The composition of the choice set modulates probability weighting in risky decisions.

Probability distortion-the tendency to underweight larger probabilities and overweight smaller ones-is a robust empirical phenomenon and an important driver of suboptimal choices. We reveal a novel contextual effect on probability distortion that depends on the composition of the choice set. Probability distortion was larger in a magnitude-diverse choice set (in which participants encountered more unique magnitudes than probabilities) but declined, resulting in more veridical weighting, in a probability-diverse choice set (more unique probabilities than magnitudes). This effect was consistent in two, large, independent datasets (N = 481, N = 100) and held for a subset of lotteries that were identical in the two contexts. It also developed gradually as a function of exposure to the choice set, was independent of attentional biases to probability versus magnitude information, and was specific to probability weighting, leaving risk attitudes unaffected. The results highlight the importance of context when processing probabilistic information.

Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects.

The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1,796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7 mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5 ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7 nmol/s (23.6, 29.2), n=214 vs. 28.9 nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3 nmol/s (21.3, 26.1), n=117 vs. 24.6 nmol/s (22.2, 27.5), n=38, p=0.22. These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

In vivo imaging neurotransmitter function. The rat 6-hydroxydopamine model and its relevance for human Parkinson's disease.

This article gives an overview of those small animal imaging studies which have been conducted on neurotransmitter function in the rat 6-hydoxydopamine (6-OHDA) model of Parkinson's disease, and discusses findings with respect to the outcome of clinical studies on Parkinsonian patients.

Depression and anxiety in different thyroid function states.

Previous studies on hypothyroid subjects have indicated serious psychiatric symptoms affecting the patients' quality of life. The present prospective cross-sectional study's aim was to examine these symptoms in thyroid patients with different functional states. A total of 254 patients (age: 56 +/- 14 years [mean +/- standard deviation], 181 female, 73 male) referred to a hospital for radioiodine treatment of hyperthyroidism or for follow-up of differentiated thyroid cancer, respectively, were included. All patients underwent the twelve-item general health questionnaire, which is an instrument for detecting mood disturbances. Euthyroid and hyperthyroid patients did not differ significantly in their general health questionnaire score (11 +/- 5 vs. 11 +/- 7), nor did subclinical hyperthyroid (11 +/- 6) or subclinical hypothyroid subjects (12 +/- 5). In contrast, hypothyroid patients showed a significantly higher mean score (17 +/- 7, p < 0.001, ANOVA). Binary logistic regression revealed that hypothyroidism increases age and gender-adjusted risk for critical mood deterioration by seven-fold. Thus, hypothyroidism represents a widely underestimated functional condition that may severely affect mental health.

Distribution of 5HT2A receptors in the human brain: comparison of data in vivo and post mortem.

AIM: The study presented here firstly compares the distribution of the binding potential of the serotonin-5HT2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. METHODS: Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT2A ligand 18F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. RESULTS: The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p < 0.0001). A difference in the receptor density between two regions could be detected with p < 0.05 when it amounted at least to 18%. CONCLUSION: This study demonstrates a good agreement between in vivo data obtained with 18F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%.

Imaging of striatal dopamine D(2) receptors with a PET system for small laboratory animals in comparison with storage phosphor autoradiography: a validation study with (18)F-(N-methyl)benperidol.

UNLABELLED: Several groups have developed high-resolution PET systems and shown the feasibility of in vivo studies on small laboratory animals. In this investigation, one of these systems was validated for the performance of receptor imaging studies. For this, the radiotracer concentrations obtained in the same animals with PET and with autoradiography were quantified, and the correspondence between both methods was assessed by means of correlation analysis. METHODS: Striatal radioactivity was measured in 10 Sprague-Dawley rats after injection of 60 +/- 10 MBq of the dopamine D(2) receptor ligand (18)F-(N-methyl)benperidol in 6 time frames of 6 min each. On completion of the scans, animals were killed, and their brains were removed and sectioned using a cryostat microtome. Coronal slices were subjected to storage phosphor autoradiography with BaFBr:Eu(2+)-coated imaging plates. Striatal radioactivity was quantified in both modalities using region-of-interest analysis and activity standards. RESULTS: After partial-volume correction, the median of striatal radioactivity concentration measured with PET was 0.40 MBq/cm(3) (25th percentile, 0.32; 75th percentile, 0.44). Radioactivity concentrations determined by means of storage phosphor autoradiography amounted to 0.42 MBq/cm(3) (25th percentile, 0.24; 75th percentile, 0.51). Correlation of striatal radioactivity values yielded a Pearson correlation coefficient of 0.818 (P = 0.002). Radioactivity accumulation in Harder's glands led to an overestimation of striatal activity concentrations by approximately 5%. The median of striatal radioactivity concentration after spillover correction decreased slightly to 0.38 MBq/cm(3) (25th percentile, 0.30; 75th percentile, 0.43). Correlation of striatal radioactivity values after spillover correction yielded a Pearson correlation coefficient of 0.824 (P = 0.002). CONCLUSION: The results show a significant positive correlation between radioactivity values obtained with PET and storage phosphor autoradiography used as the gold standard. Because we applied a selective dopamine D(2) receptor radioligand and because radioactivity concentrations could be reliably quantified in the target region, we may infer that in vivo receptor binding studies will be possible in small laboratory animals.

Disturbance of serotonin 5HT2 receptors in remitted patients suffering from hereditary depressive disorder.

AIM: The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using positron emission tomography and the radioligand F-18-altanserin. METHODS: Twelve patients from families with high loading of depression living in a geographically restricted region were examined and compared with normal control subjects. At the time of the PET measurement all patients were remitted; in some of them remission was sustained by antidepressive medication. Binding potential was assessed by Logan's graphical analysis method. RESULTS: The binding of F-18-altanserin was about 38% lower in patients than in healthy controls (p < 0.001). A multiple regression analysis revealed that this difference was mainly induced by depression rather than by medication. CONCLUSIONS: The data suggest that 5HT2 receptors are altered in depression. We present evidence for a reduction of the receptor density, which might be usable as trait marker of subjects susceptible for depressive illness.

Striatal dopamine release in reading and writing measured with [123I]iodobenzamide and single photon emission computed tomography in right handed human subjects.

Competition between endogenous dopamine and a radioligand for postsynaptic dopamine D(2) receptor binding was examined in two groups of eight subjects each who had to read or write off a text, respectively, and in a control group. Single photon emission computed tomography (SPECT) and the ligand [(123)I]iodobenzamide (IBZM) were used for in vivo imaging. Subjects commenced reading or writing immediately before IBZM injection and continued for 30min thereafter. SPECT images were acquired 60min later. Striatum-to-parietal-cortex IBZM uptake ratios were lower in subjects who wrote off the text than in controls indicating competition of IBZM and dopamine. There was no difference between subjects who read the text and controls. Thus, dopamine release occurs as a consequence of the motoric activity involved in writing rather than of cognitive functions necessary for reading the text.

Diffuse cortical reduction of neuronal activity in unipolar major depression: a retrospective analysis of 337 patients and 321 controls.

Reduction of neuronal activity in frontocortical and limbic circuits is considered a characteristic of depression. We aimed to test this hypothesis by pooling all available data from experimental literature. All investigations were included comparing regional cerebral blood flow (rCBF) or glucose metabolism (rCMRGlc) between acutely depressed unipolar major depressive patients and healthy controls. For cortical and subcortical regions we computed the percentage difference between depressives (n = 337) and controls (n = 321). In patients with unipolar major depression rCBF and rCMRGlc were lowered in left (-4.4%, P = 0.022) and right frontal (-3.2%, P = 0.053), left (-1.7%, P = 0.061) and right temporal (-3.0%, P=0.003), left (-6.5%, P = 0.002), and right parietal (-8.8%, P=0.001), and left (-6.6%, P = 0.083) and right occipital cortex (-4.2%, P = 0.02). Moreover, there were reductions in left (-6.3%, P = 0.029) and right basal ganglia (-4.8%, P = 0.002), left (-3.4%, P = 0.114) and right thalamus (-3.1%, P = 0.036), and left limbic system (-2.2%, P = 0.127). Parameters were increased by 1.0% (P = 0.714) only in the right limbic system. There were no hemispheric asymmetries (P > 0.05). Moreover, there was no indication for an anterior-posterior gradient (P > 0.05), and thus no 'hypofrontality'. In contrast to the current view, the data indicate a diffuse cortical rather than regionalized reduction of neuronal activity in unipolar major depression.

Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT.

Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D2 receptor antagonist [123I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D2 receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n = 17), which was investigated once with [123I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D2 receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.

Influence of motor activity on striatal dopamine release: A study using iodobenzamide and SPECT.

Pharmacologically induced dopamine release can influence the postsynaptic receptor binding of dopaminergic radioligands. This effect has recently been described using in vivo imaging methods and has been attributed to competition of radiotracers with the endogenous ligand. The present study examines the effect of a motor activation task on dopamine release and the consequences of this release on the binding of the selective D(2) receptor ligand (123)I-iodobenzamide (IBZM) to striatal dopamine D(2) receptors. Eight subjects were asked to write a text beginning immediately before IBZM injection and continuing for 30 min thereafter. Eighteen other subjects remained in a supine resting state during this period and served as a control group. All subjects were right handed. We hypothesized that the writing task would lead to an increase of dopamine release. The increased competition of the endogenous ligand with IBZM should lead to a decreased postsynaptic IBZM binding in the experimental group. Images were acquired and reconstructed identically and anatomically normalized to a computerized brain atlas. Regions of interest were drawn covering the striatum and three different reference regions. Ratios of striatal-to-reference-tissue radioactivity accumulation were calculated as semi-quantitative estimates of D(2) receptor binding potential. This decreased bilaterally, although right-sided significantly more than left, regardless of the choice of reference region. These data show that writing with the right hand compared to a supine resting state leads to a decrease of striatal IBZM accumulation. According to our primary hypothesis this reflects dopamine release.

Motivation effects in a dichotic listening task as evident from functional magnetic resonance imaging in human subjects.

The present study addresses the effect of motivation on cerebral activity using functional magnetic resonance imaging. Five healthy volunteers performed a dichotic listening task in two sets of three trials during which high or low levels of achievement motivation were introduced. They were told that the first set would be used for calculation of intellectual capacity (high achievement motivation) and the second set for scanner calibration (neutral motivation). In three volunteers, high compared with neutral motivation produced activation in the right prefrontal cortex and the dorsal cingulate. We conclude that motivational effects may lead to significant activations and should be controlled in future cognitive imaging studies. We present preliminary evidence that right prefrontal and dorsal cingulate regions might be involved in motivational processes.

[Clinical impact of cerebral dopamine-D2 receptor scintigraphy]. / Zur klinischen Wertigkeit der zerebralen Dopamin-D2-Rezeptorszintigraphie.

The present review describes findings and clinical indications for the dopamine D2 receptor scintigraphy. Methods for the examination of D2 receptors are positron emission tomography (PET) using 11C- or 18F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using 123l-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: patients with early Parkinson's disease show an increased D2 receptor binding (D2-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D2-RB and are generally non-responsive to treatment. Postsynaptic blockade of D2 receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D2 scintigraphy. Further possible indications occur in psychiatry: the assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D2 receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D2 receptor binding can simplify the choice of therapy in depressive disorder: patients showing a low D2 binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D2 binding.

Left-right asymmetry of striatal dopamine D2 receptors.

Brain functions may be lateralized to the right or the left hemisphere. However, the biochemical characteristics accompanying these functions are largely unknown. To test possible lateralization of striatal dopamine D2 receptors, we examined 18 volunteers using 123I-iodobenzamide and single photon emission tomography. The striatum-to-cerebellum D2 binding ratio was 1.93 +/- 0.22 (mean +/- S.D.) on the right side and 1.85 +/- 0.19 on the left side. In 14 subjects, D2 binding was higher in the right compared to the left striatum (P < 0.05). These results are supported by a meta-analysis performed on 15 studies reported in the literature. We conclude that side differences of striatal dopamine D2 receptors exist. We propose that motor activity could be responsible for our findings.

Differential accumulation of iodine-123-iodobenzamide in melanotic and amelanotic melanoma metastases in vivo.

UNLABELLED: Iodine-123-iodobenzamide (IBZM) is a specific antagonist of dopamine D2 receptors and usually is used to study neuropsychiatric disorders. It also has a substantial affinity for malignant melanomas. This has been attributed to specific dopamine D2 receptor binding on melanoma cells because melanocytes and dopaminergic neurons share the same ectodermal origin and are both able to produce melanin. However, IBZM binding to melanoma metastases occurs predominantly 24 hr after injection, which is much later than maximal specific D2 receptor binding is expected. Furthermore, IBZM binding is not consistent in melanoma patients. This points to another mechanism of IBZM binding to melanoma cells. The aim of this study was to characterize IBZM-binding metastatic melanoma patients clinically and histologically to shed light on the nature of this mechanism. METHODS: Twenty-one patients with proven or suspected metastases of a malignant melanoma entered this prospective study after surgical removal of the primary tumor. Whole-body scans, planar scintigrams and SPECT scans were performed 2-5 hr and 1 day after intravenous injection of 185 MBq IBZM. RESULTS: The suspected diagnosis of metastatic cancer was later confirmed in 17 patients by histology, clinical follow-up, x-ray, CT or other radiologic methods. Four patients were free of tumor tissue at the time of investigation and remained stable for 2 yr thereafter. Twelve of the 17 patients had a melanotic and 5 had an amelanotic subtype of the tumor. Iodine-123-IBZM accumulation occurred in the metastases of 10 of the 12 patients with melanotic melanoma and in 0 of the 5 patients with the amelanotic tumor type (p < 0.01; chi-square test). Furthermore, IBZM accumulation occurred in 0 of the 11 amelanotic metastases but in 20 of the 25 melanotic metastases (p < 0.001). The sensitivity is, thus, 83% for the detection of melanotic melanoma metastases on a patient basis and 80% on a lesion basis. Iodine-123-IBZM scintigraphy demonstrated one previously unknown metastasis. Six initially suspected lesions were not due to melanoma metastases and were IBZM-negative. No false-positive IBZM accumulations occurred in our patients. CONCLUSION: Iodine-123-IBZM binds to melanotic malignant melanomas with high specificity and moderate sensitivity but not to amelanotic melanomas. Our data suggest that the tracer does not bind to membrane dopamine receptors of the tumor but is built in or closely bound to intracellular melanin.

[Clinical value of positron emission tomography in neuromedicine. Position paper on results of an interdisciplinary consensus conference]. / Klinische Wertigkeit der Positronen-Emissions-Tomographie in der Neuromedizin. Positionspapier zu den Ergebnissen einer interdisziplinären Konsensuskonferenz.

To date, positron emission tomography (PET) is the most powerful method for the in-vivo investigation of human brain metabolism. Besides extensive application of this technology in the neurosciences, PET is also being increasingly used as a clinical tool. However, despite its acceptance in clinical practice a major obstacle is its high costs. The present article reviews the literature on the clinical use of PET in neurology, neurosurgery, and psychiatry in order to substantiate the clinical indications for PET in these specialties as established by an interdisciplinary conference.

In vivo evidence for the involvement of dopamine-D2 receptors in striatum and anterior cingulate gyrus in major depression.

The dopaminergic system is a candidate neurotransmitter system thought to be involved in the pathogenesis of depression. This study addresses the issue whether the antidepressant efficacy of serotonin reuptake inhibition is related to changes in the cerebral dopaminergic system. Cerebral dopamine-D2 receptors were characterized in 13 patients with major depression using the dopamine-D2 receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D2 receptor binding during serotonin reuptake inhibition was found in striatum and anterior cingulate gyrus in treatment responders, but not in nonresponders. The increase in dopamine-D2 receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r = 0.59 for right and left striatum respectively, P < 0.05; r = 0.79 for the anterior cingulate gyrus, P < 0.05 after Bonferroni correction). Qualitatively similar correlations were observed in the precentral gyrus, the medial frontal gyrus, the inferior frontal gyrus, and the frontal part of the opercular gyrus, but these correlations failed to reach statistical significance after correction for the effects of multiple testing. No such correlations were found in the superior frontal gyrus, the orbitofrontal gyrus, the gyrus rectus, the superior parietal gyrus, or the superior temporal gyrus. The data strengthen the concept that the striatum and the anterior cingulate gyrus are involved in mood regulation. Dopamine-D2 receptors may constitute a central role in this domain.