Mardjan Raptis

In vivo evidence of deep brain stimulation-induced dopaminergic modulation in Tourette's syndrome

To the Editor: D ue to its large effect size, deep brain stimulation (DBS) is progressively considered in the treatment of medicationresistant Tourette’s syndrome (TS) (1). Nevertheless, the underlying beneficial mechanisms of DBS in TS are still a matter of debate (2,3). Treatment strategies (D2-receptor antagonists) as well as previous research results point to a dysfunction of basal gangliarelated circuits and hyperactive dopaminergic innervations (4 – 8). It might thus be hypothesized that DBS acts via modulation of dopamine transmission; however, corresponding in vivo evidence is lacking, except for one positive single-patient [F]fallypride-positron emission tomography (FP) investigation (9). In fact, FP allows for quantification of D2/3-receptor availability in striatal and extrasriatal regions within a single positron emission tomography (PET) can but requires more than 3 hours of acquisition time. Because TS atients suffer from heavy motor tics, a long-term anesthesia was ecessary during the PET scan. Encouraged by the observation of elevant FP-binding changes within the pilot-investigation, we proeeded to enlarge the number of such investigations. This investigation was approved by the local ethics committee nd the German drug safety and radiation safety authorities. Three atients (two men, one woman) (Table 1) suffering from medicaion-resistant TS were investigated. The two male patients underent prior bilateral thalamic DBS in the pallidal and nigral input egions of the thalamus (Th). The female patient (Patient 3) underent a left-sided unilateral thalamic stimulation, because the leftided intraoperative test-stimulation revealed already-complete tic uppression (detailed electrode positions) (Table 2). They all responded with substantial improvements in the Yale Global Tic Severity Scale (YGTSS) (reductions of 30%– 80%) (Table 1). The PET scans were scheduled 6 months after the surgery. For an orientating comparison with stimulation-free conditions we used FP-PET results of eight age-matched healthy subjects (seven men/ one woman; age: 19 –29 years; mean SD: 23.6 3.8). The FP-radiosynthesis has been described previously (10). Each patient experienced two PET scans (first: “stimulator-on”; second: “stimulator-off”) under general propofol/remifentanil anesthesia of 4 –5 hours in duration (3 hours: FP-scan; 1 hour: anesthesia preparation; 1 hour: latency between stimulation deactivation and ligand injection [second scan]). Control subjects were scanned without

The applicability of SRTM in [18F]fallypride PET investigations: Impact of scan durations

The high-affinity radioligand [18F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential (BPND) of the putamen, thalamus, and temporal cortex were calculated using the SRTM and the transient equilibrium model. Furthermore, receptor occupancies were calculated for AP-treated patients. Transient equilibrium in the unblocked putamen occurred after 121 ± 29.6 minutes. The transient equilibrium occurred much earlier in the extrastriatal regions or under AP treatment. Stepwise scan shortening caused BPND under-estimations of 0.58% for the first 10-minute reduction (putamen, SRTM), finally reaching 5.76% after 1 hour scan-time reduction. We observed preferential extrastriatal AP binding irrespective of the analytical method. [18F]fallypride scan durations of 180 minutes reliably reach equilibrium even in D2/3-receptor-rich regions. Moderate reductions in FP scan durations only caused small changes to SRTM results even in receptor-rich regions. Apparently, the D2/3 receptor occupancy results of APs, especially preferential extrastriatal binding observations, are not relevantly biased by inappropriate scan durations.

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas.

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-life, striatal and extrastriatal binding potentials could be determined in one single scan. Receptor occupancy was calculated as percent reduction in binding potential relative to age-matched medication-free patients suffering from schizophrenia. Quetiapine occupied 44+/-18% in the temporal cortex and 26+/-17% in the putamen, a difference significant at the level of p=0.005 (Students t test). Quetiapine showed a mean occupancy of 36+/-16% and in the thalamus. In the caudate nucleus there was an occupancy of 29+/-16% (p=0.0072). Individual occupancy levels did not exceed 59% in any of the striatal volumes of interest. The time-interval between scan and last drug ingestion did not influence the relationship between plasma concentration and central D2/3R occupancy. Taken together, quetiapine shows preferential extrastriatal binding at D2/3Rs; the extent of this difference is comparable to that previously described for clozapine. Both antipsychotics show very low affinity for D2/3Rs.

Vulnerability to psychotogenic effects of ketamine is associated with elevated D2/3-receptor availability

Previous positron emission tomography (PET) studies employing competition paradigms have shown either no change or substantial declines in striatal [(11)C]-raclopride binding after challenge with psychotogenic doses of the N-methyl-D-aspartate antagonist ketamine. We sought to probe the relationship between the severity of ketamine-induced psychotic symptoms and altered dopamine D(2/3) receptor availability throughout brain using the high affinity ligand [(18)F]-fallypride (FP). PET recordings were obtained in a group of 10 healthy, young male volunteers, in a placebo condition, and in the course of an infusion with ketamine at a psychotomimetic dose. Administration of the Positive and Negative Syndrome Scale and the Thought and Language Index in both conditions revealed a substantial emergence of mainly negative symptoms of schizophrenia, persisting until the end of the 3 h PET recordings. The baseline FP binding in cortex, caudate nucleus and other brain regions was highly predictive of the individual severity of psychotic symptoms in the ketamine condition. However, there was no evidence of ketamine-evoked reductions in FP binding. In the context of earlier findings, we speculate that high baseline D(2/3)-receptor availability may impart benefits with regard to cognitive flexibility, but increases the risk of maladaptive information processing in the face of environmental stresses and challenges.

Opiate-Induced Dopamine Release Is Modulated by Severity of Alcohol Dependence: An [18F]Fallypride Positron Emission Tomography Study

BACKGROUND Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. METHODS Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). RESULTS The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. CONCLUSIONS The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found.

Gated Myocardial Perfusion SPECT: Algorithm-Specific Influence of Reorientation on Calculation of Left Ventricular Volumes and Ejection Fraction

Gated myocardial perfusion SPECT allows calculation of end-diastolic and end-systolic volumes (EDV and ESV, respectively) and left ventricular ejection fraction (LVEF). The quantification algorithms QGS (quantitative gated SPECT), 4D-MSPECT, and CARE heart show a good correlation with cardiac MRI. Nevertheless, differences in contour finding suggest algorithm-specific effects if heart axes vary. The effect of tilting heart axes on gated SPECT was quantified as a possible source of error. Methods: Sixty men underwent gated SPECT (450 MBq of 99mTc-tetrofosmin or sestamibi, 8 gates/cycle). After correct reorientation (R0), datasets were tilted by 5°, 10°, 15°, 20°, 30°, and 45° along both long axes (R5, R10, R15, R20, R30, and R45, respectively). EDV, ESV, and LVEF were calculated using QGS, 4D-MSPECT, and CARE heart. Because a 15° tilt could be a maximum possible misreorientation in routine, R0 and R15 results were analyzed in detail. Absolute-difference values between results of tilted and correctly reoriented datasets were calculated for all tilts and algorithms. Results: QGS and CARE heart succeeded for R0 and R15 in all cases, whereas 4D-MSPECT failed to find the basal plane in 1 case (patient B). R2 values between paired R15/R0 results were 0.992 (QGS), 0.796 (4D-MSPECT; R2 = 0.919 in n = 59 after exclusion of the failed case), and 0.916 (CARE heart) for EDV; 0.994 (QGS), 0.852 (4D-MSPECT; R2 = 0.906 in n = 59), and 0.899 (CARE heart) for ESV; and 0.988 (QGS), 0.814 (4D-MSPECT; R2 = 0.810 in n = 59), and 0.746 (CARE heart) for LVEF. Concerning all levels of misreorientation, 1 patient was excluded for all algorithms because of multiple problems in contour finding; additionally for 4D-MSPECT patient B was excluded. In the 45° group, QGS succeeded in 58 of 59 cases, 4D-MSPECT in 58 of 58, and CARE heart in 33 of 59. Mean absolute differences for EDV ranged from 5.1 ± 4.1 to 12.8 ± 10.5 mL for QGS, from 6.7 ± 6.3 to 34.2 ± 20.7 mL for 4D-MSPECT, and from 5.4 ± 5.6 to 25.2 ± 16.1 mL for CARE heart (tilts between 5° and 45°). Mean absolute differences for ESV ranged from 4.1 ± 3.7 to 8.0 ± 9.4 mL for QGS, from 5.6 ± 8.0 to 10.0 ± 10.5 mL for 4D-MSPECT, and from 5.4 ± 5.6 to 25.5 ± 16.1 mL for CARE heart. Mean absolute differences for LVEF ranged from 1.1% ± 1.0% to 2.2% ± 1.8% for QGS, from 4.0% ± 3.5% to 8.0% ± 7.1% for 4D-MSPECT, and from 3.4% ± 2.9% to 9.2% ± 6.0% for CARE heart. Conclusion: Despite tilted heart axes, QGS showed stable results even when using tilts up to 45°. 4D-MSPECT and CARE heart results varied with reorientation of the heart axis, implying that published validation results apply to correctly reoriented data only.

Acute and chronic effects of bithalamic deep brain stimulation on dopaminergic transmission

Deep brain stimulation (DBS) in Tourettes syndrome (GTS) is one of the few accepted surgical treatment options in psychiatry. However, the choice of target areas and stimulation parameters are principally based on empirical knowledge because the underlying physiological principles of DBS are not entirely understood, yet. To this end, we performed an [18F]fallypride positron-emission tomography investigation (FP-PET) in order to elucidate DBS-effects on dopamine transmission. Two patients suffering from treatment resistant GTS (age: both 22 years) underwent bithalamical (mediodorsal nuclei) DBS approximately 6 months before the PET-scans. Both of the patients improved significantly in their symptomatology. We performed two PET scan using the high-affinity D2/3-receptor ligand [18F]fallypride (FP): the first scan under stimulator-“on”, the second scan under “off”-conditions (electrodes turned off 1 h before tracer injection). The scans necessarily had to be performed under anesthesia (propofol/remifentanil) in order to avoid tics during the 4 h of acquisition. Time–activity curves have been obtained after anatomical coregistration and normalization using our standard VOI-template. BP(nd) calculation was performed according to the simplified reference tissue (SRTM) model using the cerebellum as reference region. In both patients we found region-specific reductions of FP-BP(nd): in the medial thalamus VOI, BP(nd)reductions ranged from 6 to 16% indicating an increased dopaminergic transmission during “off”-conditions. Conversely, in the putamen the BP(nd) increased from “on” to “off” conditions in a range from 4 to 6%. In other regions we found only little or inconsistent changes in BP(nd)s. Interestingly, the receptor availability under both conditions was much higher than in a group of age-matched control subjects (+80 and +94% in the thalamus). The binding equilibrium was reached in all scans for all regions within the 3 h of acquisition. The region-specific reduction of BP(nd) values during “off” conditions suggests a strong increase of dopamine release. This, inversely, points to an inhibition of thalamic dopamine transmission by DBS. Due to the highly experimental therapeutic approach, we have not been able to investigate a suitable number of patients for statistical analysis. The much higher FP-BP(nd) values in DBS-GTS patients suggests an upregulation of central D2/3-receptor as a counterregulative effect after prolonged DBS. That might explain the slow process of recurrence of symptoms after DBS-surgery.

Quantitative myocardial perfusion-SPECT: algorithm-specific influence of reorientation on calculation of summed stress score.

Purpose Myocardial perfusion SPECT (MPS) with software-assisted determination of summed stress score (SSS) is of established importance for diagnosis/therapy planning in coronary artery disease. Differences in contour finding suggest algorithm-specific influence on quantification if heart axes are chosen incorrectly. Thus, this study quantified the influence of heart-axis tilt on SSS calculation using Quantitative Perfusion SPECT and 4D-MSPECT. Patients and Methods Stress MPS of 50 men acquired on a triple-head gamma camera were correctly reoriented by experienced technologists (R0) and then tilted by 5 degrees/10 degrees/15 degrees/20 degrees/30 degrees/45 degrees along both long axes (R5–R45). SPECT images were quantified for SSS using QPS and 4D-MSPECT. SSS values for R0 and R5–R45 were analyzed using correlation analysis. Weighted kappa values (&kgr;) were calculated to measure agreement regarding perfusion abnormality severity (4-step SSS rating: 0–3, 4–8, 9–13, and ≥14). Results For QPS SSS correlation, R0 vs. tilted datasets remained very high (R2 > 0.97) up to 20 degrees, but degraded for higher tilts (R2 = 0.895/0.780 for 30 degrees/45 degrees). 4D-MSPECT showed comparable SSS correlation only up to 10 degrees (R2 > 0.95) and strong deterioration thereafter (R2 = 0.863–0.347 for 15–45 degrees). Deviation in severity class from R0 increased from 6/50 (R5; &kgr; = 0.914) to 25/50 (R45; &kgr; = 0.252) using QPS and from 7/50 (R5; &kgr; = 0.899) to 33/50 (R45; &kgr; = 0.065) using 4D-MSPECT. Conclusion For tilted MPS datasets, considerable differences in SSS calculation emerge using QPS and 4D-MSPECT. QPS showed more stable results than 4D-MSPECT.

Changes in D2/D3-receptor availability in detoxified patients with alcohol addiction compared to healthy subjects - a PET study with [18F]fallypride

This journal supplement has title: Abstracts from the XXVII CINP Congress, Hong Kong, 6–10 June 2010Abstract from the XXVII CINP Congress, 6-10 June 2010, Hong KongAbstract from the XXVII CINP Congress, 6-10 June 2010, Hong Kong