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%.

Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study.

Differentiated thyroid cancer is a malignant tumour that has a fairly good prognosis, with patients surviving for many years. Multimodal therapy with surgery, radioiodine therapy and TSH suppressive medication is of proven efficacy. However, loss of differentiation is observed in up to one-third of patients with differentiated thyroid cancer, paralleled by an increase in tumour grading and loss of thyroid-specific functions (thyrotropin receptor, iodine accumulation). Such tumours may no longer be amenable to standard treatment protocols, including TSH suppression and radioiodide therapy. Retinoic acids have been shown to exert re-differentiating effects on thyrocytes in various experimental studies and case reports, and it was on this basis that this pilot study was initiated. Patients with advanced thyroid cancer and without the therapeutic options of operation or radioiodide therapy were treated with 13- cis-retinoic acid at a dosage of 1.5 mg/kg body weight daily over 5 weeks. Parameters for assessment of the therapeutic effect were serum thyroglobulin (TG) levels, radioiodine uptake, and tumour size prior to and after retinoid treatment. Fifty patients were evaluated for response, classified as reduction in tumour size and TG levels, stable disease or disease progression. Thirteen patients showed a clear increase in radioiodine uptake, and eight a mild increase. TG levels were unchanged or decreased in 20 patients. Tumour size was assessable in 37 patients; tumour regression was observed in six, and there was no change in 22. In total, a response was seen in 19 patients (38%). Response to retinoid therapy did not always correlate with increased radioiodine uptake, so other direct antiproliferative effects have to be assumed. The encouraging results of the study and the low rate of side-effects with good tolerability of retinoids warrant further studies with altered inclusion criteria and employment of other redifferentiating drugs or combinations of agents.

Topographic segregation and convergence of verbal, object, shape and spatial working memory in humans.

This functional magnetic resonance imaging study investigates commonalties and differences in working memory (WM) processes employing different types of stimuli. We specifically sought to characterize topographic convergence and segregation with respect to prefrontal cortex involvement using verbal, spatial, real object and shape memory items in a two-back WM task. Both the dorsolateral and ventrolateral prefrontal cortices are conjointly activated across all stimulus types. No stimulus-specific differences in the activation patterns of the prefrontal cortex could be demonstrated giving support to the view of an amodal prefrontal involvement during WM processes. However, extra-frontal regions specialized on feature processing and involved in the preprocessing of the stimuli were selectively activated by these different subtypes of WM. These selectively activated regions are assigned to parts of the ventral and dorsal stream.

Brain systems engaged in encoding and retrieval of word-pair associates independent of their imagery content or presentation modalities.

In this study, we aimed to characterize commonalities and differences of activation patterns during verbal episodic memory processes across different presentation modalities (visual or auditory) and different imagery content (low or high) of the presented verbal memory items. Twelve right-handed normal male volunteers took part in the study. Each subject underwent six O-15-butanol positron emission tomography scans. In six of the subjects the verbal material was presented visually, and in six subjects auditorily. The subjects had to encode and retrieve two sets of 12 word-pair associates of high (set 1) or low (set 2) imagery content (not semantically related). The presentation of nonsense words served as reference condition. Images were analyzed with statistical parametric mapping. Conjunction analysis was used to identify commonalities, and cognitive subtraction analysis was used to identify differences. The use of conjunction analyses enabled us to identify commonly activated regions involved in episodic encoding and retrieval of verbal material irrespective of the presentation modality or the imagery content. Our results add further evidence to recent findings that bilateral prefrontal activations are important for episodic retrieval and thus the role of the left prefrontal cortex has been underestimated during episodic retrieval. Furthermore, our results support the idea of functionally segregated areas in the prefrontal cortex. Finally, our results provide strong evidence that mesial parietal cortex (precuneus) involvement is not restricted to processes involving imagery.

[The (11C) acetate positron emission tomography in prostatic carcinoma. New prospects in metabolic imaging]. / Die [11C]Acetat-Positronenemissionstomographie beim Prostatakarzinom. Neue Perspektiven in der metabolischen Bildgebung.

The exact staging of prostate cancer is mandatory to allow selection of the appropriate primary therapy. In addition, if the PSA level rises again it is extremely important to find the site(s) of local recurrence or metastatic spread as soon as possible. However, with the morphological and metabolic imaging techniques currently available it is often not possible to answer these questions with adequate sensitivity and specificity, since small metastases < or = 1 cm in diameter are likely to remain undetected by them. In the last few years new radioactive labelled tracers have been introduced for use in positron emission tomography (PET), and it is hoped that the shortcomings in the diagnostic procedures used for prostate carcinoma might be compensated by their use. Besides 11C- or 18F-labelled choline, [11C]Acetate is also attracting attention as a promising PET tracer. In this paper we review the various PET tracers available and evaluate the advantages and the drawbacks of [11C]Acetate in three case studies by comparing [11C]Acetate-PET with histology and with other imaging techniques. The use of [11C]Acetate appears to be feasible and helpful in the diagnosis of prostate carcinoma. However, its final value relative to other imaging techniques needs further investigation, with special reference to initial lymph node involvement, early localisation of recurrence and possible noninvasive differentiation between prostate cancer, prostatis and benign hyperplasia of the prostate.

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.

3-[123I]Iodo-alpha-methyl-L-tyrosine uptake in cerebral gliomas: relationship to histological grading and prognosis.

3-[123I]Iodo-alpha-methyl-L-tyrosine (IMT) is employed clinically as a tracer of amino acid transport in brain tumours using single-photon emission tomography (SPET). This study investigates the role of IMT SPET in the non-invasive histological grading and prognostic evaluation of cerebral gliomas. The files of patients investigated by IMT SPET in our clinic between 1988 and 1996 were evaluated retrospectively. Complete follow-up was available for 58 patients with cerebral gliomas investigated by IMT SPET shortly after tumour diagnosis. Seventeen patients had low-grade gliomas (WHO grade II), 14 had anaplastic gliomas (WHO grade III) and 27 had glioblastomas (WHO grade IV). Thirty-six cases were primary tumours and 22 cases, recurrences. Maximal and mean tumour-to-brain (T/B) ratios of IMT uptake at the first IMT SPET investigation were related to histological grading and survival time. Patients with low-grade gliomas showed significantly longer survival than patients with high-grade (grade III or IV) tumours. Gliomas without contrast enhancement on computed tomography or magnetic resonance imaging scans were associated with longer patient survival than tumours with contrast enhancement. The T/B ratios of IMT SPET showed no differences in relation to histological grading [WHO grade II: 1.73+/-0.59; WHO grade III: 1.74+/-0.38; WHO grade IV: 1.59+/-0.35, (mean+/-SD, T/B ratios of mean tumour uptake)]. The median survival time of patients with a high T/B ratio on IMT SPET was not significantly different from that of patients with a low T/B ratio (T/B ratio <1.6, 14.8 months; T/B ratio > or =1.6, 13.0 months). Thus, no evidence could be found for a relationship between IMT uptake in cerebral gliomas and either histological grading or survival time. Nevertheless, IMT SPET constitutes a useful method for the detection of primary and recurrent gliomas, determination of tumour extent and individual follow-up.

High resolution SPECT in small animal research.

Single Photon Emission Computed Tomography (SPECT) is a technique used to assess physiological and biochemical processes under in vivo conditions. SPECT generates tomographic images from blood flow, glucose metabolism and receptor characteristics using radioactively labelled substances. This paper reviews the state of the art of in vivo imaging of laboratory animals in modified human and dedicated animal SPECT scanners. SPECT cameras with special collimators currently reach spatial resolutions up to 1 mm and sensitivities of about 1000 cps/MBq, allowing observation of receptor activity concentration changes in the pico-mole range. The time resolution of such cameras strongly depends on the pharmacological behaviour of the tracer and can range from several minutes to hours. Within these limits the functional characterization of many processes is possible. SPECT also offers the possibility to set up dynamic study protocols and repeated measurements of the same animal. This technique reduces the need for sacrificing animals, as was commonly practiced before the development of animal cameras. Animal SPECT gives the opportunity to monitor physiological and biochemical processes in animals in vivo, without interfering with the system under observation, and may become a valuable adjunct to the instrumentation (autoradiography, in vitro methods) of animal research.

Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study.

Studies investigating the cerebral representations of pain using functional imaging techniques failed to elucidate the affective aspects of pain. This investigation used functional magnetic resonance imaging to measure pain-related changes in cerebral activity during painful stimulation with a strong affective component. Vascular pain was induced via balloon dilatation of a dorsal foot vein of healthy volunteers. The subjects rated their perceived pain uninterruptedly during imaging, allowing cerebral activity to be correlated with both stimulus function (boxcar) and, more importantly, subjective ratings reflecting individual pain experience. The findings indicated signal increases in subcortical-limbic regions, particularly in the amygdala. This region is suggested to be involved in the affective dimension of pain.

The motion aftereffect: more than area V5/MT? Evidence from 15O-butanol PET studies.

The motion aftereffect is a perceptual phenomenon which has been extensively investigated both psychologically and physiologically. Neuroimaging techniques have recently demonstrated that area V5/MT is activated during the perception of this illusion. The aim of this study was to test the hypothesis if a more broadly distributed network of brain regions subserves the motion aftereffect. To identify the neuronal structures involved in the perception of the motion aftereffect, regional cerebral blood flow (rCBF) measurements with positron emission tomography were performed in six normal volunteers. Data were analysed using SPM96. The motion-sensitive visual areas including area V5/MT were activated in both hemispheres. Additionally, the lateral parietal cortex bilaterally, the right dorsolateral prefrontal cortex, the anterior cingulate cortex and the left cerebellum showed significant increases in rCBF values during the experience of the waterfall illusion. In a further reference condition with identical attentional demand but no perception of a motion aftereffect elevated rCBF were found in these regions as well. In conclusion, our findings support the notion that the perceptual illusion of motion arises exclusively in the motion-sensitive visual area V5/MT. In addition, a more widespread network of brain regions including the prefrontal and parietal cortex is activated during the waterfall illusion which represents a non-motion aftereffect-specific subset of brain areas but is involved in more basic attentional processing and cognition.

[Comparison of PET and fMRI activation patterns durnig declarative memory processes]. / Vergleich von PET und fMRT-Aktivierungsmustern während deklarativer Gedächtnisvorgänge.

AIM: In this study neuronal correlates of encoding and retrieval in paired association learning were compared using two different neuroimaging methods: positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). METHODS: 6 right-handed normal male volunteers took part in the study. Each subject underwent six 0-15-butanol PET scans and on fMRI study comprising four single epochs on a different day. The subjects had to learn and retrieve 12 word pairs which were visually presented (highly imaginable words, not semantically related). RESULTS: Mean recall accuracy was 93% in the PET as well as in the fMRI experiment. During encoding and retrieval we found anterior cingulate cortex activation, and bilateral prefrontal cortex activation in both imaging modalities. Furthermore, we demonstrate the importance of the precuneus in episodic memory. With PET the results demonstrate frontopolar activations whereas fMRI fails to show activations in this area probably due to susceptibility artifacts. In fMRI we found additionally parahippocampal activation and due to the whole-brain coverage cerebellar activation during encoding. The distance between the center-of-mass activations in both modalities was 7.2 +/- 6.5 mm. CONCLUSION: There is a preponderance of commonalities in the activation patterns yielded with fMRI and PET. However, there are also important differences. The decision to choose one or the other neuroimaging modality should among other aspects depend on the study design (single subject vs. group study) and the task of interest.

Functional imaging of conditioned aversive emotional responses in antisocial personality disorder.

Individuals with antisocial personality disorder (n = 12) and healthy controls (n = 12) were examined for cerebral regional activation involved in the processing of negative affect. A differential aversive classical conditioning paradigm was applied with odors as unconditioned stimuli and faces as conditioned stimuli. Functional magnetic resonance imaging (fMRI) based on echo-planar imaging was used while cerebral activity was studied during habituation, acquisition, and extinction. Individually defined cerebral regions were analyzed. Both groups indicated behavioral conditioning following subjective ratings of emotional valence to conditioned stimuli. Differential effects were found during acquisition in the amygdala and dorsolateral prefrontal cortex. Controls showed signal decreases, patients signal increases. These preliminary results revealed unexpected signal increases in cortical/subcortical areas of patients. The increases may result from an additional effort put in by these individuals to form negative emotional associations, a pattern of processing that may correspond to their characteristic deviant emotional behavior.

Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation.

We studied the effect of repetitive transcranial magnetic stimulation (rTMS) on changes in regional cerebral blood flow (rCBF) as revealed by positron emission tomography (PET) while subjects performed a 2-back verbal working memory (WM) task. rTMS to the right or left dorsolateral prefrontal cortex (DLPFC), but not to the midline frontal cortex, significantly worsened performance in the WM task while inducing significant reductions in rCBF at the stimulation site and in distant brain regions. These results for the first time demonstrate the ability of rTMS to produce temporary functional lesions in elements of a neuronal network thus changing its distributed activations and resulting in behavioral consequences.

Response of high mobility group proteins of human kidney T1 and murine L 929 cell lines to heat shock.

High mobility group (HMG) proteins in human kidney T1 and murine L 929 cells have been investigated after exposure to heat shock at 41 degrees C and their influence on the organizational change of chromatin under heat shock condition has been examined. Results reveal that the two cell lines show differential response of the HMG proteins 1 & 2 and 14 & 17 to heat shock. Neither T1 nor L 929 cells show significant differences in response to heat shock with respect to the binding affinities of HMG proteins 1 & 2 or 14 & 17 to DNA, as revealed by DNase I sensitivity and chromatin reconstitution assays. Furthermore, the HMG proteins of both the non-heat shocked and the heat shocked T1 and L 929 cells can recover their chromatin activity following reconstitution. These findings suggest that although the HMG proteins might undergo some change in response to heat shock, their inherent potential of reassociation with DNA is still retained.

Imaging and neural modelling in episodic and working memory processes.

Neuroimaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have revealed the involvement of distributed brain regions in memory processes mainly by the use of subtraction strategy based data analyses. Covariance analysis based data analysis strategies have been introduced more recently which allow functional interactions between brain regions of a neuronal network to be assessed. This contribution focuses on studies aiming to (1) establish the functional topography of episodic and working memory processes in young and old normal volunteers, (2) to assess functional interactions between modules of networks of brain regions by means of covariance based analyses and systems level modelling, (3) to characterise the temporal dynamics by the use of magnetoencephalography (MEG) and (4) to relate neuroimaging data to the underpinning neural networks. Male normal young and old volunteers without neurological or psychiatric illness participated in neuroimaging studies (PET, fMRI, MEG). Studies were approved by the ethical committee and federal authorities. Our results in young volunteers show distributed brain areas that are involved in memory processes (episodic and working memory) and show much of an overlap with respect to the network components. Systems level modelling analyses support the hypothesis of bihemispheric, asymmetric networks subserving memory processes and revealed both similarities in general and differences in the interactions between brain regions during episodic encoding and retrieval as well as working memory. Changes in memory function with ageing are evident from functional topographic studies in old volunteers activating more brain regions as compared to young volunteers. There are more and stronger influences of prefrontal regions in elderly volunteers comparing the functional models between old and young subjects. We discuss the way that the systems level models of the PET and fMRI results have implications for the underlying neural network functioning of the brain. This is done by developing simplifying assumptions, which lead from the equations describing the activities of the coupled neural modules to the systems level model equations. The resulting implications for the neural interactions are then discussed, in terms of a set of synaptically coupled neural modules. Finally, we consider how a similar analysis could be extended from the spatial to the temporal domain thus including the EEG and MEG results. The implication of preliminary MEG results presented here for the temporality arising in the interaction between the coupled neural modules in a working memory paradigm is discussed in terms of the previously developed neural network models arising from the PET and fMRI data.

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.

Neuronal correlates of encoding and retrieval in episodic memory during a paired-word association learning task: a functional magnetic resonance imaging study.

The investigation of memory function using functional magnetic resonance imaging (fMRI) is an expanding field of research. The aim of this study was to demonstrate brain-activity patterns related to a word-pair association task employing a whole-brain EPI sequence. Six right-handed, healthy male volunteers (mean age: 27.5 years) took part in the study. fMRI was performed at a field strength of 1. 5 Tesla with 26-32 slices parallel to the AC-PC line, depending on individual brain size. Distributed brain regions were activated in episodic encoding and retrieval with similarities, but also (distinct) differences in activation patterns. Bilateral prefrontal cortical areas were involved when comparing encoding as well as retrieval to the reference condition (nonsense words). Furthermore, activation was observed in cerebellar areas during encoding, and activation in bilateral parietal areas (precuneus and inferior parietal cortex) was differentially more pronounced during retrieval. The activation of left dorsomedial thalamus during retrieval of high imagery-content word-pair associates may point to the role of this structure in episodic retrieval. The direct cognitive subtraction of encoding minus retrieval yielded a differentially larger left prefrontal activation. There was a differentially higher right prefrontal activation during retrieval than during encoding, underlining the proposed right/left asymmetry for episodic memory processes.