Infrared thermography and behavioral biometrics associated with estrus indicators and ovulation in estrus-synchronized dairy cows housed in tiestalls.

Most Canadian dairy herds operate in tiestall housing (61%), where average estrus detection rates may be lower than 54%. The objective of this study was to evaluate infrared thermography and behavioral biometrics as indicators of estrus in dairy cows. Eighteen cyclic multiparous cows (Synch) were subjected to an estrus synchronization protocol, and 18 pregnant cows (control) received a sham protocol on the same schedule and frequency as the cyclic cow treatment. A decline in plasma concentrations of progesterone and the appearance of a dominant follicle using transrectal ultrasonography were used as indirect indicators of estrus, and the disappearance of a dominant follicle was used to confirm ovulation. All cows were monitored via visual cameras to determine the frequency of treading, drinking, neighbor interaction, tail movement, lying, and shifting behaviors. Infrared thermograms were recorded at the eye, muzzle, cheek, neck, front right foot, front left foot, rump, flank, vulva area, tail head, and withers. To evaluate the accuracy of behavioral and thermal parameters, a predefined minimum acceptable value (i.e., threshold) for estrus alerts (>0.30 Youden J index and >0.60 area under the curve) was used. Ovulation was confirmed in 14 (77.7%) out of 18 Synch cows. Eye, cheek, neck, rump, flank, vulva area, and wither thermograms exhibited higher temperatures at 48 h [cycle threshold (Δt) = +0.30 to 1.20°C] and 24 h before ovulation compared with 4 d prior to ovulation (Δt = 0.06 to 0.11°C) and during ovulation day (Δt = 0.03 to 0.32°C) in the Synch group. In addition, control cows exhibited greater treading activity per day compared with Synch cows (20.84 ± 0.39 vs. 16.35 events/5 min ± 0.34), and tail movement frequency was greater in Synch cows compared with control cows (14.84 ± 2.7 vs. 10.11 ± 4.7 events/5 min). However, within Synch cows, tail movement was the only behavior that significantly increased in frequency 2 d before ovulation (11.81 ± 1.71 events/5 min) followed by a decrease in frequency 1 d before ovulation (4.67 ± 1.05 events/5 min) compared with ovulation day (0 d; 6.10 ± 1.25 events/5 min) and during luteolysis (3 d before ovulation; 6.01 ± 1.25 events/5 min). Upon evaluation of all variables (thermograms and behavior frequencies) as estrus indicators at 48 and 24 h before ovulation, treading and tail movements before milking and 9 thermal locations satisfied the predefined minimum acceptable value for estrus alerts. This study demonstrates that fluctuations in radiated temperature measured at specific anatomical locations and the frequency of tail movements and treading behaviors can be used as a noninvasive estrus alerts in multiparous cows housed in a tiestall system.

Use of fidget and drinking behaviour in combination with facial infrared thermography for diagnosis of bovine respiratory disease in a spontaneous model.

Bovine respiratory disease (BRD) is a highly prevalent multi pathogen infectious disease (70-80%) in newly received feedlot cattle, causing significant economic losses and reduced animal welfare. Current BRD diagnosis involves stressful and invasive methods that can increase the incidence and transmission of BRD. An alternative is the use of an automated infrared thermography (IR) platform that can monitor facial temperature and behaviour traits to diagnose BRD in a non-invasive manner. The objective of this study was to investigate the use of fidget and drinking behaviours in conjunction with facial temperature as method of BRD diagnosis in beef calves. Sixty-five weaned calves (N = 65) were monitored over a 21-d period after 6 h transportation to predispose calves to BRD infection. Data collected from an automated IR platform placed at a water station included the number of IR frames during drinking (Fidget), number of drinking visits (Drinking bouts), total drinking duration, average drinking duration, average cheek temperature (AVG temp), and maximum orbital temperature (Max temp). Fidget, drinking behaviours, and IR were compared to a clinical score assessment based on respiratory, digestive, and lethargy signs (visual observation) and haematology analysis using a receiver operating characteristics curve analysis to identify the accuracy of each metric and combinations of metrics for BRD diagnosis. The greater accuracies observed were Fidget, Youden's index (J): 0.25 J), Drinking bout (0.28 J), and Total drinking duration (0.22 J). The average IR temperature accuracy resulted in 0.88 J and Max temp 0.77 J. Thirty-five combinations of drinking behaviour and facial IR metrics were evaluated to identify BRD calves. Optimum accuracy (100%) was achieved when combining Fidget, Drinking bout, Average drinking duration, AVG temp, and Max temp 1.00 J. Similar evaluations were performed at 48 and 24 h before d 0 using the most accurate Fidget, Drinking behaviour, and IR combination, resulting in 0.44 J 48 h prior to d 0 and 0.45 J 24 h prior to d 0. Combining fidget and drinking behaviour metrics increased the sensitivity to detect the onset of BRD infection and the specificity to discriminate true positive BRD calves from true negative BRD calves.

Business analysis of IRT, Visual observation, and Ovsynch as breeding strategies in Alberta dairies.

The dairy industry is searching for new technologies to address low (<50%) estrus detection. However, the lack of information on the potential economic benefits regarding new technology implementation has led some dairy producers to continue using conventional estrus detection methods (e.g. visual observation of standing to be mounted). The objective of this study was to compare the costs of infrared thermography (IRT), visual observation (VO) and ovulation synchronization (Ovsynch: OVS) as breeding strategies at different accuracy levels (Sensitivity [Se], Specificity [Sp]) and pregnancy rates (PR). The costs associated with Breeding, Feeding, Operation Costs, Return to Equity and Culling Risk per estrus detection rate (ER; 30-100%, conception rate for OVS; 30-100%), PR [PR per Parity group; 1-2 (50%), 3-4 (43%), and >4 (41%)], and ER accuracy determined the potential financial benefit of each breeding method for a representative farm. Breeding Cost results (Canadian dollars per cow; CAD/cow) showed a higher cost of OVS (138.99) as compared to VO (115.78) and IRT (127.69). Pregnancy Costs were affected by Breeding Cost; however, ER had a significant effect on PR expense for each method, IRT (ER; 30%: 210.38; 100%: 132.19), VO (ER; 30%: 205.93; 100%: 129.39), and OVS (ER; 30%: 247.21; 100%: 155.33). The minimum Se level with a positive Financial Effect for IRT and VO was 60% with a Sp of 100%, and for the OVS was Se 65% and Sp 100%. However, when the Se was 100% a positive Financial Effect was observed with a minimum Sp of 85% for IRT and 75% for VO. Culling Risk was reduced if ER increases differently depending on the parity group. Implementing of IRT as an estrus detection method yields a competitive breeding cost compared to VO and OVS. Further, breeding methods must accomplish at least ∼60% accuracy to have a positive net return.

Evaluating automated infrared thermography and vulva exposure tracking as components of an estrus detection platform in a commercial dairy herd.

The primary objective of this study was to develop an automated infrared thermography platform (Estrus BenchMark) capable of measuring skin temperature and tail movements as a means of identifying cows in estrus. The secondary objective was to evaluate the accuracy of Estrus BenchMark to detect estrus compared to in-line milk progesterone (P4) analysis (Herd Navigator System) in a commercial dairy herd managed under a robotic milking system. Data were collected on forty-six cows from 45 to 120 d after calving. Cows were flagged in estrus when milk P4 fell below 5 ng/mL. The Estrus BenchMark true positive estrus alerts (Sensitivity; Se%) were compared to Herd Navigator System estrus alerts at different time-windows (±12 h, ±24 h, ±48 h, and ±72 h) relative to the Estrus BenchMark estrus alerts for all the estrus alerts (AE) and confidence-quality estrus (CQE; >80% quality) alerts identified by Herd Navigator System. The Estrus BenchMark captured skin temperature and tail movements resulting in vulva exposure (left tail movements, LTail; right tail movements, RTail; and pooled tail movements, PTail) for each milking event. Skin temperature tended to increase when the milk P4 concentration (Least-Squares Means ±â€¯SE) dropped for AE (estrus day [d 0]; P4; 3.51 ±â€¯0.05 ng/mL, Skin temperature; 33.31 ±â€¯2.38 °C) compared with d -7 (P4; 20.22 ±â€¯0.73 ng/mL; Skin temperature: 32.05 ±â€¯3.77 °C). The increase in skin temperature, however, was significant in cows with CQE > 80% at d 0 (32.75 ±â€¯0.29 °C) compared to d -7 (31.80 ±â€¯0.28 °C). The prevalence of tail movements to expose vulva was greater (P = 0.01) in AE at d 0 (LTail: 62.50%; PTail; 68.75%; and RTail: 56.25%) compared with d -7 (LTail: 18.75%; PTail: 9.37%: and RTail: 9.37%), and d +4 (LTail: 9.37%; PTail: 9.37%; and RTail: 12.5%). Moreover, the higher prevalence of tail movements at d 0 was observed in cows with CQE > 80% (LTail; 65%, PTail; 80%, and RTail; 70%) compared to those with CQE < 80%. The highest Estrus BenchMark Youden index (YJ; 0.45), diagnostic odds ratio (DOR; 9.04), and Efficiency (0.77) were achieved for AE in a ±48 h window and at ±72 h window for CQE (YJ; 0.66, DOR; 25.29, and Efficiency 0.76) relative to Herd Navigator System estrus alerts. The highest Estrus BenchMark resulted in 58% estrus detection rates for AE and 80% for cows with CQE compared to the Herd Navigator System.

Evaluation of infrared thermography combined with behavioral biometrics for estrus detection in naturally cycling dairy cows.

Low estrus detection rates (>50%) are associated to extended calving intervals, low economic profit and reduced longevity in Holstein dairy cows. The objective of this study was to evaluate the accuracy of infrared thermography and behavioral biometrics combined as potential estrus alerts in naturally (not induced) cycling dairy cows housed in a tie-stall barn. Eighteen first lactation cows were subjected to transrectal ultrasonography to determine spontaneous ovulation. The dominant follicle (DF) disappearance was used retrospectively as an indirect indicator of ovulation, and to establish the estrus period (48-24 h prior the DF disappearance). Raw skin temperature (Raw IR) and residual skin temperature (Res IR) were recorded using an infrared camera at the Vulva area with the tail (Vtail), Vulva area without the tail (Vnotail), and Vulva's external lips (Vlips) at AM and PM milking from Day 14 until two days after ovulation was confirmed. Behavioral biometrics were recorded on the same schedule as infrared scan. Behavioral biometrics included large hip movements (L-hip), small hip movements (S-hip), large tail movements and small tail movements to compare behavioral changes between estrus and nonestrus periods. Significant increases in Raw IR skin temperature were observed two days prior to ovulation (Vtail; 35.93 ±â€¯0.27 °C, Vnotail; 35.59 ±â€¯0.27 °C, and Vlips; 35.35 ±â€¯0.27 °C) compared to d -5 (Proestrus; Vtail; 35.29 ±â€¯0.27 °C, Vnotail; 34.93 ±â€¯0.31 °C, and Vlips; 34.68 ±â€¯0.27 °C). No significant changes were found for behavioral parameters with the exception of S-hip movements, which increased at two days before ovulation (d -2; 11.13 ±â€¯1.44 Events/5min) compared to d -5 (7.30 ±â€¯1.02 Events/5min). To evaluate the accuracy of thermal and behavioral biometrics, receiver operating characteristic curve analysis was performed using Youden index (YJ), diagnostic odds ratio, positive likelihood ratio (LR+), Sensitivity, Specificity and Positive predicted value to score the estrus alerts. The greatest accuracy achieved using thermal parameters was for Res IR Vtail PM (YJ = 0.34) and L-hip PM (YJ = 0.27) for behavioral biometrics. Combining thermal and behavioral parameters did not improve the YJ index score but reduced the false-positive occurrence observed by increasing the diagnostic odds ratio (26.62), LR+ (12.47), Specificity (0.97) and positive predicted value (0.90) in a Res IR Vtail PM, S-hip AM, S-hip PM combination. The combination of thermal and behavioral parameters increased the accuracy of estrus detection compared to either thermal or behavioral biometrics, independently in naturally cycling cows during milking.

Evidence for endogenous opioid release in the amygdala during positive emotion.

Endogenous opioid release has been linked to relief from aversive emotional memories, thereby promoting a euphoric state and subsequent interactions towards social stimuli resulting in the formation of social preferences. However, this theory remains controversial. Using positron emission tomography and [(11)C]diprenorphine (DPN) in healthy volunteers, we found significantly reduced DPN binding to opioid receptor in the hippocampus during positive mood induction compared to neutral mood. Furthermore, the magnitude of positive mood change correlated negatively with DPN binding in the amygdala bilaterally. Our finding of reduced DPN binding is consistent with increased release of endogenous opioids, providing direct evidence that localised release of endogenous opioids is involved in the regulation of positive emotion in humans.

Effects of feeding frequency of an elevated plane of milk replacer and calf age on behavior, and glucose and insulin kinetics in male Holstein calves.

Optimizing feeding regimens in early life to maximize lifelong growth and production are essential in the dairy industry. This study investigated the effects of milk replacer (MR) feeding frequency and calf age on behavior, and glucose and insulin kinetics of pre- and post-weaned calves fed an elevated plane of MR. Ten male Holstein calves (42.2±1.8 kg BW) were blocked by BW and randomly assigned to two treatments offering 8 l MR/day (150 g/l) in two (2×; meal size 4 l) or four (4×; meal size 2 l) feedings via an automated calf feeder. Milk replacer was gradually stepped down by 1 l/day during week 8, with calves being weaned by week 9. Water and pelleted calf starter were offered ad libitum. Individual intake of MR and starter were recorded daily, and BW was recorded weekly. The number of visits to the MR feeder (rewarded and unrewarded), and behaviors such as lying, cross-sucking, non-nutritive sucking and occupancy time in the feeder were recorded for individual calves from weeks 4 to 10. Jugular catheters were placed on weeks 4, 7 and 10 to facilitate postprandial blood sampling and glucose tolerance tests. Statistical analysis was conducted using the PROC GLIMMIX procedure (SAS) for behavioral observations, and the MIXED procedure (SAS) with repeated measures for BW, intake, plasma glucose and plasma insulin data. Final BW, starter and MR intake did not differ between treatments. There were no differences in observed calf behaviors; with the exception that 2× calves visited the MR feeder more often (P<0.01; total: unrewarded and rewarded). Baseline concentrations (mmol/l) and the maximum change in glucose (delta, mmol/l) were greater and lower (P=0.02) in 4×compared to 2×calves, respectively. Postprandial insulin AUC240 tended (P=0.09) to be greater in 2×calves, compared to 4×calves at week 7. Similarly, T max (min), AUC240 and delta values (µU/ml) were greater (P⩽0.05) in 2×calves, compared to 4×calves. No treatment ×age interactions were observed for glucose or insulin during the glucose tolerance tests. Therefore, we conclude that feeding an elevated plane of MR (8 l/day) at a lower frequency (2× v. 4×) increased feeder visits, but not other hunger-related behaviors, and while postprandial glucose and insulin parameters varied, insulin sensitivity remained stable in Holstein dairy calves up to 10 weeks of age in calves consuming similar levels of calf starter.

The automated analysis of clustering behaviour of piglets from thermal images in response to immune challenge by vaccination.

An automated method of estimating the spatial distribution of piglets within a pen was used to assess huddling behaviour under normal conditions and during a febrile response to vaccination. The automated method was compared with a manual assessment of clustering activity. Huddling behaviour was partly related to environmental conditions and clock time such that more huddling occurred during the night and at lower ambient air temperatures. There were no positive relationships between maximum pig temperatures and environmental conditions, suggesting that the narrow range of air temperatures in this study was not a significant factor for pig temperature. Spatial distribution affected radiated pig temperature measurements by IR thermography. Higher temperatures were recorded in groups of animals displaying huddling behaviour. Huddling behaviour was affected by febrile responses to vaccination with increased huddling occurring 3 to 8 h post-vaccination. The automated method of assessing spatial distribution from an IR image successfully identified periods of huddling associated with a febrile response, and to changing environmental temperatures. Infrared imaging could be used to quantify temperature and behaviour from the same images.

Human cortical areas selectively activated by apparent sound movement.

BACKGROUND: Positron emission tomography (PET) measures cerebral blood flow, an indicator of neural activity. PET has been used successfully to identify visual association areas in the human brain, which are involved in the analysis of different aspects of visual stimuli. However, comparable studies have not yet been carried out for the human auditory system. RESULTS: We have attempted to identify human cortical areas that are selectively activated during sound movement analysis. Using PET, we have identified cortical areas that appeared to be selectively activated while human subjects attended to the position of a moving sound image compared to when they attended to a stationary sound image. The areas are in the right insula, adjacent to the right posterior cingulate, and in the cerebellum. CONCLUSIONS: We suggest that the insula may be acting as an auditory association cortex involved in sound movement analysis, analogous to area V5 in the visual system.

Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment.

BACKGROUND: Pharmacological and postmortem investigations suggest that patients with major depressive disorder have alterations in function or density of brain serotonin1A (5-HT1A) receptors. The aim of the present study was to use positron emission tomography with the selective 5-HT1A receptor antagonist [11C]WAY-100635 to measure 5-HT1A receptor binding in depressed patients before and during treatment with selective serotonin reuptake inhibitors. METHODS: Positron emission tomographic scans with [11C]WAY-100635 were performed on 25 patients with major depressive disorder. These included 15 unmedicated depressed patients. Ten of these unmedicated patients were scanned again during selective serotonin reuptake inhibitor treatment. A further 10 patients with major depressive disorder were scanned on one occasion only while taking selective serotonin reuptake inhibitors. Comparisons were made with [11C]WAY-100635 positron emission tomographic scans in 18 healthy volunteer subjects. Region of interest analysis and statistical parametric mapping were performed on binding potential images generated using a reference tissue model. RESULTS: Binding potential values were reduced across many of the regions examined, including frontal, temporal, and limbic cortex in both unmedicated and medicated depressed patients compared with healthy volunteers. Binding potential values in medicated patients were similar to those in unmedicated patients. CONCLUSIONS: Major depressive disorder is associated with a widespread reduction in 5-HT1A receptor binding. This reduced 5-HT1A receptor binding was not changed by selective serotonin reuptake inhibitor treatment.

Infrared thermography detects febrile and behavioural responses to vaccination of weaned piglets.

An automated, non-invasive system for monitoring of thermoregulation has the potential to mitigate swine diseases through earlier detection. Measurement of radiated temperature of groups of animals by infrared thermography (IRT) is an essential component of such a system. This study reports on the feasibility of monitoring the radiated temperature of groups of animals as a biomarker of immune response using vaccination as a model for febrile disease. In Study A, weaned pigs were either treated with an intramuscular vaccine (FarrowSure Gold), a sham injection of 0.9% saline or left as untreated controls. An infrared thermal camera (FLIR A320) was fixed to the ceiling directly above the pen of animals, and recorded infrared images of the treatment groups at 5 min intervals. The effect on temperature of the spatial distribution of pigs within the pen was significant, with higher temperatures recorded when pigs were grouped together into a single cluster. A higher frequency of clustering behaviour was observed in vaccinated animals compared with controls during a period of the afternoon ~4 to 7 h post-vaccination. The daily mean of the maximum image temperature was significantly higher in vaccinated animals compared with control and sham-treated animals. In the vaccination treated group, the 24 h mean of the maximum temperature was significantly higher during the post-vaccination period compared with the 24 h period before vaccination. Increased temperature in the vaccinated animals occurred from ~3 h, peaked at ~10 h, and remained elevated for up to 20 h post-vaccination. In Study B, the effect of prevalence was tested in terms of the difference in maximum temperature between control and vaccination days. A thermal response to vaccination was detected in a pen of 24 to 26 animals when <10% of the animals were vaccinated. The results support the concept of radiated temperature measurements of groups of animals by IRT as a screening tool for febrile diseases in pig barns.

PET measurement of the influence of corticosteroids on serotonin-1A receptor number.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis and serotonergic system interact functionally. The modulatory effect of corticosteroids on 5-HT(1A) receptor number and function has been repeatedly demonstrated in preclinical studies suggesting that raised corticosteroid levels decrease 5-HT(1A) receptor number and function in the hippocampus. METHODS: We used positron emission tomography (PET) to quantify the number of 5-HT(1A) receptors in two studies, the first in normal subjects given a single dose of hydrocortisone using a random-order, double-blind, placebo-controlled design and second in patients treated long-term with corticosteroids. RESULTS: We did not find that exposure to elevated levels of corticosteroids in either the short or long term alters 5-HT(1A) receptor binding in the hippocampus or other brain regions examined. CONCLUSIONS: This study does not support the hypothesis that corticosteroids exert a major inhibitory regulatory control over the 5-HT(1A) receptor binding in the human brain.

Comparison of methods for analysis of clinical [11C]raclopride studies.

Five different methods for the estimation of the binding potential, a measure of Bmax/Kd, of [11C]raclopride in human striatum were compared using data from a dose ranging study of the neuroleptic CP-88,059-01. Binding potential was estimated indirectly, from distribution volumes in striatum and cerebellum, using both single- and two-tissue compartment models with a metabolite-corrected plasma curve as input function. The two-tissue compartment model was also used for a direct estimate of the binding potential. In addition, a direct estimate was obtained from the reference tissue compartment model using the cerebellum as indirect input function. Finally, an estimate of binding potential was calculated from the ratio of striatum over cerebellum counts at late times after injection. The estimates of striatum binding potential from all methods, except the direct determination using a two-tissue compartment model with metabolite-corrected plasma input function, correlated with each other. Use of an average metabolite correction resulted in only a small reduction in accuracy in this series of normal subjects. The reference tissue model provided estimates of the binding potential with the same sensitivity for detecting changes as those methods that required a metabolite-corrected plasma input function. This indicates that for routine analysis of clinical [11C]raclopride studies, no arterial cannulation is required. The range of normal values was significantly less variable with the reference tissue method than when simple striatum-to-cerebellum ratios were used.

Measurement of cerebral monoamine oxidase B activity using L-[11C]deprenyl and dynamic positron emission tomography.

A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET). The kinetic model consisted of two tissue compartments with irreversible binding to the second compartment (three rate constants). In addition, a blood volume component was included. Special attention was given to the accurate measurement of the plasma and whole blood input functions. The method was applied to the measurement of the dose-response curve of a reversible MAO-B inhibitor (Ro 19-6327). From the results, it followed that the rate constant for irreversible binding (k3) appeared to be a better index of MAO-B activity than the net influx constant Ki. Furthermore, regional analysis demonstrated that Ki, but not k3, was flow dependent. This implies that full kinetic analysis is required for an accurate assessment of MAO-B activity.

Pindolol augmentation of selective serotonin reuptake inhibitors: PET evidence that the dose used in clinical trials is too low.

OBJECTIVE: Positron emission tomography (PET) was used to examine whether the dose of pindolol used to augment antidepressant medication achieves a significant occupancy of the serotonin type 1A (5-HT(1A)) autoreceptor in depressed patients receiving medication. METHOD: The authors examined eight depressed patients on one of two regimes of pindolol (2.5 mg t.i.d. and 5.0 mg t.i.d.) with PET and [11C]WAY-100635. RESULTS: The 5-mg t.i.d. regime achieved a modest (19%) but significant occupancy of the 5-HT(1A) autoreceptor, while the regime used in the vast majority of clinical trials (2.5 mg t.i.d.) did not achieve a significant occupancy. CONCLUSIONS: The dose of pindolol used in clinical trials is suboptimal and may explain the inconsistent results. Therefore, a thorough test of pindolol's efficacy will necessitate doses higher than those used in present clinical trials.

Investigations of the functional anatomy of attention using the Stroop test.

In two separate experiments positron emission tomography (PET) was used to measure changes in regional cerebral blood flow while normal subjects performed the Stroop colour word interference test, a test of selective attention. In the first experiment performance of the Stroop task was associated with activation of right orbito-frontal and bilateral parietal structures, an unexpected result in view of previously reported findings. In addition, there were highly significant time related focal changes in rCBF. A second experiment was therefore carried out which altered the experimental parameters to replicate an earlier study. In this second experiment focal activation of the right anterior cingulate and right frontal polar cortex occurred during the Stroop task. As in the first experiment significant time effects were again apparent. To determine the functionally related brain systems during the performance of the Stroop task a correlation analysis was carried out in relation to blood flow changes induced by experimental manipulation in the right anterior cingulate. This analysis indicated the engagement of a widespread network of anterior brain regions and reciprocal inhibition of posterior brain regions during the performance of the task. The results provide evidence for the involvement of anterior right hemisphere and medial frontal structures in attentional tasks but also indicate that time effects can confound task specific activations. Furthermore subtle experimental treatment parameters, such as stimulus presentation rate, influence the degree and distribution of observed activations.

beta-blocker binding to human 5-HT(1A) receptors in vivo and in vitro: implications for antidepressant therapy.

A novel strategy for improving the treatment of depressive illness is augmentation of antidepressants with a 5-HT1(1A) autoreceptor antagonist. However, trials using the 5-HT1(1A)/beta-blocker pindolol are proving inconsistent. We report how positron emission tomography (PET) and in vitro autoradiography can inform trials of antidepressant augmentation. We show that in healthy volunteers, in vivo, pindolol (n = 10) and penbutolol (n = 4), but not tertatolol (n = 4) occupy the human 5-HT(1A) receptors, at clinical doses. Pindolol, as well as the beta-blockers penbutolol and tertatolol, has high affinity for human 5-HT(1A) receptors in post-mortem brain slices (n = 4). Pindolol shows preference for 5-HT(1A) autoreceptors versus the post-synaptic receptors both in vitro and in vivo. Our data reveal that pindolol doses used in antidepressant trials so far are suboptimal for significant occupancy at the 5-HT(1A) autoreceptor. Penbutolol or higher doses of pindolol are candidates for testing as antidepressant augmenting regimes in future clinical trials.

Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88,059-01: a study using positron emission tomography and 11C-raclopride.

Positron emission tomography (PET) and 11C-raclopride were used to measure the occupancy of central dopamine D2 receptors by a new neuroleptic, CP-88,059-1. In a double blind dose escalation study, seven healthy male subjects received a predose of between 2 mg and 60 mg CP-88,059-1, 5 h before PET scanning. One additional subject was assigned to placebo predose. Receptor occupancy was defined as the percentage reduction in binding potential compared with that seen in the subject predosed with placebo and with that seen in seven unmedicated normal volunteers previously studied. Binding of 11C-raclopride decreased in a dose dependent manner, and 85% dopamine D2 receptor occupancy was achieved with the highest dose of CP-88,059-1. The findings confirm that brain dopamine D2 receptors are blocked by CP-88,059-1 and suggest that an effective antipsychotic dose will be between 20 mg and 40 mg. The study high-lights the potential of positron emission tomography in the preclinical evaluation of new drugs.

The time course of binding to striatal dopamine D2 receptors by the neuroleptic ziprasidone (CP-88,059-01) determined by positron emission tomography.

Positron emission tomography (PET) and 11C-raclopride were used to assess the time course of binding to central dopamine D2 receptors by the novel neuroleptic ziprasidone. In a third party blind study, six healthy male control subjects received a predose of 40 mg ziprasidone and were scanned at an interval of between 4 and 36 h post-dose. One additional subject was assigned to placebo predose and was scanned at 4 h post-dose. Binding potential (BP) was compared with that seen in the subject predosed with placebo and with that seen in nine unmedicated normal volunteers. Subjects studied up to 12 h post-dose had BPs that were greater than 2 SD less than the mean BP, indicative of extensive D2 receptor binding by ziprasidone. With increasing time between dosing and PET scanning there was a curvilinear increase in BP, so that all studies performed at or after 18 h post-dose gave BPs in the normal range (mean +/- 2 SD). Elevated prolactin levels returned to within the normal range by 18 h post-dose. PET measures of binding potential correlated significantly with serum levels of ziprasidone at the time of scanning and less significantly with absolute prolactin levels at the same time.

Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635.

The 5-HT1A receptor antagonist, WAY-100635 [N-(2-(4-(2-methoxyphenyl)- 1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide], was labelled in its carbonyl group with carbon-11 (t1/2 = 20.4 min), injected intravenously into healthy male volunteers and studied with positron emission tomography (PET). The acquired data provide exquisite delineation of 5-HT1A receptors in brain, with the ratio of radioactivity uptake in receptor-rich regions, such as medial temporal cortex, to that in receptor-devoid cerebellum reaching 25 by 60 min after radioligand injection. Application of biomathematical modelling to the data revealed high values (7.8) for binding potential, a measure of Bmax/Kp, in receptor-rich regions. Only very polar radioactive metabolites were present in plasma, a finding consistent with the low level of nonspecific binding seen in cerebellum. [carbonyl-11C]WAY-100635 is concluded to be far superior to the previously reported [0-methyl-11C]WAY-100635 as a radioligand for PET studies of 5-HT1A receptors in human brain.