Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Validation of Lead-DBS ß-Oscillation Localization with Directional Electrodes.

In deep brain stimulation (DBS) studies in patients with Parkinson's disease, the Lead-DBS toolbox allows the reconstruction of the location of ß-oscillations in the subthalamic nucleus (STN) using Vercise Cartesia directional electrodes (Boston Scientific). The objective was to compare these probabilistic locations with those of intraoperative monopolar ß-oscillations computed from local field potentials (0.5-3 kHz) recorded by using shielded single wires and an extracranial shielded reference electrode. For each electrode contact, power spectral densities of the ß-band (13-31 Hz) were compared with those of all eight electrode contacts on the directional electrodes. The DBS Intrinsic Template AtLas (DISTAL), electrophysiological, and DBS target atlases of the Lead-DBS toolbox were applied to the reconstructed electrodes from preoperative MRI and postoperative CT. Thirty-six electrodes (20 patients: 7 females, 13 males; both STN electrodes for 16 of 20 patients; one single STN electrode for 4 of 20 patients) were analyzed. Stimulation sites both dorsal and/or lateral to the sensorimotor STN were the most efficient. In 33 out of 36 electrodes, at least one contact was measured with stronger ß-oscillations, including 23 electrodes running through or touching the ventral subpart of the ß-oscillations' probabilistic volume, while 10 did not touch it but were adjacent to this volume; in 3 out of 36 electrodes, no contact was found with ß-oscillations and all 3 were distant from this volume. Monopolar local field potentials confirmed the ventral subpart of the probabilistic ß-oscillations.

Gut-Brain Coupling and Multilevel Physiological Response to Biofeedback Relaxation After a Stressful Task Under Virtual Reality Immersion: A Pilot Study.

Human physiological reactions to the environment are coordinated by the interactions between brain and viscera. In particular, the brain, heart, and gastrointestinal tract coordinate with each other to provide physiological equilibrium by involving the central, autonomic, and enteric nervous systems. Recent studies have demonstrated an electrophysiological coupling between the gastrointestinal tract and the brain (gut-brain axis) under resting-state conditions. As the gut-brain axis plays a key role in individual stress regulation, we aimed to examine modulation of gut-brain coupling through the use of an overwhelming and a relaxing module as a first step toward modeling of the underlying mechanisms. This study was performed in 12 participants who, under a virtual reality environment, performed a 9-min cognitive stressful task followed by a 9-min period of relaxation. Brain activity was captured by electroencephalography, autonomic activities by photoplethysmography, and electrodermal and gastric activities by electrogastrography. Results showed that compared with the stressful task, relaxation induced a significant decrease in both tonic and phasic sympathetic activity, with an increase in brain alpha power and a decrease in delta power. The intensity of gut-brain coupling, as assessed by the modulation index of the phase-amplitude coupling between the normogastric slow waves and the brain alpha waves, decreased under the relaxation relative to the stress condition. These results highlight the modulatory effect of biofeedback relaxation on gut-brain coupling and suggest noninvasive multilevel electrophysiology as a promising way to investigate the mechanisms underlying gut-brain coupling in physiological and pathological situations.

Electrophysiological confrontation of Lead-DBS-based electrode localizations in patients with Parkinson's disease undergoing deep brain stimulation.

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 ß-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 ß-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.

Cortical hemodynamic mechanisms of reversal learning using high-resolution functional near-infrared spectroscopy: A pilot study.

OBJECTIVES: 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. METHODS: During this pilot study on 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: The results of this pilot study 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.

A Unified Functional Network Target for Deep Brain Stimulation in Obsessive-Compulsive Disorder.

BACKGROUND: Multiple deep brain stimulation (DBS) targets have been proposed for treating intractable obsessive-compulsive disorder (OCD). Here, we investigated whether stimulation effects of different target sites would be mediated by one common or several segregated functional brain networks. METHODS: First, seeding from active electrodes of 4 OCD patient cohorts (N = 50) receiving DBS to anterior limb of the internal capsule or subthalamic nucleus zones, optimal functional connectivity profiles for maximal Yale-Brown Obsessive Compulsive Scale improvements were calculated and cross-validated in leave-one-cohort-out and leave-one-patient-out designs. Second, we derived optimal target-specific connectivity patterns to determine brain regions mutually predictive of clinical outcome for both targets and others predictive for either target alone. Functional connectivity was defined using resting-state functional magnetic resonance imaging data acquired in 1000 healthy participants. RESULTS: While optimal functional connectivity profiles showed both commonalities and differences between target sites, robust cross-predictions of clinical improvements across OCD cohorts and targets suggested a shared network. Connectivity to the anterior cingulate cortex, insula, and precuneus, among other regions, was predictive regardless of stimulation target. Regions with maximal connectivity to these commonly predictive areas included the insula, superior frontal gyrus, anterior cingulate cortex, and anterior thalamus, as well as the original stereotactic targets. CONCLUSIONS: Pinpointing the network modulated by DBS for OCD from different target sites identified a set of brain regions to which DBS electrodes associated with optimal outcomes were functionally connected-regardless of target choice. On these grounds, we establish potential brain areas that could prospectively inform additional or alternative neuromodulation targets for obsessive-compulsive disorder.

A unified connectomic target for deep brain stimulation in obsessive-compulsive disorder.

Multiple surgical targets for treating obsessive-compulsive disorder with deep brain stimulation (DBS) have been proposed. However, different targets may modulate the same neural network responsible for clinical improvement. We analyzed data from four cohorts of patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens or the subthalamic nucleus (STN). The same fiber bundle was associated with optimal clinical response in cohorts targeting either structure. This bundle connected frontal regions to the STN. When informing the tract target based on the first cohort, clinical improvements in the second could be significantly predicted, and vice versa. To further confirm results, clinical improvements in eight patients from a third center and six patients from a fourth center were significantly predicted based on their stimulation overlap with this tract. Our results show that connectivity-derived models may inform clinical improvements across DBS targets, surgeons and centers. The identified tract target is openly available in atlas form.

Modeling of Electric Fields in Individual Imaging Atlas for Capsular Threshold Prediction of Deep Brain Stimulation in Parkinson's Disease: A Pilot Study.

Background: Modeling of deep brain stimulation electric fields and anatomy-based software might improve post-operative management of patients with Parkinson's disease (PD) who have benefitted from subthalamic nucleus deep brain stimulation (STN-DBS). Objective: We compared clinical and software-guided determination of the thresholds for current diffusion to the pyramidal tract, the most frequent limiting side effect in post-operative management of STN-DBS PD patients. Methods: We assessed monopolar reviews in 16 consecutive STN-DBS PD patients and retrospectively compared clinical capsular thresholds, which had been assessed according to standard clinical practice, to those predicted by volume of tissue activated (VTA) model software. All the modeling steps were performed blinded from patients' clinical evaluations. Results: At the group level, we found a significant correlation (p = 0.0001) when performing statistical analysis on the z-scored capsular thresholds, but with a low regression coefficient (r = 0.2445). When considering intra-patient analysis, we found significant correlations (p < 0.05) between capsular threshold as modeled with the software and capsular threshold as determined clinically in five patients (31.2%). Conclusions: In this pilot study, the VTA model software was of limited assistance in identifying capsular thresholds for the whole cohort due to a large inter-patient variability. Clinical testing remains the gold standard in selecting stimulation parameters for STN-DBS in PD.

Dyskinesia-inducing lead contacts optimize outcome of subthalamic stimulation in Parkinson's disease.

BACKGROUND: Acute dyskinesias elicited by STN-DBS, here referred to as stimulation-induced dyskinesias, predict optimal clinical outcome in PD. However, it remains elusive whether stimulation-induced dyskinesias can guide DBS programming. OBJECTIVES: Here, we characterized stimulation-induced dyskinesias clinically and anatomically. We then tested whether dyskinesia-inducing contacts could be effectively programmed using independent current source technology. METHODS: We characterized stimulation-induced dyskinesias with directional and ring stimulation retrospectively in 20 patients. We then localized dyskinesia-inducing contacts by imaging coregistration and eventually programmed those contacts. RESULTS: We elicited dyskinesias in half of our patients. Dyskinesia-inducing contacts were mainly directional and were all located ventrally within the dorsolateral motor STN. When these dyskinesia-inducing contacts were programmed using independent current source technology, dyskinesia disappeared and robust antibradykinetic effects were obtained. CONCLUSION: We confirm that stimulation-induced dyskinesias are helpful clinical observations, which may guide programming of directional STN-DBS in PD. © 2019 International Parkinson and Movement Disorder Society.

Affective modulation of the associative-limbic subthalamic nucleus: deep brain stimulation in obsessive-compulsive disorder.

Affective states underlie daily decision-making and pathological behaviours relevant to obsessive-compulsive disorders (OCD), mood disorders and addictions. Deep brain stimulation targeting the motor and associative-limbic subthalamic nucleus (STN) has been shown to be effective for Parkinson's disease (PD) and OCD, respectively. Cognitive and electrophysiological studies in PD showed responses of the motor STN to emotional stimuli, impairments in recognition of negative affective states and modulation of the intensity of subjective emotion. Here we studied whether the stimulation of the associative-limbic STN in OCD influences the subjective emotion to low-intensity positive and negative images and how this relates to clinical symptoms. We assessed 10 OCD patients with on and off STN DBS in a double-blind randomized manner by recording ratings of valence and arousal to low- and high-intensity positive and negative emotional images. STN stimulation increased positive ratings and decreased negative ratings to low-intensity positive and negative stimuli, respectively, relative to off stimulation. We also show that the change in severity of obsessive-compulsive symptoms pre- versus post-operatively interacts with both DBS and valence ratings. We show that stimulation of the associative-limbic STN might influence the negative cognitive bias in OCD and decreasing the negative appraisal of emotional stimuli with a possible relationship with clinical outcomes. That the effect is specific to low intensity might suggest a role of uncertainty or conflict related to competing interpretations of image intensity. These findings may have implications for the therapeutic efficacy of DBS.

Different effects of levodopa and subthalamic stimulation on emotional conflict in Parkinson's disease.

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.

Electroencephalographic correlates of low-frequency vagus nerve stimulation therapy for Crohn's disease.

OBJECTIVES: In the context of the first clinical trial of vagus nerve stimulation (VNS) in Crohn's disease (CD), our main objective was to quantify the acute and chronic effects of VNS on brain activity in CD patients. METHODS: We measured the electroencephalogram (EEG) in 9CD patients under VNS at 10 Hz just before VNS initiation, after 6 weeks and after 12 months of chronic VNS. RESULTS: Acute VNS induced increased spectral power in delta and theta bands on frontal, temporal and occipital electrodes. The main significant modulation was the 12 months' chronic effect of VNS which consisted mainly in a decreased power in the alpha frequency band which was correlated with the normalization of bowel mucosal inflammation, anxiety state and vagal tone. CONCLUSIONS: In addition to the activation of vagal efferent fibers that regulate the autonomic nervous system, our data suggest that chronic VNS has a regulatory action via afferent vagal fibers on anxio-depressive symptomatology associated to CD, which could be directly highlighted by the modulation of EEG alpha power known to be associated to depressed states. SIGNIFICANCE: This is the first report of the central effects of VNS in CD patients.

Electroencephalographic read-outs of the modulation of cortical network activity by deep brain stimulation.

Deep brain stimulation (DBS), a reversible and adjustable treatment for neurological and psychiatric refractory disorders, consists in delivering electrical currents to neuronal populations located in subcortical structures. The targets of DBS are spatially restricted, but connect to many parts of the brain, including the cortex, which might explain the observed clinical benefits in terms of symptomatology. The DBS mechanisms of action at a large scale are however poorly understood, which has motivated several groups to recently conduct many research programs to monitor cortical responses to DBS. Here we review the knowledge gathered from the use of electroencephalography (EEG) in patients treated by DBS. We first focus on the methodology to record and process EEG signals concurrently to DBS. In the second part of the review, we address the clinical and scientific benefits brought by EEG/DBS studies so far.

Stimulation of subgenual cingulate area decreases limbic top-down effect on ventral visual stream: A DBS-EEG pilot study.

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.

Response inhibition rapidly increases single-neuron responses in the subthalamic nucleus of patients with Parkinson's disease.

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.

In vivo pink-beam imaging and fast alignment procedure for rat brain tumor radiation therapy.

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.

A simple way to track single gold-loaded alginate microcapsules using x-ray CT in small animal longitudinal studies.

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.