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Epilepsy biomarkers from electroencephalogram recordings are routinely used to assess seizure risk and localization. Two widely adopted biomarkers include: (i) interictal spikes, and (ii) high frequency ripple oscillations. The combination of these two biomarkers, ripples co-occurring with spikes (spike ripples), has been proposed as an improved biomarker for the epileptogenic zone and epileptogenicity in humans and rodent models. Whether spike ripples translate to predict seizure risk in rodent seizure models is unknown. Further, recent evidence suggests ictal networks can include deep gray nuclei in humans. Whether pathologic spike ripples and seizures are also observed in the basal ganglia in rodent models has not been explored. We addressed these questions using local field potential recordings from mice with and without striatal seizures after carbachol or 6-hydroxydopamine infusions into the striatum. We found increased spike ripples in the interictal and ictal periods in mice with seizures compared to pre-infusion and post-infusion seizure-free recordings. These data provide evidence of electrographic seizures involving the striatum in mice and support the candidacy of spike ripples as a translational biomarker for seizure risk in mouse models., 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., (© 2022 The Authors.)

Dopamine degeneration in Parkinson's disease (PD) dysregulates the striatal neural network and causes motor deficits. However, it is unclear how altered striatal circuits relate to dopamine-acetylcholine chemical imbalance and abnormal local field potential (LFP) oscillations observed in PD. We perform a multimodal analysis of the dorsal striatum using cell-type-specific calcium imaging and LFP recording. We reveal that dopamine depletion selectively enhances LFP beta oscillations during impaired locomotion, supporting beta oscillations as a biomarker for PD. We further demonstrate that dynamic cholinergic interneuron activity during locomotion remains unaltered, even though cholinergic tone is implicated in PD. Instead, dysfunctional striatal output arises from elevated coordination within striatal output neurons, which is accompanied by reduced locomotor encoding of parvalbumin interneurons and transient pathological LFP high-gamma oscillations. These results identify a pathological striatal circuit state following dopamine depletion where distinct striatal neuron subtypes are selectively coordinated with LFP oscillations during locomotion., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ultrasound modulates brain activity. However, it remains unclear how ultrasound affects individual neurons in the brain, where neural circuit architecture is intact and different brain regions exhibit distinct tissue properties. Using a high-resolution calcium imaging technique, we characterized the effect of ultrasound stimulation on thousands of individual neurons in the hippocampus and the motor cortex of awake mice. We found that brief 100-ms-long ultrasound pulses increase intracellular calcium in a large fraction of individual neurons in both brain regions. Ultrasound-evoked calcium response in hippocampal neurons exhibits a rapid onset with a latency shorter than 50 ms. The evoked response in the hippocampus is shorter in duration and smaller in magnitude than that in the motor cortex. These results demonstrate that noninvasive ultrasound stimulation transiently increases intracellular calcium in individual neurons in awake mice, and the evoked response profiles are brain region specific., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Purpose: The current study aimed to evaluate the psychometric properties of the Dutch version of the Multiple Sclerosis Work Difficulties Questionnaire-23 (MSWDQ-23)., Methods: Two hundred and thirty-nine employed persons with multiple sclerosis (MS) and 59 healthy controls completed the MSWDQ-23. To verify the factor structure, a confirmatory factor analysis was conducted. To assess construct validity, the MSWDQ-23 scores were correlated to measures of physical disability, fatigue, cognitive and neuropsychiatric problems, depression, health-related quality of life, and work-related variables. MSWDQ-23 scores were compared within different age groups, gender, education levels, and job types. Predictive validity was assessed using a logistic regression analysis to predict a deterioration in employment status after one year based on MSWDQ-23 scores., Results: The internal consistency of the MSWDQ-23 was acceptable ( α  = 0.913, 95% CI = 0.897-0.928) and the results indicated a fair fit. The MSWDQ-23 showed acceptable construct validity, confirming 94% of the hypotheses. The total scale and the psychological/cognitive subscale were able to predict a deterioration in employment status after one year ( χ 2 (1)=18.164, p  < 0.001)., Conclusions: The Dutch version of the MSWDQ-23 is a valid and internally consistent instrument to measure self-reported work difficulties in persons with MS.Implications for rehabilitationThe Dutch version of the 23-item Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ-23) is a reliable and valid tool to measure self-reported work difficulties in people with multiple sclerosis (MS).More psychological and cognitive work difficulties are predictive of a deteriorated employment status after one year.The MSWDQ-23 is a helpful tool for researchers and (occupational) health professionals to identify current work difficulties in persons with MS and identify persons at risk for a deterioration in employment one year later.

Optical microscopy has been an indispensable tool for studying complex biological systems, but is often hampered by problems of speed and complexity when performing 3D volumetric imaging. Here, we present a multifocus imaging strategy based on the use of a simple z-splitter prism that can be assembled from off-the-shelf components. Our technique enables a widefield image stack to be distributed onto a single camera and recorded simultaneously. We exploit the volumetric nature of our image acquisition by further introducing a novel extended-volume 3D deconvolution strategy to suppress far-out-of-focus fluorescence background to significantly improve the contrast of our recorded images, conferring to our system a capacity for quasi-optical sectioning. By swapping in different z-splitter configurations, we can prioritize high speed or large 3D field-of-view imaging depending on the application of interest. Moreover, our system can be readily applied to a variety of imaging modalities in addition to fluorescence, such as phase-contrast and darkfield imaging. Because of its simplicity, versatility, and performance, we believe our system will be a useful tool for general biological or biomedical imaging applications., Competing Interests: Disclosures. The authors declare no conflicts of interest.

Fibronectin intrabodies generated with mRNA display (FingRs) are a recently developed tool for labeling excitatory or inhibitory synapses, with the benefit of not altering endogenous synaptic protein expression levels or synaptic transmission. Here, we generated a viral vector FingR toolbox that allows for multi-color, neuron-type-specific labeling of excitatory or inhibitory synapses in multiple brain regions. We screened various fluorophores, FingR fusion configurations, and transcriptional control regulations in adeno-associated virus (AAV) and retrovirus vector designs. We report the development of a red FingR variant and demonstrated dual labeling of excitatory and inhibitory synapses in the same cells. Furthermore, we developed cre-inducible FingR AAV variants and demonstrated their utility, finding that the density of inhibitory synapses in aspiny striatal cholinergic interneurons remained unchanged in response to dopamine depletion. Finally, we generated FingR retroviral vectors, which enabled us to track the development of excitatory and inhibitory synapses in hippocampal adult-born granule cells., Competing Interests: Declaration of Interests The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cognitive functioning has been linked to employment outcomes in multiple sclerosis (MS) in cross-sectional studies. Longitudinal studies are however lacking and previous studies did not extensively examine executive functioning., Objectives: We examined whether baseline cognitive functioning predicts a change in employment status after 2 years, while taking into account mood, fatigue and disability level., Methods: A total of 124 patients with relapsing-remitting MS (pwMS) and 60 healthy controls were included. They underwent neurological and neuropsychological examinations and completed online questionnaires. PwMS were divided into a stable and deteriorated employment status group (SES and DES), based on employment status 2 years after baseline. We first examined baseline differences between the SES and DES groups in cognitive functioning, mood, fatigue and disability level. A logistic regression analysis was performed, with change in employment status (SES/DES) as dependent variable., Results: The DES group included 22% pwMS. Group differences were found in complex attention, executive functioning, self-reported cognitive functioning, fatigue and physical disability. More physical disability (OR = 1.90, p = 0.01) and lower executive functioning (OR = 0.30, p = 0.03) were retained as independent predictors of DES (R 2  = 0.22, p ≤ 0.001)., Conclusions: Baseline physical disability and executive functioning, but none of the other variables, moderately predicted a deterioration in employment status 2 years later., Trial Registration: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. This study is registered at the Dutch CCMO register (https://www.toetsingonline.nl).

Striatal parvalbumin (PV) and cholinergic interneurons (CHIs) are poised to play major roles in behavior by coordinating the networks of medium spiny cells that relay motor output. However, the small numbers and scattered distribution of these cells have hindered direct assessment of their contribution to activity in networks of medium spiny neurons (MSNs) during behavior. Here, we build on recent improvements in single-cell calcium imaging combined with optogenetics to test the capacity of PVs and CHIs to affect MSN activity and behavior in mice engaged in voluntary locomotion. We find that PVs and CHIs have unique effects on MSN activity and dissociable roles in supporting movement. PV cells facilitate movement by refining the activation of MSN networks responsible for movement execution. CHIs, in contrast, synchronize activity within MSN networks to signal the end of a movement bout. These results provide new insights into the striatal network activity that supports movement.

CD148 is a transmembrane tyrosine phosphatase that is expressed at cell junctions. Recent studies have shown that CD148 associates with the cadherin/catenin complex and p120 catenin (p120) may serve as a substrate. However, the role of CD148 in cadherin cell-cell adhesion remains unknown. Therefore, here we addressed this issue using a series of stable cells and cell-based assays. Wild-type (WT) and catalytically inactive (CS) CD148 were introduced to A431D (lacking classical cadherins), A431D/E-cadherin WT (expressing wild-type E-cadherin), and A431D/E-cadherin 764AAA (expressing p120-uncoupled E-cadherin mutant) cells. The effects of CD148 in cadherin adhesion were assessed by Ca2+ switch and cell aggregation assays. Phosphorylation of E-cadherin/catenin complex and Rho family GTPase activities were also examined. Although CD148 introduction did not alter the expression levels and complex formation of E-cadherin, p120, and β-catenin, CD148 WT, but not CS, promoted cadherin contacts and strengthened cell-cell adhesion in A431D/E-cadherin WT cells. This effect was accompanied by an increase in Rac1, but not RhoA and Cdc42, activity and largely diminished by Rac1 inhibition. Further, we demonstrate that CD148 reduces the tyrosine phosphorylation of p120 and β-catenin; causes the dephosphorylation of Y529 suppressive tyrosine residue in Src, a well-known CD148 site, increasing Src activity and enhancing the phosphorylation of Y228 (a Src kinase site) in p120, in E-cadherin contacts. Consistent with these findings, CD148 dephosphorylated both p120 and β-catenin in vitro. The shRNA-mediated CD148 knockdown in A431 cells showed opposite effects. CD148 showed no effects in A431D and A431D/E-cadherin 764AAA cells. In aggregate, these findings provide the first evidence that CD148 promotes E-cadherin adhesion by regulating Rac1 activity concomitant with modulation of p120, β-catenin, and Src tyrosine phosphorylation. This effect requires E-cadherin and p120 association.