Three-Dimensional Atlas System for Mouse and Rat Brain Imaging Data

Tomographic neuroimaging techniques allow visualization of functionally and structurally specific signals in the mouse and rat brain. The interpretation of the image data relies on accurate determination of anatomical location, which is frequently obstructed by the lack of structural information in the data sets. Positron emission tomography (PET) generally yields images with low spatial resolution and little structural contrast, and many experimental magnetic resonance imaging (MRI) paradigms give specific signal enhancements but often limited anatomical information. Side-by-side comparison of image data with conventional atlas diagram is hampered by the 2-D format of the atlases, and by the lack of an analytical environment for accumulation of data and integrative analyses. We here present a method for reconstructing 3-D atlases from digital 2-D atlas diagrams, and exemplify 3-D atlas-based analysis of PET and MRI data. The reconstruction procedure is based on two seminal mouse and brain atlases, but is applicable to any stereotaxic atlas. Currently, 30 mouse brain structures and 60 rat brain structures have been reconstructed. To exploit the 3-D atlas models, we have developed a multi-platform atlas tool (available via The Rodent Workbench, http://rbwb.org) which allows combined visualization of experimental image data within the 3-D atlas space together with 3-D viewing and user-defined slicing of selected atlas structures. The tool presented facilitates assignment of location and comparative analysis of signal location in tomographic images with low structural contrast

Experiences from Introducing Standardized High Dose 131I-mIBG Treatment of Children with Refractory Neuroblastoma: Differences in Effective Dose to Patients and Exposure to Caregivers

Aims: High dose 131I-meta iodobenzylguanidine (131I-mIBG) combined with radiosensitizing topotecan and peripheral blood stem cell support is a promising treatment regimen for children with neuroblastoma (NB). Here we present our first experiences, with particular focus on in vivo whole-body dosimetry and radiation exposure to family caregivers and hospital staff. Methods: Five children with relapsed or refractory NB were treated during 2012-2014. 131I-mIBG was administered in two fractions at two weeks apart, aiming for a total whole-body radiation-absorbed dose of 4 Gy. The 131I-mIBG activity for the 2nd administration was calculated on the basis of the measured whole-body dose following the 1st administration. Patients were isolated in a lead-shielded room, and all caregivers and staff received radiation safety training, and carried an electronic personal dosimeter. Results: The total administered activity ranged from 5.1 to 28.6 GBq (median: 22.9 GBq), resulting in effective whole-body doses ranging from 2.1 to 4.3 Gy (median: 3.8 Gy). Two out of five patients deviated from the anticipated dose exposure defined by the treatment protocol; one patient received 4.3 Gy after a single administration, and for one patient the total whole-body dose was lower than anticipated (2.1 Gy). Radiation dose to family caregivers ranged from 0.1 to 8.0 mSv. For staff members, the overall radiation dose was low, and provided no concern regarding personal dosimetry. Conclusion: High-dose 131I-mIBG treatment of children with NB has been successfully established at our institution. Radiation doses to caregivers and hospital staff are acceptable and in compliance with national and international guidelines. Two out of five patients deviated from the anticipated dose exposure, hence, accurate dosimetry-guidance during administration of high dose 131I-mIBG treatment is necessary

Morphine reduced perceived anger from neutral and implicit emotional expressions

The μ-opioid system modulates responses to pain and psychosocial stress and mediates non-social and social reward. In humans, the μ-opioid agonist morphine can increase overt attention to the eye-region and visual exploration of faces with neutral expressions. However, little is known about how the human μ-opioid system influences sensitivity to and appraisal of subtle and explicit cues of social threats and reward. Here, we examined the effects of selective μ-opioid stimulation on perception of anger and happiness in faces with explicit, neutral or implicit emotion expressions. Sixty-three healthy adults (32 females) attended two sessions where they received either placebo or 10 mg per oral morphine in randomised order under double-blind conditions. Based on the known μ-opioid reduction of pain and discomfort, as well as reports suggesting that the non-specific partial agonist buprenorphine or the non-specific antagonist naltrexone affect appraisal of social emotional stimuli, we hypothesised that morphine would reduce threat sensitivity and enhance perception of happy facial expressions. While overall perception of others’ happiness was unaffected by morphine treatment, morphine reduced perception of anger in stimuli with neutral and implicit expressions without affecting perception of explicit anger. This effect was statistically unrelated to gender, subjective drug effects, mood and autism trait measures. The finding that a low dose of μ-agonist reduced the propensity to perceive anger in photos with subtle facial expressions is consistent with the notion that μ-opioids mediate social confidence and reduce sensitivity to threat cues

Discovery of a Lead Brain‐Penetrating Gonadotropin‐Releasing Hormone Receptor Antagonist with Saturable Binding in Brain

We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [125l]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain

Discovery of a lead brain-penetrating gonadotropin-releasing hormone receptor antagonist with saturable binding in brain

We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [125l]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain

Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent C-11-raclopride positron emission tomography and functional magnetic resonance imaging investigation

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the corticostriatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and C-11-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and C-11-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.Funding Agencies|Weston Havens Foundation</p