Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

XIX-10
In Vivo Functional Neurochemistry of Anxiety Disorders
Andrea L. Malizia, Brian Martis and Scott L. Rauch
INTRODUCTION
Human 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 IMAGING
Two 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 pools.
Changes in Brain Metabolism or Activation
The 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 PET).

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

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