bluuebunny/crossref_metadata_2025 huggingface dataset:
Profiling of Differentially Expressed MicroRNAs in Saliva of Parkinson's Disease Patients
Authors: Jiang Yanyan , Chen Jing , Sun Yunchuang , Li Fan , Wei Luhua , Sun Wei , Deng Jianwen , Yuan Yun , Wang Zhaoxia
Published: December 2021

Objective: This study aims to identify differentially expressed salivary miRNAs and validate the diagnostic potential for idiopathic Parkinson's disease (PD). Also, the disease specificity of candidate miRNAs was evaluated between PD, multiple system atrophy (MSA), and essential tremor (ET).

Methods: We collected salivary samples from 50 PD, 20 ET, and 20 MSA patients, as well as 30 healthy controls (HCs). In the discovery phase, salivary miRNA microarray analysis was performed. In-silico analysis was used to investigate the target genes of differentially expressed miRNAs and clustered pathways. In validation phase, RT-qPCR was performed with samples from 30 PD patients and 30 HCs. Subsequently, we investigated candidate miRNAs in all recruited subjects. Receiver operating characteristic curve and Spearman correlation analysis was performed to determine diagnostic usefulness.

Results: We identified 43 miRNAs that were differentially expressed between 5 PD patients and 5 HCs by miRNA microarray analysis. Computational analysis revealed the target genes were clustered in the pathways associated with ubiquitin protein ligase activity. The result of RT-qPCR showed that the miR-29a-3p and miR-29c-3p were found to be significantly downregulated (p = 0.004, p = 0.027), whereas the miR-6756-5p was significantly upregulated in 30 PD patients compared with 30 HCs (p = 0.032). The miR-29a-3p expression level in PD patients was significantly lower than ET patients (p = 0.035), but higher than MSA patients (p < 0.0001). The diagnostic efficacy reached a little higher when the combination of miR-29a-3p and miR-29c-3p.

Conclusion: The miRNA combination of salivary miR-29a-3p and miR-29c-3p has potential to be a diagnostic biomarker for idiopathic PD.
Staff and Facility Utilization in Direct Patient Transfer to the Comprehensive Stroke Center: Testing a Real-Time Location System for Automatic Patient Pathway Characterization
Authors: Moreira Tiago , Furnica Alexander , Daemen Elke , Mazya Michael V. , Sjöstrand Christina , Kaijser Magnus , Loenen Evert van
Published: December 2021

Introduction: Starting reperfusion therapies as early as possible in acute ischemic strokes are of utmost importance to improve outcomes. The Comprehensive Stroke Centers (CSCs) can use surveys, shadowing personnel or perform journal analysis to improve logistics, which can be labor intensive, lack accuracy, and disturb the staff by requiring manual intervention. The aim of this study was to measure transport times, facility usage, and patient–staff colocalization with an automated real-time location system (RTLS).

Patients and Methods: We tested IR detection of patient wristbands and staff badges in parallel with a period when the triage of stroke patients was changed from admission to the emergency room (ER) to direct admission to neuroradiology.

Results: In total, 281 patients were enrolled. In 242/281 (86%) of cases, stroke patient logistics could be detected. Consistent patient–staff colocalizations were detected in 177/281 (63%) of cases. Bypassing the ER led to a significant decrease in median time neurologists spent with patients (from 15 to 9 min), but to an increase of the time nurses spent with patients (from 13 to 22 min; p = 0.036). Ischemic stroke patients used the most staff time (median 25 min) compared to hemorrhagic stroke patients (median 13 min) and stroke mimics (median 15 min).

Discussion: Time spent with patients increased for nurses, but decreased for neurologists after direct triage to the CSC. While lower in-hospital transport times were detected, time spent in neuroradiology (CT room and waiting) remained unchanged.

Conclusion: The RTLS could be used to measure the timestamps in stroke pathways and assist in staff allocation.
New Epidermal-Growth-Factor-Related Insights Into the Pathogenesis of Multiple Sclerosis: Is It Also Epistemology?
Authors: Scalabrino Giuseppe
Published: December 2021

Recent findings showing that epidermal growth factor (EGF) is significantly decreased in the cerebrospinal fluid (CSF) and spinal cord (SC) of living or deceased multiple sclerosis (MS) patients, and that its repeated administration to rodents with chemically- or virally-induced demyelination of the central nervous system (CNS) or experimental allergic encephalomyelitis (EAE) prevents demyelination and inflammatory reactions in the CNS, have led to a critical reassessment of the MS pathogenesis, partly because EGF is considered to have little or no role in immunology. EGF is the only myelinotrophic factor that has been tested in the CSF and spinal cord of MS patients, and it has been shown there is a good correspondence between liquid and tissue levels. This review: (a) briefly summarises the positive EGF effects on neural stem cells, oligodendrocyte cell lineage, and astrocytes in order to explain, at least in part, the biological basis of the myelin loss and remyelination failure in MS; and (b) after a short analysis of the evolution of the principle of cause-effect in the history of Western philosophy, highlights the lack of any experimental immune-, toxin-, or virus-mediated model that precisely reproduces the histopathological features and “clinical” symptoms of MS, thus underlining the inapplicability of Claude Bernard's crucial sequence of “observation, hypothesis, and hypothesis testing.” This is followed by a discussion of most of the putative non-immunologically-linked points of MS pathogenesis (abnormalities in myelinotrophic factor CSF levels, oligodendrocytes (ODCs), astrocytes, extracellular matrix, and epigenetics) on the basis of Popper's falsification principle, and the suggestion that autoimmunity and phologosis reactions (surely the most devasting consequences of the disease) are probably the last links in a chain of events that trigger the reactions. As it is likely that there is a lack of other myelinotrophic growth factors because myelinogenesis is controlled by various CNS and extra-CNS growth factors and other molecules within and outside ODCs, further studies are needed to investigate the role of non-immunological molecules at the time of the onset of the disease. In the words of Galilei, the human mind should be prepared to understand what nature has created.
Temporal Lobe Epilepsy and Psychiatric Comorbidity
Authors: Vinti Valerio , Dell'Isola Giovanni Battista , Tascini Giorgia , Mencaroni Elisabetta , Cara Giuseppe Di , Striano Pasquale , Verrotti Alberto
Published: December 2021

Most focal seizures originate in the temporal lobe and are commonly divided into mesial and lateral temporal epilepsy, depending upon the neuronal circuitry involved. The hallmark features of the mesial temporal epilepsy are aura, unconsciousness, and automatisms. Symptoms often overlap with the lateral temporal epilepsy. However, the latter present a less evident psychomotor arrest, frequent clones and dystonic postures, and common focal to bilateral tonic–clonic seizures. Sclerosis of the hippocampus is the most frequent cause of temporal lobe epilepsy (TLE). TLE is among all epilepsies the most frequently associated with psychiatric comorbidity. Anxiety, depression, and interictal dysphoria are recurrent psychiatric disorders in pediatric patients with TLE. In addition, these alterations are often combined with cognitive, learning, and behavioral impairment. These comorbidities occur more frequently in TLE with hippocampal sclerosis and with pharmacoresistance. According to the bidirectional hypothesis, the close relationship between TLE and psychiatric features should lead to considering common pathophysiology underlying these disorders. Psychiatric comorbidities considerably reduce the quality of life of these children and their families. Thus, early detection and appropriate management and therapeutic strategies could improve the prognosis of these patients. The aim of this review is to analyze TLE correlation with psychiatric disorders and its underlying conditions.
Event-Related Desynchronization and Corticomuscular Coherence Observed During Volitional Swallow by Electroencephalography Recordings in Humans
Authors: Koganemaru Satoko , Mizuno Fumiya , Takahashi Toshimitsu , Takemura Yuu , Irisawa Hiroshi , Matsuhashi Masao , Mima Tatsuya , Mizushima Takashi , Kansaku Kenji
Published: December 2021

Swallowing in humans involves many cortical areas although it is partly mediated by a series of brainstem reflexes. Cortical motor commands are sent to muscles during swallow. Previous works using magnetoencephalography showed event-related desynchronization (ERD) during swallow and corticomuscular coherence (CMC) during tongue movements in the bilateral sensorimotor and motor-related areas. However, there have been few analogous works that use electroencephalography (EEG). We investigated the ERD and CMC in the bilateral sensorimotor, premotor, and inferior prefrontal areas during volitional swallow by EEG recordings in 18 healthy human subjects. As a result, we found a significant ERD in the beta frequency band and CMC in the theta, alpha, and beta frequency bands during swallow in those cortical areas. These results suggest that EEG can detect the desynchronized activity and oscillatory interaction between the cortex and pharyngeal muscles in the bilateral sensorimotor, premotor, and inferior prefrontal areas during volitional swallow in humans.
Individual Differences in Sensorimotor Adaptation Are Conserved Over Time and Across Force-Field Tasks
Authors: Moore Robert T. , Cluff Tyler
Published: December 2021

Sensorimotor adaptation enables the nervous system to modify actions for different conditions and environments. Many studies have investigated factors that influence adaptation at the group level. There is growing recognition that individuals vary in their ability to adapt motor skills and that a better understanding of individual differences in adaptation may inform how motor skills are taught and rehabilitated. Here we examined individual differences in the adaptation of upper-limb reaching movements. We quantified the extent to which participants adapted their movements to a velocity-dependent force field during an initial session, at 24 h, and again 1-week later. Participants (n = 28) displayed savings, which was expressed as greater initial adaptation when re-exposed to the force field. Individual differences in adaptation across various stages of the experiment displayed weak-strong reliability, such that individuals who adapted to a greater extent in the initial session tended to do so when re-exposed to the force field. Our second experiment investigated if individual differences in adaptation are also present when participants adapt to different force fields or a force field and visuomotor rotation. Separate groups of participants adapted to position- and velocity-dependent force fields (Experiment 2a; n = 20) or a velocity-dependent force field and visuomotor rotation in a single session (Experiment 2b; n = 20). Participants who adapted to a greater extent to velocity-dependent forces tended to show a greater extent of adaptation when exposed to position-dependent forces. In contrast, correlations were weak between various stages of adaptation to the force-field and visuomotor rotation. Collectively, our study reveals individual differences in adaptation that are reliable across repeated exposure to the same force field and present when adapting to different force fields.
What’s “up”? Impaired Spatial Preposition Processing in Posterior Cortical Atrophy
Authors: Shebani Zubaida , Nestor Peter J. , Pulvermüller Friedemann
Published: December 2021

This study seeks to confirm whether lesions in posterior regions of the brain involved in visuo-spatial processing are of functional relevance to the processing of words with spatial meaning. We investigated whether patients with Posterior Cortical Atrophy (PCA), an atypical form of Alzheimer’s Disease which predominantly affects parieto-occipital brain regions, is associated with deficits in working memory for spatial prepositions. Case series of patients with PCA and matched healthy controls performed tests of immediate and delayed serial recall on words from three lexico-semantic word categories: number words (twelve), spatial prepositions (behind) and function words (e.g., shall). The three word categories were closely matched for a number of psycholinguistic and semantic variables including length, bi-/tri-gram frequency, word frequency, valence and arousal. Relative to controls, memory performance of PCA patients on short word lists was significantly impaired on spatial prepositions in the delayed serial recall task. These results suggest that lesions in posterior parieto-occipital regions specifically impair the processing of spatial prepositions. Our findings point to a pertinent role of posterior cortical regions in the semantic processing of words with spatial meaning and provide strong support for modality-specific semantic theories that recognize the necessary contributions of sensorimotor regions to conceptual semantic processing.
Facilitating Word Retrieval in Aphasia: Which Type of Cues for Which Aphasic Speakers?
Authors: Python Grégoire , Pellet Cheneval Pauline , Bonnans Caroline , Laganaro Marina
Published: December 2021

Background: Even if both phonological and semantic cues can facilitate word retrieval in aphasia, it remains unclear if their respective effectiveness varies according to the underlying anomic profile.

Aim: The aim of the present facilitation study is to compare the effect of phonological and semantic cues on picture naming accuracy and speed in different types of anomia.

Methods: In the present within-subject design study, 15 aphasic persons following brain damage underwent picture naming paradigms with semantic cues (categorically- or associatively related) and phonological cues (initial phoneme presented auditorily, visually or both).

Results: At the group level, semantic cueing was as effective as phonological cueing to significantly speed up picture naming. However, while phonological cues were effective regardless of the anomic profile, semantic cueing effects varied depending on the type of anomia. Participants with mixed anomia showed facilitation after both semantic categorical and associative cues, but individuals with lexical-phonological anomia only after categorical cues. Crucially, semantic cues were ineffective for participants with lexical-semantic anomia. These disparities were confirmed by categorical semantic facilitation decreasing when semantic/omission errors prevailed in the anomic profile, but increasing alongside phonological errors.

Conclusion: The effectiveness of phonological vs semantic cues seems related to the underlying anomic profile: phonological cues benefit any type of anomia, but semantic cues only lexical-phonological or mixed anomia.
Language Assessment in Multilingualism and Awake Neurosurgery
Authors: De Martino Maria , Talacchi Andrea , Capasso Rita , Mazzotta Annapina , Miceli Gabriele
Published: December 2021

Multilingualism has become a worldwide phenomenon that poses critical issues about the language assessment in patients undergoing awake neurosurgery in eloquent brain areas. The accuracy and sensitivity of multilingual perioperative language assessment procedures is crucial for a number of reasons: they should be appropriate to detect deficits in each of the languages spoken by the patient; they should be suitable to identify language-specific cortical regions; they should ensure that each of the languages of a multilingual patient is tested at an adequate and comparable level of difficulty. In clinical practice, a patient-tailored approach is generally preferred. This is a necessary compromise since it is impossible to predict all the possible language combinations spoken by individuals and thus the availability of standardized testing batteries is a potentially unattainable goal. On the other hand, this leads to high inconsistency in how different neurosurgical teams manage the linguistic features that determine similarity or distance between the languages spoken by the patient and that may constrain the neuroanatomical substrate of each language. The manuscript reviews the perioperative language assessment methodologies adopted in awake surgery studies on multilingual patients with brain tumor published from 1991 to 2021 and addresses the following issues: (1) The language selected for the general neuropsychological assessment of the patient. (2) The procedures adopted to assess the dimensions that may constrain language organization in multilingual speakers: age and type of acquisition, exposure, proficiency, and use of the different languages. (3) The type of preoperative language assessment used for all the languages spoken by the patient. (4) The linguistic tasks selected in the intraoperative setting. The reviewed data show a great heterogeneity in the perioperative clinical workup with multilingual patients. The only exception is the task used during language mapping, as the picture naming task is highly preferred. The review highlights that an objective and accurate description of both the linguistic profile of multilingual patients and the specific properties of the languages under scrutiny can profitably support clinical management and decision making in multilingual awake neurosurgery settings.
Influence of Atomoxetine on Relationship Between ADHD Symptoms and Prefrontal Cortex Activity During Task Execution in Adult Patients
Authors: Sugimoto Atsunori , Suzuki Yutaro , Yoshinaga Kiyohiro , Orime Naoki , Hayashi Taketsugu , Egawa Jun , Ono Shin , Sugai Takuro , Someya Toshiyuki
Published: December 2021

Objective: We conducted this non-randomized prospective interventional study to clarify the relationship between improved attention-deficit hyperactivity disorder (ADHD) symptoms and regional brain activity.

Methods: Thirty-one adult patients underwent near-infrared spectroscopy examinations during a go/no-go task, both before and 8 weeks after atomoxetine administration.

Results: Clinical symptoms, neuropsychological results of the go/no-go task, and bilateral lateral prefrontal activity significantly changed. A positive correlation was observed between right dorsolateral prefrontal cortex activity and Conners’ Adult ADHD Rating Scales scores. Before atomoxetine administration, no correlations between prefrontal cortex activity and clinical symptoms were observed in all cases. When participants were divided into atomoxetine-responder and non-responder groups, a positive correlation was observed between prefrontal cortex activity and clinical symptoms in the non-responder group before treatment but not in the responder group, suggesting that non-responders can activate the prefrontal cortex without atomoxetine.

Conclusions: Individuals with increased ADHD symptoms appear to recruit the right dorsolateral prefrontal cortex more strongly to perform the same task than those with fewer symptoms. In clinical settings, individuals with severe symptoms are often observed to perform more difficultly when performing the tasks which individuals with mild symptoms can perform easily. The atomoxetine-responder group was unable to properly activate the right dorsolateral prefrontal cortex when necessary, and the oral administration of atomoxetine enabled these patients to activate this region. In brain imaging studies of heterogeneous syndromes such as ADHD, the analytical strategy used in this study, involving drug-responsivity grouping, may effectively increase the signal-to-noise ratio.
Deep Brain Stimulation of the Forel’s Field for Dystonia: Preliminary Results
Authors: Horisawa Shiro , Kohara Kotaro , Murakami Masato , Fukui Atsushi , Kawamata Takakazu , Taira Takaomi
Published: December 2021

The field of Forel (FF) is a subthalamic area through which the pallidothalamic tracts originating from the globus pallidus internus (GPi) traverse. The FF was used as a stereotactic surgical target (ablation and stimulation) to treat cervical dystonia in the 1960s and 1970s. Although recent studies have reappraised the ablation and stimulation of the pallidothalamic tract at FF for Parkinson’s disease, the efficacy of deep brain stimulation of FF (FF-DBS) for dystonia has not been well investigated. To confirm the efficacy and stimulation-induced adverse effects of FF-DBS, three consecutive patients with medically refractory dystonia who underwent FF-DBS were analyzed (tongue protrusion dystonia, cranio-cervico-axial dystonia, and hemidystonia). Compared to the Burke-Fahn-Marsden Dystonia Rating Scale-Movement Scale scores before surgery (23.3 ± 12.7), improvements were observed at 1 week (8.3 ± 5.9), 3 months (5.3 ± 5.9), and 6 months (4.7 ± 4.7, p = 0.0282) after surgery. Two patients had stimulation-induced complications, including bradykinesia and postural instability, all well controlled by stimulation adjustments.
The Effects of Working Memory Load on Auditory Distraction in Adults With Attention Deficit Hyperactivity Disorder
Authors: Blomberg Rina , Johansson Capusan Andrea , Signoret Carine , Danielsson Henrik , Rönnberg Jerker
Published: December 2021

Cognitive control provides us with the ability tointer alia, regulate the locus of attention and ignore environmental distractions in accordance with our goals. Auditory distraction is a frequently cited symptom in adults with attention deficit hyperactivity disorder (aADHD)–yet few task-based fMRI studies have explored whether deficits in cognitive control (associated with the disorder) impedes on the ability to suppress/compensate for exogenously evoked cortical responses to noise in this population. In the current study, we explored the effects of auditory distraction as function of working memory (WM) load. Participants completed two tasks: an auditory target detection (ATD) task in which the goal was to actively detect salient oddball tones amidst a stream of standard tones in noise, and a visualn-back task consisting of 0-, 1-, and 2-back WM conditions whilst concurrently ignoring the same tonal signal from the ATD task. Results indicated that our sample of young aADHD (n= 17), compared to typically developed controls (n= 17), had difficulty attenuating auditory cortical responses to the task-irrelevant sound when WM demands were high (2-back). Heightened auditory activity to task-irrelevant sound was associated with both poorer WM performance and symptomatic inattentiveness. In the ATD task, we observed a significant increase in functional communications between auditory and salience networks in aADHD. Because performance outcomes were on par with controls for this task, we suggest that this increased functional connectivity in aADHD was likely an adaptive mechanism for suboptimal listening conditions. Taken together, our results indicate that aADHD are more susceptible to noise interference when they are engaged in a primary task. The ability to cope with auditory distraction appears to be related to the WM demands of the task and thus the capacity to deploy cognitive control.
Structural and Functional Abnormalities in Knee Osteoarthritis Pain Revealed With Multimodal Magnetic Resonance Imaging
Authors: Guo Hua , Wang Yuqing , Qiu Lihua , Huang Xiaoqi , He Chengqi , Zhang Junran , Gong Qiyong
Published: December 2021

The knee osteoarthritis (KOA) pain is the most common form of arthritis pain affecting millions of people worldwide. Long-term KOA pain causes motor impairment and affects affective and cognitive functions. However, little is known about the structural and functional abnormalities induced by long-term KOA pain. In this work, high-resolution structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) data were acquired in patients with KOA and age-, sex-matched healthy controls (HC). Gray matter volume (GMV) and fractional amplitude of low-frequency fluctuation (fALFF) were used to study the structural and functional abnormalities in patients with KOA. Compared with HC, patients with KOA showed reduced GMV in bilateral insula and bilateral hippocampus, and reduced fALFF in left cerebellum, precentral gyrus, and the right superior occipital gyrus. Patients with KOA also showed increased fALFF in left insula and bilateral hippocampus. In addition, the abnormal GMV in left insula and fALFF in left fusiform were closely correlated with the pain severity or disease duration. These results indicated that long KOA pain leads to brain structural and functional impairments in motor, visual, cognitive, and affective functions that related to brain areas. Our findings may facilitate to understand the neural basis of KOA pain and the future therapy to relieve disease symptoms.
Difference in Analgesic Effects of Repetitive Transcranial Magnetic Stimulation According to the Site of Pain
Authors: Mori Nobuhiko , Hosomi Koichi , Nishi Asaya , Dong Dong , Yanagisawa Takufumi , Khoo Hui Ming , Tani Naoki , Oshino Satoru , Saitoh Youichi , Kishima Haruhiko
Published: December 2021

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex for neuropathic pain has been shown to be effective, according to systematic reviews and therapeutic guidelines. However, our large, rigorous, investigator-initiated, registration-directed clinical trial failed to show a positive primary outcome, and its subgroup analysis suggested that the analgesic effect varied according to the site of pain. The aim of this study was to investigate the differences in analgesic effects of rTMS for neuropathic pain between different pain sites by reviewing our previous clinical trials. We included three clinical trials in this mini meta-analysis: a multicenter randomized controlled trial at seven hospitals (N = 64), an investigator-initiated registration-directed clinical trial at three hospitals (N = 142), and an exploratory clinical trial examining different stimulation parameters (N = 22). The primary efficacy endpoint (change in pain scale) was extracted for each patient group with pain in the face, upper limb, or lower limb, and a meta-analysis of the efficacy of active rTMS against sham stimulation was performed. Standardized mean difference (SMD) with 95% confidence interval (CI) was calculated for pain change using a random-effects model. The analgesic effect of rTMS for upper limb pain was favorable (SMD = −0.45, 95% CI: −0.77 to −0.13). In contrast, rTMS did not produce significant pain relief on lower limb pain (SMD = 0.04, 95% CI: −0.33 to 0.41) or face (SMD = −0.24, 95% CI: −1.59 to 1.12). In conclusion, these findings suggest that rTMS provides analgesic effects in patients with neuropathic pain in the upper limb, but not in the lower limb or face, under the conditions of previous clinical trials. Owing to the main limitation of small number of studies included, many aspects should be clarified by further research and high-quality studies in these patients.
Comparing the Performance of Two Radiomic Models to Predict Progression and Progression Speed of White Matter Hyperintensities
Authors: Shao Yuan , Ruan Jingru , Xu Yuyun , Shu Zhenyu , He Xiaodong
Published: December 2021

Purpose: The aim of this study was to compare two radiomic models in predicting the progression of white matter hyperintensity (WMH) and the speed of progression from conventional magnetic resonance images.

Methods: In this study, 232 people were retrospectively analyzed at Medical Center A (training and testing groups) and Medical Center B (external validation group). A visual rating scale was used to divide all patients into WMH progression and non-progression groups. Two regions of interest (ROIs)—ROI whole-brain white matter (WBWM) and ROI WMH penumbra (WMHp)—were segmented from the baseline image. For predicting WMH progression, logistic regression was applied to create radiomic models in the two ROIs. Then, age, sex, clinical course, vascular risk factors, and imaging factors were incorporated into a stepwise regression analysis to construct the combined diagnosis model. Finally, the presence of a correlation between radiomic findings and the speed of progression was analyzed.

Results: The area under the curve (AUC) was higher for the WMHp-based radiomic model than the WBWM-based radiomic model in training, testing, and validation groups (0.791, 0.768, and 0.767 vs. 0.725, 0.693, and 0.691, respectively). The WBWM-based combined model was established by combining age, hypertension, and rad-score of the ROI WBWM. Also, the WMHp-based combined model is built by combining the age and rad-score of the ROI WMHp. Compared with the WBWM-based model (AUC = 0.779, 0.716, 0.673 in training, testing, and validation groups, respectively), the WMHp-based combined model has higher diagnostic efficiency and better generalization ability (AUC = 0.793, 0.774, 0.777 in training, testing, and validation groups, respectively). The speed of WMH progression was related to the rad-score from ROI WMHp (r = 0.49) but not from ROI WBWM.

Conclusion: The heterogeneity of the penumbra could help identify the individuals at high risk of WMH progression and the rad-score of it was correlated with the speed of progression.
Temporal Clustering of Skin Sympathetic Nerve Activity Bursts in Acute Myocardial Infarction Patients
Authors: Liu Chun , Lee Chien-Hung , Lin Shien-Fong , Tsai Wei-Chung
Published: December 2021

Backgrounds: Acute myocardial infarction (AMI) affects the autonomic nervous system (ANS) function. The aim of our study is to detect the particular patterns of ANS regulation in AMI. We hypothesize that altered ANS regulation in AMI patients causes synchronized neural discharge (clustering phenomenon) detected by non-invasive skin sympathetic nerve activity (SKNA).

Methods: Forty subjects, including 20 AMI patients and 20 non-AMI controls, participated in the study. The wide-band bioelectrical signals (neuECG) were continuously recorded on the body surface for 5 min. SKNA was signal processed to depict the envelope of SKNA (eSKNA). By labeling the clusters, the AMI subjects were separated into non-AMI, non-cluster appearing (AMINCA), and cluster appearing (AMICA) groups.

Results: The average eSKNA was significantly correlated with HRV low-frequency (LF) power (rho = −0.336) and high-frequency power (rho = −0.372). The cross-comparison results demonstrated that eSKNA is a valid surrogate marker to assess ANS in AMI patients. The frequency of cluster occurrence was 0.01–0.03 Hz and the amplitude was about 3 μV. The LF/HF ratio of AMICA (median: 1.877; Q1–Q3: 1.483–2.413) revealed significantly lower than AMINCA (median: 3.959; Q1–Q3: 1.840–6.562). The results suggest that the SKNA clustering is a unique temporal pattern of ANS synchronized discharge, which could indicate the lower sympathetic status (by HRV) in AMI patients.

Conclusion: This is the first study to identify SKNA clustering phenomenon in AMI patients. Such a synchronized nerve discharge pattern could be detected with non-invasive SKNA signals. SKNA temporal clustering could be a novel biomarker to classify ANS regulation ability in AMI patients.

Clinical and Translational Significance: SKNA is higher in AMI patients than in control and negatively correlates with parasympathetic parameters. SKNA clustering is associated with a lower LF/HF ratio that has been shown to correlate with sudden cardiac death in AMI. The lack of SKNA temporal clustering could indicate poor ANS regulation in AMI patients.
A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases
Authors: Fischell Jonathan M. , Fishman Paul S.
Published: December 2021

Despite major advancements in gene therapy technologies, there are no approved gene therapies for diseases which predominantly effect the brain. Adeno-associated virus (AAV) vectors have emerged as the most effective delivery vector for gene therapy owing to their simplicity, wide spread transduction and low immunogenicity. Unfortunately, the blood–brain barrier (BBB) makes IV delivery of AAVs, to the brain highly inefficient. At IV doses capable of widespread expression in the brain, there is a significant risk of severe immune-mediated toxicity. Direct intracerebral injection of vectors is being attempted. However, this method is invasive, and only provides localized delivery for diseases known to afflict the brain globally. More advanced methods for AAV delivery will likely be required for safe and effective gene therapy to the brain. Each step in AAV delivery, including delivery route, BBB transduction, cellular tropism and transgene expression provide opportunities for innovative solutions to optimize delivery efficiency. Intra-arterial delivery with mannitol, focused ultrasound, optimized AAV capsid evolution with machine learning algorithms, synthetic promotors are all examples of advanced strategies which have been developed in pre-clinical models, yet none are being investigated in clinical trials. This manuscript seeks to review these technological advancements, and others, to improve AAV delivery to the brain, and to propose novel strategies to build upon this research. Ultimately, it is hoped that the optimization of AAV delivery will allow for the human translation of many gene therapies for neurodegenerative and other neurologic diseases.
Three-Dimensional Iron Oxide Nanoparticle-Based Contrast-Enhanced Magnetic Resonance Imaging for Characterization of Cerebral Arteriogenesis in the Mouse Neocortex
Authors: de Bortoli Till , Boehm-Sturm Philipp , Koch Stefan P. , Nieminen-Kelhä Melina , Wessels Lars , Mueller Susanne , Ielacqua Giovanna D. , Klohs Jan , Vajkoczy Peter , Hecht Nils
Published: December 2021

Purpose: Subsurface blood vessels in the cerebral cortex have been identified as a bottleneck in cerebral perfusion with the potential for collateral remodeling. However, valid techniques for non-invasive, longitudinal characterization of neocortical microvessels are still lacking. In this study, we validated contrast-enhanced magnetic resonance imaging (CE-MRI) for in vivo characterization of vascular changes in a model of spontaneous collateral outgrowth following chronic cerebral hypoperfusion.

Methods: C57BL/6J mice were randomly assigned to unilateral internal carotid artery occlusion or sham surgery and after 21 days, CE-MRI based on T2*-weighted imaging was performed using ultra-small superparamagnetic iron oxide nanoparticles to obtain subtraction angiographies and steady-state cerebral blood volume (ss-CBV) maps. First pass dynamic susceptibility contrast MRI (DSC-MRI) was performed for internal validation of ss-CBV. Further validation at the histological level was provided by ex vivo serial two-photon tomography (STP).

Results: Qualitatively, an increase in vessel density was observed on CE-MRI subtraction angiographies following occlusion; however, a quantitative vessel tracing analysis was prone to errors in our model. Measurements of ss-CBV reliably identified an increase in cortical vasculature, validated by DSC-MRI and STP.

Conclusion: Iron oxide nanoparticle-based ss-CBV serves as a robust, non-invasive imaging surrogate marker for neocortical vessels, with the potential to reduce and refine preclinical models targeting the development and outgrowth of cerebral collateralization.
Plasma Cell-Free DNA Methylomics of Bipolar Disorder With and Without Rapid Cycling
Authors: Ho Ada Man-Choi , Winham Stacey J. , McCauley Bryan M. , Kundakovic Marija , Robertson Keith D. , Sun Zhifu , Ordog Tamas , Webb Lauren M. , Frye Mark A. , Veldic Marin
Published: December 2021

Rapid cycling (RC) burdens bipolar disorder (BD) patients further by causing more severe disability and increased suicidality. Because diagnosing RC can be challenging, RC patients are at risk of rapid decline due to delayed suitable treatment. Here, we aimed to identify the differences in the circulating cell-free DNA (cfDNA) methylome between BD patients with and without RC. The cfDNA methylome could potentially be developed as a diagnostic test for BD RC. We extracted cfDNA from plasma samples of BD1 patients (46 RC and 47 non-RC). cfDNA methylation levels were measured by 850K Infinium MethylationEPIC array. Principal component analysis (PCA) was conducted to assess global differences in methylome. cfDNA methylation levels were compared between RC groups using a linear model adjusted for age and sex. PCA suggested differences in methylation profiles between RC groups (p = 0.039) although no significant differentially methylated probes (DMPs; q > 0.15) were found. The top four CpG sites which differed between groups at p < 1E-05 were located in CGGPB1, PEX10, NR0B2, and TP53I11. Gene set enrichment analysis (GSEA) on top DMPs (p < 0.05) showed significant enrichment of gene sets related to nervous system tissues, such as neurons, synapse, and glutamate neurotransmission. Other top notable gene sets were related to parathyroid regulation and calcium signaling. To conclude, our study demonstrated the feasibility of utilizing a microarray method to identify circulating cfDNA methylation sites associated with BD RC and found the top differentially methylated CpG sites were mostly related to the nervous system and the parathyroid.
Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review
Authors: Poulin-Brière Amélie , Rezaei Edris , Pozzi Silvia
Published: December 2021

Amyotrophic Lateral Sclerosis (ALS) is a mid-life onset neurodegenerative disease that manifests its symptomatology with motor impairments and cognitive deficits overlapping with Frontotemporal Lobar Degeneration (FTLD). The etiology of ALS remains elusive, with various mechanisms and cellular targets implicated, and no treatment can reverse or stop the progression of the pathology. Therapeutic interventions based on passive immunization are gaining attention for neurodegenerative diseases, and FDA recently approved the first antibody-based approach for Alzheimer's disease. The present systematic review of the literature aims to highlight the efforts made over the past years at developing antibody-based strategies to cure ALS. Thirty-one original research papers have been selected where the therapeutic efficacy of antibodies were investigated and described in patients and animal models of ALS. Antibody-based interventions analyzed, target both extracellular molecules implicated in the pathology and intracellular pathogenic proteins known to drive the disease, such as SOD1, TDP-43 or C9ORF72 repeats expansions. The potentials and limitations of these therapeutic interventions have been described and discussed in the present review.
Refinement of Active and Passive Membrane Properties of Layer V Pyramidal Neurons in Rat Primary Motor Cortex During Postnatal Development
Authors: Perez-García Patricia , Pardillo-Díaz Ricardo , Geribaldi-Doldán Noelia , Gómez-Oliva Ricardo , Domínguez-García Samuel , Castro Carmen , Nunez-Abades Pedro , Carrascal Livia
Published: December 2021

Achieving the distinctive complex behaviors of adult mammals requires the development of a great variety of specialized neural circuits. Although the development of these circuits begins during the embryonic stage, they remain immature at birth, requiring a postnatal maturation process to achieve these complex tasks. Understanding how the neuronal membrane properties and circuits change during development is the first step to understand their transition into efficient ones. Thus, using whole cell patch clamp recordings, we have studied the changes in the electrophysiological properties of layer V pyramidal neurons of the rat primary motor cortex during postnatal development. Among all the parameters studied, only the voltage threshold was established at birth and, although some of the changes occurred mainly during the second postnatal week, other properties such as membrane potential, capacitance, duration of the post-hyperpolarization phase or the maximum firing rate were not defined until the beginning of adulthood. Those modifications lead to a decrease in neuronal excitability and to an increase in the working range in young adult neurons, allowing more sensitive and accurate responses. This maturation process, that involves an increase in neuronal size and changes in ionic conductances, seems to be influenced by the neuronal type and by the task that neurons perform as inferred from the comparison with other pyramidal and motor neuron populations.
Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy
Authors: Roy Achira , Han Victor Z. , Bard Angela M. , Wehle Devin T. , Smith Stephen E. P. , Ramirez Jan-Marino , Kalume Franck , Millen Kathleen J.
Published: December 2021

Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA, encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo, we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.
SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice
Authors: Lutz Anne-Kathrin , Pérez Arévalo Andrea , Ioannidis Valentin , Stirmlinger Nadine , Demestre Maria , Delorme Richard , Bourgeron Thomas , Boeckers Tobias M.
Published: December 2021

SHANK2 (ProSAP1) is a postsynaptic scaffolding protein of excitatory synapses in the central nervous system and implicated in the development of autism spectrum disorders (ASD). Patients with mutations in SHANK2 show autism-like behaviors, developmental delay, and intellectual disability. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying a heterozygous deletion of SHANK2 and from the unaffected parents. In patient hiPSCs and derived neurons SHANK2 mRNA and protein expression was reduced. During neuronal maturation, a reduction in growth cone size and a transient increase in neuronal soma size were observed. Neuronal proliferation was increased, and apoptosis was decreased in young and mature neurons. Additionally, mature patient hiPSC-derived neurons showed dysregulated excitatory signaling and a decrease of a broad range of signaling molecules of the ERK-MAP kinase pathway. These findings could be confirmed in brain samples from Shank2(−/−) mice, which also showed decreased mGluR5 and phospho-ERK1/2 expression. Our study broadens the current knowledge of SHANK2-related ASD. We highlight the importance of excitatory-inhibitory balance and mGluR5 dysregulation with disturbed downstream ERK1/2 signaling in ASD, which provides possible future therapeutic strategies for SHANK2-related ASD.
Genetic Code Expansion and Click-Chemistry Labeling to Visualize GABA-A Receptors by Super-Resolution Microscopy
Authors: Kuhlemann Alexander , Beliu Gerti , Janzen Dieter , Petrini Enrica Maria , Taban Danush , Helmerich Dominic A. , Doose Sören , Bruno Martina , Barberis Andrea , Villmann Carmen , Sauer Markus , Werner Christian
Published: December 2021

Fluorescence labeling of difficult to access protein sites, e.g., in confined compartments, requires small fluorescent labels that can be covalently tethered at well-defined positions with high efficiency. Here, we report site-specific labeling of the extracellular domain of γ-aminobutyric acid type A (GABA-A) receptor subunits by genetic code expansion (GCE) with unnatural amino acids (ncAA) combined with bioorthogonal click-chemistry labeling with tetrazine dyes in HEK-293-T cells and primary cultured neurons. After optimization of GABA-A receptor expression and labeling efficiency, most effective variants were selected for super-resolution microscopy and functionality testing by whole-cell patch clamp. Our results show that GCE with ncAA and bioorthogonal click labeling with small tetrazine dyes represents a versatile method for highly efficient site-specific fluorescence labeling of proteins in a crowded environment, e.g., extracellular protein domains in confined compartments such as the synaptic cleft.
Brain Activity Reflects Subjective Response to Delayed Input When Using an Electromyography-Controlled Robot
Authors: Kim Hyeonseok , Kim Yeongdae , Miyakoshi Makoto , Stapornchaisit Sorawit , Yoshimura Natsue , Koike Yasuharu
Published: December 2021

In various experimental settings, electromyography (EMG) signals have been used to control robots. EMG-based robot control requires intrinsic parameters for control, which makes it difficult for users to understand the input protocol. When a proper input is not provided, the response time of the system varies; as such, the user’s subjective delay should be investigated regardless of the actual delay. In this study, we investigated the influence of the subjective perception of delay on brain activation. Brain recordings were taken while subjects used EMG signals to control a robot hand, which requires a basic processing delay. We used muscle synergy for the grip command of the robot hand. After controlling the robot by grasping their hand, one of four additional delay durations (0 ms, 50 ms, 125 ms, and 250 ms) was applied in every trial, and subjects were instructed to answer whether the delay was natural, additional, or whether they were not sure. We compared brain activity based on responses (“sure” and “not sure”). Our results revealed a significant power difference in the theta band of the parietal lobe, and this time range included the interval in which the subjects could not feel the delay. Our study provides important insights that should be considered when constructing an adaptive system and evaluating its usability.