Background:Levodopa equivalent dopaminergic dose (LEDD) reduction after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease varies widely. Identifying predictors may guide patient selection and programming. Our objectives were to identify predictors of LEDD reduction and to test whether motor improvement mediates this association. Methods:Data from 144 patients treated by STN-DBS were analysed. Predictors of LEDD reduction were selected using the Boruta algorithm, a machine-learning method comparing variable importance to randomised features and then tested in a structural equation model for direct and motor-mediated effects. Results:Mean LEDD reduction was 41.7% (±38.2%) and motor improvement was 48.6% (±26.7%) at 1 year. Among the four predictors identified by Boruta, lower baseline LEDD (β=0.39, p=0.001), greater axial impairment (β=-0.25, p=0.003) and higher total volume of tissue activated (β=-0.17, p=0.031) were directly associated with lower LEDD reduction, independent of motor improvement. Sensorimotor STN overlap was not directly linked to LEDD reduction but was positively associated with motor improvement (β=0.34, p=0.001), which showed a trend-level effect on LEDD reduction (β=0.16, p=0.065). The total effect of sensorimotor STN overlap on LEDD reduction was not significant. Discussion:Dopaminergic dose reduction after STN-DBS is constrained by preoperative axial symptoms and stimulation spread, independently of motor improvement, while sensorimotor STN overlap improves motor symptoms but not dose reduction. Integrating motor phenotype with anatomical guidance may enhance medication management post DBS.

We propose for the first time a direct comparison between brain and endocast characteristics-the number, position, length and proportion of sulci as revealed by the evidence on the brain and their corresponding marks on the endocast that is the internal surface of the skull-in the same living individuals. Using a tailored MRI imaging methodology developed to overcome the limitations inherent to medical imaging on healthy subjects, we compare 3D models of the brain and of the endocast obtained from the same cohort of 75 volunteers. These data were quantified in terms of observation frequency, proportion of dimension for the same structures on the endocast compared to the brain and variation among the analysed sample. We show that identifiable marks on the endocast are often short, discontinuous, and primarily located in the lower regions (particularly in the inferior frontal and temporal lobes areas). This observation contradicts previous practices of drawing long, straight marks on fossil endocasts. An unexpected result of the study is the discovery of endocranial marks unrelated to cerebral sulci, called MNAS (for endocranial Marks Not Associated with Sulci). These marks represent approximately 12% of the depressions observed and pose a challenge for the interpretation of fossil endocasts. Finally, we propose with this work a new standardised approach to studying fossil endocasts, which combines precise guidelines for sulci variation description as well as for inter-individual comparisons, and cross-validation by several researchers. The development of a new approach based on a large quantity of anatomical information presented in the present study, offers new perspectives for reconstructing the anatomy of fossil hominin's brain in a more objective framework, and will have a lasting impact for the study of the evolution of the hominin brain, particularly functional lateralisation and cognitive abilities.

BACKGROUND:MR-guided focused ultrasound (MRgFUS) has been developed to treat essential tremor effectively and noninvasively. Currently, clinical examination is used to identify therapeutic efficacy during treatment, but MRgFUS surgery could benefit from real-time, rater-independent quantitative monitoring of tremor, such as accelerometry data. METHODS:Fourteen patients with medically refractory essential tremor underwent MRgFUS thalamotomy. Patients were instructed to hold postures during treatment. Tremor was monitored during each ultrasonic thermal sonication with MR-compatible accelerometers. Real-time feedback based on tremor amplitude in the 2-20 Hz band was calculated to evaluate the efficacy of each thermal ablation. RESULTS:On average 6 ± 2 ablative sonications only were required to induce improvement in tremor on the clinical rating scale for tremor (CRST) of 89 ± 11% at D + 7, 79 ± 12% at M + 1, 74 ± 19% at M + 3 and 72 ± 23% at M + 12. The overall predictive efficacy measured with accelerometry during the treatment was 70 ± 30%. The tremor amplitude reduction measured with accelerometry was correlated with CRST scores tremor reduction at multiple timepoints (ρ = 0.79 at D + 7, ρ = 0.75 at M + 1, ρ = 0.86 at M + 3, and ρ = 0.63 at M + 12) and accelerometric data gathered during treatment predicted CRST tremor improvement at M + 3 (0.88 area under ROC curve). CONCLUSION:This exploratory study is a proof of concept suggesting that accelerometry measurements can provide real-time feedback on tremor reduction and can complement visual evaluation. In the future, the use of the outcome prediction introduced in this paper may shorten procedure time and limit adverse events by reducing the number of ablative administered sonications.

Research on brain evolution centres mainly on internal mouldings of the skull, known as endocasts; however, the relationship between the size and asymmetry of the brain and endocasts has been poorly investigated in humans. Therefore, the main objective of this study was to investigate whether endocasts can be reliable indicators of brain size and asymmetry. Magnetic Resonance Imaging (MRI) of 75 participants was used to calculate the volume and surface area of the brain, the endocast, and their respective hemispheres. Two asymmetry indices (i.e. directional and absolute asymmetry) were used to assess the differences in volume and surface area between the sides of the brain and endocast. The Pearson correlation coefficient was calculated to assess the relationships between the parameters, and a Monte Carlo simulation for linear regression was performed to generate prediction equations for brain volume. The relationships between the level and direction of asymmetry indices were investigated using the Pearson correlation and McNemar's test, respectively. All correlations were statistically significant; however, correlation coefficients between volumes were stronger (0.894-0.931) than between volumes and surface areas (0.783-0.834). Brain volume can be predicted with high accuracy (ranging between 0.80 and 0.87) using the endocast total volume or the volume of one of the sides. The associations between the levels of asymmetry indices of the brain and endocast were non-significant; however, the McNemar's test indicated that endocasts show the same left- or right-biased asymmetry as the brain. This was the first study conducted on a large sample of brain and endocast data from the same individuals. The results demonstrated that brain volume can be accurately reconstructed using the volume of the endocast or one of its sides. This finding is especially important in the context of reconstructing fossil skulls, which are usually fragmented. Conversely, the asymmetry levels of endocast parameters are not reliable indicators of the actual level of brain volume asymmetry. Future research on fossils should focus on endocast asymmetry direction (left- or right-biased) as this closely corresponds with brain lateralisation.

Background: Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. Objective: /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. Methods: The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. Results: VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 +/- 1.4 degrees C compared to 36.8 +/- 1.4 degrees C for a 3 cm away control point. Conclusions: MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Followup studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

Physical activity combined with virtual reality and exergaming has emerged as a new technique to improve engagement and provide clinical benefit for gait and balance disorders in people with Parkinson’s disease (PD). To investigate the effects of a training protocol using a home-based exergaming system on brain volume and resting-state functional connectivity (rs-FC) in persons with PD. A single blind randomized controlled trial was conducted in people with PD with gait and/or balance disorders. The experimental (active) group performed 18 training sessions at home by playing a custom-designed exergame with full body movements, standing in front of a RGB-D Kinect® motion sensor, while the control group played using the computer keyboard. Both groups received the same training program. Clinical scales, gait recordings, and brain MRI were performed before and after training. We assessed the effects of both training on both the grey matter volumes (GVM) and rs-FC, within and between groups. Twenty-three patients were enrolled and randomly assigned to either the active (n = 11) or control (n = 12) training groups. Comparing pre- to post-training, the active group showed significant improvements in gait and balance disorders, with decreased rs-FC between the sensorimotor, attentional and basal ganglia networks, but with an increase between the cerebellar and basal ganglia networks. In contrast, the control group showed no significant changes, and rs-FC significantly decreased in the mesolimbic and visuospatial cerebellar and basal ganglia networks. Post-training, the rs-FC was greater in the active relative to the control group between the basal ganglia, motor cortical and cerebellar areas, and bilaterally between the insula and the inferior temporal lobe. Conversely, rs FC was lower in the active relative to the control group between the pedunculopontine nucleus and cerebellar areas, between the temporal inferior lobes and the right thalamus, between the left putamen and dorsolateral prefrontal cortex, and within the default mode network. Full-body movement training using a customized exergame induced brain rs-FC changes within the sensorimotor, attentional and cerebellar networks in people with PD. Further research is needed to comprehensively understand the neurophysiological effects of such training approaches. Trial registration ClinicalTrials.gov NCT03560089.

OBJECTIVE:To investigate the effects of directional subthalamic deep brain stimulation (STN-dDBS) on gait and balance disorders, including freezing of gait (FOG), in patients with advanced Parkinson's disease (PD). METHODS:We included 10 participants who underwent STN-DBS and presented severe preoperative FOG, in a randomized, double-blind, crossover study. We used segmented DBS electrodes to investigate whether directing the predicted volume of tissue activated (VTA) to overlap the central STN preferentially improved gait and balance disorders compared to directional DBS applied in the more posterior STN (sensorimotor). We also assessed non-directional (ring-mode) STN-DBS. Our primary outcome was gait and balance control measured using instrumented gait recordings. Each patient had a pre-operative structural and diffusion-weighted imaging to model individual VTAs and to examine cortico-subthalamic connectivity. We used linear mixed-effects models to contrast the effects of central STN-dDBS, posterior STN-dDBS, and ring-mode STN-DBS. RESULTS:Central STN-dDBS produced significantly better improvement in gait and balance control compared to posterior STN-dDBS (p = 0.027), with fewer FOG episodes (p < 0.001). Conversely, ring-mode STN-DBS resulted in worsened postural control compared to central STN-dDBS (p = 0.009). The cortico-subthalamic connectivity with the STN VTAs involved mostly primary sensorimotor, premotor, and medial frontal cortices, with a higher overall cortico-STN connectivity with ring-mode STN-DBS. INTERPRETATION:Central STN-dDBS represents the best option to improve gait and balance disorders in PD patients, including FOG. Our findings raise the possibility of reprogramming STN-DBS toward the central area in selected patients with disabling FOG and/or postural instability after surgery. ANN NEUROL 2024.

Palaeoneurology is a complex field as the object of study, the brain, does not fossilize. Studies rely therefore on the (brain) endocranial cast (often named endocast), the only available and reliable proxy for brain shape, size and details of surface. However, researchers debate whether or not specific marks found on endocasts correspond reliably to particular sulci and/or gyri of the brain that were imprinted in the braincase. The aim of this study is to measure the accuracy of sulcal identification through an experiment that reproduces the conditions that palaeoneurologists face when working with hominin endocasts. We asked 14 experts to manually identify well-known foldings in a proxy endocast that was obtained from an MRI of an actual in vivo Homo sapiens head. We observe clear differences in the results when comparing the non-corrected labels (the original labels proposed by each expert) with the corrected labels. This result illustrates that trying to reconstruct a sulcus following the very general known shape/position in the literature or from a mean specimen may induce a bias when looking at an endocast and trying to follow the marks observed there. We also observe that the identification of sulci appears to be better in the lower part of the endocast compared to the upper part. The results concerning specific anatomical traits have implications for highly debated topics in palaeoanthropology. Endocranial description of fossil specimens should in the future consider the variation in position and shape of sulci in addition to using models of mean brain shape. Moreover, it is clear from this study that researchers can perceive sulcal imprints with reasonably high accuracy, but their correct identification and labelling remains a challenge, particularly when dealing with extinct species for which we lack direct knowledge of the brain.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, which is often associated with psychiatric comorbidities. Dysfunction of basal ganglia pathways might account for the wide spectrum of symptoms in TS patients. Although psychiatric symptoms may be related to limbic networks, the specific contribution of different limbic structures remains unclear. We used tractography to investigate cortical connectivity with the striatal area (caudate, putamen, core and shell of the nucleus accumbens), the subthalamic nucleus (STN), and the adjacent medial subthalamic region (MSR) in 58 TS patients and 35 healthy volunteers. 82% of TS patients showed psychiatric comorbidities, with significantly higher levels of anxiety and impulsivity compared to controls. Tractography analysis revealed significantly increased limbic cortical connectivity of the left MSR with the entorhinal (BA34), insular (BA48), and temporal (BA38) cortices in TS patients compared to controls. Furthermore, we found that left insular-STN connectivity was positively correlated with impulsivity scores for all subjects and with anxiety scores for all subjects, particularly for TS. Our study highlights a heterogenous modification of limbic structure connectivity in TS, with specific abnormalities found for the subthalamic area. Abnormal connectivity with the insular cortex might underpin the higher level of impulsivity and anxiety observed in TS.

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions.

BACKGROUND:Dopa-resistant freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced Parkinson's disease (PD). OBJECTIVE:We investigate the effects of deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR), comprised of the pedunculopontine (PPN) and cuneiform (CuN) nuclei, for treating gait and balance disorders, in a randomized double-blind cross-over trial. METHODS:Six PD patients with dopa-resistant FOG and/or falls were operated for MLR-DBS. Patients received three DBS conditions, PPN, CuN, or Sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory-postural-adjustments (APAs) during gait initiation on a force platformResults:The anteroposterior APAs were not significantly different between the DBS conditions (median displacement [1st-3rd quartile] of 3.07 [3.12-4.62] cm with sham-DBS, 1.95 [2.29-3.85] cm with PPN-DBS and 2.78 [1.66-4.04] cm with CuN-DBS; p = 0.25). Step length and velocity were significantly higher with CuN-DBS vs. both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs. sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs. inclusion. We did not find any significant change in clinical scales between DBS conditions or one year after surgery. CONCLUSION:Two months of PPN-DBS or CuN-DBS does not effectively improve clinically dopa-resistant gait and balance disorders in PD patients.

BACKGROUND Parkinson's disease mild cognitive impairment (PD-MCI) is frequent and heterogenous. There is no consensus about its influence on subthalamic deep brain stimulation (STN-DBS) outcomes. OBJECTIVE To determine the prevalence of PD-MCI and its subtypes in candidates to STN-DBS. Secondarily, we sought to identify MRI structural markers associated with cognitive impairment in these subgroups. METHODS Baseline data from the French multicentric PREDISTIM cohort were used. Candidates to STN-DBS were classified according to their cognitive performance in normal cognition (PD-NC) or PD-MCI. The latter included frontostriatal (PD-FS) and posterior cortical (PD-PC) subtypes. Between-group comparisons were performed on demographical and clinical variables as well as on T1-weighted MRI sequences at the cortical and subcortical levels. RESULTS 320 patients were included: 167 (52%) PD-NC and 153 (48%) PD-MCI patients. The latter group included 123 (80%) PD-FS and 30 (20%) PD-PC patients. There was no between-group difference regarding demographic and clinical variables. PD-PC patients had significantly lower global efficiency than PD-FS patients and significantly worse performance on visuospatial functions, episodic memory, and language. Compared to PD-NC, PD-MCI patients had cortical thinning and radiomic-based changes in the left caudate nucleus and hippocampus. There were no significant differences between the PD-MCI subtypes. CONCLUSION Among the candidates to STN-DBS, a significant proportion has PD-MCI which is associated with cortical and subcortical alterations. Some PD-MCI patients have posterior cortical deficits, a subtype known to be at higher risk of dementia.