An Exploration Based Cognitive Bias Test for Mice: Effects of Handling Method and Stereotypic Behaviour

Behavioural tests to assess affective states are widely used in human research and have recently been extended to animals. These tests assume that affective state influences cognitive processing, and that animals in a negative affective state interpret ambiguous information as expecting a negative outcome (displaying a negative cognitive bias). Most of these tests however, require long discrimination training. The aim of the study was to validate an exploration based cognitive bias test, using two different handling methods, as previous studies have shown that standard tail handling of mice increases physiological and behavioural measures of anxiety compared to cupped handling. Therefore, we hypothesised that tail handled mice would display a negative cognitive bias. We handled 28 female CD-1 mice for 16 weeks using either tail handling or cupped handling. The mice were then trained in an eight arm radial maze, where two adjacent arms predicted a positive outcome (darkness and food), while the two opposite arms predicted a negative outcome (no food, white noise and light). After six days of training, the mice were also given access to the four previously unavailable intermediate ambiguous arms of the radial maze and tested for cognitive bias. We were unable to validate this test, as mice from both handling groups displayed a similar pattern of exploration. Furthermore, we examined whether maze exploration is affected by the expression of stereotypic behaviour in the home cage. Mice with higher levels of stereotypic behaviour spent more time in positive arms and avoided ambiguous arms, displaying a negative cognitive bias. While this test needs further validation, our results indicate that it may allow the assessment of affective state in mice with minimal training— a major confound in current cognitive bias paradigms.

What was I thinking? Eye-tracking experiments underscore the bias that architecture exerts on nuclear grading in prostate cancer

We previously reported that nuclear grade assignment of prostate carcinomas is subject to a cognitive bias induced by the tumor architecture. Here, we asked whether this bias is mediated by the non-conscious selection of nuclei that "match the expectation" induced by the inadvertent glance at the tumor architecture. 20 pathologists were asked to grade nuclei in high power fields of 20 prostate carcinomas displayed on a computer screen. Unknown to the pathologists, each carcinoma was shown twice, once before a background of a low grade, tubule-rich carcinoma and once before the background of a high grade, solid carcinoma. Eye tracking allowed to identify which nuclei the pathologists fixated during the 8 second projection period. For all 20 pathologists, nuclear grade assignment was significantly biased by tumor architecture. Pathologists tended to fixate on bigger, darker, and more irregular nuclei when those were projected before kigh grade, solid carcinomas than before low grade, tubule-rich carcinomas (and vice versa). However, the morphometric differences of the selected nuclei accounted for only 11% of the architecture-induced bias, suggesting that it can only to a small part be explained by the unconscious fixation on nuclei that "match the expectation". In conclusion, selection of « matching nuclei » represents an unconscious effort to vindicate the gravitation of nuclear grades towards the tumor architecture.

Effects of stereotypic behaviour and chronic mild stress on judgement bias in laboratory mice

Cognitive processes are influenced by underlying affective states, and tests of cognitive bias have recently been developed to assess the valence of affective states in animals. These tests are based on the fact that individuals in a negative affective state interpret ambiguous stimuli more pessimistically than individuals in a more positive state. Using two strains of mice we explored whether unpredictable chronic mild stress (UCMS) can induce a negative judgement bias and whether variation in the expression of stereotypic behaviour is associated with variation in judgement bias. Sixteen female CD-1 and 16 female C57BL/6 mice were trained on a tactile conditional discrimination test with grade of sandpaper as a cue for differential food rewards. Once they had learned the discrimination, half of the mice were subjected to UCMS for three weeks to induce a negative affective state. Although UCMS induced a reduced preference for the higher value reward in the judgement bias test, it did not affect saccharine preference or hypothalamic–pituitary–adrenal (HPA) activity. However, UCMS affected responses to ambiguous (intermediate) cues in the judgement bias test. While control mice showed a graded response to ambiguous cues, UCMS mice of both strains did not discriminate between ambiguous cues and tended to show shorter latencies to the ambiguous cues and the negative reference cue. UCMS also increased bar-mouthing in CD-1, but not in C57BL/6 mice. Furthermore, mice with higher levels of stereotypic behaviour made more optimistic choices in the judgement bias test. However, no such relationship was found for stereotypic bar-mouthing, highlighting the importance of investigating different types of stereotypic behaviour separately.

Effects of a Transdiagnostic Internet Intervention («velibra») for Anxiety Disorders in Primary Care: Results of a Randomized Controlled Trial

Internet-based cognitive behavioral self-help treatment (ICBT) for anxiety disorders has shown promising results in several trials, but there is yet a lack of studies of ICBT in „real world” primary care settings. In this randomized controlled trial we recruited participants through general practitioners. The aim of the study was to examine whether treatment-as-usual (TAU) in primary care settings plus ICBT is superior to TAU alone in reducing anxiety symptoms and other outcome measures among individuals meeting diagnostic criteria of a least one of three anxiety disorders (social anxiety disorder, panic disorder with or without agoraphobia, generalized anxiety disorder). 150 adults fulfilling diagnostic criteria for a least one of the anxiety disorders according to a diagnostic interview are randomly assigned to one of the two conditions: TAU plus ICBT versus TAU. Randomization is stratified by primary disorder, medication (yes/no) and concurrent psychotherapy. ICBT consists of a transdiagnostic and tailored Internet-based self-help program for several anxiety disorders which also includes cognitive bias modification for interpretation (CBM-I). Primary outcomes are symptoms of disorder-specific anxiety measures and diagnostic status after the intervention (9 weeks). Secondary outcomes include primary outcomes at 3-month follow-up and secondary measures such as general symptomatology, depression, quality of life, adherence to ICBT and satisfaction with ICBT. The study is currently being completed. Primary results along with results for specific subgroups (e.g. primary diagnosis, concurrent medication and/or psychotherapy) will be presented and discussed.

Effect of Cage-Induced Stereotypies on Measures of Affective State and Recurrent Perseveration in CD-1 and C57BL/6 Mice.

Stereotypies are abnormal repetitive behaviour patterns that are highly prevalent in laboratory mice and are thought to reflect impaired welfare. Thus, they are associated with impaired behavioural inhibition and may also reflect negative affective states. However, in mice the relationship between stereotypies and behavioural inhibition is inconclusive, and reliable measures of affective valence are lacking. Here we used an exploration based task to assess cognitive bias as a measure of affective valence and a two-choice guessing task to assess recurrent perseveration as a measure of impaired behavioural inhibition to test mice with different forms and expression levels of stereotypic behaviour. We trained 44 CD- 1 and 40 C57BL/6 female mice to discriminate between positively and negatively cued arms in a radial maze and tested their responses to previously inaccessible ambiguous arms. In CD-1 mice (i) mice with higher stereotypy levels displayed a negative cognitive bias and this was influenced by the form of stereotypy performed, (ii) negative cognitive bias was evident in back-flipping mice, and (iii) no such effect was found in mice displaying bar-mouthing or cage-top twirling. In C57BL/6 mice neither route-tracing nor bar-mouthing was associated with cognitive bias, indicating that in this strain these stereotypies may not reflect negative affective states. Conversely, while we found no relation of stereotypy to recurrent perseveration in CD-1 mice, C57BL/6 mice with higher levels of route-tracing, but not bar-mouthing made more repetitive responses in the guessing task. Our findings confirm previous research indicating that the implications of stereotypies for animal welfare may strongly depend on the species and strain of animal as well as on the form and expression level of the stereotypy. Furthermore, they indicate that variation in stereotypic behaviour may represent an important source of variation in many animal experiments.

Development of the Davos Assessment of Cognitive Biases Scale (DACOBS)

Objective: Cognitive problems and biases play an important role in the development and continuation of psychosis. A self-report measure of these deficits and processes was developed (Davos Assessment of Cognitive Biases Scale: DACOBS) and is evaluated in this study. Methods: An item pool made by international experts was used to develop a self-report scale on a sample of 138 schizophrenia spectrum patients. Another sample of 71 patients was recruited to validate the subscales. A group of 186 normal control subjects was recruited to establish norms and examine discriminative validity. Results: Factor analyses resulted in seven factors, each with six items (jumping to conclusions, belief inflexibility bias, attention for threat bias, external attribution bias, social cognition problems, subjective cognitive problems and safety behavior). All factors independently explained the variance (eigenvalues > 2) and total explained variance was 45%. Reliability was good (Cronbach's alpha = .90; split-half reliability = .92; test–retest reliability = .86). The DACOBS discriminates between schizophrenia spectrum patients and normal control subjects. Validity was affirmed for five of seven subscales. The scale ‘Subjective Cognitive problems’ was not associated with objective cognitive functioning and ‘Social cognition problems’ was not associated with the Hinting task, but with the scale measuring ideas of social reference. Conclusions: The DACOBS scale, with seven independent subscales, is reliable and valid for use in clinical practice and research.

Can eye movements bias memory recall?

A large body of research suggests that when we retrieve visual information from memory, we look back to the location where we encoded these objects. It has been proposed that the oculomotor trace we act out during encoding is stored in long-term memory, along other contents of the episodic representation. If memory recall triggers the eyes to revisit the location where the stimulus was encoded, is there also an effect in the reverse direction? Can eye movements trigger memory recall? In Experiment 1 participants encoded two faces at two different locations on the computer screen. Then, the average face (morph) of these two faces appeared in either of the two encoding locations and participants had to indicate whether it resembles more the first or second face. In Experiment 2 the morph appeared in a new location, but participants had to repeat one of the oculomotor traces that was used during encoding. Participants’ morph perception was influenced both by the location and the eye-movement it was presented with. Our results suggest that eye-movements can bias memory recall, but only in a short-lasting and rather fragile way.

Brain systems underlying encounter expectancy bias in spider phobia.

Spider-phobic individuals are characterized by exaggerated expectancies to be faced with spiders (so-called encounter expectancy bias). Whereas phobic responses have been linked to brain systems mediating fear, little is known about how the recruitment of these systems relates to exaggerated expectancies of threat. We used fMRI to examine spider-phobic and control participants while they imagined visiting different locations in a forest after having received background information about the likelihood of encountering different animals (spiders, snakes, and birds) at these locations. Critically, imagined encounter expectancies modulated brain responses differently in phobics as compared with controls. Phobics displayed stronger negative modulation of activity in the lateral prefrontal cortex, precuneus, and visual cortex by encounter expectancies for spiders, relative to snakes or birds (within-participants analysis); these effects were not seen in controls. Between-participants correlation analyses within the phobic group further corroborated the hypothesis that these phobia-specific modulations may underlie irrationality in encounter expectancies (deviations of encounter expectancies from objective background information) in spider phobia; the greater the negative modulation a phobic participant displayed in the lateral prefrontal cortex, precuneus, and visual cortex, the stronger was her bias in encounter expectancies for spiders. Interestingly, irrationality in expectancies reflected in frontal areas relied on right rather than left hemispheric deactivations. Our data accord with the idea that expectancy biases in spider phobia may reflect deficiencies in cognitive control and contextual integration that are mediated by right frontal and parietal areas.

Internet-based interpretation bias modification for social anxiety: A pilot study

BACKGROUND AND OBJECTIVES: The biased interpretation of ambiguous social situations is considered a maintaining factor of Social Anxiety Disorder (SAD). Studies on the modification of interpretation bias have shown promising results in laboratory settings. The present study aims at pilot-testing an Internet-based training that targets interpretation and judgmental bias. METHOD: Thirty-nine individuals meeting diagnostic criteria for SAD participated in an 8-week, unguided program. Participants were presented with ambiguous social situations, were asked to choose between neutral, positive, and negative interpretations, and were required to evaluate costs of potential negative outcomes. Participants received elaborate automated feedback on their interpretations and judgments. RESULTS: There was a pre-to-post-reduction of the targeted cognitive processing biases (d = 0.57-0.77) and of social anxiety symptoms (d = 0.87). Furthermore, results showed changes in depression and general psychopathology (d = 0.47-0.75). Decreases in cognitive biases and symptom changes did not correlate. The results held stable accounting for drop-outs (26%) and over a 6-week follow-up period. Forty-five percent of the completer sample showed clinical significant change and almost half of the participants (48%) no longer met diagnostic criteria for SAD. LIMITATIONS: As the study lacks a control group, results lend only preliminary support to the efficacy of the intervention. Furthermore, the mechanism of change remained unclear. CONCLUSION: First results promise a beneficial effect of the program for SAD patients. The treatment proved to be feasible and acceptable. Future research should evaluate the intervention in a randomized-controlled setting.