18F-FDG-PET/CT in relapsed multiple myeloma: Are prognostic thresholds different from first-line therapy?

PURPOSE: While 18F-FDG PET/CT yields valuable prognostic information for patients in first-line therapy of multiple myeloma (MM), its prognostic relevance in relapse is not established. Available studies of relapsed MM describe prognostic thresholds for frequently used PET/CT parameters that are significantly higher than those identified in the first-line setting. The purpose of this study was to evaluate the prognostic role of PET/CT in relapsed MM, based on parameters used in the first-line setting. METHODS: Our retrospective study included 36 patients with MM who had received autologous or allogeneic stem cell transplantation, suffered at least one relapse, and underwent FDG-PET/CT at relapse. Number of focal bone lesions (FL), maximal standardised uptake value (SUVmax), and presence of PET-positive extramedullary lesions (EMD) were analysed. RESULTS: For the number of FLs, the prognostic value was demonstrated with a cut-off of > 3 (median OS 3.8 months vs. not reached, p = 0.003). Median OS of patients with SUVmax ≤ 4 was not reached, while it was 3.9 months in patients with SUVmax > 4 (p = 0.014). Presence of EMD was a significant prognostic parameter too, with median OS of 3.6 months versus not reached (p = 0.004). The above-mentioned parameters showed prognostic significance for PFS as well. Combination of higher ISS stage and PET/CT parameters identified patients with particularly short OS (3.7 months vs. not reached, p < 0.001) and PFS (3.6 vs. 11.7 months p < 0.001). CONCLUSION: The PET/CT parameters SUVmax > 4, nFL > 3, and presence of EMD identify patients with poor prognosis not only in the first-line setting but also in relapsed MM.

Prospective comparison of whole-body MRI and 68Ga-PSMA PET/CT for the detection of biochemical recurrence of prostate cancer after radical prostatectomy.

PURPOSE: To assess whole-body magnetic resonance imaging (wb-MRI) for detection of biochemical recurrence in comparison to 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) in prostate cancer (Pca) patients after radical prostatectomy. METHODS: This was a prospective trial including 28 consecutive patients (mean age 65.3 ± 9.0 years) with newly documented biochemical recurrence of Pca (mean prostate-specific antigen, PSA, 2.09 ± 1.95 ng/ml) following radical prostatectomy. All patients underwent both wb-MRI including a dedicated pelvic imaging protocol and PET/CT with 166 ± 35 MBq 68Ga-PSMA within a time window of 11 ± 10 days. PET/CT and MRI datasets were separately evaluated regarding Pca lesion count, type, localization and diagnostic confidence (three-point Likert scale, 1-3) by two nuclear medicine specialists and two radiologists, respectively. The reference standard was based on histopathological results, PSA levels following targeted salvage irradiation and follow-up imaging. Lesion-based and patient-based detection rates were compared using the chi-squared test. Differences in diagnostic confidence were assessed using the Welch test. RESULTS: A total of 56 Pca lesions were detected in 20 of the 28 patients. 68Ga-PSMA PET/CT detected 56 of 56 lesions (100%) in 20 patients (71.4%), while wb-MRI detected 13 lesions (23.2%) in 11 patients (39.3%). The higher detection rate with 68Ga-PSMA PET/CT was statistically significant on both a per-lesion basis (p < 0.001) and a per-patient basis (p = 0.0167). In 8 patients (28.6%) no relapse was detectable by either modality. All lesions detected by wb-MRI were also detected by 68Ga-PSMA PET/CT. Additionally, 68Ga-PSMA PET/CT provided superior diagnostic confidence in identifying Pca lesions (2.7 ± 0.7 vs. 2.3 ± 0.6, p = 0.044). CONCLUSION: 68Ga-PSMA PET/CT significantly out-performed wb-MRI in the detection of biochemical recurrence in Pca patients after radical prostatectomy.

DAT versus D2 receptor binding in the rat striatum: l-DOPA-induced motor activity is better predicted by reuptake than release of dopamine.

The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc.

FP-CIT- and IBZM-SPECT in Corticobasal Syndrome: Results from a Clinical Follow-Up Study.

OBJECTIVE: To evaluate the striatal presynaptic dopamine transporter (FP-CIT-SPECT) and postsynaptic D2 receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS). BACKGROUND: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available. METHODS: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration ≤4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 ± 15.2 months (mean ± SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 ± 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 ± 0.91 years; clinical follow-up: 32 ± 29.6 months) and neurologically normal control subjects (n = 19). RESULTS: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences. CONCLUSION: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding.

Neurochemical dysfunction in treated and nontreated schizophrenia - a retrospective analysis of in vivo imaging studies.

To evaluate the contribution of individual synaptic constituents, all available in vivo imaging studies on schizophrenic patients were subjected to a retrospective analysis. For the pool of drug-naïve, drug-free, and acutely medicated patients, major findings were increases in neostriatal dopamine (DA) synthesis and release and decreases in neostriatal DA transporters and D1 receptors, neostriatal, thalamic, frontal, and parietal D2 receptors, mesencephalic/pontine and temporal 5-HT1A receptors, frontal and temporal HT2A and µ-amino butyric acid (GABA)A receptors. Based on the findings on drug-naïve and drug-free patients, it may be hypothesized that schizophrenia initially is characterized by an impaired mechanism of D2 autoreceptor and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA. Neuroleptic medication blocks neostriatal D2 autoreceptor and heteroreceptors, reducing neostriatal DA and disinhibiting DA action mediated by D2 heteroreceptor binding sites. Ultimately, this may result in a restitution of GABA function, leading to a recovery of inhibitory input to the target regions of the descending corticothalamostriatal efferents. Furthermore, a blockade of inhibitory and excitatory neocortical 5-HT function may be inferred, which is likely to reduce (excitatory) DAergic input to the mesolimbic target regions of corticothalamostriatal projections.

2,5-Dimethoxy-4-iodoamphetamine and altanserin induce region-specific shifts in dopamine and serotonin metabolization pathways in the rat brain.

PURPOSE: For understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat. METHODS: Rats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography. RESULTS: DOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP. CONCLUSIONS: DOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.

5-HT1A and 5-HT2A receptor effects on recognition memory, motor/exploratory behaviors, emotionality and regional dopamine transporter binding in the rat.

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.

Boosted dopamine and blunted serotonin in Tourette syndrome - evidence from in vivo imaging studies.

The precise cortical and subcortical mechanisms of Tourette syndrome (TS) are still not fully understood. In the present retrospective analysis, adolescent and adult medication-naïve patients showed increased DA transporter (DAT) binding in nucleus caudate (CAUD), putamen (PUT) and/or whole neostriatum (NSTR). D2 receptor (R) binding and DA release were not different from controls throughout the nigrostriatal and mesolimbocortical system. When patients were medication-free (either medication-naïve or under withdrawal), DAT was still increased in PUT, but not different from controls in CAUD, NSTR and ventral striatum (VSTR). SERT was unaltered in midbrain/pons (MP), but decreased in PUT, thalamus (THAL) and hypothalamus. D2R was unaltered throughout the nigrostriatal and mesolimbocortical system, while DA release was not different from controls in PUT, CAUD and NSTR, but elevated in VSTR. 5-HT2AR binding was unaltered in neocortex and cingulate. In acutely medicated adults, DAT was unaltered in PUT, but still increased in CAUD, whereas DA release remained unaltered throughout the nigrostriatal and mesolimbocortical system. When part of the patients was acutely medicated, vesicular monoamine transporter (VMAT2), DAT, SERT and DA synthesis were not different from controls in striatal regions, whereas D2R was decreased in NSTR, THAL, frontal cortex and limbic regions. Conversely, 5-HT2AR binding was unaltered in striatal regions and THAL, but increased in neocortical and limbic areas. It may be hypothesized that both the DA surplus and the 5-HT shortage in key regions of the nigrostriatal and mesolimbic system are relevant for the bouts of motor activity and the deficiencies in inpulse control.

Monoaminergic hypo- or hyperfunction in adolescent and adult attention-deficit hyperactivity disorder?

Disturbances of dopamine (DA), serotonin (5-HT) and/or norepinephrine (NE) functions are implied in attention-deficit hyperactivity disorder (ADHD). However, the precise cortical and subcortical mechanisms are still not fully understood. In the present survey, we conducted a PUBMED search, which provided 37 in vivo investigations with PET and SPECT on 419 ADHD patients and 490 controls. The retrospective analysis revealed increased striatal DA transporter (DAT) in adolescent as well as adult medication-naïve and not acutely medicated patients. In acutely medicated adults, DAT was not different from controls. Midbrain DAT was normal in adults, but decreased in adolescents. Striatal D2 receptor (R) binding was normal in both adolescents (not acutely medicated) and adults (acutely medicated and not acutely medicated). In medication-naïve adults, DA synthesis was decreased in putamen and amygdala, but normal in the whole striatum and midbrain. In not acutely medicated adults, DA synthesis was reduced in putamen, whole striatum, prefrontal cortex, frontal cortex, amygdala and midbrain, whereas, in adolescents, no regional differences were observed. In adult (not acutely medicated) subjects, cingulate D1R was reduced. 5-HT transporter (SERT) binding was decreased in striatum and thalamus, but normal in midbrain, neocortex and limbic regions, whereas, in medication-naïve adults, SERT was diminished in striatum and midbrain, but normal in thalamus and neocortex. The findings suggest transient stages of synaptic DA shortage as well as DA surplus in individual brain regions, which elicit presynaptic as well as postsynaptic compensatory mechanisms, striving to attain functional homeostasis. Thereby, it remains a matter of debate, whether ADHD may be characterized by a general hypo- or hyperactivity of DA and/or 5-HT function.

The 5-HT1A receptor antagonist WAY-100635 decreases motor/exploratory behaviors and nigrostriatal and mesolimbocortical dopamine D2/3 receptor binding in adult rats.

Serotonin(5-HT)ergic projections run from the raphe nuclei to dopamin(DA)ergic cells in substantia nigra/ventral tegmental area (SN/VTA) and to the terminal fields of DA neurons in nucleus accumbens, caudateputamen and neocortex. In the present studies, we assessed the effect of the 5-HT1A receptor (R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarbox-amide maleate (WAY-100635) on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. D2/3R binding was determined in the same animals after systemic application of WAY-100635 (0.4 mg/kg) and 0.9% saline (SAL), respectively, with [123I]IBZM as SPECT ligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after treatment with WAY-100635 or SAL, motor/exploratory behaviors were assessed for 30 min in two different batches of animals in an open field. WAY-100635 reduced D2/3R binding in caudateputamen, thalamus, frontal cortex, parietal cortex and ventral hippocampus relative to SAL. Network analysis of regional binding data after WAY-100635 yielded positive connections between (1) caudateputamen and substantia nigra/ventral tegmental area, (2) caudateputamen and ventral hippocampus, (3) substantia nigra/ventral tegmental area and parietal cortex, (4) thalamus and dorsal hippocampus and (5) frontal cortex and parietal cortex, which were not present after SAL. Moreover, WAY-100635 decreased parameters of motor activity (overall activity, ambulation duration and frequency) but increased the duration of grooming behavior relative to SAL. The effect on exploration was time-dependent with an early increase and a subsequent decrease of behavioral parameters (rearing duration and frequency, frequency of head-shoulder motility). For WAY-100635, findings imply a region-specificity as well as a time-dependency of DAergic action.

Cognition-induced modulation of serotonin in the orbitofrontal cortex: a controlled cross-over PET study of a delayed match-to-sample task using the 5-HT2a receptor antagonist [18F]altanserin.

Behavioral and cellular studies indicate that serotonin interacting with the 5-HT2a receptor (5-HT2aR) is involved in cognitive processes supporting working memory (WM). However, 5-HT receptor neuroimaging studies directly relating WM-induced neuronal activations to concomitant changes in the availability of 5-HT receptors as a functional measure for serotonin release are lacking. This controlled cross-over PET study aimed to identify brain regions with WM-induced changes in the binding potential (BP(nd)) of the 5-HT2aR antagonist [(18)F]altanserin. Ten young males underwent a delayed match-to-sample task using photographs of faces and a control task. The BP(nd)s for both conditions were calculated by applying Ichise's noninvasive plot. Statistics were performed with the SPM toolbox statistical nonparametric mapping (SnPM3) particularly suited for analyzing whole-brain PET data in an exploratory way. A higher BP(nd) for [(18)F]altanserin during WM versus control was found in the orbitofrontal cortex (OFC) pointing towards an increased [(18)F]altanserin/5-HT2aR interaction in OFC while BP(nd) decreases during WM were not found. Furthermore, no BP(nd) changes in regions known from functional neuroimaging studies to be more specifically involved in WM were identified. These findings may suggest that the increased [(18)F]altanserin BP(nd) under WM challenge and hence the increased availability of 5-HT2aR reflects a decrease in local OFC serotonin. As the OFC plays a prominent role in decision-making and supports cognitive processes related to the central executive functions of WM it might be modulated by the serotoninergic system via the 5-HT2aR in order to support and optimize basic cognitive functions.

Pharmacological challenge and synaptic response - assessing dopaminergic function in the rat striatum with small animal single-photon emission computed tomography (SPECT) and positron emission tomography (PET).

Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3-(4'fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson's disease, Huntington's disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.

Binding of [123I]iodobenzamide to the rat D2 receptor after challenge with various doses of methylphenidate: an in vivo imaging study with dedicated small animal SPECT.

PURPOSE: The effect of various doses of methylphenidate on the binding of [(123)I]iodobenzamide ([(123)I]IBZM) to the rat D(2) receptor was assessed using small animal SPECT. METHODS: D(2) receptor binding was measured at baseline and after pretreatment with various doses of methylphenidate. For baseline and methylphenidate challenge, striatal equilibrium ratios (V(3)″) were computed as an estimation of the binding potential. RESULTS: After methylphenidate, striatal V(3)″ was 1.61 ± 0.61 (mean ± SD; 0.3 mg/kg), 0.91 ± 0.44 (3 mg/kg), 1.01 ± 0.44 (10 mg/kg), 0.91 ± 0.34 (30 mg/kg) and 0.99 ± 0.51 (60 mg/kg). Baseline values amounted to 1.73 ± 0.48, 1.32 ± 0.35, 1.50 ± 0.27, 1.82 ± 0.55 and 1.66 ± 0.41, respectively. Differences between baseline and methylphenidate were significant for the doses 3, 10, 30 and 60 mg/kg, whereas no significant difference was obtained for 0.3 mg/kg methylphenidate. Between-group differences of percentage reduction of D(2) receptor binding were only significant for the groups pretreated with 0.3 and 30 mg/kg methylphenidate, respectively. CONCLUSION: Methylphenidate between 0.3 and 60 mg/kg decreased D(2) receptor binding with a maximum reduction after 30 mg/kg. As no between-group differences were evident between the groups pretreated with 3, 10, 30 and 60 mg/kg, it may be inferred that doses ≥ 3 mg/kg were sufficient to induce maximum dopamine concentration in the synaptic cleft. Further investigations are needed in order to clarify whether the variation between subjects can be accounted for by different synaptic mechanisms at the presynaptic binding site.

Serotonergic Modulation of Nigrostriatal and Mesolimbic Dopamine and Motor/Exploratory Behaviors in the Rat.

Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brain. Altanserin (ALT) and 2,5-dimethoxy-4-iodoamphetamine (DOI) act as 5-HT2AR antagonist and agonist, respectively. In the present study, we assessed the effects of ALT and DOI on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. Methods: D2/3R binding was determined after systemic application of ALT (10 mg/kg) or DOI (0.5 mg/kg) and the respective vehicles [dimethyl sulfoxide (DMSO) and 0.9% saline (SAL)] with [123I]IBZM as a single-photon emission computed tomography (SPECT) radioligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after 5-HT2AR antagonistic or agonistic treatment, motor/exploratory behaviors were assessed for 45 (ALT) or 30 min (DOI) in an open field. Additional rats underwent behavioral measurements after injection of DMSO or SAL. Results: ALT increased D2/3R binding in the ventral hippocampus relative to vehicle, while DOI augmented D2/3R binding in caudate putamen, frontal cortex, motor cortex, and ventral hippocampus. The 5-HT2AR agonist as well as antagonist decreased parameters of motor activity and active exploration. However, ALT, in contrast to DOI, decreased explorative head-shoulder motility and increased sitting. Conclusions: The regional increases of D2/3R binding after ALT and DOI (90 and 75 min post-challenge) may be conceived to reflect decreases of synaptic DA. The reductions of motor/exploratory activities (min 1-45 and min 1-30 after challenge with ALT and DOI, respectively) contrast the regional reductions of D2/3R binding, as they indicate elevated DA levels at the time of behavioral measurements. It may be concluded that ALT and DOI modulate DA in the individual regions of the nigrostriatal and mesolimbocortical pathways differentially and in a time-dependent fashion.

Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders--results from in vivo imaging studies.

Various factors are discussed in the pathophysiology of anxiety disorders, including dysfunctions of the (DA)ergic, serotonin (5-HT)ergic and GABAergic system. We assessed the contribution of the individual synaptic constituents by subjecting all available in vivo imaging studies on patients with anxiety disorders to a retrospective analysis. On a total of 504 patients with obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder (PD), phobia, or posttraumatic stress-disorder (PTSD) and 593 controls, investigations of VMAT2, DAT, SERT, D1, D2, 5-HTIA, 5-HT2A, GABA(A), and NK1 receptor binding in neostriatum, ventral striatum, thalamus, neocortex, limbic system, cingulate, midbrain/ pons or cerebellum were performed using either PET or SPECT. Separate analyses of the individual disorders showed significant decreases of striatal D2 receptors in OCD (-18%), mesencephalic SERT in OCD (-13%), frontocortical GABAA receptors in PD (-13%) and temporocortical GABAA receptors in GAD (-16%). Pooling of all disorders yielded a significant reduction of mesencephalic SERT (-13%), mesencephalic (-27%) as well as cingulate 5-HT1A receptors (-18%), striatal D2 receptors (-21%) and frontal (-14%), temporal (-14%), occipital (-13%) and cingulate GABAA receptors (-15%). The results show that DA, 5-HT, and GABA play a major role in all subtypes of anxiety disorders. In particular, the findings imply that the regulation state of DA as modulated by GABA and 5-HT may be crucial for the development of anxiety- and compulsion-related disorders. As GABA and 5-HT inhibit DAergic neurotransmission, the reductions of GABAA, 5-HT1A and SERT can be assumed to result in an enhanced activity of the mesolimbic DAergic system. This notion is also reflected by the decrease of striatal D2 receptor binding, which is indicative of an increased availability of synaptic DA.

Increased activation of the supragenual anterior cingulate cortex during visual emotional processing in male subjects with high degrees of alexithymia: an event-related fMRI study.

BACKGROUND: One of the most prominent neurobiological models of alexithymia assumes an altered function of the anterior cingulate cortex (ACC) as the crucial neural correlate of alexithymia. So far functional imaging studies have yielded inconclusive results. Therefore, we tested this hypothesis in healthy alexithymics and nonalexithymics in an event-related fMRI study. METHODS: Thirty high- and 30 low-alexithymic right-handed male subjects (selected by the 20-item Toronto Alexithymia Scale, TAS-20) were investigated with event-related fMRI using a picture viewing paradigm. The stimuli consisted of happy, fearful and neutral facial expressions (Ekman-Friesen) as well as positive, negative and neutral pictures from the International Affective Picture System. RESULTS: Contrasting the high-alexithymic with the low-alexithymic group we observed increased activation of the supragenual ACC for different emotional valences as well as for different emotional stimuli. Moreover, there was a positive correlation of the ACC with the individual TAS-20 scores but no correlations with the individual Beck Depression Inventory scores. Additionally, there was no difference in activity of the amygdala. CONCLUSIONS: We demonstrated that the supragenual ACC is constantly activated more strongly in alexithymic subjects and that this activation is related to the symptoms of alexithymia and not to associated symptoms such as depression. Therefore, our findings support the hypothesis of an altered function of the ACC in alexithymia.

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat.

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.

Joint Imaging Platform for Federated Clinical Data Analytics.

PURPOSE: Image analysis is one of the most promising applications of artificial intelligence (AI) in health care, potentially improving prediction, diagnosis, and treatment of diseases. Although scientific advances in this area critically depend on the accessibility of large-volume and high-quality data, sharing data between institutions faces various ethical and legal constraints as well as organizational and technical obstacles. METHODS: The Joint Imaging Platform (JIP) of the German Cancer Consortium (DKTK) addresses these issues by providing federated data analysis technology in a secure and compliant way. Using the JIP, medical image data remain in the originator institutions, but analysis and AI algorithms are shared and jointly used. Common standards and interfaces to local systems ensure permanent data sovereignty of participating institutions. RESULTS: The JIP is established in the radiology and nuclear medicine departments of 10 university hospitals in Germany (DKTK partner sites). In multiple complementary use cases, we show that the platform fulfills all relevant requirements to serve as a foundation for multicenter medical imaging trials and research on large cohorts, including the harmonization and integration of data, interactive analysis, automatic analysis, federated machine learning, and extensibility and maintenance processes, which are elementary for the sustainability of such a platform. CONCLUSION: The results demonstrate the feasibility of using the JIP as a federated data analytics platform in heterogeneous clinical information technology and software landscapes, solving an important bottleneck for the application of AI to large-scale clinical imaging data.

Evidence of a modality-dependent role of the cerebellum in working memory? An fMRI study comparing verbal and abstract n-back tasks.

In working memory (WM), functional imaging studies demonstrate cerebellar involvement indicating a cognitive role of the cerebellum. These cognitive contributions were predominantly interpreted as part of the phonological loop within the Baddeley model of WM. However, those underlying investigations were performed in the context of visual verbal WM which could pose a bias when interpreting the results. The aim of this fMRI study was to address the question of whether the cerebellum supports additional aspects of WM in the context of higher cognitive functions. Furthermore, laterality effects were investigated to further disentangle the cerebellar role in the context of the phonological loop and the visuospatial sketchpad. A direct comparison of verbal and abstract visual WM was performed in 17 young volunteers by applying a 2-back paradigm and extracting the % change in BOLD signal from the fMRI data. To minimize potential verbal strategies, Attneave and Arnoult shapes of non-nameable objects were chosen for the abstract condition. The analyses revealed no significant differences in verbal vs. abstract WM. Moreover, no laterality effects were demonstrated in both verbal and abstract WM. These results provide further evidence of a broader cognitive involvement of the cerebellum in WM that is not only confined to the phonological loop but also supports central executive subfunctions. The fact that no lateralization effects are found might be attributed to the characteristics of the n-back paradigm which emphasizes central executive subfunctions over the subsidiary slave systems.

Pretreatment with haloperidol reduces (123)I-FP-CIT binding to the dopamine transporter in the rat striatum: an in vivo imaging study with a dedicated small-animal SPECT camera.

UNLABELLED: Synaptic dopamine is mainly regulated by presynaptic dopamine transporter (DAT) activity. We hypothesized that variations in synaptic dopamine are reflected by variations of DAT radioligand binding. The effect of haloperidol, which increases synaptic dopamine concentrations, was therefore assessed in the rat striatum using (123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)-nortropane ((123)I-FP-CIT) as a DAT radioligand. METHODS: Striatal (123)I-FP-CIT binding was measured in 24 rats under baseline conditions (no pretreatment) and at 1 h after injection of haloperidol or a vehicle (1 mg/kg) using a small-animal SPECT camera. RESULTS: Baseline equilibrium ratios (V(3)'') were 1.32 +/- 0.24 (mean +/- SD). After the haloperidol injection, V(3)'' decreased to 0.99 +/- 0.38 (P(2-tailed) < 0.0001), corresponding to a mean reduction of DAT binding by 25%. CONCLUSION: Our results are indicative of competition between the DAT ligand (123)I-FP-CIT and synaptic dopamine elevated by haloperidol, suggesting that the assessment of (123)I-FP-CIT binding may be suitable to study variations in synaptic dopamine in vivo.