ReviewConsideration of species differences in developing novel molecules as cognition enhancers
Highlights
► Cross-species translation is vital for the development of cognition enhancers. ► Ordinarily arguments are made for translatability (preclinical to clinic). ► Differences in cognition between species are discussed. ► From tests of attention, to reversal and paired associates learning. ► Practical implications of species differences on drug development also provided.
Introduction
CNTRICS is a NIH-funded initiative ultimately aimed at developing procognitive therapeutics for schizophrenia. In order to develop these treatments, it is understood that the drug discovery process requires testing putative treatments in animals first, prior to testing in humans. Moreover, the likelihood that an efficacious treatment in animals will be efficacious in humans is increased if the behavioral tasks used for these species examine the same cognitive construct, because it is reasoned that construct validity increases the involvement of common biological mechanisms across species. Hence, CNTRICS has identified specific cognitive constructs that require treatment in schizophrenia and have attempted to identify tasks that measure these specific constructs in animals and in man. While there exist examples of well-developed tasks with cross-species translational validity from mouse, to rat, to non-human primate (NHP), and to human primate, species differences in performance of otherwise identical cognitive tasks have been observed. The purpose of this review is to: (1) provide a structure by which the cross-species translational validity of tasks can be assessed; (2) give examples of (a) divergent behavior between species despite similarities in testing protocols and (b) convergent behavior in similar tasks – particularly from those chosen to represent specific cognitive constructs identified by CNTRICS; (3) highlight the differences in techniques that may be utilized when developing tests for mice, rats, NHPs, and human primates; and (4) comment on the practical implications of these technical differences for the drug discovery process.
There are numerous criteria that one can use to determine whether a task used to assess a cognitive function is similarly performed by laboratory animal species and humans. The primary interest of CNTRICS has been to develop tasks that measure a specific cognitive construct utilizing the same neurocircuitry between species. Evidence for such similarities is often referred to as construct validity. It is tempting to assume that a task is valid when tasks performed by humans activate certain structures that when lesioned in animals impair performance of a similar task. While this might indeed confer some construct validity, there are other aspects to validation that require examination because brain activations measured in humans may correlate with, but not causally mediate, performance, while lesions can sometimes exert non-specific effects on cognitive task performance. Within construct validity one can examine convergent and divergent validities (see below). Moreover, though construct validity is thought to confer predictive validity, the latter is the primary goal of the research. On the other hand, face validity, though often cited as important, can ultimately have limited impact on the cross-species translational validity of the task.
Most simply defined as the accuracy to which the test measures that which it is intended to measure (Geyer et al., 1999), construct validity is usually considered as the most important property to establish the cross-species translational validity of a test (Geyer et al., 1999, Lipska et al., 1995), but its establishment can be challenging and is – consequently – rare. Problems arise as conceptions about what a test is supposed to measure can change as scientific theories and theoretical constructs are modified. Thus, a task's usefulness and hence its overall validity cannot be determined simply by the degree of construct validation that it has. The process of construct validation is extremely valuable in establishing the overall development, refinement and validity of the task. As new experimental and observational evidence accrues from both preclinical and clinical testing, the task can be refined and therefore enable more accurate predictions.
A test has convergent (or concurrent) and discriminant validity only in relation to other tests. Convergent validity is the degree to which a test correlates with other tests that attempt to measure the same construct (Taiminen et al., 2000). Discriminant validity is the degree to which a test measures aspects of a phenomenon that differ from other aspects that is assessed by other tests (Taiminen et al., 2000). Testing these aspects of validity of the tasks chosen by CNTRICS for each construct will be essential.
This aspect of validity concerns the ability of a test to make correct predictions about the clinical test of interest (Geyer and Braff, 1987, Geyer and Markou, 1995). Predictive validity is often used narrowly to refer only to the test's ability to identify drugs that have therapeutic value in humans (referred to as pharmacological isomorphism (Matthysse, 1986)). This utilization is limited however, because it ignores other important aspects of a task that can be validated by making successful predictions (Ellenbroek and Cools, 2000). Predictive validation of the experimental preparation is also observed whereby variables have similar influences in the preclinical task and the clinical task and can enhance one's understanding of the phenomenon. For example, a vigilance decrement – where attention wanes over time – is observed in numerous human continuous performance tests (Parasuraman, 1998, Riccio et al., 2002), and is also observed in mice performing the 5-choice continuous performance test (5C-CPT) (Young et al., 2009a, Young et al., 2011). Another example is that in the intradimensional/extradimensional (ID/ED) shifting task in humans (Owen et al., 1991), more trials are required to complete the ED vs. ID shifts, which is also the case for the animal versions of the task (Birrell and Brown, 2000, Bissonette et al., 2008, Dias et al., 1996b, Young et al., 2009b).
Refers to the phenomenological similarity between the task used in preclinical testing to that used in the clinic (Lieberman et al., 1997). Although face validity is an intuitively appealing criterion with which to validate tasks, appearing desirable (Lipska and Weinberger, 2000, Weiner et al., 1996), it (a) is not actually necessary, (b) can be misleading, and (c) is difficult to defend rigorously. The latter proves most difficult as these tasks almost invariably involve subjective, arbitrary arguments that are not necessarily accepted by all investigators in the field (see Lipska and Weinberger, 1995). Thus, while face validity may provide a heuristic starting point for the development of a cross-species task with translational validity, it cannot be used to establish the validity of the task.
Various aspects of validity exist and can be described both in terms of the validity that (a) animal tasks have for those used in man, and (b) models of disease states. Translating a molecule from preclinical studies to clinical efficacy is of paramount importance however. Hence, it is possible to utilize tasks that have limited validity to what is being tested in man as long as the model predicts effective treatment. An example of such targeted drug discovery is apomorphine-induced disruption of prepulse inhibition in rats, the reversal of which reliably predicts the clinical efficacy of treatments for the positive symptoms of schizophrenia (Swerdlow et al., 1994). Latterly, it was discovered that this model was effective because it revealed the ability of the compound to block dopamine D2-family of receptors at levels sufficient to treat psychosis (Kapur et al., 2000). This model was only available however, because treatments were available at the time of its development and thus novel molecules could be compared with positive controls, resulting in treatments with similar mechanisms of action (pharmacological isomorphism). Given that no procognitive treatments exist for schizophrenia however, CNTRICS has proposed a more structured task valid approach in order to assess novel molecules as procognitives for schizophrenia. As such, the validity of disease models is not discussed in this review.
Examining the validity of a task across species is vital for assessing the suitability of novel molecules to treat schizophrenia. Because divergent performance levels can be observed between species performing similar tasks (see Section 2) due to innate differences in the approach species take to such tasks, evidence for consistency of effects of the molecule across species in the same task – as opposed to evidence in one species only – would increase the confidence of a positive effect when translated to human clinical trials. Positive effects of a molecule across species would also be beneficial so that it can be tested in animal models of schizophrenia where some are more prevalent in mice (e.g., genetic models), compared with rats and NHPs (e.g., pharmacological models). Hence, convergent validation of a molecule could be generated using a range of models. Convergent validation of a molecule could also arise if the molecule improved of animals in tasks that reportedly assess the same cognitive domain (e.g., the 5C-CPT and the sustained attention task; see (Lustig et al., 2013)). Hence, in these series of meetings CNTRICS has identified at least two tasks per cognitive domain in which a molecule could be tested for convergent validation.
Before such novel molecules are tested in various models however, the cognitive tasks utilized should have cross-species translational validity. An example of a task with some reliable validity is described below (Section 3.1) with examples where validation of this task across species has been conducted. In brief, the validity of reversal learning was established by demonstrating aspects of construct, predictive, and face validities across mice, rats, NHPs, and humans. Face validity was simply established by training subjects to learn the reinforcement contingencies between two stimuli which are then swapped once pre-established criterion is attained. Construct validity in this case has been established by the necessity of an intact orbitofrontal cortex to learn reversed contingencies, while unaffecting simple learning. Multiple aspects of predictive validity are observed for this task. For example, more trials are required to learn reversed contingencies as opposed to the number required to learn the initial relationship of these stimuli. Moreover, pharmacological predictive validity is supported whereby altered regulation of the dopamine D2-like receptor produces impairments in the ability to update behavior during reversed contingencies. Thus, by performing similar experimental manipulations across species, the validity of a task to assess a cognitive construct can be established.
Section snippets
Examples of tasks where differences between species’ performance have been observed
Identifying possible differences between species is not only important for bringing a drug from preclinical to clinical testing, but also when comparing results between preclinical species. For example, the importance of genetic influences to psychiatric diseases is becomingly increasingly apparent and the generation of transgenics that possess such mutations increasingly important. NIH first sponsored a Request For Applications and now a mainstream R21/R33 program announcement for researchers
Examples of tasks whereby consistency between species have been observed
A considerable amount of cross-species research has focused on aspects of executive control, which are defined as a set of processes that contribute to voluntary (top-down) modulation of behavior, affective reactions and thought processes. The rationale guiding these studies stems from the observation that a variety of forms of executive control impairment are present in most forms of major psychiatric disorders, including psychoses.
Executive control over behavior can be assessed using very
Practical implications for the drug discovery process
The development of novel molecules for the treatment of cognitive impairments in schizophrenia remains an important unmet medical need. The effective translation of preclinical research findings into proof of concept clinical trials remains a challenge and contributes to the high attrition rate of molecules entering into human populations (Kola and Landis, 2004). Focusing our efforts on the construct validity of particular tests and improving our understanding of the strengths and limitations
Conclusions
In order to facilitate vertical translation during the drug discovery process, it will be important for the cognitive testing that occurs in preclinical species is consistent with the cognitive testing that occurs in humans. Consistency is required in terms of the cognitive construct being assessed, the neurobiology underlying that construct, and the pharmacological effects of the treatment on that construct. In this review we have described some of the underlying differences and similarities
Acknowledgements
The authors would like to acknowledge the support of everyone from the CNTRICS initiative. JWY receives support from NIH R21MH091571. TJB receives support from the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013). TJB consults for Campden Instruments.
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