Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

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Our findings indicate that connectivity decreases associated with propofol sedation, involving the thalamus and insula, are relatively small compared with those already caused by DOC-associated structural brain injury. Nonetheless, given the known importance of the thalamus in brain arousal, its disruption could well reflect the diminished movement obtained in these patients. However, more research is needed on this topic to fully address the research question.

Main objective: Disorders of consciousness (DOC; encompassing coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state minus/plus (MCS-/+)) are associated with structural brain injury. The extent of this damage remains poorly understood and merits a detailed examination using novel analysis techniques. Research design/methods and procedures: This study used voxel-based morphometry (VBM) on structural magnetic resonance imaging scans of 61 patients with DOC to examine grey and white matter injury associated with DOC, time spent in DOC, aetiology and diagnosis. Main outcomes and results: DOC and time spent in DOC were found to be associated with widespread structural brain injury, although the latter did not correlate strongly with injury in the right cerebral hemisphere. Traumatic, as compared to non-traumatic aetiology, was related to more injury in the brainstem, midbrain, thalamus, hypothalamus, basal forebrain, cerebellum, and posterior corpus callosum. Potential structural differences were found between VS/ UWS and MCS and between MCS-and MCS+, but need further examination. Conclusions: The findings indicate that both traumatic and non-traumatic DOC are associated with widespread structural brain injury, although differences exist that could lead to aetiologyspecific treatment strategies. Furthermore, the high degree of atrophy occurring after initial brain injury prompts the development and use of neuroprotective techniques to potentially increase patients' chances of recovery. KeywordsVegetative state/unresponsive wakefulness syndrome, minimally conscious state, structural brain injury, voxel-based morphometry History

Propofol is one of the most commonly used anesthetics in the world, but much remains unknown about the mechanisms by which it induces loss of consciousness. In this resting-state functional magnetic resonance imaging study, we examined qualitative and quantitative changes of resting-state networks (RSNs), total brain connectivity, and mean oscillation frequencies of the regional blood oxygenation level-dependent (BOLD) signal, associated with propofol-induced mild sedation and loss of responsiveness in healthy subjects. We found that detectability of RSNs diminished significantly with loss of responsiveness, and total brain connectivity decreased strongly in the frontal cortex, which was associated with increased mean oscillation frequencies of the BOLD signal. Our results suggest a pivotal role of the frontal cortex in propofol-induced loss of responsiveness.

Parkinson’s disease (PD) is a neurodegenerative synucleinopathy characterized by the degeneration of neuromelanin (NM)-containing dopaminergic neurons and deposition of iron in the substantia nigra (SN). How regional NM loss and iron accumulation within specific areas of SN relate to nigro-striatal dysfunction needs to be clarified. We measured dopaminergic function in pre- and postcommissural putamen by [18F]DOPA PET in 23 Parkinson’s disease patients and 23 healthy control (HC) participants in whom NM content and iron load were assessed in medial and lateral SN, respectively, by NM-sensitive and quantitative R2* MRI. Data analysis consisted of voxelwise regressions testing the group effect and its interaction with NM or iron signals. In PD patients, R2* was selectively increased in left lateral SN as compared to healthy participants, suggesting a local accumulation of iron in Parkinson’s disease. By contrast, NM signal differed between PD and HC, without specific regional specificity within SN. Dopaminergic function in posterior putamen decreased as R2* increased in lateral SN, indicating that dopaminergic function impairment progresses with iron accumulation in the SN. Dopaminergic function was also positively correlated with NM signal in lateral SN, indicating that dopaminergic function impairment progresses with depigmentation in the SN. A complex relationship was detected between R2* in the lateral SN and NM signal in the medial SN. In conclusion, multimodal imaging reveals regionally specific relationships between iron accumulation and depigmentation within the SN of Parkinson’s disease and provides in vivo insights in its neuropathology.

Brain structure abnormalities throughout the course of Parkinson's Disease (PD) have yet to be fully elucidated. Inconsistent findings across studies may be partly due to small sample sizes and heterogeneous analysis methods. Using a multicenter approach and harmonized analysis methods, we aimed to overcome these limitations and shed light on disease stage-specific profiles of PD pathology as suggested by in vivo neuroimaging. Individual brain MRI and clinical data from 2,367 PD patients and 1,183 healthy controls were collected from 19 sites, deriving from 20 countries. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effect linear models. Patients were grouped according to the Hoehn & Yahr (HY) disease stages and compared to age- and sex-matched controls. Within the PD sample, we investigated associations between Montreal Cognitive Assessment (MoCA) scores and brain morphology. The main analysis showed a thinner cortex in 38 of 68 regions in PD patients compared to controls (dmax = -0·25, dmin = -0·13). The bilateral putamen (left: d = -0·16, right: d = -0·16) and left amygdala (d = -0·15) were smaller in patients, while the left thalamus was larger (d = 0·17). HY staging indicated that a thinner cortex initially presents in the occipital, parietal and temporal cortex, and extends towards caudally located brain regions with increased disease severity. From HY stage 2 and onwards the bilateral putamen and amygdala were consistently smaller with larger effects denoting each increment. Finally, we found that poorer cognitive cognitive performance was associated with widespread cortical thinning as well as lower volumes of core limbic structures. Our findings offer robust and novel imaging signatures that are specific to the disease severity stages and in line with an ongoing neurodegenerative process, highlighting the importance of such multicenter collaborations. Funding: NIH Big Data to Knowledge program, ENIGMA World Aging Center, and ENIGMA Sex Differences Initiative, and other international agencies (listed in full in the Acknowledgments).

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