Indian Journal of Clinical Psychology

2009, No.36, Issue 2, 1-6

Copyright, 2009, Indian Association of

Clinical Psychologists (ISSN 0303-2582)

Editorial

Imaging the Anxious Brain

Mapping human brain has been a fascinating and absorbing obsession of the modern neuroscience. It helps in isolating the regions of the
brain that are connected with various behaviours
and its abnormalities. The procedure has provided
exciting new insights into functioning of the human brain.
Functional imaging is one of the most recent
additions to the family of techniques used for
brain mapping. It provides an opportunity to map
neuronal activity of the working brain. The technique has evolved considerably during the past
15 years. Initially what was called for positron
emission tomography (PET), has now been advanced, and called functional magnetic resonance imaging (fMRI). The idea first introduced
into psychology in 1868 by Dutch physiologist
Franciscus C. Donders, who attempted to isolate
and measure the mental process through some
measures of brain activity. In his experiment on
colour discrimination, he attempted to subtract a
control state (e.g, time taken for responding to
any light) from a task state (e.g, time taken for
responding to a particular color of light), to measure the time taken by the brain for processing
this information. The brain took about 30 milliseconds to detect discriminate a colour from other
light onset. The modern functional imaging strategy is designed to accomplish a comparable subtraction regarding information about the areas of
the brain that distinguishes the task state from
the control state. In the case of fMRI images of
blood flow obtained in a control state are subtracted from those obtained when the brain is
engaged in the task. These two states are carefully chosen and isolated. Subtracting blood flowdependent measures taken in the control state
and then from the task state, those parts of the
brain uniquely responsible for performing the task
are isolated. The difference in blood flow between

the two states is the basis of fMRI analysis of

brain activity. Once such a difference image is
obtained, computer techniques transform it to a
standard brain image so that comparisons can be
made with other individuals. From these individual difference images an averaged or mean
difference image is made. Because the changes
in blood flow are small, individual difference images tend to be somewhat variable due to the
presence of statistical noise in the images and
variation among the subjects. Significant average changes reflect changes common to the
sample of individuals. All of the images appearing subsequently in this chapter are mean difference images formed in the above manner. It provided valuable data about the activity of different
regions of the brain with reference to specific
stimulation. Detailed account of the technology
is beyond the scope of this editorial. For further
reading , the readers may refer to Raichle (1997).
Now, functional imaging is used extensively
in investigating behavioural and mental disorders
as well. Here, we focus on anxiety, which is
generally considered as an objectless state
causing fear and distress to the individual.
Psychoanalysts call it free-floating anxiety. The
disorder is clinically diagnosed as generalized
anxiety disorder (GAD). The most prominent
feature of anxiety is a sense of uncontrollability
focused on possible future threat, danger, or other
upcoming, potentially negative effects (Barlow,
et al.1996), expressed as fear (Izard, &
Youngstrom, 1996) and helplessness (Barlow,
et al., 1996).
Marr (1982) explained that an adequate
analysis of psychopathology must use three
levels of description of such mental phenomena.
The highest level of which is psychological (i.e.
experiential and phenomenological), the
intermediate level is computational (i. e.. process
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that computes or discriminates it from other

states) and the lowest level is neurobiological
which must explain how these computational
processes are implemented in the brain. In case
of GAD, the analysis should include the
psychological experience of anxiety (Level 1),
the computational processes involve in threat
perception, and precisely the detection of threat
signals (signal detection) (Level 2). The
neurobiological structures conceptualized as
danger-detection system (that includes
amygdala and its anatomically connected
structures) which plays a significant role in
mediating anxiety response (Level 3). Analysis
confined to any one of these levels would not
provide a complete understanding of psychopathology.
Advent of event-related fMRI has added a
temporal element that has not only added a new
dimension to the understanding of human brain
(e.g. Buckner, et al. 1996; Dale & Buckner, 1997;
Josephs, et al., 1997), but also facilitated better
understanding of the psychological (Level 1)
phenomena. Many of these current studies are
homologous to the even-related potentials in
psychophysiology. The target stimuli are
presented repeatedly over time then sampled and
averaged out both during the experimental as well
as control condition. Repeated measures are taken
with the same subjects during acquisition as well
as extinction phases.
In 1976 Gray reported that lesion of either
the septal region, or hippocampus or both of
these structures cause behavioural changes that
are induced by anxiolytic drugs. As a
consequence he suggested that septohippocampal system as the brain substrate
causes anxiety termed as brain inhibition
system (BIS). This is activated by: (1) former
conditioned aversive stimuli that have acquired
aversive property through Pavlovian
conditioning with punishment, (2) novel stimuli
that bring about opposed exploratory (approach)
or avoidance tendencies and (3) a set of speciesspecific stimuli that have acquired aversive
properties, by natural selection. Once activated,

the BIS generates three types of behaviour

changes that make up manifestation of anxiety.
The behaviours include slowing down and
stopping of cognitive activity., increased
vigilance and focusing on environmental threats.
In his classic work The Neuropsychology of
Anxiety, Gray (2002) presented a cognitive
version of anxiety, describing the BIS as a conflict
detector. Conflict between two incompatible
tendenciesapproach
and
avoidance
tendencies are activated when the same
environmental stimulus act as reinforcers or
punishers. In fact, conflict occupies the central
position in explaining the construct anxiety.
In an early experiment, while studying
monkeys with bilateral lesion of the anterior
temporal lobe (that included amygdala,
hippocampus and surrounding cerebral regions),
Kluver and Busy (1939) found substantial
attenuation of fear to threatening stimuli
popularly known as Kluver-Busy syndrome.
Subsequent studies also confirmed that central
administration of benzodiazepines to the
amygdala has specific antianxiety effects
(Thomas, et al, 1985). Further psychopharmacological study revealed the anxiolytic effects of
peripherally administered benzodiazepines can
also be blocked by GABA-A, and other
benzodiazepine antagonists (Sanders, & Sekhar,
1995). Even electrical stimulation of the amygdala
could elicit fear, anxiety and autonomic arousal
(Chapman, et al, 1950; Gloor, et al, 1982). A
number of such studies have identified the central
role of amygdala in mediating neural substrate
for experience of anxiety.
Most brain imaging studies have used
classical conditioning as a major paradigmatic
model for understanding acquisition and
maintenance of anxiety states and have reached
similar conclusion. Under this paradigm, two
distinct approaches have been followed for
analyzing the brain images, --a traditional
neurobiological approach studying the
differences in brain activity of an anxious and
another non-anxious group or that of a single
individual or group tested under control and
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experimental conditions and then comparing their

brain images. In most conditioning experiments,
used for brain imaging of anxiety the conditioned
fear is treated synonymous with anxiety. Very
few studies have examined patient-controlled
differences in GAD. Rauch et al. (1997) pooled
data from three studies in which anxiety was one
of the core features such as OCD, phobia and
PTSD. They attempted to obtain diagnosisindependent measures of anxiety and attempted
to correlate it with the cerebral blood flow (rCBF).
The study revealed that there was significant
correlation in right posterior medial orbito-frontal
cortex, right inferior frontal cortex, bilateral insular
cortices, and bilateral brainstem. However, for
explaining generalized anxiety disorders one must
be able to distinguish it from panic anxiety that
occurs due to actual danger, phobia, and also
posttraumatic stress disorder that occur in
presence of specific objects or situations.
Unfortunately, the brain imaging studies have
not been able to distinguish these clinical
conditions, that can be distinguishable at
psychological and behavioural levels.
Apart from isolating the neural substrates in
various mental disorders, imaging of brain activity
is now used for assessing effective of treatment
of generalized anxiety disorder (GAD). Therapist
could predict more accurately which treatment
will be effective for whom by conducting preand post therapy assessment of the brain images
of the patients. The approach has widened the
scope of personalized therapy in clinical
conditions such as GAD. Recently, Whalen and
associates (Whalen, et al., 2008) conducted fMRI
scanning of their GAD patients to study their
brain activity and thereafter administered
Venlafaxinean anxiolytic drug used for
treatment of anxiety disorders. There were
significant differences in brain activity of the
clients, particularly those who benefited from the
treatment. Patients who showed high prefrontal
cortex activation with low amygdala activation in
response to fearful faces, showed reverse
activation (i. e. high amydala, and low prefrontal
activation and reported significant decrease in

their anxiety symptoms. Although, the authors

cautioned that such studies require proper
matching of treatment and samples, as well as
further validation.
Chronic high levels of sympathetic arousal
is considered as the hallmarks of anxiety and
stress-related disorders (Russek et al., 1990 ;
Steptoe et al., 1999 ). Interventions that lower
autonomic arousal result in a reduction of stress
and anxiety and therefore, electrodermal activity
(EDR) biofeedback is one of the best known
techniques of relaxation for reducing autonomic
arousal in people suffering from anxiety disorders.
The subjects learn to decrease their EMD through
biofeedback training. The mechanisms by which
cognitive processes used in biofeedback training
influence states of bodily arousal are important
for understanding the pathogenesis and
maintenance of anxiety disorders. In an
experiment, Critchley et al. (2001) used PET to
investigate cerebral activity relating to the
cognitively driven modulation of EDR. Four
different tasks were assigned to the subjects:
biofeedback-induced relaxation, (2) relaxation
without biofeedback and two corresponding
control conditions in which the subjects were
instructed not to relax. It was observed that
relaxation was associated with significant
increases in left anterior cingulate and globus
pallidus activity, whereas no significant increases
in activity were associated with biofeedback
compared with random feedback. The interaction
between biofeedback and relaxation, highlighting
activity unique to biofeedback relaxation, was
associated with enhanced anterior cingulate and
cerebellar activity. These data demonstrate the
role of anterior cingulate cortex in the intentional
modulation of bodily arousal. Precisely, these
findings indicate how therapeutic interventions,
such as relaxation training in stress-related
disorders, mediate their effects. The authors claim
that although, earlier, studies have also examined
brain activity relating to meditation (Lazar et al.,
2000 ) and hypnosis (Rainville et al., 1999 ), in
which the activity accompanying these processes
highlights a pivotal role for the anterior cingulate
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preattentively by a subcortical circuit involving

the amygdala; and second, stimuli deemed
emotionally significant are given priority in the
competition for access to selective attention. This
process involves bottom-up inputs from the
amygdala as well as top-down influences from
frontal lobe regions involved in goal setting and
maintaining representations in working memory.
Therefore, considering amydala as the principal
brain substrate for experiencing anxiety, as
revealed in brain imaging study can be challenged
on theoretical as well as empirical grounds.
Compton also highlighted limitations in the
current literature that dichotomized cognition
versus emotion.. There are weak activation in
the brain that may no be detected by the present
neuroimaging technique to unfold the entire
story of detection and experience and expression
of generalized anxiety disorders.
Thirdly, the learning paradigm which is used
as a model for study of generalized anxiety is
rather focused on fear conditioning, where the
stimulus is well defined, it does not speak of
generalized anxiety as such. Modelling of
generalized anxiety in laboratory setting still
remains a challenge. Further, many of these
studies have used fearful facial expressions as
stimulus for fear conditioning. In a recent review
of studies on amygdala activation, Baas and
associates (Baas, et al., 2004) found that at least
in 22 out of 54 contemporary studies on
functional neuroimaging of amygdala reveal its
role in face recognition. Hence, distinguishing
this cognitive process from experience of
generalized anxiety through neuroimaging still
remains a challenging task. Future research, on
neuroimaging should overcome these limitations,
not only in explaining generalized anxiety
disorders but also in interpreting neuroimages of
posttreatment data. Convergence of data from
neuropsychology, cognitive-behaviour therapies
and psychopharmacology may help in
overcoming some of the limitations.

cortex, the present one is more rigorous in terms

of experimental analysis, in the sense that these
studies, did not investigate in a systematic way
the relationship between regional brain activity,
intentional states and physiological measures of
autonomic relaxation.
The neuroimaging technologies are now not
only used as means of exploring brain-behaviour
relationship in investigating the disease process
but also employed to understand brains
response to therapeutic procedures. It is
speculated that now population-based brain
atlases may be made available for various central
nervous system disorders including anxiety. New
methods of analysis of brain images are now
capable of detecting group-specific features not
apparent in individual patients. It is believed that
once built, these brain atlases can be stratified to
subpopulations to reflect a particular clinical
groups. This can be linked with several
demographic factors such as age, gender,
handedness and other cognitive, behavioural and
genetic parameters (Mazziotta, et al., 1995; Toga,
Mazziotta, 1996; Toga, & Thompson, 1999a).
However, in spite of its considerable
contribution to the understanding brainbehaviour relationship, the neuroimging
techniques have their own limitations, some are
theoretical ad some are practical. The crucial
question that remains to be answered is, whether
the neuroimaging differentiate between anxiety,
fears and phobias. The brain imaging techniques
are not in a position to make finer distinction
between these disorders in order to make
differential diagnosis. As discussed earlier, such
a diagnosis would rely largely on the third level
of analysis which is rather psychological and
experiential.
Secondly, to what extent the neurobiological
system identifies fear processing has implication
for explaining functional neuroimaging.

Examining the evidence from psychology

and neuroscience on emotional processing,
Compton (2003) suggested a two-stage process:
First, emotional significance is evaluated
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S. P. K. Jena
Editor