The GABAergic system is thought to play a central role in mediating the effects of alcohol. This is substantiated by the finding that besides binding sites for gamma-aminobutyric acid (GABA) and benzodiazepines, the GABAa receptor also contains a binding site for alcohol. Direct measurements using PET and [11C]flumazenil, an inverse agonist at the GABAa receptor, have found a reduction in the concentration of these receptors in the medial frontal lobes and cingulate gyrus of alcoholic subjects and the cerebellum of patients with alcoholic cerebellar degeneration (Gilman et al., 1996).
Similarly, a SPECT investigation also found decreased binding of [123I]iomazenil to GABAa receptors in the anterior cingulate gyrus, frontal lobe, and cerebellum of alcoholic patients. However, based on these findings alone it is not possible to discern whether the described reduction in GABAa receptors represents a preexisting susceptibility factor or the result of chronic alcohol abuse.
Currently, functional neuroimaging in psychiatry serves as a tool in basic research to understand the underlying pathophysiology of neuropsychiatry disorders and to elucidate basic principles of psychopharmacology at the synaptic/molecular level. In the coming years, one can expect better technology (i.e., better spatial and temporal resolution) and a better approach to methods, leading to more precise analysis. However, the main challenge for the field will be to deliver these basic science findings to the bedside. Whether the field can do that is a question to be answered over the next decade.
The current abundance of neuroimaging findings has been very useful in changing the theoretical conception of many psychiatric illnesses; prevalent concepts such as the "mood circuit" and the "occupancy threshold" are directly attributable to neuroimaging. However, this is not the same as a diagnostic test. The main challenge in turning these and other findings into clinical tools has been the small effect size. All the findings noted above have been ascertained using groups of approximately a dozen patients and comparing them to similar numbers of normal subjects. While these groups may differ, and this can be evaluated with appropriate statistical tests, such procedures do not solve the problems faced by the clinician. Clinicians are typically more interested in single individuals, and therefore they are especially interested in issues of sensitivity, specificity, and the positive predictive power of new data. Providing findings of high predictive power is the challenge for neuropsychiatric imaging.
There is hope on this front. In the field of geriatric psychiatry, fluorodeoxyglucose (FDG) PET (or similar SPECT) approaches are increasingly being incorporated into routine clinical use for the diagnosis or differential diagnosis of dementia and related illnesses (also see Chapter 15). It is conceivable that new specific ligands for neurofibrillary tangles and plaques in patients suffering from dementia of Alzheimer's type will provide major breakthroughs in the diagnostic assessment of this disorder, providing the first in vivo proof of these pathognomonic brain alterations. Another promising future clinical application of functional neuroimaging may be in predicting clinical response to specific pharmacological or nonpharmacological therapeutic interventions. And last but not least, functional neuroimaging can be combined with genetic studies with the aim of finding genotype-phenotype associations typical for specific neuropsy-chiatric disorders (also see Chapter 14). If the fast pace of developments in this field are any guide, there is every reason to be hopeful that clinical psychiatry may soon be transformed by these techniques in a manner comparable to their impact on basic psychiatric research.
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