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Background: Reversal learning is widely used to analyze cognitive flexibility and characterize behavioral abnormalities associated with impulsivity and disinhibition. Recent studies using fMRI have focused on regions involved in reversal learning with negative and positive reinforcers. Although the frontal cortex has been consistently implicated in reversal learning, few studies have focused on whether reward and punishment may have different effects on lateral frontal structures in these tasks. Here, in eight healthy subjects, we used functional near infra-red spectroscopy (fNIRS) to characterize brain activity dynamics and differentiate the involvement of frontal structures in learning driven by reward and punishment. Results: We observed functional hemispheric asymmetries between punishment and reward processing by fNIRS following reversal of a learned rule. Moreover, the left dorsolateral prefrontal cortex (l-DLPFC) and inferior frontal gyrus (IFG) were activated under the reward condition only, whereas the orbito-frontal cortex (OFC) was significantly activated under the punishment condition, with a tendency towards activation for the right cortical hemisphere (r-DLPFC and r-IFG). Our results are compatible with the suggestion that the DLPFC is involved in the detection of contingency change. We propose a new representation for reward and punishment, with left lateralization for the reward process. Conclusions: These results provide insights into the indirect neural mechanisms of reversal learning and behavioral flexibility and confirm the use of fNIRS imaging in reversal-learning tasks as a translational strategy, particularly in subjects who cannot undergo fMRI recordings.

Microelectrode recordings (MERs) are often used during deep brain stimulation (DBS) surgeries to confirm the position of electrodes in patients with advanced Parkinson's disease. The present study focused on 32 patients who had undergone DBS surgery for advanced Parkinson's disease. The first objective was to confront the anatomical locations of intraoperative individual MERs as determined electrophysiologically with those determined postoperatively by image reconstructions. The second aim was to search for differences in cell characteristics among the three subthalamic nucleus (STN) subdivisions and between the STN and other identified subcortical structures. Using the DISTAL atlas implemented in the Lead-DBS image reconstruction toolbox, each MER location was determined postoperatively and attributed to specific anatomical structures (sensorimotor, associative or limbic STN; substantia nigra [SN], thalamus, nucleus reticularis polaris, zona incerta [ZI]). The STN dorsal borders determined intraoperatively from electrophysiology were then compared with the STN dorsal borders determined by the reconstructed images. Parameters of spike clusters (firing rates, amplitudes - with minimum amplitude of 60 μV -, spike durations, amplitude spectral density of β-oscillations) were compared between structures (ANOVAs on ranks). Two hundred and thirty one MERs were analyzed (144 in 34 STNs, 7 in 4 thalami, 5 in 4 ZIs, 34 in 10 SNs, 41 others). The average difference in depth of the electrophysiological dorsal STN entry in comparison with the STN entry obtained with Lead-DBS was found to be of 0.1 mm (standard deviation: 0.8 mm). All 12 analyzed MERs recorded above the electrophysiologically-determined STN entry were confirmed to be in the thalamus or zona incerta. All MERs electrophysiologically attributed to the SN were confirmed to belong to this nucleus. However, 6/34 MERs that were electrophysiologically attributed to the ventral STN were postoperatively reattributed to the SN. Furthermore, 44 MERs of 3 trajectories, which were intraoperatively attributed to the STN, were postoperatively reattributed to the pallidum or thalamus. MER parameters seemed to differ across the STN, with higher spike amplitudes (H = 10.64, p 0.01) and less prevalent β-oscillations (H = 9.81, p 0.01) in the limbic STN than in the sensorimotor and associative subdivisions. Some cells, especially in the SN, showed longer spikes with lower firing rates, in agreement with described characteristics of dopamine cells. However, these probabilistic electrophysiological signatures might become clinically less relevant with the development of image reconstruction tools, which deserve to be applied intraoperatively.

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Multiple surgical targets have been proposed for treating obsessive-compulsive disorder (OCD) with deep brain stimulation (DBS). However, different targets may modulate the same neural network responsible for clinical improvement. Here we analyzed data from four cohorts of OCD patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NAcc) or the subthalamic nucleus (STN). Fiber tracts that were predominantly connected to electrodes in good or poor DBS responders were isolated from a normative structural connectome and assigned a predictive value. Strikingly, the same fiber bundle was related to treatment response when independently analyzing two large training cohorts that targeted either ALIC or STN. This discriminative tract is a subsection of the ALIC and connects frontal regions (such as the dorsal anterior cingulate, dACC, and ventral prefrontal, vlPFC, cortices to the STN). When informing the tract solely based on one cohort (e.g. ALIC), clinical improvements in the other (e.g. STN) could be significantly predicted, and vice versa. Finally, clinical improvements of eight patients from a third center with electrodes in the NAcc and six patients from a fourth center in which electrodes had been implanted in both STN and ALIC were significantly predicted based on this novel tract-based DBS target. Results suggest a functional role of a limbic hyperdirect pathway that projects from dACC and vlPFC to anteriomedial STN. Obsessive-compulsive symptoms seem to be tractable by modulating the specific bundle isolated here. Our results show that connectivity-derived improvement models can inform clinical improvement across DBS targets, surgeons and centers. The identified tract is now three-dimensionally defined in stereotactic standard space and will be made openly available.

The subthalamic nucleus (STN) plays a critical role during action inhibition, perhaps by acting like a fast brake on the motor system when inappropriate responses have to be rapidly suppressed. However, the mechanisms involving the STN during motor inhibition are still unclear, particularly because of a relative lack of single-cell responses reported in this structure in humans. In this study, we used extracellular microelectrode recordings during deep brain stimulation surgery in patients with Parkinson's disease (PD) to study STN neurophysiological correlates of inhibitory control during a stop signal task. We found two neuronal subpopulations responding either during motor execution (GO units) or during motor inhibition (STOP units). GO units fired selectively before patients' motor responses whereas STOP units fired selectively when patients successfully withheld their move at a latency preceding the duration of the inhibition process. These results provide electrophysiological evidence for the hypothesized role of the STN in current models of response inhibition.

Parkinson's disease impairs the decoding of emotional stimuli reflecting alterations of the limbic cortico-subcortical network. The objective of this study was to assess and compare the behavioral and electrophysiological effects of both levodopa and subthalamic stimulation on emotional processing in Parkinson's disease. Operated patients (n =16) and matched healthy subjects performed an emotional Stroop task, in which the emotion expressed by a face must be recognized while ignoring an emotional distractive word and that includes a neutral control sub-task. Patients were tested in the four possible treatment conditions (off stim/off med; on stim/off med; off stim/on med; and on stim/on med). High-resolution electroencephalography was recorded while performing the task. Patients made significantly more mistakes in facial emotion recognition than healthy subjects (p < .005). Untreated patients performed worse in the emotional trials than in the control sub-task (p < .05). Fearful faces induced significantly slower reaction times than happy faces in patients (p = .0002), but not in the healthy subjects. The emotional Stroop effect with levodopa was significantly higher than with subthalamic stimulation when fearful faces were assessed (p = .0243). Conversely, treatments did not modulate the Stroop effect of the control sub-task. EEG demonstrated that, compared with the untreated state, levodopa but not subthalamic stimulation significantly increases the amplitude of the event-related potential N170 (p = .002 vs. p = .1, respectively), an electrophysiological biomarker of early aspects of facial processing. The activity of the N170 cortical sources within the right fusiform gyrus was increased by levodopa (p < .05) but not by stimulation. While levodopa normalizes the recognition of emotional facial expression and early EEG markers of emotional processing, subthalamic stimulation does not. Thus, operated patients require dopaminergic medication in addition to stimulation to treat emotional symptoms of Parkinson's disease.

International audience; Deep brain stimulation (DBS) of the subgenual cingulate gyrus (area CG25) is beneficial in treatment resistant depression. Though the mechanisms of action of Cg25 DBS remain largely unknown, it is commonly believed that Cg25 DBS modulates limbic activity of large networks to achieve thymic regulation of patients. To investigate how emotional attention is influenced by Cg25 DBS, we assessed behavioral and electroencephalographic (EEG) responses to an emotional Stroop task in 5 patients during ON and OFF stimulation conditions. Using EEG source localization, we found that the main effect of DBS was a reduction of neuronal responses in limbic regions (temporal pole, medial prefrontal and posterior cingulate cortices) and in ventral visual areas involved in face processing. In the dynamic causal modeling (DCM) approach, the changes of the evoked response amplitudes are assumed to be due to changes of long range connectivity induced by Cg25 DBS. Here, using a simplified neural mass model that did not take explicitly into account the cytoarchitecture of the considered brain regions, we showed that the remote action of Cg25 DBS could be explained by a reduced top-down effective connectivity of the amygdalo-temporo-polar complex. Overall, our results thus indicate that Cg25 DBS during the emotional Stroop task causes a decrease of top-down limbic influence on the ventral visual stream itself, rather than a modulation of prefrontal cognitive processes only. Tuning down limbic excitability in relation to sensory processing might be one of the biological mechanisms through which Cg25 DBS produces positive clinical outcome in the treatment of resistant depression.

International audience; A fast positioning method for brain tumor microbeam irradiations for preclinical studies at third-generation X-ray sources is described. The three-dimensional alignment of the animals relative to the X-ray beam was based on the X-ray tomography multi-slices after iodine infusion. This method used pink-beam imaging produced by the ID17 wiggler. A graphical user interface has been developed in order to define the irradiation parameters: field width, height, number of angles and X-ray dose. This study is the first reporting an image guided method for soft tissue synchrotron radiotherapy. It allowed microbeam radiation therapy irradiation fields to be reduced by a factor of $ 20 compared with previous studies. It permitted more targeted, more efficient brain tumor microbeam treatments and reduces normal brain toxicity of the radiation treatment.

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The use of alginate based microcapsules to deliver drugs and cells with a minimal host interaction is increasingly being proposed. A proficient method to track the position of the microcapsules during such therapies, particularly if they are amenable to commonly used instrumentation, would greatly help the development of such treatments. Here we propose to label the microcapsules with gold nanoparticles to provide a bright contrast on small animal x-ray micro-CT systems enabling single microcapsule detection. The microcapsules preparation is based on a simple protocol using inexpensive compounds. This, combined with the widespread availability of micro-CT apparatus, renders our method more accessible compared with other methods. Our labeled microcapsules showed good mechanical stability and low cytotoxicity in-vitro . Our post-mortem rodent model data strongly suggest that the high signal intensity generated by the labeled microcapsules permits the use of a reduced radiation dose yielding a method fully compatible with longitudinal in-vivo studies. From the Clinical Editor The authors of this study report the development of a micro-CT based tracking method of alginate-based microcapsules by incorporating gold nanoparticles in the microcapsules. They demonstrate the feasibility of this system in rodent models, where due to the high signal intensity, even reduced radiation dose is sufficient to track these particles, providing a simple and effective method to track these commonly used microcapsules and allowing longitudinal studies.

High-frequency deep brain stimulation of the subthalamic nucleus can be used to treat severe obsessive-compulsive disorders that are refractory to conventional treatments. The mechanisms of action of this approach possibly rely on the modulation of associative-limbic subcortical–cortical loops, but remain to be fully elucidated. Here in 12 patients, we report the effects of high-frequency stimulation of the subthalamic nucleus on behavior, and on electroencephalographic responses and inferred effective connectivity during motor inhibition processes involved in the stop signal task. First, we found that patients were faster to respond and had slower motor inhibition processes when stimulated. Second, the subthalamic stimulation modulated the amplitude and delayed inhibition-related electroencephalographic responses. The power of reconstructed cortical current densities decreased in the stimulation condition in a parietal–frontal network including cortical regions of the inhibition network such as the superior parts of the inferior frontal gyri and the dorsolateral prefrontal cortex. Finally, dynamic causal modeling revealed that the subthalamic stimulation was more likely to modulate efferent connections from the basal ganglia, modeled as a hidden source, to the cortex. The connection from the basal ganglia to the right inferior frontal gyrus was significantly decreased by subthalamic stimulation. Beyond motor inhibition, our study thus strongly suggests that the mechanisms of action of high-frequency subthalamic stimulation are not restricted to the subthalamic nucleus, but also involve the modulation of distributed subcortical–cortical networks.