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P.1.g.001 The 5-HT6 receptor agonist EMD 386088 promotes cognitive flexibility in rats
P.1.g. Basic and clinical neuroscience − Cognitive neuroscience P.1.f.002 Autism spectrum disorders in adults affected by schizophrenia and obsessive compulsive disorders F. Magnano1 ° , G. Crisafulli1 , A. Petralia1 , E. Aguglia1 1 A.O.U. Policlinico-Vittorio Emanuele, U.O.P.I. of Psychiatry, Catania, Italy Introduction: Autism Spectrum Disorders (ASDs) are developmental disorders characterized by abnormalities in the domain of social interaction, communication, and presence of stereotyped and repetitive behaviors. ASDs, once considered rare, now account for a group of relatively common and disabling condition, usually diagnosed in childhood and persist throughout the lifespan. Individuals with ASDs seem especially prone to developing psychiatric problems. Psychiatric symptoms in patients with autism often appear with atypical manifestations (challenging behaviors). Although the literature has shown a high prevalence of psychiatric disorders in individuals with ASDs, in common clinical practice the diagnosis is often underestimated or even confused with other nosographic entities. Obsessive Compulsive Disorders (OCD) and Schizophrenia (SCZ) show aspects that appear to overlap with autism ‘core symptoms’ [1]. Objectives: The primary objective of this study was to investigate the presence of ASDs in adults with OCD and SCZ. Materials and Methods: We included patients with OCD and SCZ, of both sexes and aged 18−65 years. A control group was selected from the general population. 55 participants were included in which, prior to enrollment, were given a consent form. The subjects were screened for ASD with AQ (Autism Spectrum Quotient) [2]. Those who have received score above the threshold for DSA were subjected to semi-structured interview ADOS module 4 [3] for the diagnosis of ASD. For people with OCD and SCH was also assigned a CGI-S score. Results: We found a highly significant difference between the control population and people suffering from psychiatric disorders examined (p < 0.01), in fact, both patients diagnosed with obsessive-compulsive disorder and those diagnosed with schizophrenia scored AQ significantly higher than controls. In line with the data of the prevalence of autism spectrum disorders, a positive screening AQ was detected more frequently in males. Participants in both groups positive at diagnostic screening AQ and assessed by ADOS, showed no statistically significant differences. Of particular importance is that all the subjects in the OCD group met the ADOS criteria for spectrum autistic. Unlike what was observed with AQ, ADOS in the assessment of positivity did not observe statistically significant differences between the sexes. With regard to the severity of the psychopathological detected by the CGI-S, are not observed statistically significant differences between the two groups (p = 0.86); the average score of the CGI-S is 4 for the OCD group and 4.5 for the group SCZ. In subjects with a score higher than t AQ cut-off, there is a greater clinical severity, as reflected by higher average values ??of the CGI-S scores. Conclusions: ADOS has proven the data on the prevalence of ASDs in participants suffering from OCD and SCZ. In the sample under study, in particular, the presence of a diagnosis of schizophrenia and male sex were correlated to a greater probability of a positive result to screening AQ. It can be assumed that the formulation of a diagnosis of autism spectrum, though with standardized methods, can be affected by the presence of other symptomatic manifestations from both OCD and SCZ.
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References [1] Goldstein, G., Minshew, N. J., Allen, D. N., & Seaton, B. E. (2002). High-functioning autism and schizophrenia: a comparison of an early and late onset neurodevelopmental disorder. Archives of Clinical Neuropsychology, 17(5), 461–475. [2] Woodbury-Smith MR, Robinson J, Wheelwright S, Baron-Cohen S. (2005) Screening Adults for Asperger Syndrome Using the AQ: A Preliminary Study of its Diagnostic Validity in Clinical Practice. Journal of Autism and Developmental Disorders, 35, 331–336. [3] Lord, C., Risi, S., Lambrecht, L., Cook, E. H., et al. 2000. The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223.
P.1.g. Basic and clinical neuroscience − Cognitive neuroscience P.1.g.001 The 5-HT6 receptor agonist EMD 386088 promotes cognitive flexibility in rats D. Rafa1 ° , A. Nikiforuk1 1 Polish Academy of Sciences, Department of Behavioural Neuroscience and Drug Development, Krak´ow, Poland The prefrontal cortex (PFC) mediates higher order executive functions, including cognitive flexibility, i.e., the ability to modify behaviour in response to changing task demands. Impairments in cognitive flexibility are observed in a range of psychiatric disorders, including schizophrenia and depression. This aspect of executive function is commonly assessed in humans using the Wisconsin Card Sorting Test and its modified version, the Intradimensional / Extradimensional Shift (ID/ED) task. Cognitive flexibility may also be assessed in the rodent version of the ID/ED task, i.e., in the attentional set-shifting task (ASST) [1]. In this paradigm, rats must select a bowl containing a food reward based on the ability to discriminate the odours and the media covering the bait. The ASST requires rats to initially learn a rule and form an attentional ‘set’ within the same stimulus dimensions. At the extradimensional (ED) shift, animals must switch their attention to a new, previously irrelevant stimulus dimension and, for example, discriminate between the odours and no longer between the media covering the bait. The ED phase, regarded as an index of cognitive flexibility, is impaired by lesions of the medial prefrontal cortex (mPFC). The beneficial effect of a potential cognitive enhancer on ED set-shifting performance may predict its efficacy in disorders that are characterized by frontal disturbances. A wide body of evidence suggests that 5-HT6 (5hydroxytryptamine 6, serotonin 6) receptor, one of the most recently identified members of the serotonin receptor family, may be a potential target for developing new therapies against psychiatric disorders. Preclinical data provide support for the use of serotonin 5-HT6 receptor antagonists as promising medications for treating cognitive dysfunctions. Specifically, the facilitation of rats’ ED set-shifting performance has been demonstrated after pharmacological blockade of 5-HT6 receptors [2]. Interestingly, recent evidence indicates that also activation of 5-HT6 receptors enhances cognitive flexibility [3]. Therefore, the aim of the present study was to investigate the effect of the 5-HT6 receptor agonist, EMD 386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1Hindole hydrochloride), on rats’ performance in the ASST. EMD 386088 (0, 2.5 and 5 mg/kg) was administered to Sprague–Dawley rats intraperitoneally (IP) immediately before
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testing. The number of trials required to achieve the criterion of 6 consecutive correct responses was recorded for each rat and for each discrimination phase. Data were calculated using two-way mixed-design ANOVA followed by the Newman-Keuls post-hoc test. Rats treated with EMD 386088 at a dose of 5 mg/kg (but not 2.5 mg/kg) required significantly fewer trials to criterion during the ED phase of the ASST. There was no significant drug effect during any other discrimination stage. The ANOVA demonstrated significant effect of drug treatment [F(2,15) = 24.40, p < 0.001], discrimination phase [F(6,90) = 72.71, p < 0.001] and their interaction [F(12,90) = 10.27, p < 0.001]. The present study demonstrated that the agonist of 5-HT6 receptors, EMD 386088, promoted cognitive flexibility in rats. Therefore, it seems likely that the activation of 5-HT6 receptor may represent a useful pharmacological approach in the treatment of frontal-like cognitive disturbances. This work was supported by the grant POIG.01.01.02-12004/09 ‘Depresja − mechanizmy − terapia’, co-financed by the European Union from the European Fund of Regional Development (EFRD). References [1] Birrell, J.M., Brown, V.J., 2000 Medial frontal cortex mediatesperceptual attentional set shifting in the rat. J Neurosci 20, 4320–4324. [2] Hatcher, P.D., Brown, V.J., Tait, D.S., Bate, S., Overend, P., Hagan, J.J., Jones, D.N., 2005 5-HT6 receptor antagonists improve performance in an attentionalset shifting task in rats. Psychopharmacology (Berl) 181, 253–259. [3] Burnham, K.E., Baxter, M.G., Bainton, J.R., Southam, E., Dawson, L.A., Bannerman, D.M., Sharp, T., 2010 Activation of 5-HT(6) receptors facilitates attentional setshifting. Psychopharmacology (Berl) 208, 13−21.
P.1.g.002 Cognitive functioning in cardiac patients is associated with demographic and psychological factors, but not with cardiac functional class J. Burkauskas1 ° , J. Brozaitiene1 , R. Bunevicius1 1 Lithuanian University of Health Sciences, Institute of Psychophysiology and Rehabilitation, Palanga, Lithuania Introduction: Cognitive decline coexists with coronary artery disease (CAD) and affects functioning of patients. We have demonstrated recently in CAD patients that patient-oriented outcomes including health related quality of life [1] and fatigue [2] are associated with psychological factors such as depression, anxiety, life events and social support as well as with demographic factors such as age, gender and education. Contribution of cardiac clinical factors to patient-oriented outcomes was less evident. Cognitive functioning in CAD patients may be affected by both psychological factors and by clinical factor such as heart functional class. Answer to this question is important, considering treatment strategies and interventions in patients with CAD. The aim of our study was to investigate if cognitive functioning is associated with demographic, clinical and psychological characteristics in CAD patients. Methods: This was a 3-year study of CAD patients two weeks after acute myocardial infarction or unstable angina attending cardiac rehabilitation program. In total, 568 patients were enrolled to the study; 406 (71%) women and 162 (29%) men; mean age of 59 years (SD = 9). Cardiovascular functional status was assessed
according to the New York Heart Association (NYHA) functional class guidelines. Depressive symptoms were assessed with Beck Depression Inventory-II (BDI-II), state anxiety with State-Trait Anxiety Inventory (STAI-S). Digit Span Test and Digit Symbol Test were used to assess auditory attention, mental flexibility, psychomotor performance and incidental learning. Trail Making Test A and B was used to measure perceptual speed, task switching and executive control. Multivariate and univariate linear regression was used to examine relationship between cognitive functions and age, gender, education, depression, state anxiety, and NYHA class. By using univariate linear regression all variables found to be statistically significant (probability of 0.05 or less) at this model were included into the stepwise multivariate linear regression models. Results: In univariate analysis we found that almost all demographic, psychological and clinical characteristics were significantly associated with different cognitive functions. In multivariate analysis the Digit symbol test raw scores were associated with age (b = −0.417), education (b = 0.324), gender (b = 0.167) and BDI-II scores (b = −0.116) predicting 31.5% of the variance. Time which individuals took to complete the Digit Symbol Test was associated with age (b = 0.373), education (b = −0.353), gender (b = −0.146), BDI-II scores (b = 0.128) predicting 33.2% of the variance. Strong significant associations remained between Trail Making Test A scores and age (b = 0.399), education (b = −0.235) and STAI-S scores (b = 0.116) predicting 27.2% of the variance. We found no significant associations between cognitive function and NYHA functional class. Conclusions: In CAD patients two weeks after acute cardiac events demographic and psychological factors, but not cardiac functional class are associated with cognitive dysfunction. Presence of symptom of depression, older age and lower education worsens psychomotor performance, perceptual speed and test completion time; higher levels of situational anxiety worsen perceptual speed and mental flexibility. References [1] Staniute, M.J., Brozaitiene, J., Bunevicius, R., 2011. Effects of Social Support and Stressful Life Events on Health-Related Quality of Life in Coronary Artery Disease Patients [Epub ahead of print]. [2] Bunevicius, A., Stankus, A., Brozaitiene, J., Girdler, S.S., Bunevicius, R., 2012. Relationship of fatigue and exercise capacity with emotional and physical state in patients with coronary artery disease admitted for rehabilitation program. American Heart Journal 162, 310– 316.
P.1.g.003 The effects of chronic lower back pain on cognitive function K. Wesnes1 ° , P. Annas2 1 Bracket Global, Research, Goring-onThames, United Kingdom; 2 Astra Zeneca, Research, Stockholm, Sweden Background: Pain is known to impair cognitive function. The present evaluation was designed to characterise and quantify the profile of disruption to cognitive function in patients with chronic pain. Methods: 56 adults aged 23 to 64 years with a diagnosis of chronic low back pain according to the inclusion criteria of Quebec Task Force Class 1 to 3. They were assessed on the CDR System, a widely used automated cognitive test system. Their scores on the various tasks were compared to age-matched healthy controls.
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References [1] Goldstein, G., Minshew, N. J., Allen, D. N., & Seaton, B. E. (2002). High-functioning autism and schizophrenia: a comparison of an early and late onset neurodevelopmental disorder. Archives of Clinical Neuropsychology, 17(5), 461–475. [2] Woodbury-Smith MR, Robinson J, Wheelwright S, Baron-Cohen S. (2005) Screening Adults for Asperger Syndrome Using the AQ: A Preliminary Study of its Diagnostic Validity in Clinical Practice. Journal of Autism and Developmental Disorders, 35, 331–336. [3] Lord, C., Risi, S., Lambrecht, L., Cook, E. H., et al. 2000. The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223.
P.1.g. Basic and clinical neuroscience − Cognitive neuroscience P.1.g.001 The 5-HT6 receptor agonist EMD 386088 promotes cognitive flexibility in rats D. Rafa1 ° , A. Nikiforuk1 1 Polish Academy of Sciences, Department of Behavioural Neuroscience and Drug Development, Krak´ow, Poland The prefrontal cortex (PFC) mediates higher order executive functions, including cognitive flexibility, i.e., the ability to modify behaviour in response to changing task demands. Impairments in cognitive flexibility are observed in a range of psychiatric disorders, including schizophrenia and depression. This aspect of executive function is commonly assessed in humans using the Wisconsin Card Sorting Test and its modified version, the Intradimensional / Extradimensional Shift (ID/ED) task. Cognitive flexibility may also be assessed in the rodent version of the ID/ED task, i.e., in the attentional set-shifting task (ASST) [1]. In this paradigm, rats must select a bowl containing a food reward based on the ability to discriminate the odours and the media covering the bait. The ASST requires rats to initially learn a rule and form an attentional ‘set’ within the same stimulus dimensions. At the extradimensional (ED) shift, animals must switch their attention to a new, previously irrelevant stimulus dimension and, for example, discriminate between the odours and no longer between the media covering the bait. The ED phase, regarded as an index of cognitive flexibility, is impaired by lesions of the medial prefrontal cortex (mPFC). The beneficial effect of a potential cognitive enhancer on ED set-shifting performance may predict its efficacy in disorders that are characterized by frontal disturbances. A wide body of evidence suggests that 5-HT6 (5hydroxytryptamine 6, serotonin 6) receptor, one of the most recently identified members of the serotonin receptor family, may be a potential target for developing new therapies against psychiatric disorders. Preclinical data provide support for the use of serotonin 5-HT6 receptor antagonists as promising medications for treating cognitive dysfunctions. Specifically, the facilitation of rats’ ED set-shifting performance has been demonstrated after pharmacological blockade of 5-HT6 receptors [2]. Interestingly, recent evidence indicates that also activation of 5-HT6 receptors enhances cognitive flexibility [3]. Therefore, the aim of the present study was to investigate the effect of the 5-HT6 receptor agonist, EMD 386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1Hindole hydrochloride), on rats’ performance in the ASST. EMD 386088 (0, 2.5 and 5 mg/kg) was administered to Sprague–Dawley rats intraperitoneally (IP) immediately before
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testing. The number of trials required to achieve the criterion of 6 consecutive correct responses was recorded for each rat and for each discrimination phase. Data were calculated using two-way mixed-design ANOVA followed by the Newman-Keuls post-hoc test. Rats treated with EMD 386088 at a dose of 5 mg/kg (but not 2.5 mg/kg) required significantly fewer trials to criterion during the ED phase of the ASST. There was no significant drug effect during any other discrimination stage. The ANOVA demonstrated significant effect of drug treatment [F(2,15) = 24.40, p < 0.001], discrimination phase [F(6,90) = 72.71, p < 0.001] and their interaction [F(12,90) = 10.27, p < 0.001]. The present study demonstrated that the agonist of 5-HT6 receptors, EMD 386088, promoted cognitive flexibility in rats. Therefore, it seems likely that the activation of 5-HT6 receptor may represent a useful pharmacological approach in the treatment of frontal-like cognitive disturbances. This work was supported by the grant POIG.01.01.02-12004/09 ‘Depresja − mechanizmy − terapia’, co-financed by the European Union from the European Fund of Regional Development (EFRD). References [1] Birrell, J.M., Brown, V.J., 2000 Medial frontal cortex mediatesperceptual attentional set shifting in the rat. J Neurosci 20, 4320–4324. [2] Hatcher, P.D., Brown, V.J., Tait, D.S., Bate, S., Overend, P., Hagan, J.J., Jones, D.N., 2005 5-HT6 receptor antagonists improve performance in an attentionalset shifting task in rats. Psychopharmacology (Berl) 181, 253–259. [3] Burnham, K.E., Baxter, M.G., Bainton, J.R., Southam, E., Dawson, L.A., Bannerman, D.M., Sharp, T., 2010 Activation of 5-HT(6) receptors facilitates attentional setshifting. Psychopharmacology (Berl) 208, 13−21.
P.1.g.002 Cognitive functioning in cardiac patients is associated with demographic and psychological factors, but not with cardiac functional class J. Burkauskas1 ° , J. Brozaitiene1 , R. Bunevicius1 1 Lithuanian University of Health Sciences, Institute of Psychophysiology and Rehabilitation, Palanga, Lithuania Introduction: Cognitive decline coexists with coronary artery disease (CAD) and affects functioning of patients. We have demonstrated recently in CAD patients that patient-oriented outcomes including health related quality of life [1] and fatigue [2] are associated with psychological factors such as depression, anxiety, life events and social support as well as with demographic factors such as age, gender and education. Contribution of cardiac clinical factors to patient-oriented outcomes was less evident. Cognitive functioning in CAD patients may be affected by both psychological factors and by clinical factor such as heart functional class. Answer to this question is important, considering treatment strategies and interventions in patients with CAD. The aim of our study was to investigate if cognitive functioning is associated with demographic, clinical and psychological characteristics in CAD patients. Methods: This was a 3-year study of CAD patients two weeks after acute myocardial infarction or unstable angina attending cardiac rehabilitation program. In total, 568 patients were enrolled to the study; 406 (71%) women and 162 (29%) men; mean age of 59 years (SD = 9). Cardiovascular functional status was assessed
according to the New York Heart Association (NYHA) functional class guidelines. Depressive symptoms were assessed with Beck Depression Inventory-II (BDI-II), state anxiety with State-Trait Anxiety Inventory (STAI-S). Digit Span Test and Digit Symbol Test were used to assess auditory attention, mental flexibility, psychomotor performance and incidental learning. Trail Making Test A and B was used to measure perceptual speed, task switching and executive control. Multivariate and univariate linear regression was used to examine relationship between cognitive functions and age, gender, education, depression, state anxiety, and NYHA class. By using univariate linear regression all variables found to be statistically significant (probability of 0.05 or less) at this model were included into the stepwise multivariate linear regression models. Results: In univariate analysis we found that almost all demographic, psychological and clinical characteristics were significantly associated with different cognitive functions. In multivariate analysis the Digit symbol test raw scores were associated with age (b = −0.417), education (b = 0.324), gender (b = 0.167) and BDI-II scores (b = −0.116) predicting 31.5% of the variance. Time which individuals took to complete the Digit Symbol Test was associated with age (b = 0.373), education (b = −0.353), gender (b = −0.146), BDI-II scores (b = 0.128) predicting 33.2% of the variance. Strong significant associations remained between Trail Making Test A scores and age (b = 0.399), education (b = −0.235) and STAI-S scores (b = 0.116) predicting 27.2% of the variance. We found no significant associations between cognitive function and NYHA functional class. Conclusions: In CAD patients two weeks after acute cardiac events demographic and psychological factors, but not cardiac functional class are associated with cognitive dysfunction. Presence of symptom of depression, older age and lower education worsens psychomotor performance, perceptual speed and test completion time; higher levels of situational anxiety worsen perceptual speed and mental flexibility. References [1] Staniute, M.J., Brozaitiene, J., Bunevicius, R., 2011. Effects of Social Support and Stressful Life Events on Health-Related Quality of Life in Coronary Artery Disease Patients [Epub ahead of print]. [2] Bunevicius, A., Stankus, A., Brozaitiene, J., Girdler, S.S., Bunevicius, R., 2012. Relationship of fatigue and exercise capacity with emotional and physical state in patients with coronary artery disease admitted for rehabilitation program. American Heart Journal 162, 310– 316.
P.1.g.003 The effects of chronic lower back pain on cognitive function K. Wesnes1 ° , P. Annas2 1 Bracket Global, Research, Goring-onThames, United Kingdom; 2 Astra Zeneca, Research, Stockholm, Sweden Background: Pain is known to impair cognitive function. The present evaluation was designed to characterise and quantify the profile of disruption to cognitive function in patients with chronic pain. Methods: 56 adults aged 23 to 64 years with a diagnosis of chronic low back pain according to the inclusion criteria of Quebec Task Force Class 1 to 3. They were assessed on the CDR System, a widely used automated cognitive test system. Their scores on the various tasks were compared to age-matched healthy controls.