Obsessive-compulsive disorder (OCD), ranked by the World Health Organization as the tenth most disabling illness, is a neuropsychiatric disease affecting 2.5-3% of the population and characterized by recurrent, persistent thoughts, repetitive compulsive behaviours with chronic evolution with severe complications such as depression, suicide and substance use disorders. Although some forms of OCD can be alleviated with pharmacological and cognitive-behavioural approaches, more than 40% of patients are resistant to these standard treatments and about 10% show severe disability and require institutionalization. Resistant patients may benefit from new surgical therapeutic approaches such as deep brain stimulation (DBS) of specific cerebral regions to modulate neural networks. So far, the number of OCD patients treated with DBS is very limited. Although strict inclusion criteria have been defined based primarily on lesion surgery criteria (e.g. clinical severity, co-morbidity and treatment resistance), DBS outcome varies from excellent to poor between patients for reasons that are still unclear. The goal of PHYSIOBS is to map cortical regions that are modulated by DBS of the subthalamic nucleus (STN) in patients suffering from severe OCD. Brain activation elicited by STN DBS will be compared to that of Parkinson’s disease (PD) patients, in order to identify specific markers of the associative limbic loop as opposed to the motor loop that are the respective DBS targets in those diseases. Neurophysiological activations will be complemented with neuroanatomical measurements and will be correlated to DBS outcome. In particular, we want to provide a neuroimaging approach for the optimisation of stimulation protocols targeting frontal regions. PHYSIOBS methodology will be based upon acquisition and processing of high-density electroencephalography (EEG), high-density functional near infrared optical imaging (fNIRS) and structural magnetic resonance images (MRI, T1 and diffusion tensor imaging – DTI). Those modalities will be used to characterise neuromodulation mechanisms underlying clinical effects of STN DBS. An important concern for therapeutic tuning of DBS parameters in OCD is the delay between the onset of the stimulation procedure and the first detectable positive clinical effects. Therefore, we will specifically search for neurophysiological markers that would predict patients’ outcome and/or that would indicate optimal stimulation parameters. In addition, invasive recordings (multiunit activity, MUA, and local field potentials, LFP) will be recorded during electrodes implantation to relate functional properties of targeted STN subdivisions with modulation of cortical regions by DBS. The expertise gathered in PHYSIOBS is optimal for conducting the proposed research. The coordinating group, Inserm U836 GIN, Grenoble, has been developing for many years electrophysiology and DBS for psychiatric disorders. The consortium also includes the Inserm U1105 GRAMFC, Amiens, for the development of new fNIRS DBS methodology, and the CEA Neurospin, Gif-sur-Yvette, for MRI tractography of stimulated subcortico-cortical tracts.

State of the art. Changes in brain white matter may serve as a biomarker for numerous neurological diseases. Diffusion Weighted Imaging (DWI) is a non-invasive MRI technique providing information on white matter tracts (tractography) by studying water diffusion. Despite being based on mathematical models that only indirectly evaluates the underlying anatomy, tractography is frequently used for research and clinical purposes. Several validation techniques were proposed, none of them being fully convincing in human. General objective. We propose a novel validation approach by qualitatively, but also quantitatively, comparing tracts obtained in the same subjects from in and ex vivo tractography, to dissection considered as a ground truth. Specific aims 1) To build up a database containing, for the same subjects, in vivo (3D and DWI-MRI, neuropsychological evaluation) and ex vivo data (DWI-MRI and tracts reconstructions from dissection), 2) To qualitatively and quantitatively compare in and ex vivo MR-tractography to dissection, 3) To develop a website giving free access to data and to this comparison method for research and teaching. Scientific program (9 tasks 4 years) 1) Project management 2) Quality insurance of the used MR-scanner will use a set of test objects to limit the variability across scanners 3) In vivo MRI and neuropsychological testing. 184 healthy volunteers aged 82 years and over, previously enrolled in a body donation program, will be recruited. Each of them will have a DTI and a QBI DWI-MRI sequence, and a neuropsychological evaluation. Main fiber tracts will be reconstructed using a predefined set of deterministic and probabilistic algorithms 4) Brain extraction and collection. After death (20 expected in 4 years), brains of volunteers will be extracted, formalin-fixed and scanned ex vivo at a high definition using 2 cutting edges MR-scanners: 5) The Connectom scanner (Martinos Center, Charlestown) a unique ultrahigh-gradient-strength MR scanner (300mT/m, 3T) providing high quality ex vivo DWI. 6) The 7T (80mT/M) Neurospin scanner 7) Tracts will also be reconstructed from dissection thanks to the method we previously developed: after anatomical preparation, hemispheres will have a 3D-MRI and then will be dissected after Klingler. Surface of the specimens will be iteratively captured at each step of dissection by 2 techniques: a 3D laser scanner to accurately capture the geometry of the specimen, and a digital camera adding texture to this surface. White matter tracts will be interactively segmented on these surfaces and 3D-reconstructed. 8) Prior to comparison of tractography results to dissections, ex vivo data (tractography and dissection) will be registered onto in vivo MR space. For this purpose, we will use the Combined Volume Surface approach. It was proposed for such a registration with promising results but needs a full validation. We will first quantitatively evaluate and improve this approach, and then qualitatively and quantitatively compare tractography data to dissection regarded as a ground truth. 7) Development of a website giving access to data and comparison method, and to an on-line anatomy teaching tool. Direct related advances 1) Assessment of in vivo tractography algorithms/DWI protocols against dissection 2) Assessment of ex vivo tractography algorithms/DWI protocols against dissection 3) Since diffusion and dissection data will be available to the community, other labs will use them for Validation/improvement of emerging tractography algorithms. 4) Distribution of a neuroanatomy-teaching tool. Indirect related advances 1) Comparison of results from several tractography algorithms. 2) Construction of a probabilistic multimodal anatomical atlas of white matter for the studied population (DWI and dissection data). 3) Study of correlation between neuropsychological data and white matter lesions that may exist in the studied population