Search

Two-photon high-speed fluorescence calcium imaging stands as a mainstream technique in neuroscience for capturing neural activities with high spatiotemporal resolution. However, challenges arise from the inherent tradeoff between acquisition speed and image quality, grappling with a low signal-to-noise ratio (SNR) due to limited signal photon flux. Here, a contrast-enhanced video-rate volumetric system, integrating a tunable acoustic gradient (TAG) lens-based high-speed microscopy with a TAG-SPARK denoising algorithm is demonstrated. The former facilitates high-speed dense z-sampling at sub-micrometer-scale intervals, allowing the latter to exploit the spatial redundancy of z-slices for self-supervised model training. This spatial redundancy-based approach, tailored for 4D (xyzt) dataset, not only achieves >700% SNR enhancement but also retains fast-spiking functional profiles of neuronal activities. High-speed plus high-quality images are exemplified by in vivo Purkinje cells calcium observation, revealing intriguing dendritic-to-somatic signal convolution, i.e., similar dendritic signals lead to reverse somatic responses. This tailored technique allows for capturing neuronal activities with high SNR, thus advancing the fundamental comprehension of neuronal transduction pathways within 3D neuronal architecture., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched healthy controls completed two separate tasks that required learning about reward contingencies from trial-and-error. To probe the selectivity of reward learning processes, the tasks differed in their underlying structure: while one task measured incremental reward learning ability alone, the other allowed participants to use an alternative learning strategy based on episodic memory alongside incremental reward learning. We found that individuals with cerebellar ataxia were profoundly impaired at reward learning from trial-and-error feedback on both tasks, but retained the ability to learn to predict reward based on episodic memory. These findings provide evidence from humans for a specific and necessary role for the cerebellum in incremental learning of reward associations based on reinforcement. More broadly, the findings suggest that alongside its role in motor learning, the cerebellum likely operates in concert with the basal ganglia to support reinforcement learning from reward., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion 1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control., Competing Interests: Declaration of interests: All authors declare no competing interests.

Introduction: Previous research has identified that people with cerebellar ataxia (CA) showed impaired reward-related decision-making in the Iowa Gambling Task (IGT). To investigate the mechanisms underlying this impairment, we examined CA participants' combination of performance in the IGT, which predominantly tests reward seeking, and the modified IGT (mIGT), which mainly assesses punishment avoidance., Methods: Fifty participants with CA and one hundred controls completed the IGT and mIGT. Task performance in each of the five twenty-trial blocks was compared between groups and the learning rates were assessed with simple linear regressions. Each participant's IGT score and mIGT score were compared., Results: CA participants performed worse than controls in both the IGT and the mIGT, especially in the last block (IGT: -0.24 ± 10.05 vs. 3.88 ± 10.31, p = 0.041; mIGT: 2.72 ± 7.62 vs. 8.65 ± 8.64, p < 0.001). In contrast to the controls, those with CA did not significantly improve their scores over time in either task. Controls performed better in the mIGT than the IGT, while CA participants' scores in the two tasks showed no significant difference. IGT and mIGT performance did not correlate with ataxia severity or depressive symptoms., Conclusion: Individuals with CA showed impaired performance in both the IGT and mIGT, which indicates disruption in both short-term reward seeking and short-term punishment avoidance. Therefore, these results suggest that reduced sensitivity to long-term consequences drives the risky decision-making in CA., (Copyright © 2023. Published by Elsevier B.V.)

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2 dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

The cerebellum plays an important role in movement disorders, specifically in symptoms of ataxia, tremor, and dystonia. Understanding the physiological signals of the cerebellum contributes to insights into the pathophysiology of these movement disorders and holds promise in advancing therapeutic development. Non-invasive techniques such as electroencephalogram and magnetoencephalogram can record neural signals with high temporal resolution at the millisecond level, which is uniquely suitable to interrogate cerebellar physiology. These techniques have recently been implemented to study cerebellar physiology in healthy subjects as well as individuals with movement disorders. In the present review, we focus on the current understanding of cerebellar physiology using these techniques to study movement disorders., (© 2022. The Author(s).)

Essential Tremor (ET) is a prevalent neurological disease characterized by an 8-10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca 2+ ) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca 2+ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a "leaky channel" biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This 'leaky' RyR1 signature was not seen in control or Parkinson's disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca 2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca 2+ leak via RyR1 may contribute to tremor pathophysiology., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim of this chapter is to provide an overview of the advances and emerging techniques during these last 2 decades in the neurophysiological tests useful in cerebellar patients for clinical and research purposes. Clinically, patients exhibit various combinations of a vestibulocerebellar syndrome, a cerebellar cognitive affective syndrome and a cerebellar motor syndrome which will be discussed throughout this chapter. Cerebellar patients show abnormal Bereitschaftpotentials (BPs) and mismatch negativity. Cerebellar EEG is now being applied in cerebellar disorders to unravel impaired electrophysiological patterns associated within disorders of the cerebellar cortex. Eyeblink conditioning is significantly impaired in cerebellar disorders: the ability to acquire conditioned eyeblink responses is reduced in hereditary ataxias, in cerebellar stroke and after tumor surgery of the cerebellum. Furthermore, impaired eyeblink conditioning is an early marker of cerebellar degenerative disease. General rules of motor control suggest that optimal strategies are needed to execute voluntary movements in the complex environment of daily life. A high degree of adaptability is required for learning procedures underlying motor control as sensorimotor adaptation is essential to perform accurate goal-directed movements. Cerebellar patients show impairments during online visuomotor adaptation tasks. Cerebellum-motor cortex inhibition (CBI) is a neurophysiological biomarker showing an inverse association between cerebellothalamocortical tract integrity and ataxia severity. Ataxic gait is characterized by increased step width, reduced ankle joint range of motion, increased gait variability, lack of intra-limb inter-joint and inter-segmental coordination, impaired foot ground placement and loss of trunk control. Taken together, these techniques provide a neurophysiological framework for a better appraisal of cerebellar disorders., 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 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T-type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T-type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T-type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond., (© 2023 Praxis Precision Medicines Inc. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: The cerebellum has been identified as the key brain region that modulates reward processing in animal models. Consistently, we recently found that people with cerebellar ataxia have impulsive and compulsive behaviors (ICBs), the main symptoms related to abnormal reward processing. Due to the lack of a validated scale to quantitatively measure ICBs in cerebellar disorders, we aim to develop and validate a new scale, Cerebellar Impulsivity-Compulsivity Assessment (CIA)., Methods: We recruited 62 cerebellar ataxia cases, categorized into those with ICBs and those without. We developed a preliminary version of CIA, containing 17 questions. We studied the internal consistency, test-retest reliability, and inter-rater reliability to formulate the final version of CIA, which constitutes only 10 questions. The receiver operating characteristic curve (ROC) was generated to assess the sensitivity and specificity of CIA., Results: Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test-retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity., Interpretation: CIA is a novel tool to assess ICBs in cerebellar ataxia and broaden our understanding of the cerebellum-related cognitive and behavioral symptoms., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Tracking kinematic details of motor behaviors is a foundation to study the neuronal mechanism and biology of motor control. However, most of the physiological motor behaviors and movement disorders, such as gait, balance, tremor, dystonia, and myoclonus, are highly dependent on the overall momentum of the whole-body movements. Therefore, tracking the targeted movement and overall momentum simultaneously is critical for motor control research, but it remains an unmet need. Here, we introduce the intrinsic oscillatory property (IOP), a fundamental mechanical principle of physics, as a method for motion tracking in a force plate. The overall kinetic energy of animal motions can be transformed into the oscillatory amplitudes at the designed IOP frequency of the force plate, while the target movement has its own frequency features and can be tracked simultaneously. Using action tremor as an example, we reported that force plate-based IOP approach has superior performance and reliability in detecting both tremor severity and tremor frequency, showing a lower level of coefficient of variation (CV) compared with video- and accelerometer-based motion tracking methods and their combination. Under the locomotor suppression effect of medications, therapeutic effects on tremor severity can still be quantified by dynamically adjusting the overall locomotor activity detected by IOP. We further validated IOP method in optogenetic-induced movements and natural movements, confirming that IOP can represent the intensity of general rhythmic and nonrhythmic movements, thus it can be generalized as a common approach to study kinematics., Competing Interests: The authors have no conflict of interest to declare., (© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Enhanced cerebellar oscillations have recently been identified in essential tremor (ET) patients as a key pathophysiological change. Since ET is considered a heterogeneous group of diseases, we investigated whether cerebellar oscillations differ in ET subtypes (familial vs. sporadic). This study aims to determine cerebellar physiology in familial and sporadic ET. Using surface electroencephalogram, we studied cerebellar physiology in 40 ET cases (n = 22 familial and n = 18 sporadic) and 20 age-matched controls. Both familial and sporadic ET cases had an increase in the intensity of cerebellar oscillations when compared to controls. Interestingly, cerebellar oscillations correlated with tremor severity in familial ET but not in sporadic ET. Our study demonstrated that ET cases have enhanced cerebellar oscillations, and the different relationships between cerebellar oscillations and tremor severity in familial and sporadic ET suggest diverse cerebellar pathophysiology., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Essential tremor (ET) is one of the most common neurological disorders and can be highly disabling. In recent years, studies on the clinical perspectives and pathophysiology have advanced our understanding of ET. Specifically, clinical heterogeneity of ET, with co-existence of tremor and other neurological features such as dystonia, ataxia, and cognitive dysfunction, has been identified. The cerebellum has been found to be the key brain region for tremor generation, and structural alterations of the cerebellum have been extensively studied in ET. Finally, four main ET pathophysiologies have been proposed: 1) environmental exposures to β-carboline alkaloids and the consequent olivocerebellar hyper-excitation, 2) cerebellar GABA deficiency, 3) climbing fiber synaptic pathology with related cerebellar oscillatory activity, 4) extra-cerebellar oscillatory activity. While these four theories are not mutually exclusive, they can represent distinctive ET subtypes, indicating multiple types of abnormal brain circuitry can lead to action tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes β-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.

Background: Climbing fibers (CFs) innervate Purkinje cells (PCs) with 1:1 relationship to ensure proper cerebellar function. Although CFs abnormally extend into the parallel fiber domain of PC dendrites in essential tremor (ET), the architecture of CFs in relation to PCs has yet to be investigated in detail., Objective: The aim of this work was to study the architecture of CFs in relation to PCs in ET., Methods: The number of PC somas and PC dendrites that a single CF crossed was quantified in the postmortem cerebellum of 15 ET cases and 15 control cases., Results: In ET, CFs crossed a greater number of PC somas and PC dendrites than in control cases, raising the possibility that there is abnormal CF wiring onto the PCs. Interestingly, the increase in CF-PC crossings positively correlated with tremor severity., Conclusions: Patients with ET have increased CF crossings on PC dendrites. This abnormal architectural arrangement may contribute to synchronous brain activity and tremor. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Modulation of subthalamic nucleus (STN) firing patterns with injections of depolarizing currents into the STN is an important advance for the treatment of hypokinetic movement disorders, especially Parkinson's disease (PD). Chorea, ballism and dystonia are prototypical examples of hyperkinetic movement disorders. In our previous study, normal rats without nigro-striatal lesion were rendered hypokinetic with hyperpolarizing currents injected into the STN. Therefore, modulation of the firing pattern by injection of a hyperpolarizing current into the STN could be an effective treatment for hyperkinetic movement disorders. We investigated the effect of injecting a hyperpolarizing current into the STNs of two different types of hyperkinetic animal models and a patient with an otherwise uncontrollable hyperkinetic disorder. The two animal models included levodopa-induced hyperkinetic movement in parkinsonian rats (L-DOPA-induced dyskinesia model) and hyperkinesia induced by an intrastriatal injection of 3-nitropropionic acid (Huntington disease model), covering neurodegeneration-related as well as neurotoxin-induced derangement in the cortico-subcortical re-entrant loops. Delivering hyperpolarizing currents into the STN readily alleviated the hyperkinetic behaviors in the two animal models and in the clinical case, with an evident increase in subthalamic burst discharges in electrophysiological recordings. Application of a hyperpolarizing current into the STN via a Deep brain stimulation (DBS) electrode could be an effective general therapy for a wide spectrum of hyperkinetic movement disorders.

Conventional histological analysis and cell culture systems are insufficient to simulate in vivo physiological and pathological dynamics completely. Multiphoton microscopy (MPM) has become one of the most popular imaging modalities for biomedical study at cellular levels in vivo, advantages include high resolution, deep tissue penetration and minimal phototoxicity. We have designed an MPM imaging platform with a customized mouse eye holder and a stereotaxic stage for imaging ocular surface in vivo. Dual fluorescent protein reporter mouse enables visualization of cell nuclei, cell membranes, nerve fibers, and capillaries within the ocular surface. In addition to multiphoton fluorescence signals, acquiring second harmonic generation (SHG) simultaneously allows for the characterization of collagenous stromal architecture. This platform can be employed for intravital imaging with accurate positioning across the entire ocular surface, including cornea and conjunctiva.

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.

In this study, the physicochemical properties of an ammonium oxalate extraction pectin (AOP) from Premna microphylla turcz was investigated. Moreover, its cold gelation with undenatured whey protein concentrate (WPC) was studied at room temperature and different pHs. Characterizations of AOP demonstrated that AOP was a linear low-methoxyl pectin rich in homogalacturonan with low branching degree of RG-I, leading to its good gelling properties. Gelation between AOP and WPC was mainly investigated by turbidity measurement, FTIR, CLSM and ITC. The results showed that an optimal complex ratio for gelation was observed at 1:5 at pH 6.0. Moreover, AOP was the backbone of the composite gel and WPC might act as crosslinking agents through electrostatic or hydrophobic interaction at different pHs. When pH was around the pH Φ of the complex, composite gel was mainly constructed by electrostatic interaction. With the increase of pH, the electrostatic interaction between AOP and WPC gradually weakened, while the hydrophobic interaction constantly increased. When pH was higher than the pH c of the complex, composite gel was mainly formed by hydrophobic interaction. The results of this study are conducive to further utilization of Premna microphylla turcz pectin to develop related food products., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Tremor is the most common movement disorder; however, the pathophysiology of tremor remains elusive. While several neuropathological alterations in tremor disorders have been observed in post-mortem studies of human brains, a full understanding of the relationship between brain circuitry alterations and tremor requires testing in animal models. Additionally, tremor animal models are critical for our understanding of tremor pathophysiology, and/or to serve as a platform for therapy development., Methods: A PubMed search was conducted in May 2018 to identify published papers for review., Results: The methodology used in most studies on animal models of tremor lacks standardized measurement of tremor frequency and amplitude; instead, these studies are based on the visual inspection of phenotypes, which may fail to delineate tremor from other movement disorders such as ataxia. Of the animal models with extensive tremor characterization, harmaline-induced rodent tremor models provide an important framework showing that rhythmic and synchronous neuronal activities within the olivocerebellar circuit can drive action tremor. In addition, dopamine-depleted monkey and mouse models may develop rest tremor, highlighting the role of dopamine in rest tremor generation. Finally, other animal models of tremor have involvement of the cerebellar circuitry, leading to altered Purkinje cell physiology., Discussion: Both the cerebellum and the basal ganglia are likely to play a role in tremor generation. While the cerebellar circuitry can generate rhythmic movements, the nigrostriatal system is likely to modulate the tremor circuit. Tremor disorders are heterogeneous in nature. Therefore, each animal model may represent a subset of tremor disorders, which collectively can advance our understanding of tremor., Competing Interests: Funding: Dr. Pan is supported by the Ministry of Science and Technology in Taiwan: MOST 104-2314-B-002-076-MY3 and 107-2321-B-002-020 (principal investigator). Dr. Kuo has received funding from the National Institutes of Health: NINDS #K08 NS083738 (principal investigator) and #R01 NS104423 (principle investigator), and the Louis V. Gerstner Jr. Scholar Award, Parkinson’s Foundation, and International Essential Tremor Foundation. Conflicts of Interest: The authors report no conflict of interest. Ethics Statement: This study was reviewed by the authors' institutional ethics committee and was considered exempted from further review.

Changes in external light patterns can alter cell activities in peripheral tissues through slow entrainment of the central clock in suprachiasmatic nucleus (SCN). It remains unclear whether cells in otherwise photo-insensitive tissues can achieve rapid responses to changes in external light. Here we show that light stimulation of animals' eyes results in rapid activation of hair follicle stem cells with prominent hair regeneration. Mechanistically, light signals are interpreted by M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs), which signal to the SCN via melanopsin. Subsequently, efferent sympathetic nerves are immediately activated. Increased norepinephrine release in skin promotes hedgehog signaling to activate hair follicle stem cells. Thus, external light can directly regulate tissue stem cells via an ipRGC-SCN autonomic nervous system circuit. Since activation of sympathetic nerves is not limited to skin, this circuit can also facilitate rapid adaptive responses to external light in other homeostatic tissues., Competing Interests: The authors declare no conflict of interest.

Familial and sporadic essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes has yet to be studied. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes, a host of associated axonal changes, heterotopic PCs, and hairy basket ratings) in 60 ET cases and 30 controls. Familial ET was defined using both liberal criteria (n = 27) and conservative criteria (n = 20). When compared with controls, ET cases had lower PC counts, more torpedoes, more heterotopic PCs, a higher hairy basket rating, an increase in PC axonal collaterals, an increase in PC thickened axonal profiles, and an increase in PC axonal branching. Familial and sporadic ET had similar postmortem changes, with few exceptions, regardless of the definition criteria. The PC counts were marginally lower in familial than sporadic ET (respective p values = 0.059 [using liberal criteria] and 0.047 [using conservative criteria]). The PC thickened axonal profile count was marginally lower in familial ET than sporadic ET (respective p values = 0.037 [using liberal criteria] and 0.17 [using conservative criteria]), and the PC axonal branching count was marginally lower in familial than sporadic ET (respective p values = 0.045 [using liberal criteria] and 0.079 [using conservative criteria]). After correction for multiple comparisons, however, there were no significant differences. Overall, familial and sporadic ET cases share very similar cerebellar postmortem features. These data indicate that pathological changes in the cerebellum are a part of the pathophysiological cascade of events in both forms of ET.

Early onset and late onset essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes remains to be determined. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes and associated axonal changes, heterotopic PCs, and hairy basket ratings) in 30 ET cases with age of tremor onset <50 years, 30 ET cases with age of tremor onset ≥50 years, and 30 controls (total n = 90). We also used two alternative age of onset cut-points (<40 vs. ≥40 years, and <60 vs. ≥60 years) to define early onset vs. late onset ET. We found that ET cases with tremor onset <50 years and tremor onset ≥50 years had similar PC counts (8.78 ± 1.70 vs. 8.86 ± 1.24, p = 0.839), PC axonal torpedo counts (17.87 ± 18.27 [median =13.00] vs. 12.90 ± 10.60 [median =9.0], p = 0.486) and associated axonal pathology (all p values >0.05), heterotopic PC counts (9.90 ± 11.55 [median =6.00] vs. 5.40 ± 5.10 [median =3.50], p = 0.092), and hairy basket ratings (1.95 ± 0.62 [median =2.00] vs. 2.05 ± 0.92 [median =2.00], p = 0.314). When using the age of onset cut-points of 40 or 60 years, results were similar. Early onset and late onset ET cases share similar cerebellar postmortem features. These data do not support the notion that these age-of-onset related forms of ET represent distinct clinical-pathological entities.

Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson's disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy., Competing Interests: The authors have declared that no conflict of interest exists.

Essential tremor (ET) patients have abnormal climbing fiber (CF) synapses in the parallel fiber territory in the cerebellum, and these abnormal CF synapses are inversely correlated with tremor severity. We therefore examined CF synaptic pathology in ET cases with and without thalamic deep brain stimulation (DBS) and assessed the association with tremor severity. We found that CF synaptic pathology was inversely correlated with tremor severity in ET cases without DBS, and this correlation disappeared in ET cases with DBS. Our data suggest that DBS might have effects in modulating excitatory synapses in ET cerebellum, in addition to its symptomatic effects on tremor. Ann Neurol 2016;80:461-465., (© 2016 American Neurological Association.)

Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.

Parkinson's disease (PD) is one of the most prevalent movement disorder caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Deep brain stimulation (DBS) at the subthalamic nucleus (STN) has been a new and effective treatment of PD. It is interesting how a neurological disorder caused by the deficiency of a specific chemical substance (i.e., dopamine) from one site could be so successfully treated by a pure physical maneuver (i.e., DBS) at another site. STN neurons could discharge in the single-spike or the burst modes. A significant increase in STN burst discharges has been unequivocally observed in dopamine-deprived conditions such as PD, and was recently shown to have a direct causal relation with parkinsonian symptoms. The occurrence of burst discharges in STN requires enough available T-type Ca(2+) currents, which could bring the relatively negative membrane potential to the threshold of firing Na(+) spikes. DBS, by injection of negative currents into the extracellular space, most likely would depolarize the STN neuron and then inactivate the T-type Ca(2+) channel. Burst discharges are thus decreased and parkinsonian locomotor deficits ameliorated. Conversely, injection of positive currents into STN itself could induce parkinsonian locomotor deficits in animals without dopaminergic lesions. Local application of T-type Ca(2+) channel blockers into STN would also dramatically decrease the burst discharges and improve parkinsonian locomotor symptoms. Notably, zonisamide, which could inhibit T-type Ca(2+) currents in STN, has been shown to benefit PD patients in a clinical trial. From the pathophysiological perspectives, PD can be viewed as a prototypical disorder of "brain arrhythmias". Modulation of relevant ion channels by physical or chemical maneuvers may be important therapeutic considerations for PD and other diseases related to deranged neural rhythms.

We examine how haptic feedback could enable an implicit human-computer interaction, in the context of an audio stream listening use case where a device monitors a user's electrodermal activity for orienting responses to external interruptions. When such a response is detected, our previously developed system automatically places a bookmark in the audio stream for later resumption of listening. Here, we investigate two uses of haptic feedback to support this implicit interaction and mitigate effects of noisy (false-positive) bookmarking: (a) low-attention notification when a bookmark is placed, and (b) focused-attention display of bookmarks during resumptive navigation. Results show that haptic notification of bookmark placement, when paired with visual display of bookmark location, significant improves navigation time. Solely visual or haptic display of bookmarks elicited equivalent navigation time; however, only the inclusion of haptic display significantly increased accuracy. Participants preferred haptic notification over no notification at interruption time, and combined haptic and visual display of bookmarks to support navigation to their interrupted location at resumption time. Our contributions include an approach to handling noisy data in implicit HCI, an implementation of haptic notifications that signal implicit system behavior, and discussion of user mental models that may be active in this context.

Background: Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. Electroencephalogram (EEG) signals play a critical role in the diagnosis of epilepsy. Multichannel EEGs contain more information than do single-channel EEGs. Automatic detection algorithms for spikes or seizures have traditionally been implemented on single-channel EEG, and algorithms for multichannel EEG are unavailable., Methodology: This study proposes a physiology-based detection system for epileptic seizures that uses multichannel EEG signals. The proposed technique was tested on two EEG data sets acquired from 18 patients. Both unipolar and bipolar EEG signals were analyzed. We employed sample entropy (SampEn), statistical values, and concepts used in clinical neurophysiology (e.g., phase reversals and potential fields of a bipolar EEG) to extract the features. We further tested the performance of a genetic algorithm cascaded with a support vector machine and post-classification spike matching., Principal Findings: We obtained 86.69% spike detection and 99.77% seizure detection for Data Set I. The detection system was further validated using the model trained by Data Set I on Data Set II. The system again showed high performance, with 91.18% detection of spikes and 99.22% seizure detection., Conclusion: We report a de novo EEG classification system for seizure and spike detection on multichannel EEG that includes physiology-based knowledge to enhance the performance of this type of system.

Background and Purpose: ARHSP-TCC is characterized by progressive leg spasticity, ataxia, and cognitive dysfunction. Although mutations in the human SPG11 gene were identified as responsible for ARHSP-TCC, the cerebral fiber integrity has not been assessed systemically. The objective of this study was to assess cerebral fiber integrity and its clinical significance in patients with ARHSP-TCC., Materials and Methods: Five patients from 2 families who were clinically and genetically confirmed to have ARHSP-TCC were examined by neuropsychological evaluation and DSI of the brain. We performed voxel-based GFA analysis for global white matter evaluation, tractography-based analysis for tract-to-tract comparisons, and tract-specific analysis of the CST to evaluate microstructural integrity along the axonal direction., Results: The neuropsychological evaluation revealed widespread cognitive decline across all domains. Voxel-based analysis showed global reduction of GFA in the cerebral white matter. Tractography-based analysis revealed a significant reduction of the microstructural integrity in all neural fiber types, while commissure and association fibers had more GFA reduction than projection fibers (P < .00001). Prefrontal and motor portions of the CC were most severely affected among all fiber tracts (P < .00001, P = .018). Tract-specific analysis of the CST validated a "dying-back" phenomenon (R(2) = 0.68, P < .00001)., Conclusions: There was a characteristic gradation in the reduction of microstructural integrity among fiber types and within the CC in patients with the SPG11 mutation. The dying-back process in CST might explain the pathogenic mechanisms for ARHSP-TCC.

Biomedical data analytic system has played an important role in doing the clinical diagnosis for several decades. Today, it is an emerging research area of analyzing these big data to make decision support for physicians. This paper presents a parallelized web-based tool with cloud computing service architecture to analyze the epilepsy. There are many modern analytic functions which are wavelet transform, genetic algorithm (GA), and support vector machine (SVM) cascaded in the system. To demonstrate the effectiveness of the system, it has been verified by two kinds of electroencephalography (EEG) data, which are short term EEG and long term EEG. The results reveal that our approach achieves the total classification accuracy higher than 90%. In addition, the entire training time accelerate about 4.66 times and prediction time is also meet requirements in real time.

Objective: We have reported that intrinsic membrane properties, especially T-type Ca2+ channels, play a key role in the genesis of burst discharges in the subthalamic nucleus (STN) and parkinsonian locomotor symptoms. Whether deep brain stimulation (DBS) exerts its clinical benefits on Parkinson disease (PD) with changes in T currents or other conductances, however, remains elusive., Methods: Different stimulation protocols, including constant currents of opposite polarity, were applied to STN in vivo or in vitro, and the electrophysiological and behavioral effects were documented in normal and parkinsonian rodents. The effect of correlatively adjusted DBS protocols was also explored in 3 PD patients., Results: Delivery of negative constant current into STN dramatically ameliorated locomotor deficits in parkinsonian rats. It also depolarized STN neurons and decreased T-channel availability as well as burst discharges. In contrast, delivery of positive constant currents to STN induced PD-like locomotor deficits and increased STN burst discharges in normal rats. In addition, the therapeutic effect of DBS was greatly improved in 3 PD patients simply by increasing the pulse width from 60 to 240 microseconds, even at a lower stimulation frequency of 60 Hz., Interpretation: The increased tendency of STN burst discharges may by itself serve as a direct cause of parkinsonian locomotor deficits, even in the absence of deranged dopaminergic innervation. Effective DBS therapy in PD very likely relies on adequate depolarization, and consequent modification of the relevant ionic currents and discharge patterns, of STN neurons., (Copyright © 2012 American Neurological Association.)

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.

Background and Purpose: Deep brain stimulation (DBS) surgery has been performed using frame-based stereotaxy traditionally; however, in recent years, it has also been performed using frameless stereotaxy. The purpose of this study was to compare the experience at our centre in performing DBS surgery using frameless surgery for patients with Parkinson's disease with that of using frame-based surgery., Methods: Twenty-four patients with advanced Parkinson's disease underwent DBS surgery, 12 with frameless and 12 with frame-based stereotaxy. After identifying the subthalamus by microelectrode recording (MER), the DBS electrodes were implanted and connected to an implanted programmable generator in all patients. Programming was started 1 month after the operation and the outcome of the patients was followed up regularly for at least 12 months., Results: After 1 year of follow-up, the patients who received frameless surgery showed no difference in the degree of improvement in clinical motor function compared with the patients who received frame-based surgery (P = 0.819); the average improvement was 60.9% and 56.9%, respectively, in the stimulation alone/medication-off state, as evaluated by the Unified Parkinson's Disease Rating Scale-III motor subscore. However, the frameless group had significantly shorter total MER time (P = 0.0127) and a smaller number of trajectories (P = 0.0096) than the frame-based group., Conclusions: Our data indicate that frameless DBS surgery has a similar outcome when compared with frame-based surgery; however, frameless surgery can decrease the operation time, MER time, and MER trajectory number., (© 2010 The Author(s). Journal compilation © 2010 EFNS.)

Cortico-basal ganglia circuit model has been studied extensively after it was first proposed by Alexander and Crutcher in 1990. This model accurately predicted the hyperactivity of indirect pathway and subthalamic nucleus(STN) in the dopamine deficiency state of Parkinson's disease (PD), prompting the experimental approaches of lesioning STN in parkinsonian primates. Application of these successful experiences with STN lesions in the reversal of parkinsonian symptoms to human PD patients facilitates the development of STN deep brain stimulation (DBS), which has become one of the most important therapies for PD in recent years. Although the classical model of the cortico-basal ganglia circuits by Alexander and Crutcher has provided many important insights into the basal ganglia function, the functional role of cortico-subthalamic "hyperdirect" pathway in the circuits has been relatively neglected. The first part of this article summarizes recent development concerning the cortico-basal ganglia circuits, especially emphasizing the importance of the hyperdirect pathway. In the second part of this article, we would describe the analyses of gross corticobasal ganglia circuit electrophysiological findings, especially emphasizing the coherence between two oscillating signals. We would also discuss the correlation between these parameters and the motor dysfunction, and its pathophysiological implications in PD.

Nephrogenic systemic fibrosis (NSF) is an idiopathic, progressive, systemic fibrosis that occurs in patients with renal diseases. Recently, gadolinium-containing contrast (Gd-contrast) has become a suspected causal factor for NFS. This report discusses two female patients with end-stage renal disease, aged 70 and 51 years, respectively, who developed histologically proven NSF after exposure to Gd-contrast. Clinically, both patients were characterized by fibrosis and induration of skin and muscle mainly in the limbs with joint contracture. In the first case, NSF developed gradually after undergoing evaluation by Gd-contrast magnetic resonance imaging (MRI) and subsequent surgery for her urothelial carcinoma. In the second patient, NSF developed after undergoing evaluation by Gd-contrast MRI for her right shoulder bursitis with calcification, and the conditions of NSF continued to worsen after the surgical treatment of this right shoulder lesion. Although the role of Gd-contrast in NSF is still not well known, the correlation in our cases strongly suggests that it should be used with cautioned in patients with end-stage renal disease. Both of our patients underwent surgery before or during the development of NSF, indicating that the surgical procedure may be a contributing factor.