C. J. Bench

Investigations of the functional anatomy of attention using the Stroop test

In two separate experiments positron emission tomography (PET) was used to measure changes in regional cerebral blood flow while normal subjects performed the Stroop colour word interference test, a test of selective attention. In the first experiment performance of the Stroop task was associated with activation of right orbito-frontal and bilateral parietal structures, an unexpected result in view of previously reported findings. In addition, there were highly significant time related focal changes in rCBF. A second experiment was therefore carried out which altered the experimental parameters to replicate an earlier study. In this second experiment focal activation of the right anterior cingulate and right frontal polar cortex occurred during the Stroop task. As in the first experiment significant time effects were again apparent. To determine the functionally related brain systems during the performance of the Stroop task a correlation analysis was carried out in relation to blood flow changes induced by experimental manipulation in the right anterior cingulate. This analysis indicated the engagement of a widespread network of anterior brain regions and reciprocal inhibition of posterior brain regions during the performance of the task. The results provide evidence for the involvement of anterior right hemisphere and medial frontal structures in attentional tasks but also indicate that time effects can confound task specific activations. Furthermore subtle experimental treatment parameters, such as stimulus presentation rate, influence the degree and distribution of observed activations.

THE ANATOMY OF MELANCHOLIA - FOCAL ABNORMALITIES OF CEREBRAL BLOOD-FLOW IN MAJOR DEPRESSION

Using positron emission tomography (PET) and 15Oxygen, regional cerebral blood flow (rCBF) was measured in 33 patients with primary depression, 10 of whom had an associated severe cognitive impairment, and 23 age-matched controls. PET scans from these groups were analysed on a pixel-by-pixel basis and significant differences between the groups were identified on Statistical Parametric Maps (SPMs). In the depressed group as a whole rCBF was decreased in the left anterior cingulate and the left dorsolateral prefrontal cortex (P less than 0.05 Bonferroni-corrected for multiple comparisons). Comparing patients with and without depression-related cognitive impairment, in the impaired group there were significant decreases in rCBF in the left medial frontal gyrus and increased rCBF in the cerebellar vermis (P less than 0.05 Bonferroni-corrected). Therefore an anatomical dissociation has been described between the rCBF profiles associated with depressed mood and depression-related cognitive impairment. The pre-frontal and limbic areas identified in this study constitute a distributed anatomical network that may be functionally abnormal in major depressive disorder.

Changes in regional cerebral blood flow on recovery from depression

We have previously described focal abnormalities of regional cerebral blood flow (rCBF) in the left dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex and angular gyrus in 40 patients with major depression. We now report on the patterns of change in rCBF in a subgroup of 25 of the same patients who were rescanned following clinical remission of depression. Fifteen patients were scanned when optimally matched for drug treatment (4) or drug free on both occasions (11). The other 10 patients were fully recovered but could not be matched for drug status for clinical and ethical reasons. In a paired comparison of the same patients when ill and following recovery it was evident that remission was associated with a significant increase in rCBF in the left DLPFC and medial prefrontal cortex including anterior cingulate. Increases in rCBF in the angular gyrus were not seen when the comparison of depressed and recovered scans was matched for medication. The previously described relationship between clinical symptoms and brain perfusion in the depressed state was no longer present in the recovered state; this supports the hypothesis of state relatedness. Thus, recovery from depression is associated with increases in rCBF in the same areas in which focal decreases in rCBF are described in the depressed state in comparison with normal controls.

Dorsolateral prefrontal cortex dysfunction in the major psychoses; symptom or disease specificity?

Neurophysiological deficits in the left dorsolateral prefrontal cortex (DLPFC) have been described in positron emission tomography studies of schizophrenia and depression. In schizophrenia and depression this deficit has been associated with the syndromes of psychomotor poverty and psychomotor retardation, respectively. Such findings lead to a prediction that DLPFC dysfunction is symptom rather than disease related. This prediction was empirically tested in a retrospective study that pooled data from 40 patients meeting research diagnostic criteria for depression and 30 patients meeting DSM-III R criteria for schizophrenia. The patients were categorised into those with and without poverty of speech, a symptom that is an observable manifestation of psychomotor impairment. The profile of regional cerebral blood flow (rCBF), measured in all subjects under resting conditions, was subsequently compared in these two groups. Patients with poverty of speech had significantly lower rCBF in the left DLFPC. This reduction of rCBF was independent of diagnosis. The findings support the view that the study of symptoms, or symptom clusters, can provide information additional to that of traditional diagnostic systems in the study of the major psychoses.

Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment

Depression with cognitive impairment, so called depressive pseudodementia, is commonly mistaken for a neurodegenerative dementia. Using positron emission tomography (PET) derived measures of regional cerebral blood flow (rCBF) a cohort of 33 patients with major depression was studied. Ten patients displayed significant and reversible cognitive impairment. The patterns of rCBF of these patients were compared with a cohort of equally depressed non-cognitively impaired depressed patients. In the depressed cognitively impaired patients a profile of rCBF abnormalities was identified consisting of decreases in the left anterior medial prefrontal cortex and increases in the cerebellar vermis. These changes were additional to those seen in depression alone and are distinct from those described in neurodegenerative dementia. The cognitive impairment seen in a proportion of depressed patients would seem to be associated with dysfunction of neural systems distinct from those implicated in depression alone or the neurodegenerative dementias.

Neuropsychological dysfunction in depression: the relationship to regional cerebral blood flow.

The relationship between neuropsychological test performance and regional cerebral blood flow (rCBF) was examined in 29 patients meeting Research Diagnostic Criteria (RDC) for major depression. Following a comprehensive neuropsychological assessment two subsets of tests, comprising tests that discriminated between patients and controls or between patients with varying degrees of global cognitive impairment, were selected. These subtests were entered into a principal components analysis (PCA) which generated a two-factor solution, accounting for 50% of the overall variance in test scores. Individual patient loadings on each of these factors were subsequently correlated with regional cerebral blood flow (rCBF), as measured by positron emission tomography (PET). Both factors demonstrated significant correlations with rCBF in the medial prefrontal cortex and frontal polar cortex while for each factor there were also unique patterns of correlations with posterior brain regions. The findings provide additional evidence that neuropsychological deficits in depression are associated with abnormalities in regional brain function and in particular with the function of the medial prefrontal cortex.

Cognitive function in depression: its relationship to the presence and severity of intellectual decline

Cognitive dysfunction is an integral feature of depression, in some cases of sufficient severity to warrant a diagnosis of dementia. There has been little systematic investigation of whether cognitive dysfunction is an inevitable consequence of depression, or is specific to a subgroup of depressed patients. Related to this is the distribution of cognitive dysfunction, whether there is a continuum of impairment or a distinct demented subgroup. Finally, there is the question of which aspects of cognitive function are most sensitive to the intellectual decline seen in depression. A study is described which addresses these issues. The distribution of global cognition was found to be normally distributed in the sample of 29 patients assessed. Based on this distribution and the scores of a control sample, the patients were classified as unimpaired, borderline or impaired. Two sets of independent comparisons were carried out. First, the unimpaired depressed patients were compared to matched non-depressed controls. Significant deficits were found on a range of neuropsychological measures covering aspects of language function, memory, both recall and recognition, attention and behavioural regulation. These same patients were also compared with two groups of matched depressed patients, with varying degrees of global cognitive impairment. In general, the cognitive measures showed a gradient of dysfunction across the three patients groups. Significant differences between the depressed groups were shown on measures of immediate recall, attention and behavioural regulation. The possible significance of attentional factors for the observed memory dysfunction is discussed.

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01 : a study using positron emission tomography and 11C-raclopride

Positron emission tomography (PET) and11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study highlights the potential of positron emission tomography in the preclinical evaluation of new drugs.

MEASURING THE NEUROMODULATORY EFFECTS OF DRUGS IN MAN WITH POSITRON EMISSION TOMOGRAPHY

Cognitive activation in conjunction with pharmacological challenge was used to demonstrate neuromodulation in man. Using positron emission tomography (PET), measurements of regional cerebral blood flow were made during the performance of memory tasks, before and after the administration of apomorphine (dopamine agonist), buspirone (5-HT1A partial agonist) or placebo. Drug effects on memory-induced increases in regional cerebral blood flow were assessed, on a voxel-by-voxel basis, using statistical parametric mapping. Increases of regional cerebral blood flow in response to the memory challenge were attenuated by apomorphine in the dorsolateral prefrontal cortex and augmented in the retrosplenial region of the posterior cingulate. Conversely, buspirone attenuated blood flow increases in the retrosplenial region. These interactions between drugs and a cognitive challenge can best be interpreted as neuromodulatory effects.

The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography

Positron emission tomography (PET) and11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean±2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.