Brain Sciences — Open Access Journal

Background: Patients with Fabry’s disease (FD) may be asymptomatic or show a spectrum of clinical manifestations, including cerebrovascular disease, mainly affecting posterior circulation. Few and conflicting studies on cerebral blood flow (CBF) velocity by transcranial Doppler sonography (TCD) in asymptomatic FD (aFD) subjects have been published. Our study aims to assess TCD in aFD subjects to identify any preclinical CBF change. Methods: A total of 30 aFD subjects were consecutively recruited and compared to 28 healthy controls. Brain magnetic resonance imaging was normal in all participants. TCD was used to study blood flow velocity and indices of resistance of intracranial arteries from the middle cerebral artery (MCA), bilaterally, and from the basilar artery (BA). Cerebral vasomotor reactivity (CVR) was also evaluated from MCA. Results: No difference was found between groups for MCA parameters of CBF velocity and CVR. Compared to controls, a higher mean blood flow velocity and a lower resistance index from BA were observed in FD subjects. No correlation was found between any BA-derived TCD parameter and the level of lyso-globotriaosylceramide. Conclusions: aFD subjects show evidence of altered CBF velocity in posterior circulation. Preclinical detection of neurovascular involvement in FD might allow appropriate management and prevention of future cerebrovascular complications and disability. Full article

Valproic acid (VPA) is a multifunctional medication used for the treatment of epilepsy, mania associated with bipolar disorder, and migraine. The pharmacological effects of VPA involve a variety of neurotransmitter and cell signaling systems, but the molecular mechanisms underlying its clinical efficacy is to date largely unknown. In this study, we used the isobaric tags for relative and absolute quantitation shotgun proteomic analysis to screen differentially expressed proteins in VPA-treated SH-SY5Y cells. We identified changes in the expression levels of multiple proteins involved in Alzheimer’s disease, Parkinson’s disease, chromatin remodeling, controlling gene expression via the vitamin D receptor, ribosome biogenesis, ubiquitin-mediated proteolysis, and the mitochondrial oxidative phosphorylation and electron transport chain. Our data indicate that VPA may modulate the differential expression of proteins involved in mitochondrial function and vitamin D receptor-mediated chromatin transcriptional regulation and proteins implicated in the pathogenesis of neurodegenerative diseases. Full article

In this study, we investigated the associations between implicit associative learning with the cortisol and salivary alpha-amylase (sAA) stress response to an acute stressor as well as their associations with attention. Eighty one healthy adults (25 male) participated and either performed the socially evaluated cold-pressor test (SECPT) or a warm-water control task (WWT). Either prior to or immediately after the SECPT/WWT, participants implicitly learned digit-symbol pairs. A not-previously announced recall test was conducted about 20 min after the SECPT/WWT. Attention was assessed by means of a Stroop task at nine time points over the course of the experiment. Memory recall performance was not significantly associated with the acquisition time point (pre or post stressor) and did not significantly differ between the responder groups (i.e., non-responders, sAA-and-cortisol responders, only sAA responders, and only cortisol responders). Attentional performance increased throughout the experiment (i.e., reaction times in the Stroop task decreased). No differences in the attentional time course were found between the responder groups. However, some associations were found (p_uncorrected < 0.05) that did not pass the multiple comparison adjusted alpha level of α_adjusted = 0.002, indicating different associations between attention and implicit learning between the responder groups. We conclude that the associations of sAA and cortisol responses with implicit learning are complex and are related to each other. Further studies in which both (sAA and cortisol responses) are selectively (de-) activated are needed. Furthermore, different learning tasks and less—potentially stressful—attentional assessments should be used in future research. Moreover, field studies are needed in which the associations between acute stress and implicit associative learning are investigated in everyday life. Full article

Reports of behavioral disturbance in Juvenile-Onset Huntington’s Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young adults (12 female) with JOHD and 115 children/young adults (64 female) with a family history of Huntington’s Disease, but who did not inherit the disease themselves (Gene-Non-Expanded; GNE) completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Pediatric Behavior Scale (PBS). Mixed linear regression models (age/sex adjusted) were conducted to assess group differences on these measures. The JOHD group had significantly higher scores, indicating more problems, than the GNE group on all BRIEF subscales, and measures of Aggression/Opposition and Hyperactivity/Inattention of the PBS (all p < 0.05). There were no group differences in Depression/Anxiety. Inhibit, Plan/Organize, Initiate, and Aggression/Opposition had significant negative correlations with Cytosine-Adenine-Guanine (CAG) repeat length (all p < 0.05) meaning that individuals with higher CAG repeats scored lower on these measures. There was greater discrepancy between higher informant-vs. lower self-reported scores in the JOHD group, supporting the notion of lack of insight for the JOHD-affected group. These results provide quantitative evidence of behavioral characteristics of JOHD. Full article

Visual working memory (VWM) resources have been shown to be flexibly distributed according to item priority. This flexible allocation of resources may depend on attentional control, an executive function known to decline with age. In this study, we sought to determine how age differences in attentional control affect VWM performance when attention is flexibly allocated amongst targets of varying priority. Participants performed a delayed-recall task wherein item priority was varied. Error was modelled using a three-component mixture model to probe different aspects of performance (precision, guess-rate, and non-target errors). The flexible resource model offered a good fit to the data from both age groups, but older adults showed consistently lower precision and higher guess rates. Importantly, when demands on flexible resource allocation were highest, older adults showed more non-target errors, often swapping in the item that had a higher priority at encoding. Taken together, these results suggest that the ability to flexibly allocate attention in VWM is largely maintained with age, but older adults are less precise overall and sometimes swap in salient, but no longer relevant, items possibly due to their lessened ability to inhibit previously attended information. Full article

Kava roots have been extensively studied in clinical trials as potential candidate anti-anxiety drugs. However, anti-convulsive properties of various tissues of stems of Kava have not been reported to date. The objective of the study was to evaluate the anti-convulsive potential of aqueous extracts prepared from specific tissues of Kava (Piper methysticum) stems in zebrafish, using the PTZ-induced seizure model. The potency of each extract was compared in terms of the intensity of seizure scores and onset time after pre-treating the zebrafish before the PTZ challenge. The results indicate that aqueous extract of Kava stems without peel after 45 min of pre-treatment exhibited anti-convulsive potential at the dose of 50 mg/L. This study provides evidence to the anti-convulsive properties of peeled Kava stems and its potential for investigation and design of candidate anti-convulsive drugs. Full article

Background: Visual hallucinations (VH) are a common symptom in dementia with Lewy bodies (DLB); however, their cognitive underpinnings remain unclear. Hallucinations have been related to cognitive slowing in DLB and may arise due to impaired sensory input, dysregulation in top-down influences over perception, or an imbalance between the two, resulting in false visual inferences. Methods: Here we employed a drift diffusion model yielding estimates of perceptual encoding time, decision threshold, and drift rate of evidence accumulation to (i) investigate the nature of DLB-related slowing of responses and (ii) their relationship to visuospatial performance and visual hallucinations. The EZ drift diffusion model was fitted to mean reaction time (RT), accuracy and RT variance from two-choice reaction time (CRT) tasks and data were compared between groups of mild cognitive impairment (MCI-LB) LB patients (n = 49) and healthy older adults (n = 25). Results: No difference was detected in drift rate between patients and controls, but MCI-LB patients showed slower non-decision times and boundary separation values than control participants. Furthermore, non-decision time was negatively correlated with visuospatial performance in MCI-LB, and score on visual hallucinations inventory. However, only boundary separation was related to clinical incidence of visual hallucinations. Conclusions: These results suggest that a primary impairment in perceptual encoding may contribute to the visuospatial performance, however a more cautious response strategy may be related to visual hallucinations in Lewy body disease. Interestingly, MCI-LB patients showed no impairment in information processing ability, suggesting that, when perceptual encoding was successful, patients were able to normally process information, potentially explaining the variability of hallucination incidence. Full article

(1) Introduction: Epiconus and conus medullary syndromes that consisted of drop foot, pain, numbness, bladder or bowel dysfunction are serious problems might be caused by lumbar disc(s) herniation (LDH) compression. (2) Objective: To evaluate percutaneous discectomy effectivity for decompressing LDH lesions. (3) Case Report: Three patients suffered from drop feet, numbness, and bowel and bladder problems due to LDH compression. Patient #1 is a male (35 years old, basal metabolism index (BMI) = 23.9), point 1 on manual muscle test (MMT), with protrusion on L3 to S1 discs; Patient #2 is a female (62 years old, BMI = 22.4), point 3 on MMT, with protrusion on L2-4 and L5-S1 discs; Patient #3 is a female (43 years old, BMI = 26.6), point 4 on MMT, with extrusion on T12-L1 and L1-2 and L3-4 protruded discs. Six months follow-up showed of stand and walkability improvement with Patient #1 and #2. Patient #3 showed improvement in bowel and bladder problems within 10 weeks, without suffering of postoperative pain syndromes. (4) Discussion: Patient #1 and #2 showed better outcomes than Patient #3 who affected epiconus and cauda equina syndromes. Triamcinolone and lidocaine have analgesic and anti-inflammatory properties for improving intraepidural circulation adjacent to the lesion sites. (5) Conclusion: Drop foot caused by mechanical compression of LDH ought to be treated immediately. Lateral or posterolateral compression has better outcomes associated with anatomical structures. Discectomy through transforaminal approach that is followed by caudal epidural steroid injection (CESI) under fluoroscopic guidance is a safer and minimally invasive treatment with promising outcomes. Full article

(1) Background: Distal aneurysms of cerebellar arteries are very rare. The authors report their case series of distal aneurysms of the cerebellar arteries solved successfully by microsurgery or by endovascular treatment (Table 1) (2) Materials and Methods: Between January 2010 and March 2020, 346 aneurysms were treated in our institution. Eleven aneurysms in seven patients were located on distal cerebellar arteries and, in three patients, the aneurysms were combined with arteriovenous malformations. There were four women and three men, ranging from 50 to 72 years of age. Five patients presented with different grades of subarachnoid hemorrhage or intraventricular bleeding, and two patients were diagnosed because of headache. Aneurysm location was the posterior inferior cerebellar artery in six cases, the superior cerebellar artery in three cases, and the anterior inferior cerebellar artery in 2 cases. One patient had three aneurysms, and two patients had two aneurysms. (3) Results: Nine aneurysms were treated by microsurgery trapping or clipping and, in two patients, the associated arteriovenous malformation (AVM) was resected. Two aneurysms were treated by endovascular coiling, and one associated AVM was successfully embolized. Clinical follow-up was a mean of 11.5 months (range, 3–45 months). (4) Conclusion: The authors present their experience with the treatment of 11 peripheral aneurysms on distal branches of the cerebellar circulation in seven patients which were excluded from circulation by microsurgery or endovascular treatment. In three patients, the associated AVM was treated (two with microsurgery, one with embolization). Full article

The progress of technology has increased research on neuropsychological emotion and attention with virtual reality (VR). However, direct comparisons between conventional two-dimensional (2D) and VR stimulations are lacking. Thus, the present study compared electroencephalography (EEG) correlates of explicit task and implicit emotional attention between 2D and VR stimulation. Participants (n = 16) viewed angry and neutral faces with equal size and distance in both 2D and VR, while they were asked to count one of the two facial expressions. For the main effects of emotion (angry vs. neutral) and task (target vs. nontarget), established event related potentials (ERP), namely the late positive potential (LPP) and the target P300, were replicated. VR stimulation compared to 2D led to overall bigger ERPs but did not interact with emotion or task effects. In the frequency domain, alpha/beta-activity was larger in VR compared to 2D stimulation already in the baseline period. Of note, while alpha/beta event related desynchronization (ERD) for emotion and task conditions were seen in both VR and 2D stimulation, these effects were significantly stronger in VR than in 2D. These results suggest that enhanced immersion with the stimulus materials enabled by VR technology can potentiate induced brain oscillation effects to implicit emotion and explicit task effects. Full article

Most human actions are composed of two fundamental movement types, discrete and rhythmic movements. These movement types, or primitives, are analogous to the two elemental behaviors of nonlinear dynamical systems, namely, fixed-point and limit cycle behavior, respectively. Furthermore, there is now a growing body of research demonstrating how various human actions and behaviors can be effectively modeled and understood using a small set of low-dimensional, fixed-point and limit cycle dynamical systems (differential equations). Here, we provide an overview of these dynamical motorprimitives and detail recent research demonstrating how these dynamical primitives can be used to model the task dynamics of complex multiagent behavior. More specifically, we review how a task-dynamic model of multiagent shepherding behavior, composed of rudimentary fixed-point and limit cycle dynamical primitives, can not only effectively model the behavior of cooperating human co-actors, but also reveals how the discovery and intentional use of optimal behavioral coordination during task learning is marked by a spontaneous, self-organized transition between fixed-point and limit cycle dynamics (i.e., via a Hopf bifurcation). Full article

Humans employ a number of strategies to improve their position in their given social hierarchy. Overclaiming involves presenting oneself as having more knowledge than one actually possesses, and it is typically invoked to increase one’s social standing. If increased expectations to possess knowledge is a perceived social pressure, such expectations should increase bouts of overclaiming. As the medial prefrontal cortex (MPFC) is sensitive to social pressure and disruption of the MPFC leads to decreases in overclaiming, we predicted that transcranial magnetic stimulation (TMS) applied to the MPFC would reduce overclaiming and the effects would be enhanced in the presence of social pressure. Twelve participants were given a test in which half of the words were real and half were fake, and they were asked how well they knew each word. They were not told that any of the words were fake. Half of the participants were exposed to social pressure while the other half were not. Following TMS delivered to the MPFC, overclaiming rates decreased, specifically under conditions of high social pressure. Medial PFC TMS did not influence real word responses and real words did not interact with the MPFC and social pressure. These preliminary findings support the significant role the MPFC plays in social cognition and the importance of the MPFC in mediating socially meaningful situations. We suggest the role of the MPFC as being highly influenced by the premium placed on social manipulation in human evolution. Full article

The blood–cerebrospinal fluid barrier (BCB) is important in maintaining brain manganese (Mn) homeostasis. This barrier consists of a single layer of epithelial cells, connected by tight junctions, that restrict the passage of nutrients to only allow molecules to be carried through the membrane by a transporter. These epithelial cells are polarized with asymmetrical blood-facing and cerebrospinal fluid-facing sides. Here, we have established a polarized model of a human choroid plexus papilloma cell line, HIBCPP. For the first time, Mn importers ZIP14 and ZIP8 were identified in HIBCPP cells and were found to be enriched at the basolateral and apical sides of the cell monolayer, respectively. The localization of each ZIP protein adds to the understanding of Mn transport across the HIBCPP BCB model to help understand the mechanism of Mn homeostasis within the brain. Full article

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington’s disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T_1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T_1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T_1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T_1ρ relaxation times and Universal Huntington’s Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants’ motor function, cognitive function, behavior, and functional capacity. Mean T_1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T_1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD. Full article

The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive. Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro. Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity. Full article

Transcranial electrical stimulation (tES) can adjust the membrane potential by applying a weak current on the scalp to change the related nerve activity. In recent years, tES has proven its value in studying the neural processes involved in human behavior. The study of central auditory processes focuses on the analysis of behavioral phenomena, including sound localization, auditory pattern recognition, and auditory discrimination. To our knowledge, studies on the application of tES in the field of hearing and the electrophysiological effects are limited. Therefore, we reviewed the neuromodulatory effect of tES on auditory processing, behavior, and cognitive function and have summarized the physiological effects of tES on the auditory cortex. Full article

We recently reported that refocusing attention between temporal and spatial tasks becomes more difficult with increasing age, which could impair daily activities such as driving (Callaghan et al., 2017). Here, we investigated the extent to which difficulties in refocusing attention extend to naturalistic settings such as simulated driving. A total of 118 participants in five age groups (18–30; 40–49; 50–59; 60–69; 70–91 years) were compared during continuous simulated driving, where they repeatedly switched from braking due to traffic ahead (a spatially focal yet temporally complex task) to reading a motorway road sign (a spatially more distributed task). Sequential-Task (switching) performance was compared to Single-Task performance (road sign only) to calculate age-related switch-costs. Electroencephalography was recorded in 34 participants (17 in the 18–30 and 17 in the 60+ years groups) to explore age-related changes in the neural oscillatory signatures of refocusing attention while driving. We indeed observed age-related impairments in attentional refocusing, evidenced by increased switch-costs in response times and by deficient modulation of theta and alpha frequencies. Our findings highlight virtual reality (VR) and Neuro-VR as important methodologies for future psychological and gerontological research. Full article

Excessive daytime sleepiness is a frequent condition among children and adolescents that may lead to several and significant daytime consequences, including impaired neurocognitive skills and scholastic performance. Here, we evaluated in one hundred and ninety-one unselected primary school children, the relationship between sleepiness and a wide range of cognitive and academic skills through a standardized neuropsychological test battery. In order to assess the statistical relationship, we performed a partial least squares path modelling, a non-parametrical approach which combined a model of paths between latent variables and the coefficients between indicators and dimensions. Results were validated through the bootstrap approach and suggest that sleepiness is not associated with all cognitive and scholastic abilities, but only with those relying on verbal abilities and complex cognitive functions (i.e., reading comprehension, oral/syntactic comprehension, spelling, and mathematic skills). Our data suggest the idea that sleepiness in children is associated mostly with “higher” (mainly verbal) cognitive function(s), while the visuospatial domain was not affected. Full article

Background: Fabry disease (FD) causes cerebrovascular disease (CVD) even if asymptomatic, and this is why it is important to identify non-invasive methods to monitor the disease. We evaluated the usefulness of the cerebral autoregulation, vasoreactivity, and neurovascular coupling assessed by transcranial Doppler (TCD) in FD. Methods: Ten adult patients with classic phenotype FD, without clinical expression of CVD, and ten healthy controls, were included. We monitored cerebral blood flow velocity with TCD in the middle and posterior cerebral arteries, blood pressure, heart rate, and non-invasive expired carbon dioxide (CO₂). Cerebral autoregulation was calculated from the spontaneous oscillations of blood pressure, cerebral vasoreactivity through CO₂ inhalation and hyperventilation and neurovascular coupling by the flow velocity change to visual stimulation. Results: FD male patients showed blunted vasoreactivity in posterior circulation (0.70 ± 0.36%/mmHg vs. 1.09 ± 0.18%/mmHg CO₂, p = 0.01) and impaired neurovascular coupling (overshoot 15 ± 2.9% vs. 28 ± 6.1%, p < 0.01). Cerebral autoregulation was similar to controls. Conclusion: Male patients with FD classic phenotype and hitherto clinical expression of CVD already show impairment of cerebral vasoreactivity and neurovascular coupling. It supports the notion of an early dysfunction of cerebral microvascular in a presymptomatic stage of CVD in FD and that TCD could be useful in its assessment. Full article