P. M. Grasby

A fronto-parietal network for rapid visual information processing: A PET study of sustained attention and working memory.

The rapid visual information processing (RVIP) task, a test of sustained attention which also requires working memory for its successful execution, has been used in a number of human psychopharmacological studies. Single digits are presented in quick succession (100 or 200 digits/min) on a computer screen, and target sequences of numbers must be detected with a button press. Although previous neuroimaging studies have implicated the frontal and parietal cortices in performance of simple sustained attention tasks, the neuroanatomical substrates of RVIP performance are not yet known. This information would prove invaluable in the interpretation of drug effects on this task, possibly delineating a neuronal network for neurotransmitter action. Therefore, this study investigated the functional anatomy of the RVIP task using positron emission tomography (PET) derived measures of regional cerebral blood flow (rCBF) in eight healthy volunteers. Subjects were required to perform variants of the RVIP task which manipulated both the level of working memory load and the speed of stimulus presentation. Compared with a rest condition (eyes closed), the RVIP task increased rCBF bilaterally in the inferior frontal gyri, parietal cortex and fusiform gyrus, and also in the right frontal superior gyrus rostrally. In comparison with a simple sustained attention control condition, the aforementioned right frontal activations were no longer apparent. We suggest that these data are consistent with the existence of a right fronto-parietal network for sustained, and possibly selective, attention, and a left fronto-parietal network for the phonological loop component of working memory.

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.

The neural correlates of the noradrenergic modulation of human attention, arousal and learning.

The prefrontal cortex has been suggested as a site of action for the noradrenergic modulation of cognition. In healthy volunteers attentional deficits can be induced by the α2 adrenoceptor agonist clonidine, without impairment of more explicit tests of frontal lobe function. It is therefore possible that the effects of noradrenaline cannot be localized to a specific brain area such as the prefrontal cortex, but instead involve structures in a more widespread attentional network. A 1.5 μg/kg dose of clonidine or placebo was administered to 13 healthy male volunteers performing the rapid visual information processing task, which places demands on both sustained attention and working memory. Twelve positron emission tomography measurements of regional cerebral blood flow (rCBF) were collected during performance of this task and also during a rest state. A second experiment in 12 healthy volunteers examined the effects of a 1.3 μg/kg dose of clonidine on the rCBF changes associated with performance of a paired associates learning task compared with passive listening to word pairs. Comparison of each of the experimental tasks with its respective control replicated previous findings. A significant drug × task interaction, common to the two studies, was found in the right thalamus. Inspection of the adjusted rCBF values showed that the effect was due to attenuation of thalamic rCBF during the control states rather than to any effects of clonidine during performance of the cognitive tasks, although the effect was stronger in the rapid visual information processing study than in the paired associates learning study. The significant effect of clonidine during the control as opposed to the ‘cognitive’ activation state is consistent with previous findings in animals and humans demonstrating greater effects of clonidine during states of relatively low arousal. The results suggest neuroanatomical dissociation of the noradrenergic modulation of arousal (via the thalamus) and attention.

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.

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.

The effect of the dopamine agonist, apomorphine, on regional cerebral blood flow in normal volunteers.

Apomorphine, a non-selective dopamine agonist, has been used as a pharmacological probe for investigating central dopaminergic neurotransmission in psychiatric illness. In this study repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of apomorphine (5 or 10 micrograms/kg), or placebo. The difference in rCBF, before and after drug (apomorphine versus placebo), was used to identify brain areas affected by apomorphine. Compared to placebo, both doses of apomorphine increased blood flow in the anterior cingulate cortex. Apomorphine 10 micrograms/kg also increased prefrontal rCBF (right > left). No decreases in rCBF were noted following either dose of apomorphine. Apomorphine-induced increases of anterior cingulate blood flow might serve as an in vivo index of central dopamine function. Such an approach would complement established neuroendocrine challenge paradigms for investigating central dopamine neurotransmission in psychiatric illness.

THE EFFECT OF THE MUSCARINIC ANTAGONIST SCOPOLAMINE ON REGIONAL CEREBRAL BLOOD-FLOW DURING THE PERFORMANCE OF A MEMORY TASK

Scopolamine, a muscarinic antagonist, impairs memory performance in both humans and animals. In this study, repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers whilst performing auditory verbal memory tasks, before and after the administration of scopolamine (0.4 mg s.c.) or placebo. Compared to placebo, scopolamine increased blood flow in the lateral occipital cortex bilaterally and the left orbitofrontal region. Scopolamine decreased rCBF in the region of the right thalamus, the precuneus and the right and left lateral premotor areas. Scopolamine attenuated memory-task-induced increases of rCBF in the left and right prefrontal cortex and the right anterior cingulate region. These data suggest that acute blockade of cholinergic neurotransmission affects diverse brain areas, including components of the visual and motor systems, and, in addition, modulates memory task activations at distinct points in a distributed network for memory function.

Effect of the 5-HT1A partial agonist buspirone on regional cerebral blood flow in man

Repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of the 5-HT1A partial agonist, buspirone, or placebo. The difference in rCBF, before and after drug, (buspirone versus placebo) was used to identify brain areas affected by buspirone. Buspirone-induced changes in rCBF were studied under two behavioural conditions (5 word-list learning and 15 word-list learning). Compared to placebo, buspirone increased blood flow in the cuneus during both behavioural states. However, decreases in blood flow, centred in the left dorso-lateral prefrontal cortex and posterior cingulate cortex, were only observed under one of the two behavioural conditions. It is concluded that buspirone-induced alterations in regional cerebral blood flow are better understood, not in relation to the known distribution of monoamine neurotransmitter systems (particularly ascending 5-HT projections), but rather in relation to putative neuronal circuits possibly many synapses “downstream” of buspirones pharmacological site of action.

Is benzodiazepine-induced amnesia due to deactivation of the left prefrontal cortex?

Abstract. The amnesic properties of benzodiazepines result from an impairment in explicit (conscious) acquisition of new material. Rationale: Explicit encoding of new material has consistently resulted in an increase in regional cerebral blood flow (rCBF) in the left prefrontal cortex, as measured by positron emission tomography (PET). Objective: PET was used to determine whether an amnesic dose of midazolam (0.075xa0mg/kg) attenuated activation in this area during explicit memory encoding. Methods: A second condition (condition A) used a task to control for the automatic processing that occurs during explicit learning (condition E). Results: The subjects who received midazolam (n=7) recognised significantly fewer words than those who received placebo (n=8), but were not impaired with regard to automatic processing. rCBF was significantly increased in the left prefrontal cortex during explicit encoding of word lists in all subjects and in the temporal lobe and parieto-occipital regions during automatic processing. rCBF was significantly decreased in the prefrontal, superior temporal and parieto-occipital regions following midazolam. The midazolam-induced deactivation in the prefrontal cortex did not affect rCBF activations induced by the explicit memory condition (E–A). Conclusions: These results suggest that a specific interaction with prefrontal cortex activation does not underlie the amnesic effect of midazolam. However, it remains possible that a threshold level of prefrontal rCBF is necessary for encoding and that, after midazolam, this was not reached.

Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk

BACKGROUNDnPET studies of verbal fluency in schizophrenia report a failure of deactivation of left superior temporal gyrus (STG) in the presence of activation of left dorsolateral prefrontal cortex (DLPFC), which deficit has been attributed to underlying functional disconnectivity.nnnAIMnTo test whether these findings provide trait-markers for schizophrenia.nnnMETHODnWe used H2(15)O PET to examine verbal fluency in 10 obligate carriers of the predisposition to schizophrenia, 10 stable patients and 10 normal controls.nnnRESULTSnWe found no evidence of a failure of left STG deactivation in carriers or patients. Instead, patients failed to deactivate the precuneus relative to other groups. We found no differences in functional connectivity between left DLPFC and left STG but patients exhibited significant disconnectivity between left DLPFC and anterior cingulate cortex.nnnCONCLUSIONSnFailure of left STG deactivation and left fronto-temporal disconnectivity are not consistent findings in schizophrenia; neither are they trait-markers for genetic risk. Prefrontal functional disconnectivity here may characterise the schizophrenic phenotype.