Brain Sciences — Open Access Journal

While significant research has been performed regarding the use of thrombolytic agents and thrombectomy in the setting of acute stroke, other factors, such as nutritional status of stroke patients, is a less explored topic. The topic of nutrition is critical to the discussion of stroke, as up to half of stroke survivors may be considered malnourished at discharge. Dysphagia, old age, restricted upper limb movement, visuospatial impairment, and depression are all important risk factors for malnutrition in this cohort. The purpose of this review is to analyze current literature discussing neuroprotective diets, nutritional, vitamin, and mineral supplementation, dysphagia, and post-stroke coaching in stroke patients. Full article

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABA_C receptors in MSNs. Furthermore, there was a reduction in the effect of the GABA_C antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition. Full article

Using an animal model of hemolysis elevated liver enzymes low platelets (HELLP) that has systemic inflammation and neuroinflammation we wanted to determine if blood brain barrier (BBB) permeability, cerebral edema, vascular tone, and occludin expression were altered in pregnant rats. Anti-angiogenic proteins sFlt-1 and sEng (4.7 and 7 µg/kg/day, respectively) were chronically infused into normal pregnant (NP) rats beginning on gestational day 12 via a mini-osmotic pump. On gestational day 19, blood pressure was measured via a carotid catheter and brains were collected. BBB permeability was assessed in select brain regions from rats infused with 0.5 mg/mL Texas Red Dextran and phenylephrine. Occludin, sFlt-1, and sEng were analyzed via western blot or ELISA. Infusion of sFlt-1 and sEng into NP rats increased hemolysis and liver enzymes, and decreased platelets and led to hypertension. HELLP rats had significant impairment in the myogenic response and increased BBB permeability in the posterior cortex and brainstem. Brain water content in the posterior cortex was increased and sEng protein expression in the brainstem was significantly increased in HELLP rats. The results from this study suggest that a peripheral anti-angiogenic imbalance during pregnancy is associated with decreased myogenic tone, vasogenic edema, and an increase in BBB permeability, but not anti-angiogenic imbalance in the brain. Full article

The selective retrieval of some information may lead to the forgetting of related, but non-retrieved information. This memory phenomenon is termed retrieval-induced forgetting (RIF). Active inhibition is thought to function to resolve interference from competing information during retrieval, which results in forgetting. Epilepsy is associated with impaired inhibitory control that contributes to executive dysfunction. The purpose of this study is to investigate whether rats in a kindling model of epilepsy demonstrate normal levels of RIF. Rats were divided into two groups: saline and kindling. Pentylenetetrazole was injected intraperitoneally until the rats kindled. RIF was tested using a modified version of the spontaneous object recognition test, consisting of a sample phase, retrieval or interference phase, and a test phase. Exploration time for each object was analyzed. RIF was demonstrated in the saline group when rats subjected to the retrieval phase failed to discriminate between the familiar object and the novel object later in the test phase. Kindled rats, on the other hand, did not suffer forgetting even when they were subjected to the retrieval phase, as they spent significantly longer times exploring the novel rather than the familiar object in the test phase. Therefore, RIF was not observed in the kindling group. These findings indicate impaired retrieval-induced forgetting in kindled rats, which may be suggestive of a deficit in the inhibitory control of memory. Full article

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials. Full article

Background: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system. Methods: In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)_82–98 encephalitogenic sequence (dirucotide), the linear altered peptide ligand MBP_82–98 (Ala⁹¹), and their cyclic counterparts. Results: The synthesized peptides were evaluated for their binding to human leukocyte antigen (HLA)-DR2 and HLA-DR4 alleles, with cyclic MBP_82–98 being a strong binder with the HLA-DR2 allele and having lower affinity binding to the HLA-DR4 allele. In a further step, conformational analyses were performed using NMR spectroscopy in solution to describe the conformational space occupied by the functional amino acids of both linear and cyclic peptide analogues. This structural data, in combination with crystallographic data, were used to study the molecular basis of their interaction with HLA-DR2 and HLA-DR4 alleles. Conclusion: The cyclic and APL analogues of dirucotide are promising leads that should be further evaluated for their ability to alter T cell responses for therapeutic benefit against MS. Full article

Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritized as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles and molecular pathways, including metabolism of proteins and vesicle-mediated transport—both of which converge on endoplasmic reticulum (ER)-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases. Full article

Although ageing is known to affect memory, the precise nature of its effect on retrieval and encoding processes is not well understood. Here, we examine the effect of ageing on the free recall of word lists, in which the semantic structure of word sequences was manipulated from unrelated words to pairs of associated words with various separations (between pair members) within the sequence. We find that ageing is associated with reduced total recall, especially for sequences with associated words. Furthermore, we find that the degree of semantic clustering (controlled for chance clustering) shows an age effect and that it interacts with the distance between the words within a pair. The results are consistent with the view that age effects in memory are mediated both by retrieval and by encoding processes associated with frontal control and working memory. Full article

Recent evidence suggests the existence of shared neural resources for rhythm processing in language and music. Such overlaps could be the basis of the facilitating effect of regular musical rhythm on spoken word processing previously reported for typical children and adults, as well as adults with Parkinson’s disease and children with developmental language disorders. The present study builds upon these previous findings by examining whether non-linguistic rhythmic priming also influences visual word processing, and the extent to which such cross-modal priming effect of rhythm is related to individual differences in musical aptitude and reading skills. An electroencephalogram (EEG) was recorded while participants listened to a rhythmic tone prime, followed by a visual target word with a stress pattern that either matched or mismatched the rhythmic structure of the auditory prime. Participants were also administered standardized assessments of musical aptitude and reading achievement. Event-related potentials (ERPs) elicited by target words with a mismatching stress pattern showed an increased fronto-central negativity. Additionally, the size of the negative effect correlated with individual differences in musical rhythm aptitude and reading comprehension skills. Results support the existence of shared neurocognitive resources for linguistic and musical rhythm processing, and have important implications for the use of rhythm-based activities for reading interventions. Full article

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25–28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS. Full article

The present study examined differences in operant responses in adult male and female rats during distinct phases of addiction. Males and females demonstrated escalation in methamphetamine (0.05 mg/kg, i.v.) intake with females showing enhanced latency to escalate, and bingeing. Following protracted abstinence, females show reduced responses during extinction, and have greater latency to extinguish compared with males, indicating reduced craving. Females demonstrated lower context-driven reinstatement compared to males, indicating that females have less motivational significance to the context associated with methamphetamine. Whole-cell patch-clamp recordings on dentate gyrus (DG) granule cell neurons (GCNs) were performed in acute brain slices from controls and methamphetamine experienced male and female rats, and neuronal excitability was evaluated from GCNs. Reinstatement of methamphetamine seeking reduced spiking in males, and increased spiking in females compared to controls, demonstrating distinct neuroadaptations in intrinsic excitability of GCNs in males and females. Reduced excitability of GCNs in males was associated with enhanced levels of neural progenitor cells, expression of plasticity-related proteins including CaMKII, and choline acetyltransferase in the DG. Enhanced excitability in females was associated with an increased GluN2A/2B ratio, indicating changes in postsynaptic GluN subunit composition in the DG. Altered intrinsic excitability of GCNs was associated with reduced mossy fiber terminals in the hilus and pyramidal projections, demonstrating compromised neuroplasticity in the DG in both sexes. The alterations in excitability, plasticity-related proteins, and mossy fiber density were correlated with enhanced activation of microglial cells in the hilus, indicating neuroimmune responses in both sexes. Together, the present results indicate sexually dimorphic adaptive biochemical changes in excitatory neurotransmitter systems in the DG and highlight the importance of including sex as a biological variable in exploring neuroplasticity and neuroimmune changes that predict enhanced relapse to methamphetamine-seeking behaviors. Full article

Poor comparability of social groups is one of the major methodological problems that threatens the validity of health disparities (HD) research findings. We illustrate a methodological solution that can additionally unpack the mechanisms behind differential effects on depression and anxiety. We describe racial/ethnic differences in the prevalence of depression and anxiety scores between Black and White women using classic methods, and then we illustrate a 1:1 matching procedure that allows for building of individual-level difference scores, i.e., actual HD difference score variables, for each pair of comparable participants. We compare the prevalence of depression disorder between Black and White young women after matching them 1:1 on common socio-economic characteristics (age, employment, education, and marital status). In essence, we follow matching or stratification methods, but make a step further and match cases 1:1 on propensity scores, i.e., we create Black–White ‘dyads’. Instead of concluding from plain comparisons that 11% more White young women (18–30 years old) report a depressive disorder than Black young women, the matched data confirms the trend, but provides more nuances. In 27% of the pairs of comparable pairs the White woman was depressed (and the comparable Black woman was not), while in 15% of the pairs the Black woman was depressed (and the comparable White woman was not). We find that Black-to-White disparities in neighborhood disorder do not predict depression differences (HDs), while such an effect is evident for anxiety HDs. The 1:1 matching approach allows us to examine more complex HD effects, like differential mediational or resilience mechanisms that appear to be protective of Black women’s mental health. Full article

Binding sensory features of multiple modalities of what we hear and see allows formation of a coherent percept to access semantics. Previous work on object naming has focused on visual confrontation naming with limited research in nonverbal auditory or multisensory processing. To investigate neural substrates and sensory effects of lexical retrieval, we evaluated healthy adults (n = 118) and left hemisphere stroke patients (LHD, n = 42) in naming manipulable objects across auditory (sound), visual (picture), and multisensory (audiovisual) conditions. LHD patients were divided into cortical, cortical–subcortical, or subcortical lesions (CO, CO–SC, SC), and specific lesion location investigated in a predictive model. Subjects produced lower accuracy in auditory naming relative to other conditions. Controls demonstrated greater naming accuracy and faster reaction times across all conditions compared to LHD patients. Naming across conditions was most severely impaired in CO patients. Both auditory and visual naming accuracy were impacted by temporal lobe involvement, although auditory naming was sensitive to lesions extending subcortically. Only controls demonstrated significant improvement over visual naming with the addition of auditory cues (i.e., multisensory condition). Results support overlapping neural networks for visual and auditory modalities related to semantic integration in lexical retrieval and temporal lobe involvement, while multisensory integration was impacted by both occipital and temporal lobe lesion involvement. The findings support modality specificity in naming and suggest that auditory naming is mediated by a distributed cortical–subcortical network overlapping with networks mediating spatiotemporal aspects of skilled movements producing sound. Full article

Down syndrome (DS) is the most common genetically-defined cause of intellectual disability. Neurodevelopmental deficits displayed by individuals with DS are generally global, however, disproportionate deficits in cognitive processes that depend heavily on the hippocampus and prefrontal cortex are also well documented. Additionally, DS is associated with relative strengths in visual processing and visuospatial short-term memory, and weaknesses in the verbal domain. Although reports of pharmacological rescuing of learning and memory deficits in mouse models of DS abound in the literature, proving the principle that cognitive ability of persons with DS can be boosted through pharmacological means is still an elusive goal. The design of customized batteries of neuropsychological efficacy outcome measures is essential for the successful implementation of clinical trials of potential cognitive enhancing strategies. Here, we review the neurocognitive phenotype of individuals with DS and major broad-based test batteries designed to quantify specific cognitive domains in these individuals, including the one used in a pilot trial of the drug memantine. The main goal is to illustrate the essential considerations in planning trials to enhance cognitive functions in individuals with DS, which should also have implications for the design of similar studies in individuals with other forms of intellectual disability. Full article

Background: Poor sleep quality is a common complaint, affecting over one third of people in the United States. While sleep quality is thought to be related to slow-wave sleep (SWS), there has been little investigation to address whether modulating slow-wave oscillations (SWOs) that characterize SWS could impact sleep quality. Here we examined whether closed-loop transcranial alternating current stimulation (CL-tACS) applied during sleep impacts sleep quality and efficiency. Methods: CL-tACS was used in 21 participants delivered at the same frequency and in phase with endogenous SWOs during sleep. Sleep quality was assessed in the morning following either verum or sham control stimulation during sleep, with order counterbalanced within participants. Results: Higher sleep quality and efficiency were found after verum stimulation nights compared to control. The largest effects on sleep quality were found immediately following an adaptation night in the laboratory for which sleep quality was reduced. Conclusions: Applying CL-tACS at the same frequency and phase as endogenous SWOs may offer a novel method to improve subjective sleep quality after a night with poor quality sleep. CL-tACS might be helpful for increasing sleep quality and efficiency in otherwise healthy people, and in patients with clinical disorders that involve sleep deficits. Full article

The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its preferential conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently-marketed drugs—the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat—that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial. Full article

Maximal safe resection represents the gold standard for surgery of malignant brain tumors. As regards gross-total resection, accurate localization and precise delineation of the tumor margins are required. Intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography-IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in brain tumor surgery, allowing for a more radical and safer tumor resection. IOUS guidance for brain tumor surgery is accurate in distinguishing tumor from normal parenchyma, and it allows a real-time intraoperative visualization. We aim to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. We performed a literature research through the Pubmed database by selecting each article which was focused on the use of IOUS in brain tumor surgery, and in particular in glioma surgery, published in the last 15 years (from 2003 to 2018). We selected 39 papers concerning the use of IOUS in brain tumor surgery, including gliomas. IOUS exerts a notable attraction due to its low cost, minimal interruption of the operational flow, and lack of radiation exposure. Our literature review shows that increasing the use of ultrasound in brain tumors allows more radical resections, thus giving rise to increases in survival. Full article

Borderline personality disorder (BPD) is a chronic psychiatric disorder characterized by pervasive affective instability, self-image disturbances, impulsivity, marked suicidality, and unstable interpersonal relationships as the core dimensions of psychopathology underlying the disorder. Across a wide range of situations, BPD causes significant impairments. Patients with BPD suffer considerable morbidity and mortality compared with other populations. Although BPD is more widely studied than any other personality disorder, it is not understood sufficiently. This paper briefly reviews the recent evidence on the prevalence, etiology, comorbidity, and treatment approaches of borderline personality disorder (BPD) by examining published studies, and aims to offer a more coherent framework for the understanding and management of borderline personality disorder. Full article

Diffuse intrinsic pontine glioma (DIPG) is a devastating and incurable paediatric brain tumour with a median overall survival of 9 months. Until recently, DIPGs were treated similarly to adult gliomas, but due to the advancement in molecular and imaging technologies, our understanding of these tumours has increased dramatically. While extensive research is being undertaken to determine the function of the molecular aberrations in DIPG, there are significant gaps in understanding the biology and the influence of the tumour microenvironment on DIPG growth, specifically in regards to the developing pons. The precise orchestration and co-ordination of the development of the brain, the most complex organ in the body, is still not fully understood. Herein, we present a brief overview of brainstem development, discuss the developing microenvironment in terms of DIPG growth, and provide a basis for the need for studies focused on bridging pontine development and DIPG microenvironment. Conducting investigations in the context of a developing brain will lead to a better understanding of the role of the tumour microenvironment and will help lead to identification of drivers of tumour growth and therapeutic resistance. Full article