The netrin-1 receptor DCC promotes the survival of a subpopulation of midbrain dopaminergic neurons: Relevance for ageing and Parkinson's disease.

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 DATcre /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 DATcre /DCCfl/fl mice, with further reduction in aged DATcre /DCCfl/fl animals. In contrast to young adults, aged mice also exhibited a gene dosage effect, with fewer SNc mDA neurons in DCC heterozygotes (DATcre /DCCfl/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 DATcre /DCCfl/fl and DATcre /DCCfl/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.

BAG3P215L/KO Mice as a Model of BAG3P209L Myofibrillar Myopathy.

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.

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia.

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.

Spatial memory formation requires netrin-1 expression by neurons in the adult mammalian brain.

Netrin-1 was initially characterized as an axon guidance molecule that is essential for normal embryonic neural development; however, many types of neurons continue to express netrin-1 in the postnatal and adult mammalian brain. Netrin-1 and the netrin receptor DCC are both enriched at synapses. In the adult hippocampus, activity-dependent secretion of netrin-1 by neurons potentiates glutamatergic synapse function, and is critical for long-term potentiation, an experimental cellular model of learning and memory. Here, we assessed the impact of neuronal expression of netrin-1 in the adult brain on behavior using tests of learning and memory. We show that adult mice exhibit impaired spatial memory following conditional deletion of netrin-1 from glutamatergic neurons in the hippocampus and neocortex. Further, we provide evidence that mice with conditional deletion of netrin-1 do not display aberrant anxiety-like phenotypes and show a reduction in self-grooming behavior. These findings reveal a critical role for netrin-1 expressed by neurons in the regulation of spatial memory formation.

Mesolimbic connectivity signatures of impulsivity and BMI in early adolescence.

Across age groups, differences in connectivity of the mesolimbic and the prefrontal cortex co-vary with trait impulsivity and sensation-seeking. Impulsivity and sensation-seeking are also known to increase during early adolescence as maturation of subcortical structures outpaces that of the prefrontal cortex. While an imbalance between the striatum and prefrontal cortex is considered a normal developmental process, higher levels of adolescent impulsivity and sensation-seeking are associated with an increased risk for diverse problems, including obesity. To determine how the relationship between sensation-seeking, impulsivity and body mass index (BMI) is related to shared neural correlates we measured their relationships with the connectivity of nuclei in the striatum and dopaminergic midbrain in young adolescents. Data were collected from 116 children between the ages of 12 and 14, and included resting state functional magnetic resonance imaging, personality measures from the Substance Use Risk Profile Scale, and BMI Z-score for age. The shared variance for the connectivity of regions of interest in the substantia nigra, ventral tegmental area, ventral striatum and sub-thalamic nucleus, personality measures and BMI Z-score for age, were analyzed using partial least squares correlation. This analysis identified a single significant striato-limbic network that was connected with the substantia nigra, ventral tegmental area and sub-thalamic nuclei (p = 0.002). Connectivity within this network which included the hippocampi, amygdalae, parahippocampal gyri and the regions of interest, correlated positively with impulsivity and BMI Z-score for age and negatively with sensation-seeking. Together, these findings emphasize that, in addition to the well-established role that frontostriatal circuits play in the development of adolescent personality traits, connectivity of limbic regions with the striatum and midbrain also impact impulsivity, sensation-seeking and BMI Z-score in adolescents.

A brain network model explaining tremor in Parkinson's disease.

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.

Metacognitive knowledge of olfactory dysfunction in Parkinson's disease.

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.

Progressive disorganization of paranodal junctions and compact myelin due to loss of DCC expression by oligodendrocytes.

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.

Subthalamic stimulation improves motor function but not home and neighborhood mobility.

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.

Equivalent-time-active-cavitation-imaging enables vascular-resolution blood-brain-barrier-opening-therapy planning.

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.

Dynamic Ultrasound Localization Microscopy Without ECG-Gating.

OBJECTIVE: Dynamic Ultrasound Localization Microscopy (DULM) has first been developed for non-invasive Pulsatility measurements in the rodent brain. DULM relies on the localization and tracking of microbubbles (MBs) injected into the bloodstream, to obtain highly resolved velocity and density cine-loops. Previous DULM techniques required ECG-gating, limiting its application to specific datasets, and increasing acquisition time. The objective of this study is to eliminate the need for ECG-gating in DULM experiments by introducing a motion-matching method for time registration. METHODS: We developed a motion-matching algorithm based on tissue Doppler that leverages the cyclic tissue motion within the brain. Tissue Doppler was estimated for each group of frames in the acquisitions, at multiple locations identified as local maxima in the skin above the skull. Subsequently, each group of frames was time-registered to a reference group by delaying it based on the maximum correlation value between their respective tissue Doppler signals. This synchronization ensured that each group of frames aligned with the brain tissue motion of the reference group, and consequently, with its cardiac cycle. As a result, velocities of MBs could be averaged to retrieve flow velocity variations over time. RESULTS: Initially validated in ECG-gated acquisitions in a rat model (n = 1), the proposed method was successfully applied in a mice model in 2D (n = 3) and in a feline model in 3D (n = 1). Performing time-registration with the proposed motion-matching method or by using ECG-gating leads to similar results. For the first time, dynamic velocity and density cine-loops were extracted without the need for any information on the animal ECG, and complex dynamic markers such as the Pulsatility index were estimated. CONCLUSION: Results suggest that DULM can be performed without external gating, enabling the use of DULM on any ULM dataset where enough MBs are detectable. Time registration by motion-matching represents a significant advancement in DULM techniques, making DULM more accessible by simplifying its experimental complexity.

Glutamate corelease promotes growth and survival of midbrain dopamine neurons.

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.

The transcription factor Pitx3 is expressed selectively in midbrain dopaminergic neurons susceptible to neurodegenerative stress.

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.

Drug-induced dyskinesia in Parkinson's disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia?

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.

Gel nail polish as an alternative to traditional coverslip sealants: A quick solution to a sticky situation.

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.

Reproducibility of cerebellar involvement as quantified by consensus structural MRI biomarkers in advanced essential tremor.

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 .

A standardized accelerometry method for characterizing tremor: Application and validation in an ageing population with postural and action tremor.

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.

Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with 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.

Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease.

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.

Equivalent time active cavitation imaging.

Rationale. Despite the development of a large number of neurologically active drugs, brain diseases are difficult to treat due to the inability of many drugs to penetrate the blood-brain barrier. High-intensity focused ultrasound (HIFU) blood-brain barrier opening in a site-specific manner could significantly expand the spectrum of available drug treatments. However, without monitoring, brain damage and off-target effects can occur during these treatments. While some methods can monitor inertial cavitation, temperature increase, or passively monitor cavitation events, to the best of our knowledge none of them can actively and spatiotemporally map the HIFU pressure field during treatment.Methods. Here we detail the development of a novel ultrasound imaging modality called equivalent time active cavitation imaging (ETACI) capable of characterizing the HIFU pressure field through stable cavitation events across the field of view with an ultrafast active imaging setup. This work introduces (1) a novel plane wave sequence whose transmit delays increase linearly with transmit events enabling the sampling of high-frequency cavitation events, and (2) an algorithm allowing the processing of the microbubble signal for pressure field mapping. The pressure measurements with our modality were first carried outin vitrofor hydrophone comparison and thenin vivoduring blood-brain barrier opening treatment in mice.Results. This study demonstrates the capability of ETACI to spatiotemporally characterize a modulation pressure field with an active imaging setup. The resulting pressure field mapping reveals a good correlation with hydrophone measurements. Further results iareprovided experimentallyin vivowith promising results.Conclusion. This proof of concept establishes the first steps towards a novel ultrasound modality for monitoring focused ultrasound blood-brain barrier opening, allowing new possibilities for a safe and precise monitoring method.