- Email: [email protected]
PL.06.01 Anxious temperament: results from a translational neuroscience approach
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PL.06. Anna Monika Award Lecture
of functional magnetic resonance imaging and positron emission tomography revealed dopaminergic correlates of this bias towards automatic responding. Dimensional approaches can thus help to compare similarities and differences of reward related learning and its respective impact on decision making in and across different psychiatric disorders.
PL.05. Brain Prize Award Lecture
PL.04. Plenary lecture
PL.05.01 Impulsivity and compulsivity: neural substrates and neuropsychiatric implications
PL.04.01 Is it time for immuno-psychiatry?
T.W. Robbins1 ° Kingdom
M. Leboyer1 ° Creteil, France
1 Hˆ opital
Albert Chenevier Pˆole Psychiatrie,
Major psychiatric disorders such as bipolar disorder (BD) and schizophrenia (SZ) are best conceived as multifactorial disorder, caused by gene-environment interactions, such as infections and stress interacting in multiple hit models with immuno-genetically background resulting in low grade immuno-inflammatory abnormalities which may in turn induce the development of metabolic and autoimmune comorbidities, reactivate human endogenous retroviruses and/or increased gastro intestinal barriers permeability. Exploring the control of innate immune responses in BD, we found that associations between functional genetic variants of Toll-Like-Receptors may reduce defense against infections during perinatal period [1,2]. We also reported interaction between earlylife stress and TLR2 risk genotype [3]. This fits with a two-hit model where immune-related genetic susceptibility contributes to abnormal responses to perinatal infections establishing a lower threshold for subsequent stress-triggered events. Persistence of infectious stigma may also be responsible for the reactivation of human endogenous retroviruses whose envelope protein, displaying inflammation and neurotoxicity, is over-expressed in patients with BD or SZ [4,5]. Recently, circulating auto-antibodies against the neuronal glutamate NMDA receptor were described in immune encephalitis, but also in psychotic patients, where they show capacities to disorganize NMDAR molecular complexes (Jezequel et al, submitted). Targeting these dysimmune pathways open up new avenues for biomarker discovery and innovative therapeutic strategies in major psychiatric disorders. Auto-antibodies against the neuronal glutamate NMDA receptor were described in immune encephalitis, but also in psychotic patients, where they show capacities to disorganize NMDAR molecular complexes (Jezequel et al, submitted). References [1] Oliveira J., Busson M., Etain B., Jamain S., Hamdani N., Boukouaci W., Amokrane K., Bennabi M., Le Guen E., Darg´el A., Houenou J., Ivanova R., Bellivier F., Henry C., Kahn J.P., Charron D., Krishnamoorthy R., Vervoitte L., Tamouza R., Leboyer M. 2014. Polymorphism of Toll-like receptor 4 gene in Bipolar Disorder. J Aff Disord. 152–154: 395–402. [2] Oliveira J., Hamdani N., Busson. M, Etain B., Bennabi M., Amokrane K., Boukouaci W., Fortier C., Marzais F., Bengoufa D., Bellivier F., Henry C., Kahn J.P., Charron D., Krishnamoorthy R., Le Corvoisier P., Leboyer M., Tamouza R. 2014. Association between tolllike receptor 2 gene diversity and early-onset bipolar disorder. J Affect Disord.165: 135−41. [3] Oliveira J., Etain B., Lajnef M., Hamdani N., Bennabi M., Bengoufa D., Sundaresh A., Ben Chaabane A., Bellivier F., Henry C., Kahn J.P., Charron D., Krishnamoorthy R., Leboyer M., & Tamouza R. Combined
effect of TLR2 gene polymorphism and early life stress on the age at onset of bipolar disorders, Plos One, in press. Disclosure statement: a speech honoraria for Servier and Otsuka, grants from Roche and Takeda
1 University
of Cambridge, Cambridge, United
Impulsivity and compulsivity are behavioural constructs hypothetically underlying a range of impulsive-compulsive disorders, including ADHD, drug addiction and OCD [1,2]. These constructs may represent dimensional neurobehavioural endophenotypes, analogous to the NIMH Research Domain Criteria of proposed relevance to neuropsychiatric research and drug discovery. Impulsivity is the tendency to act prematurely without foresight. Behavioral and neurobiological analysis of this construct, with evidence from both animal and human studies, defines several dissociable forms, including ‘waiting’ and ‘stopping’ impulsivity, depending on distinct fronto-striatal substrates. Impulsivity can arise from exposure to drugs of abuse but may also contribute to the tendency to compulsive drug-taking, both in rodents and in human stimulant drug abusers. Hypothetically, this corresponds to a shift in control from goal-directed to more habitual behaviour, paralleled by shifts in fronto-striatal functional ‘loops’ [1]. Compulsivity, the maladaptive repetition of behaviour, can be postulated on the basis of heterogeneity in reversal learning in rats, some animals exhibiting excessive perseveration. This form of cognitive flexibility depends on serotonergic mechanisms of the orbitofrontal cortex and striatum in rodents, monkeys and, hypothetically, humans, including those with OCD or exhibiting compulsive cocaine seeking behaviour. I will review evidence of a similar imbalance of control from goal-directed to habitual behaviour in OCD to what may occur in addiction [2]. I will also survey common psychopharmacological treatments for impulsivity and compulsivity, possibly relevant to the treatment of other psychiatric or neurological disorders, such as Parkinson’s disease. References [1] Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity and top-down control. Neuron 69, 680–694. [2] Robbins, T.W., Gillan, C.M., Smith, D.G., de Wit, S. & Ersche, K.D. (2012) Neurocognitive endophenoypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends in Cognitive Sciences, 16, 81−91. Disclosure statement: Consultancy for Cambridge Cognition, Lundbeck, Lilly, Teva, Shire Pharmaceuticals, Otsuka. Research grants from Lillly, Lundbeck and GSK Royalties from Cambridge Cognition Editorial honoraria from Springer and Elsevier.
PL.06. Anna Monika Award Lecture PL.06.01 Anxious temperament: results from a translational neuroscience approach N.H. Kalin1 ° 1 University of Wisconsin, Department of Psychiatry, Madison, USA Anxiety and depressive disorders commonly present early in life. Therefore, an opportunity exists for early identification and
PL.06. Anna Monika Award Lecture intervention prior to the long-term sequelae of these disorders. Studies demonstrate that childhood anxious temperament (AT) is the phenotype most predictive of the later development of anxiety and depression. We characterized AT in developing rhesus monkeys and discovered the altered neural circuitry that underlies AT. Using lesioning strategies, we established that the central nucleus of the amygdala (Ce), is one region that causally underlies the expression of AT. We also characterized phenotypic variation in relation to AT demonstrating common and selective neural substrates that underlie different symptomatic presentations of AT. Heritability analyses demonstrate that AT is approximately 35% heritable and using genetic covariation analyses we further identified the heritable neural substrate responsible for mediating AT. Our work points to the possibility of selectively targeting different components of the neural circuit some of which are more genetically determined while others are more influenced by environment. To investigate molecular mechanisms underlying AT and its neural substrate, we performed genome wide transcriptome analyses that demonstrate a reduction in Ce neuroplasticity gene expression in individuals with extreme AT. We currently are using viral vector infection strategies in young monkeys to test the mechanistic role of these identified alterations in Ce gene regulation. These data provide the foundation for the development of novel early individualized treatment strategies aimed at the prevention of the later development of severe psychopathology. Disclosure statement: Consultant NOT relevant to this activity Corcept Therapeutics. Speaker’s Bureau NOT relevant to this activity CME Outfitters. Grant/Research Support (Secondary Investigators need not disclose) NOT relevant to this activity NIMH. Stock Shareholder (self-managed) NOT relevant to this activity Corcept Therapeutics. Honoraria NOT relevant to this activity Elsevier. Other (Describe) NOT relevant to this activity US Patents 7071323, 7087385, 7122650.
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PL.06. Anna Monika Award Lecture
of functional magnetic resonance imaging and positron emission tomography revealed dopaminergic correlates of this bias towards automatic responding. Dimensional approaches can thus help to compare similarities and differences of reward related learning and its respective impact on decision making in and across different psychiatric disorders.
PL.05. Brain Prize Award Lecture
PL.04. Plenary lecture
PL.05.01 Impulsivity and compulsivity: neural substrates and neuropsychiatric implications
PL.04.01 Is it time for immuno-psychiatry?
T.W. Robbins1 ° Kingdom
M. Leboyer1 ° Creteil, France
1 Hˆ opital
Albert Chenevier Pˆole Psychiatrie,
Major psychiatric disorders such as bipolar disorder (BD) and schizophrenia (SZ) are best conceived as multifactorial disorder, caused by gene-environment interactions, such as infections and stress interacting in multiple hit models with immuno-genetically background resulting in low grade immuno-inflammatory abnormalities which may in turn induce the development of metabolic and autoimmune comorbidities, reactivate human endogenous retroviruses and/or increased gastro intestinal barriers permeability. Exploring the control of innate immune responses in BD, we found that associations between functional genetic variants of Toll-Like-Receptors may reduce defense against infections during perinatal period [1,2]. We also reported interaction between earlylife stress and TLR2 risk genotype [3]. This fits with a two-hit model where immune-related genetic susceptibility contributes to abnormal responses to perinatal infections establishing a lower threshold for subsequent stress-triggered events. Persistence of infectious stigma may also be responsible for the reactivation of human endogenous retroviruses whose envelope protein, displaying inflammation and neurotoxicity, is over-expressed in patients with BD or SZ [4,5]. Recently, circulating auto-antibodies against the neuronal glutamate NMDA receptor were described in immune encephalitis, but also in psychotic patients, where they show capacities to disorganize NMDAR molecular complexes (Jezequel et al, submitted). Targeting these dysimmune pathways open up new avenues for biomarker discovery and innovative therapeutic strategies in major psychiatric disorders. Auto-antibodies against the neuronal glutamate NMDA receptor were described in immune encephalitis, but also in psychotic patients, where they show capacities to disorganize NMDAR molecular complexes (Jezequel et al, submitted). References [1] Oliveira J., Busson M., Etain B., Jamain S., Hamdani N., Boukouaci W., Amokrane K., Bennabi M., Le Guen E., Darg´el A., Houenou J., Ivanova R., Bellivier F., Henry C., Kahn J.P., Charron D., Krishnamoorthy R., Vervoitte L., Tamouza R., Leboyer M. 2014. Polymorphism of Toll-like receptor 4 gene in Bipolar Disorder. J Aff Disord. 152–154: 395–402. [2] Oliveira J., Hamdani N., Busson. M, Etain B., Bennabi M., Amokrane K., Boukouaci W., Fortier C., Marzais F., Bengoufa D., Bellivier F., Henry C., Kahn J.P., Charron D., Krishnamoorthy R., Le Corvoisier P., Leboyer M., Tamouza R. 2014. Association between tolllike receptor 2 gene diversity and early-onset bipolar disorder. J Affect Disord.165: 135−41. [3] Oliveira J., Etain B., Lajnef M., Hamdani N., Bennabi M., Bengoufa D., Sundaresh A., Ben Chaabane A., Bellivier F., Henry C., Kahn J.P., Charron D., Krishnamoorthy R., Leboyer M., & Tamouza R. Combined
effect of TLR2 gene polymorphism and early life stress on the age at onset of bipolar disorders, Plos One, in press. Disclosure statement: a speech honoraria for Servier and Otsuka, grants from Roche and Takeda
1 University
of Cambridge, Cambridge, United
Impulsivity and compulsivity are behavioural constructs hypothetically underlying a range of impulsive-compulsive disorders, including ADHD, drug addiction and OCD [1,2]. These constructs may represent dimensional neurobehavioural endophenotypes, analogous to the NIMH Research Domain Criteria of proposed relevance to neuropsychiatric research and drug discovery. Impulsivity is the tendency to act prematurely without foresight. Behavioral and neurobiological analysis of this construct, with evidence from both animal and human studies, defines several dissociable forms, including ‘waiting’ and ‘stopping’ impulsivity, depending on distinct fronto-striatal substrates. Impulsivity can arise from exposure to drugs of abuse but may also contribute to the tendency to compulsive drug-taking, both in rodents and in human stimulant drug abusers. Hypothetically, this corresponds to a shift in control from goal-directed to more habitual behaviour, paralleled by shifts in fronto-striatal functional ‘loops’ [1]. Compulsivity, the maladaptive repetition of behaviour, can be postulated on the basis of heterogeneity in reversal learning in rats, some animals exhibiting excessive perseveration. This form of cognitive flexibility depends on serotonergic mechanisms of the orbitofrontal cortex and striatum in rodents, monkeys and, hypothetically, humans, including those with OCD or exhibiting compulsive cocaine seeking behaviour. I will review evidence of a similar imbalance of control from goal-directed to habitual behaviour in OCD to what may occur in addiction [2]. I will also survey common psychopharmacological treatments for impulsivity and compulsivity, possibly relevant to the treatment of other psychiatric or neurological disorders, such as Parkinson’s disease. References [1] Dalley JW, Everitt BJ, Robbins TW (2011) Impulsivity, compulsivity and top-down control. Neuron 69, 680–694. [2] Robbins, T.W., Gillan, C.M., Smith, D.G., de Wit, S. & Ersche, K.D. (2012) Neurocognitive endophenoypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends in Cognitive Sciences, 16, 81−91. Disclosure statement: Consultancy for Cambridge Cognition, Lundbeck, Lilly, Teva, Shire Pharmaceuticals, Otsuka. Research grants from Lillly, Lundbeck and GSK Royalties from Cambridge Cognition Editorial honoraria from Springer and Elsevier.
PL.06. Anna Monika Award Lecture PL.06.01 Anxious temperament: results from a translational neuroscience approach N.H. Kalin1 ° 1 University of Wisconsin, Department of Psychiatry, Madison, USA Anxiety and depressive disorders commonly present early in life. Therefore, an opportunity exists for early identification and
PL.06. Anna Monika Award Lecture intervention prior to the long-term sequelae of these disorders. Studies demonstrate that childhood anxious temperament (AT) is the phenotype most predictive of the later development of anxiety and depression. We characterized AT in developing rhesus monkeys and discovered the altered neural circuitry that underlies AT. Using lesioning strategies, we established that the central nucleus of the amygdala (Ce), is one region that causally underlies the expression of AT. We also characterized phenotypic variation in relation to AT demonstrating common and selective neural substrates that underlie different symptomatic presentations of AT. Heritability analyses demonstrate that AT is approximately 35% heritable and using genetic covariation analyses we further identified the heritable neural substrate responsible for mediating AT. Our work points to the possibility of selectively targeting different components of the neural circuit some of which are more genetically determined while others are more influenced by environment. To investigate molecular mechanisms underlying AT and its neural substrate, we performed genome wide transcriptome analyses that demonstrate a reduction in Ce neuroplasticity gene expression in individuals with extreme AT. We currently are using viral vector infection strategies in young monkeys to test the mechanistic role of these identified alterations in Ce gene regulation. These data provide the foundation for the development of novel early individualized treatment strategies aimed at the prevention of the later development of severe psychopathology. Disclosure statement: Consultant NOT relevant to this activity Corcept Therapeutics. Speaker’s Bureau NOT relevant to this activity CME Outfitters. Grant/Research Support (Secondary Investigators need not disclose) NOT relevant to this activity NIMH. Stock Shareholder (self-managed) NOT relevant to this activity Corcept Therapeutics. Honoraria NOT relevant to this activity Elsevier. Other (Describe) NOT relevant to this activity US Patents 7071323, 7087385, 7122650.
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