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Project
Deep brain stimulation and recording using the Synapse platform: applications in obsessive-compulsive disorder and anorexia nervosa.
Deep brain stimulation (DBS) is a neurosurgical intervention occasionally used to treat selective otherwise-refractory psychiatric disorders. Conventional DBS applies constant amplitude of electrical stimulation to a target brain structure without receiving any forms of biological feedback. Technological advancement allows simultaneous DBS and recording through implanted electrodes, and real-time adjustment of electrical stimulation based on neural feedback. Preliminary experiments have already shown superiority of closed-loop DBS over conventional DBS in Parkinsons disease, but this has not yet been tested in psychiatric indications.
Obsessive-compulsive disorder (OCD) is the first psychiatric indication treated with DBS, and the clinical efficacy of DBS in the region of the bed nucleus of the stria terminalis (BNST) for otherwise-refractory OCD has been recognized over the last decades. The BNST, as part of the extended amygdala, is implicated in anxiety and reward processing, both of which are involved in the clinical symptoms of OCD. Although specific neuronal groups in the BNST related to anxiety and reward processing have been identified, the information carried by local field potentials (LFPs), a form of neural signals more applicable for clinical closed-loop DBS, during obsession/compulsion has not yet been studied. A neuroelectrophysiological biomarker of obsession/compulsion, in the form of LFP, is essential in closed-loop DBS for OCD.
Our main goal in this research project is to gain knowledge about different aspects of closed-loop DBS in the BNST in the schedule-induced polydipsia (SIP) model, an animalmodel of OCD (specifically compulsive drinking). Ultimately we would like to improve current DBS therapy for OCD by implementing closed-loop technology.
In the present work, we first validated the SIP model, tested a newly developed behavioral analysis, and examined the effect of DBSin the BNST on compulsion. Our data showed that the SIP conditioning successfully induced compulsive drinking behavior in rats, and our behavioral analysis system based on video was able to extract and analyze this compulsive behavior. DBS in the BNST significantly suppressed compulsivedrinking but had no significant effect on non-compulsive drinking; DBS applied in random control brain regions had no significant effect on compulsive drinking.
We then performed time-frequency analysis on LFPs recorded in the BNST during compulsive drinking, and discovered a correlation between the relative delta (1-4 Hz) oscillations and compulsion. Specifically, the relative delta power in the right BNST was significantly higher during than before and after compulsion. Moreover, the compulsion-suppressing effect of BNST DBS was significantly correlated withthe percentage change of the relative right-BNST delta power during compulsion. These results suggested delta oscillations in the right BNST asa potential neural biomarker of compulsion.
Finally, a custom closed-loop DBS system for experimental purposes was built and validated in rat. We implemented an open-source microcontroller, which allowed us to use hippocampal LFPs to steer DBS in the mesencephalic reticular formation(mRt). It was well documented that hippocampal theta oscillations were highly related to locomotion, while electrical stimulation in the mRt induced freezing. Our results validated the custom closed-loop DBS system by showing that closed-loop DBS significantly suppressed locomotion, whereas continuous and randomly applied DBS did not have significant effects on locomotion compared to no stimulation.
Besides investigation of closed-loop DBS in OCD, we reviewed DBS for anorexia nervosa, an emerging psychiatric indication of DBS, and designed a clinical trial for future investigation. An analysis on behavioral characteristics in a rat model of anorexia nervosa was also performed.
Lastly, we reviewed some ofthe legal and ethical aspects of neurosurgery for psychiatric disorders. Together with many other expert groups around the world, we published a document of consensus on clinical guidelines for neurosurgery for psychiatric disorders.
Obsessive-compulsive disorder (OCD) is the first psychiatric indication treated with DBS, and the clinical efficacy of DBS in the region of the bed nucleus of the stria terminalis (BNST) for otherwise-refractory OCD has been recognized over the last decades. The BNST, as part of the extended amygdala, is implicated in anxiety and reward processing, both of which are involved in the clinical symptoms of OCD. Although specific neuronal groups in the BNST related to anxiety and reward processing have been identified, the information carried by local field potentials (LFPs), a form of neural signals more applicable for clinical closed-loop DBS, during obsession/compulsion has not yet been studied. A neuroelectrophysiological biomarker of obsession/compulsion, in the form of LFP, is essential in closed-loop DBS for OCD.
Our main goal in this research project is to gain knowledge about different aspects of closed-loop DBS in the BNST in the schedule-induced polydipsia (SIP) model, an animalmodel of OCD (specifically compulsive drinking). Ultimately we would like to improve current DBS therapy for OCD by implementing closed-loop technology.
In the present work, we first validated the SIP model, tested a newly developed behavioral analysis, and examined the effect of DBSin the BNST on compulsion. Our data showed that the SIP conditioning successfully induced compulsive drinking behavior in rats, and our behavioral analysis system based on video was able to extract and analyze this compulsive behavior. DBS in the BNST significantly suppressed compulsivedrinking but had no significant effect on non-compulsive drinking; DBS applied in random control brain regions had no significant effect on compulsive drinking.
We then performed time-frequency analysis on LFPs recorded in the BNST during compulsive drinking, and discovered a correlation between the relative delta (1-4 Hz) oscillations and compulsion. Specifically, the relative delta power in the right BNST was significantly higher during than before and after compulsion. Moreover, the compulsion-suppressing effect of BNST DBS was significantly correlated withthe percentage change of the relative right-BNST delta power during compulsion. These results suggested delta oscillations in the right BNST asa potential neural biomarker of compulsion.
Finally, a custom closed-loop DBS system for experimental purposes was built and validated in rat. We implemented an open-source microcontroller, which allowed us to use hippocampal LFPs to steer DBS in the mesencephalic reticular formation(mRt). It was well documented that hippocampal theta oscillations were highly related to locomotion, while electrical stimulation in the mRt induced freezing. Our results validated the custom closed-loop DBS system by showing that closed-loop DBS significantly suppressed locomotion, whereas continuous and randomly applied DBS did not have significant effects on locomotion compared to no stimulation.
Besides investigation of closed-loop DBS in OCD, we reviewed DBS for anorexia nervosa, an emerging psychiatric indication of DBS, and designed a clinical trial for future investigation. An analysis on behavioral characteristics in a rat model of anorexia nervosa was also performed.
Lastly, we reviewed some ofthe legal and ethical aspects of neurosurgery for psychiatric disorders. Together with many other expert groups around the world, we published a document of consensus on clinical guidelines for neurosurgery for psychiatric disorders.
Date:1 Jan 2011 → 31 Dec 2014
Keywords:Deep brain stimulation, anorexia nervosa., Synapse platform, obsessive-compulsive disorder, recording
Disciplines:Morphological sciences, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences, Biomechanics, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing
Project type:PhD project