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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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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 <1 mm FWHM. Temporal: few seconds, although event-related designs can resolve more rapid events

Disadvantages Low-dose radiation exposure. Requires on-site cyclotron. Expense restricts routine clinical use. Requires inter-subject averaging

Low-dose radiation exposure. Short half-life tracers requires on-site cyclotron. Expense restricts clinical use. Requires inter-subject averaging

Localization of neural generators of evoked responses unresolved

No localization of function

Excellent spatial resolution; Restrictive scanning environment. temporal resolution beginning Susceptible to movement artefacts to approach that of electrophysiological techniques. Non-invasive. Analysis of single subject data. Flexible event-related designs

Less expensive than PET. Low-dose radiation exposure. Radiotracers have longer half- Poor spatial resolution precludes life than those used in PET precise localization. Requires inter-subject averaging

Greater spatial resolution than that of SPECT (though less than fMRI)

Temporal resolution in the millisecond range

Assessment of distributed patterns of brain function

Provides in vivo local neuroField of view restricted to small chemical assay, previously regions of interest in the brain. available only indirectly via CSF Low concentrations of some metabolites are undetectable

Advantages Provides in vivo neuropharmacological assay, previously available only in animal models or post mortem

FDG – [18F]fluorodeoxyglucose; PET – positron emission tomography; MRS – magnetic resonance spectroscopy; EEG – electroencephalography; ERP – evoked response potential; SPECT – single photon emission computed tomography; fMRI – functional magnetic resonance imaging; CSF – cerebrospinal fluid; FWHM – full width half maximum (conventional measure of image resolution)

Localization of resting or cognitive (dys)function. Pre-surgical mapping. Assessment of pharmacological effects on brain function

Assessment of receptor distribution Spatial: 6–7 mm FWHM and ligand binding. Temporal: 3–4 mins Determination of receptor occupancy at clinical dosage/side-effects

Localization of resting or cognitive (dys)function

Assessment of rapid neural response to stimuli

Investigation of patterns of electrical activity, particularly in epilepsy

Neurochemical investigations of amino acids, neurotransmitters and their metabolites

Changes in recovery of nuclei following radio-frequency stimulation due to the local (chemical) environment

MRS

Spatial: <1 mm FWHM

Neuropsychiatric application Approximate resolution Assessment of receptor distribution Spatial: 3.5–4 mm FWHM and ligand binding. Determination of receptor occupancy at clinical efficacy/side-effects

Technique Mechanism FDG-PET Detection of gamma rays as a result of collision of emitted proton with an electron following decay of radio-labelled glucose

Summary of neurophysiological measurements available in psychiatry

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evident in humans in vivo, and these techniques will be critical in relating this finding to treatment response in patients. Radioligand binding techniques have also been applied in pharmacological challenge studies, using psychotomimetic compounds as pharmacological models of psychosis, or to transiently exacerbate existing symptoms in patients. Reduced dopaminergic ligand binding following amphetamine administration, for example, has been used to demonstrate increased endogenous dopaminergic transmission in patients compared to controls. Similarly, reduced raclopride binding in the basal ganglia has been consistently demonstrated in healthy subjects treated with the dissociative anaesthetic ketamine. Frontal lobe function Both Kraepelin and Bleuler predicted frontal lobe dysfunction to be of fundamental importance in schizophrenia, and functional neuroimaging has provided a means to investigate these hypotheses directly. Early functional imaging studies involving patients with schizophrenia noted a reversal of the anteroposterior gradient of cerebral bloodflow evident in healthy controls (Ingvar and Franzen, 1974), a phenomenon termed ‘hypofrontality’. Numerous subsequent studies of resting state regional cerebral bloodflow (rCBF) in schizophrenia have provided supporting evidence. However, a comparable number of studies have failed to find evidence of hypofrontality, or have observed a hyperfrontal response in schizophrenic patients. The use of the term ‘hypofrontality’ has also been extended to describe a failure of task-induced frontal cerebral response; indeed, this has proved to be a more reliable finding. Using cognitive tasks which are associated with increased pre-frontal response in healthy volunteers – particularly tasks involving executive functioning and attention, such as the Wisconsin Card Sorting Task (see pages 31–2), Tower of London task, verbal fluency, and the Continuous Performance Test – numerous studies have shown that patients with schizophrenia fail to show this task-related increase in pre-frontal functioning. However, a number of studies have demonstrated normal frontal activation in patients with schizophrenia, or that it is task- or state-dependent. Several of the studies that failed to find hypofrontality reported comparable task performance between the patient and control groups, indicating that poor performance may account for at least some of the reports of hypofrontality. Recently, studies involving parametric manipulations of working memory load have been effectively employed to elucidate the complex nature of the hypofrontal response in schizophrenic patients under conditions of increasing cognitive load. These studies have demonstrated that schizophrenic patients exhibit hypofrontality only when the physiological capacity of the prefrontal cortex to respond to task-related requirements is exceeded by the cognitive load of working memory tasks (Figure 2).

a

b Pharmacological modulation of prefrontal response to a working memory task in patients with schizophrenia following treatment with risperidone. a regions highlighted in red represent fronto-parietal activation associated with working memory in all subjects (treated with typical and atypical antipsychotics); b regions highlighted in green indicate areas of enhanced activation after 6 weeks’ treatment with risperidone (Honey et al., 1999). 2

Numerous functional neuroimaging investigations have demonstrated deficits of temporal lobe functioning in schizophrenia. DeLisi et al. (1989) reported evidence of increased temporal lobe glucose metabolism in schizophrenic patients compared to controls, particularly in the left superior and anterior temporal region. Increased left temporal perfusion in patients during the performance of a verbal fluency task was demonstrated in the first study to report the use of SPECT for functional imaging in schizophrenic patients. This finding was supported by Siegel et al. (1993), who observed increased left lateral temporal metabolic activity in a large cohort of 70 unmedicated patients. However, in a recent meta-analysis of structural and functional neuroimaging studies investigating the temporal lobe in schizophrenia, Zakzanis et al. (2000) concluded that the weak effect size observed was difficult to reconcile with the view that temporal

Temporal lobe function The temporal lobes have been implicated in the pathophysiological mechanisms underlying the positive symptoms of schizophrenia, following the demonstration of perceptual disturbances resembling psychotic features after temporal lesions, the evocation of hallucinations by temporal electrostimulation and the prevalence of psychosis in patients with temporal lobe epilepsy.

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lobe pathology is of central importance in a single-disease model of schizophrenia.

REFERENCES Bullmore E, Horwitz B, Honey G, Brammer M, Williams S, Sharma T. How good is good enough in path analysis of fMRI data? Neuroimage 2000; 11: 289–301. DeLisi L E, Buchsbaum M S, Holcomb H H et al. Increased temporal lobe glucose use in chronic schizophrenic patients. Biol Psychiatry 1989; 25: 835–51. Fletcher P, McKenna P J, Friston K J, Frith C D, Dolan R J. Abnormal cingulate modulation of fronto-temporal connectivity in schizophrenia. Neuroimage 1999; 9: 337–42. Honey G D, Bullmore E T, Soni W, Varatheesan M, Williams S C, Sharma T. Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci U S A 1999; 96: 13432–7. Honey G D, Fletcher P C, Bullmore E T. Functional brain mapping of psychopathology. J Neurol Neurosurg Psychiatry 2002; 72: 432–9. Ingvar D H, Franzen G. Distribution of cerebral activity in chronic schizophrenia. Lancet 1974; 2(7895): 1484–6. Pilowsky L S, Costa D C, Ell P J, Murray R M, Verhoeff N P, Kerwin R W. Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 1992; 340: 199–202. Siegel B V Jr, Buchsbaum M S, Bunney W E Jr et al. Corticalstriatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients. Am J Psychiatry 1993; 150: 1325–36. Wong D F, Wagner H N Jr, Tune L E et al. Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics [published erratum appears in Science 1987; 235: 623]. Science 1986; 234: 1558–63. Zakzanis K K, Poulin P, Hansen K T, Jolic D. Searching the schizophrenic brain for temporal lobe deficits: a systematic review and meta-analysis. Psychol Med 2000; 30: 491–504.

Fronto-temporal connectivity Dysfunction of the temporal lobe has also been implicated by studies investigating functional integration of the frontal and temporal cortices. Relative decrease in activity of the temporal lobe during tasks that engage the frontal cortex has been demonstrated in PET studies, which implies functional connectivity between frontal and temporal cortices. Frontotemporal connectivity has been shown to be abnormal in patients with schizophrenia (Fletcher et al., 1999). However, more recent findings suggest that patients in remission of psychotic illness, including both schizophrenia and bipolar disorder, do not exhibit a failure of temporal deactivation, indicating that fronto-temporal dysconnectivity, like hypofrontality, may be state-related. Developments in the analysis of functional connectivity in imaging data may shed more light on this issue (Bullmore et al., 2000).

Current issues in neuropsychiatric imaging Conceptual issues: functional imaging research in schizophrenia has demonstrated widespread deficits affecting a range of cognitive functions distributed throughout the brain. However, there is a degree of inconsistency in reported findings, and a pattern of brain dysfunction that would serve as a biological trait marker or predict treatment response has not emerged to date. There are a number of possible reasons for this (for a more detailed review of these issues, see Honey, Fletcher and Bullmore, 2002). Perhaps most fundamentally, equivocal findings may be related to the historical difficulties in psychiatric nosology in conceptualizing and categorizing a heterogeneous disorder such as schizophrenia. This is still a topical issue: the diagnosis itself remains a disjunctive concept – two patients diagnosed with the illness may not have any symptoms in common. Further developments in psychiatric classification are required if cognitive neuroscience in general is ultimately to have an impact on the clinical management of schizophrenia.

FURTHER READING Andreasen N C, Rezai K, Alliger R et al. Hypofrontality in neurolepticnaïve patients and in patients with chronic schizophrenia. Arch Gen Psychiatry 1992; 49: 943–58. Dye S M, Spence S A, Bench C J. No evidence for left superior temporal dysfunction in asymptomatic schizophrenia and bipolar disorder. PET study of verbal fluency. Br J Psychiatry 1999; 175: 367–74. Farde L, Nordstrom A L, Wiesel F A, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992; 49: 538–44. Fletcher P C, McKenna P J, Frith C D, Grasby P M, Friston KJ, Dolan R J. Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging. Arch Gen Psychiatry 1998; 55: 1001–8. Friston K J, Frith C D. Schizophrenia: a disconnection syndrome? Clin Neurosci 1995; 3: 89–97. Smith G S, Schloesser R, Brodie J D et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology 1998; 18: 18–25.

Applying functional imaging: in addition to these conceptual issues, there are also inherent challenges in the application of functional imaging to schizophrenia. Antipsychotic medication is a critical consideration in psychiatric functional imaging studies, given the increased functional activation of the prefrontal cortex associated with atypical antipsychotic treatment (Honey et al., 1999). Other confounds that may have been inadequately controlled in some studies include cognitive performance deficits, the age of onset of psychosis, illness chronicity and the patient’s sex, all of which are likely to contribute to equivocal research findings in schizophrenia. Progress in our understanding of the pathophysiological basis of schizophrenia depends fundamentally on a precise definition of a homogeneous clinical population, in order to address specific and targeted issues of human brain dysfunction. The development of functional neuroimaging has provided the technological advance necessary to examine these issues; the scientific challenge is to incorporate these factors appropriately through prudent experimental design. u

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