Evaluation of microglia activation related markers following a clinical course of TBS: A non-human primate study.

While the applicability and popularity of theta burst stimulation (TBS) paradigms remain, current knowledge of their neurobiological effects is still limited, especially with respect to their impact on glial cells and neuroinflammatory processes. We used a multimodal imaging approach to assess the effects of a clinical course of TBS on markers for microglia activation and tissue injury as an indirect assessment of neuroinflammatory processes. Healthy non-human primates received continuous TBS (cTBS), intermittent TBS (iTBS), or sham stimulation over the motor cortex at 90% of resting motor threshold. Stimulation was delivered to the awake subjects 5 times a week for 3-4 weeks. Translocator protein (TSPO) expression was evaluated using Positron Emission Tomography and [11C]PBR28, and myo-inositol (mI) and N-acetyl-aspartate (NAA) concentrations were assessed with Magnetic Resonance Spectroscopy. Animals were then euthanized, and immunofluorescence staining was performed using antibodies against TSPO. Paired t-tests showed no significant changes in [11C]PBR28 measurements after stimulation. Similarly, no significant changes in mI and NAA concentrations were found. Post-mortem TSPO evaluation showed comparable mean immunofluorescence intensity after active TBS and sham delivery. The current study suggests that in healthy brains a clinical course of TBS, as evaluated with in-vivo imaging techniques (PET and MRS), did not measurably modulate the expression of glia related markers and metabolite associated with neural viability.

Cholinergic and Nadph-δ neurons in the pedunculopontine and laterodorsal tegmental nuclei of human and nonhuman primates.

The brainstem pedunculopontine (PPN) and laterodorsal tegmental (LDTg) nuclei are involved in multifarious activities, including motor control. Yet, their exact cytoarchitectural boundaries are still uncertain. We therefore initiated a comparative study of the topographical and neurochemical organization of the PPN and LDTg in cynomolgus monkeys (Macaca fascicularis) and humans. The distribution and morphological characteristics of neurons expressing choline acetyltransferase (ChAT) and/or nicotinamide adenine dinucleotide phosphate diaphorase (Nadph-δ) were documented. The number and density of the labeled neurons were obtained by stringent stereological methods, whereas their topographical distribution was reported upon corresponding magnetic resonance imaging (MRI) planes. In both human and nonhuman primates, the PPN and LDTg are populated by three neurochemically distinct types of neurons (ChAT-/Nadph-δ+, ChAT+/Nadph-δ-, and ChAT+/Nadph-δ+), which are distributed according to a complex spatial interplay. Three-dimensional reconstructions reveal that ChAT+ neurons in the PPN and LDTg form a continuum with some overlaps with pigmented neurons of the locus coeruleus, dorsally, and of the substantia nigra (SN) complex, ventrally. The ChAT+ neurons in the PPN and LDTg are -two to three times more numerous in humans than in monkeys but their density is -three to five times higher in monkeys than in humans. Neurons expressing both ChAT and Nadph-δ have a larger cell body and a longer primary dendritic arbor than singly labeled neurons. Stereological quantification reveals that 25.6% of ChAT+ neurons in the monkey PPN are devoid of Nadph-δ staining, a finding that questions the reliability of Nadph-δ as a marker for cholinergic neurons in primate brainstem.

Metformin rescues migratory deficits of cells derived from patients with periventricular heterotopia.

Periventricular neuronal heterotopia (PH) is one of the most common forms of cortical malformation in the human cortex. We show that human neuronal progenitor cells (hNPCs) derived from PH patients with a DCHS1 or FAT4 mutation as well as isogenic lines had altered migratory dynamics when grafted in the mouse brain. The affected migration was linked to altered autophagy as observed in vivo with an electron microscopic analysis of grafted hNPCs, a Western blot analysis of cortical organoids, and time-lapse imaging of hNPCs in the presence of bafilomycin A1. We further show that deficits in autophagy resulted in the accumulation of paxillin, a focal adhesion protein involved in cell migration. Strikingly, a single-cell RNA-seq analysis of hNPCs revealed similar expression levels of autophagy-related genes. Bolstering AMPK-dependent autophagy by metformin, an FDA-approved drug, promoted migration of PH patients-derived hNPCs. Our data indicate that transcription-independent homeostatic modifications in autophagy contributed to the defective migratory behavior of hNPCs in vivo and suggest that modulating autophagy in hNPCs might rescue neuronal migration deficits in some forms of PH.

Conditional deletion of neurexins dysregulates neurotransmission from dopamine neurons.

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which in addition to DA, glutamate or GABA are also released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. An emerging literature suggests that neuroligins, trans-synaptic cell adhesion molecules, regulate both DA neuron connectivity and neurotransmission. However, the contribution of their major interaction partners, neurexins (Nrxns), is unexplored. Here, we tested the hypothesis that Nrxns regulate DA neuron neurotransmission. Mice with conditional deletion of all Nrxns in DA neurons (DAT::NrxnsKO) exhibited normal basic motor functions. However, they showed an impaired locomotor response to the psychostimulant amphetamine. In line with an alteration in DA neurotransmission, decreased levels of the membrane DA transporter (DAT) and increased levels of the vesicular monoamine transporter (VMAT2) were detected in the striatum of DAT::NrxnsKO mice, along with reduced activity-dependent DA release. Strikingly, electrophysiological recordings revealed an increase of GABA co-release from DA neuron axons in the striatum of these mice. Together, these findings suggest that Nrxns act as regulators of the functional connectivity of DA neurons.

The human brain contains billions of nerve cells, known as neurons, which receive input from the outside world and process this information in the brain. Neurons communicate with each other by releasing chemical messengers from specialized structures, called axon terminals, some of which form junctions known as synapses. These messengers then generate signals in the target neurons. Based on the type of chemical they release, neurons can be classified into different types. For example, neurons releasing dopamine are considered to act as key regulators of learning, movements and motivation. Such neurons establish very large numbers of axon terminals, but very few of them form synapses. Specific sets of proteins, including neurexins and neuroligins, are thought to help regulate the activity of the connexions between these neurons. Previous research has shown that when neuroligins were removed from the neurons of worms or mice, it affected the ability of the animals to move. So far, the role of neurexins in managing the connectivity of regulatory neurons, such as those releasing dopamine, has received much less attention. To bridge this knowledge gap, Ducrot et al. explored how removing neurexins from dopamine neurons in mice affected their behaviour. The experiments revealed that eliminating neurexins did not affect their motor skills on a rotating rod, but it did reduce their movements in response to the psychostimulant amphetamine, a molecule known to enhance dopamine-associated behaviours. The cellular structure of dopamine neurons lacking neurexins was the same as in neurons containing this protein. But dopamine neurons without neurexins were slower to recycle dopamine, and they released a higher amount of the inhibitory messenger GABA. This suggests that neurexin acts as an important suppressor of GABA secretion to help regulate the signals released by dopamine neurons. These findings set the stage for further research into the role of neurexins in regulating dopamine and other populations of neurons in conditions such as Parkinson's disease, where movement and coordination are affected.

Astrocytes display ultrastructural alterations and heterogeneity in the hippocampus of aged APP-PS1 mice and human post-mortem brain samples.

The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer's disease (AD). To provide novel insights into the roles of astrocytes in the pathophysiology of AD, we performed a quantitative ultrastructural characterization of their intracellular contents and parenchymal interactions in an aged mouse model of AD pathology, as aging is considered the main risk factor for developing AD. We compared 20-month-old APP-PS1 and age-matched C57BL/6J male mice, among the ventral hippocampus CA1 strata lacunosum-moleculare and radiatum, two hippocampal layers severely affected by AD pathology. Astrocytes in both layers interacted more with synaptic elements and displayed more ultrastructural markers of increased phagolysosomal activity in APP-PS1 versus C57BL6/J mice. In addition, we investigated the ultrastructural heterogeneity of astrocytes, describing in the two examined layers a dark astrocytic state that we characterized in terms of distribution, interactions with AD hallmarks, and intracellular contents. This electron-dense astrocytic state, termed dark astrocytes, was observed throughout the hippocampal parenchyma, closely associated with the vasculature, and possessed several ultrastructural markers of cellular stress. A case study exploring the hippocampal head of an aged human post-mortem brain sample also revealed the presence of a similar electron-dense, dark astrocytic state. Overall, our study provides the first ultrastructural quantitative analysis of astrocytes among the hippocampus in aged AD pathology, as well as a thorough characterization of a dark astrocytic state conserved from mouse to human.

Evolving characterization of the human hyperdirect pathway.

The hyperdirect pathway (HDP) represents the main glutamatergic input to the subthalamic nucleus (STN), through which the motor and prefrontal cerebral cortex can modulate basal ganglia activity. Further, direct activation of the motor HDP is thought to be an important component of therapeutic deep brain stimulation (DBS), mediating the disruption of pathological oscillations. Alternatively, unintended recruitment of the prefrontal HDP may partly explain some cognitive side effects of DBS therapy. Previous work describing the HDP has focused on non-human primate (NHP) histological pathway tracings, diffusion-weighted MRI analysis of human white matter, and electrophysiology studies involving paired cortical recordings with DBS. However, none of these approaches alone yields a complete understanding of the complexities of the HDP. As such, we propose that generative modeling methods hold promise to bridge anatomy and physiology results, from both NHPs and humans, into a more detailed representation of the human HDP. Nonetheless, numerous features of the HDP remain to be experimentally described before model-based methods can simulate corticosubthalamic activity with a high degree of scientific detail. Therefore, the goals of this review are to examine the experimental evidence for HDP projections from across the primate neocortex and discuss new data which are required to improve the utility of anatomical and biophysical models of the human corticosubthalamic system.

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer's disease pathology and in human post-mortem brain samples.

A diverse heterogeneity of microglial cells was previously described in Alzheimer's disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1 stratum lacunosum-moleculare of 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aß) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aß plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.

Continuous but not intermittent theta burst stimulation decreases striatal dopamine release and cortical excitability.

Dopamine modulation is thought to underpin some of the therapeutic effects associated with repetitive transcranial magnetic stimulation (rTMS). However, patient studies have failed to demonstrate consistent changes in the dopamine system in vivo after a therapeutic course of rTMS. Here, we evaluated acute and chronic changes in striatal dopamine release elicited by a clinically relevant course of theta burst (TBS) or sham stimulation using [11C]raclopride in healthy non-human primates (n = 11). Subjects were scanned immediately after the first session of TBS and the day after a 3 week course of daily TBS delivery. After experiment completion, animals were euthanized, and immunofluorescence staining was carried out using antibodies targeting D2 receptors (D2R). Continuous TBS (cTBS, an inhibitory form of rTMS) over the left primary motor cortex acutely decreased dopamine release bilaterally in the putamen. However, no significant changes in dopamine receptors nor D2R immunoreactivity were noted 24 h after the last stimulation, while a decrease in cortical excitability, as measured by an increase in resting motor threshold, could still be quantified. On the opposite, intermittent TBS (iTBS, an excitatory form of rTMS) did not affect dopamine release, acutely or chronically, D2R immunoreactivity or cortical excitability. These findings suggest that the long-term therapeutic effects of TBS might be facilitated through the modulation of different neurotransmission systems beyond the dopamine system. However, given the small sample size, these results should be interpreted with caution.

A Topographic Atlas of the Human Brainstem in the Ponto-Mesencephalic Junction Plane.

The human brainstem harbors neuronal aggregates that ensure the maintenance of several vital functions. It also acts as a major relay structure for the neuronal information that travels between the cerebral cortex, the cerebellum and the spinal cord. As such, this relatively small portion of the human brain houses a multitude of ascending and descending fibers that course among numerous nuclei whose exact boundaries are still uncertain. Such a large number of nuclei and fiber tracts confined to a relatively small and compact brain region imposes upon the brainstem a highly complex cytoarchitectonic organization that still needs to be deciphered. The present work provides a topographic atlas of the human brainstem composed of 45 anatomical plates, each containing a pair of adjacent sections stained with Cresyl Violet and Luxol Fast Blue to help delineating brainstem nuclei and fiber tracts, respectively. The plates, which cover the entire midbrain, pons and medulla oblongata, are composed of equally-spaced sections referenced and aligned parallel to the ponto-mesencephalic junction rather than the fastigium or the obex. This topographic landmark is particularly suitable for neurosurgical interventions aiming at specific nuclei of the mesencephalic tegmentum. In complement, we provide 8 anatomical plates containing adjacent sections stained for choline acetyltransferase and Luxol Fast Blue, taken through the midbrain and the pons. This open access atlas of the human brainstem is intended to assist neuroanatomists, neurosurgeons and neuropathologists in their work.

Dopaminergic neurons establish a distinctive axonal arbor with a majority of non-synaptic terminals.

Chemical neurotransmission typically occurs through synapses. Previous ultrastructural examinations of monoamine neuron axon terminals often failed to identify a pre- and postsynaptic coupling, leading to the concept of "volume" transmission. Whether this results from intrinsic properties of these neurons remains undefined. We find that dopaminergic neurons in vitro establish a distinctive axonal arbor compared to glutamatergic or GABAergic neurons in both size and propensity of terminals to avoid direct contact with target neurons. While most dopaminergic varicosities are active and contain exocytosis proteins like synaptotagmin 1, only ~20% of these are synaptic. The active zone protein bassoon was found to be enriched in dopaminergic terminals that are in proximity to a target cell. Finally, we found that the proteins neurexin-1αSS4- and neuroligin-1A+B play a critical role in the formation of synapses by dopamine (DA) neurons. Our findings suggest that DA neurons are endowed with a distinctive developmental connectivity program.

Histology-driven model of the macaque motor hyperdirect pathway.

Emerging appreciation for the hyperdirect pathway (HDP) as an important cortical glutamatergic input to the subthalamic nucleus (STN) has motivated a wide range of recent investigations on its role in motor control, as well as the mechanisms of subthalamic deep brain stimulation (DBS). However, the pathway anatomy and terminal arbor morphometry by which the HDP links cortical and subthalamic activity are incompletely understood. One critical hindrance to advancing understanding is the lack of anatomically detailed population models which can help explain how HDP pathway anatomy and neuronal biophysics give rise to spatiotemporal patterns of stimulus-response activity observed in vivo. Therefore, the goal of this study was to establish a population model of motor HDP axons through application of generative algorithms constrained by recent histology and imaging data. The products of this effort include a de novo macaque brain atlas, detailed statistical analysis of histological reconstructions of macaque motor HDP axons, and the generation of 10,000 morphometrically constrained synthetic motor HDP axons. The synthetic HDP axons exhibited a 3.8% mean error with respect to parametric distributions of the fiber target volume, total length, number of bifurcations, bifurcation angles, meander angles, and segment lengths measured in BDA-labeled HDP axon reconstructions. As such, this large population of synthetic motor HDP axons represents an anatomically based foundation for biophysical simulations that can be coupled to electrophysiological and/or behavioral measurements, with the goal of better understanding the role of the HDP in motor system activity.

The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migration in vivo.

Cell migration is a dynamic process that entails extensive protein synthesis and recycling, structural remodeling, and considerable bioenergetic demand. Autophagy is one of the pathways that maintain cellular homeostasis. Time-lapse imaging of autophagosomes and ATP/ADP levels in migrating cells in the rostral migratory stream of mouse revealed that decreases in ATP levels force cells into the stationary phase and induce autophagy. Pharmacological or genetic impairments of autophagy in neuroblasts using either bafilomycin, inducible conditional mice, or CRISPR/Cas9 gene editing decreased cell migration due to the longer duration of the stationary phase. Autophagy is modulated in response to migration-promoting and inhibiting molecular cues and is required for the recycling of focal adhesions. Our results show that autophagy and energy consumption act in concert in migrating cells to dynamically regulate the pace and periodicity of the migratory and stationary phases to sustain neuronal migration.

Levodopa partially rescues microglial numerical, morphological, and phagolysosomal alterations in a monkey model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative motor disorder. The mechanisms underlying the onset and progression of Levodopa (L-Dopa)-induced dyskinesia (LID) during PD treatment remain elusive. Emerging evidence implicates functional modification of microglia in the development of LID. Thus, understanding the link between microglia and the development of LID may provide the knowledge required to preserve or promote beneficial microglial functions, even during a prolonged L-Dopa treatment. To provide novel insights into microglial functional alterations in PD pathophysiology, we characterized their density, morphology, ultrastructure, and degradation activity in the sensorimotor functional territory of the putamen, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cynomolgus monkeys. A subset of MPTP monkeys was treated orally with L-Dopa and developed LID similar to PD patients. Using a combination of light, confocal and transmission electron microscopy, our quantitative analyses revealed alterations of microglial density, morphology and phagolysosomal activity following MPTP intoxication that were partially normalized with L-Dopa treatment. In particular, microglial density, cell body and arborization areas were increased in the MPTP monkeys, whereas L-Dopa-treated MPTP animals presented a microglial phenotype similar to the control animals. At the ultrastructural level, microglia did not differ between groups in their markers of cellular stress or aging. Nevertheless, microglia from the MPTP monkeys displayed reduced numbers of endosomes, compared with control animals, that remained lower after L-Dopa treatment. Microglia from MPTP monkeys treated with L-Dopa also had increased numbers of primary lysosomes compared with non-treated MPTP animals, while secondary and tertiary lysosomes remained unchanged. Moreover, a decrease microglial immunoreactivity for CD68, considered a marker of phagocytosis and lysosomal activity, was measured in the MPTP monkeys treated with L-Dopa, compared with non-treated MPTP animals. Taken together, these findings revealed significant changes in microglia during PD pathophysiology that were partially rescued by L-Dopa treatment. Albeit, this L-Dopa treatment conferred phagolysosomal insufficiency on microglia in the dyskinetic Parkinsonian monkeys.

Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease.

Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adult neurogenesis by perturbed lipid metabolism predisposes patients to AD. However, it remains unknown what causes aberrant expression of Mgll in AD and how Mgll-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify Mgll as an aging-induced factor that impairs adult neurogenesis and spatial memory in AD, and show that metformin, an FDA-approved anti-diabetic drug, can reduce the expression of Mgll to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce ß-amyloid accumulation. Methods: Mgll expression was assessed in both human AD patient post-mortem hippocampal tissues and 3xTg-AD mouse model. In addition, we used both the 3xTg-AD animal model and the CbpS436A genetic knock-in mouse model to identify that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway, involving atypical protein kinase C (aPKC)-stimulated Ser436 phosphorylation of histone acetyltransferase CBP through biochemical methods. Furthermore, we performed in vivo adult neurogenesis assay with BrdU/EdU labelling and Morris water maze task in both animal models following pharmacological treatments to show the key role of Mgll in metformin-corrected neurogenesis and spatial memory deficits of AD through reactivating the aPKC-CBP pathway. Finally, we performed in vitro adult neurosphere assays using both animal models to study the role of the aPKC-CBP mediated Mgll repression in determining adult neural stem/progenitor cell (NPC) fate. Results: Here, we demonstrate that aging-dependent induction of Mgll is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of Mgll in the 3xTg-AD mice reduces the genesis of newborn neurons and perturbs spatial memory. However, we find that metformin-stimulated aPKC-CBP pathway decreases Mgll expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated Mgll levels in cultured adult NPCs from both 3xTg-AD and CbpS436A animal models are responsible for their NPC neuronal differentiation deficits. Conclusion: Our findings set the stage for development of a clinical protocol where Mgll would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory.

Rise of Raman spectroscopy in neurosurgery: a review.

SIGNIFICANCE: Although the clinical potential for Raman spectroscopy (RS) has been anticipated for decades, it has only recently been used in neurosurgery. Still, few devices have succeeded in making their way into the operating room. With recent technological advancements, however, vibrational sensing is poised to be a revolutionary tool for neurosurgeons. AIM: We give a summary of neurosurgical workflows and key translational milestones of RS in clinical use and provide the optics and data science background required to implement such devices. APPROACH: We performed an extensive review of the literature, with a specific emphasis on research that aims to build Raman systems suited for a neurosurgical setting. RESULTS: The main translatable interest in Raman sensing rests in its capacity to yield label-free molecular information from tissue intraoperatively. Systems that have proven usable in the clinical setting are ergonomic, have a short integration time, and can acquire high-quality signal even in suboptimal conditions. Moreover, because of the complex microenvironment of brain tissue, data analysis is now recognized as a critical step in achieving high performance Raman-based sensing. CONCLUSIONS: The next generation of Raman-based devices are making their way into operating rooms and their clinical translation requires close collaboration between physicians, engineers, and data scientists.

Anisotropic light scattering from myelinated axons in the spinal cord.

Optogenetics has become an integral tool for studying and dissecting the neural circuitries of the brain using optical control. Recently, it has also begun to be used in the investigation of the spinal cord and peripheral nervous system. However, information on these regions' optical properties is sparse. Moreover, there is a lack of data on the dependence of light propagation with respect to neural tissue organization and orientation. This information is important for effective simulations and optogenetic planning, particularly in the spinal cord where the myelinated axons are highly organized. To this end, we report experimental measurements for the scattering coefficient, validated with three different methods in both the longitudinal and radial directions of multiple mammalian spinal cords. In our analysis, we find that there is indeed a directional dependence of photon propagation when interacting with organized myelinated axons. Specifically, light propagating perpendicular to myelinated axons in the white matter of the spinal cord produced a measured reduced scattering coefficient ( µ s ' ) of 3.52 ± 0.1 mm - 1 , and light that was propagated along the myelinated axons in the white matter produced a measured µ s ' of 1.57 ± 0.03 mm - 1 , across the various species considered. This 50% decrease in scattering power along the myelinated axons is observed with three different measurement strategies (integrating spheres, observed transmittance, and punch-through method). Furthermore, this directional dependence in scattering power and overall light attenuation did not occur in the gray matter regions where the myelin organization is nearly random. The acquired information will be integral in preparing future light-transport simulations and in overall optogenetic planning in both the spinal cord and the brain.

The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu2/3 ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu2 activation in the anti-dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1 mg/kg), started concurrently with l-DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1 mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository.

BACKGROUND: Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository. OBJECTIVE: To present the QPN and to perform preliminary analysis of the QPN data. METHODS: A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups. RESULTS: QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN. CONCLUSIONS: The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

Holographic Reconstruction of Axonal Pathways in the Human Brain.

Three-dimensional documentation of the axonal pathways connecting gray matter components of the human brain has wide-ranging scientific and clinical applications. Recent attempts to map human structural connectomes have concentrated on using tractography results derived from diffusion-weighted imaging data, but tractography is an indirect method with numerous limitations. Advances in holographic visualization platforms provide a new medium to integrate anatomical data, as well as a novel working environment for collaborative interaction between neuroanatomists and brain-imaging scientists. Therefore, we developed the first holographic interface for building axonal pathways, populated it with human histological and structural MRI data, and assembled world expert neuroanatomists to interactively define axonal trajectories of the cortical, basal ganglia, and cerebellar systems. This blending of advanced visualization hardware, software development, and neuroanatomy data enabled the translation of decades of amassed knowledge into a human axonal pathway atlas that can be applied to educational, scientific, or clinical investigations.

Convolutional Neural Networks for Spectroscopic Analysis in Retinal Oximetry.

Retinal oximetry is a non-invasive technique to investigate the hemodynamics, vasculature and health of the eye. Current techniques for retinal oximetry have been plagued by quantitatively inconsistent measurements and this has greatly limited their adoption in clinical environments. To become clinically relevant oximetry measurements must become reliable and reproducible across studies and locations. To this end, we have developed a convolutional neural network algorithm for multi-wavelength oximetry, showing a greatly improved calculation performance in comparison to previously reported techniques. The algorithm is calibration free, performs sensing of the four main hemoglobin conformations with no prior knowledge of their characteristic absorption spectra and, due to the convolution-based calculation, is invariable to spectral shifting. We show, herein, the dramatic performance improvements in using this algorithm to deduce effective oxygenation (SO2), as well as the added functionality to accurately measure fractional oxygenation ([Formula: see text]). Furthermore, this report compares, for the first time, the relative performance of several previously reported multi-wavelength oximetry algorithms in the face of controlled spectral variations. The improved ability of the algorithm to accurately and independently measure hemoglobin concentrations offers a high potential tool for disease diagnosis and monitoring when applied to retinal spectroscopy.