Implications of using rat models for ADHD research

Transcription

1 Implications of using rat models for ADHD research by Espen A. Sjøberg This presentation was part of Per Holth s symposium «From laboratory to natural environments», presented at the the Norwegian Behavior Analysis Society Conference, Storefjell, April 25th To downloaders: These yellow text boxes are «speech bubbles», which contains some additional information presented verbally. This presentation was given in Norwegian, but has been translated for international viewers.

2 Why use rat models to learn about ADHD? By using animal models for ADHD we can gain insight into fundamental mechanisms underlying the condition, and this knowledge can be transferred to humans. Advantages with using rats: Controlled environment Homogenous groups Less risk for humans Easier recruitment 2

3 Spontaneously Hypertensive Rat (SHR) The SHR model is currently the best validated model for ADHD (Sagvolden & Johansen, 2012; Sagvolden, 2000). By using WKY rats as controls the SHR rats will show the same behavioral deficits as ADHD children. SHR rats are bred to have high blood pressure in other words they are not bred spesifically for ADHD studies (Okamoto & Aoki, 1963). 3

4 Observable behavior in SHR and ADHD Behavior ADHD vs Kontroll SHR vs WKY Motor impulsiveness Sagvolden et al. (1998) Wultz & Sagvolden (1992) Cognitive impulsiveness Malloy-Diniz et al. (2007) Evenden (1998) Inattention Sagvolden et al. (1998) Sagvolden (2000) Behavioral variability Uedel et al. (2010) Johansen et al. (2007) Hyperactivity Sagvolden et al. (1998) Berger & Sagvolden (1998) Spatial learning Bellgrove et al. (2010) Terry et al. (2000) Delay aversion Tripp & Alsop (2001) Hand, Fox & reilly (2009) *Inattention is not necessarily a criteria for ADHD Both ADHD children/adults and SHR rats relative to their controls show the same behavioral deficits, giving support to the idea that you can learn about ADHD by studying rats. 4

5 Responses Meta-Graph: Number of responses during extinction SHR In this graph both SHR rats and ADHD children show a higher rate of response during extinction compared to their controls. We may therefore say that SHR behavioral deficits reflect those we see in ADHD children. There is a problem with this conclusion, however, which will be addressed in a later slide. 15 ADHD 10 WKY 5 non-adhd Extinction sequence Adapted from Sagvolden (2000) 5

6 Neurological similarities SHR rats possess multiple neurological properties that are similar to ADHD, such as: Reduced dopamine release in the prefrontal cortex, nucleus accumbens, and caudate nucleus (e.g. Russell, 2000). Higher expression of noradrenalin in the locus coeruleus, substantia niagra and prefrontal cortex (de Villiers et al., 1995). Methylphenidate reduces impulsivity (Solanto, 2000; Sagvolden et al., 1992). o SHR rats have high blood pressure, which ADHD patients generally don t have, but evidence suggests that the behavioral deficits are not a result of this high blood pressure (Sontag et al., 2010) 6

7 Implications Based on these similarities we can do behavioral studies on SHR rats, where we improve our understanding of ADHD. In applied practice this can contribute to better diagnostics, treatment, and learning in children with ADHD. 7

8 Limitations and critiques Not all experiments can be operationalized and therefore transferrable from human studies to the rat lab, or vice versa. Argument from analogy (Salmon, 2013): That similarities exist between two models does not mean that we can automatically apply new knowledge from SHR studies to ADHD. Currently there are no animal models which are perfect as models for ADHD, but the SHR model is the most used (Sontag et al., 2010). Shortly put: Just because two groups share a common property does not mean that a second property is also shared. In our case finding a new behavior mechanism in SHR rat does not mean that we can conclude that ADHD patients also show this behavior. Unfortunately, this is largely how the SHR/ADHD field operates. 8

9 A mathematical approach Simply comparing the outcome of results between two studies means that you have a probably between 33-50% of getting the same result merely by chance (depending oninterpretation)! If we simply compare results from SHR and ADHD studies we are vulnerable to the possibility that the results are similar by chance, due to the fact that you only have three possible outcomes (positive, negative, null). The foundation of SHR as an appropriate model for ADHD is therefore primarily based on a range of subjective comparisons. A mathematical approach, such as a meta-analysis of SHR studies related to ADHD, may provide less subjective evidence of efficacy. If the group differences between ADHD/Control and SHR/Control are relatively similar in strength (measured by effect sizes), then this adds support for the SHR as an appropriate model for ADHD. This is problematic in behavioral analysis: very few publications report the necessary data needed to systematically evaluate results (t, F, means, sd, d, etc). 9

10 Responses Meta-Graph: Number of responses during extinction d = 2.75 SHR ADHD What really matters is not so much that SHR rats and ADHD children show the same behavior, but rather that the behavior deficit is relatively equal in magnitude. We need to find out how big the difference is between SHR vs controls, as well as ADHD vs controls, and then measure if these results are similar. In this example, doing so gives a different graph -> 10 d = 2.36 WKY 5 non-adhd Extinction sequence Adapted from Sagvolden (2000) 10

11 Responses 30 Group comparison of responses during extinction It is now much clearer how similar the behavioral deficits are between SHR and ADHD (in this example). While there is still some subjectivity at play here, we have added a statistical component to our analysis, allowing us to directly compare performance between SHR and ADHD. This is better than simply looking at whether the behavioral pattern appears to move in the same direction d = 0.35 SHR/Kontroll ADHD/Kontroll Extinction sequence Adapted from Sagvolden (2000) 11

12 Summary The implication of using rat models is that we can gain new knowledge which will further our understanding of ADHD. It is easier to control the environment and confounding variables with animal studies. But one cannot draw conclusions about ADHD based solely on results from rat studies: replications with humans are required. A systematic review of SHR s efficacy as an animal model of ADHD is planned, and it will grant a more mathematical insight into the efficacy of rat models for ADHD. 12