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Purpose: Navigation systems commonly used in neurosurgery suffer from two main drawbacks: (1) their accuracy degrades over the course of the operation and (2) they require the surgeon to mentally map images from the monitor to the patient. In this paper, we introduce the Intraoperative Brain Imaging System (IBIS), an open-source image-guided neurosurgery research platform that implements a novel workflow where navigation accuracy is improved using tracked intraoperative ultrasound (iUS) and the visualization of navigation information is facilitated through the use of augmented reality (AR)., Methods: The IBIS platform allows a surgeon to capture tracked iUS images and use them to automatically update preoperative patient models and plans through fast GPU-based reconstruction and registration methods. Navigation, resection and iUS-based brain shift correction can all be performed using an AR view. IBIS has an intuitive graphical user interface for the calibration of a US probe, a surgical pointer as well as video devices used for AR (e.g., a surgical microscope)., Results: The components of IBIS have been validated in the laboratory and evaluated in the operating room. Image-to-patient registration accuracy is on the order of [Formula: see text] and can be improved with iUS to a median target registration error of 2.54 mm. The accuracy of the US probe calibration is between 0.49 and 0.82 mm. The average reprojection error of the AR system is [Formula: see text]. The system has been used in the operating room for various types of surgery, including brain tumor resection, vascular neurosurgery, spine surgery and DBS electrode implantation., Conclusions: The IBIS platform is a validated system that allows researchers to quickly bring the results of their work into the operating room for evaluation. It is the first open-source navigation system to provide a complete solution for AR visualization.

This paper presents a novel model of tremor in Parkinson's disease (PD) based on extensive literature review as well as novel results stemming from functional stereotactic neurosurgery for the alleviation of tremor in PD. Specifically, evidence that suggests the basal ganglia induces PD tremor via excessive inhibitory output to the thalamus and altered firing patterns which in turn generate rhythmic bursting activity of thalamic cells is presented. Then, evidence that the thalamus generates PD tremor by facilitating the generation and consolidation of rhythmic bursting activity of neurons within its nuclei is also offered. Finally, evidence that the cerebellum may modulate characteristics of PD tremor by treating it as if it was a voluntary motor behavior is presented. Accordingly, the current paper proposes that PD tremor is induced by abnormal basal ganglia activity; it is generated by the thalamus, and modulated or reinforced by the cerebellum., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Parkinson's disease (PD) is the second leading neurodegenerative disease after Alzheimer's disease. In PD research and its surgical treatment, such as deep brain stimulation (DBS), anatomical structural identification and references for spatial normalization are essential, and human brain atlases/templates are proven highly instrumental. However, two shortcomings affect current templates used for PD. First, many templates are derived from a single healthy subject that is not sufficiently representative of the PD-population anatomy. This may result in suboptimal surgical plans for DBS surgery and biased analysis for morphological studies. Second, commonly used mono-contrast templates lack sufficient image contrast for some subcortical structures (i.e., subthalamic nucleus) and biochemical information (i.e., iron content), a valuable feature in current PD research., Methods: We employed a novel T1-T2* fusion MRI that visualizes both cortical and subcortical structures to drive groupwise registration to create co-registered multi-contrast (T1w, T2*w, T1-T2* fusion, phase, and an R2* map) unbiased templates from 15 PD patients, and a high-resolution histology-derived 3D atlas is co-registered. For validation, these templates are compared against the Colin27 template for landmark registration and midbrain nuclei segmentation., Results: While the T1w, T2*w, and T1-T2* fusion templates provide excellent anatomical details for both cortical and subcortical structures, the phase and R2* map contain the biochemical features. By one-way ANOVA tests, our templates significantly ([Formula: see text]) outperform the Colin27 template in the registration-based tasks., Conclusion: The proposed unbiased templates are more representative of the population of interest and can benefit both the surgical planning and research of PD.

Careful trajectory planning on preoperative vascular imaging is an essential step in deep brain stimulation (DBS) to minimize risks of hemorrhagic complications and postoperative neurological deficits. This paper compares 2 MRI methods for visualizing cerebral vasculature and planning DBS probe trajectories: a single data set T1-weighted scan with double-dose gadolinium contrast (T1w-Gd) and a multi-data set protocol consisting of a T1-weighted structural, susceptibility-weighted venography, and time-of-flight angiography (T1w-SWI-TOF). Two neurosurgeons who specialize in neuromodulation surgery planned bilateral STN DBS in 18 patients with Parkinson's disease (36 hemispheres) using each protocol separately. Planned trajectories were then evaluated across all vascular data sets (T1w-Gd, SWI, and TOF) to detect possible intersection with blood vessels along the entire path via an objective vesselness measure. The authors' results show that trajectories planned on T1w-SWI-TOF successfully avoided the cerebral vasculature imaged by conventional T1w-Gd and did not suffer from missing vascular information or imprecise data set registration. Furthermore, with appropriate planning and visualization software, trajectory corridors planned on T1w-SWI-TOF intersected significantly less fine vasculature that was not detected on the T1w-Gd (p < 0.01 within 2 mm and p < 0.001 within 4 mm of the track centerline). The proposed T1w-SWI-TOF protocol comes with minimal effects on the imaging and surgical workflow, improves vessel avoidance, and provides a safe cost-effective alternative to injection of gadolinium contrast.

DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is highly expressed by mesencephalic dopaminergic (DA) neurons during development; however, the contribution of DCC to DA development remains largely uncharacterized. DA neurons in ventral mesencephalic nuclei also express UNC5 homologue netrin receptors from late embryogenesis to adulthood, raising the possibility that DA axons could be attracted or repelled by netrins. Examining newborn dcc null mice, we report that loss of DCC function results in profound alterations of DA circuitry, including DA progenitor cell migration defects, reduced numbers of DA cells in midbrain nuclei, an anomalous DA ventral commissure, malformed DA innervation of the ventral striatum, and reduced DA innervation of the cerebral cortex. Caspase-3 activation was detected in inappropriately localized DA cells, consistent with apoptosis contributing to reduced cell numbers. Dcc heterozygous mice express reduced levels of DCC protein. Although less severely disrupted than dcc nulls, newborn and adult dcc heterozygotes also have fewer DA neurons in ventral mesenscephalic nuclei. Despite the reduced numbers of DA neurons, newborn dcc heterozygotes and nulls exhibit similar DA innervation density as wild-type littermates in the nucleus accumbens core, and adult dcc heterozygotes exhibit increased DA innervation in medial prefrontal cortex. A trend towards increased innervation of medial prefrontal cortex was detected in newborn dcc heterozygotes, but did not reach statistical significance, suggesting that the increase in adult heterozygotes results from enhanced DA arborization during postnatal development. Consistent with the hypothesis that DCC regulates DA axonal projections, disrupting DCC function in culture inhibits netrin-1 induced DA axon extension and axon branching. Furthermore, disrupting DCC function in isolated DA neurons grown as micro-island cultures reduces the number of autaptic synapses per cell. We conclude that DCC regulates appropriate precursor cell migration, axon guidance, and terminal arborization by DA neurons., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Pre-operative magnetic resonance (MRI) and computed tomography (CT) image volumes are often used for planning and guidance during functional neurosurgical procedures. These operations can include the creation of lesions in the thalamus (thalamotomy) or the globus pallidus (pallidotomy), or the insertion of deep brain stimulation (DBS) electrodes in the subcortical nuclei. These subcortical targets are often difficult to localize in pre-operative imaging data due to the limited resolution and contrast available in standard MRI or CT techniques. To address this problem, digital atlases of subcortical nuclei are often used to accurately identify surgical targets since they can be warped to fit each patient's unique anatomy. Targeting accuracy thus depends on the quality of the atlas-to-patient warp. In this paper, three atlas-to-patient warping techniques are compared. Two methods rely on an MRI template as an intermediary to estimate a nonlinear atlas-to-patient transformation. The third is novel, and uses a pseudo-MRI derived from an atlas of the basal ganglia and thalamus to estimate the nonlinear atlas-to-patient transformation directly. The methods are compared using (1) manual segmentations of subcortical nuclei and (2) functional data from intra-operative thalamic stimulation. The results demonstrate that the template-based atlas-to-patient warping technique is the best of the three for customizing the atlas onto patient data.

In this study, we evaluated the ability of the selective sigma1 agonist SA 4503 to produce changes in brain function, similar to those elicited by classical antidepressants. We focused more specifically on the influence of SA 4503 on central serotonergic (5-HT) transmission, and on hippocampal cell proliferation. A 2-d continuous treatment with SA 4503 (1-40 mg/kg.d) increased 5-HT neuron firing rate in a dose-dependent, bell-shaped manner, with a culminating effect of +90% at 10 mg/kg.d. The same dose induced the appearance of a 5-HT1A receptor-mediated inhibitory tonus on hippocampal pyramidal neurons, as revealed by intravenous injections of the selective 5-HT1A antagonist WAY 100635. Moreover, continuous administration of SA 4503 (3 and 10 mg/kg.d, 3 d) dose-dependently enhanced the number of bromodeoxyuridine-positive cells in the subgranular zone of the hippocampus (+48% and +94%, respectively), thus indicating an increased cell proliferation. Finally, a single administration of SA 4503 (3 and 10 mg/kg i.p.) increased the time spent swimming in the forced swimming test. Together, these results provide both functional and behavioural evidence that this compound has an important antidepressant potential. Further, the fact that the functional changes occurred within a short time-frame (2-3 d) suggest that this antidepressant potential might have a rapid onset of action.

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

We compared the level of bradykinesia during rapid alternating movements (RAM) in patients with essential tremor (ET) with that of patients with Parkinson's disease (PD) having either the "tremor dominant" or "akinetic-rigid" form of PD, and 10 healthy controls. We found an increase of pronation-supination cycle duration in the PD and ET group, suggestive of bradykinesia. RAM range was, however, similar between groups. The akinetic-rigid group showed a distinct increase in RAM amplitude fluctuation, suggesting that rigidity modified the characteristics of the observed bradykinesia. In conclusion, slow movements should then be considered as part of the ET symptomatology.

Digital and print brain atlases have been used with success to help in the planning of neurosurgical interventions. In this paper, a technique presented for the creation of a brain atlas of the basal ganglia and the thalamus derived from serial histological data. Photographs of coronal histological sections were digitized and anatomical structures were manually segmented. A slice-to-slice nonlinear registration technique was used to correct for spatial distortions introduced into the histological data set at the time of acquisition. Since the histological data were acquired without any anatomical reference (e.g., block-face imaging, post-mortem MRI), this registration technique was optimized to use an error metric which calculates a nonlinear transformation minimizing the mean distance between the segmented contours between adjacent pairs of slices in the data set. A voxel-by-voxel intensity correction field was also estimated for each slice to correct for lighting and staining inhomogeneity. The reconstructed three-dimensional (3D) histological volume can be viewed in transverse and sagittal directions in addition to the original coronal. Nonlinear transformations used to correct for spatial distortions of the histological data were applied to the segmented structure contours. These contours were then tessellated to create three-dimensional geometric objects representing the different anatomic regions in register with the histological volumes. This yields two alternate representations (one histological and one geometric) of the atlas. To register the atlas to a standard reference MR volume created from the average of 27 T1-weighted MR volumes, a pseudo-MRI was created by setting the intensity of each anatomical region defined in the geometric atlas to match the intensity of the corresponding region of the reference MR volume. This allowed the estimation of a 3D nonlinear transformation using a correlation based registration scheme to fit the atlas to the reference MRI. The result of this procedure is a contiguous 3D histological volume, a set of 3D objects defining the basal ganglia and thalamus, both of which are registered to a standard MRI data set, for use for neurosurgical planning.

Digital brain atlases can be used in conjuction with magnetic resonance imaging (MRI) and computed tomography (CT) for planning and guidance during neurosurgery. Digital atlases are advantageous since they can be warped nonlinearly to fit each patient's unique anatomy. Functional neurosurgery with implantation of deep brain stimulating (DBS) electrodes requires accurate targeting, and has become a popular surgical technique in Parkinsonian patients. In this paper, we present a method for integrating postoperative data from subthalamic (STN) DBS implantation into an antomical atlas of the basal ganglia and thalamus. The method estimates electrode position from post-operative magnetic resonance imaging (MRI) data. These electrodes are then warped back into the atlas space and are modelled in three dimensions. The average of these models is then taken to show the region where the majority of STN DBS electrodes were implanted. The group with more favorable post-operative results was separated from the group which responded to the STN DBS implantation procedure less favourably to create a probablisitic distribution of DBS in the STN electrodes.

Netrins are guidance cues that play a fundamental role in organizing the developing brain. The netrin receptor, DCC (deleted in colorectal cancer), is highly expressed by dopaminergic (DA) neurons. DCC may therefore participate in the organization of DA circuitry during development and also influence DA function in the adult. Here we show that adult dcc heterozygous mice exhibit a blunted behavioral response to the indirect DA agonist amphetamine and do not develop sensitization to its effects when treated repeatedly. These behavioral alterations are associated with profound changes in DA function. In the medial prefrontal cortex, dcc heterozygotes exhibit increased tyrosine hydroxylase (TH) protein levels and dramatic increases in basal concentrations of DA and DA metabolites. In contrast, in the nucleus accumbens, dcc heterozygotes show no changes in either TH or DA levels, but exhibit decreased concentrations of DA metabolites, suggesting reduced DA activity. In addition, dcc heterozygous mice exhibit a small, but significant reduction in total number of TH-positive neurons in midbrain DA cell body regions. These results demonstrate for the first time that alterations in dcc expression lead to selective changes in DA function and, in turn, to differences in DA-related behaviors in adulthood. These findings raise the possibility that changes in dcc function early in life are implicated in the development of DA dysregulation observed in certain psychiatric disorders, such as schizophrenia, or following chronic use of drugs of abuse.

Digital brain atlases can be used in conjunction with magnetic resonance imaging (MRI) and computed tomography (CT) for planning and guidance during neurosurgery. Digital atlases are advantageous, since they can be warped nonlinearly to fit each patient's unique anatomy. Two atlas-to-patient warping techniques are compared in this paper. The first technique uses an MRI template as an intermediary to estimate a nonlinear atlas-to-patient transformation. The second, is novel, and uses a pseudo-MRI volume, derived from the voxel-label-atlas, to estimate the atlas-to-patient transformation directly. Manual segmentations and functional data are used to validate the two methods.

Many critical functionally distinct subcortical structures are not distinguishable on anatomical magnetic resonance imaging (MRI) scans. In order to provide the neurosurgeon with this missing information, a deformable volumetric atlas of the basal ganglia and thalamus has been created from the Schaltenbrand and Wahren atlas of cryogenic slices. The volumetric atlas can be automatically deformed to an individual patient's MRI. To facilitate the clinical use of the atlas, a visualization platform has been developed for preoperative and intraoperative use which permits manipulation of the merged atlas and MRI data sets in two- and three-dimensional views. The platform includes graphical tools which allow the visualization of projections of a leukotome and other surgical tools with respect to the atlas data, as well as preregistered images from any other imaging modality. In addition, a graphical interface has been designed to create custom virtual lesions using computer models of neurosurgical tools for intraoperative planning. To date this system has been employed as an adjunct to over 30 functional neurosurgical cases including surgery for movement disorders.