Appetitive position discrimination in the T-maze

This protocol details a method to perform appetitively motivated tasks in rodents to test cognitive ability. When testing cognition in animals, the simplest paradigms can potentially yield quick results with minimal investment from the experimenter. Although appetitively motivated tasks are generally learnt more slowly than aversively motivated ones, they may be essential for distinguishing the effects of a treatment on learning from its effects on aversive motivation per se. For example, if a treatment improves learning in both types of paradigm, this is better evidence that it affects cognition rather than sensorimotor processes. Rats and mice easily learn position discriminations in a T-maze, especially if multiple cues, such as different objects and floor textures in the goal arms, are provided. To start, the rodent is placed in the maze and it chooses an arm. This Trial 1, however, is the only one on which this arm will be rewarded. From now on, it must always choose the other arm. The rule is simple: for example, always turn left into the arm with diagonal black stripes on the walls and gravel glued to the floor. High levels of correct responding can be achieved within 20-40 trials. The test may therefore be particularly useful with animals of low cognitive ability, such as transgenic mice derived from some 129 or SJL strains. Once the animals are habituated, each trial should take approximately 1 min. Thus, to test ten animals for 40 trials would take around 7 h.     

Induction of habits in rats by a forced-choice procedure in T-maze and the effect of pre-test free exploration

A forced-choice procedure in T-maze designed for the induction of habits was used to induce strong habits in rats. The response choices of rats in 20 free-choice trials were compared after the rats had been subjected to 1 or 200 forced-choice trials to one side of the T-maze. After 200 forced-choice trials the rats showed a significant (p < .001) propensity for the habitual arm of the maze in the subsequent free-choice trials. The habit was at least as pronounced when analysed over the last 10 free-choice trials as when it was analysed over the first 10 free-choice trials. When the rats were given the opportunity to explore the entire maze immediately before the free-choice challenge after 200 forced-choice trials, this resulted in a large variation in the choice pattern of the individual rats, and a subgroup of rats choose the newly opened maze arm in 95-100% of the 20 free-choice trials.     

The development of water maze-learning ability in rats. (2) Effect of pretraining with the water-filled straight channel

To determine whether pretraining with the water-filled straight channel affects learning acquisition, we studied the water filled multiple T-maze learning ability in 8-weeks-old SPF Wistar-Imamichi rats. The performance time for the straight channel was markedly shortened at the 2nd and 3rd trial compared to the time at the 1st trial on the 1st day. But at subsequent trials on days 2 and 3 it was longer than at the 3rd trial on day 1. At the 1st trial on day 1, the performance time of the group unexperienced in the straight channel was more than three times that of the experienced group. In subsequent trials, however, both groups showed similar performance times. More errors were observed in the unexperienced group than in the experienced group at the 1st trial on day 1. No difference was found between the two groups in subsequent trials. These results indicate that the learning acquisition was largely influenced by pretraining in the straight channel at the 1st trial on day 1.     

Studies on the development of water maze-learning ability in rats (3). Effect of the learning schedule on learning acquisition

The effect of different learning schedules massed or distributed practice conditions (3 trials a day for 3 days), on water-filled multiple T-maze learning ability of 8-week-old SPF Wistar-Imamichi rats was investigated. Although the mean number of errors decreased day by day in both groups, the number of errors in a given day and the total number of errors in 3 days did not differ significantly between the two groups. A tendency toward a decrease in the number of errors was observed as the trials proceeded in the group with distributed practice but not in the group with massed practice. The result suggests that a certain time period for rest after each trial is necessary to acquire the memory.     

Influence of the estrous cycle on the behavior of rats in the elevated T-maze

The elevated T-maze is an animal anxiety model which can discriminate between anxiety-like and fear-like behaviors. The estrous cycle is an important variable of the response in animal anxiety tests and is known to affect other models. The aim of the present study was to investigate the influence of the estrous cycle on behavior displayed in the elevated T-maze test. Seventeen male and 60 female rats were submitted to one session in this test, with the females being screened for the estrous cycle and divided into groups according to the various phases. The elevated T-maze had three arms of equal dimensions ( 50 cm x 10 cm), one enclosed by 40-cm high walls and perpendicular to the others, the apparatus being elevated 50 cm above the floor. Each rat was placed in the end of the enclosed arm and the latency for it to leave this arm was recorded. These measurements were repeated three times separated by 30-s intervals (passive avoidance). After trial 3, each rat was placed at the distal end of the right open arm and the latency to exit this arm was recorded. Whenever latencies were greater than 300 s the trial was finished. The results demonstrated females in diestrus exhibited anxiety-like behaviors while females in metaestrus behaved in a similar way as the males. There were no differences between groups in fear-like behaviors. The results also indicate the elevated T-maze to be a sensitive test to measure anxiety.     

Do we want more cancer patients on clinical trials If so, what are the barriers to greater accrual

It is often stated that only a small proportion of adult cancer patients participate in clinical trials. This is said to be a bad thing, with calls for more trials to include more patients. Here I argue that whether or not greater accrual to clinical trials would be a good thing depends on the trials we conduct. The vast majority of clinical trials in cancer are currently early phase trials, and most do not lead to further studies even if they have encouraging results. The key metric is thus not the number of patients on clinical trials, but the number on the sort of large, randomized, Phase III trials that can be used as a basis for clinical decisions. I also address two important barriers to greater clinical trial participation. The first barrier is financial: clinical research has long been the poor cousin of basic research, with perhaps no more than a nickel in the cancer research dollar going to clinical research. The second barrier is regulatory: clinical research has become so overburdened by regulation that it takes years to initiate a trial, and dedicated staff just to deal with the paperwork once the trial starts. This not only adds significantly to the costs of clinical research, but scares many young investigators away. It has been estimated that nearly half of all US-sponsored trials are being conducted abroad, and it is plausible that excessive regulation is at least partly responsible. That statistic should serve as a wake-up call to the US clinical research community to implement the recommendations of the now decade-old report of National Cancer Institute Clinical Trials Program Review Group, which largely center around simplifying trials and streamlining trial procedures.     

Retention of Learning through Metamorphosis in the Grain Beetle Tenebrio molitor)

Two groups of 15 larve were trained to go consistently to oneside of a T-maze, using escape from light as a reinforcer forcorrect performance. Two yoked control groups received non-responsecontingent reinforcement on trials when individuals in the experimentalgroups were reinforced. A third control group received non-responsecontingent reinforcement on every trial, and a fourth controlgroup was left untrained. After metamorphosis, one experimentalgroup was trained to turn in the same direction as in originallearning (relearning), while the other experimental group wasnamed to turn in the opposite direction (rexersal learning).All the control groups were also trained as adults. In the experimentalgroups, relearning occurred significanty faster and reversallearning occurred significantly slower than learning in anyof the control conditions. These findings are interpreted asprovinding evidence of retention of leirning through metamorphosis.     

End-stage heart disease, high-risk research, and competence to consent: the case of the AbioCor artificial heart

Some commentators believe that persons facing imminent death are incapable of making autonomous, informed decisions about whether to enter high-risk, end-of-life research trials. Using the AbioCor artificial heart trial as an example, this essay argues to the contrary. Although some people are incapacitated, many are capable of making such decisions. To forbid dying people to make a decision about whether to enter a clinical trial may insult deeply held personal values at a time when honoring those values may be most important. Moreover, to deny dying persons entry into high-risk clinical trials leaves ethically worse alternatives: using healthier people, requiring surrogates to decide even when the patient is competent, or simply forgoing all research featuring high-risk, potentially life-saving interventions. Once we agree that it is at least sometimes acceptable to permit dying persons to choose high-risk research, a number of practical safeguards can be implemented to ameliorate the challenges that can hinder decision making in this difficult area.     

Power priors based on multiple historical studies for binary outcomes

Incorporating historical information into the design and analysis of a new clinical trial has been the subject of much recent discussion. For example, in the context of clinical trials of antibiotics for drug resistant infections, where patients with specific infections can be difficult to recruit, there is often only limited and heterogeneous information available from the historical trials. To make the best use of the combined information at hand, we consider an approach based on the multiple power prior that allows the prior weight of each historical study to be chosen adaptively by empirical Bayes. This choice of weight has advantages in that it varies commensurably with differences in the historical and current data and can choose weights near 1 if the data from the corresponding historical study are similar enough to the data from the current study. Fully Bayesian approaches are also considered. The methods are applied to data from antibiotics trials. An analysis of the operating characteristics in a binomial setting shows that the proposed empirical Bayes adaptive method works well, compared to several alternative approaches, including the meta‐analytic prior.     

Effects of accelerated growth during rearing on reproduction and lactation in ewes lambing at 13 to 15 months of age

Three trials were conducted using ewe lambs to determine the effects of accelerated growth during rearing on reproduction and lactation. Data were obtained on 113 ewes. Early weaned ewe lambs were randomly assigned to the following prebreeding treatments: (1) thin (T, moderate gain) and (2) fat (F, accelerated gain). They were bred to lamb at 13 to 15 months of age. After breeding, one half of the ewes on the T and F treatments were switched to the other treatment so that postbreeding treatments were TT, TF, FF and FT. Prebreeding treatment did not affect conception rate (T, 95%; F, 96%), but lambing rates were 43, 28 and 27% higher (P<0.05) for F than T ewes in trials 1, 2 and 3, respectively. Daily milk production was higher in T ewes than F ewes for each trial, but the differences were significant only in trial 3. Estimated daily milk yields over the 60-day period were: T ewes, 1482, 1571, 1614 g; F ewes, 1183, 1373, 1321 g for trials 1, 2 and 3, respectively. Number of alveoli also favored T ewes. Switching ewes to the alternate treatment after breeding did not affect reproduction or milk production. Correlations between weight to height ratio and milk yield were negative in trials 1 and 3 but were positive in trial 2. There was no indication that serum T(4) levels affected milk production or reproduction. The results of this study show that accelerated growth during rearing increased lambing rate but may impair milk production. These effects appeared to be fixed by the time the ewes were bred.     

Measuring the Subjective Value of Risky and Ambiguous Options using Experimental Economics and Functional MRI Methods

Most of the choices we make have uncertain consequences. In some cases the probabilities for different possible outcomes are precisely known, a condition termed "risky". In other cases when probabilities cannot be estimated, this is a condition described as "ambiguous". While most people are averse to both risk and ambiguity^1,2, the degree of those aversions vary substantially across individuals, such that the subjective value of the same risky or ambiguous option can be very different for different individuals. We combine functional MRI (fMRI) with an experimental economics-based method³ to assess the neural representation of the subjective values of risky and ambiguous options⁴. This technique can be now used to study these neural representations in different populations, such as different age groups and different patient populations.In our experiment, subjects make consequential choices between two alternatives while their neural activation is tracked using fMRI. On each trial subjects choose between lotteries that vary in their monetary amount and in either the probability of winning that amount or the ambiguity level associated with winning. Our parametric design allows us to use each individual''s choice behavior to estimate their attitudes towards risk and ambiguity, and thus to estimate the subjective values that each option held for them. Another important feature of the design is that the outcome of the chosen lottery is not revealed during the experiment, so that no learning can take place, and thus the ambiguous options remain ambiguous and risk attitudes are stable. Instead, at the end of the scanning session one or few trials are randomly selected and played for real money. Since subjects do not know beforehand which trials will be selected, they must treat each and every trial as if it and it alone was the one trial on which they will be paid. This design ensures that we can estimate the true subjective value of each option to each subject. We then look for areas in the brain whose activation is correlated with the subjective value of risky options and for areas whose activation is correlated with the subjective value of ambiguous options.     

Aromatase inhibitors versus tamoxifen for management of postmenopausal breast cancer in the advanced disease and neoadjuvant settings

The third-generation aromatase inhibitors anastrozole, exemestane and letrozole have become firmly established as the agents of choice in patients with tamoxifen-resistant tumors. Large, well-conducted, double-blind clinical trials directly comparing the non-steroidal aromatase inhibitors anastrozole and letrozole with tamoxifen in the advanced disease setting have matured. Based on these trials, there is sufficient evidence to choose one of these agents over tamoxifen because of a superior time to disease progression and acceptable toxicity which includes a lower incidence of thromboembolic complications. Information for the steroidal aromatase inhibitor exemestane will be forthcoming from a phase III trial which has completed accrual. Consistent with the findings in the advanced disease setting, a double-blind trial comparing letrozole with tamoxifen in the neoadjuvant setting revealed superiority for letrozole in terms of clinical response rate. This provides a strong impetus for further study of the aromatase inhibitors in the preoperative setting.     

A human rights approach to low data reporting in clinical trials of psychiatric deep brain stimulation

The reporting of clinical trial data is necessary not only for doctors to determine treatment efficacy, but also to explore new questions without unnecessarily repeating trials, and to protect patients and the public from dangers when data are withheld. This issue is particularly salient in those trials involving invasive neurosurgical interventions, such as deep brain stimulation (DBS), for ‘treatment refractory’ psychiatric disorders. Using the federal database ClinicalTrials.gov, it was discovered that out of the completed or unknown‐status trials related to psychiatric DBS up to November 2018, only two had submitted results to ClinicalTrials.gov. These results suggest that, despite federal requirements to report clinical trial data, reporting on psychiatric DBS trials is problematically minimal. It is argued that a human rights approach to this problem establishes a legal and ethical foundation for the need to report clinical trial results in this area.     

Vitamin E in angina pectoris

The claim that the symptoms of angina pectoris can usually be relieved by large doses of vitamin E has been reinvestigated by means of a randomized double-blind trial. The trial lasted nine weeks and consisted of two parts. One part was conducted as a regular double-blind trial involving 40 patients, half of whom received 3200 IU of vitamin E daily, while an equal number received an indistinguishable placebo. The second part of the trial involved 15 patients who were already taking a regular daily dose of between 400 and 2400 IU of vitamin E. Eight patients were assigned the same (or a larger) dose of vitamin E, while seven received placebo. Neither part of the trial yielded statistically convincing evidence that vitamin E is of value in the treatment of angina, but a small beneficial effect could not be ruled out. Taken in conjunction with the positive (but statistically non-significant) results obtained in the only other double-blind trial of vitamin E ever carried out on angina, and the encouraging results reported by other investigators in the treatment of intermittent claudication, it is suggested that further double-blind trials are justified.     

Measurement of methane emission from sheep by the sulphur hexafluoride tracer technique and by the calorimetric chamber: failure and success

The aim of this study was to evaluate the sulphur hexafluoride (SF6) tracer technique for methane (CH4) emission measurement in sheep. Ten cryptorchid Romney sheep were involved in two indoor trials (T1 and T2), where daily CH4 emissions were individually measured both by the SF6 tracer ('tracer CH4') and by the indirect calorimetry chamber ('chamber CH4') techniques while fed on lucerne hay at 1.2 times maintenance requirements. Separate sets of permeation tubes with pre-calibrated permeation rates ('pre-calibrated PRs') were used in the two trials (for tracer CH4) and at the time of T1 and T2 these tubes had been deployed in the rumen for 250 and 30 days, respectively. The tracer CH4 measurements were carried out for 2 (T1) and 5 (T2) days in digestibility crates housed within a building (T1) or a well-ventilated covered yard (T2). Sheep were transferred to calorimetry chambers for 3 days acclimatisation, followed by measurement of CH4 emission for 7 (T1) and 3 (T2) days. In T1 samples from the chamber, outflow and inflow (collected over ～22 h) were analysed for CH4 and SF6 concentrations using the tracer protocol. Thus, PRs of SF6 at the time of the trials ('calculated PRs') could be inferred and the corresponding CH4 emissions are then calculated using either the pre-calibrated PR or calculated PR. Permeation tubes were recovered at the end of the animal trials and their 'post-recovery PR' determined. In trial T1, the tracer CH4 estimates (based on the pre-calibrated PR) were much higher and more variable than the chamber CH4 values. In this trial, the calculated PR and the post-recovery PR were similar from each other but smaller than the pre-calibrated PR, and when the calculated PR was used in place of the pre-calibrated PR the CH4 emission estimates agreed well with the chamber CH4 values. This suggested that the discrepancy was due to a declining PR during the long deployment time of the tubes in T1, an observation reported elsewhere. When the long intra-ruminal deployment was avoided in T2, good agreement between the techniques for CH4 emission measurement was observed.     

Measuring quality of life in clinical trials: a taxonomy and review.

Measurement of quality of life is becoming increasingly relevant to controlled clinical trials. Two basic types of instrument are available: generic instruments, which include health profiles and utility measurements based on the patient''s preferences in regard to treatment and outcome; and specific instruments, which focus on problems associated with individual diseases, patient groups or areas of function. The two approaches are not mutually exclusive; each has its strengths and weaknesses and may be suitable under different circumstances. We surveyed 75 randomized trials published in three medical journals in 1986 and categorized them according to the importance of quality of life as a measure of outcome and the extent to which quality of life was actually measured. Although a number of the investigators used quality-of-life instruments in a sophisticated manner, in only 10 of 55 trials in which the measurement had been judged to be crucial or important were instruments with established validity and responsiveness used. We conclude that although accurate measurement of quality of life in randomized trials is now feasible it is still not widely done. Using the framework we have outlined, investigators can choose generic or specific instruments according to the purpose and the focus of their trial.     

Noninferiority trials

Noninferiority trials are intended to show that the effect of a new treatment is not worse than that of an active control by more than a specified margin. These trials have a number of inherent weaknesses that superiority trials do not: no internal demonstration of assay sensitivity, no single conservative analysis approach, lack of protection from bias by blinding, and difficulty in specifying the noninferiority margin. Noninferiority trials may sometimes be necessary when a placebo group can not be ethically included, but it should be recognized that the results of such trials are not as credible as those from a superiority trial.     

Effects of temporal clumping and payoff accumulation on impulsiveness and cooperation

Animals show impulsiveness when they prefer a smaller more immediate option, even though a larger more delayed option produces a higher intake rate. This impulsive behavior has implications for several behavioral problems including social cooperation. This paper presents two experiments using captive blue jays (Cyanocitta cristata) that consider the effects of payoff accumulation and temporal clumping on impulsiveness and cooperation. Payoff accumulation refers to a situation where the benefits gained from each choice trial accumulate from one trial to the next, and only become available to the animal after it has completed a fixed number of trials. We hypothesized that this would reduce impulsiveness because it removes the advantage of quickly realizing food gains. Clumping refers to situation in which the animal experiences several choice trials in quick succession followed by a long pause before the next clump. We hypothesized that if payoffs accumulated over a clump of trials this would enhance the effect of accumulation. We tested the effects of accumulation and clumping on impulsiveness in a self-control situation. We found a significant interaction between clumping and accumulation. Payoff accumulation reduced impulsiveness, but only when trials were clumped. Post hoc analyses suggest that clumping alone increases impulsiveness. A second experiment applied these results to cooperation. This experiment reveals an interaction between payoff accumulation and trial's position within the clump. Jays were more likely to cooperate on the first trial of a clump, but the likelihood of cooperation dropped after the first trial. However, this drop was larger when payoffs did not accumulate. This observation suggests that the difference between accumulated and un-accumulated treatments that we reported previously may be largely due to differences in how animals behave in the first trial of a clump.     

Condition dependence of female choosiness in a field cricket

Females generally choose mates that produce the loudest, brightest or most elaborate sexual displays, and these costly male displays are predicted to be condition dependent. However, mate choice itself is a costly behaviour also expected to be condition dependent. Male fall field crickets, Gryllus pennsylvanicus, produce a conspicuous long‐distance calling song that attracts females and is condition dependent. In this study, we tested the condition dependence of female preferences (preference function and choosiness) for male calling effort in G. pennsylvanicus. We manipulated female condition by raising crickets from hatching on either a low‐ or high‐quality diet. In a series of two‐speaker phonotaxis trials, both low‐ and high‐condition females preferred playbacks reflecting greater calling effort. However, relative to low‐condition females, high‐condition females took significantly longer to make a choice, were more likely to fail to choose within the time allotted for a phonotaxis trial and significantly increased their latency to choose over the course of multiple trials. We discuss these results with respect to the possibility that female G. pennsylvanicus may be foraging for direct benefits when they choose their mates.