data across the
seven-second epoch as a whole. Fig. 2 (left) shows the mean
SSVEP maps specic to the AA condition. Hotellings T
data is presented as a topographic map illustrating the sta-
tistical signicance of AA specic differences in SSVEP
data (considering both amplitude and latency differences).
Across the entire 7 sec epoch, AA was associated with
signicant alterations in SSVEPs within the medial (mid-
line) anterior frontal cortex, left dorsolateral prefrontal cor-
tex, bilateral temporal lobes, and left occipital cortex. Fig. 2
also illustrates differences in both the amplitude and latency
components of the SSVEPs. Warmer colours indicate re-
duced SSVEP amplitude and latency in the AA condition
relative to the baseline scan. Signicant alterations within
frontal and temporal electrodes are associated predomi-
nately with increases in SSVEP latency. SSVEP amplitude
increases are evident only within the occipital cortex. Wide-
spread latency reductions are evident within bilateral occip-
ital lobes; however, only a smaller portion of the left oc-
cipital lobe reached statistical signicance.
In order to examine the temporal nature of the observed
alterations in SSVEPs, we generated a Hotellings T statis-
tical cluster plot which displays the signicant SSVEP dif-
ferences for all electrodes (y-axis) across time (x-axis) (see
Fig. 2, right). An examination of the statistical cluster plot
indicates that the majority of signicant frontal and tempo-
ral differences occur in two bursts, an initial early compo-
nent (6921692 ms) and a later component (50006000 ms)
indicated by the white banded regions in Fig. 2. The occip-
ital activations conversely are relatively stable and consis-
tent throughout the windowing period, and are therefore
reasonably illustrated within the 7 sec epoch mean topo-
graphic maps. In order to examine frontal and temporal
activations, we generated SSVEP mean topographic maps
for both these early and late components (see Fig. 3).
Within both the early (6921692 ms) and late (5000
6000 ms) epochs, signicant differences are again primarily
driven by alterations in SSVEP latency. During the early
component epoch (6921692 ms), SSVEP latency increases
reached signicance within midline prefrontal electrodes
and left dorsolateral prefrontal electrodes. Further examina-
tion reveals the largest latency increases within temporal
electrodes (particularly left hemisphere) and left dorsolat-
eral electrodes. As in the entire epoch mean (Fig. 2), occip-
ital latency reductions are evident, reaching signicance
within the left occipital lobe. SSVEP amplitude changes are
relatively modest, with minor amplitude reductions within
the left frontal lobe and amplitude increases within the right
frontal and temporal lobes and within bilateral occipital
lobes. During the later component epoch (50006000 ms),
signicant differences are observed within large regions of
the bilateral frontal lobes, within the right temporal lobe,
and bilateral occipital lobes. Occipital amplitude and la-
tency increases are more pronounced during the later com-
ponent. Relative to the early component, SSVEP latency
increases are attenuated within the temporal lobes, particu-
larly within the left hemisphere, whilst within prefrontal
electrodes, larger latency increases are evident, particularly
within bilateral anterior frontal electrodes.
Further examination of the temporal prole of SSVEP
latency changes within the temporal lobes revealed some
evidence of hemispheric differences. Fig. 4 displays the
SSVEP latency changes recorded at 3 temporal lobe elec-
trodes within each hemisphere across the entire 7 sec epoch.
During the early component, the left hemisphere latency
increases are larger, more uniform, and more sharply de-
ned than within the right hemisphere.
979M. Gray et al. / NeuroImage 20 (2003) 975986
Discussion
The current study examined the temporal processing of
AA within healthy male subjects. Our ndings suggest that
AA is associated with two predominant electrophysiological
changes; (1) signicant SSVEP latency increases within
prefrontal and temporal cortical regions, and (2) signicant
SSVEP latency decreases and amplitude increases within
occipital regions. Whilst occipital SSVEP latency decreases
and amplitude increases were evident throughout the anx-
ious anticipatory epoch, frontal and temporal lobe latency
increases were more transitory, appearing within the rst
sec, and again within the fth sec of the imaging window.
These cortical activations were associated with concomitant
increases in self-reported anxiety and electrodermal activ-
ity.
In terms of regional cortical alterations, the present nd-
ings are consistent with a large amount of previous research
amongst both patient groups and healthy controls. Anxiety
associated prefrontal increases in rCBF have been fre-
quently reported by metabolic imaging studies (Paquette et
al., 2003; Rauch et al., 2002, 1997; Meyer et al., 2000;
Zubieta et al., 1999; Shin et al., 1999; Malizia et al., 1999;
Liberzon et al., 1999; Johanson et al., 1998; Nordahl et al.,
1998, 1990; Breiter et al., 1996; Semple et al., 1993; Rubin
et al., 1992; Wu et al., 1991; Swedo et al., 1989; Baxter et
al., 1987). Previously reported increased rCBF within ante-
rior temporal lobes and insula are also consistent with the
signicant SSVEP alterations we observed within temporal
lobe electrodes (Boshuisen et al., 2002; Osuch et al., 2001;
Meyer et al., 2000; Liotti et al., 2000; Chua et al., 1999;
Shin et al., 1999; Rauch et al., 1997, 1996, 1995; Breiter et
Fig. 1. Skin conductance and visual analogue scale (Anxiety) measures during baseline and anticipatory anxiety conditions.
Fig. 2. SSVEP amplitude and latency changes and Hotellings T values during anticipatory anxiety induction (left) and statistical cluster plot illustrating the
selection of the early and late epochs (right).
980 M. Gray et al. / NeuroImage 20 (2003) 975986
Fig. 3. Mean SSVEP amplitude, latency and Hotellings T during early and late components.
Fig. 4. SSVEP latency changes within temporal lobe electrodes across the seven second imaging epoch. Early and late components are indicated by red
banded regions.
981M. Gray et al. / NeuroImage 20 (2003) 975986
al., 1996; Johanson et al., 1992; Wu et al., 1991; Reiman et
al., 1989). Likewise, regional anxiety associated changes
within the occipital cortex previously reported are also ev-
ident in the present results (Paquette et al., 2003; Mirzaei et
al., 2001; Fredrikson et al., 1997; Rauch et al., 1996; De
Cristofaro et al., 1993; Wu et al., 1991, Zohar et al., 1989;
Stewart et al., 1988; Buchsbaum et al., 1987).
SSVEPs are comprised of both amplitude and latency
components, each of which reect different aspects of re-
gional cortical network activation. Variations in SSVEP
latency have been previously interpreted as an index of
variations in neural information processing speed, and are
likely to result from alterations in the loop transmission time
of local cortico-cortical feedback loops (Kemp et al., 2002;
Silberstein et al., 2001, 1995). Previous research within our
institute has illustrated correlations between reaction time
during a visual vigilance task and SSVEP latency (Silber-
stein et al., 1996). In addition, SSVEP latency reductions
within prefrontal electrodes observed within normal chil-
dren during attentional tasks are attenuated among children
with attention decit hyperactivity disorder (Silberstein et
al., 1998), further strengthening the association between
latency decreases and normal excitatory processes. Alter-
ations in SSVEP latency are understood to result from the
excitatory and inhibitory neuromodulation of regional cor-
tico-cortical resonances (Silberstein et al., 2000, Regan,
1989). The release of neurotransmitters such as acetylcho-
line (ACh) are believed to reduce the cortico-cortical loop
time in a similar way to the increases in thalamocortical
transmission speeds following cortical ACh release ob-
served within animal research (Metherate and Ashe, 1993).
Likewise increases in latency are likely to be associated
with inhibitory neuromodulation of cortico-cortical feed-
back loops, possibly via inhibitory interneurons such as
golgi, basket and stellate cells (Attwell and Iadecola, 2002;
Koos et al., 1999). SSVEP amplitude is, in some respects,
analogous to EEG amplitude within the alpha bandwidth,
such that regional event related desynchronisation results in
relative EEG alpha and SSVEP amplitude reductions
(Pfurtscheller and Lopes da Silva, 1999). Conversely, in-
creases in the number of neurons recruited into synchro-
nously activated cortico-cortical rhythmic activity results in
cortico-cortical loop gain, or relative SSVEP amplitude
increases.
The present ndings of increased SSVEP latency within
frontal electrodes may be interpreted as evidence of an
increase in neurochemically modulated inhibitory cortical
activity. These results suggest that previously reported PFC
increases in rCBF may be associated with increased lo-
calised inhibition. Regions within the prefrontal cortex have
long been understood to have a role in the modulation and
inhibition of subcortical limbic structures including the
amygdala and cingulate (Carr et al., 2003; Quirk and Geh-
lert, 2003; Davidson et al., 2002; Cardinal et al., 2002;
Niemer and Goodfellow, 1966). The amygdala is well
known to be necessary for the development of conditioned
fear (LeDoux, 1996) and communicates with regions within
the prefrontal cortex including the orbitofrontal cortex via
direct excitatory efferents and the dorsolateral prefrontal
cortex through a smaller number of excitatory efferents as
well as pathways through the orbitofrontal cortex (Barbas,
2000). Glutamatergic projections from the PFC are believed
to project to GABAergic neurons which synapse on the
amygdala, allowing both the PFC and amygdala to modu-
late each other during cognitive-emotional processing (Da-
vidson et al., 2002; LeDoux, 1996). Disruption of this co-
modulation may underlie increased PFC activation observed
within clinical populations (Barbas, 2000). The increased
SSVEP latency within dorsolateral and anterior PFC elec-
trodes amongst our healthy subjects during AA may be
associated with increased inhibition within localised PFC
circuits occurring in response to increased excitatory input
from the amygdala, although without the ability to concur-
rently image amygdala activity, this interpretation must
remain speculative. The signicant SSVEP alterations
within the left dorsolateral PFC evident in the epoch mean
data and also within both the early and late frontal compo-
nents lies approximately over Brodmanns area 8, an area
which is known to receive robust projections from visual
association cortices within primates, and may be associated
with visual attentive aspects of the PFCs selection of emo-
tionally appropriate responding (Barbas, 2000). In addition,
anxiety induced increases in inhibitory activity within pre-
frontal regions accords well with decits in processes sub-
served by prefrontal information processing during anxiety,
including attentional biases and working memory decits
(Ninan and Berger, 2001; Mogg and Bradley, 1998; Beck,
1976).
Increases in localised inhibitory processes associated
with the observed signicant SSVEP latency increases
within the right temporal lobe are consistent with many
previous reports of anxiety associated rCBF increases
within the temporal lobes of both patients and healthy con-
trols (Paquette et al., 2003; Boshuisen et al., 2002; Liotti et
al., 2000; Meyer et al., 2000; Chua et al., 1999; Rauch et al.,
1997, 1995; Breiter et al., 1996; Johanson et al., 1992; Wu
et al., 1991; Reiman et al., 1989). The frequently reported
activity within temporal cortices observed during the imag-
ing of human anxiety has previously been related to visceral
processing by the agranular neurons within the medial wall
of the temporal lobe and insula (Chua et al., 1999; Mesulam
and Mufsom 1982a). The temporal poles and insula form
part of the paralimbic cortex, reciprocally connected to the
amygdala, orbitofrontal and dorsolateral PFC and cingulate
gyrus, and are thought to integrate internal and external
environmental information useful for selection of appropri-
ate responses during situations involving threat, helpless-
ness or danger (Barbas, 2000; Pandya, 1995, Reiman et al.,
1989; Mesulam and Mufsom, 1982b). Our ndings of in-
creased SSVEP latency within temporal lobe electrodes
suggests that within these regions AA is again associated
with increased localised inhibitory modulation of cortico-
cortical oscillatory activity. Our ndings of larger latency
increases and more frequently signicant right temporal
982 M. Gray et al. / NeuroImage 20 (2003) 975986
lobe alterations, relative to the left hemisphere within both
the later component and overall epoch means are consistent
with the more frequent reports of rCBF increases within the
right temporal lobe, relative to the left associated with
anxiety specically, and emotional processing generally
(Heilman, 1997; Heller et al., 1997; Ross, 1981). It is
interesting to note, however, that the largest SSVEP latency
increases were observed within the left hemisphere during
the early component. This is consistent with largest rCBF
increases within the left insula of healthy males anticipating
an electric shock reported by Chua et al. (1999). Davidson
et al. (2002) suggests that the left PFC particularly may be
involved with inhibitory control of amygdala activity. Our
results indicate that this latency increase was more clearly
dened within the left hemisphere, providing some evi-
dence of hemispheric differences in the temporal lobe in-
volvement during AA.
The results from the EMG artefact condition have par-
ticular relevance to the observed changes within the tempo-
ral lobes. Acute periods of anxiety are commonly associated
with increases in muscle tension, which signicantly in-
creases the risk of EMG artefact during electrophysiological
recordings of brain activity. Previous reports on anxiety
induced alterations in temporal lobe function have had to
defend against claims of EMG artefact (Benkelfat et al.,
1995; Drevets et al., 1992). Our ndings of no signicant
SSVEP differences between the baseline and EMG artefact
conditions suggest that the observed results are indeed re-
lated to temporal lobe function.
A signicant amount of research has reported increased
activation of the occipital cortex associated with both the
visual processing of emotionally valanced stimuli (Kemp et
al., 2002; Phan et al., 2002; Lane et al., 1999; Lang et al.,
1998; Morris et al., 1998), and with anxiety, within patient
groups and anxious controls (Paquette 2003; Fredrikson et
al., 1997, 1993; Rauch et al., 1996; Breiter et al., 1996; De
Cristofaro et al., 1993; Wik et al., 1993; Wu et al., 1991;
Zohar et al., 1989; Gur et al., 1987). Wik et al., (1996)
observed anxiety related decreases in rCBF within primary
visual cortical regions amongst phobics which may be as-
sociated with anticipatory coping. Within occipital elec-
trodes, we also observed signicant SSVEP alterations dur-
ing periods of anxious anticipation. These were generally
observed within the left hemisphere, and were localised
with decreases in SSVEP latency observed within occipital
electrodes. Regions of the limbic cortex including the ante-
rior temporal lobes, orbitofrontal and dorsolateral PFC and
the magnocellular portion of the basal nucleus of the amyg-
dala are reciprocally connected to the primary visual cortex
and widespread regions of the extra-striate cortex (Weller et
al., 2002; Linke et al., 1999; Barbas, 1995). This connec-
tivity is likely to underlie visual cortex alterations observed
not only during anxiety induction, but also more generally
during emotional processing (Phan et al., 2002; Davis and
Whalen, 2001; Lang et al., 1998; Morris et al., 1998; Breiter
et al., 1996). The decreased SSVEP latency observed within
occipital electrodes is consistent with an increase in lo-
calised excitatory processes, possibly associated with in-
creased modulation of visual processing by regions of the
limbic system including the amygdala (LeDoux, 1996). Our
previous studies have reported SSVEP amplitude decreases
within extra-striate visual areas associated with increased
visual vigilance during continuous performance attentional
tasks (Nield et al., 1998; Silberstein et al., 1990). In con-
trast, the present results indicate SSVEP amplitude in-
creases within extra-striate cortex during periods of AA. We
hypothesise that this may be due to a shift in attentional
focus away from the visual aspects of the task in the face of
intense emotional induction. This is consistent with previ-
ous ndings that while highly trait anxious controls shift
attention towards anxiety inducing stimuli, normal controls
tend to divert attention from anxiety inducing stimuli (Wil-
son and MacLeod, 2003; Mogg and Bradley, 2002; Clark,
1999; Vasey et al., 1996).
Scalp recorded SSVEPs are generated by the synchro-
nised ring of pyramidal neurons lying within layers 2 and
3 of the cortex (Silberstein et al., 2001; Regan, 1989).
Alterations in rCBF measured by metabolic imaging meth-
odologies, such as PET and fMRI are understood to be
driven by the synaptic energy requirements of re-establish-
ing ionic concentrations and neurotransmitter repackaging
(Arthurs et al., 2002, Attwell and Iadecola, 2002, Attwell
and Laughlin, 2001; Jueptner and Weiller, 1995). Logoth-
etis and colleagues have recently shown in a fascinating
series of articles that rCBF as indexed by the BOLD re-
sponse is closely correlated with local eld potentials within
the occipital cortex, strengthening the association between
excitatory driven BOLD responses and cortical local eld
potentials (Logothetis et al., 2003, 2001; Logothetis, 2002).
A number of researchers have argued that both inhibitory
and excitatory activity is associated with increased rCBF
resulting from ion recycling and ion gradient restoration
(Arthurs et al., 2002, Jueptner and Weiller, 1995, Nudo and
Masterton, 1986, Ackermann et al., 1984). Although meta-
bolic imaging methodologies and electro-cortically re-
corded eld potentials gauge information processing within
cortical regions, the differing neurological basis of each
methodology may provide complementary perspectives on
regional cortical activity. Our ndings of region specic
excitatory and inhibitory processes in areas previously as-
sociated with rCBF increases suggests that further research
could benet from the simultaneous investigation of SSVEP
latency and rCBF alterations within the same region of the
cortex.
In summary, the results from the present study support
alterations in regions previously found to undergo increases
in rCBF during anxious anticipation, including the anterior
and dorsolateral PFC, anterior temporal cortices, and the
extra-striate cortex. While previous research has reported
increases in rCBF within prefrontal, temporal and occipital
cortical regions, our results suggests an increase in localised
inhibitory processes within the PFC and anterior temporal
lobes, and an increase of localised excitatory processes
within regions of the extra-striate occipital cortex during
983M. Gray et al. / NeuroImage 20 (2003) 975986
anticipatory anxiety. These ndings may provide further
insight into the nature of the neurophysiological mecha-
nisms underlying anticipatory anxiety.
Acknowledgments
The authors would like to thank Cindy Van Roy, Peter
Line, and Andrew Pipingas for technical assistance.
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Anxiety disorders are characterised by distorted beliefs about the dangerousness of certain situations and/or internal stimuli. Why do such beliefs persist? Six processes (safety-seeking behaviours, attentional deployment, spontaneous imagery, emotional reasoning, memory processes and the nature of the threat representation) that could maintain anxiety-related negative beliefs are outlined and their empirical status is reviewed. Ways in which knowledge about maintenance processes has been used to develop focussed cognitive therapy programmes are described and evaluations of the effectiveness of such programmes are summarized. Finally, ways of identifying the effective ingredients in cognitive therapy programmes are discussed.