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S.21.04 The mechanism of action of deep brain stimulation: preclinical and clinical evidence
S.22. TEM symposium − Is depression a disorder of reward? She fully remitted with DBS, and showed several relapses with pacer dysfunctions [2]. Additionally, DBS lead to a brain-derived nerve growth factor serum level increase in this patient. Most interestingly, all of her relapses showed rapid relapses (about 1 week) and comparable slow remissions (8−12 weeks). A very similar pattern has been reported from patients with DBS of the subgenual cingulate [3]. We would like hypothesize from our data that the asymmetric time course (rapid relapses versus slow remissions) has to be seen in the context of perturbations of specific neurocircuitries and possible alterations of neuroplasticity within modern theories of depression. References [1] Vollmayr, B., Winter, C., Djodari-Irani, A., Klein, J., and Sartorius, A. 2011. Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav. Brain Res. 216, 463–465. [2] Sartorius, A., Kiening, K.L., Kirsch, P., von Gall, C.C., Haberkorn, U., Unterberg, A.W., Henn, F.A., and Meyer-Lindenberg, A. 2010. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol. Psychiatry 67, e9-e11. [3] Holtzheimer, P.E., Kelley, M.E., Gross, R.E., Filkowski, M.M., Garlow, S.J., Barrocas, A., Wint, D., Craighead, M.C., Kozarsky, J., Chismar, R., Moreines, J.L., Mewes, K., Posse, P.R., Gutman, D.A., and Mayberg, H.S. 2012. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch. Gen. Psychiatry 69, 150–158.
S.21.04 The mechanism of action of deep brain stimulation: preclinical and clinical evidence D. Denys1 ° 1 Academic Medical Center (AMC) University of Amsterdam and the Institute for Neuroscience an institute of the Royal Netherlands Academy of Arts and Sciences, Department of Psychiatry, Amsterdam, The Netherlands The use of deep brain stimulation (DBS) in psychiatric disorders has received great interest owing to the small risk of the operation, the reversible nature of the technique, and the possibility of optimizing treatment postoperatively. Currently, DBS in psychiatry is investigated for obsessive-compulsive disorder, addiction and major depression. Little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. Moreover, the speed of the effect of DBS causes fundamental assumptions on the pathophysiology of psychiatry to come into question. In animals, we evaluated the effects of DBS in the nucleus accumbens core on the extracellular concentration of monoaminergic neurotransmitters in the medial prefrontal cortex (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated with 300 mA (120 Hz, pulse width 80 ms) in the nucleus accumbens. In humans, we examined the impact of nucleus accumbens DBS targeted at the nucleus accumbens on local and global brain activity in humans with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Our results suggest that DBS down-regulated the excessive ventral striatal and frontal processing of obsessive-compulsive stimuli, which in turn leads to a shift from compulsive behavior to voluntary control. This re-balancing of frontostriatal dysfunction highlights the potential of DBS for other disorders of compulsivity. Disclosure statement: The research was supported by an unrestricted research grant from Medtronic.
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S.22. TEM symposium − Is depression a disorder of reward? S.22.01 The role of dopamine in antidepressant drug action P.S. D’Aquila1 ° 1 University of Sassari, Dipartimento di Scienze Biomediche, Sassari, Italy Animal and human studies suggest that a sensitization of dopamine-mediated responses underlie the therapeutic effect of antidepressants, with dopamine D2-like receptors playing a prominent role [1]. Although dopamine’s role in antidepressant action has been related to its role in reward-related responses, impaired in depression, the characterization of the functions mediated by dopamine is still matter of debate. Recently, based on the effects of dopamine D1-like and D2-like receptor antagonists on the response to the forced swimming test (FST), a paradigm widely used in the pre-clinical screening of antidepressants, we suggested that dopamine D1-like receptors are involved in behavioural activation, and the level of this activation is “reboosted” on the basis of a dopamine D2-like receptor mediated evalutation of response efficacy [2]. Since antidepressants increase active behaviours in this test, one might speculate that they induce a positive bias on this evaluation mechanism. Preliminary results from our laboratory have shown that the increased activity in the FST observed immediately after a subacute treatment with imipramine was still observable in a subsequent FST session performed 24 h later. Importantly, the effect in the second session was strictly dependent on the experience of the first session under the effect of the drug. Consistently with the view that early changes in emotional processing underlie subsequent mood improvement following antidepressant treatment [3], the FST might reveal an emotional response (perception of response efficacy) which might be relevant in explaining the role of dopamine in the therapeutic effect of antidepressants. References [1] Gershon, A.A., Vishne, T., Grunhaus, L., 2007. Dopamine D2-like receptors and the antidepressant response. Biol Psychiatry 61, 145– 153. [2] D’Aquila, P.S., Galistu, A., 2012. Possible role of dopamine D1-like and D2-like receptors in behavioural activation and evaluation of response efficacy in the forced swimming test. Neuropharmacology 62, 1717– 1729. [3] Pringle, A., Browning, M., Cowen, P.J., Harmer, C.J., 2011. A cognitive neuropsychological model of antidepressant drug action. Prog Neuropsychopharmacol Biol Psychiatry 35, 1586–1592.
S.22.02 Changes in dopamine function in depression C. Martin Soelch1 ° 1 University Fribourg, Department of Clinical Psychology, Fribourg, Switzerland Several observations point to a dysfunction of the central dopamine function in Major Depressive Disorder (MDD). However, the exact nature of this dysfunction remains unclear. Because the mesocorticolimbic dopamine system is involved in reward processing, it has been hypothesized that a reduced function of the DA system could underlie the core symptoms of anhedonia and lack of motivation in depression. Recent findings evidenced a reduced neural activity in response to rewards in regions associated with the cerebral reward system, such as the striatum. Pharmacological
S.21.04 The mechanism of action of deep brain stimulation: preclinical and clinical evidence D. Denys1 ° 1 Academic Medical Center (AMC) University of Amsterdam and the Institute for Neuroscience an institute of the Royal Netherlands Academy of Arts and Sciences, Department of Psychiatry, Amsterdam, The Netherlands The use of deep brain stimulation (DBS) in psychiatric disorders has received great interest owing to the small risk of the operation, the reversible nature of the technique, and the possibility of optimizing treatment postoperatively. Currently, DBS in psychiatry is investigated for obsessive-compulsive disorder, addiction and major depression. Little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. Moreover, the speed of the effect of DBS causes fundamental assumptions on the pathophysiology of psychiatry to come into question. In animals, we evaluated the effects of DBS in the nucleus accumbens core on the extracellular concentration of monoaminergic neurotransmitters in the medial prefrontal cortex (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated with 300 mA (120 Hz, pulse width 80 ms) in the nucleus accumbens. In humans, we examined the impact of nucleus accumbens DBS targeted at the nucleus accumbens on local and global brain activity in humans with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Our results suggest that DBS down-regulated the excessive ventral striatal and frontal processing of obsessive-compulsive stimuli, which in turn leads to a shift from compulsive behavior to voluntary control. This re-balancing of frontostriatal dysfunction highlights the potential of DBS for other disorders of compulsivity. Disclosure statement: The research was supported by an unrestricted research grant from Medtronic.
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S.22. TEM symposium − Is depression a disorder of reward? S.22.01 The role of dopamine in antidepressant drug action P.S. D’Aquila1 ° 1 University of Sassari, Dipartimento di Scienze Biomediche, Sassari, Italy Animal and human studies suggest that a sensitization of dopamine-mediated responses underlie the therapeutic effect of antidepressants, with dopamine D2-like receptors playing a prominent role [1]. Although dopamine’s role in antidepressant action has been related to its role in reward-related responses, impaired in depression, the characterization of the functions mediated by dopamine is still matter of debate. Recently, based on the effects of dopamine D1-like and D2-like receptor antagonists on the response to the forced swimming test (FST), a paradigm widely used in the pre-clinical screening of antidepressants, we suggested that dopamine D1-like receptors are involved in behavioural activation, and the level of this activation is “reboosted” on the basis of a dopamine D2-like receptor mediated evalutation of response efficacy [2]. Since antidepressants increase active behaviours in this test, one might speculate that they induce a positive bias on this evaluation mechanism. Preliminary results from our laboratory have shown that the increased activity in the FST observed immediately after a subacute treatment with imipramine was still observable in a subsequent FST session performed 24 h later. Importantly, the effect in the second session was strictly dependent on the experience of the first session under the effect of the drug. Consistently with the view that early changes in emotional processing underlie subsequent mood improvement following antidepressant treatment [3], the FST might reveal an emotional response (perception of response efficacy) which might be relevant in explaining the role of dopamine in the therapeutic effect of antidepressants. References [1] Gershon, A.A., Vishne, T., Grunhaus, L., 2007. Dopamine D2-like receptors and the antidepressant response. Biol Psychiatry 61, 145– 153. [2] D’Aquila, P.S., Galistu, A., 2012. Possible role of dopamine D1-like and D2-like receptors in behavioural activation and evaluation of response efficacy in the forced swimming test. Neuropharmacology 62, 1717– 1729. [3] Pringle, A., Browning, M., Cowen, P.J., Harmer, C.J., 2011. A cognitive neuropsychological model of antidepressant drug action. Prog Neuropsychopharmacol Biol Psychiatry 35, 1586–1592.
S.22.02 Changes in dopamine function in depression C. Martin Soelch1 ° 1 University Fribourg, Department of Clinical Psychology, Fribourg, Switzerland Several observations point to a dysfunction of the central dopamine function in Major Depressive Disorder (MDD). However, the exact nature of this dysfunction remains unclear. Because the mesocorticolimbic dopamine system is involved in reward processing, it has been hypothesized that a reduced function of the DA system could underlie the core symptoms of anhedonia and lack of motivation in depression. Recent findings evidenced a reduced neural activity in response to rewards in regions associated with the cerebral reward system, such as the striatum. Pharmacological