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S.09.03 From rats to men: deep brain stimulation in rodent models of psychiatric symptoms
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S.09. Targeted neuromodulatory interventions
[2] Verhagen LA, Egecioglu E, Luijendijk MC, Hillebrand JJ, Adan RA, Dickson SL. 2010 Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity. Eur Neuropsychopharmacol 2010 Jul 8 [Epub ahead of print].
S.09. Targeted neuromodulatory interventions S.09.01 New anatomical and computational perspectives on brain networks involved in compulsive behaviours D. Joel1 ° . 1 Tel Aviv University, Department of Psychology, Tel Aviv, Israel Obsessive-compulsive disorder (OCD) is a psychiatric disorder affecting 1−3% of the population. Although several brain regions have been implicated in the pathophysiology of OCD, including the orbitofrontal cortex, the striatum and the dopaminergic and serotonergic systems, the ways in which these neural systems interact to produce obsessions and compulsions in patients is currently unknown. Work in the signal attenuation rat model of OCD found that lesions to the orbitofrontal cortex decrease striatal serotonin and dopamine content and increase compulsive leverpressing, and that this increase is blocked by intra-striatal administration of a selective serotonin reuptake inhibitor [1]. Lesions to the subthalamic nucleus similarly decrease striatal serotonin and dopamine and increase compulsive lever-pressing [2]. Consistent with these findings, high frequency stimulation of the subthalamic nucleus, which exerts an anti-compulsive effect in OCD patients and in the signal attenuation model, increases dopamine content in the striatum. Taken together, these results suggest that alterations in striatal serotonin and/or dopamine underlie compulsive behaviors. This conclusion adds to previous findings on the effects of dopamine D1 and D2 agonists and antagonists on compulsive lever-pressing, which led to the hypothesis that hypersensitivity of D1 receptors underlies compulsive lever-pressing [3]. Combined with computational models of reinforcement learning in which phasic dopamine signals play a central role, and with recent findings of altered dopamine signal following orbitofrontal lesions, these results suggest that abnormal dopamine signals may be the final common pathway in the production of compulsive behaviors. References [1] Schilman E.A., Klavir O., Winter C., Sohr R., Joel D. 2010 The role of the striatum in compulsive behavior in intact and orbitofrontal cortex lesioned rats: possible involvement of the serotonergic system. Neuropsychopharmacology 35, 1026–1039. [2] Winter C., Flash S., Klavir O., Klein J., Sohr R., Joel D. 2008 The role of the subthalamic nucleus in ‘compulsive’ behavior in rats. Eur. J. Neurosci. 27, 1902–1911. [3] Joel D., Doljansky J. 2003 Selective alleviation of ‘compulsive’ leverpressing in rats by D1, but not D2, blockade: Possible implications for the involvement of D1 receptors in obsessive compulsive disorder. Neuropsychopharmacology 28, 77−85.
S.09.02 Cross-frequency coupling and phase synchronization link nucleus accumbens and medial frontal cortex M. Cohen1 ° . 1 University of Amsterdam, Department of Psychology, Amsterdam, The Netherlands The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated
rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using non-invasive techniques. Here I will provide an overview of our work measuring electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deepbrain-stimulation treatment for obsessive-compulsive disorder. We find that “top-down” directed synchrony from cortex to nucleus accumbens is maximal over medial frontal sites, and significantly stronger when patients anticipate receiving rewards [1]. Additional experiments confirm that these interactions take place within the theta-frequency band [2], which is often associated with memory and cognitive control processes. Studying interactions between the medial frontal cortex and nucleus accumbens are not limited to patients with implanted electrodes; surface EEG can be combined with structural MR imaging to reveal that subjects with stronger anatomical connectivity linking the medial frontal cortex to the ventral striatum have stronger cortical theta-band activity during cognitive control tasks [3]. These findings provide both direct and indirect electrophysiological evidence for a role of the medial frontal cortex in modulating nucleus accumbens activity during reward processing and cognitive control. It is possible that dysfunction within this MFC->accumbens synchronization contributes to pathologies including major depression and obsessive compulsive disorder. References [1] Cohen MX, Bour L, Mantione M, Figee M, et al., 2011 Top-downdirected synchrony from medial frontal cortex to nucleus accumbens during reward anticipation. Human Brain Mapping, 2011, [Epub ahead of print]. [2] Cohen MX Axmacher N, Lenartz D, Elger CE, Sturm V, Schlaepfer TE, 2009 Nuclei accumbens phase synchrony predicts decision-making reversals following negative feedback. J Neurosci. 29(23): 7591−8. [3] Cohen MX. 2011 Error-related medial frontal theta activity predicts cingulate-related structural connectivity. Neuroimage 55(3): 1373−83.
S.09.03 From rats to men: deep brain stimulation in rodent models of psychiatric symptoms C. Winter1 ° . 1 University Hospital Carl Gustav Carus, Dept. of Psychiatry and Psychotherapy, Dresden, Germany Deep brain stimulation (DBS) allows the reversible and specific modulation of neural activity of targeted brain areas as well as associated networks via application of an electric current. As such, it may not only serve as a focal therapeutic strategy in the treatment of otherwise refractory neuro-psychiatric syndromes but also as an experimental approach in mapping brain regions and in understanding the interaction of neural circuits implicated in the pathogenesis of those disorders that in summary are the hypothesized clinical presentation of specific neural dysfunctions and dysfunctional neural networks. The present lecture discusses the use of animal models of psychiatric syndromes as an important source of information for such a mapping attempt: experiments studying the effects of DBS on behavioral as well as neurobiological deficits in animal models of obsessive compulsive disorders, major depression, and schizophrenia are presented. The entirety of the presented studies allows statements on optimal stimulation sites, stimulation parameters and mechanisms underlying DBS effectiveness, each of it as a function of the entity of the modelled disorder. However, the validity and translational significance in promoting
S.10. The role of state versus trait psychiatric symptoms in substance use disorders the understanding of the neural mechanisms and in supporting the advanced establishment of DBS in the treatment of these disorders is variable among the studies and critically depends on the animal model used as well as the experimental design. In conclusion further studies are needed to understand mechanism and effectiveness of DBS in the differentially diseased brain. S.09.05 fTMS and treatment of psychiatric disorders Sommer1 ° ,
Diederen1 ,
Neggers1 ,
Kahn1 .
K.M.J. S.W. R.S. I. 1 University Medical Centre Utrecht, Department of Psychiatry, Utrecht, The Netherlands Functional imaging techniques enable the localisation of specific psychiatric symptoms in individual patients. Especially symptoms that are alternatingly present and absent, such as hallucinations, obsessions, compulsions, tics and thought insertion are readily scanned using an on/off-paradigm. Functional scans when symptoms are present are compared to scans while symptoms are absent, resulting in an activation map. Auditory verbal hallucinations are investigated most extensively with such protocols, showing that activation during this symptom can be on rather various locations, including Broca’s and Wernicke’s area and their contralateral homologues [1]. For focal intervention, as with rTMS, it is important to know if an individual shows most activation during hallucinations in right or left sided areas [2]. Functional imaging can therefore help to direct the rTMS coil to the side where activation was most pronounced [3]. While functional imaging seems apt to determine the SIDE for rTMS stimulation, it is more complicated to use functional imaging for specification of the optimal SITE for stimulation. fMRI is notorious for its rather poor test-retest reliability and hallucinations are no exception to this rule. We scanned hallucinations in 40 patients twice using the on/off-paradigm and compared the focus of maximal activation. While the side of this focus was generally similar between scans, the site showed quite pronounced variation between the two scans. This restricts the use of functional imaging to guide focal intervention, as for example more invasive stimulation with cortical or deep brain electrodes would need more consistent determination of symptom location.
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S.10. The role of state versus trait psychiatric symptoms in substance use disorders S.10.01 Behavioural and neurochemical correlates of relapse vulnerability to cocaine and oxycodone seeking in laboratory rats F. Leri1 ° , Y. Zhou2 , M.J. Kreek2 , C. Allen1 , A.M. Levy1 . 1 University of Guelph, Department of Psychology, Guelph, Canada; 2 Lab of the Biol of Addictive Dis, Rockefeller, New York, USA Two studies were designed to explore behavioral and neural correlates of relapse vulnerability using an animal model whereby all subjects are exposed to identical amounts of drug [1]. SpragueDawley male rats (n = 96 cocaine; n = 75 oxycodone) received a forced-swim test, tests of locomotion reactivity to a novel environment and to cocaine (15 mg/kg IP) or oxycodone (0.25 mg/kg SC), and a hot-plate test. Then, they were implanted with intravenous catheters and, after cocaine (0.05 mg/kg/inf) or oxycodone (0.1 mg/kg/infusion) conditioning and extinction, they were tested for reinstatement induced by a cocaine prime (15 mg/kg IP), an oxycodone prime (0.25 mg/kg SC), and foot-shock stress. Three days following the conclusion of operant testing, rats were challenged with cocaine (15 mg/kg IP) or oxycodone (0.25 mg/kg SC), and sacrificed within 90 min to collect brain and plasma. Low and high drug seekers were identified by median split on responses emitted on reinstatement (prime + stress). In the cocaine study, high drug seekers displayed lower levels of active escape behaviors in the forced-swim test, as well as higher activity in a novel environment. In the oxycodone study, high drug seekers displayed lower pain threshold. High drug seekers in both studies displayed higher levels of plasma corticosterone and lower levels of orexin mRNA expression in the lateral hypothalamus [2]. From these data, it is concluded that although behavioural correlates of relapse vulnerability can differ across drug classes, neurochemical adaptations that develop in particular sub-groups of individuals at risk may be common. References
References [1] Sommer IE, Slotema CW, de Weijer AD, Blom JD, Daalman K, Neggers SF, Somers M, Hoek HW, Aleman A, Kahn RS: Can fMRIguidance improve the efficacy of rTMS treatment for auditory verbal hallucinations? Schizophr. Res. 2007 93(1−3): 406−8. [2] Sommer IE, Diederen KMJ, Blom JD, Neggers SFW and Kahn RS: Auditory Verbal Hallucinations predominantly activate the Right Inferior Frontal Area. Brain 2008 131: 3169−77. [3] Slotema CW, Blom JD, de Weijer AD, Diederen KM, Goekoop R, Looijestijn J, Daalman K, Rijkaart AM, Kahn RS, Hoek HW, Sommer IE: Can low-frequency rTMS really relieve medication-resistant Auditory Verbal Hallucinations? Negative results from a large RCT Biological Psychiatry Dec 6 2010.
[1] Goddard, B., Leri, F. 2006 Reinstatement of conditioned reinforcing properties of cocaine-conditioned stimuli. Pharmacol Biochem Behav 83, 540–546. [2] Leri, F., Zhou, Y., Goddard, B., Levy, A., Jacklin, D., Kreek, M.J. 2008 Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain. Eur Neuropsychopharmacol 19, 238–249.
S.10.02 Current major depression and its role in tobacco dependence: state effects on craving, dopamine release, and smoking cessation L. Zawertailo1 ° , U. Busto1 , P. Selby1 . 1 University of Toronto, Centre for Addiction and Mental HealthDept. of Pharmacology and Toxicology, Toronto, Canada Rates of comorbidity between major depression and tobacco dependence range between 40 and 60%. Furthermore, there is a linear relationship between cigarettes smoked per day and lifetime prevalence of major depression [1]. Depressed smokers are more likely to progress to a more severe level of tobacco
S.09. Targeted neuromodulatory interventions
[2] Verhagen LA, Egecioglu E, Luijendijk MC, Hillebrand JJ, Adan RA, Dickson SL. 2010 Acute and chronic suppression of the central ghrelin signaling system reveals a role in food anticipatory activity. Eur Neuropsychopharmacol 2010 Jul 8 [Epub ahead of print].
S.09. Targeted neuromodulatory interventions S.09.01 New anatomical and computational perspectives on brain networks involved in compulsive behaviours D. Joel1 ° . 1 Tel Aviv University, Department of Psychology, Tel Aviv, Israel Obsessive-compulsive disorder (OCD) is a psychiatric disorder affecting 1−3% of the population. Although several brain regions have been implicated in the pathophysiology of OCD, including the orbitofrontal cortex, the striatum and the dopaminergic and serotonergic systems, the ways in which these neural systems interact to produce obsessions and compulsions in patients is currently unknown. Work in the signal attenuation rat model of OCD found that lesions to the orbitofrontal cortex decrease striatal serotonin and dopamine content and increase compulsive leverpressing, and that this increase is blocked by intra-striatal administration of a selective serotonin reuptake inhibitor [1]. Lesions to the subthalamic nucleus similarly decrease striatal serotonin and dopamine and increase compulsive lever-pressing [2]. Consistent with these findings, high frequency stimulation of the subthalamic nucleus, which exerts an anti-compulsive effect in OCD patients and in the signal attenuation model, increases dopamine content in the striatum. Taken together, these results suggest that alterations in striatal serotonin and/or dopamine underlie compulsive behaviors. This conclusion adds to previous findings on the effects of dopamine D1 and D2 agonists and antagonists on compulsive lever-pressing, which led to the hypothesis that hypersensitivity of D1 receptors underlies compulsive lever-pressing [3]. Combined with computational models of reinforcement learning in which phasic dopamine signals play a central role, and with recent findings of altered dopamine signal following orbitofrontal lesions, these results suggest that abnormal dopamine signals may be the final common pathway in the production of compulsive behaviors. References [1] Schilman E.A., Klavir O., Winter C., Sohr R., Joel D. 2010 The role of the striatum in compulsive behavior in intact and orbitofrontal cortex lesioned rats: possible involvement of the serotonergic system. Neuropsychopharmacology 35, 1026–1039. [2] Winter C., Flash S., Klavir O., Klein J., Sohr R., Joel D. 2008 The role of the subthalamic nucleus in ‘compulsive’ behavior in rats. Eur. J. Neurosci. 27, 1902–1911. [3] Joel D., Doljansky J. 2003 Selective alleviation of ‘compulsive’ leverpressing in rats by D1, but not D2, blockade: Possible implications for the involvement of D1 receptors in obsessive compulsive disorder. Neuropsychopharmacology 28, 77−85.
S.09.02 Cross-frequency coupling and phase synchronization link nucleus accumbens and medial frontal cortex M. Cohen1 ° . 1 University of Amsterdam, Department of Psychology, Amsterdam, The Netherlands The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated
rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using non-invasive techniques. Here I will provide an overview of our work measuring electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deepbrain-stimulation treatment for obsessive-compulsive disorder. We find that “top-down” directed synchrony from cortex to nucleus accumbens is maximal over medial frontal sites, and significantly stronger when patients anticipate receiving rewards [1]. Additional experiments confirm that these interactions take place within the theta-frequency band [2], which is often associated with memory and cognitive control processes. Studying interactions between the medial frontal cortex and nucleus accumbens are not limited to patients with implanted electrodes; surface EEG can be combined with structural MR imaging to reveal that subjects with stronger anatomical connectivity linking the medial frontal cortex to the ventral striatum have stronger cortical theta-band activity during cognitive control tasks [3]. These findings provide both direct and indirect electrophysiological evidence for a role of the medial frontal cortex in modulating nucleus accumbens activity during reward processing and cognitive control. It is possible that dysfunction within this MFC->accumbens synchronization contributes to pathologies including major depression and obsessive compulsive disorder. References [1] Cohen MX, Bour L, Mantione M, Figee M, et al., 2011 Top-downdirected synchrony from medial frontal cortex to nucleus accumbens during reward anticipation. Human Brain Mapping, 2011, [Epub ahead of print]. [2] Cohen MX Axmacher N, Lenartz D, Elger CE, Sturm V, Schlaepfer TE, 2009 Nuclei accumbens phase synchrony predicts decision-making reversals following negative feedback. J Neurosci. 29(23): 7591−8. [3] Cohen MX. 2011 Error-related medial frontal theta activity predicts cingulate-related structural connectivity. Neuroimage 55(3): 1373−83.
S.09.03 From rats to men: deep brain stimulation in rodent models of psychiatric symptoms C. Winter1 ° . 1 University Hospital Carl Gustav Carus, Dept. of Psychiatry and Psychotherapy, Dresden, Germany Deep brain stimulation (DBS) allows the reversible and specific modulation of neural activity of targeted brain areas as well as associated networks via application of an electric current. As such, it may not only serve as a focal therapeutic strategy in the treatment of otherwise refractory neuro-psychiatric syndromes but also as an experimental approach in mapping brain regions and in understanding the interaction of neural circuits implicated in the pathogenesis of those disorders that in summary are the hypothesized clinical presentation of specific neural dysfunctions and dysfunctional neural networks. The present lecture discusses the use of animal models of psychiatric syndromes as an important source of information for such a mapping attempt: experiments studying the effects of DBS on behavioral as well as neurobiological deficits in animal models of obsessive compulsive disorders, major depression, and schizophrenia are presented. The entirety of the presented studies allows statements on optimal stimulation sites, stimulation parameters and mechanisms underlying DBS effectiveness, each of it as a function of the entity of the modelled disorder. However, the validity and translational significance in promoting
S.10. The role of state versus trait psychiatric symptoms in substance use disorders the understanding of the neural mechanisms and in supporting the advanced establishment of DBS in the treatment of these disorders is variable among the studies and critically depends on the animal model used as well as the experimental design. In conclusion further studies are needed to understand mechanism and effectiveness of DBS in the differentially diseased brain. S.09.05 fTMS and treatment of psychiatric disorders Sommer1 ° ,
Diederen1 ,
Neggers1 ,
Kahn1 .
K.M.J. S.W. R.S. I. 1 University Medical Centre Utrecht, Department of Psychiatry, Utrecht, The Netherlands Functional imaging techniques enable the localisation of specific psychiatric symptoms in individual patients. Especially symptoms that are alternatingly present and absent, such as hallucinations, obsessions, compulsions, tics and thought insertion are readily scanned using an on/off-paradigm. Functional scans when symptoms are present are compared to scans while symptoms are absent, resulting in an activation map. Auditory verbal hallucinations are investigated most extensively with such protocols, showing that activation during this symptom can be on rather various locations, including Broca’s and Wernicke’s area and their contralateral homologues [1]. For focal intervention, as with rTMS, it is important to know if an individual shows most activation during hallucinations in right or left sided areas [2]. Functional imaging can therefore help to direct the rTMS coil to the side where activation was most pronounced [3]. While functional imaging seems apt to determine the SIDE for rTMS stimulation, it is more complicated to use functional imaging for specification of the optimal SITE for stimulation. fMRI is notorious for its rather poor test-retest reliability and hallucinations are no exception to this rule. We scanned hallucinations in 40 patients twice using the on/off-paradigm and compared the focus of maximal activation. While the side of this focus was generally similar between scans, the site showed quite pronounced variation between the two scans. This restricts the use of functional imaging to guide focal intervention, as for example more invasive stimulation with cortical or deep brain electrodes would need more consistent determination of symptom location.
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S.10. The role of state versus trait psychiatric symptoms in substance use disorders S.10.01 Behavioural and neurochemical correlates of relapse vulnerability to cocaine and oxycodone seeking in laboratory rats F. Leri1 ° , Y. Zhou2 , M.J. Kreek2 , C. Allen1 , A.M. Levy1 . 1 University of Guelph, Department of Psychology, Guelph, Canada; 2 Lab of the Biol of Addictive Dis, Rockefeller, New York, USA Two studies were designed to explore behavioral and neural correlates of relapse vulnerability using an animal model whereby all subjects are exposed to identical amounts of drug [1]. SpragueDawley male rats (n = 96 cocaine; n = 75 oxycodone) received a forced-swim test, tests of locomotion reactivity to a novel environment and to cocaine (15 mg/kg IP) or oxycodone (0.25 mg/kg SC), and a hot-plate test. Then, they were implanted with intravenous catheters and, after cocaine (0.05 mg/kg/inf) or oxycodone (0.1 mg/kg/infusion) conditioning and extinction, they were tested for reinstatement induced by a cocaine prime (15 mg/kg IP), an oxycodone prime (0.25 mg/kg SC), and foot-shock stress. Three days following the conclusion of operant testing, rats were challenged with cocaine (15 mg/kg IP) or oxycodone (0.25 mg/kg SC), and sacrificed within 90 min to collect brain and plasma. Low and high drug seekers were identified by median split on responses emitted on reinstatement (prime + stress). In the cocaine study, high drug seekers displayed lower levels of active escape behaviors in the forced-swim test, as well as higher activity in a novel environment. In the oxycodone study, high drug seekers displayed lower pain threshold. High drug seekers in both studies displayed higher levels of plasma corticosterone and lower levels of orexin mRNA expression in the lateral hypothalamus [2]. From these data, it is concluded that although behavioural correlates of relapse vulnerability can differ across drug classes, neurochemical adaptations that develop in particular sub-groups of individuals at risk may be common. References
References [1] Sommer IE, Slotema CW, de Weijer AD, Blom JD, Daalman K, Neggers SF, Somers M, Hoek HW, Aleman A, Kahn RS: Can fMRIguidance improve the efficacy of rTMS treatment for auditory verbal hallucinations? Schizophr. Res. 2007 93(1−3): 406−8. [2] Sommer IE, Diederen KMJ, Blom JD, Neggers SFW and Kahn RS: Auditory Verbal Hallucinations predominantly activate the Right Inferior Frontal Area. Brain 2008 131: 3169−77. [3] Slotema CW, Blom JD, de Weijer AD, Diederen KM, Goekoop R, Looijestijn J, Daalman K, Rijkaart AM, Kahn RS, Hoek HW, Sommer IE: Can low-frequency rTMS really relieve medication-resistant Auditory Verbal Hallucinations? Negative results from a large RCT Biological Psychiatry Dec 6 2010.
[1] Goddard, B., Leri, F. 2006 Reinstatement of conditioned reinforcing properties of cocaine-conditioned stimuli. Pharmacol Biochem Behav 83, 540–546. [2] Leri, F., Zhou, Y., Goddard, B., Levy, A., Jacklin, D., Kreek, M.J. 2008 Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain. Eur Neuropsychopharmacol 19, 238–249.
S.10.02 Current major depression and its role in tobacco dependence: state effects on craving, dopamine release, and smoking cessation L. Zawertailo1 ° , U. Busto1 , P. Selby1 . 1 University of Toronto, Centre for Addiction and Mental HealthDept. of Pharmacology and Toxicology, Toronto, Canada Rates of comorbidity between major depression and tobacco dependence range between 40 and 60%. Furthermore, there is a linear relationship between cigarettes smoked per day and lifetime prevalence of major depression [1]. Depressed smokers are more likely to progress to a more severe level of tobacco