subjects treated with the dissociative anaesthetic ketamine. Frontal lobe function. Both Kraepelin and Bleuler predicted
RESEARCH ASPECTS OF SCHIZOPHRENIA
sented typical stimuli). These techniques focus on the temporal dynamics of the brain’s capacity to process information and how this may be disrupted in schizophrenia. In order to localize anatomically the physiological deficits of the illness, other imaging techniques that provide topographical mapping of brain function are used.
Functional Neuroimaging and Schizophrenia Garry D Honey
Positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI) provide both temporal and spatial information that can be used to localize regional brain activity during the resting state or precisely controlled cognitive conditions. These techniques have considerably advanced our understanding of human brain function and the pathophysiology of schizophrenia. The development of fMRI in particular has been of great significance in schizophrenia research. An important advantage of fMRI is its dependence on an endogenous contrast agent (vascular oxygenation), which means it does not require the patient to be exposed to radiation, as in PET and SPECT. This is particularly advantageous in schizophrenia research as it facilitates repeated longitudinal assessments, thus allowing researchers to characterize neurodevelopmental changes in brain function from childhood and throughout the progressive course of the illness during periods of exacerbation and remission, and in response to clinical interventions such as pharmacotherapy.
Edward T Bullmore
The application of functional neuroimaging to schizophrenia has facilitated the investigation of critical questions regarding disturbances of higher brain function and provides an opportunity to attempt to elucidate the pathophysiological basis of the disorder. This contribution aims to: • provide an overview of the functional imaging techniques available in schizophrenia research • summarize current findings in frontal and temporal lobe function – brain regions that are thought to be critically involved in the disorder • consider some current issues in interpretation of functional imaging data in neuropsychiatry.
The application of functional imaging technology in psychiatry As a result of rapid technological development in recent years, a range of functional imaging techniques is now available for the assessment in vivo of human brain function. The application of a particular imaging technique is determined by the researcher’s clinical question, and there are several advantages and disadvantages to each of the techniques available, which must be taken into account (Figure 1).
Overview of functional imaging research in schizophrenia Neurochemical imaging PET and SPECT have had a considerable impact on molecular neuropharmacology, enabling in vivo assessment in humans of the level of receptor availability in schizophrenia, and also the level of receptor occupancy by antipsychotic medications at doses leading to clinical efficacy and treatment side-effects. These studies have been critical in current theories about the neurobiology of schizophrenia. Wong et al. (1986) reported that striatal D2 receptor density was increased in drug-naive patients with schizophrenia, which appeared to support the prevailing hyper-dopaminergic hypothesis of the illness. However, subsequent larger studies (e.g. Pilowsky et al., 1992) failed to replicate these findings, indicating that while subtle deficits may exist in a subgroup of patients, the dopamine hypothesis could not be confirmed. Neurochemical imaging has been similarly influential in understanding the mechanisms of pharmacotherapeutic strategies. In vivo receptor imaging studies have demonstrated that clinically effective doses of typical antipsychotics are associated with 70–90% striatal D2 blockade. However, the considerably reduced D2 receptor occupancy observed at clinically effective doses of clozapine has strongly suggested a revision of the dopamine hypothesis, implicating other neurotransmitter systems in the pathophysiology of the illness, such as glutamate and serotonin. High affinity for the 5-HT2A receptor, and comparably reduced midbrain dopaminergic blockade, has been suggested as a mechanism for the improved efficacy of novel atypical antipsychotics and their reduced propensity to cause extrapyramidal side-effects. Imaging studies have now demonstrated that this relationship is
Electrophysiological techniques, including electroencephalography (EEG) and evoked response potentials (ERPs), measure the electrical activity of the brain within the millisecond range. This allows the investigation of basic neurophysiological processes found to be disrupted in psychiatric conditions; typical examples include pre-pulse inhibition – the attenuation of the neural response to a stimulus (pulse) when preceded by a weaker stimulus (pre-pulse), and ‘oddball recognition’ – detection of an atypical infrequent stimulus within a series of repeatedly pre-
Garry D Honey is Pinsent-Darwin Fellow in Mental Pathology at the University of Cambridge, UK. He completed his master’s and doctoral theses at the Institute of Psychiatry, London, specializing in functional neuroimaging and neuropharmacology. His research interests include the application of fMRI to psychiatric disorders and cognitive function. Edward T Bullmore is Professor of Psychiatry at the University of Cambridge, UK. He trained in clinical psychiatry at the Maudsley Hospital, London, and has a PhD in statistical analysis of MRI data from the University of London.
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© 2002 The Medicine Publishing Company Ltd
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Scalp recordings of electrical activity
Event-related time-locked scalp recordings of electrical activity
Detection of gamma rays as a result of collision of emitted proton with an electron following decay of radio-labelled water
Detection of gamma emissions due to radionuclide decay
Local changes in magnetic field due to changes in ratio of oxyhaemoglobin to deoxyhaemoglobin
EEG
ERP
H2150-PET
SPECT
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fMRI
Spatial: 3.5–4 mm FWHM Temporal: 1–2 mins
Spatial: several centimetres Temporal: milliseconds
Spatial: several centimetres Temporal: milliseconds
Spatial: in plane resolution of
