Locked-in syndrome after central pontine myelinolysis, an outstanding outcome of two patients.

OBJECTIVE: Central pontine myelinolysis (CPM) is a rare demyelinating disease that affects the pons and which can cause extreme disabilities such as locked-in syndrome (LIS) in the initial phase. The aim of the study was to describe the evolution over a 12-month period of two patients with CPM causing an initial LIS. METHOD: We retrospectively report the unexpected clinical outcome of these two patients in relation with the anatomical damages documented by brain MRI, associated with diffusion tensor imaging and reconstruction of corticospinal tracts in tractography. The following clinical parameters systematically assessed at 3, 6, 9, and 12 months: muscle testing on 12 key muscles (Medical Research Council), prehension metrics (box and block test and purdue pegboard), and independence for acts of daily living (functional independence measure). RESULTS: Both patients showed a progressive recovery beginning between 2 and 3 months after the onset of symptoms, leading to almost complete autonomy at 12 months (FIM > 110), with motor strength greater than 4/5 in all joint segments (MRC > 50/60). On brain MRI with tractography, CST appeared partially preserved at pons level. INTERPRETATION: The possibility of a near-complete functional recovery at 12 months is important to consider given the ethical issues at stake and the discussions about limiting care that may take place initially. It seems to be the consequence of reversible myelin damage combined with partially preserved neurons. Development of collateral pathways or resolution of conduction block may explain this recovery. MRI comprising DTI and tractography could play a key role in the prognosis of motor recovery.

Self-processing in coma, unresponsive wakefulness syndrome and minimally conscious state.

Introduction: Behavioral and cerebral dissociation has been now clearly established in some patients with acquired disorders of consciousness (DoC). Altogether, these studies mainly focused on the preservation of high-level cognitive markers in prolonged DoC, but did not specifically investigate lower but key-cognitive functions to consciousness emergence, such as the ability to take a first-person perspective, notably at the acute stage of coma. We made the hypothesis that the preservation of self-recognition (i) is independent of the behavioral impairment of consciousness, and (ii) can reflect the ability to recover consciousness. Methods: Hence, using bedside Electroencephalography (EEG) recordings, we acquired, in a large cohort of 129 severely brain damaged patients, the brain response to the passive listening of the subject's own name (SON) and unfamiliar other first names (OFN). One hundred and twelve of them (mean age ± SD = 46 ± 18.3 years, sex ratio M/F: 71/41) could be analyzed for the detection of an individual and significant discriminative P3 event-related brain response to the SON as compared to OFN ('SON effect', primary endpoint assessed by temporal clustering permutation tests). Results: Patients were either coma (n = 38), unresponsive wakefulness syndrome (UWS, n = 30) or minimally conscious state (MCS, n = 44), according to the revised version of the Coma Recovery Scale (CRS-R). Overall, 33 DoC patients (29%) evoked a 'SON effect'. This electrophysiological index was similar between coma (29%), MCS (23%) and UWS (34%) patients (p = 0.61). MCS patients at the time of enrolment were more likely to emerged from MCS (EMCS) at 6 months than coma and UWS patients (p = 0.013 for comparison between groups). Among the 72 survivors' patients with event-related responses recorded within 3 months after brain injury, 75% of the 16 patients with a SON effect were EMCS at 6 months, while 59% of the 56 patients without a SON effect evolved to this favorable behavioral outcome. Discussion: About 30% of severely brain-damaged patients suffering from DoC are capable to process salient self-referential auditory stimuli, even in case of absence of behavioral detection of self-conscious processing. We suggest that self-recognition covert brain ability could be an index of consciousness recovery, and thus could help to predict good outcome.

Optimising recovery of consciousness after coma. From bench to bedside and vice versa.

BACKGROUND: Several methods have been proposed to foster recovery of consciousness in patients with disorders of consciousness (DoC). OBJECTIVE: Critically assess pharmacological and non-pharmacological treatments for patients with chronic DoC. METHODS: A narrative mini-review, and critical analysis of the scientific literature on the various proposed therapeutic approaches, with particular attention to level of evidence, risk-benefit ratio, and feasibility. RESULTS AND DISCUSSION: Personalised sensory stimulation, median nerve stimulation, transcranial direct current stimulation (tDCS), amantadine and zolpidem all have favourable risk-benefit ratios and are easy to implement in clinical practice. These treatments should be proposed to every patient with chronic DoC. Comprehensive patient management should also include regular lifting, pain assessment and treatment, attempts to restore sleep and circadian rhythms, implementation of rest periods, comfort and nursing care, and a rehabilitation program with a multi-disciplinary team with expertise in this field. More invasive treatments may cause adverse effects and require further investigation to confirm preliminary, encouraging results and to better define responders' intervention parameters. Scientific studies are essential and given the severity of the disability and handicap that results from DoC, research in this area should aim to develop new therapeutic approaches.

Spatio-Temporal Characterization of Brain Inflammation in a Non-human Primate Stroke Model Mimicking Endovascular Thrombectomy.

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [11C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [11C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [11C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [15O2]H2OPET imaging. [11C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation.

Prior MDMA administration aggravates MPTP-induced Parkinsonism in macaque monkeys.

The aim of this study was to investigate the causal role of an early serotonin injury on parkinsonian-like motor symptomatology. Monkeys were pretreated with 3,4-methylenedioxy-N-methamphetamine (MDMA, or "ecstasy"), known to lesion serotonergic fibers, before being administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We combined behavioural assessment, PET imaging, and immunohistochemistry. Strikingly, prior MDMA administration aggravated MPTP-induced Parkinsonism and associated dopaminergic injury. Monkeys with early MDMA lesions developed parkinsonian deficits more rapidly and more severely. Interestingly, not all symptoms were impacted. Bradykinesia, rigidity and freezing were not affected by early MDMA lesions, whereas spontaneous activities, tremor and abnormal posture were significantly aggravated. Finally, as expected, MDMA induced a decrease of the serotonergic transporter availability. More surprisingly, we found that MDMA evoked also a decreased availability of the dopaminergic transporter to a lesser extent. Altogether, these results show that MDMA administration in non-human primates not only damage serotonergic terminals, but also injure dopaminergic neurons and enhance MPTP neurotoxic action, a completely new result in primates.

Pathophysiology of levodopa-induced dyskinesia: Insights from multimodal imaging and immunohistochemistry in non-human primates.

BACKGROUND: Dopaminergic and serotonergic degenerations alter pharmacological neurotransmission and structural markers in Parkinson's disease (PD). Alteration of diffusion measures in key brain regions depict MPTP/MDMA lesions in the monkey model of PD. Whether dopatherapy impacts such diffusion measures remains an open question. OBJECTIVES: The aim of this study was to investigate the consequences of l-DOPA treatment on diffusion alterations, PET imaging and immunohistochemical markers in MPTP/MDMA-intoxicated monkeys. METHODS: We acquired PET imaging and measures of mean diffusivity and fractional anisotropy longitudinally and correlated them with behavior and post-mortem fiber quantification. RESULTS: Severity of l-DOPA-induced dyskinesia was correlated to serotonin transporter radioligand binding increases in the ventral striatum and the anterior cingulate cortex and decreases of mean diffusivity in the ventral striatum. After lesion of serotonergic fibers by MDMA and the second l-DOPA period, diffusion measures were no more altered while the serotonergic binding still increased in all regions of interest, despite abolition of dyskinesia. Interestingly, in the anterior cingulate cortex, the SERT radioligand binding was negatively correlated to the number of SERT fibers. CONCLUSION: These results show that the increase of SERT radioligand binding is not systematically paralleled by an increase of SERT fibers and does not always reflect the presence of LID. More specifically, our study suggest that SERT increase may be underpinned by an increased density of serotonergic fibers after MPTP and the first l-DOPA period, and by an elevation of SERT itself after MDMA and the second l-DOPA period. This highlights that DTI is complementary to PET imaging to decipher pathophysiological mechanisms underlying l-DOPA-induced dyskinesia in a non-human primate model of PD.

Diffusion tensor imaging marks dopaminergic and serotonergic lesions in the Parkinsonian monkey.

BACKGROUND: Diffusion tensor imaging has received major interest to highlight markers of neurodegeneration in Parkinson's disease. Whether the alteration of diffusion parameters mostly depicts dopaminergic lesions or can also reveal serotonergic denervation remains a question. OBJECTIVES: The aim of this study was to determine the best diffusion tensor imaging markers of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylene-dioxy-methamphetamine (MDMA; also known as ecstasy) lesions in the nonhuman primate. METHODS: We acquired measures of mean diffusivity and fractional anisotropy longitudinally (before and after MPTP and MDMA) and correlated them with severity of parkinsonism, PET imaging, and postmortem fiber quantification. RESULTS: MPTP-induced lesions were associated with increases of mean diffusivity within both the caudate nucleus and the anterior cingulate cortex, whereas MDMA-induced lesions caused an increase of fractional anisotropy within the caudate nucleus. These variations of diffusion tensor imaging correlated with the motor score. CONCLUSION: Taken together, these results demonstrate that diffusion measures within specific brain regions can mark severity of dopaminergic and serotonergic induced lesions in a neurotoxic nonhuman primate model of Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms.

It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([(18)F]DOPA), dopamine D2/D3 receptors ([(11)C]raclopride), and serotonin transporter (11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB) and serotonin 1A receptor ([(18)F]MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [(18)F]DOPA uptake in the anterior putamen, [(11)C]raclopride binding in the posterior striatum, and 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine [(18)F]MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [(11)C]raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms, with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [(18)F]MPPF PET imaging might be a promising biomarker of early degenerative changes in PD. SIGNIFICANCE STATEMENT: The present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.

Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate.

Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.

Serotonergic pharmacology in animal models: from behavioral disorders to dyskinesia.

Serotonin (5-HT) dysfunction has been involved in both movement and behavioral disorders. Serotonin pharmacology improves dyskinetic movements as well as depressive, anxious, aggressive and anorexic symptoms. Animal models have been useful to investigate more precisely to what extent 5-HT is involved and whether drugs targeting the 5-HT system can counteract the symptoms exhibited. We review existing rodent and non-human primate (NHP) animal models in which selective 5-HT or dual 5-HT-norepinephrine (NE) transporter inhibitors, as well as specific 5-HT receptors agonists and antagonists, monoamine oxidase A inhibitors (IMAO-A) and MDMA (Ecstasy) have been used. We review overlaps between the various drug classes involved. We confront behavioral paradigms and treatment regimen. Some but not all animal models and associated pharmacological treatments have been extensively studied in the litterature. In particular, the impact of selective serotonin reuptake inhibitors (SSRI) has been extensively investigated using a variety of pharmacological or genetic rodent models of depression, anxiety, aggressiveness. But the validity of these rodent models is questioned. On the contrary, few studies did address the potential impact of targeting the 5-HT system on NHP models of behavioral disorders, despite the fact that those models may match more closely to human pathologies. Further investigations with carefull behavioral analysis will improve our understanding of neural bases underlying the pathophysiology of movement and behavioral disorders.

A multi-atlas based method for automated anatomical Macaca fascicularis brain MRI segmentation and PET kinetic extraction.

UNLABELLED: MRI templates and digital atlases are needed for automated and reproducible quantitative analysis of non-human primate PET studies. Segmenting brain images via multiple atlases outperforms single-atlas labelling in humans. We present a set of atlases manually delineated on brain MRI scans of the monkey Macaca fascicularis. We use this multi-atlas dataset to evaluate two automated methods in terms of accuracy, robustness and reliability in segmenting brain structures on MRI and extracting regional PET measures. METHODS: Twelve individual Macaca fascicularis high-resolution 3DT1 MR images were acquired. Four individual atlases were created by manually drawing 42 anatomical structures, including cortical and sub-cortical structures, white matter regions, and ventricles. To create the MRI template, we first chose one MRI to define a reference space, and then performed a two-step iterative procedure: affine registration of individual MRIs to the reference MRI, followed by averaging of the twelve resampled MRIs. Automated segmentation in native space was obtained in two ways: 1) Maximum probability atlases were created by decision fusion of two to four individual atlases in the reference space, and transformation back into the individual native space (MAXPROB)(.) 2) One to four individual atlases were registered directly to the individual native space, and combined by decision fusion (PROPAG). Accuracy was evaluated by computing the Dice similarity index and the volume difference. The robustness and reproducibility of PET regional measurements obtained via automated segmentation was evaluated on four co-registered MRI/PET datasets, which included test-retest data. RESULTS: Dice indices were always over 0.7 and reached maximal values of 0.9 for PROPAG with all four individual atlases. There was no significant mean volume bias. The standard deviation of the bias decreased significantly when increasing the number of individual atlases. MAXPROB performed better when increasing the number of atlases used. When all four atlases were used for the MAXPROB creation, the accuracy of morphometric segmentation approached that of the PROPAG method. PET measures extracted either via automatic methods or via the manually defined regions were strongly correlated, with no significant regional differences between methods. Intra-class correlation coefficients for test-retest data were over 0.87. CONCLUSIONS: Compared to single atlas extractions, multi-atlas methods improve the accuracy of region definition. They also perform comparably to manually defined regions for PET quantification. Multiple atlases of Macaca fascicularis brains are now available and allow reproducible and simplified analyses.