Mesencephalic Reticular Formation Research Articles

Altered functional connectivity of brainstem nuclei in new daily persistent headache: Evidence from resting-state functional magnetic resonance imaging.

The new daily persistent headache (NDPH) is a rare primary headache disorder. However, the underlying mechanisms of NDPH remain incompletely understood. This study aims to apply seed-based analysis to explore the functional connectivity (FC) of brainstem nuclei in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). The FC analysis from the region of interest (ROI) to whole brain voxels was used to investigate 29 patients with NDPH and 37 well-matched healthy controls (HCs) with 3.0 Tesla MRI. The 76 nuclei in the brainstem atlas were defined as ROIs. Furthermore, we explored the correlations between FC and patients' clinical characteristics and neuropsychological evaluations. Patients with NDPH exhibited reduced FC in multiple brainstem nuclei compared to HCs (including right inferior medullary reticular formation, right mesencephalic reticular formation, bilateral locus coeruleus, bilateral laterodorsal tegmental nucleus-central gray of the rhombencephalon, median raphe, left medial parabrachial nucleus, periaqueductal gray, and bilateral ventral tegmental area-parabrachial pigmented nucleus complex) and increased FC in periaqueductal gray. No significant correlations were found between the FC of these brain regions and clinical characteristics or neuropsychological evaluations after Bonferroni correction (p > 0.00016). Our results demonstrated that patients with NDPH have abnormal FC of brainstem nuclei involved in the perception and regulation of pain and emotions.

An autonomic mode of brain activity.

The relevance of interactions between autonomic and central nervous systems remains unclear for human brain function and health, particularly when both systems are challenged under sleep deprivation (SD). We measured brain activity (with fMRI), pulse and respiratory signals, and baseline brain amyloid beta burden (with PET) in healthy participants. We found that SD relative to rested wakefulness (RW) resulted in a significant increase in synchronized low frequency (LF, < 0.1Hz) activity in an autonomically-related network (AN), including dorsal attention, visual, and sensorimotor regions, which we previously found to have consistent temporal coupling with LF pulse signal changes (regulated by sympathetic tone). SD resulted in a significant phase coherence between the LF component of the pulse signal and a medial network with peak effects in the midbrain reticular formation, and between LF component of the respiratory variations (regulated by respiratory motor output) and a cerebellar network. The LF power of AN during SD was significantly and independently correlated with pulse-medial network and respiratory-cerebellar network phase coherences (total adjusted R2 = 0.78). Higher LF power of AN during SD (but not RW) was associated with lower amyloid beta burden (Cohen's d = 0.8). In sum, SD triggered an autonomic mode of synchronized brain activity that was associated with distinct autonomic-central interactions. Findings highlight the direct relevance of global cortical synchronization to brain clearance mechanisms.

Brainstem sources of input to the central mesencephalic reticular formation in the macaque.

Physiological studies indicate that the central mesencephalic reticular formation (cMRF) plays a role in gaze changes, including control of disjunctive saccades. Neuroanatomical studies have demonstrated strong interconnections with the superior colliculus, along with projections to extraocular motor nuclei, the preganglionic nucleus of Edinger-Westphal, the paramedian pontine reticular formation, nucleus raphe interpositus, medullary reticular formation and cervical spinal cord, as might be expected for a structure that is intimately involved in gaze control. However, the sources of input to this midbrain structure have not been described in detail. In the present study, the brainstem cells of origin supplying the cMRF were labeled by retrograde transport of tracer (wheat germ agglutinin conjugated horseradish peroxidase) in macaque monkeys. Within the diencephalon, labeled neurons were noted in the ventromedial nucleus of the hypothalamus, pregeniculate nucleus and habenula. In the midbrain, labeled cells were found in the substantia nigra pars reticulata, medial pretectal nucleus, superior colliculus, tectal longitudinal column, periaqueductal gray, supraoculomotor area, and contralateral cMRF. In the pons they were located in the paralemniscal zone, parabrachial nucleus, locus coeruleus, nucleus prepositus hypoglossi and the paramedian pontine reticular formation. Finally, in the medulla they were observed in the medullary reticular formation. The fact that this list of input sources is very similar to those of the superior colliculus supports the view that the cMRF represents an important gaze control center.

Is the central mesencephalic reticular formation a purely horizontal gaze center?

Historically, the central mesencephalic reticular formation has been regarded as a purely horizontal gaze center based on the fact that electrical stimulation of this region produces horizontal saccades, it provides monosynaptic input to medial rectus motoneurons, and cells recorded in this region often display a peak in firing when horizontal saccades are made. We tested the proposition that the central mesencephalic reticular formation is purely a horizontal gaze center by examining whether this region also supplies terminals to superior rectus and levator palpebrae superioris motoneurons, both of which fire when making vertical eye movements. The experiments were carried out using dual tracer techniques at the light and electron microscopic level in macaque monkeys. Injections of biotinylated dextran amine or Phaseolus vulgaris leukoagglutinin into the central mesencephalic reticular formation produced anterogradely labeled terminals that were in synaptic contact with superior rectus and levator palpebrae superioris motoneurons that had been retrogradely labeled. These results indicate that this region is not purely connected with horizontal gaze motoneurons. In addition, we found that the number of contacts on vertical gaze motoneurons increased with more rostral injections involving the mesencephalic reticular formation adjacent to the interstitial nucleus of Cajal. This suggests that there is a caudal to rostral gradient for horizontal to vertical saccades, respectively, represented within the midbrain reticular formation. Finally, we utilized post-embedding immunohistochemistry to show that a portion of the labeled terminals were GABAergic, indicating they likely originate from downgaze premotor neurons.

Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM-sleep regulatory neurons.

The midbrain reticular formation (MRF) is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including sleep regulation. However, the molecular characteristics and development of MRF neurons are poorly understood. As the transcription factor, Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is required for the expression of several GABAergic lineage-specific transcription factors, including Nkx2-2 and Skor2, which are co-expressed in a restricted group of post-mitotic GABAergic precursors in the MRF. Both Gata2 and Nkx2-2 function is required for Skor2 expression in GABAergic precursors. In the adult mouse and rat midbrain, Nkx2-2-and Skor2-expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the MRF, an area containing REM-off neurons regulating REM sleep. In addition to the characteristic localization, Skor2+ cells increase their activity upon REM-sleep inhibition, send projections to the dorsolateral pons, a region associated with sleep control, and are responsive to orexins, consistent with the known properties of midbrain REM-off neurons.

Abstinence following intermittent methylphenidate exposure dose-dependently modifies brain glucose metabolism in the rat brain.

Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays," which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3weeks on-treatment and 1week off-treatment for a period of 13weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD model.

A Novel Tectal/Pretectal Population of Premotor Lens Accommodation Neurons.

PurposeUnder real-world conditions, saccades are often accompanied by changes in vergence angle and lens accommodation that compensate for changes in the distance between the current fixation point and the next target. As the superior colliculus directs saccades, we examined whether it contains premotor neurons that might control lens compensation for target distance.MethodsRabies virus or recombinant rabies virus was injected into the ciliary bodies of Macaca fascicularis monkeys to label circuits controlling lens accommodation via retrograde transsynaptic transport. In addition, conventional anterograde tracers were used to confirm the rabies findings with respect to projections to preganglionic Edinger–Westphal motoneurons.ResultsAt time courses that rabies virus labeled lens-related premotor neurons in the supraoculomotor area and central mesencephalic reticular formation, labeled neurons were not found within the superior colliculus. They were, however, found bilaterally in the medial pretectal nucleus continuing caudally into the tectal longitudinal column, which lies on the midline, between the colliculi. A bilateral projection by this area to the preganglionic Edinger–Westphal nucleus was confirmed by anterograde tracing. Only at longer time courses were cells labeled in the superior colliculus.ConclusionsThe superior colliculus does not provide premotor input to preganglionic Edinger–Westphal nucleus motoneurons, but may provide input to lens-related premotor populations in the supraoculomotor area and central mesencephalic reticular formation. There is, however, a novel third population of lens-related premotor neurons in the tectal longitudinal column and rostrally adjacent medial pretectal nucleus. The specific function of this premotor population remains to be determined.

Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM).

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction. Methods: Activated midbrain nuclei were inferred by a re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI, indicating reciprocal patterns of activation. The controls had no changes. Conclusions: Exercise caused the opposite effects with increased activation in ME/CFS but decreased activation in GWI, indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

Structural and functional connectivity of the ascending arousal network for prediction of outcome in patients with acute disorders of consciousness

To determine the role of early acquisition of blood oxygen level-dependent (BOLD) signals and diffusion tensor imaging (DTI) for analysis of the connectivity of the ascending arousal network (AAN) in predicting neurological outcomes after acute traumatic brain injury (TBI), cardiopulmonary arrest (CPA), or stroke. A prospective analysis of 50 comatose patients was performed during their ICU stay. Image processing was conducted to assess structural and functional connectivity of the AAN. Outcomes were evaluated after 3 and 6 months. Nineteen patients (38%) had stroke, 18 (36%) CPA, and 13 (26%) TBI. Twenty-three patients were comatose (44%), 11 were in a minimally conscious state (20%), and 16 had unresponsive wakefulness syndrome (32%). Univariate analysis demonstrated that measurements of diffusivity, functional connectivity, and numbers of fibers in the gray matter, white matter, whole brain, midbrain reticular formation, and pontis oralis nucleus may serve as predictive biomarkers of outcome depending on the diagnosis. Multivariate analysis demonstrated a correlation of the predicted value and the real outcome for each separate diagnosis and for all the etiologies together. Findings suggest that the above imaging biomarkers may have a predictive role for the outcome of comatose patients after acute TBI, CPA, or stroke.

The Cortical Motor System in the Domestic Pig: Origin and Termination of the Corticospinal Tract and Cortico-Brainstem Projections.

The anatomy of the cortical motor system and its relationship to motor repertoire in artiodactyls is for the most part unknown. We studied the origin and termination of the corticospinal tract (CST) and cortico-brainstem projections in domestic pigs. Pyramidal neurons were retrogradely labeled by injecting aminostilbamidine in the spinal segment C1. After identifying the dual origin of the porcine CST in the primary motor cortex (M1) and premotor cortex (PM), the axons descending from those regions to the spinal cord and brainstem were anterogradely labeled by unilateral injections of dextran alexa-594 in M1 and dextran alexa-488 in PM. Numerous corticospinal projections from M1 and PM were detected up to T6 spinal segment and showed a similar pattern of decussation and distribution in the white matter funiculi and the gray matter laminae. They terminated mostly on dendrites of the lateral intermediate laminae and the internal basilar nucleus, and some innervated the ventromedial laminae, but were essentially absent in lateral laminae IX. Corticofugal axons terminated predominantly ipsilaterally in the midbrain and bilaterally in the medulla oblongata. Most corticorubral projections arose from M1, whereas the mesencephalic reticular formation, superior colliculus, lateral reticular nucleus, gigantocellular reticular nucleus, and raphe received abundant axonal contacts from both M1 and PM. Our data suggest that the porcine cortical motor system has some common features with that of primates and humans and may control posture and movement through parallel motor descending pathways. However, less cortical regions project to the spinal cord in pigs, and the CST neither seems to reach the lumbar enlargement nor to have a significant direct innervation of cervical, foreleg motoneurons.

Magnetic resonance imaging investigations reveal that PM2.5 exposure triggers visual dysfunction in mice

ObjectivesTo investigate how PM2.5 exposure affects the microstructure, metabolites or functions of the visual system. MethodsC57BL/6J mice were randomly assigned to groups exposed to the filtered air (the control group) or the concentrated ambient PM2.5 (the PM2.5 group). Visual evoked potentials (VEP), electroretinograms (ERG), diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS) and resting-state functional MRI (rsfMRI) were performed. Parameters were obtained and compared between the two groups, including latencies and amplitudes of the P1 wave, N1 wave and P2 wave from VEP, latencies and amplitudes of the a wave and b wave from ERG, fractional anisotropy (FA), mean diffusion (MD), axial diffusivity (AD) and radial diffusivity (RD) from DTI, visual cortex (VC) metabolites from 1H-MRS, and regional homogeneity (ReHo) from rsfMRI. ResultsCompared with the values of the control group, the PM2.5 group showed a prolonged N1 latency (43.11 ± 7.94 ms vs. 38.75 ± 4.60 ms) and lowered P1 amplitude (5.62 ± 4.38 μV vs. 8.56 ± 5.92 μV) on VEP (all p < 0.05). On ERG, the amplitude of the a wave was lowered (− 91.39 ± 56.29 μV vs. − 138.68 ± 89.05 μV), the amplitude of the b wave was lowered (194.38 ± 126.27 μV vs. 284.72 ± 170.99 μV), and the latency of the b wave was prolonged (37.78 ± 10.72 ms vs. 33.01 ± 4.34 ms) than the values of the control group (all p < 0.05). DTI indicated FA increase in the bilateral piriform cortex (Pir), FA decrease in the bilateral somatosensory cortex (S) and the bilateral striatum (Stri), AD decrease in the bilateral VC, the right S and the bilateral Pir, MD decrease in the bilateral Pir, and RD decrease in the bilateral Pir in the PM2.5 mice (all p < 0.05, Alphasim corrected). 1H-MRS showed Glutamate (Glu) increase and Phosphocholine (PCh) increase in the VC of the PM2.5 group than those of the control group (PCh 1.63 ± 0.25 vs. 1.50 ± 0.25; PCh/total creatine(tCr) 0.19 ± 0.03 vs. 0.18 ± 0.03; Glu 10.46 ± 1.50 vs. 9.60 ± 1.19; Glu/tcr 1.23 ± 0.11 vs. 1.12 ± 0.11) (all p < 0.05). rsfMRI showed higher ReHo in the PM2.5 mice in the left superior colliculus, the left motor cortex, the hippocampus, the periaqueductal gray and the right mesencephalic reticular formation (all p < 0.01, AlphaSim corrected). ConclusionsThis study revealed that PM2.5 exposure triggered visual dysfunction, and altered microstructure, metabolite and function in the retina and visual brain areas along the visual system.

Whole-brain mapping of afferent projections to the suprachiasmatic nucleus of the tree shrew

The suprachiasmatic nucleus (SCN) is essential for the neural control of mammalian circadian timing system. The circadian activity of the SCN is modulated by its afferent projections. In the present study, we examine neuroanatomical characteristics and afferent projections of the SCN in the tree shrew (Tupaia belangeri chinensis) using immunocytochemistry and retrograde tracer Fluoro-Gold (FG). Distribution of the vasoactive intestinal peptide was present in the SCN from rostral to caudal, especially concentrated in its ventral part. FG-labeled neurons were observed in the lateral septal nucleus, septofimbrial nucleus, paraventricular thalamic nucleus, posterior hypothalamic nucleus, posterior complex of the thalamus, ventral subiculum, rostral linear nucleus of the raphe, periaqueductal gray, mesencephalic reticular formation, dorsal raphe nucleus, pedunculopontine tegmental nucleus, medial parabrachial nucleus, locus coeruleus, parvicellular reticular nucleus, intermediate reticular nucleus, and ventrolateral reticular nucleus. In summary, the morphology of the SCN in tree shrews is described from rostral to caudal. In addition, our data demonstrate for the first time that the SCN in tree shrews receives inputs from numerous brain regions in the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. This comprehensive knowledge of the afferent projections of the SCN in tree shrews provides further insights into the neural organization and physiological processes of circadian rhythms.

Probabilistic Atlas of the Mesencephalic Reticular Formation, Isthmic Reticular Formation, Microcellular Tegmental Nucleus, Ventral Tegmental Area Nucleus Complex, and Caudal-Rostral Linear Raphe Nucleus Complex in Living Humans from 7 Tesla Magnetic Resonance Imaging.

Introduction: The mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental area-parabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. Yet, these nuclei are difficult to identify with magnetic resonance imaging (MRI) of living humans. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive ultra-high-field MRI. Methods: We acquired single-subject, multicontrast (diffusion and T2-weighted), 1.1-mm isotropic resolution, 7 Tesla MRI images of 12 healthy subjects. After preprocessing and alignment to the stereotactic space, these images were used to delineate (in each subject) the nuclei of interest based on the image contrast as well as on neighboring nuclei and landmarks. Nucleus labels were averaged across subjects to yield probabilistic labels. The latter were further validated by assessment of the label inter-rater agreement, internal consistency, and volume. Results: Labels were delineated for each nucleus with good overlap across subjects. The inter-rater agreement and internal consistency were below (p < 10-8) the linear spatial imaging resolution (1.1 mm), thus validating the generated probabilistic atlas labels. The volumes of our labels did not differ from literature volumes (p < 0.05), further validating our atlas. Discussion and Conclusion: The probabilistic atlas of these five mesopontine nuclei expands current in vivo brainstem nuclei atlases and can be used as a tool to identify the location of these areas in conventional (e.g., 3 Tesla) images. This might serve to unravel the brainstem structure-to-function link and thus improve clinical outcomes. Impact statement The mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental area-parabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive, ultra-high-field magnetic resonance imaging. The probabilistic atlas of these five mesopontine nuclei expands current in vivo brainstem nuclei atlases and can be used as a tool to identify the location of these areas in conventional (e.g., 3 Tesla) images. This might serve to unravel the brainstem structure-to-function link and thus improve clinical outcomes.

Location of Subcortical Microbleeds and Recovery of Consciousness After Severe Traumatic Brain Injury.

In patients with severe traumatic brain injury (TBI), coma is associated with impaired subcortical arousal mechanisms. However, it is unknown which nuclei involved in arousal (arousal nuclei) are implicated in coma pathogenesis and are compatible with coma recovery. We mapped an atlas of arousal nuclei in the brainstem, thalamus, hypothalamus, and basal forebrain onto 3 tesla susceptibility-weighted images (SWI) in 12 patients with acute severe TBI who presented in coma and recovered consciousness within 6 months. We assessed the spatial distribution and volume of SWI microbleeds and evaluated the association of microbleed volume with the duration of unresponsiveness and functional recovery at 6 months. There was no single arousal nucleus affected by microbleeds in all patients. Rather, multiple combinations of microbleeds in brainstem, thalamic, and hypothalamic arousal nuclei were associated with coma and were compatible with recovery of consciousness. Microbleeds were frequently detected in the midbrain (100%), thalamus (83%), and pons (75%). Within the brainstem, the microbleed incidence was largest within the mesopontine tegmentum (e.g., pedunculotegmental nucleus, mesencephalic reticular formation) and ventral midbrain (e.g., substantia nigra, ventral tegmental area). Brainstem arousal nuclei were partially affected by microbleeds, with microbleed volume not exceeding 35% of brainstem nucleus volume on average. Compared to microbleed volume within nonarousal brainstem regions, the microbleed volume within arousal brainstem nuclei accounted for a larger proportion of variance in the duration of unresponsiveness and 6-month Glasgow Outcome Scale-Extended scores. These results suggest resilience of arousal mechanisms in the human brain after severe TBI.

A Confocal Microscopic Study of Gene Transfer into the Mesencephalic Tegmentum of Juvenile Chum Salmon, Oncorhynchus keta, Using Mouse Adeno-Associated Viral Vectors.

To date, data on the presence of adenoviral receptors in fish are very limited. In the present work, we used mouse recombinant adeno-associated viral vectors (rAAV) with a calcium indicator of the latest generation GCaMP6m that are usually applied for the dorsal hippocampus of mice but were not previously used for gene delivery into fish brain. The aim of our work was to study the feasibility of transduction of rAAV in the mouse hippocampus into brain cells of juvenile chum salmon and subsequent determination of the phenotype of rAAV-labeled cells by confocal laser scanning microscopy (CLSM). Delivery of the gene in vivo was carried out by intracranial injection of a GCaMP6m-GFP-containing vector directly into the mesencephalic tegmentum region of juvenile (one-year-old) chum salmon, Oncorhynchus keta. AAV incorporation into brain cells of the juvenile chum salmon was assessed at 1 week after a single injection of the vector. AAV expression in various areas of the thalamus, pretectum, posterior-tuberal region, postcommissural region, medial and lateral regions of the tegmentum, and mesencephalic reticular formation of juvenile O. keta was evaluated using CLSM followed by immunohistochemical analysis of the localization of the neuron-specific calcium binding protein HuCD in combination with nuclear staining with DAPI. The results of the analysis showed partial colocalization of cells expressing GCaMP6m-GFP with red fluorescent HuCD protein. Thus, cells of the thalamus, posterior tuberal region, mesencephalic tegmentum, cells of the accessory visual system, mesencephalic reticular formation, hypothalamus, and postcommissural region of the mesencephalon of juvenile chum salmon expressing GCaMP6m-GFP were attributed to the neuron-specific line of chum salmon brain cells, which indicates the ability of hippocampal mammal rAAV to integrate into neurons of the central nervous system of fish with subsequent expression of viral proteins, which obviously indicates the neuronal expression of a mammalian adenoviral receptor homolog by juvenile chum salmon neurons.

Specific populations of basal ganglia output neurons target distinct brain stem areas while collateralizing throughout the diencephalon

Basal ganglia play a central role in regulating behavior, but the organization of their outputs to other brain areas is incompletely understood. We investigate the largest output nucleus, the substantia nigra pars reticulata (SNr), and delineate the organization and physiology of its projection populations in mice. Using genetically targeted viral tracing and whole-brain anatomical analysis, we identify over 40 SNr targets that encompass a roughly 50-fold range of axonal densities. Retrograde tracing from the volumetrically largest targets indicates that the SNr contains segregated subpopulations that differentially project to functionally distinct brain stem regions. These subpopulations are electrophysiologically specialized and topographically organized and collateralize to common diencephalon targets, including the motor and intralaminar thalamus as well as the pedunculopontine nucleus and the midbrain reticular formation. These findings establish that SNr signaling is organized as dense, parallel outputs to specific brain stem targets concurrent with extensive collateral branches that encompass the majority of SNr axonal boutons.

Cerebellar projections to the macaque midbrain tegmentum: Possible near response connections.

Since most gaze shifts are to targets that lie at a different distance from the viewer than the current target, gaze changes commonly require a change in the angle between the eyes. As part of this response, lens curvature must also be adjusted with respect to target distance by the ciliary muscle. It has been suggested that projections by the cerebellar fastigial and posterior interposed nuclei to the supraoculomotor area (SOA), which lies immediately dorsal to the oculomotor nucleus and contains near response neurons, support this behavior. However, the SOA also contains motoneurons that supply multiply innervated muscle fibers (MIFs) and the dendrites of levator palpebrae superioris motoneurons. To better determine the targets of the fastigial nucleus in the SOA, we placed an anterograde tracer into this cerebellar nucleus in Macaca fascicularis monkeys and a retrograde tracer into their contralateral medial rectus, superior rectus, and levator palpebrae muscles. We only observed close associations between anterogradely labeled boutons and the dendrites of medial rectus MIF and levator palpebrae motoneurons. However, relatively few of these associations were present, suggesting these are not the main cerebellar targets. In contrast, labeled boutons in SOA, and in the adjacent central mesencephalic reticular formation (cMRF), densely innervated a subpopulation of neurons. Based on their location, these cells may represent premotor near response neurons that supply medial rectus and preganglionic Edinger-Westphal motoneurons. We also identified lens accommodation-related cerebellar afferent neurons via retrograde trans-synaptic transport of the N2c rabies virus from the ciliary muscle. They were found bilaterally in the fastigial and posterior interposed nuclei, in a distribution which mirrored that of neurons retrogradely labeled from the SOA and cMRF. Our results suggest these cerebellar neurons coordinate elements of the near response during symmetric vergence and disjunctive saccades by targeting cMRF and SOA premotor neurons.

Deep brain stimulation of the brainstem.

Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been increasingly explored for their application to neuropsychiatric and cognitive disorders. The brainstem constitutes another DBS substrate, although the existing literature on the indications for and the effects of brainstem stimulation remains comparatively sparse. The objective of this review was to provide a comprehensive overview of the pertinent anatomy, indications, and reported stimulation-induced acute and long-term effects of existing white and grey matter brainstem DBS targets. We systematically searched the published literature, reviewing clinical trial articles pertaining to DBS brainstem targets. Overall, 164 studies describing brainstem DBS were identified. These studies encompassed 10 discrete structures: periaqueductal/periventricular grey (n = 63), pedunculopontine nucleus (n = 48), ventral tegmental area (n = 22), substantia nigra (n = 9), mesencephalic reticular formation (n = 7), medial forebrain bundle (n = 8), superior cerebellar peduncles (n = 3), red nucleus (n = 3), parabrachial complex (n = 2), and locus coeruleus (n = 1). Indications for brainstem DBS varied widely and included central neuropathic pain, axial symptoms of movement disorders, headache, depression, and vegetative state. The most promising results for brainstem DBS have come from targeting the pedunculopontine nucleus for relief of axial motor deficits, periaqueductal/periventricular grey for the management of central neuropathic pain, and ventral tegmental area for treatment of cluster headaches. Brainstem DBS has also acutely elicited numerous motor, limbic, and autonomic effects. Further work involving larger, controlled trials is necessary to better establish the therapeutic potential of DBS in this complex area.

Neural control of rapid binocular eye movements: Saccade-vergence burst neurons

During normal viewing, we direct our eyes between objects in three-dimensional (3D) space many times a minute. To accurately fixate these objects, which are usually located in different directions and at different distances, we must generate eye movements with appropriate versional and vergence components. These combined saccade-vergence eye movements result in disjunctive saccades with a vergence component that is much faster than that generated during smooth, symmetric vergence eye movements. The neural control of disjunctive saccades is still poorly understood. Recent anatomical studies suggested that the central mesencephalic reticular formation (cMRF), located lateral to the oculomotor nucleus, contains premotor neurons potentially involved in the neural control of these eye movements. We have therefore investigated the role of the cMRF in the control of disjunctive saccades in trained rhesus monkeys. Here, we describe a unique population of cMRF neurons that, during disjunctive saccades, display a burst of spikes that are highly correlated with vergence velocity. Importantly, these neurons show no increase in activity for either conjugate saccades or symmetric vergence. These neurons are termed saccade-vergence burst neurons (SVBNs) to maintain consistency with modeling studies that proposed that such a class of neuron exists to generate the enhanced vergence velocities observed during disjunctive saccades. Our results demonstrate the existence and characteristics of SVBNs whose activity is correlated solely with the vergence component of disjunctive saccades and, based on modeling studies, are critically involved in the generation of the disjunctive saccades required to view objects in our 3D world.

Is Primate Lens Accommodation Unilaterally or Bilaterally Controlled?

PurposeIn frontal-eyed mammals such as primates, eye movements are coordinated so that the lines of sight are directed at targets in a manner that adjusts for target distance. The lens of each eye must also be adjusted with respect to target distance to maintain precise focus. Whether the systems for controlling eye movements are monocularly or binocularly organized is currently a point of contention. We recently determined that the premotor neurons controlling the lens of one eye are bilaterally distributed in the midbrain. In this study, we examine whether this is due to premotor neurons projecting bilaterally to the preganglionic Edinger-Westphal nuclei, or by a mixture of ipsilaterally and contralaterally projecting cells supplying each nucleus.MethodsThe ciliary muscles of Macaca fasicularis monkeys were injected with recombinant forms of the N2c rabies virus, one eye with virus that produced a green fluorescent marker and the other eye with a virus that produced a red fluorescent marker.ResultsPreganglionic motoneurons in the Edinger-Westphal nucleus displayed the same marker as the ipsilateral injected muscle. Many of the premotor neurons in the supraoculomotor area and central mesencephalic reticular formation were doubly labeled. Others were labeled from either the ipsilateral or contralateral eye.ConclusionsThese results suggest that both monocular control and binocular control of lens accommodation are present. Binocular inputs yoke the accommodation in the two eyes. Monocular inputs may allow modification related to differences in each eye's target distance or differences in the capacities of the two ciliary muscles.