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Ultrasound Localization Microscopy (ULM) has proven effective in resolving microvascular structures and local mean velocities at sub-diffraction-limited scales, offering high-resolution imaging capabilities. Dynamic ULM (DULM) enables the creation of angiography or velocity movies throughout cardiac cycles. Currently, these techniques rely on a Localization-and-Tracking (LAT) workflow consisting in detecting microbubbles (MB) in the frames before pairing them to generate tracks. While conventional LAT methods perform well at low concentrations, they suffer from longer acquisition times and degraded localization and tracking accuracy at higher concentrations, leading to biased angiogram reconstruction and velocity estimation. In this study, we propose a novel approach to address these challenges by reversing the current workflow. The proposed method, Tracking-and-Localization (TAL), relies on first tracking the MB and then performing localization. Through comprehensive benchmarking using both in silico and in vivo experiments and employing various metrics to quantify ULM angiography and velocity maps, we demonstrate that the TAL method consistently outperforms the reference LAT workflow. Moreover, when applied to DULM, TAL successfully extracts velocity variations along the cardiac cycle with improved repeatability. The findings of this work highlight the effectiveness of the TAL approach in overcoming the limitations of conventional LAT methods, providing enhanced ULM angiography and velocity imaging.

Objective . Linking cavitation and anatomy was found to be important for predictable outcomes in focused-ultrasound blood-brain-barrier-opening and requires high resolution cavitation mapping. However, cavitation mapping techniques for planning and monitoring of therapeutic procedures either (1) do not leverage the full resolution capabilities of ultrasound imaging or (2) place constraints on the length of the therapeutic pulse. This study aimed to develop a high-resolution technique that could resolve vascular anatomy in the cavitation map. Approach . Herein, we develop BandPass-sampled-equivalent-time-active-cavitation-imaging (BP-ETACI), derived from bandpass sampling and dual-frequency contrast imaging at 12.5 MHz to produce cavitation maps prior and during blood-brain barrier opening with long therapeutic bursts using a 1.5 MHz focused transducer in the brain of C57BL/6 mice. Main results . The BP-ETACI cavitation maps were found to correlate with the vascular anatomy in ultrasound localization microscopy vascular maps and in histological sections. Cavitation maps produced from non-blood-brain-barrier disrupting doses showed the same cavitation-bearing vasculature as maps produced over entire blood-brain-barrier opening procedures, allowing use for (1) monitoring focused-ultrasound blood-brain-barrier-opening (FUS-BBBO), but also for (2) therapy planning and target verification. Significance . BP-ETACI is versatile, created high resolution cavitation maps in the mouse brain and is easily translatable to existing FUS-BBBO experiments. As such, it provides a means to further study cavitation phenomena in FUS-BBBO., (Creative Commons Attribution license.)

A widespread protocol to seal coverslips on a microscope slide for histological analysis utilizes air-drying nail polish. Nail polish is applied to glue the coverslip in place and prevent the leakage of mounting media. Air drying takes time, typically overnight, and generates an unpleasant smell. Equally familiar is the waiting game, lightly touching the polish to check its dryness, while being careful not to disrupt the coverslip, often leaving sticky spots on one's fingertips. An advantageous solution to these drawbacks is to use gel nail polish, which rapidly hardens and dries by being cured under a LED/UV lamp. We show that UV-cured gel nail polish provides a rapid, stable, scentless, nontoxic, and cost-effective solution for coverslip sealing. Cured in 10 s, with no impact on fluorescent labels, gel polish hardens completely and the slide is ready to be imaged. Furthermore, we show that gel nail polish can be used to generate 3D ridges and structures to support coverslipping thicker samples. Gel nail polish is purposefully unscented, and the brands used in our study employ environmentally conscious, vegan, and cruelty-free ingredients. UV-cured gel nail polish is a cost-effective alternative that presents an easy, accessible, and inexpensive solution to traditional coverslip sealing methods.•Inexpensive method to rapidly seal coverslips onto a microscope slide to immediately image samples for Histological analyses.•Utilizes LED/UV light to cure gel nail polish in 10 s without bleaching fluorophores.•Can be used to generate 3D ridges and structures to support coverslipping thicker samples., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Essential tremor (ET) is the most prevalent movement disorder with poorly understood etiology. Some neuroimaging studies report cerebellar involvement whereas others do not. This discrepancy may stem from underpowered studies, differences in statistical modeling or variation in magnetic resonance imaging (MRI) acquisition and processing. To resolve this, we investigated the cerebellar structural differences using a local advanced ET dataset augmented by matched controls from PPMI and ADNI. We tested the hypothesis of cerebellar involvement using three neuroimaging biomarkers: VBM, gray/white matter volumetry and lobular volumetry. Furthermore, we assessed the impacts of statistical models and segmentation pipelines on results. Results indicate that the detected cerebellar structural changes vary with methodology. Significant reduction of right cerebellar gray matter and increase of the left cerebellar white matter were the only two biomarkers consistently identified by multiple methods. Results also show substantial volumetric overestimation from SUIT-based segmentation-partially explaining previous literature discrepancies. This study suggests that current estimation of cerebellar involvement in ET may be overemphasized in MRI studies and highlights the importance of methods sensitivity analysis on results interpretation. ET datasets with large sample size and replication studies are required to improve our understanding of regional specificity of cerebellum involvement in ET. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 21 March 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.6084/m9.figshare.19697776 ., (© 2023. The Author(s).)

Background: Ordinal scales based on qualitative observation are the mainstay in the clinical assessment of tremor, but are limited by inter-rater reliability, measurement precision, range, and ceiling effects. Quantitative tremor evaluation is well-developed in research, but clinical application has lagged, in part due to cumbersome mathematical application and lack of established standards., Objectives: To develop a novel method for evaluating tremor that integrates a standardized clinical exam, wrist-watch accelerometers, and a software framework for data analysis that does not require advanced mathematical or computing skills. The utility of the method was tested in a sequential cohort of patients with predominant postural and action tremor presenting to a specialized surgical clinic with the presumptive diagnosis of Essential Tremor (ET)., Methods: Wristwatch accelerometry was integrated with a standardized clinical exam. A MATLAB application was developed for automated data analysis and graphical representation of tremor. Measures from the power spectrum of acceleration of tremor in different upper limb postures were derived in 25 consecutive patients. The linear results from accelerometry were correlated with the commonly used non-linear Clinical Rating Scale for Tremor (CRST)., Results: The acceleration power spectrum was reliably produced in all consecutive patients. Tremor frequency was stable in different postures and across patients. Both total and peak power of acceleration during postural conditions correlated well with the CRST. The standardized clinical examination with integrated accelerometry measures was therefore effective at characterizing tremor in a population with predominant postural and action tremor. The protocol is also illustrated on repeated measures in an ET patient who underwent Magnetic Resonance-Guided Focused Ultrasound thalamotomy., Conclusion: Quantitative assessment of tremor as a continuous variable using wristwatch accelerometry is readily applicable as a clinical tool when integrated with a standardized clinical exam and a user-friendly software framework for analysis. The method is validated for patients with predominant postural and action tremor, and can be adopted for characterizing tremor of different etiologies with dissemination in a wide variety of clinical and research contexts in ageing populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gauthier-Lafreniere, Aljassar, Rymar, Milton and Sadikot.)

Mechanisms that determine the survival of midbrain dopaminergic (mDA) neurons in the adult central nervous system (CNS) are not fully understood. Netrins are a family of secreted proteins that are essential for normal neural development. In the mature CNS, mDA neurons express particularly high levels of netrin-1 and its receptor Deleted in Colorectal Cancer (DCC). Recent findings indicate that overexpressing netrin-1 protects mDA neurons in animal models of Parkinson's disease (PD), with a proposed pro-apoptotic dependence function for DCC that triggers cell death in the absence of a ligand. Here, we sought to determine if DCC expression influences mDA neuron survival in young adult and ageing mice. To circumvent the perinatal lethality of DCC null mice, we selectively deleted DCC from mDA neurons utilizing DAT cre /loxP gene-targeting and examined neuronal survival in adult and aged animals. Reduced numbers of mDA neurons were detected in the substantia nigra pars compacta (SNc) of young adult DAT cre /DCC fl/fl mice, with further reduction in aged DAT cre /DCC fl/fl animals. In contrast to young adults, aged mice also exhibited a gene dosage effect, with fewer SNc mDA neurons in DCC heterozygotes (DAT cre /DCC fl/wt ). Notably, loss of mDA neurons in the SN was not uniform. Neuronal loss in the SN was limited to ventral tier mDA neurons, while mDA neurons in the dorsal tier of the SN, which resist degeneration in PD, were spared from the effect of DCC deletion in both young and aged mice. In the ventral tegmental area (VTA), young adult mice with conditional deletion of DCC had normal mDA neuronal numbers, while significant loss occurred in aged DAT cre /DCC fl/fl and DAT cre /DCC fl/wt mice compared to age-matched wild-type mice. Our results indicate that expression of DCC is required for the survival of subpopulations of mDA neurons and may be relevant to the degenerative processes in PD., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Music perception deficits are common following acquired brain injury due to stroke, epilepsy surgeries, and aneurysmal clipping. Few studies have examined these deficits following traumatic brain injury (TBI), resulting in an under-diagnosis in this population. We aimed to (1) compare TBI patients to controls on pitch and rhythm perception during the acute phase; (2) determine whether pitch and rhythm perception disorders co-occur; (3) examine lateralization of injury in the context of pitch and rhythm perception; and (4) determine the relationship between verbal short-term memory (STM) and pitch and rhythm perception. Music perception was examined using the Scale and Rhythm tests of the Montreal Battery of Evaluation of Amusia, in association with CT scans to identify lesion laterality. Verbal short-term memory was examined using Digit Span Forward. TBI patients had greater impairment than controls, with 43% demonstrating deficits in pitch perception, and 40% in rhythm perception. Deficits were greater with right hemisphere damage than left. Pitch and rhythm deficits co-occurred 31% of the time, suggesting partly dissociable networks. There was a dissociation between performance on verbal STM and pitch and rhythm perception 39 to 42% of the time (respectively), with most individuals (92%) demonstrating intact verbal STM, with impaired pitch or rhythm perception. The clinical implications of music perception deficits following TBI are discussed.

Background: The dentatorubrothalamic tract (DRTT) remains understudied in idiopathic cervical dystonia (CD), despite evidence that the pathway is relevant in the pathophysiology of the disorder., Objective: The aim of this study was to examine the DRTT in patients with CD using diffusion tensor imaging (DTI)-based tractography., Methods: Magnetic resonance imaging scans from 67 participants were collected to calculate diffusion tractography metrics using a binary tractography-based DRTT template. Fractional anisotropy and diffusivity measures of left and right DRTT were computed and compared between 32 subjects with CD and 35 age-matched healthy volunteers., Results: Fractional anisotropy of right DRTT and mean and axial diffusivity of left DRTT were significantly reduced in patients with CD. Similar abnormalities were observed in patients with focal CD and patients with CD without tremor. DTI metrics did not correlate with disease duration or severity., Conclusions: Significant reductions in DTI measures suggest microstructural abnormalities within the DRTT in CD, characterized by a tractography pattern consistent with decreased axonal integrity. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Inhibiting inappropriate actions in a context is an important part of the human cognitive repertoire, and deficiencies in this ability are common in neurological and psychiatric disorders. An anti-saccade is a simple oculomotor task that tests this ability by requiring inhibition of saccades to peripheral targets (pro-saccade) and producing voluntary eye movements toward the mirror position (anti-saccades). Previous studies provide evidence for a possible contribution from the basal ganglia in anti-saccade behavior, but the precise role of different components is still unclear. Parkinson's disease patients with implanted deep brain stimulators (DBS) in subthalamic nucleus (STN) provide a unique opportunity to investigate the role of the STN in anti-saccade behavior. Previous attempts to show the effect of STN DBS on anti-saccades have produced conflicting observations. For example, the effect of STN DBS on anti-saccade error rate is not yet clear. Part of this inconsistency may be related to differences in dopaminergic states in different studies. Here, we tested Parkinson's disease patients on anti- and pro-saccade tasks ON and OFF STN DBS, in ON and OFF dopaminergic medication states. First, STN DBS increases anti-saccade error rate while patients are OFF dopamine replacement therapy. Second, dopamine replacement therapy and STN DBS interact: L-dopa reduces the effect of STN DBS on anti-saccade error rate. Third, STN DBS induces different effects on pro- and anti-saccades in different patients. These observations provide evidence for an important role for the STN in the circuitry underlying context-dependent modulation of visuomotor action selection.

BCL-2-associated athanogene 3 (BAG3) is a co-chaperone to heat shock proteins important in degrading misfolded proteins through chaperone-assisted selective autophagy. The recurrent dominant BAG3-P209L mutation results in a severe childhood-onset myofibrillar myopathy (MFM) associated with progressive muscle weakness, cardiomyopathy, and respiratory failure. Because a homozygous knock-in (KI) strain for the mP215L mutation homologous to the human P209L mutation did not have a gross phenotype, compound heterozygote knockout (KO) and KI mP215L mice were generated to establish whether further reduction in BAG3 expression would lead to a phenotype. The KI/KO mice have a significant decrease in voluntary movement compared with wild-type and KI/KI mice in the open field starting at 7 months. The KI/KI and KI/KO mice both have significantly smaller muscle fiber cross-sectional area. However, only the KI/KO mice have clear skeletal muscle histologic changes in MFM. As in patient muscle, there are increased levels of BAG3-interacting proteins, such as p62, heat shock protein B8, and αB-crystallin. The KI/KO mP215L strain is the first murine model of BAG3 myopathy that resembles the human skeletal muscle pathologic features. The results support the hypothesis that the pathologic development of MFM requires a significant decrease in BAG3 protein level and not only a gain of function caused by the dominant missense mutation., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is an autosomal dominant trinucleotide repeat disorder characterized by choreiform movements, dystonia and striatal neuronal loss. Amongst multiple cellular processes, abnormal neurotransmitter signalling and decreased trophic support from glutamatergic cortical afferents are major mechanisms underlying striatal degeneration. Recent work suggests that the thalamostriatal (TS) system, another major source of glutamatergic input, is abnormal in HD although its phenotypical significance is unknown. We hypothesized that TS dysfunction plays an important role in generating motor symptoms and contributes to degeneration of striatal neuronal subtypes. Our results using the R6/2 mouse model of HD indicate that neurons of the parafascicular nucleus (PF), the main source of TS afferents, degenerate at an early stage. PF lesions performed prior to motor dysfunction or striatal degeneration result in an accelerated dystonic phenotype and are associated with premature loss of cholinergic interneurons. The progressive loss of striatal medium spiny neurons and parvalbumin-positive interneurons observed in R6/2 mice is unaltered by PF lesions. Early striatal cholinergic ablation using a mitochondrial immunotoxin provides evidence for increased cholinergic vulnerability to cellular energy failure in R6/2 mice, and worsens the dystonic phenotype. The TS system therefore contributes to trophic support of striatal interneuron subtypes in the presence of neurodegenerative stress, and TS deafferentation may be a novel cell non-autonomous mechanism contributing to the pathogenesis of HD. Furthermore, behavioural experiments demonstrate that the TS system and striatal cholinergic interneurons are key motor-network structures involved in the pathogenesis of dystonia. This work suggests that treatments aimed at rescuing the TS system may preserve important elements of striatal structure and function and provide symptomatic relief in HD.

The cause of midbrain dopaminergic (mDA) neuron loss in sporadic Parkinson's disease (PD) is multifactorial, involving cell autonomous factors, cell-cell interactions, and the effects of environmental toxins. Early loss of neurons in the locus coeruleus (LC), the main source of ascending noradrenergic (NA) projections, is an important feature of PD and other neurodegenerative disorders. We hypothesized that NA afferents provide trophic support for vulnerable mDA neurons. We demonstrate that depriving mDA neurons of NA input increases postnatal apoptosis and decreases cell survival in young adult rodents, with relative sparing of calbindin-positive subpopulations known to be resistant to degeneration in PD. As a mechanism, we propose that the neurotrophin brain-derived neurotrophic factor (BDNF) modulates anterograde survival effects of LC inputs to mDA neurons. We demonstrate that the LC is rich in BDNF mRNA in postnatal and young adult brains. Early postnatal NA denervation reduces both BDNF protein and activation of TrkB receptors in the ventral midbrain. Furthermore, overexpression of BDNF in NA afferents in transgenic mice increases mDA neuronal survival. Finally, increasing NA activity in primary cultures of mDA neurons improves survival, an effect that is additive or synergistic in the presence of different concentrations of BDNF. Taken together, our results point to a novel mechanism whereby LC afferents couple BDNF effects and NA activity to provide anterograde trophic support for vulnerable mDA neurons. Early loss of NA activity and anterograde neurotrophin support may contribute to degeneration of vulnerable neurons in PD and other neurodegenerative disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Patients with Parkinson's disease (PD) often present with bimanual coordination deficits whose exact origins remain unclear. One aspect of bimanual coordination is inter-limb coupling. This is characterized by the harmonization of movement parameters between limbs. We assessed different aspects of bimanual coordination in patients with PD, including inter-limb coupling, and determined whether they are altered by subthalamic (STN) deep brain stimulation (DBS) or dopaminergic medication. Twenty PD patients were tested before STN DBS surgery; with and without medication. Post- surgery, patients were tested with their stimulators on and off as well as with and without medication. Patients were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference in mean amplitude and mean duration of cycles between hands was computed in order to assess inter-limb coupling. Also, mean angular velocity of both hands and structural coupling were computed for the bimanual task. There was a positive effect of medication and stimulation on mean angular velocity, which relates to clinical improvement. PD patients exhibited temporal inter-limb coupling that was not altered by either medication or STN stimulation. However, PD patients did not exhibit spatial inter-limb coupling. Again, this was not altered by medication or stimulation. Collectively, the results suggest that structures independent of the dopaminergic system and basal ganglia may mediate temporal and spatial inter-limb coupling., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

It is well known that patients with Parkinson's Disease (PD) suffer from olfactory impairments, but it is not clear whether patients are aware of their level of deficit in olfactory functioning. Since PD is a neurodegenerative disorder and its progression may be correlated with olfactory loss (Ansari & Johnson, 1975; but see also Doty, Deems, & Stellar, 1988), it is possible that these patients would be subject to metacognitive errors of over-estimation of olfactory ability (White & Kurtz, 2003). Nineteen non-demented PD patients and 19 age-matched controls were each given an objective measure of olfactory identification (the UPSIT, Doty, Shaman, Kimmelman, & Dann, 1984) and a subjective measure involving a questionnaire that asked them to self-rate both their olfactory function generally and their ability to smell each of 20 odors, 12 of which were assessed on the UPSIT. All of the PD patients showed impaired olfactory ability, as did 7 of the controls, according to the UPSIT norms. Self-rated and performance-based olfactory ability scores were significantly correlated in controls (r=.49, p=.03) but not in patients with PD (r=.20, p=.39). When the 12 odors common to both the self-rated questionnaire and UPSIT were compared, PD patients were less accurate than controls (t(36)=-4.96, p<.01) at estimating their own ability and the number of over-estimation errors was significantly higher (tone-tailed(29)=1.80, p=.04) in PD patients than in the control group, showing less metacognitive awareness of their ability than controls. These results support the idea that olfactory metacognition is often impaired in PD, as well as in controls recruited for normosmic ability (Wehling, Nordin, Espeseth, Reinvang, & Lundervold, 2011), and indicate that people with PD generally exhibit over-estimation of their olfactory ability at a rate that is higher than controls. These findings imply that PD patients, unaware of their olfactory deficit, are at greater risk of harm normally detected through olfaction, such as smoke or spoiled foods., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The principal projection neurons of the striatum are critically dependent on an afferent supply of brain derived neurotrophic factor (BDNF) for neurotrophic support. These neurons express TrkB, the cognate receptor for BDNF, which activates signaling pathways associated with neuronal survival and phenotypic maintenance. Impairment of the BDNF-TrkB pathway is suspected to underlie the early dysfunction and prominent degeneration of striatal neurons in Huntington disease (HD). Some studies in HD models indicate that BDNF supply is reduced, while others suggest that TrkB signaling is impaired earlier in disease progression. It remains important to determine whether a primary defect in TrkB signaling underlies reduced neurotrophic support and the early vulnerability of striatal neurons in HD. Using the transgenic R6/2 mouse model of HD we found that prior to striatal degeneration there are early deficits in striatal protein levels of activated phospho-TrkB and the downstream-regulated protein DARPP-32. In contrast, total-TrkB and BDNF protein levels remained normal. Primary neurons cultured from R6/2 striatum exhibited reduced survival in response to exogenous BDNF applications. Moreover, BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures. These results suggest that neurotrophic support of striatal neurons is attenuated early in disease progression due to defects in TrkB signal transduction in the R6/2 model of HD.

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.)

Patients with neurodegenerative diseases often exhibit deficits in bimanual coordination. One characteristic of bimanual movements is inter-limb coupling. It is the property of motor performance harmonization between hands during a bimanual task. The objective of this study was to identify whether spatial and temporal inter-limb coupling occurred in Parkinson's disease (PD) and Huntington's disease (HD) patients. Twenty-three PD patients and 15 healthy controls were tested. Data from 12 choreic HD patients were also taken from a databank. Participants were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference between hands in mean amplitude and mean duration of cycles was computed in the unimanual and bimanual tasks for each group. Results show that healthy controls exhibited temporal and spatial inter-limb coupling during the bimanual diadochokinesis task. Conversely, PD and HD patients exhibited temporal inter-limb coupling; but failed to exhibit spatial inter-limb coupling during the bimanual diadochokinesis task. Furthermore, HD patients exhibited reduced levels of structural coupling compared to controls and PD patients. These results suggest that alterations in basal ganglia-thalamo-cortical networks due to PD and HD do not affect temporal inter-limb coupling. However, common pathophysiological changes related to PD and HD may cause altered spatial inter-limb coupling during a rapid repetitive bimanual diadochokinesis task., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Purpose: Parkinson's disease (PD) is a neurodegenerative disorder that impairs the motor functions. Both surgical treatment and study of PD require delineation of basal ganglia nuclei morphology. While many automatic volumetric segmentation methods have been proposed for the lentiform nucleus, few have attempted to identify the key brainstem substructures including the subthalamic nucleus (STN), substantia nigra (SN), and red nucleus (RN) due to their small size and poor contrast in conventional T1W MRI., Methods: A dual-contrast patch-based label fusion method was developed to segment the SN, STN, and RN using multivariate cross-correlation. Two different MRI contrasts (T2*w and phase) are produced from a multi-contrast multi-echo FLASH MRI sequence, enabling visualization of these nuclei. T1-T2* fusion MRI was used to resolve the issue of poor nuclei (i.e., the STN, SN, and RN) contrast on T1w MRI, and to mitigate susceptibility artifacts that may hinder accurate nonlinear registration on T2*w MRI. Unbiased group-wise registration was used for anatomical normalization between the atlas library and the target subject. The performance of the proposed method was compared with a state-of-the-art single-contrast label fusion technique., Results: The proposed method outperformed a state-of-the-art single-contrast patch-based method in segmenting the STN, RN and SN, and the results were better than those reported in previous literature., Conclusion: Our dual-contrast patch-based label fusion method was superior to a single-contrast method for segmenting brainstem nuclei using a multi-contrast multi-echo FLASH MRI sequence. The method is promising for the treatment and research of Parkinson's disease. This method can be extended for multiple alternative image contrasts and other fields of applications.

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.

Background: Maintaining a physically active lifestyle promotes general health. Recent studies have demonstrated that patients with Parkinson's disease (PD) fail to meet the suggested levels of physical activity and that targeted interventions do not always improve this behavior. One validated treatment for motor symptoms in PD is subthalamic stimulation (STN DBS)., Objective: Assess whether motor symptom improvement following STN DBS translated into increased physical activity behavior., Methods: Twenty patients with PD scheduled for bilateral STN DBS filled-out the Phone-FITT physical activity questionnaire and the SF-36 quality of life questionnaire prior to surgery and 6 to 9 months postoperatively. Data were compared to age- and gender-matched healthy controls., Results: Our results demonstrate that PD patients' quality of life is significantly lower than healthy controls. While STN DBS improves motor symptoms in the intermediate term, it only improves some aspects of quality of life related to physical function. Furthermore, STN DBS does not modify physical activity behavior measured by the Phone-FITT, whether for household or recreational activities., Conclusion: The current study demonstrates that the motor improvements observed after STN DBS do not lead to systematic improvements in all aspects of quality of life or increased levels of physical activity. This highlights the need to develop and implement intervention strategies to promote an active lifestyle in this population, even if clinical improvement is evident following surgery.

Objective: Subthalamic (STN) deep brain stimulation (DBS) is a recognized therapy for alleviating motor symptoms of Parkinson's disease (PD). However, little is known about its impact on mobility, an important component of quality of life (QoL). To address this issue, we assessed the impact of STN DBS on life-space mobility and QoL., Methods: Twenty surgical patients with PD were assessed using mobility and QoL scales and the United Parkinson's disease rating scale, and results were compared before surgery and 6 to 9 months postoperatively., Results: STN DBS significantly improved motor dysfunction but had a limited impact on measures of life-space mobility and QoL., Interpretation: STN DBS improves motor function and some components of QoL. However, motor recovery does not translate into improved life-space in the intermediate term. In addition to a focus on motor function, multidisciplinary attention to increasing mobility may further improve QoL in the intermediate and long-term., (© 2014 International Parkinson and Movement Disorder Society.)

Paranodal axoglial junctions are critical for maintaining the segregation of axonal domains along myelinated axons; however, the proteins required to organize and maintain this structure are not fully understood. Netrin-1 and its receptor Deleted in Colorectal Cancer (DCC) are proteins enriched at paranodes that are expressed by neurons and oligodendrocytes. To identify the specific function of DCC expressed by oligodendrocytes in vivo, we selectively eliminated DCC from mature myelinating oligodendrocytes using an inducible cre regulated by the proteolipid protein promoter. We demonstrate that DCC deletion results in progressive disruption of the organization of axonal domains, myelin ultrastructure, and myelin protein composition. Conditional DCC knock-out mice develop balance and coordination deficits and exhibit decreased conduction velocity. We conclude that DCC expression by oligodendrocytes is required for the maintenance and stability of myelin in vivo, which is essential for proper signal conduction in the CNS., (Copyright © 2014 the authors 0270-6474/14/349768-11$15.00/0.)

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.

Introduction: Bradykinesia is usually assessed using clinical rating scales. In some circumstances, a laboratory assessment of bradykinesia using tools of higher resolution is required. One task often used for the evaluation of bradykinesia is a rapid alternating movement (RAM) of the hand. However, the relationship between clinical scores of bradykinesia and the properties of a RAM task assessed quantitatively has yet to be determined., Objective: Identify which of the commonly used properties of a RAM task are related to a clinical score of bradykinesia and assess the strength of this relationship., Methods: Nineteen patients with idiopathic Parkinson's disease were tested ON and OFF medication. They performed three trials of the RAM task and were assessed clinically using the Unified Parkinson's disease rating scale in each condition and with each hand., Results: A statistically significant correlation was observed between the clinical score of bradykinesia and two of the properties of the RAM task; namely mean and maximal velocity., Comparison With Existing Methods: These results indicate that a RAM task does provide a measure of bradykinesia but it is only moderately correlated to a clinical rating of this motor symptom., Conclusion: We propose that the results from the RAM task represent a measure of "core bradykinesia" while a clinical evaluation represents a composite score of bradykinesia, movement amplitude and motor coordination., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The homeodomain transcription factor Pitx3 is critical for the survival of midbrain dopaminergic (mDA) neurons. Pitx3-deficient mice exhibit severe but selective developmental loss of mDA neurons, with accompanying locomotor deficits resembling those seen in Parkinson's disease (PD) models. Here, we identify specific mDA cell subpopulations that are consistently spared in adult Pitx3-hypomorphic (aphakia) mice, demonstrating that Pitx3 is not indiscriminately required by all mDA neurons for their survival. In aphakia mice, virtually all surviving mDA neurons in the substantia nigra (SN) and the majority of neurons in the adjacent ventral tegmental area (VTA) also express calbindin-D28k, a calcium-binding protein previously associated with resistance to injury in PD and in animal models. Cell-mapping studies in wild-type mice revealed that Pitx3 is primarily expressed in the ventral SN, a region particularly susceptible to MPTP and other dopaminergic neurotoxins. Furthermore, Pitx3-expressing SN cells are preferentially lost following MPTP treatment. Finally, SN mDA neurons in Pitx3 hemizygous mice show increased sensitivity when exposed to MPTP. Thus, SN mDA neurons are represented by at least two distinct subpopulations including MPTP-resistant Pitx3-autonomous, calbindin-positive neurons, and calbindin-negative Pitx-3-dependent cells that display elevated vulnerability to toxic injury, and probably correspond to the subpopulation that degenerates in PD. Impairment of Pitx3-dependent pathways therefore increases vulnerability of mDA neurons to toxic injury. Together, these data suggest a novel link between Pitx3 function and the selective pattern of mDA cell loss observed in PD., (© 2013 International Society for Neurochemistry.)

Background: Dyskinesia, a major complication in the treatment of Parkinson's disease (PD), can require prolonged monitoring and complex medical management., Discussion: The current paper proposes a new way to view the management of dyskinesia in an integrated fashion. We suggest that dyskinesia be considered as a factor in a signal-to-noise ratio (SNR) equation where the signal is the voluntary movement and the noise is PD symptomatology, including dyskinesia. The goal of clinicians should be to ensure a high SNR in order to maintain or enhance the motor repertoire of patients. To understand why such an approach would be beneficial, we first review mechanisms of dyskinesia, as well as their impact on the quality of life of patients and on the health-care system. Theoretical and practical bases for the SNR approach are then discussed., Summary: Clinicians should not only consider the level of motor symptomatology when assessing the efficacy of their treatment strategy, but also breadth of the motor repertoire available to patients.

Patients with Huntington's disease (HD) and transgenic mouse models of HD show neuronal loss in the striatum as a major feature, which contributes to cognitive and motor manifestations. Reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in striatal afferents may play a role in neuronal loss. How progressive loss of BDNF expression in different cortical or subcortical afferents contributes to striatal atrophy and behavioral dysfunction in HD is not known, and may best be determined in animal models. We compared age-dependent alterations of BDNF mRNA expression in major striatal afferents from the cerebral cortex, thalamus and midbrain in the R6/2 transgenic mouse model of HD. Corresponding changes in striatal morphology were quantified using unbiased stereology. Changes in motor behavior were measured using an open field, grip strength monitor, limb clasping and a rotarod apparatus. BDNF expression in cortical limbic and midbrain striatal afferents is reduced by age 4 weeks, prior to onset of motor abnormalities. BDNF expression in motor cortex and thalamic afferents is reduced by 6 weeks, coinciding with early motor dysfunction and reduced striatum volume. BDNF loss in afferents progresses until death at 13-15 weeks, correlating with progressive striatal neuronal loss and motor abnormalities. Mutant huntingtin protein expression in R6/2 mice results in progressive loss of BDNF in both cortical and subcortical striatal afferents. BDNF loss in limbic and dopaminergic striatal inputs may contribute to cognitive/psychiatric dysfunction in HD. Subsequent BDNF loss in cortical motor and thalamic afferents may accelerate striatal degeneration, resulting in progressive involuntary movements., (© 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.)

Introduction: Smart phones are becoming ubiquitous and their computing capabilities are ever increasing. Consequently, more attention is geared toward their potential use in research and medical settings. For instance, their built-in hardware can provide quantitative data for different movements. Therefore, the goal of the current study was to evaluate the capabilities of a standalone smart phone platform to characterize tremor., Results: Algorithms for tremor recording and online analysis can be implemented within a smart phone. The smart phone provides reliable time- and frequency-domain tremor characteristics. The smart phone can also provide medically relevant tremor assessments., Discussion: Smart phones have the potential to provide researchers and clinicians with quantitative short- and long-term tremor assessments that are currently not easily available., Methods: A smart phone application for tremor quantification and online analysis was developed. Then, smart phone results were compared to those obtained simultaneously with a laboratory accelerometer. Finally, results from the smart phone were compared to clinical tremor assessments.

Recent studies have proposed that glutamate corelease by mesostriatal dopamine (DA) neurons regulates behavioral activation by psychostimulants. How and when glutamate release by DA neurons might play this role remains unclear. Considering evidence for early expression of the type 2 vesicular glutamate transporter in mesencephalic DA neurons, we hypothesized that this cophenotype is particularly important during development. Using a conditional gene knock-out approach to selectively disrupt the Vglut2 gene in mouse DA neurons, we obtained in vitro and in vivo evidence for reduced growth and survival of mesencephalic DA neurons, associated with a decrease in the density of DA innervation in the nucleus accumbens, reduced activity-dependent DA release, and impaired motor behavior. These findings provide strong evidence for a functional role of the glutamatergic cophenotype in the development of mesencephalic DA neurons, opening new perspectives into the pathophysiology of neurodegenerative disorders involving the mesostriatal DA system.

Purpose: Both frame-based and frameless approaches to deep brain stimulation (DBS) require planning of insertion trajectories that mitigate hemorrhagic risk and loss of neurological function. Currently, this is done by manual inspection of multiple potential electrode trajectories on MR-imaging data. We propose and validate a method for computer-assisted DBS trajectory planning., Method: Our framework integrates multi-modal MRI analysis (T1w, SWI, TOF-MRA) to compute suitable DBS trajectories that optimize the avoidance of specific critical brain structures. A cylinder model is used to process each trajectory and to evaluate complex surgical constraints described via a combination of binary and fuzzy segmented datasets. The framework automatically aggregates the multiple constraints into a unique ranking of recommended low-risk trajectories. Candidate trajectories are represented as a few well-defined cortical entry patches of best-ranked trajectories and presented to the neurosurgeon for final trajectory selection., Results: The proposed algorithm permits a search space containing over 8,000 possible trajectories to be processed in less than 20 s. A retrospective analysis on 14 DBS cases of patients with severe Parkinson's disease reveals that our framework can improve the simultaneous optimization of many pre-formulated surgical constraints. Furthermore, all automatically computed trajectories were evaluated by two neurosurgeons, were judged suitable for surgery and, in many cases, were judged preferable or equivalent to the manually planned trajectories used during the operation., Conclusions: This work provides neurosurgeons with an intuitive and flexible decision-support system that allows objective and patient-specific optimization of DBS lead trajectories, which should improve insertion safety and reduce surgical time.

Object: Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression., Methods: Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50)., Results: Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery., Conclusions: Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

We present a novel method for preoperative computer-assisted deep brain stimulation (DBS) electrode targeting that takes into account the multiplicity of available contacts and their polarity. Our framework automatically evaluates the efficacy of many possible electrode orientations to optimize the interplay between the extracellular electric field, created from distinct arrangements of active contacts, and anatomical structures responsible for therapeutic and potential side effects. Experimental results on subthalamic DBS cases suggest bipolar configurations provide more flexibility and control on the spread of electric field and, consequently, are most robust to targeting imprecision. Visualization of predicted efficacy maps provides surgeons with complementary feedback that can bridge the gap between insertion safety and optimal therapeutic efficacy. Overall, this work adds a new dimension to preoperative DBS planning and suggests new insights regarding multi-target stimulation.

Functional brain imaging and neurosurgery in subcortical areas often requires visualization of brain nuclei beyond the resolution of current magnetic resonance imaging (MRI) methods. We present techniques used to create: (1) a lower resolution 3D atlas, based on the Schaltenbrand and Wahren print atlas, which was integrated into a stereotactic neurosurgery planning and visualization platform (VIPER); and (2) a higher resolution 3D atlas derived from a single set of manually segmented histological slices containing nuclei of the basal ganglia, thalamus, basal forebrain, and medial temporal lobe. Both atlases were integrated to a canonical MRI (Colin27) from a young male participant by manually identifying homologous landmarks. The lower resolution atlas was then warped to fit the MRI based on the identified landmarks. A pseudo-MRI representation of the high-resolution atlas was created, and a non-linear transformation was calculated in order to match the atlas to the template MRI. The atlas can then be warped to match the anatomy of Parkinson's disease surgical candidates by using 3D automated non-linear deformation methods. By way of functional validation of the atlas, the location of the sensory thalamus was correlated with stereotactic intraoperative physiological data. The position of subthalamic electrode positions in patients with Parkinson's disease was also evaluated in the atlas-integrated MRI space. Finally, probabilistic maps of subthalamic stimulation electrodes were developed, in order to allow group analysis of the location of contacts associated with the best motor outcomes. We have therefore developed, and are continuing to validate, a high-resolution computerized MRI-integrated 3D histological atlas, which is useful in functional neurosurgery, and for functional and anatomical studies of the human basal ganglia, thalamus, and basal forebrain.

Object: The somatotopic organization of the motor fibers within the posterior limb of the internal capsule (IC) in humans remains unclear. Several electrophysiological atlases created from stimulation during stereotactic neurosurgery have suggested that there is considerable overlap between representations of body parts. Overlap reported in these studies may have been due to linear scaling methods applied to the data that were unable to account for individual anatomical variability. In the current work, the authors attempted to overcome these limitations by using a nonlinear registration technique to better understand the spatial location and extent of the body-part representations in the IC., Methods: Data were acquired during 30 cases of deep brain neurosurgery in which the IC was electrically stimulated to localize the ventrolateral nucleus for a subsequent thalamotomy or implantation of a thalamic deep brain stimulator. Motor responses from the tongue, face, arm, or leg were evoked in the IC and coded in the patient's native MR imaging space. The tagged MR images were then nonlinearly registered to a high-resolution template MR image. This work resulted in a functional electrophysiological atlas demonstrating the locations of body-part representations in the posterior limb of the IC that takes individual anatomical variability into account. To further understand the spatial location and extent of the motor responses, the electrophysiological data points were transformed into 3D probability maps that describe the likelihood of obtaining motor responses in the posterior limb of the IC., Results: The analyses suggest a reliable face-anterior, arm-intermediate, and leg-posterior somatotopic organization in the posterior limb of the IC with little overlap between the body-part representations., Conclusions: This probabilistic atlas of functional responses evoked by stimulating the posterior limb of the IC provides better understanding of the anatomical organization of descending motor fibers, can be used for indirect intraoperative confirmation of the location of the ventrolateral thalamus, and is applicable to clinical and research MR imaging studies requiring information on spatial organization of motor fibers at the thalamic level in the human brain.

Background. Although the clinical effectiveness of deep brain stimulation (DBS) in Parkinson's disease is established, there has been less examination of its social aspects. Methods and Results. Building on qualitative comments provided by healthcare providers, we present four different social and relational issues (need for social support, changes in relationships (with self and partner) and challenges with regards to occupation and the social system). We review the literature from multiple disciplines on each issue. We comment on their ethical implications and conclude by establishing the future prospects for research with the possible expansion of DBS for psychiatric indications. Conclusions. Our review demonstrates that there are varied social issues involved in DBS. These issues may have significant impacts on the perceived outcome of DBS by patients. Moreover, the fact that the social impact of DBS is still not well understood in emerging psychiatric indications presents an important area for future examination.

We propose an automated method for preoperative trajectory planning of deep brain stimulation image-guided neurosurgery. Our framework integrates multi-modal MRI analysis (T1w, SWI, TOF-MRA) to determine an optimal trajectory to DBS targets (subthalamic nuclei and globus pallidus interna) while avoiding critical brain structures for prevention of hemorrhages, loss of function and other complications. Results show that our method is well suited to aggregate many surgical constraints and allows the analysis of thousands of trajectories in less than 1/10th of the time for manual planning. Finally, a qualitative evaluation of computed trajectories resulted in the identification of potential new constraints, which are not addressed in the current literature, to better mimic the decision-making of the neurosurgeon during DBS planning.

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.)

Digital atlases are commonly used in pre-operative planning in functional neurosurgical procedures performed to minimize the symptoms of Parkinson's disease. These atlases can be customized to fit an individual patient's anatomy through atlas-to-patient warping procedures. Once fitted to pre-operative magnetic resonance imaging (MRI) data, the customized atlas can be used to plan and navigate surgical procedures. Linear, piece-wise linear and nonlinear registration methods have been used to customize different digital atlases with varying accuracies. Our goal was to evaluate eight different registration methods for atlas-to-patient customization of a new digital atlas of the basal ganglia and thalamus to demonstrate the value of nonlinear registration for automated atlas-based subcortical target identification in functional neurosurgery. In this work, we evaluate the accuracy of two automated linear techniques, two piece-wise linear techniques (requiring the identification of manually placed anatomical landmarks), and four different automated nonlinear atlas-to-patient warping techniques (where two of the four nonlinear techniques are variants of the ANIMAL algorithm). Since a gold standard of the subcortical anatomy is not available, manual segmentations of the striatum, globus pallidus, and thalamus are used to derive a silver standard for evaluation. Four different metrics, including the kappa statistic, the mean distance between the surfaces, the maximum distance between surfaces, and the total structure volume are used to compare the warping techniques. The results show that nonlinear techniques perform statistically better than linear and piece-wise linear techniques. In addition, the results demonstrate statistically significant differences between the nonlinear techniques, with the ANIMAL algorithm yielding better results.

In addition to the cerebral cortex, the striatum receives excitatory input from the thalamus. The centromedian (centre median, CM) and parafascicular (Pf) nuclei are an important source of thalamostriatal projections. Anterograde tract-tracing indicates the CM-Pf complex provides dense afferents to the matrix compartment of the striatum. Whereas CM projects to the entire sensorimotor territory of the striatum, the Pf provides complementary input to the entire associative sector. The Pf also provides lighter input to the nucleus accumbens. Both CM and Pf provide light to moderately dense inputs to other components of the basal ganglia in a largely complementary manner, covering motor or associative-limbic territories of the subthalamic nucleus, globus pallidus and ventral midbrain. In turn, the CM and Pf receive mainly segregated input from parallel motor and associative-limbic circuits of the basal ganglia. The CM and Pf may therefore be considered important participants in parallel processing of motor and associative-limbic information in the basal ganglia. Connections of the CM and Pf with other thalamic nuclei suggest they also participate in integrative functions within the thalamus. In addition, inputs from the brainstem reticular core, reciprocal connections with the cerebral cortex and reticular thalamic nucleus suggest a role in state-dependant information processing. Consideration of the differential connections of the CM and Pf, and better understanding of their role in pathophysiology, may eventually lead to development of an important new target for relief of a variety of neurological and psychiatric disorders.

Netrins are a family of secreted proteins that function as axon guidance cues during neural development. High levels of netrin-1 expressed by the embryonic ganglionic eminence, the precursor of the adult striatum, direct axons that pioneer the internal capsule. Here we describe netrin-1 expression by neurons distributed throughout the striatum of the adult mouse. Differences were detected in the number and type of neurons expressing netrin-1 in different regions of the striatum. Most neurons in the ventral striatum, including projection neurons and cholinergic interneurons, express netrin-1. In contrast, netrin-1 expression is largely limited to cholinergic interneurons in the dorsal striatum, and the proportion of cholinergic interneurons that express netrin-1 decreases along rostral-caudal and ventral-dorsal axes. Regional differences in expression in the adult striatum suggest that netrin-1 not only influences the development of striatal circuitry but may also participate in the maintenance and plasticity of connections in the adult brain.

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.

The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.

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.

Major classical neurotransmitters including GABA and glutamate play novel morphogenic roles during development of the mammalian CNS. During forebrain neurogenesis, glutamate regulates neuroblast proliferation in different germinal domains using receptor subtype-specific mechanisms. For example, ionotropic N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors mediate distinct proliferative effects in ventral or dorsal forebrain germinal domains, and regulate the correct number of neurons that populate the striatum or cerebral cortex. Recent work suggests metabotropic receptors may also mediate glutamate's proliferative effects. Group I mGluR5 receptor subtypes are highly expressed in forebrain germinal zones. Using in vitro and in vivo methods, we demonstrate mGluR5 receptor activation plays an important role in neuroblast proliferation in the ventral telencephalon, and helps determine the complement of striatum projection neurons. mGluR5 receptor-mediated effects on striatal neuronal progenitors are restricted mainly to early cycling populations in the ventricular zone, with little effect on secondary proliferative populations in the subventricular zone. In contrast to proliferative effects in the ventral telencephalon, mGluR5 receptors do not modulate proliferation of dorsal telencephalon-derived cortical neuroblasts. Heterogeneous domain-specific proliferative effects of glutamate-mediated by specific receptor subtypes provide an important developmental mechanism allowing generation of the correct complement of neuronal subtypes that populate the mammalian forebrain.

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.

Acute and chronic behavioral effects of subthalamic stimulation (STN-DBS) for Parkinson's disease (PD) are reported in the literature. As the technique is relatively new, few systematic studies on the behavioral effects in long-term treated patients are available. To further study the putative effects of STN-DBS on mood and emotional processing, 15 consecutive PD patients under STN-DBS for at least 1 year, were tested ON and OFF stimulation while on or off medication, with instruments sensitive to short-term changes in mood and in emotional discrimination. After acute changes in experimental conditions, mood core dimensions (depression, elation, anxiety) and emotion discrimination processing remained remarkably stable, in the face of significant motor changes. Acute stimulator challenge in long-term STN-DBS-treated PD patients does not appear to provoke clinically relevant mood effects.

Pioneering work indicates that the final position of neurons in specific layers of the mammalian cerebral cortex is determined primarily by birthdate. Glutamatergic projection neurons are born in the cortical proliferative zones of the dorsal telencephalon, and follow an "inside-out" neurogenesis gradient: later-born cohorts migrate radially past earlier-born neurons to populate more superficial layers. GABAergic interneurons, the major source of cortical inhibition, comprise a heterogeneous population and are produced in proliferative zones of the ventral telencephalon. Mechanisms by which interneuron subclasses find appropriate layer-specific cortical addresses remain largely unexplored. Major cortical interneuron subclasses can be identified based on expression of distinct calcium-binding proteins including parvalbumin, calretinin, or calbindin. We determined whether cortical layer-patterning of interneurons is dependent on phenotype. Parvalbumin-positive interneurons populate cortical layers with an inside-out gradient, and birthdate is isochronous to projection neurons in the same layers. In contrast, another major GABAergic subtype, labeled using calretinin, populates the cerebral cortex using an opposite "outside-in" gradient, heterochronous to neighboring neurons. In addition to birthdate, phenotype is also a determinant of cortical patterning. Discovery of a cortical subpopulation that does not follow the well-established inside-out gradient has important implications for mechanisms of layer formation in the cerebral cortex., (2007 Wiley-Liss, Inc.)