XIX-10Andrea L. Malizia, Brian Martis and Scott L. Rauch
In Vivo Functional Neurochemistry of Anxiety Disorders
INTRODUCTIONHuman anxiety disorders are the most prevalent psychiatric conditions affecting at least two fifths of the population in their lifetime.
About one in 20 of the population has enduring or recurrent anxiety disorders and therefore these conditions are responsible for the
highest societal global (medical and social) costs of any psychiatric
condition. For instance, out of 92 million working days lost in the
UK. due to mental illness in 1993 (18% of all lost days), 49%
were due to anxiety or stress representing a cost of over £3 billion
(approximately ∈/$ 4.5 billion).In order to understand the aetiology of these disorders, possibly leading to better treatments, research has been carried out
on the biological basis of healthy and pathological anxiety. Compared with other emotions and other psychiatric conditions, anxiety
and fear (as defined in Martis et al., Chapter XIX-9) are constructs which have a reasonable mapping between animals and
man. Therefore, the study of anxiety and fear in preclinical experiments can provide leads for human research. Animal experiments have generated two overlapping sets of information. One
set describes the sufficient or necessary neuroanatomical structures
underlying the expression of these emotions (whether innate or
conditioned) in animals and the other the neurochemical changes
which predispose to or accompany the behavioural changes. However, despite the similarities in anxiety expression between man
and other animals, data from preclinical experiments are not sufficient to understand the biology of human anxiety or anxiety
disorders.Direct human experimentation has also contributed to increase
our knowledge about brain function and anxiety. Yet, the traditional investigation of human brain processes in vivo has many
constraints related to the inaccessibility of the tissue under study
and to functional complexity whereby understanding of individual modules from lesion studies, pharmacological challenges and
electrophysiological recordings cannot provide sufficiently comprehensive hypotheses of system architecture. Indeed, up to the
late 1980s, the most informative experimental strategies employed
in clinical psychopharmacology recorded behavioural, physiological and cognitive responses to pharmacological probes where the
aim was to characterize the central neurochemical changes underlying particular processes or diseases based on preclinical knowledge. These challenges were, and are, limited by their intrinsic
inability to characterize neural networks in detail and by the fact
that ligand binding and neurotransmitter release cannot be quantified ex vivo or by microdialysis in man (except recently in very
selected samples of neurosurgical patients). These limitations prevent the conduct of any quantitative human research which aims
to relate changes in physiology or behaviour to synaptic parameters. Further, many of the probes used to selectively affect
one system or one subset of receptors have often subsequently
been discovered to be relatively less selective than originally
postulated.Since the late 1980s, human imaging (Table XIX-10.1) has
been used to describe the functional anatomy (discussed in Chapter XTX–9), pharmacology and functional neurochemistry (this
chapter) of human anxiety and anxiety disorders with macroanatomical (up to about 1 cm) brain resolution. The use of these
technological advances is still in its infancy as novel paradigms
and analytical methods are developed; however, the vision for the
future is that their utilization should lead to a more robust understanding of the brain mechanisms underlying disease and response
to treatments.This chapter has two aims: a brief commentary on the technical
issues related to pharmacological imaging and a review of the
current human psychopharmacology imaging knowledge regarding
anxiety and anxiety disorders, including some preliminary data.
PHARMACOLOGICAL IMAGINGTwo strategies can be employed to detect drug effects on the brain:
detection of changes in brain metabolism or activation induced
by pharmacological agents and radioligand assay of binding to
receptors, transporters, enzymes and of tracer kinetics of precursor
Changes in Brain Metabolism or ActivationThe paradigms used here depend on the detection of changes in
regional brain metabolism or blood flow following the administration of pharmaceuticals. The principles are as follows.
|• ||Changes in local brain metabolism are mostly induced by changes
in neuronal activity; while there is debate on the cellular location
of the metabolic changes (i.e., neurons or glia), energy is mosdy
expended at synaptic sites.|
|• ||Changes in local metabolism are tightly linked to changes in
local blood perfusion, which overcompensates for the increases in
oxygen demands by delivering an excess of deoxyhaemoglobin.|
|• ||Imaging techniques can measure changes in local metabolism
([11C] glucose PET or 18fluorodeoxyglucose (FDG) PET), in local
perfusion (H2150 PET or C15O2 PET or [11C]butanol PET; 99Tc
HMPAO SPECT; ASL (arterial spin labelling) or gadolinium
MRI), in local deoxyhaemoglobin concentration (fMRI), in
oxygen extraction (15O2 PET) or in local blood volume (Cl5O
One complicating factor in the interpretation of these techniques
is the fact that pharmacological manipulations have effects not only
on the brain processes of interest but also on other neuronal or
Questia, a part of Gale, Cengage Learning. www.questia.com
Book title: Biological Psychiatry.
Contributors: Hugo D'Haenen - Editor, J.A. Den Boer - Editor, P. Willner - Editor.
Place of publication: Hoboken, NJ.
Publication year: 2002.
Page number: 1003.
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