- Email: [email protected]
Reversal learning in patients with obsessive-compulsive disorder (OCD) and their unaffected relatives: Is orbitofrontal dysfunction an endophenotype of OCD?
Author’s Accepted Manuscript REVERSAL LEARNING IN PATIENTS WITH OBSESSİVE-COMPULSİVE DİSORDER (OCD) AND THEIR UNAFFECTED RELATIVES: IS ORBITOFRONTAL DYSFUNCTION AN ENDOPHENOTYPE OF OCD? Didem Tezcan, Selim Tumkaya, Emre Bora www.elsevier.com/locate/psychres
PII: DOI: Reference:
S0165-1781(16)31267-7 http://dx.doi.org/10.1016/j.psychres.2017.03.001 PSY10368
To appear in: Psychiatry Research Received date: 1 August 2016 Revised date: 26 November 2016 Accepted date: 1 March 2017 Cite this article as: Didem Tezcan, Selim Tumkaya and Emre Bora, REVERSAL LEARNING IN PATIENTS WITH OBSESSİVE-COMPULSİVE DİSORDER (OCD) AND THEIR UNAFFECTED RELATIVES: IS ORBITOFRONTAL DYSFUNCTION AN ENDOPHENOTYPE OF OCD?, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2017.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REVERSAL LEARNING IN PATIENTS WITH OBSESSİVECOMPULSİVE DİSORDER (OCD) AND THEIR UNAFFECTED RELATIVES: IS ORBITOFRONTAL DYSFUNCTION AN ENDOPHENOTYPE OF OCD?
* Didem Tezcana, Selim Tumkayaa , Emre Borab
a
Pamukkale University, Medicine Faculty, Department of Psychiatry, Denizli,
(20070), Turkey. b
Melbourne Neuropsychiatry Centre, Department of Psychiatry. University of
Melbourne, VIC, Australia; Department of Psychiatry, University of Dokuz Eylül, İzmir, Turkey.
*
Corresponding author. Selim Tumkaya Pamukkale University, Medicine
Faculty, Department of Psychiatry, Kınıklı, Denizli (20070), Turkey. Tel.: +90 4440728-5016; fax: +90(258)2134922; [email protected]
SUMMARY It has been suggested that reversal learning deficits might be an endophenotype of OCD. To investigate this hypothesis, we administered a probabilistic reversal learning task (ProbRev) to OCD patients, their unaffected first-degree relatives, and healthy controls. Although the relatives had a performance in between OCDs and controls at the early 1
phase of the ProbRev, their performance was similar to controls and was significantly better than OCD patients at the later stages of the test. Our findings imply that reversal learning impairment might be partly a trait-related feature of OCD but state-related factors can also contribute to observed deficits.
Keywords: obsessive-compulsive disorder, reversal learning, endophenotype, relatives
Introduction Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurrent, persistent, unwanted thoughts or repetitive, ritualistic behaviors and associated with significant disability. OCD is associated with a dysfunction in frontostriatal circuitry. OCD is a heritable disorder (Menzies et al., 2008). OCD symptoms are observed more commonly in relatives of probands with OCD. Therefore, identifying the genes contributing to OCD is important. It was suggested that certain neurobiological markers and neurocognitive tests might be more proximal to the genotype of the condition
in
comparison
to
symptoms
and
these
intermediate
phenotypes
(endophenotypes) can help in establishing the genetic causes of disorders including OCD (Menzies et al., 2007). According to Gottesman and Gould (2003) endophenotypes are associated with the illness, are primarily state-independent, are heritable and are found in unaffected family members at a higher rate than in the general population. Orbitofrontal cortex (OFC) related cognitive impairment is an important candidate for being an endophenotype of OCD. OFC is a brain region that facilitates behavioral flexibility after negative feedback (reversal learning), might be particularly relevant for understanding the underlying pathophysiology of OCD (Chamberlain et al., 2007; Menzies et al., 2008). OFC and its subcortical connections are important for behavioral flexibility and habit formation which are important concepts to understand compulsions. Brain imaging studies in OCD have found evidence of structural and functional abnormalities in OFC (Menzies et al., 2008). Neuropsychological studies have found that patients with OCD underperform healthy individuals in reversal learning tasks (Chamberlain et al., 2007; Remijnse et al., 2006; Valerius et al.,2008). 2
Reduced
activation of OFC during reversal learning in OCD has been reported by several studies (Chamberlain et al., 2008; Remijnse et al., 2009). We are aware of only a single study which investigated reversal learning deficits in first-degree relatives of probands with OCD. In their influential paper, published in Science, Chamberlain et al (2008) suggested that reversal learning related hypofunction is an endophenotype of OCD. In their study, authors were not able to show a behavioral deficit in reversal learning task in unaffected relatives of patients with OCD. However, authors explained this negative finding by the fact that participants were pre-trained for the task before going to the scanner. Also, the study of Chamberlain et al. was very likely underpowered to detect behavioral deficits in relatives due to small sample size (n=12 relatives). In this study, we aimed to investigate reversal learning abilities in patients with OCD, their unaffected first-degree relatives and healthy controls. The main hypothesis of the study was that both the patients and their unaffected first-degree relatives would be impaired in a probabilistic reversal task in comparison to healthy controls.
Method Sixty-five (mean age=36.7±11.9, 51 females) patients with OCD, 50 (mean age=37.9±15.3, 31 females) first-degree unaffected relatives of these probands, and 41 (mean age=35.8±12.5, 28 females) healthy controls who have no personal and familial history of psychiatric disorders participated in this study. Healthy controls have been matched to the other groups with regard to age, gender and duration of education. The all participants evaluated by SCID-I interview. The age range of the participants was 18-65. The exclusion criteria included having psychotic disorders, bipolar disorder, mental retardation, alcohol and substance use disorder, scoring 17 or higher in the Hamilton Depression Rating Scale (HDRS), history of ECT and TMS within last 6 months and neurological and medical disorders associated with cognitive impairment. The Yale–Brown Obsessive Compulsive Scale (Y-BOCS, in OCD) and Maudsley Obsessional Compulsive Inventory (MOCI, in all participants) were used to assess the type and severity of OCD symptoms. The mean age of onset for OCD was 25.4±10,7 and the average number of psychiatric inpatient admissions was 0.86±1.78. For the assessment of the reversal learning ability, the Probabilistic Reversal Learning 3
(ProbRev) test, which is part of The Psychology Experiment Building Language (PEBL) Test battery Version 0.13 was used (Mueller and Piper, 2014). All participants completed ProbRev on a 15.4-inch touchscreen (1440×900 pixel resolution), HP Pro One 400 series computer. The participants were seated at a distance of approximately 25 cm from the computer screen. All participants provided written informed consent and the study was approved by the local ethics committee. All but 2 patients with OCD were receiving pharmacotherapy treatment. Demographic characteristics of OCD, relatives, and healthy controls groups were compared with ANOVA and chi-square tests. MANOVA was used to compare ProbRev performances of three groups. Post-hoc comparisons were conducted with Bonferroni correction. Partial correlation analyses were used to explore the relationship between ProbRev performances and rating scales.
Results There were no significant differences in gender, age and duration of education between OCD, unaffected relatives and healthy controls groups (all p˃ 0.05). The mean YBOCS was 22.5 (obsession subscore=11.7±4.7 and compulsion subscore=10.8±5.5). MOCI-total and HDRS scores of the OCD, relatives and control groups were 6.44±4.0, 20.43±7.6; 4.06±2.0, 11.42±5.0; 3.36±1.7, 11.41±5.7, respectively. The comparisons of the group with regard to mean errors per reversals are shown in Figure 1. There was no significant difference of the mean error numbers in between the each groups in block 1 when post-hoc analyzes were performed to comparing of each group with MANOVA (F=2.77, p=0.066). In block 2, OCD group had more errors than control group (F=5.46, p=0.005), but did not differ with relatives. However, in block 3 and block 4, the OCD group had more errors than both controls and relatives (F=8.46, p=0.000). With regard to reaction times, the only significant difference in between the groups was that OCD patients were slower than controls in Block 2 (F=3.97, p=0.021). In OCD (among patients scoring Y-BOCS>15) and relatives groups, mean errors in block 2 and 3 were correlated with MOCI-rumination (r=0.337-0.499). Also, in OCD
4
group (among patients scoring Y-BOCS>15), errors in block 4 was correlated with MOCI-doubt (r=0.450).
Discussion In this study, performances of 65 OCD patients, 50 of their unaffected first-degree relatives, and 41 matched controls were compared using a reversal learning task. The results of the current study imply that OCD patients have prominent and persistent deficits in reversal learning, and also their relatives have difficulties at the initial stages of reversal learning. This is the first study that indicated a behavioral deficit of reversal learning in relatives of OCD patients. According to the results of the current study, although the relatives had a performance in between OCDs and controls at the early phase of the ProbRev, their performance was similar to controls and was significantly better than OCD patients at the later stages of the test. Current results might be partly supporting hypothesis that reversal learning deficit is a endophenotype for OCD. Current findings also suggest that negative behavioral findings of Chamberlain et al (2008) might be related to effect of the pretraining session. Compared to Chamberlain et al. (2008) the current study was designed to be more sensitive to detect response learning deficits as it included a reasonable number of relatives and participants had no a pre-training session. Also, reversal learning deficits were associated with clinical (in patients) or subclinical (in relatives) rumination and doubt symptoms. These findings support the notion that OCD symptoms are associated with impaired behavioral flexibility. Considering to the MOCI-rumination score can be related to forbidden (aggressive, sexual or religious) OCD symptoms, feature investigations in that subject can be useful. However, impaired behavioral flexibility seems to be both a state and a trait characteristics of OCD.
Dysfunctional goal-directed learning processes (outcome
valuation, contingency) associated with the OFC and its subcortical connections can be responsible for biases towards habitual responding in OCD (Gillan and Robbins,2014). 5
One important consideration is whether reversal learning impairment in OCD is secondary to co-morbid depression. Reversal learning deficits in OCD patients in this study cannot be explained by depression as patients with clinically significant depressive symptoms were not included in the study. Also, subclinical depressive symptoms were not significantly correlated with reversal learning deficits. One limitation of the study was that most patients were receiving medications which can influence serotonergic and dopaminergic neural pathways involved in reversal learning. Also, patient population was heterogeneous with respect to OCD symptoms. As a conclusion, our findings imply that reversal learning impairment might be a partly trait- feature of OCD. However, state-related factors might be also contributing to observed deficits.
Declaration of interest None
Acknowledgements We thank Shane T Mueller (Assoc. Prof., Department of Cognitive and Learning Sciences, University of Michigan) for his suggestion.
References Menzies, L., Chamberlain, S.R., Laird, A.R., Thelen, S.M., Sahakian, B.J., Bullmore, E.T., 2008. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neuroscience and Biobehavioral Reviews 32:, 525-549.
6
Menzies, L., Achard, S., Chamberlain, S.R., Fineberg, N., Chen, C.H., Del Campo, N., Sahakian, B.J., Robbins, T.W., Bullmore, E., 2007. Neurocognitive endophenotypes of obsessive-compulsive disorder. Brain 130, 3223-3236. Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160,636–645. Chamberlain, S.R., Fineberg, N.A., Blackwell, A.D., Clark, L., Robbins, T.W., Sahakian, B.J., 2007. A neuropsychological comparison of obsessive–compulsive disorder and trichotillomania. Neuropsychologia 45,654-662. Remijnse, P.L., Nielen, M.M., van Balkom, A.J., Cath, D.C., van Oppen, P., Uylings, H.B., Veltman, D.J., 2006. Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder. Archives of General Psychiatry 63, 1225–1236. Valerius, G., Lumpp, A., Kuelz, A.K., Freyer, T., Voderholzer, U., 2008. Reversal learning as a neuropsychological indicator for the neuropathology of obsessive compulsive disorder? A behavioral study. Journal of Neuropsychiatry Clinical Neuroscience 20,210-218. Chamberlain, S.R., Menzies, L., Hampshire, A., Suckling, J., Fineberg, N.A., del Campo, N., Aitken, M., Craig, K., Owen, A.M., Bullmore, E.T., Robbins, T.W., Sahakian, B.J., 2008. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 321, 421-422. Remijnse, P.L., Nielen, M.M., Van Balkom, A.J., Hendriks, G.J., Hoogendijk, W.J., Uylings, H.B., Veltman, D.J., 2009. Differential frontal–striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive–compulsive disorder. Psychological Medicine 39, 1503-1518. Mueller, S.T., Piper, B.J., 2014. The psychology experiment building language (PEBL) and PEBL test battery. Journal of Neuroscience Methods 2014; 222, 250-259. Gillan, C.M., Robbins, T.W., 2014. Goal-directed learning and obsessive-compulsive disorder. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 369, 20130475. 7
Legend of Figure 1: The comparisons of groups with regard to mean errors per reversal for all blocks of ProbRev.
Fig. 1
8
Highlights
Administered a reversal learning task to patients, relatives and controls
Relatives had a performance in between OCDs and controls at the early phase of test
Relatives’ performance was similar to controls at the later stages of test
Reversal learning impairment might be partly a trait-related feature of OCD
State-related factors can also contribute to reversal learning impairment in OCD
9
PII: DOI: Reference:
S0165-1781(16)31267-7 http://dx.doi.org/10.1016/j.psychres.2017.03.001 PSY10368
To appear in: Psychiatry Research Received date: 1 August 2016 Revised date: 26 November 2016 Accepted date: 1 March 2017 Cite this article as: Didem Tezcan, Selim Tumkaya and Emre Bora, REVERSAL LEARNING IN PATIENTS WITH OBSESSİVE-COMPULSİVE DİSORDER (OCD) AND THEIR UNAFFECTED RELATIVES: IS ORBITOFRONTAL DYSFUNCTION AN ENDOPHENOTYPE OF OCD?, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2017.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REVERSAL LEARNING IN PATIENTS WITH OBSESSİVECOMPULSİVE DİSORDER (OCD) AND THEIR UNAFFECTED RELATIVES: IS ORBITOFRONTAL DYSFUNCTION AN ENDOPHENOTYPE OF OCD?
* Didem Tezcana, Selim Tumkayaa , Emre Borab
a
Pamukkale University, Medicine Faculty, Department of Psychiatry, Denizli,
(20070), Turkey. b
Melbourne Neuropsychiatry Centre, Department of Psychiatry. University of
Melbourne, VIC, Australia; Department of Psychiatry, University of Dokuz Eylül, İzmir, Turkey.
*
Corresponding author. Selim Tumkaya Pamukkale University, Medicine
Faculty, Department of Psychiatry, Kınıklı, Denizli (20070), Turkey. Tel.: +90 4440728-5016; fax: +90(258)2134922; [email protected]
SUMMARY It has been suggested that reversal learning deficits might be an endophenotype of OCD. To investigate this hypothesis, we administered a probabilistic reversal learning task (ProbRev) to OCD patients, their unaffected first-degree relatives, and healthy controls. Although the relatives had a performance in between OCDs and controls at the early 1
phase of the ProbRev, their performance was similar to controls and was significantly better than OCD patients at the later stages of the test. Our findings imply that reversal learning impairment might be partly a trait-related feature of OCD but state-related factors can also contribute to observed deficits.
Keywords: obsessive-compulsive disorder, reversal learning, endophenotype, relatives
Introduction Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurrent, persistent, unwanted thoughts or repetitive, ritualistic behaviors and associated with significant disability. OCD is associated with a dysfunction in frontostriatal circuitry. OCD is a heritable disorder (Menzies et al., 2008). OCD symptoms are observed more commonly in relatives of probands with OCD. Therefore, identifying the genes contributing to OCD is important. It was suggested that certain neurobiological markers and neurocognitive tests might be more proximal to the genotype of the condition
in
comparison
to
symptoms
and
these
intermediate
phenotypes
(endophenotypes) can help in establishing the genetic causes of disorders including OCD (Menzies et al., 2007). According to Gottesman and Gould (2003) endophenotypes are associated with the illness, are primarily state-independent, are heritable and are found in unaffected family members at a higher rate than in the general population. Orbitofrontal cortex (OFC) related cognitive impairment is an important candidate for being an endophenotype of OCD. OFC is a brain region that facilitates behavioral flexibility after negative feedback (reversal learning), might be particularly relevant for understanding the underlying pathophysiology of OCD (Chamberlain et al., 2007; Menzies et al., 2008). OFC and its subcortical connections are important for behavioral flexibility and habit formation which are important concepts to understand compulsions. Brain imaging studies in OCD have found evidence of structural and functional abnormalities in OFC (Menzies et al., 2008). Neuropsychological studies have found that patients with OCD underperform healthy individuals in reversal learning tasks (Chamberlain et al., 2007; Remijnse et al., 2006; Valerius et al.,2008). 2
Reduced
activation of OFC during reversal learning in OCD has been reported by several studies (Chamberlain et al., 2008; Remijnse et al., 2009). We are aware of only a single study which investigated reversal learning deficits in first-degree relatives of probands with OCD. In their influential paper, published in Science, Chamberlain et al (2008) suggested that reversal learning related hypofunction is an endophenotype of OCD. In their study, authors were not able to show a behavioral deficit in reversal learning task in unaffected relatives of patients with OCD. However, authors explained this negative finding by the fact that participants were pre-trained for the task before going to the scanner. Also, the study of Chamberlain et al. was very likely underpowered to detect behavioral deficits in relatives due to small sample size (n=12 relatives). In this study, we aimed to investigate reversal learning abilities in patients with OCD, their unaffected first-degree relatives and healthy controls. The main hypothesis of the study was that both the patients and their unaffected first-degree relatives would be impaired in a probabilistic reversal task in comparison to healthy controls.
Method Sixty-five (mean age=36.7±11.9, 51 females) patients with OCD, 50 (mean age=37.9±15.3, 31 females) first-degree unaffected relatives of these probands, and 41 (mean age=35.8±12.5, 28 females) healthy controls who have no personal and familial history of psychiatric disorders participated in this study. Healthy controls have been matched to the other groups with regard to age, gender and duration of education. The all participants evaluated by SCID-I interview. The age range of the participants was 18-65. The exclusion criteria included having psychotic disorders, bipolar disorder, mental retardation, alcohol and substance use disorder, scoring 17 or higher in the Hamilton Depression Rating Scale (HDRS), history of ECT and TMS within last 6 months and neurological and medical disorders associated with cognitive impairment. The Yale–Brown Obsessive Compulsive Scale (Y-BOCS, in OCD) and Maudsley Obsessional Compulsive Inventory (MOCI, in all participants) were used to assess the type and severity of OCD symptoms. The mean age of onset for OCD was 25.4±10,7 and the average number of psychiatric inpatient admissions was 0.86±1.78. For the assessment of the reversal learning ability, the Probabilistic Reversal Learning 3
(ProbRev) test, which is part of The Psychology Experiment Building Language (PEBL) Test battery Version 0.13 was used (Mueller and Piper, 2014). All participants completed ProbRev on a 15.4-inch touchscreen (1440×900 pixel resolution), HP Pro One 400 series computer. The participants were seated at a distance of approximately 25 cm from the computer screen. All participants provided written informed consent and the study was approved by the local ethics committee. All but 2 patients with OCD were receiving pharmacotherapy treatment. Demographic characteristics of OCD, relatives, and healthy controls groups were compared with ANOVA and chi-square tests. MANOVA was used to compare ProbRev performances of three groups. Post-hoc comparisons were conducted with Bonferroni correction. Partial correlation analyses were used to explore the relationship between ProbRev performances and rating scales.
Results There were no significant differences in gender, age and duration of education between OCD, unaffected relatives and healthy controls groups (all p˃ 0.05). The mean YBOCS was 22.5 (obsession subscore=11.7±4.7 and compulsion subscore=10.8±5.5). MOCI-total and HDRS scores of the OCD, relatives and control groups were 6.44±4.0, 20.43±7.6; 4.06±2.0, 11.42±5.0; 3.36±1.7, 11.41±5.7, respectively. The comparisons of the group with regard to mean errors per reversals are shown in Figure 1. There was no significant difference of the mean error numbers in between the each groups in block 1 when post-hoc analyzes were performed to comparing of each group with MANOVA (F=2.77, p=0.066). In block 2, OCD group had more errors than control group (F=5.46, p=0.005), but did not differ with relatives. However, in block 3 and block 4, the OCD group had more errors than both controls and relatives (F=8.46, p=0.000). With regard to reaction times, the only significant difference in between the groups was that OCD patients were slower than controls in Block 2 (F=3.97, p=0.021). In OCD (among patients scoring Y-BOCS>15) and relatives groups, mean errors in block 2 and 3 were correlated with MOCI-rumination (r=0.337-0.499). Also, in OCD
4
group (among patients scoring Y-BOCS>15), errors in block 4 was correlated with MOCI-doubt (r=0.450).
Discussion In this study, performances of 65 OCD patients, 50 of their unaffected first-degree relatives, and 41 matched controls were compared using a reversal learning task. The results of the current study imply that OCD patients have prominent and persistent deficits in reversal learning, and also their relatives have difficulties at the initial stages of reversal learning. This is the first study that indicated a behavioral deficit of reversal learning in relatives of OCD patients. According to the results of the current study, although the relatives had a performance in between OCDs and controls at the early phase of the ProbRev, their performance was similar to controls and was significantly better than OCD patients at the later stages of the test. Current results might be partly supporting hypothesis that reversal learning deficit is a endophenotype for OCD. Current findings also suggest that negative behavioral findings of Chamberlain et al (2008) might be related to effect of the pretraining session. Compared to Chamberlain et al. (2008) the current study was designed to be more sensitive to detect response learning deficits as it included a reasonable number of relatives and participants had no a pre-training session. Also, reversal learning deficits were associated with clinical (in patients) or subclinical (in relatives) rumination and doubt symptoms. These findings support the notion that OCD symptoms are associated with impaired behavioral flexibility. Considering to the MOCI-rumination score can be related to forbidden (aggressive, sexual or religious) OCD symptoms, feature investigations in that subject can be useful. However, impaired behavioral flexibility seems to be both a state and a trait characteristics of OCD.
Dysfunctional goal-directed learning processes (outcome
valuation, contingency) associated with the OFC and its subcortical connections can be responsible for biases towards habitual responding in OCD (Gillan and Robbins,2014). 5
One important consideration is whether reversal learning impairment in OCD is secondary to co-morbid depression. Reversal learning deficits in OCD patients in this study cannot be explained by depression as patients with clinically significant depressive symptoms were not included in the study. Also, subclinical depressive symptoms were not significantly correlated with reversal learning deficits. One limitation of the study was that most patients were receiving medications which can influence serotonergic and dopaminergic neural pathways involved in reversal learning. Also, patient population was heterogeneous with respect to OCD symptoms. As a conclusion, our findings imply that reversal learning impairment might be a partly trait- feature of OCD. However, state-related factors might be also contributing to observed deficits.
Declaration of interest None
Acknowledgements We thank Shane T Mueller (Assoc. Prof., Department of Cognitive and Learning Sciences, University of Michigan) for his suggestion.
References Menzies, L., Chamberlain, S.R., Laird, A.R., Thelen, S.M., Sahakian, B.J., Bullmore, E.T., 2008. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neuroscience and Biobehavioral Reviews 32:, 525-549.
6
Menzies, L., Achard, S., Chamberlain, S.R., Fineberg, N., Chen, C.H., Del Campo, N., Sahakian, B.J., Robbins, T.W., Bullmore, E., 2007. Neurocognitive endophenotypes of obsessive-compulsive disorder. Brain 130, 3223-3236. Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. American Journal of Psychiatry 160,636–645. Chamberlain, S.R., Fineberg, N.A., Blackwell, A.D., Clark, L., Robbins, T.W., Sahakian, B.J., 2007. A neuropsychological comparison of obsessive–compulsive disorder and trichotillomania. Neuropsychologia 45,654-662. Remijnse, P.L., Nielen, M.M., van Balkom, A.J., Cath, D.C., van Oppen, P., Uylings, H.B., Veltman, D.J., 2006. Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder. Archives of General Psychiatry 63, 1225–1236. Valerius, G., Lumpp, A., Kuelz, A.K., Freyer, T., Voderholzer, U., 2008. Reversal learning as a neuropsychological indicator for the neuropathology of obsessive compulsive disorder? A behavioral study. Journal of Neuropsychiatry Clinical Neuroscience 20,210-218. Chamberlain, S.R., Menzies, L., Hampshire, A., Suckling, J., Fineberg, N.A., del Campo, N., Aitken, M., Craig, K., Owen, A.M., Bullmore, E.T., Robbins, T.W., Sahakian, B.J., 2008. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 321, 421-422. Remijnse, P.L., Nielen, M.M., Van Balkom, A.J., Hendriks, G.J., Hoogendijk, W.J., Uylings, H.B., Veltman, D.J., 2009. Differential frontal–striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive–compulsive disorder. Psychological Medicine 39, 1503-1518. Mueller, S.T., Piper, B.J., 2014. The psychology experiment building language (PEBL) and PEBL test battery. Journal of Neuroscience Methods 2014; 222, 250-259. Gillan, C.M., Robbins, T.W., 2014. Goal-directed learning and obsessive-compulsive disorder. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 369, 20130475. 7
Legend of Figure 1: The comparisons of groups with regard to mean errors per reversal for all blocks of ProbRev.
Fig. 1
8
Highlights
Administered a reversal learning task to patients, relatives and controls
Relatives had a performance in between OCDs and controls at the early phase of test
Relatives’ performance was similar to controls at the later stages of test
Reversal learning impairment might be partly a trait-related feature of OCD
State-related factors can also contribute to reversal learning impairment in OCD
9