Specific language impairment (SLI) is a common neurodevelopmental disorder (NDD) that displays high heritability estimates. Genetic studies have identified several loci, but the molecular basis of SLI remains unclear. With the aim to better understand the genetic architecture of SLI, we performed whole-exome sequencing (WES) in a single family (ID: 489; n = 11). We identified co-segregating rare variants in three new genes: BUD13, APLP2, and NDRG2. To determine the significance of these genes in SLI, we Sanger sequenced all coding regions of each gene in unrelated individuals with SLI (n = 175). We observed 13 additional rare variants in 18 unrelated individuals. Variants in BUD13 reached genome-wide significance (p-value < 0.01) upon comparison with similar variants in the 1000 Genomes Project, providing gene level evidence that BUD13 is involved in SLI. Additionally, five BUD13 variants showed cohesive variant level evidence of likely pathogenicity. Bud13 is a component of the retention and splicing (RES) complex. Additional supportive evidence from studies of an animal model (loss-of-function mutations in BUD13 caused a profound neural phenotype) and individuals with an NDD phenotype (carrying a CNV spanning BUD13), indicates BUD13 could be a target for investigation of the neural basis of language. Full article

Multiple Chemical Sensitivity (MCS), a condition also known as Chemical Sensitivity (CS), Chemical Intolerance (CI), Idiopathic Environmental Illness (IEI) and Toxicant Induced Loss of Tolerance (TILT), is an acquired multifactorial syndrome characterized by a recurrent set of debilitating symptoms. The symptoms of this controversial disorder are reported to be induced by environmental chemicals at doses far below those usually harmful to most persons. They involve a large spectrum of organ systems and typically disappear when the environmental chemicals are removed. However, no clear link has emerged among self-reported MCS symptoms and widely accepted objective measures of physiological dysfunction, and no clear dose-response relationship between exposure and symptom reactions has been observed. In addition, the underlying etiology and pathogenic processes of the disorder remain unknown and disputed, although biologic and psychologic hypotheses abound. It is currently debated whether MCS should be considered a clinical entity at all. Nevertheless, in the last few decades MCS has received considerable scientific and governmental attention in light of the many persons reporting this illness. In this review, we provide a general overview of the history, definition, demographics, prevalence, and etiologic challenges in defining and understanding MCS. Full article

Thyroid-associated ophthalmopathy (TAO) is a well-known and frequent epiphenomenon of a hyperthyroid autoimmune disease that can present with proptosis, strabismus, and diplopia. Ophthalmopathy can occur in the absence of overt Graves’ disease, even in euthyroid patients. Cavernous sinus dural fistulas (CS-DAVF) are abnormal communications between the cavernous sinus (CS) and dural branches from internal carotid or external carotid arteries. They can often present with ocular symptoms that can mimic a thyroid-associated ophthalmopathy. CS-DAVF are usually successfully treated with an endovascular embolization that can be pursued both through a transvenous or transarterial approach. TAO and CS-DAVF can coexist especially when the ocular symptoms are unilateral. In those cases, an endovascular embolization is usually curative, but sometimes the procedure can fail. Our hypothesis is that some cases of CS-DAVF may be of secondary nature (i.e., caused by compression of the venous outlet by the hypertrophic ocular muscles); therefore, treating the ocular disease with medical therapy may solve the vascular problem as well. We present a case of a CS-DAVF in a patient with TAO successfully treated with sole medical therapy after the failure of a first-line endovascular treatment. Full article

Purpose To identify cerebral radiomic features related to the diagnosis of Internet gaming disorder (IGD) and construct a radiomics-based machine-learning model for IGD diagnosis. Methods A total of 59 treatment-naïve subjects with IGD and 69 age- and sex-matched healthy controls (HCs) were recruited and underwent anatomic and diffusion-tensor magnetic resonance imaging (MRI). The features of the morphometric properties of gray matter and diffusion properties of white matter were extracted for each participant. After excluding the noise feature with single-factor analysis of variance, the remaining 179 features were included in an all-relevant feature selection procedure within cross-validation loops to identify features with significant discriminative power. Random forest classifiers were constructed and evaluated based on the identified features. Results No overall differences in the total brain volume (1,555,295.64 ± 152,316.31 mm³ vs. 154,491.19 ± 151,241.11 mm³), total gray (709,119.83 ± 59,534.46 mm³ vs. 751,018.21 ± 58,611.32 mm³) and white (465,054.49 ± 51,862.65 mm³ vs. 470,600.22 ± 47,006.67 mm³) matter volumes, and subcortical region volume (63,882.71 ± 5110.42 mm³ vs. 64,764.36 ± 4332.33 mm³) between the IGD and HC groups were observed. The mean classification accuracy was 73%. An altered cortical shape in the bilateral fusiform, left rostral middle frontal (rMFG), left cuneus, left parsopercularis (IFG), and regions around the right uncinate fasciculus (UF) and left internal capsule (IC) contributed significantly to group discrimination. Conclusions: Our study found the brain morphology alterations between IGD subjects and HCs through a radiomics-based machine-learning method, which may help revealing underlying IGD-related neurobiology mechanisms. Full article

Deep brain stimulation (DBS) requires a precise localization, which is especially difficult at the hypothalamus, because it is usually performed in anesthetized patients. We aimed to characterize the neurophysiological properties posteromedial hypothalamus (PMH), identified by the best neurophysiological response to electrical stimulation. We obtained microelectrode recordings from four patients with intractable aggressivity operated under general anesthesia. We pooled data from 1.5 mm at PMH, 1.5 mm upper (uPMH) and 1.5 mm lower (lPMH). We analyzed 178 units, characterized by the mean action potential (mAP). Only 11% were negative. We identified the next types of units: P1N1 (30.9%), N1P1N2 (29.8%), P1P2N1 (16.3%), N1P1 and N1N2P1 (6.2%) and P1N1P2 (5.0%). Besides, atypical action potentials (amAP) were recorded in 11.8%. PMH was highly different in cell composition from uPMH and lPMH, exhibiting also a higher percentage of amAP. Different kinds of cells shared similar features for the three hypothalamic regions. Although features for discharge pattern did not show region specificity, the probability mass function of inter-spike interval were different for all the three regions. Comparison of the same kind of mAP with thalamic neurons previously published demonstrate that most of cells are different for derivatives, amplitude and/or duration of repolarization and depolarization phases and also for the first phase, demonstrating a highly specificity for both brain centers. Therefore, the different properties described for PMH can be used to positively refine targeting, even under general anesthesia. Besides, we describe by first time the presence of atypical extracellular action potentials. Full article

Recognition of typical patterns of brain response to external stimuli using near-infrared spectroscopy (fNIRS) may become a gateway to detecting covert consciousness in clinically unresponsive patients. This is the first fNIRS study on the cortical hemodynamic response to favorite music using a frequency domain approach. The aim of this study was to identify a possible marker of cognitive response in healthy subjects by investigating variations in the oscillatory signal of fNIRS in the spectral regions of low-frequency (LFO) and very-low-frequency oscillations (VLFO). The experiment consisted of two periods of exposure to preferred music, preceded and followed by a resting phase. Spectral power in the LFO region increased in all the subjects after the first exposure to music and decreased again in the subsequent resting phase. After the second music exposure, the increase in LFO spectral power was less distinct. Changes in LFO spectral power were more after first music exposure and the repetition-related habituation effect strongly suggest a cerebral origin of the fNIRS signal. Recognition of typical patterns of brain response to specific environmental stimulation is a required step for the concrete validation of a fNIRS-based diagnostic tool. Full article

This study compared the effects of physical exercise (PE) and virtual training (VT) on the improvement of the visual attention mechanism in children with autism spectrum disorders (ASD). One hundred eighty-nine children with ASD were recruited from Orphan School in Liaoning Province, China. After screening, 100 children ultimately participated in the experiment. Children with ASD were randomly assigned to VT (VT, n = 34), PE (PE, n = 33) and control group (CG, n = 33). The VT group experiment was performed in a virtual environment through the game FIFA21 three times per week for 6 weeks. The PE group played physical football matches three times per week for 6 weeks. Children with ASD in the CG group did not receive VT or PE but only received psychological counseling. Visual attention of children with ASD is evaluated by using the multiple object tracking paradigm (MOT). After 6 weeks of observation, although none of the three groups saw improvements in the correct rate of ring tracking, the observations of the VT and PE groups were significant (p < 0.05) compared to the CG group in finding detection rate of probe stimulus. Through MOT tests, VT and PE improved the detection rate of probe stimulus in children with ASD. Therefore, this paper indicates that VT and PE can improve the visual attention ability of children with ASD. Full article

Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker elevated in cardiovascular diseases. The aim of this 3-year follow-up prospective study was to evaluate suPAR levels in patients with a first ischemic stroke in correlation with CRP, PCT, NT-proCNP and endothelin 1-21 and to investigate the impact of suPAR on the outcome. Fifty-one patients (mean age 73.7+ = 11.9 years, 26 female and 25 male) were included. Samples were collected on the first (suPAR 1), third (suPAR 3) and seventh days after stroke onset (suPAR 7). Plasma samples were analyzed using ELISA. A phone interview was conducted to collect follow-up information after 24 and 36 months (modified Rankin Scale, mRS). A positive correlation between suPAR levels and other inflammatory biomarkers (except endothelin 3) was observed. A positive correlation between suPAR 3 and mRS score at 24 months was observed (p = 0.042). The logistic regression model revealed no significant effect of suPAR on death occurrence in the first 24 months: suPAR 1 (p = 0.8794), suPAR 3 (p = 0.2757), and suPAR 7 (p = 0.3652). The suPAR level is a potential inflammatory marker in ischemic stroke, and there is a correlation with other markers. There is no major impact on mortality. However, the suPAR level is associated with a degree of disability or dependence in daily activities 2 years after a stroke. Full article

Attention Deficit-Hyperactivity disorder (ADHD) may influence rates of Alcohol Use Disorder (AUD) among individuals suffering from Bipolar Disorder (BD). The aim of this systematic review and meta-analysis was to estimate the strength and consistency of the potential association between ADHD and AUD in BD. We searched main electronic databases for studies indexed up to November 2020. We included observational studies investigating the association between ADHD and AUD among individuals with BD. The association between ADHD and AUD was estimated using odds ratios (ORs) with 95% Confidence Intervals (CIs). Eleven studies, involving 2734 individuals with BD (516 with ADHD), were included in the meta-analysis. Individuals with both BD and ADHD had higher rates of AUD as compared with subjects with BD only (34.0% vs. 18.3%). The estimated OR of AUD for ADHD was 2.50 (95% CI: 1.91 to 3.27; I² = 13.0%). Study-level characteristics did not influence the effect size. No risk of publication bias was estimated. Despite some limitations, this meta-analysis estimated an association between ADHD and AUD among individuals suffering from BD. At least a portion of the high rates of AUD in BD may, thereby, be related to comorbid ADHD. Longitudinal studies are needed to clarify the nature of this relationship. Full article

Purpose: electroencephalographic (EEG) information is used to monitor the level of cortical depression of a patient undergoing surgical intervention under general anesthesia. The dynamic state transitions into and out of anesthetic-induced loss and return of responsiveness (LOR, ROR) present a possibility to evaluate the dynamics of the EEG induced by different substances. We evaluated changes in the EEG power spectrum during anesthesia emergence for three different anesthetic regimens. We also assessed the possible impact of these changes on processed EEG parameters such as the permutation entropy (PeEn) and the cerebral state index (CSI). Methods: we analyzed the EEG from 45 patients, equally assigned to three groups. All patients were induced with propofol and the groups differed by the maintenance anesthetic regimen, i.e., sevoflurane, isoflurane, or propofol. We evaluated the EEG and parameter dynamics during LOR and ROR. For the emergence period, we focused on possible differences in the EEG dynamics in the different groups. Results: depending on the substance, the EEG emergence patterns showed significant differences that led to a substance-specific early activation of higher frequencies as indicated by the “wake” CSI values that occurred minutes before ROR in the inhalational anesthetic groups. Conclusion: our results highlight substance-specific differences in the emergence from anesthesia that can influence the EEG-based monitoring that probably have to be considered in order to improve neuromonitoring during general anesthesia. Full article

Age-related macular degeneration (ARMD) is one of the most debilitating eye-related illnesses worldwide. Eye-movement training is evolving to be a non-invasive, rapid, and effective method that is positively impacting vision and QoL (quality of life) in patients suffering from ARMD. This review aims to highlight why a greater adoption of eye-movement training in the clinical and research setting is of importance. A PubMed and ResearchGate search was performed for articles published between 1982 and 2020. Patients with advanced ARMD tend to experience a diminished QoL. Studies regarding eye-movement training for patients with central vision loss revealed overall significant improvements in reading speeds, fixation, and saccade performance. They also experienced less fatigue. In select studies, eye-movement training revealed an improvement in binocular vision, fixation, reading speed, and diminished reading exhaustion. The process of eye-movement training used in some of the studies was rather empirical. The latter requires standardization so that a uniform and applicable methodology can be adopted overall. Full article

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke. Full article

The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing. Full article

Cochlear implants have been used to restore hearing to more than half a million people around the world. The restored hearing allows most recipients to understand spoken speech without relying on visual cues. While speech comprehension in quiet is generally high for recipients, many complain about the sound of music. The present study examines consonance and dissonance perception in nine cochlear implant users and eight people with no known hearing loss. Participants completed web-based assessments to characterize low-level psychophysical sensitivities to modulation and pitch, as well as higher-level measures of musical pleasantness and speech comprehension in background noise. The underlying hypothesis is that sensitivity to modulation and pitch, in addition to higher levels of musical sophistication, relate to higher-level measures of music and speech perception. This hypothesis tested true with strong correlations observed between measures of modulation and pitch with measures of consonance ratings and speech recognition. Additionally, the cochlear implant users who were the most sensitive to modulations and pitch, and who had higher musical sophistication scores, had similar pleasantness ratings as those with no known hearing loss. The implication is that better coding and focused rehabilitation for modulation and pitch sensitivity will broadly improve perception of music and speech for cochlear implant users. Full article