Promoting deep brain stimulation as a therapeutic alternative for treatment-resistant psychiatric disorders

by Mareike Anka Voget

Institution: Freie Universitt Berlin
Year: 2017
Posted: 02/01/2018
Record ID: 2152378
Full text PDF: http://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000105829


Currently available treatment methods for major depression (MD) and schizophrenia (SZ) yield unsatisfactory results and as a consequence, a considerable portion of patients remains therapy- resistant. Conceptualization of psychiatric disorders as representations of dysfunctional neural networks has led to investigating new causal therapeutic interventions such as deep brain stimulation (DBS), an approach that has been granted a humanitarian device exemption for severe obsessive-compulsive disorder and is tested for MD and SZ. Despite initial promising findings, recent trials for antidepressant DBS showed no efficacy warranting further research, including preclinical studies, to improve DBS settings. This thesis aimed to elucidate optimal DBS targets and parameters on anti-depressant efficacy and to test a preventive approach of DBS application in the context of SZ using valid rat models of both dysfunctions: i) Chronic- intermittent and chronic-continuous bilateral high-frequency DBS to different depression- associated brain regions were applied in the Flinders Sensitive Line rat model of MD and behavioral effects were assessed with a variety of tests. The intracranial self-stimulation paradigm was used to investigate neurobiological circuits mediating anti-depressant DBS effects. Results show symptom-specific anti-depressant effects with chronic-intermittent DBS to the ventromedial prefrontal cortex (vmPFC) and medial forebrain bundle (MFB) being more efficient in reducing depression-like behavior than nucleus accumbens-DBS. Effects could not be enhanced using prolonged DBS protocols. Anti-depressant responses of both areas seem to be mediated by different circuits as MFB- but not vmPFC-DBS was shown to interact with the reward system. ii) chronic-continuous vmPFC-DBS was applied prior to symptom manifestation to maternally immune stimulated rats constituting a neurodevelopmental SZ-model. The effects on behavioral and neurobiological SZ-associated deficits were tested in adulthood. Results show early neuromodulation to prevent behavioral SZ-like abnormalities in adulthood. In both models, effects of vmPFC-DBS on neurotransmission in pathology-relevant brain areas were tested and revealed pathology-specific normalization of disturbances in the serotonergic and dopaminergic systems. Findings of symptom- and target-specific anti-depressant DBS effects are of potential translational relevance suggesting that stimulation targets in the clinic should be selected on an individual basis considering the patient's symptom profile. They further indicate that continuous stimulation is not necessarily favorable to intermittent DBS protocols, pointing towards the usefulness of more temporally and spatially adaptive forms of DBS. The capacity of DBS to prevent SZ-like behavioral and neurobiological disruptions calls for research into non-invasive forms of neuromodulation to interfere with disease progression in high-risk indiviuals. Derzeit verfugbare Therapiemethoden der Depression (MD) und Schizophrenie (SZ) liefern