title: Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression.
abstract: Deep brain stimulation (DBS) of several targets induces beneficial responses in approximately 60% of patients suffering from treatment-resistant depression (TRD). The remaining 40% indicate that these stimulation sites do not bear therapeutic relevance for all TRD patients and consequently DBS-targets should be selected according to individual symptom profiles. We here used two animal models of depression known to have different genetic backgrounds and behavioral responses: the therapy-responsive Flinders sensitive line (FSL) and the therapy-refractory congenitally learned helpless rats (cLH) to study symptom-specific DBS effects i) of different brain sites ii) at different stimulation parameters, and iii) at different expressions of the disease. Sham-stimulation/DBS was applied chronic-intermittently or chronic-continuously to either the ventromedial prefrontal cortex (vmPFC, rodent equivalent to subgenual cingulate), nucleus accumbens (Nacc) or subthalamic nucleus (STN), and effects were studied on different depression-associated behaviors, i.e. anhedonia, immobility/behavioral despair and learned helplessness. Biochemical substrates of behaviorally effective versus ineffective DBS were analyzed using in-vivo microdialysis and post-mortem high-performance liquid chromatography (HPLC). We found that i) vmPFC-DBS outperforms Nacc-DBS, ii) STN-DBS increases depressive states, iii) chronic-continuous DBS does not add benefits compared to chronic-intermittent DBS, iv) DBS-efficacy depends on the disease expression modeled and iv) antidepressant DBS is associated with an increase in serotonin turnover alongside site-specific reductions in serotonin contents. The reported limited effectiveness of vmPFC DBS suggests that future research may consider the specific disease expression, investigation of different DBS-targets and alternative parameter settings.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany; International Graduate Program Medical Neurosciences, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Rummel
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany; International Graduate Program Medical Neurosciences, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Voget
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Ravit
authors.initials: R
authors.lastname: Hadar
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ewing
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sohr
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Klein
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, 68159 Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, St Görans Hospital, Tomtebodavägen 18A, 17177 Stockholm, Sweden.
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.affiliation: Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, 68159 Mannheim, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vollmayr
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: christine.winter@uniklinikum-dresden.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Winter
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D046690:Deep Brain Stimulation / Q000379:methods*; D003863:Depression / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D055664:Electrochemical Techniques; D005106:Exploratory Behavior / Q000502:physiology; D005518:Food Preferences; D006380:Helplessness, Learned; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000473:pathology; D017397:Prefrontal Cortex / Q000502:physiology; D051381:Rats; D020531:Subthalamic Nucleus / Q000502:physiology; D013395:Sucrose / Q000378:metabolism; D013550:Swimming / Q000523:psychology
chemical_list: D015306:Biogenic Monoamines; D013395:Sucrose
keywords: Deep brain stimulation; Depression; Parameter settings; Rat model