Noradrenergic alterations in Parkinson's disease: a combined 11C-yohimbine PET/neuromelanin MRI study.

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson's disease, but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluated two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson's disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI; and the density of α2-adrenergic receptors (ARs) with PET using 11C-yohimbine. Thirty patients with Parkinson's disease and 30 age- and sex-matched healthy control subjects were included. The characteristics of the patients' symptoms were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared with controls and diminished 11C-yohimbine binding in widespread cortical regions, including the motor cortex, as well as in the insula, thalamus and putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-AR availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These results highlight a multifaceted alteration of the noradrenergic system in Parkinson's disease since locus coeruleus and α2-AR degeneration were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunction that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson's disease.

Circadian copeptin and oxytocin profiles in anorexia nervosa: Exploring the interplay with neurohypophysis opioid tone.

CONTEXT: Neurohypophysis (NH) function in eating disorders (ED) remains poorly elucidated. Studies on vasopressin and oxytocin display inconclusive findings regarding their levels and associations with psychological complications in ED. The profile of opioid tone, a crucial NH activity regulator, is also unknown. OBJECTIVE: To characterise the circadian profile of NH hormones and NH opioid tone using positron emission tomography/MRI (PET/MRI) imaging in patients with ED compared to healthy controls. METHODS: Twelve-point plasma circadian profiles of copeptin and oxytocin, alongside nutritional and psychological scores, were assessed in age-matched female participants: 13 patients with anorexia nervosa restrictive-type (ANR), 12 patients recovered from AN (ANrec), 14 patients with bulimia nervosa and 12 controls. Neurohypophysis PET/MRI [11C] diprenorphin binding potential (BPND) was evaluated in AN, ANrec and controls. RESULTS: Results revealed lower copeptin circadian levels in both ANR and ANrec compared to controls, with no oxytocin differences. Bulimia nervosa exhibited elevated copeptin and low oxytocin levels. [11C] diprenorphin pituitary binding was fully localised in NH. Anorexia nervosa restrictive-type displayed lower NH [11C] diprenorphin BPND (indicating higher opioid tone) and volume than controls. In ANR, copeptin inversely correlated with osmolarity. Neurohypophysis [11C] diprenorphin BPND did not correlated with copeptin or oxytocin. CONCLUSION: Copeptin demonstrated significant group differences, highlighting its potential diagnostic and prognostic value. Oxytocin levels exhibited conflicting results, questioning the reliability of peripheral blood assessment. Increased NH opioid tone in anorexia nervosa may influence the vasopressin or oxytocin release, suggesting potential therapeutic applications.

[18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1A receptors in humans.

PURPOSE: F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification. METHODS: PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test-retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF). RESULTS: [18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test-retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions. CONCLUSION: The favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640's kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry. TRIAL REGISTRATION: Trial Registration EudraCT 2017-002,722-21.

Modeling [11C]yohimbine PET human brain kinetics with test-retest reliability, competition sensitivity studies and search for a suitable reference region.

Previous work introduced the [11C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [11C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [11C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap. METHODS: Thirteen healthy humans underwent two [11C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested. RESULTS: We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTMCC (r2=0.94). Test-retest showed that the SRTMCC is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTMCERWM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTMCC, regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis. CONCLUSION: The results add experimental support for the suitability of [11C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.

The Neuro-Computational Architecture of Value-Based Selection in the Human Brain.

Current neural models of value-based decision-making consider choices as a 2-stage process, proceeding from the "valuation" of each option under consideration to the "selection" of the best option on the basis of their subjective values. However, little is known about the computational mechanisms at play at the selection stage and its implementation in the human brain. Here, we used drift-diffusion models combined with model-based functional magnetic resonance imaging, effective connectivity, and multivariate pattern analysis to characterize the neuro-computational architecture of value-based decisions. We found that 2 key drift-diffusion computations at the selection stage, namely integration and choice readout, engage distinct brain regions, with the dorsolateral prefrontal cortex integrating a decision value signal computed in the ventromedial prefrontal cortex, and the posterior parietal cortex reading out choice outcomes. Our findings suggest that this prefronto-parietal network acts as a hub implementing behavioral selection through a distributed drift-diffusion process.

Frontal Transcranial Direct Current Stimulation Induces Dopamine Release in the Ventral Striatum in Human.

A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.

Oxytocin Fails to Recruit Serotonergic Neurotransmission in the Autistic Brain.

Oxytocin (OT), a neuropeptide involved in affiliation has been shown to enhance social skills in patients with autism spectrum disorders (ASD). Nevertheless, OT improvements seem ephemeral. Animal research has demonstrated OT action on serotonin (5-HT), an interaction that we also found in the healthy human brain. Whether such synaptic interplay also occurs in ASD patients is unknown. To address this issue, we mapped the effects of intranasal OT on 5-HT in 18 patients with ASD and 24 healthy controls (HC) in a double blind, placebo controlled, within subject PET-scan experiment. Each participant underwent two scans: baseline and spray (OT or placebo). Using the radiotracer [18 F]MPPF, marking the 5-HT 1A receptor (5-HT1AR), we measured MPPF-Binding Potential (BP) as an index of OT-induced serotonin functional modulation. At baseline ASD patients did not differ from controls for 5-HT1AR concentration and distribution. However, while OT significantly increased MPPF BP in several brain regions of HC, no changes were observed in the ASD group. Serotonin serum concentration analysis corroborated these results. Our findings suggest a disturbed OT-serotonin interaction in autism. This may limit the potential benefits of OT in these patients and open the ways to investigate combined OT-serotonin treatments.

Others' Sheer Presence Boosts Brain Activity in the Attention (But Not the Motivation) Network.

The sheer presence of another member of the same species affects performance, sometimes impeding it, sometimes enhancing it. For well-learned tasks, the effect is generally positive. This fundamental form of social influence, known as social facilitation, concerns human as well as nonhuman animals and affects many behaviors from food consumption to cognition. In psychology, this phenomenon has been known for over a century. Yet, its underlying mechanism (motivation or attention) remains debated, its relationship to stress unclear, and its neural substrates unknown. To address these issues, we investigated the behavioral, neuronal, and endocrinological markers of social facilitation in monkeys trained to touch images to obtain rewards. When another animal was present, performance was enhanced, but testing-induced stress (i.e., plasma cortisol elevation) was unchanged, as was metabolic activity in the brain motivation network. Rather, task-related activity in the (right) attention frontoparietal network encompassing the lateral prefrontal cortex, ventral premotor cortex, frontal eye field, and intraparietal sulcus was increased when another individual was present compared with when animals were tested alone. These results establish the very first link between the behavioral enhancement produced by the mere presence of a peer and an increase of metabolic activity in those brain structures underpinning attention.

Switching brain serotonin with oxytocin.

Serotonin (5-HT) and oxytocin (OXT) are two neuromodulators involved in human affect and sociality and in disorders like depression and autism. We asked whether these chemical messengers interact in the regulation of emotion-based behavior by administering OXT or placebo to 24 healthy subjects and mapping cerebral 5-HT system by using 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), an antagonist of 5-HT1A receptors. OXT increased [(18)F]MPPF nondisplaceable binding potential (BPND) in the dorsal raphe nucleus (DRN), the core area of 5-HT synthesis, and in the amygdala/hippocampal complex, insula, and orbitofrontal cortex. Importantly, the amygdala appears central in the regulation of 5-HT by OXT: [(18)F]MPPF BPND changes in the DRN correlated with changes in right amygdala, which were in turn correlated with changes in hippocampus, insula, subgenual, and orbitofrontal cortex, a circuit implicated in the control of stress, mood, and social behaviors. OXT administration is known to inhibit amygdala activity and results in a decrease of anxiety, whereas high amygdala activity and 5-HT dysregulation have been associated with increased anxiety. The present study reveals a previously unidentified form of interaction between these two systems in the human brain, i.e., the role of OXT in the inhibitory regulation of 5-HT signaling, which could lead to novel therapeutic strategies for mental disorders.

Neural substrates of levodopa-responsive gait disorders and freezing in advanced Parkinson's disease: a kinesthetic imagery approach.

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2 (15) 0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery.

Structure-function relationship of the pituitary gland in anorexia nervosa and intense physical activity.

Patients with Anorexia Nervosa (AN) and athletes share intense physical activity and pituitary hormonal disturbances related to absolute (AN) or relative (athletes) undernutrition. Pituitary gland (PG) structure evaluations in those conditions are scarce, and did not differentiate anterior from posterior lobe. We evaluated the structure-function relationship of anterior and posterior PG in AN and athletes, and potential reversibility of this alteration in a group of weight-recovered patients (AN_Rec). Manual delineation of anterior (AP) and posterior (PP) PG was performed on T1-weighted MR images in 17 women with AN, 15 women with AN_Rec, 18 athletes women and 25 female controls. Anthropometric, hormonal, and psychometric parameters were explored and correlated with PG volumes. AP volume (APV) was lower in AN (448 ± 82 mm3), AN_Rec (505 ± 59 mm3), and athletes (540 ± 101 mm3) vs. Controls (615 ± 61 mm3, p < 0.00001, p < 0.00001 and p = 0.02, respectively); and smaller in AN vs. AN_Rec (p = 0.007). PP volume did not show any differences between the groups. APV was positively correlated with weight (R = 0.36, p = 0.011) in AN, and luteinizing hormone (R = 0.35, p = 0.014) in total group. In AN, mean growth hormone (GH) was negatively correlated with global pituitary volume (R = 0.31, p = 0.031) and APV (R = 0.29, p = 0.037). Absolute and relative undernutrition led to a decreased anterior pituitary gland volume, which was reversible with weight gain, correlated with low bodyweight, and blockade of gonadal hypothalamic-pituitary axis. Intriguing inverse correlation between anterior pituitary gland volume and GH plasma level could suggests a low storage capacity of anterior pituitary gland and increased reactivity to low insulin-like growth factor type 1.

MRI atlas of the pituitary gland in young female adults.

The probabilistic topography and inter-individual variability of the pituitary gland (PG) remain undetermined. The absence of a standardized reference atlas hinders research on PG volumetrics. In this study, we aimed at creating maximum probability maps for the anterior and posterior PG in young female adults. We manually delineated the anterior and posterior parts of the pituitary glands in 26 healthy subjects using high-resolution MRI T1 images. A three-step procedure and a cost function-masking approach were employed to optimize spatial normalization for the PG. We generated probabilistic atlases and maximum probability maps, which were subsequently coregistered back to the subjects' space and compared to manual delineations. Manual measurements led to a total pituitary volume of 705 ± 88 mm³, with the anterior and posterior volumes measuring 614 ± 82 mm³ and 91 ± 20 mm³, respectively. The mean relative volume difference between manual and atlas-based estimations was 1.3%. The global pituitary atlas exhibited an 80% (± 9%) overlap for the DICE index and 67% (± 11%) for the Jaccard index. Similarly, these values were 77% (± 13%) and 64% (± 14%) for the anterior pituitary atlas and 62% (± 21%) and 47% (± 17%) for the posterior PG atlas, respectively. We observed a substantial concordance and a significant correlation between the volume estimations of the manual and atlas-based methods for the global pituitary and anterior volumes. The maximum probability maps of the anterior and posterior PG lay the groundwork for automatic atlas-based segmentation methods and the standardized analysis of large PG datasets.

The PREMISE database of 20 Macaca fascicularis PET/MRI brain images available for research.

Non-human primate studies are unique in translational research, especially in neurosciences where neuroimaging approaches are the preferred methods used for cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community, while limiting the number of animals used in research. Here we present a simultaneous positron emission tomography (PET)/magnetic resonance (MR) dataset of 20 Macaca fascicularis images structured according to the Brain Imaging Data Structure standards. This database contains multiple MR imaging sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation imaging using respectively [15O]H2O and [11C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assess all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity and the pseudo-noise-equivalent-count rate (dynamic and at maximum) for PET data. Our study provides a detailed example for quality control integration in preclinical and translational PET/MR studies with the aim of increasing reproducibility. The PREMISE database is stored and available through the PRIME-DE consortium repository.

Striatal Serotonin 4 Receptor is Increased in Experimental Parkinsonism and Dyskinesia.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Distribution of α2-Adrenergic Receptors in the Living Human Brain Using [11C]yohimbine PET.

The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [11C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20-50) to perform direct quantification of regional alpha 2 adrenergic receptors' (α2-ARs) availability in the living human brain. The global map shows the highest [11C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [11C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α2-ARs is suspected.

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.

Noradrenaline and Movement Initiation Disorders in Parkinson's Disease: A Pharmacological Functional MRI Study with Clonidine.

Slowness of movement initiation is a cardinal motor feature of Parkinson's disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 µg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson's disease.

Case Report: True Motor Recovery of Upper Limb Beyond 5 Years Post-stroke.

Most of motor recovery usually occurs within the first 3 months after stroke. Herein is reported a remarkable late recovery of the right upper-limb motor function after a left middle cerebral artery stroke. This recovery happened progressively, from two to 12 years post-stroke onset, and along a proximo-distal gradient, including dissociated finger movements after 5 years. Standardized clinical assessment and quantified analysis of the reach-to-grasp movement were repeated over time to characterize the recovery. Twelve years after stroke onset, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation (TMS) analyses of the corticospinal tracts were carried out to investigate the plasticity mechanisms and efferent pathways underlying motor control of the paretic hand. Clinical evaluations and quantified movement analysis argue for a true neurological recovery rather than a compensation mechanism. DTI showed a significant decrease of fractional anisotropy, associated with a severe atrophy, only in the upper part of the left corticospinal tract (CST), suggesting an alteration of the CST at the level of the infarction that is not propagated downstream. The finger opposition movement of the right paretic hand was associated with fMRI activations of a broad network including predominantly the contralateral sensorimotor areas. Motor evoked potentials were normal and the selective stimulation of the right hemisphere did not elicit any response of the ipsilateral upper limb. These findings support the idea that the motor control of the paretic hand is mediated mainly by the contralateral sensorimotor cortex and the corresponding CST, but also by a plasticity of motor-related areas in both hemispheres. To our knowledge, this is the first report of a high quality upper-limb recovery occurring more than 2 years after stroke with a genuine insight of brain plasticity mechanisms.

The architecture of reward value coding in the human orbitofrontal cortex.

To ensure their survival, animals exhibit a number of reward-directed behaviors, such as foraging for food or searching for mates. This suggests that a core set of brain regions may be shared by many species to process different types of rewards. Conversely, many new brain areas have emerged over the course of evolution, suggesting potential specialization of specific brain regions in the processing of more recent rewards such as money. Here, using functional magnetic resonance imaging in humans, we identified the common and distinct brain systems processing the value of erotic stimuli and monetary gains. First, we provide evidence that a set of neural structures, including the ventral striatum, anterior insula, anterior cingulate cortex, and midbrain, encodes the subjective value of rewards regardless of their type, consistent with a general hedonic representation. More importantly, our results reveal reward-specific representations in the orbitofrontal cortex (OFC): whereas the anterior lateral OFC, a phylogenetically recent structure, processes monetary gains, the posterior lateral OFC, phylogenetically and ontogenetically older, processes more basic erotic stimuli. This dissociation between OFC representations of primary and secondary rewards parallels current views on lateral prefrontal cortex organization in cognitive control, suggesting an increasing trend in complexity along a postero-anterior axis according to more abstract representations. Together, our results support a modular view of reward value coding in the brain and propose that a unifying principle of postero-anterior organization can be applied to the OFC.