Assessing the nature of premature responses in the rodent continuous performance test variable intertrial interval schedule using atomoxetine and amphetamine.

BACKGROUND: Rodent operant tests that include premature responses (PR) as a measure of impulsivity commonly use variable intertrial interval (vITI) schedules. The rodent continuous performance test (rCPT) is suitable for a vITI schedule. NEW METHOD: We optimised the analysis for a rCPT vITI schedule with intertrial intervals (ITIs) of 3, 6, and 12 s. Examining the nature of first (FiT) and following touches (FoT) to the blank screen led to a separate quantification of these two behaviours into the first touches level (%FiT) and the following-to-first touches ratio (FoT/FiT). RESULTS: FiTs occurred more frequently in the 12 s ITIs than at shorter ITIs. Within 12 s ITIs, %FiT was only moderately higher during the last half than the first half, suggesting that long ITIs have a minimal effect on impulsivity, but allow a longer time for its detection. %FiT and the FoT/FiT ratio were uncorrelated. %FiT was negatively correlated with response criterion (C) and uncorrelated with discriminability. Conversely, FoT/FiT ratio was negatively correlated with discriminability, without correlation to C. Atomoxetine decreased %FiT but did not affect FoT/FiT ratio. Amphetamine increased %FiT and decreased the FoT/FiT ratio. COMPARISON WITH EXISTING METHOD(S): The results suggest that %FiT is analogous to %PR in related tasks and is a more suitable measure of waiting impulsivity in the rCPT. FoT/FiT ratio is unrelated to %FiT. CONCLUSIONS: Long ITIs increase the detectability of, but has minimal effect on, waiting impulsivity. %FiT is analogous to %PR in related tasks, while the FoT/FiT ratio is a separate behaviour requiring further characterization.

Gabor patterns as stimuli in a rodent visual attention task.

BACKGROUND: Gabor patterns are defined as the product of a sinusoid function and a Gaussian envelope and are commonly used in visual and attentional research due to their ability to selectively stimulate the primary visual cortex. The aim of this study was to investigate whether Gabor patterns can be used as visual stimuli in the rodent continuous performance test (rCPT), a newly developed task to study attentional function and impulsivity. METHODS: Sixteen male C57BL/6 J mice were trained in the rCPT using Gabor patterns as visual stimuli and their performance was compared to sixteen mice that were trained using traditional high-contrast pattern stimuli. Mice were compared during training, baseline, and a variable stimulus duration probe. RESULTS: The Gabor pattern group required more training sessions to reach criteria than the group with high-contrast patterns. At baseline, the Gabor pattern group showed a higher false alarm rate and a lower discriminability index. As task difficulty increased during the variable stimulus duration probe, differences between groups became more pronounced. Specifically, the Gabor pattern group showed decreased hit rate and discriminability index, as well as increased false alarm rate and premature responses compared to the high-contrast pattern group. CONCLUSION: This feasibility study showed that it is possible to use Gabor patterns as visual stimuli in the rCPT, although it increases task demands. We discuss the differences between Gabor patterns and high-contrast patterns in the context of translatability of animal models in visual and cognitive research and give two examples of applicability.

ADHD medication and the inverted U-shaped curve: A pharmacological study in female mice performing the rodent Continuous Performance Test (rCPT).

BACKGROUND: The rodent Continuous Performance Test (rCPT) is an analogue of human CPTs where mice have to discriminate between target and non-target stimuli. The rCPT offers a readout of attentional performance and impulsive behaviour. This study aimed to determine if female C57BL/6 J mice could be trained in the rCPT since previously published rCPT studies have only used male mice and to study whether the effects of methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (AMPH) on attention and impulsivity depend on baseline (reference) levels of performance. METHODS: 48 female mice underwent rCPT training. Effects of MPH (1, 2, and 3 mg/kg), ATX (1, 3, and 5 mg/kg) and AMPH (0.3, 0.6, and 1 mg/kg) were assessed in a variable stimulus duration probe. Drugs were administered intraperitoneally and sequentially tested following a Latin-square design. Data were analysed using a repeated measurements mixed effect model and reference-dependent effects were studied. RESULTS: ATX and AMPH improved performance as seen by increases in discriminability. These improvements were a result of a decreased false-alarm rate. AMPH showed a reference-dependent effect, improving the task performance of low-performing mice and decreasing the performance of high-performing mice. MPH also showed this reference-dependent effects, albeit to a lesser extent. ATX and AMPH decreased premature responses and increased response criterion, but no reference-dependent effects were observed for these parameters. CONCLUSION: This study presents a novel method to analyse baseline-dependent effects. It shows that the rCPT can be successfully used in pharmacological studies in female mice and demonstrates that the effect of ADHD medication is in line with the inverted U-shape theory of performance-arousal relationship.

Effect of ADHD medication in male C57BL/6J mice performing the rodent Continuous Performance Test.

RATIONALE: The rodent Continuous Performance Test (rCPT) is a novel rodent paradigm to assess attention and impulsivity that resembles the human CPT. This task measures the rodents' ability to discriminate between target and non-target stimuli. The effect of attention-deficit/hyperactivity disorder (ADHD) medication on rCPT performance in mice remains to be fully characterized. OBJECTIVE: To investigate the predictive validity of the mouse rCPT by studying the effects of ADHD medication methylphenidate, atomoxetine, amphetamine, guanfacine, and modafinil in four behavioral subgroups based on performance and impulsivity levels. METHODS: Two cohorts of male C57BL/6J mice were used, and the effect of treatment was tested in a variable stimulus duration probe. Performance and impulsive subgroups were made based on discriminability and percentage premature responses, respectively. RESULTS: Methylphenidate, atomoxetine, and amphetamine improved performance in the low-performing animals, with no effect in the high-performers. These improvements were a result of increased hit rate and/or decreased false-alarm rate. Furthermore, these drugs decreased percentage premature responses in the high-impulsive group. Methylphenidate, guanfacine, and modafinil increased premature responses in the low-impulsive group. Modafinil impaired performance in the high-performers by increasing false-alarm rate. CONCLUSION: The effect of ADHD treatment was dependent on baseline, as seen by increases in performance for the low-performers and decreases in impulsivity for the high-impulsive animals. These results agree with clinical data and may support the inverted U-shaped arousal-performance theory. The rCPT combined with behavioral separation into subgroups has high predictive validity, and our study is a step forward towards establishing the clinical translatability of the rCPT.

Theory of Visual Attention (TVA) applied to mice in the 5-choice serial reaction time task.

RATIONALE: The 5-choice serial reaction time task (5-CSRTT) is widely used to measure rodent attentional functions. In humans, many attention studies in healthy and clinical populations have used testing based on Bundesen's Theory of Visual Attention (TVA) to estimate visual processing speeds and other parameters of attentional capacity. OBJECTIVES: We aimed to bridge these research fields by modifying the 5-CSRTT's design and by mathematically modelling data to derive attentional parameters analogous to human TVA-based measures. METHODS: C57BL/6 mice were tested in two 1-h sessions on consecutive days with a version of the 5-CSRTT where stimulus duration (SD) probe length was varied based on information from previous TVA studies. Thereafter, a scopolamine hydrobromide (HBr; 0.125 or 0.25 mg/kg) pharmacological challenge was undertaken, using a Latin square design. Mean score values were modelled using a new three-parameter version of TVA to obtain estimates of visual processing speeds, visual thresholds and motor response baselines in each mouse. RESULTS: The parameter estimates for each animal were reliable across sessions, showing that the data were stable enough to support analysis on an individual level. Scopolamine HBr dose-dependently reduced 5-CSRTT attentional performance while also increasing reward collection latency at the highest dose. Upon TVA modelling, scopolamine HBr significantly reduced visual processing speed at both doses, while having less pronounced effects on visual thresholds and motor response baselines. CONCLUSIONS: This study shows for the first time how 5-CSRTT performance in mice can be mathematically modelled to yield estimates of attentional capacity that are directly comparable to estimates from human studies.