What do brain endocasts tell us? A comparative analysis of the accuracy of sulcal identification by experts and perspectives in palaeoanthropology.

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.

Structural hyperconnectivity of the subthalamic area with limbic cortices underpins anxiety and impulsivity in Tourette syndrome.

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.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of Subthalamic Deep Brain Stimulation on Impulse Control Disorders in Parkinson's Disease: A Prospective Study.

BACKGROUND: Impact of subthalamic deep brain stimulation (DBS) on impulse control disorders (ICD) in Parkinson's disease (PD) remains controversial. OBJECTIVES: The objectives of this study were to analyze the natural history of ICD between baseline and 1 year after subthalamic DBS in patients with PD and to identify predictive factors, taking into account the positions of the active contact and stimulation parameters. METHODS: We analyzed postoperative modifications of ICD based on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. ICD status and Ardouin Scale of Behaviour in PD were assessed at baseline and 1 year following subthalamic DBS. Location of active contacts within the 3 subthalamic nucleus functional territories was investigated. RESULTS: A total of 217 were patients included. Of the patients, 10.6% had ICD at baseline of which 95.6% improved at 1 year following subthalamic DBS; 3.6% of the patients experienced de novo ICD at 1 year following subthalamic DBS. Dopamine agonist dose reduction (from 309.8 to 109.3 mg) was the main driver of ICD regression (P = 0.05). Higher preoperative dyskinesias were associated with poorer ICD evolution (P = 0.04). Whereas baseline apathy was a risk factor of de novo ICD (P = 0.02), ICD improvement correlated with postoperative apathy (P = 0.004). Stimulation power and position of active contacts-mainly located within the sensorimotor part of the subthalamic nucleus-did not influence ICD. CONCLUSIONS: This 1-year, postoperative follow-up study showed ICD regression and dopaminergic drug reduction with optimal position of the active contacts within the subthalamic nucleus. Whereas patients with PD with preoperative ICD were prone to postoperative apathy, we also showed that those with preoperative apathy had a higher risk to experience postoperative de novo ICD, further highlighting the meaningful influence of postoperative management of dopaminergic medication on outcome and the continuum between apathy and ICD. © 2020 International Parkinson and Movement Disorder Society.

Anatomo-Functional Mapping of the Primate Mesencephalic Locomotor Region Using Stereotactic Lesions.

BACKGROUND: Dysfunction of the mesencephalic locomotor region has been implicated in gait disorders. However, the role of its 2 components, the pedunculopontine and the cuneiform nuclei, in locomotion is poorly understood in primates. OBJECTIVES: To analyze the effect of cuneiform lesions on gait and balance in 2 monkeys and to compare them with those obtained after cholinergic pedunculopontine lesions in 4 monkeys and after lesions in both the cuneiform and pedunculopontine nuclei in 1 monkey. METHODS: After each stereotactic lesion, we performed a neurological examination and gait and balance assessments with kinematic measures during a locomotor task. The 3-dimensional location of each lesion was analyzed on a common brainstem space. RESULTS: After each cuneiform lesion, we observed a contralateral cervical dystonia including an increased tone in the proximal forelimb and an increase in knee angle, back curvature and walking speed. Conversely, cholinergic pedunculopontine lesions increased tail rigidity and back curvature and an imbalance of the muscle tone between the ipsi- and contralateral hindlimb with decreased knee angles. The walking speed was decreased. Moreover, pedunculopontine lesions often resulted in a longer time to waking postsurgery. CONCLUSIONS: The location of the lesions and their behavioral effects revealed a somatotopic organization of muscle tone control, with the neck and forelimb represented within the cuneiform nucleus and hindlimb and tail represented within the pedunculopontine nucleus. Cuneiform lesions increased speed, whereas pedunculopontine lesions decreased it. These findings confirm the complex and specific role of the cuneiform and pedunculopontine nuclei in locomotion and suggest the role of the pedunculopontine in sleep control. © 2020 International Parkinson and Movement Disorder Society.

Multimodal Magnetic Resonance Imaging Quantification of Brain Changes in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative clinically heterogeneous disorder, formal diagnosis being based on postmortem histological brain examination. OBJECTIVE: We aimed to perform a precise in vivo staging of neurodegeneration in PSP using quantitative multimodal MRI. The ability of MRI biomarkers to differentiate PSP from PD was also evaluated. METHODS: Eleven PSP patients were compared to 26 age-matched healthy controls and 51 PD patients. Images were acquired at 3 Tesla (three-dimensional T1 -weighted, diffusion tensor, and neuromelanin-sensitive images) and 7 Tesla (three-dimensional-T2 * images). Regions of interest included the cortical areas, hippocampus, amygdala, basal ganglia, basal forebrain, brainstem nuclei, dentate nucleus, and cerebellum. Volumes, mean diffusivity, and fractional anisotropy were measured. In each region, a threshold value for group categorization was calculated, and four grades of change (0-3) were determined. RESULTS: PSP patients showed extensive volume decreases and diffusion changes in the midbrain, SN, STN, globus pallidus, basal forebrain, locus coeruleus, pedunculopontine nucleus, and dentate nucleus, in close agreement with the degrees of impairment in histological analyses. The predictive factors for the separation of PSP and healthy controls were, in descending order, the neuromelanin-based SN volume; midbrain fractional anisotropy; volumes of the midbrain, globus pallidus, and putamen; and fractional anisotropy in the locus coeruleus. The best predictors for separating PSP from PD were the neuromelanin-based volume in the SN, fractional anisotropy in the pons, volumes of the midbrain and globus pallidus, and fractional anisotropy in the basal forebrain. CONCLUSIONS: These results suggest that it is possible to evaluate brain neurodegeneration in PSP noninvasively, even in small brainstem nuclei, in close agreement with previously published histological data. © 2019 International Parkinson and Movement Disorder Society.

Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study.

BACKGROUND: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

Normal and pathological neuronal distribution of the human mesencephalic locomotor region.

BACKGROUND: Deep brain stimulation of the pedunculopontine nucleus has been performed to treat dopamine-resistant gait and balance disorders in patients with degenerative diseases. The outcomes, however, are variable, which may be the result of the lack of a well-defined anatomical target. OBJECTIVES: The objectives of this study were to identify the main neuronal populations of the pedunculopontine and the cuneiform nuclei that compose the human mesencephalic locomotor region and to compare their 3-dimensional distribution with those found in patients with Parkinson's disease and progressive supranuclear palsy. METHODS: We used high-field MRI, immunohistochemistry, and in situ hybridization to characterize the distribution of the different cell types, and we developed software to merge all data within a common 3-dimensional space. RESULTS: We found that cholinergic, GABAergic, and glutamatergic neurons comprised the main cell types of the mesencephalic locomotor region, with the peak densities of cholinergic and GABAergic neurons similarly located within the rostral pedunculopontine nucleus. Cholinergic and noncholinergic neuronal losses were homogeneous in the mesencephalic locomotor region of patients, with the peak density of remaining neurons at the same location as in controls. The degree of denervation of the pedunculopontine nucleus was highest in patients with progressive supranuclear palsy, followed by Parkinson's disease patients with falls. CONCLUSIONS: The peak density of cholinergic and GABAergic neurons was located similarly within the rostral pedunculopontine nucleus not only in controls but also in pathological cases. The neuronal loss was homogeneously distributed and highest in the pedunculopontine nucleus of patients with falls, which suggests a potential pathophysiological link. © 2018 International Parkinson and Movement Disorder Society.

Anatomical evidence for functional diversity in the mesencephalic locomotor region of primates.

The mesencephalic locomotor region (MLR) is a highly preserved brainstem structure in vertebrates. The MLR performs a crucial role in locomotion but also controls various other functions such as sleep, attention, and even emotion. The MLR comprises the pedunculopontine (PPN) and cuneiform nuclei (CuN) but their specific roles are still unknown in primates. Here, we sought to characterise the inputs and outputs of the PPN and CuN to and from the basal ganglia, thalamus, amygdala and cortex, with a specific interest in identifying functional anatomical territories. For this purpose, we used tract-tracing techniques in monkeys and diffusion weighted imaging-based tractography in humans to understand structural connectivity. We found that MLR connections are broadly similar between monkeys and humans. The PPN projects to the sensorimotor, associative and limbic territories of the basal ganglia nuclei, the centre median-parafascicular thalamic nuclei and the central nucleus of the amygdala. The PPN receives motor cortical inputs and less abundant connections from the associative and limbic cortices. In monkeys, we found a stronger connection between the anterior PPN and motor cortex suggesting a topographical organisation of this specific projection. The CuN projected to similar cerebral structures to the PPN in both species. However, these projections were much stronger towards the limbic territories of the basal ganglia and thalamus, to the basal forebrain (extended amygdala) and the central nucleus of the amygdala, suggesting that the CuN is not primarily a motor structure. Our findings highlight the fact that the PPN integrates sensorimotor, cognitive and emotional information whereas the CuN participates in a more restricted network integrating predominantly emotional information.

Pedunculopontine network dysfunction in Parkinson's disease with postural control and sleep disorders.

BACKGROUND: The objective of this study was to investigate pedunculopontine nucleus network dysfunctions that mediate impaired postural control and sleep disorder in Parkinson's disease. METHODS: We examined (1) Parkinson's disease patients with impaired postural control and rapid eye movement sleep behavior disorder (further abbreviated as sleep disorder), (2) Parkinson's disease patients with sleep disorder only, (3) Parkinson's disease patients with neither impaired postural control nor sleep disorder, and (4) healthy volunteers. We assessed postural control with clinical scores and biomechanical recordings during gait initiation. Participants had video polysomnography, daytime sleepiness self-evaluation, and resting-state functional MRIs. RESULTS: Patients with impaired postural control and sleep disorder had longer duration of anticipatory postural adjustments during gait initiation and decreased functional connectivity between the pedunculopontine nucleus and the supplementary motor area in the locomotor network that correlated negatively with the duration of anticipatory postural adjustments. Both groups of patients with sleep disorder had decreased functional connectivity between the pedunculopontine nucleus and the anterior cingulate cortex in the arousal network that correlated with daytime sleepiness. The degree of dysfunction in the arousal network was related to the degree of connectivity in the locomotor network in all patients with sleep disorder, but not in patients without sleep disorder or healthy volunteers. CONCLUSIONS: These results shed light on the functional neuroanatomy of pedunculopontine nucleus networks supporting the clinical manifestation and the interdependence between sleep and postural control impairments in Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.

Cortico-thalamic disconnection in a patient with supernumerary phantom limb.

Supernumerary phantom limb (SPL) designates the experience of an illusory additional limb occurring after brain damage. Functional neuroimaging during SPL movements documented increased response in the ipsilesional supplementary motor area (SMA), premotor cortex (PMC), thalamus and caudate. This suggested that motor circuits are important for bodily related cognition, but anatomical evidence is sparse. Here, we tested this hypothesis by studying an extremely rare patient with chronic SPL, still present 3 years after a vascular stroke affecting cortical and subcortical right-hemisphere structures. Anatomical analysis included an advanced in vivo reconstruction of white matter tracts using diffusion-based spherical deconvolution. This reconstruction demonstrated a massive and relatively selective disconnection between anatomically preserved SMA/PMC and the thalamus. Our results provide strong anatomical support for the hypothesis that cortico-thalamic loops involving motor-related circuits are crucial to integrate sensorimotor processing with bodily self-awareness.

Orthostatic tremor: a cerebellar pathology?

SEE MUTHURAMAN ET AL DOI101093/AWW164 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Primary orthostatic tremor is characterized by high frequency tremor affecting the legs and trunk during the standing position. Cerebellar defects were suggested in orthostatic tremor without direct evidence. We aimed to characterize the anatomo-functional defects of the cerebellar motor pathways in orthostatic tremor. We used multimodal neuroimaging to compare 17 patients with orthostatic tremor and 17 age- and gender-matched healthy volunteers. Nine of the patients with orthostatic tremor underwent repetitive transcranial stimulation applied over the cerebellum during five consecutive days. We quantified the duration of standing position and tremor severity through electromyographic recordings. Compared to healthy volunteers, grey matter volume in patients with orthostatic tremor was (i) increased in the cerebellar vermis and correlated positively with the duration of the standing position; and (ii) increased in the supplementary motor area and decreased in the lateral cerebellum, which both correlated with the disease duration. Functional connectivity between the lateral cerebellum and the supplementary motor area was abnormally increased in patients with orthostatic tremor, and correlated positively with tremor severity. After repetitive transcranial stimulation, tremor severity and functional connectivity between the lateral cerebellum and the supplementary motor area were reduced. We provide an explanation for orthostatic tremor pathophysiology, and demonstrate the functional relevance of cerebello-thalamo-cortical connections in tremor related to cerebellar defects.

Subthalamic stimulation may inhibit the beneficial effects of levodopa on akinesia and gait.

BACKGROUND: Gait and akinesia deterioration in PD patients during the immediate postoperative period of DBS has been directly related to stimulation in the subthalamic region. The underlying mechanisms remain poorly understood. The aim of the present study was to clinically and anatomically describe this side effect. METHODS: PD patients presenting with a worsening of gait and/or akinesia following STN-DBS, that was reversible on stimulation arrest were included. The evaluation included (1) a Stand Walk Sit Test during a monopolar survey of each electrode in the on-drug condition; (2) a 5-condition test with the following conditions: off-drug/off-DBS, off-drug/on-best-compromise-DBS, on-drug/off-DBS, on-drug/on-best-compromise-DBS, and on-drug/on-worsening-DBS, which utilized the contact inducing the most prominent gait deterioration. The following scales were performed: UPDRSIII subscores, Stand Walk Sit Test, and dyskinesia and freezing of gait scales. Localization of contacts was performed using a coregistration method. RESULTS: Twelve of 17 patients underwent the complete evaluation. Stimulation of the most proximal contacts significantly slowed down the Stand Walk Sit Test. The on-drug/on-worsening-DBS condition compared with the on-drug/off-DBS condition worsened akinesia (P = 0.02), Stand Walk Sit Test (P = 0.001), freezing of gait (P = 0.02), and improved dyskinesias (P = 0.003). Compared with the off-drug/off-DBS condition, the on-drug/on-worsening-DBS condition improved rigidity (P = 0.007) and tremor (P = 0.007). Worsening contact sites were predominantly dorsal and anterior to the STN in the anterior zona incerta and Forel fields H2. CONCLUSIONS: A paradoxical deterioration of gait and akinesia is a rare side effect following STN-DBS. We propose that this may be related to misplaced contacts, and we discuss the pathophysiology and strategies to identify and manage this complication. © 2016 International Parkinson and Movement Disorder Society.

The integrative role of the pedunculopontine nucleus in human gait.

The brainstem pedunculopontine nucleus has a likely, although unclear, role in gait control, and is a potential deep brain stimulation target for treating resistant gait disorders. These disorders are a major therapeutic challenge for the ageing population, especially in Parkinson's disease where gait and balance disorders can become resistant to both dopaminergic medication and subthalamic nucleus stimulation. Here, we present electrophysiological evidence that the pedunculopontine and subthalamic nuclei are involved in distinct aspects of gait using a locomotor imagery task in 14 patients with Parkinson's disease undergoing surgery for the implantation of pedunculopontine or subthalamic nuclei deep brain stimulation electrodes. We performed electrophysiological recordings in two phases, once during surgery, and again several days after surgery in a subset of patients. The majority of pedunculopontine nucleus neurons (57%) recorded intrasurgically exhibited changes in activity related to different task components, with 29% modulated during visual stimulation, 41% modulated during voluntary hand movement, and 49% modulated during imaginary gait. Pedunculopontine nucleus local field potentials recorded post-surgically were modulated in the beta and gamma bands during visual and motor events, and we observed alpha and beta band synchronization that was sustained for the duration of imaginary gait and spatially localized within the pedunculopontine nucleus. In contrast, significantly fewer subthalamic nucleus neurons (27%) recorded intrasurgically were modulated during the locomotor imagery, with most increasing or decreasing activity phasically during the hand movement that initiated or terminated imaginary gait. Our data support the hypothesis that the pedunculopontine nucleus influences gait control in manners extending beyond simply driving pattern generation. In contrast, the subthalamic nucleus seems to control movement execution that is not likely to be gait-specific. These data highlight the crucial role of these two nuclei in motor control and shed light on the complex functions of the lateral mesencephalus in humans.

Intrinsic signature of essential tremor in the cerebello-frontal network.

Essential tremor is a movement disorder characterized by tremor during voluntary movements, mainly affecting the upper limbs. The cerebellum and its connections to the cortex are known to be involved in essential tremor, but no task-free intrinsic signatures of tremor related to structural cerebellar defects have so far been found in the cortical motor network. Here we used voxel-based morphometry, tractography and resting-state functional MRI at 3 T to compare structural and functional features in 19 patients with essential tremor and homogeneous symptoms in the upper limbs, and 19 age- and gender-matched healthy volunteers. Both structural and functional abnormalities were found in the patients' cerebellum and supplementary motor area. Relative to the healthy controls, the essential tremor patients' cerebellum exhibited less grey matter in lobule VIII and less effective connectivity between each cerebellar cortex and the ipsilateral dentate nucleus. The patient's supplementary motor area exhibited (i) more grey matter; (ii) a lower amplitude of low-frequency fluctuation of the blood oxygenation level-dependent signal; (iii) less effective connectivity between each supplementary motor area and the ipsilateral primary motor hand area, and (iv) a higher probability of connection between supplementary motor area fibres and the spinal cord. Structural and functional changes in the supplementary motor area, but not in the cerebellum, correlated with clinical severity. In addition, changes in the cerebellum and supplementary motor area were interrelated, as shown by a correlation between the lower amplitude of low-frequency fluctuation in the supplementary motor area and grey matter loss in the cerebellum. The structural and functional changes observed in the supplementary motor area might thus be a direct consequence of cerebellar defects: the supplementary motor area would attempt to reduce tremor in the motor output by reducing its communication with M1 hand areas and by directly modulating motor output via its corticospinal projections.See Raethjen and Muthuraman (doi:10.1093/brain/awv238) for a scientific commentary on this article.

Single-voxel (1)H spectroscopy in the human hippocampus at 3 T using the LASER sequence: characterization of neurochemical profile and reproducibility.

The hippocampus is crucial for long-term episodic memory and learning. It undergoes structural change in aging and is sensitive to neurodegenerative and psychiatric diseases. MRS studies have seldom been performed in the hippocampus due to technical challenges. The reproducibility of MRS in the hippocampus has not been evaluated at 3 T. The purpose of the present study was to quantify the concentration of metabolites in a small voxel placed in the hippocampus and evaluate the reproducibility of the quantification. Spectra were measured in a 2.4 mL voxel placed in the left hippocampus covering the body and most of the tail of the structure in 10 healthy subjects across three different sessions and quantified using LCModel. High-quality spectra were obtained, which allowed a reliable quantification of 10 metabolites including glutamate and glutamine. Reproducibility of MRS was evaluated with coefficient of variation, standard errors of measurement, and intraclass correlation coefficients. All of these measures showed improvement with increased number of averages. Changes of less than 5% in concentration of N-acetylaspartate, choline-containing compounds, and total creatine and of less than 10% in concentration of myo-inositol and the sum of glutamate and glutamine can be confidently detected between two measurements in a group of 20 subjects. A reliable and reproducible neurochemical profile of the human hippocampus was obtained using MRS at 3 T in a small hippocampal volume.

Pallidal activity in myoclonus dystonia correlates with motor signs.

BACKGROUND: Myoclonus-dystonia related to epsilon-sarcoglycan gene mutations is characterized by myoclonic jerks and mild to moderate dystonia. The role of basal ganglia dysfunction in the pathogenesis is unknown. METHODS: Pallidal neuronal activity was recorded in six myoclonus-dystonia and six primary generalized dystonia patients operated on for internal globus pallidus deep brain stimulation. RESULTS: In myoclonus-dystonia patients compared with primary-dystonia patients, internal pallidum neurons showed higher burst frequency, lower mean burst, and pause durations. External pallidum neurons showed higher mean pause frequency. Oscillatory activity was present in 33% and 35% of internal pallidum neurons in myoclonus-dystonia and primary-dystonia patients, respectively, predominantly in the theta frequency band (3-8 Hz). In myoclonus-dystonia patients with more severe myoclonus, internal pallidum neurons exhibited a higher bursting activity with high intraburst frequency and lower oscillatory activity frequency. CONCLUSIONS: Myoclonus-dystonia appears to be related to specific changes in internal pallidum activity, leading to disruption in striato-pallido-thalamo-cortical circuits. © 2015 International Parkinson and Movement Disorder Society.

7 Tesla magnetic resonance imaging: a closer look at substantia nigra anatomy in Parkinson's disease.

A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Dopaminergic denervation is commonly imaged using radiotracer imaging in target structures such as the striatum. Until recently, imaging made only a modest contribution to detecting neurodegenerative changes in the substantia nigra (SN) directly. Histologically, the SN is subdivided into the ventral pars reticulata and the dorsal pars compacta, which is composed of dopaminergic neurons. In humans, dopaminergic neurons, which are known to accumulate neuromelanin, form clusters of cells (nigrosomes) that penetrate deep into the SN pars reticulata (SNr). The SNr contains higher levels of iron than the SNc in normal subjects. Neuromelanin and T2*-weighted imaging therefore better detect the SNc and the SNr, respectively. The development of ultra-high field 7 Tesla (7T) magnetic resonance imaging (MRI) provided the increase in spatial resolution and in contrast that was needed to detect changes in SN morphology. 7T MRI allows visualization of nigrosome-1 as a hyperintense signal area on T2*-weighted images in the SNc of healthy subjects and its absence in PD patients, probably because of the loss of melanized neurons and the increase of iron deposition. This review is designed to provide a better understanding of the correspondence between the outlines and subdivisions of the SN detected using different MRI contrasts and the histological organization of the SN. The recent findings obtained at 7T will then be presented in relation to histological knowledge.

RAD51 deficiency disrupts the corticospinal lateralization of motor control.

Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 ± 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 ± 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system.

Neuronal activity correlated with checking behaviour in the subthalamic nucleus of patients with obsessive-compulsive disorder.

Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.