Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system.

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.

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.

Freezing of gait depends on cortico-subthalamic network recruitment following STN-DBS in PD patients.

INTRODUCTION: Subthalamic deep-brain-stimulation (STN-DBS) is an effective means to treat Parkinson's disease (PD) symptoms. Its benefit on gait disorders is variable, with freezing of gait (FOG) worsening in about 30% of cases. Here, we investigate the clinical and anatomical features that could explain post-operative FOG. METHODS: Gait and balance disorders were assessed in 19 patients, before and after STN-DBS using clinical scales and gait recordings. The location of active stimulation contacts were evaluated individually and the volumes of activated tissue (VAT) modelled for each hemisphere. We used a whole brain tractography template constructed from another PD cohort to assess the connectivity of each VAT within the 39 Brodmann cortical areas (BA) to search for correlations between postoperative PD disability and cortico-subthalamic connectivity. RESULTS: STN-DBS induced a 100% improvement to a 166% worsening in gait disorders, with a mean FOG decrease of 36%. We found two large cortical clusters for VAT connectivity: one "prefrontal", mainly connected with BA 8,9,10,11 and 32, and one "sensorimotor", mainly connected with BA 1-2-3,4 and 6. After surgery, FOG severity positively correlated with the right prefrontal VAT connectivity, and negatively with the right sensorimotor VAT connectivity. The right prefrontal VAT connectivity also tended to be positively correlated with the UPDRS-III score, and negatively with step length. The MDRS score positively correlated with the right sensorimotor VAT connectivity. CONCLUSION: Recruiting right sensorimotor and avoiding right prefrontal cortico-subthalamic fibres with STN-DBS could explain reduced post-operative FOG, since gait is a complex locomotor program that necessitates accurate cognitive control.

Somatotopic Organization of Hyperdirect Pathway Projections From the Primary Motor Cortex in the Human Brain.

Background: The subthalamic nucleus (STN) is an effective neurosurgical target to improve motor symptoms in Parkinson's Disease (PD) patients. MR-guided Focused Ultrasound (MRgFUS) subthalamotomy is being explored as a therapeutic alternative to Deep Brain Stimulation (DBS) of the STN. The hyperdirect pathway provides a direct connection between the cortex and the STN and is likely to play a key role in the therapeutic effects of MRgFUS intervention in PD patients. Objective: This study aims to investigate the topography and somatotopy of hyperdirect pathway projections from the primary motor cortex (M1). Methods: We used advanced multi-fiber tractography and high-resolution diffusion MRI data acquired on five subjects of the Human Connectome Project (HCP) to reconstruct hyperdirect pathway projections from M1. Two neuroanatomy experts reviewed the anatomical accuracy of the tracts. We extracted the fascicles arising from the trunk, arm, hand, face and tongue area from the reconstructed pathways. We assessed the variability among subjects based on the fractional anisotropy (FA) and mean diffusivity (MD) of the fibers. We evaluated the spatial arrangement of the different fascicles using the Dice Similarity Coefficient (DSC) of spatial overlap and the centroids of the bundles. Results: We successfully reconstructed hyperdirect pathway projections from M1 in all five subjects. The tracts were in agreement with the expected anatomy. We identified hyperdirect pathway fascicles projecting from the trunk, arm, hand, face and tongue area in all subjects. Tract-derived measurements showed low variability among subjects, and similar distributions of FA and MD values among the fascicles projecting from different M1 areas. We found an anterolateral somatotopic arrangement of the fascicles in the corona radiata, and an average overlap of 0.63 in the internal capsule and 0.65 in the zona incerta. Conclusion: Multi-fiber tractography combined with high-resolution diffusion MRI data enables the identification of the somatotopic organization of the hyperdirect pathway. Our preliminary results suggest that the subdivisions of the hyperdirect pathway projecting from the trunk, arm, hand, face, and tongue motor area are intermixed at the level of the zona incerta and posterior limb of the internal capsule, with a predominantly overlapping topographical organization in both regions. Subject-specific knowledge of the hyperdirect pathway somatotopy could help optimize target definition in MRgFUS intervention.

Pedunculopontine and Cuneiform Nuclei Deep Brain Stimulation for Severe Gait and Balance Disorders in Parkinson's Disease: Interim Results from a Randomized Double-Blind Clinical Trial.

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.

Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson's disease.

This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson's disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson's disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson's disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson's disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra's morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson's disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification.

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.

The anatomo-functional organization of the hyperdirect cortical pathway to the subthalamic area using in vivo structural connectivity imaging in humans.

The subthalamic nucleus (STN) receives direct cortical inputs which constitute the so-called hyperdirect pathway. In monkeys, motor cortices innervate the whole extent of the STN whereas limbic cortices innervate only its anteromedial part extending more medially outside the nucleus. Tractography studies in humans have also identified motor cortical inputs to the STN, but little is known about the associative and limbic cortical projections. Therefore, the aim of this study was to investigate the anatomo-functional organization of the cortical projections to the STN and to the adjacent medial subthamic region (MSR). We used diffusion-weighted imaging-based tractography acquired from 30 subjects from the Human Connectome Project. We performed a whole-brain probabilistic tractography using MRTrix and extracted streamlines of interest between 39 cortical masks and both the STN and the MSR to provide track-density maps. Agglomerative clustering method was used to classify the voxels of the regions of interest. We found that the STN receives major inputs from the sensorimotor cortices and few inputs from the limbic cortices. On the other hand, the MSR receives mainly cortical limbic projections and few from the sensorimotor cortices. Weak connections were found between the associative cortices and both the STN and the MSR. We found a dominant motor cluster located in the posterolateral STN, a limbic cluster located medially in the MSR, and an intermediate motor-limbic cluster in between. Our findings show that the hyperdirect pathway is anatomo-functionally organized with a poor participation of associative cortices.

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.

Role of the pedunculopontine nucleus in controlling gait and sleep in normal and parkinsonian monkeys.

Patients with Parkinson's disease (PD) develop cardinal motor symptoms, including akinesia, rigidity, and tremor, that are alleviated by dopaminergic medication and/or subthalamic deep brain stimulation. Over the time course of the disease, gait and balance disorders worsen and become resistant to pharmacological and surgical treatments. These disorders generate debilitating motor symptoms leading to increased dependency, morbidity, and mortality. PD patients also experience sleep disturbance that raise the question of a common physiological basis. An extensive experimental and clinical body of work has highlighted the crucial role of the pedunculopontine nucleus (PPN) in the control of gait and sleep, and its potential major role in PD. Here, we summarise our investigations in the monkey PPN in the normal and parkinsonian states. We first examined the anatomy and connectivity of the PPN and the cuneiform nucleus which both belong to the mesencephalic locomotor region. Second, we conducted experiments to demonstrate the specific effects of PPN cholinergic lesions on locomotion in the normal and parkinsonian monkey. Third, we aimed to understand how PPN cholinergic lesions impair sleep in parkinsonian monkeys. Our final goal was to develop a novel model of advanced PD with gait and sleep disorders. We believe that this monkey model, even if it does not attempt to reproduce the exact human disease with all its complexities, represents a good biomedical model to characterise locomotion and sleep in the context of PD.

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.

Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model.

OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.

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.

In vivo Exploration of the Connectivity between the Subthalamic Nucleus and the Globus Pallidus in the Human Brain Using Multi-Fiber Tractography.

The basal ganglia is part of a complex system of neuronal circuits that play a key role in the integration and execution of motor, cognitive and emotional function in the human brain. Parkinson's disease is a progressive neurological disorder of the motor circuit characterized by tremor, rigidity, and slowness of movement. Deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus pars interna provides an efficient treatment to reduce symptoms and levodopa-induced side effects in Parkinson's disease patients. While the underlying mechanism of action of DBS is still unknown, the potential modulation of white matter tracts connecting the surgical targets has become an active area of research. With the introduction of advanced diffusion MRI acquisition sequences and sophisticated post-processing techniques, the architecture of the human brain white matter can be explored in vivo. The goal of this study is to investigate the white matter connectivity between the subthalamic nucleus and the globus pallidus. Two multi-fiber tractography methods were used to reconstruct pallido-subthalamic, subthalamo-pallidal and pyramidal fibers in five healthy subjects datasets of the Human Connectome Project. The anatomical accuracy of the tracts was assessed by four judges with expertise in neuroanatomy, functional neurosurgery, and diffusion MRI. The variability among subjects was evaluated based on the fractional anisotropy and mean diffusivity of the tracts. Both multi-fiber approaches enabled the detection of complex fiber architecture in the basal ganglia. The qualitative evaluation by experts showed that the identified tracts were in agreement with the expected anatomy. Tract-derived measurements demonstrated relatively low variability among subjects. False-negative tracts demonstrated the current limitations of both methods for clinical decision-making. Multi-fiber tractography methods combined with state-of-the-art diffusion MRI data have the potential to help identify white matter tracts connecting DBS targets in functional neurosurgery intervention.

Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson's disease.

Pedunculopontine nucleus (PPN) cholinergic neurons, which exert excitatory nicotinic control over substantia nigra dopaminergic neurons, degenerate in Parkinson's disease (PD). This finding and other studies showing that nicotine, the preferential agonist of nicotinic acetylcholine receptors, is neuroprotective in experimental models of PD suggest that a deficit in PPN excitatory cholinergic inputs might contribute to the death of nigral dopaminergic neurons in PD. To explore this possibility, we used lesion paradigms of dopaminergic and/or cholinergic systems in rats and monkeys. Consistent with our hypothesis, we observed that stereotaxic lesioning of PPN cholinergic neurons with diphtheria toxin coupled to urotensin II resulted in a significant loss of nigral dopaminergic neurons in rats and induced morphological changes in these neurons in macaques. Unexpectedly, a lesion of dopaminergic neurons induced by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) in rats, or by repeated systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in macaques, led to a 29% and 7% loss of PPN cholinergic neurons, respectively. Lastly, when the PPN cholinergic lesion was performed in rats in which the dopaminergic lesion induced by 6-OHDA was in progress, loss of cholinergic neurons was more drastic than when each neurotransmitter system was lesioned separately. Thus, our results suggest that strong PPN cholinergic and dopaminergic interactions may be an important mechanism in the pathophysiology of PD.

Effect of melatonin on sleep disorders in a monkey model of Parkinson's disease.

OBJECTIVES: To evaluate and compare the effects of melatonin and levodopa (L-dopa) on sleep disorders in a monkey model of Parkinson's disease. MATERIALS AND METHODS: The daytime and nighttime sleep patterns of four macaques that were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were recorded using polysomnography in four conditions: at baseline, during the parkinsonian condition; after administration of L-dopa, and after administration of a combination of melatonin with L-dopa. RESULTS: It was confirmed that MPTP intoxication induces sleep disorders, with sleep episodes during daytime and sleep fragmentation at nighttime. L-dopa treatment significantly reduced the awake time during the night and tended to improve all other sleep parameters, albeit not significantly. In comparison to the parkinsonian condition, combined treatment with melatonin and L-dopa significantly increased total sleep time and sleep efficiency, and reduced the time spent awake during the night in all animals. A significant decrease in sleep latencies was also observed in three out of four animals. Compared with L-dopa alone, combined treatment with melatonin and L-dopa significantly improved all these sleep parameters in two animals. On the other hand, combined treatment had no effect on sleep architecture and daytime sleep. CONCLUSION: These data demonstrated, for the first time, objective improvement on sleep parameters of melatonin treatment in MPTP-intoxicated monkeys, showing that melatonin treatment has a real therapeutic potential to treat sleep disturbances in people with Parkinson's disease.

What makes a frontal area of primate brain the frontal eye field?

The frontal eye field region (FEF) of the oculomotor pathways has been intensely studied. The primary goal of this review is to illustrate the phylogenetic displacement of the FEF locus in primate species. The locus is arrayed along the arcuate sulcus in monkeys and abuts into the primary motor strip region in humans. The strengths and limitations of the various functional, anatomical and histological methodologies used to identify such regions are also discussed.

PPNa-DBS for gait and balance disorders in Parkinson's disease: a double-blind, randomised study.

Gait and balance disorders are the major source of motor disabilities in advanced forms of Parkinson's disease (PD). Low-frequency stimulation of the pedunculopontine nucleus area (PPNa-DBS) has been recently proposed to treat these symptoms with variable clinical results. To further understand the effects of PPNa-DBS on resistant gait and balance disorders, we performed a randomised double-blind cross-over study in six PD patients. Evaluation included clinical assessment of parkinsonian disability, quality of life and neurophysiological recordings of gait. Evaluations were done 1 month before, 4 and 6 months after surgery with four double-blinded conditions assessed: with and without PPNa-DBS, with and without levodopa treatment. Four patients completed the study and two patients were excluded from the final analysis because of peri-operative adverse events (haematoma, infection). Clinically, the combination of PPNa-DBS and levodopa treatment produced a significant decrease of the freezing episodes. The frequency of falls also decreased in three out of four patients. From a neurophysiological point of view, PPNa-DBS significantly improved the anticipatory postural adjustments and double-stance duration, but not the length and speed of the first step. Interestingly, step length and speed improved after surgery without PPNa-DBS, suggesting that the lesioning effect of PPNa-DBS surgery alleviates parkinsonian akinesia. Quality of life was also significantly improved with PPNa-DBS. These results suggest that PPNa-DBS could improve gait and balance disorders in well-selected PD patients. However, this treatment may be riskier than others DBS surgeries in these patients with an advanced form of PD.

Sparing of orexin-A and orexin-B neurons in the hypothalamus and of orexin fibers in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques.

Several studies conducted in patients with Parkinson's disease have reported that the degeneration of substantia nigra dopaminergic neurons, which are essential for motor control, is associated with the loss of hypothalamic orexin neurons, which are involved in sleep regulation. In order to better explore the mutual interactions between these two systems, we wished to determine in macaques: (i) if the two orexin peptides, orexin-A and orexin-B, are distributed in the same hypothalamic cells and if they are localized in nerve terminals that project onto nigral dopaminergic neurons, and (ii) if there is a loss of orexin neurons in the hypothalamus and of orexin fibers innervating nigral dopaminergic neurons in macaques rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We showed that virtually all cells stained for orexin-A in the hypothalamus co-expressed orexin-B. Numerous terminals stained for both orexin-A and orexin-B immunoreactivity that innervated the whole extent of the ventral tegmental area and substantia nigra pars compacta were found in close proximity to tyrosine hydroxylase-immunoreactive dendrites. These data indicate that orexin-A and orexin-B peptides are in a position to play a role in controlling the activity of nigral dopaminergic neurons. However, no loss of orexin-A or orexin-B neurons in the hypothalamus and no loss of orexin fibers in the substantia nigra pars compacta was found in MPTP-treated macaques when compared with control macaques. We conclude that a relatively selective dopaminergic lesion, such as that performed in MPTP-treated macaques, is not sufficient to induce a loss of hypothalamic orexin neurons.

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.