Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study

IntroductionTranscranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) – a Dopamine receptor-antagonist – the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured.Methods23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen).ResultsVerum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session.ConclusionResults suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression

Dose-escalation using intensity-modulated radiotherapy for prostate cancer - evaluation of quality of life with and without 18F-choline PET-CT detected simultaneous integrated boost

<p>Abstract</p> <p>Background</p> <p>In comparison to the conventional whole-prostate dose escalation, an integrated boost to the macroscopic malignant lesion might potentially improve tumor control rates without increasing toxicity. Quality of life after radiotherapy (RT) with vs. without ¹⁸F-choline PET-CT detected simultaneous integrated boost (SIB) was prospectively evaluated in this study.</p> <p>Methods</p> <p>Whole body image acquisition in supine patient position followed 1 h after injection of 178-355MBq ¹⁸F-choline. SIB was defined by a tumor-to-background uptake value ratio > 2 (GTV_PET). A dose of 76Gy was prescribed to the prostate (PTV_prostate) in 2Gy fractions, with or without SIB up to 80Gy. Patients treated with (n = 46) vs. without (n = 21) SIB were surveyed prospectively before (A), at the last day of RT (B) and a median time of two (C) and 19 month (D) after RT to compare QoL changes applying a validated questionnaire (EPIC - expanded prostate cancer index composite).</p> <p>Results</p> <p>With a median cut-off standard uptake value (SUV) of 3, a median GTV_PETof 4.0 cm³and PTV_boost(GTV_PETwith margins) of 17.3 cm³was defined. No significant differences were found for patients treated with vs. without SIB regarding urinary and bowel QoL changes at times B, C and D (mean differences ≤3 points for all comparisons). Significantly decreasing acute urinary and bowel score changes (mean changes > 5 points in comparison to baseline level at time A) were found for patients with and without SIB. However, long-term urinary and bowel QoL (time D) did not differ relative to baseline levels - with mean urinary and bowel function score changes < 3 points in both groups (median changes = 0 points). Only sexual function scores decreased significantly (> 5 points) at time D.</p> <p>Conclusions</p> <p>Treatment planning with ¹⁸F-choline PET-CT allows a dose escalation to a macroscopic intraprostatic lesion without significantly increasing toxicity.</p

Simulation-based partial volume correction for dopaminergic PET imaging: Impact of segmentation accuracy

AimPartial volume correction (PVC) is an essential step for quantitative positron emission tomography (PET). In the present study, PVELab, a freely available software, is evaluated for PVC in 18F-FDOPA brain-PET, with a special focus on the accuracy degradation introduced by various MR-based segmentation approaches.MethodsFour PVC algorithms (M-PVC; MG-PVC; mMG-PVC; and R-PVC) were analyzed on simulated 18F-FDOPA brain-PET images. MR image segmentation was carried out using FSL (FMRIB Software Library) and SPM (Statistical Parametric Mapping) packages, including additional adaptation for subcortical regions (SPML). Different PVC and segmentation combinations were compared with respect to deviations in regional activity values and time-activity curves (TACs) of the occipital cortex (OCC), caudate nucleus (CN), and putamen (PUT). Additionally, the PVC impact on the determination of the influx constant (Ki) was assessed.ResultsMain differences between tissue-maps returned by three segmentation algorithms were found in the subcortical region, especially at PUT. Average misclassification errors in combination with volume reduction was found to be lowest for SPML (PUT 70%). Accurate recovery of activity data at OCC is achieved by M-PVC (apparent recovery coefficient varies between 0.99 and 1.10). The other three evaluated PVC algorithms have demonstrated to be more suitable for subcortical regions with MG-PVC and mMG-PVC being less prone to the largest tissue misclassification error simulated in this study. Except for M-PVC, quantification accuracy of Ki for CN and PUT was clearly improved by PVC.ConclusionsThe regional activity value of PUT was appreciably overcorrected by most of the PVC approaches employing FSL or SPM segmentation, revealing the importance of accurate MR image segmentation for the presented PVC framework. The selection of a PVC approach should be adapted to the anatomical structure of interest. Caution is recommended in subsequent interpretation of Ki values. The possible different change of activity concentrations due to PVC in both target and reference regions tends to alter the corresponding TACs, introducing bias to Ki determination. The accuracy of quantitative analysis was improved by PVC but at the expense of precision reduction, indicating the potential impropriety of applying the presented framework for group comparison studies

Comparison of automatic versus manual procedures for the quantification of dopamine D2 receptor availability using I-123-IBZM-SPECT

Introduction I-123-IBZM-SPECT is often used to differentiate between idiopathic Parkinson's syndrome and atypical parkinsonian syndromes. The aim of this study was to compare three different procedures to quantify the receptor availability of striatal dopamine D2 receptors. (a) Manual quantification performed using individually adjusted volume of interests sets (mVoi). (b) Automatic quantification applying the commercially available Hermes BRASS software (BRASS). (c) Automatic quantification applying the open-source software IBZM Toolbox (TBX).Materials and methods Using the three methods, we analyzed 100 scans. For the mVOI methods, three different investigators (two experienced, one inexperienced) carried out the analysis. We compared the different methods with each other and with the reference standard established by clinical follow-up. The diagnostic performance was assessed by calculating receiver-operating characteristic (ROC) curves.Results Correlation analyses resulted in the following: mVOI versus BRASS (r(2)=0.694) (P&lt;0.005), mVOI versus TBX (r(2)=0.557) (P&lt;0.005); BRASS versus TBX (r(2)=0.466) (P&lt;0.005). We found a fair agreement for mVOI versus BRASS; slight agreement for mVOI versus TBX; and fair agreement for BRASS versus TBX. Moreover, we found a substantial agreement between the experienced investigators, but not with the inexperienced investigator in the case of mVOI. The ROC analysis shows the largest area under the ROC curve (Az=0.7295) for mVOI, followed by BRASS (Az=0.709) and TBX (Az=0.627).Conclusion In direct comparison, the manual quantification used by experienced observers shows the best results, although it does not differ significantly from the commercial Hermes BRASS software. Both are superior to TBX. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved

The reconstruction algorithm used for [68Ga]PSMA-HBED-CC PET/CT reconstruction significantly influences the number of detected lymph node metastases and coeliac ganglia

To investigate whether the numbers of lymph node metastases and coeliac ganglia delineated on [Ga-68]PSMA-HBED-CC PET/CT scans differ among datasets generated using different reconstruction algorithms.Data were constructed using the BLOB-OS-TF, BLOB-OS and 3D-RAMLA algorithms. All reconstructions were assessed by two nuclear medicine physicians for the number of pelvic/paraaortal lymph node metastases as well the number of coeliac ganglia. Standardized uptake values (SUV) were also calculated in different regions.At least one [Ga-68]PSMA-HBED-CC PET/CT-positive pelvic or paraaortal lymph node metastasis was found in 49 and 35 patients using the BLOB-OS-TF algorithm, in 42 and 33 patients using the BLOB-OS algorithm, and in 41 and 31 patients using the 3D-RAMLA algorithm, respectively, and a positive ganglion was found in 92, 59 and 24 of 100 patients using the three algorithms, respectively. Quantitatively, the SUVmean and SUVmax were significantly higher with the BLOB-OS algorithm than with either the BLOB-OS-TF or the 3D-RAMLA algorithm in all measured regions (p &lt;0.001 for all comparisons). The differences between the SUVs with the BLOB-OS-TF- and 3D-RAMLA algorithms were not significant in the aorta (SUVmean, p = 0.93; SUVmax, p = 0.97) but were significant in all other regions (p &lt;0.001 in all cases). The SUVmean ganglion/gluteus ratio was significantly higher with the BLOB-OS-TF algorithm than with either the BLOB-OS or the 3D-RAMLA algorithm and was significantly higher with the BLOB-OS than with the 3D-RAMLA algorithm (p &lt;0.001 in all cases).The results of [Ga-68]PSMA-HBED-CC PET/CT are affected by the reconstruction algorithm used. The highest number of lesions and physiological structures will be visualized using a modern algorithm employing time-of-flight information.</p

Multistage Passive and Active Delivery of Radiolabeled Nanogels for Superior Tumor Penetration Efficiency

Development of nanosized drug delivery systems in cancer therapy is directed toward improving tumor selectivity and minimizing damages of healthy tissue. We introduce a delivery system with synergistic optimization and combination of passive and active targeting strategies. The approach is based on radiopeptide labeled redox sensitive hydrophilic nanogels, which exploit passive targeting by the enhanced permeability and retention effect while avoiding elimination by the mononuclear phagocyte system and fast hepatic and renal clearance. The targeting peptide promotes endocytotic uptake of the nanogels by cancer cells. Specific to this delivery system, tumor-specific degradation by the antioxidant glutathione enhances penetration and retention within the tumor tissue. Using in vivo molecular imaging we demonstrate the superiority of combined passive and active targeting with down-sizable nanogels over exclusive passive targeting. Furthermore, the homogeneous tumor distribution of functionalized nanogels compared to the clinically used mere radiopeptide supports the potentially high impact of our targeting concept