Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis.

Schizophrenia is characterized by altered prefrontal activity and elevated striatal dopaminergic function. To investigate the relationship between these abnormalities in the prodromal phase of the illness, we combined functional Magnetic Resonance Imaging and (18)F-Dopa Positron Emission Tomography. When performing a verbal fluency task, subjects with an At-Risk Mental State showed greater activation in the inferior frontal cortex than controls. Striatal dopamine function was greater in the At-Risk group than in controls. Within the At-Risk group, but not the control group, there was a direct correlation between the degree of left inferior frontal activation and the level of striatal dopamine function. Altered prefrontal activation in subjects with an At-Risk Mental State for psychosis is related to elevated striatal dopamine function. These changes reflect an increased vulnerability to psychosis and predate the first episode of frank psychosis.

Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

Evidence for endogenous opioid release in the amygdala during positive emotion.

Endogenous opioid release has been linked to relief from aversive emotional memories, thereby promoting a euphoric state and subsequent interactions towards social stimuli resulting in the formation of social preferences. However, this theory remains controversial. Using positron emission tomography and [(11)C]diprenorphine (DPN) in healthy volunteers, we found significantly reduced DPN binding to opioid receptor in the hippocampus during positive mood induction compared to neutral mood. Furthermore, the magnitude of positive mood change correlated negatively with DPN binding in the amygdala bilaterally. Our finding of reduced DPN binding is consistent with increased release of endogenous opioids, providing direct evidence that localised release of endogenous opioids is involved in the regulation of positive emotion in humans.

[11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS.

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.

Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635.

Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.

Imaging the neurochemical brain in health and disease.

Neurochemical transmission is a fundamental element of brain organisation that has been relatively unexplored in the living human brain. Continuing advances in radionuclide imaging, particularly positron emission tomography (PET) and single photon emission tomography (SPET), mean that elements of neurochemical transmission can now be directly measured in vivo. With these techniques convincing abnormalities of monoaminergic neurotransmitter systems have been revealed in illnesses such as Parkinson's disease and schizophrenia. Furthermore, mechanisms of drug action and treatment responses can be monitored in vivo. This brief review describes some of our recent attempts to image the neurochemical brain in health and disease at the MRC Cyclotron Unit, Hammersmith Hospital, London.

Pindolol augmentation of selective serotonin reuptake inhibitors: PET evidence that the dose used in clinical trials is too low.

OBJECTIVE: Positron emission tomography (PET) was used to examine whether the dose of pindolol used to augment antidepressant medication achieves a significant occupancy of the serotonin type 1A (5-HT(1A)) autoreceptor in depressed patients receiving medication. METHOD: The authors examined eight depressed patients on one of two regimes of pindolol (2.5 mg t.i.d. and 5.0 mg t.i.d.) with PET and [11C]WAY-100635. RESULTS: The 5-mg t.i.d. regime achieved a modest (19%) but significant occupancy of the 5-HT(1A) autoreceptor, while the regime used in the vast majority of clinical trials (2.5 mg t.i.d.) did not achieve a significant occupancy. CONCLUSIONS: The dose of pindolol used in clinical trials is suboptimal and may explain the inconsistent results. Therefore, a thorough test of pindolol's efficacy will necessitate doses higher than those used in present clinical trials.

PET measurement of the influence of corticosteroids on serotonin-1A receptor number.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis and serotonergic system interact functionally. The modulatory effect of corticosteroids on 5-HT(1A) receptor number and function has been repeatedly demonstrated in preclinical studies suggesting that raised corticosteroid levels decrease 5-HT(1A) receptor number and function in the hippocampus. METHODS: We used positron emission tomography (PET) to quantify the number of 5-HT(1A) receptors in two studies, the first in normal subjects given a single dose of hydrocortisone using a random-order, double-blind, placebo-controlled design and second in patients treated long-term with corticosteroids. RESULTS: We did not find that exposure to elevated levels of corticosteroids in either the short or long term alters 5-HT(1A) receptor binding in the hippocampus or other brain regions examined. CONCLUSIONS: This study does not support the hypothesis that corticosteroids exert a major inhibitory regulatory control over the 5-HT(1A) receptor binding in the human brain.

The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?

Increasing attention is being directed towards the role of the serotonergic system in the neurochemistry of schizophrenia and antipsychotic drug treatment. This review considers the 5-HT1A receptor in this context. In patients with schizophrenia, the majority of post-mortem studies have reported increases in 5-HT1A receptor density in the prefrontal cortex in the approximate range 15-80%. Although the pathophysiological significance of this finding is unclear, given the location of a major proportion of these receptors on pyramidal cells, it may reflect an abnormal glutamatergic network. In terms of drug treatment, 5-HT1A agonists clearly display anticataleptic activity in rats. In addition, 5-HT1A agonists consistently increase dopamine release in the prefrontal cortex in rodents, which is an effect that might be predicted to improve negative symptoms. 5-HT1A agonists augment classical neuroleptics in some rat models of antipsychotic action and may be capable of modulating the glutamatergic network therapeutically. Despite the encouraging preclinical data, there is a paucity of clinical studies of 5-HT1A agonist augmentation of neuroleptics in the treatment of schizophrenia. However, the clinical relevance may be clarified by the atypical antipsychotic drugs clozapine, quetiapine and ziprasidone which combine D2 receptor antagonism and 5-HT1A agonism. In conclusion, given the increased prefrontal 5-HT1A receptor density in the illness, and the anticataleptic activity of 5-HT1A agonists combined with their ability to evoke prefrontal dopamine release, there is now a sufficient rationale to examine thoroughly the role of the 5-HT1A receptor in schizophrenia and antipsychotic drug treatment.

Statistical modeling of positron emission tomography images in wavelet space.

A new method is introduced for the analysis of multiple studies measured with emission tomography. Traditional models of statistical analysis (ANOVA, ANCOVA and other linear models) are applied not directly on images but on their correspondent wavelet transforms. Maps of model effects estimated from these models are filtered using a thresholding procedure based on a simple Bonferroni correction and then reconstructed. This procedure inherently represents a complete modeling approach and therefore obtains estimates of the effects of interest (condition effect, difference between conditions, covariate of interest, and so on) under the specified statistical risk. By performing the statistical modeling step in wavelet space. the procedure allows the direct estimation of the error for each wavelet coefficient; hence, the local noise characteristics are accounted for in the subsequent filtering. The method was validated by use of a null dataset and then applied to typical examples of neuroimaging studies to highlight conceptual and practical differences from existing statistical parametric mapping approaches.

Quantitative analysis of [carbonyl-(11)C]WAY-100635 PET studies.

[carbonyl-(11)C]WAY-100635 ¿[(11)C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2- pyridy l)cyclohexanecarboxamide¿ is a positron-emission tomography (PET) radioligand for in vivo imaging of the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor. This paper assesses and summarises various different modeling strategies for the quantitative analysis of the radioligand. The models considered are based on a compartmental description of the ligands behaviour and include both plasma input analyses, requiring the additional monitoring of blood activity, and a reference tissue approach, which relies solely on the tomographic tissue data. Parameter estimates of specific binding are presented for a set of test-retest data, obtained from six normal volunteers who were scanned on two separate occasions, allowing for an assessment of normal binding values and their reproducibility.

Drug action at the 5-HT(1A) receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-(11)C]WAY-100635.

Serotonin(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression and are a target for novel drug development. In this qualitative study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in man in vivo by five different compounds with nanomolar affinity for this site. Occupancy by pindolol, penbutolol, buspirone, EMD 68843, and S 15535 was compared to test-retest data from 10 healthy volunteers. All drugs, apart from buspirone, displayed occupancy at the 5-HT(1A) receptor site. Pindolol demonstrated a preferential occupancy at the autoreceptor compared to the postsynaptic receptor over a plasma range of about 10-20 ng/mL. Differential occupancy may be an important component of novel drug action. The level of autoreceptor or postsynaptic occupancy needed to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyond 60%. Overall this study demonstrates the utility of PET in aiding novel drug development.

beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy.

A novel strategy for improving the treatment of depressive illness is augmentation of antidepressants with a 5-HT1(1A) autoreceptor antagonist. However, trials using the 5-HT1(1A)/beta-blocker pindolol are proving inconsistent. We report how positron emission tomography (PET) and in vitro autoradiography can inform trials of antidepressant augmentation. We show that in healthy volunteers, in vivo, pindolol (n = 10) and penbutolol (n = 4), but not tertatolol (n = 4) occupy the human 5-HT(1A) receptors, at clinical doses. Pindolol, as well as the beta-blockers penbutolol and tertatolol, has high affinity for human 5-HT(1A) receptors in post-mortem brain slices (n = 4). Pindolol shows preference for 5-HT(1A) autoreceptors versus the post-synaptic receptors both in vitro and in vivo. Our data reveal that pindolol doses used in antidepressant trials so far are suboptimal for significant occupancy at the 5-HT(1A) autoreceptor. Penbutolol or higher doses of pindolol are candidates for testing as antidepressant augmenting regimes in future clinical trials.

Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk. Focal dysfunction and distributed disconnectivity reappraised.

BACKGROUND: PET 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'. AIM: To test whether these findings provide trait-markers for schizophrenia. METHOD: We 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. RESULTS: We 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. CONCLUSIONS: Failure 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.

Discrete neurophysiological correlates in prefrontal cortex during hysterical and feigned disorder of movement.

The clinical distinction between hysterical symptoms and those that are feigned awaits objective validation. We used functional neuroimaging to examine the neural correlates of these two disorders.

Contrasting cortical and subcortical activations produced by attentional-set shifting and reversal learning in humans.

Much evidence suggests that lesions of the prefrontal cortex (PFC) produce marked impairments in the ability of subjects to shift cognitive set, as exemplified by performance of the Wisconsin Card Sorting Test (WCST). However, studies with humans and experimental primates have suggested that damage to different regions of PFC induce dissociable impairments in two forms of shift learning implicit in the WCST (that is, extradimensional (ED) shift learning and reversal shift learning), with similar deficits also being apparent after damage to basal ganglia structures, especially the caudate nucleus. In this study, we used the same visual discrimination learning paradigm over multidimensional stimuli, and the H215O positron emission tomography (PET) technique, to examine regional cerebral blood flow (rCBF) changes associated with these subcomponent processes of the WCST. In three conditions, subjects were scanned while acquiring visual discriminations involving either (i) the same stimulus dimension as preceding discriminations (intradimensional (ID) shifts); (ii) different stimulus dimensions from previous discriminations (ED shifts) or (iii) reversed stimulus-reward contingencies (reversal shifts). Additionally, subjects were scanned while responding to already learnt discriminations ('performance baseline'). ED shift learning, relative to ID shift learning, produced activations in prefrontal regions, including left anterior PFC and right dorsolateral PFC (BA 10 and 9⁄46). By contrast, reversal learning, relative to ID shift learning, produced activations of the left caudate nucleus. Additionally, compared to reversal and ID shift learning, ED shift learning was associated with relative deactivations in occipito-temporal pathways (for example, BA 17 and 37). These results confirm that, in the context of visual discrimination learning over multidimensional stimuli, the control of an acquired attentional bias or'set', and the control of previously acquired stimulus-reinforcement associations, activate distinct cortical and subcortical neural stations. Moreover, we propose that the PFC may contribute to the control of attentional-set by modulating attentional processes mediated by occipito-temporal pathways.

Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment.

BACKGROUND: Pharmacological and postmortem investigations suggest that patients with major depressive disorder have alterations in function or density of brain serotonin1A (5-HT1A) receptors. The aim of the present study was to use positron emission tomography with the selective 5-HT1A receptor antagonist [11C]WAY-100635 to measure 5-HT1A receptor binding in depressed patients before and during treatment with selective serotonin reuptake inhibitors. METHODS: Positron emission tomographic scans with [11C]WAY-100635 were performed on 25 patients with major depressive disorder. These included 15 unmedicated depressed patients. Ten of these unmedicated patients were scanned again during selective serotonin reuptake inhibitor treatment. A further 10 patients with major depressive disorder were scanned on one occasion only while taking selective serotonin reuptake inhibitors. Comparisons were made with [11C]WAY-100635 positron emission tomographic scans in 18 healthy volunteer subjects. Region of interest analysis and statistical parametric mapping were performed on binding potential images generated using a reference tissue model. RESULTS: Binding potential values were reduced across many of the regions examined, including frontal, temporal, and limbic cortex in both unmedicated and medicated depressed patients compared with healthy volunteers. Binding potential values in medicated patients were similar to those in unmedicated patients. CONCLUSIONS: Major depressive disorder is associated with a widespread reduction in 5-HT1A receptor binding. This reduced 5-HT1A receptor binding was not changed by selective serotonin reuptake inhibitor treatment.

Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient.

Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

Assessment of spatial normalization of PET ligand images using ligand-specific templates.

Recent advances allow robust computation of parametric maps of ligand-receptor binding from PET data sets. Parametric maps may be statistically analyzed at the voxel level, given suitable techniques for both the spatial normalization of image data into a standard space and the application of appropriate statistical tests. The purpose of this study was to spatially normalize parametric maps of [carbonyl-11C]WAY-100635 and [11C]raclopride binding using SPM 96 and ligand-specific templates. Ligand-specific templates were created from integral images taken from healthy subjects. For this, a MRI-based spatial normalization was used: T1-weighted MRI scans were coregistered to the PET integral images, and the spatial normalization of the MRI to the SPM 96 T1 MRI template was applied to the integral images. These integral images were meaned and smoothed to form [carbonyl-11C]WAY-100635 and [11C]raclopride templates. Reliability of spatial normalization using the ligand template method and the previous MRI-based spatial normalization was investigated by using a second set of integral images taken from a different cohort: Landmark coordinates were defined on all spatially normalized integral images. Mean coordinates were found in order to produce an overall (average) landmark for each location. For each image, at each location, the distance from the landmark coordinates to the overall landmark were found. A multivariate analysis of variance was used to examine the effects of observer variance, landmark location, and the method used. Visually acceptable templates were created. While observer variance was not significant, the landmark x method interaction was significant. The ligand template method had significantly smaller distances: Among the landmark locations with this method, the mean distances between individual image landmarks and overall image landmarks ranged from 1. 1 to 4.9 mm. The ligand template method provides a reliable approach for spatial normalization of PET ligand images.

No evidence for left superior temporal dysfunction in asymptomatic schizophrenia and bipolar disorder. PET study of verbal fluency.

BACKGROUND: Positron emission tomography (PET) studies have revealed functional left superior temporal gyrus (STG) abnormalities in symptomatic schizophrenia during word generation. AIMS: To discover if this dysfunction is present in asymptomatic schizophrenia. To determine whether, without concurrent symptomatology, schizophrenia and bipolar affective disorder (BPD) are distinguishable by differing regional cerebral blood flow (rCBF) patterns during word generation. METHOD: A PET verbal fluency protocol was applied to six patients with BPD in remission and six patients with asymptomatic schizophrenia. Analysis included 10 control subjects from a contemporaneous study. RESULTS: All groups showed relative reduction of rCBF in both superior temporal cortices. There were no quantitative differences in any group comparison. All groups exhibited negative covariation between rCBF in left prefrontal and right (but not left) temporal regions. CONCLUSIONS: Abnormal patterns of left STG function cannot be regarded as a trait marker for schizophrenia. Functional abnormalities may reflect aspects of mental state.