Brain Sciences — Open Access Journal

Alzheimer’s disease (AD) pathology begins decades before the onset of clinical symptoms. It is recognized as a clinicobiological entity, being detectable in vivo independently of the clinical stage by means of pathophysiological biomarkers. Accordingly, neuropathological studies that were carried out on healthy elderly subjects, with or without subjective experience of cognitive decline, reported evidence of AD pathology in a high proportion of cases. At present, mild cognitive impairment (MCI) represents the only clinically diagnosed pre-dementia stage. Several attempts have been carried out to detect AD as early as possible, when subtle cognitive alterations, still not fulfilling MCI criteria, appear. Importantly, pre-MCI individuals showing the positivity of pathophysiological AD biomarkers show a risk of progression similar to MCI patients. In view of successful treatment with disease modifying agents, in a clinical setting, a timely diagnosis is mandatory. In clinical routine, biomarkers assessment should be taken into consideration whenever a subject with subtle cognitive deficits (pre-MCI), who is aware of his/her decline, requests to know the cause of such disturbances. In this review, we report the available neuropsychological and biomarkers data that characterize the pre-MCI patients, thus proposing pre-MCI as the first clinical manifestation of AD. Full article

Background. Alzheimer's is a disease for which there is no cure. Diagnosing Alzheimer's disease (AD) early facilitates family planning and cost control. The purpose of this study is to predict the presence of AD using socio-demographic, clinical, and magnetic resonance imaging (MRI) data. Early detection of AD enables family planning and may reduce costs by delaying long-term care. Accurate, non-imagery methods also reduce patient costs. The Open Access Series of Imaging Studies (OASIS-1) cross-sectional MRI data were analyzed.A gradient boosted machine (GBM) predicted the presence of AD as a function of gender, age, education, socioeconomic status (SES), and a mini-mental state exam (MMSE). A residual network with 50 layers (ResNet-50) predicted the clinical dementia rating (CDR) presence and severity from MRI's (multi-class classification). The GBM achieved a mean 91.3% prediction accuracy (10-fold stratified cross validation) for dichotomous CDR using socio-demographic and MMSE variables. MMSE was the most important feature. ResNet-50 using image generation techniques based on an 80% training set resulted in 98.99% three class prediction accuracy on 4139 images (20% validation set) at Epoch 133 and nearly perfect multi-class predication accuracy on the training set (99.34%). Machine learning methods classify AD with high accuracy. GBM models may help provide initial detection based on non-imagery analysis, while ResNet-50 network models might help identify AD patients automatically prior to provider review. Full article

The incidence of dementia is on the rise and expected to continue to increase in the foreseeable future. Two of the most common subtypes of dementia are Alzheimer’s subtype and vascular dementia. Hyperhomocysteinemia has been shown to serve as a risk factor for dementia due to an associated blood–brain barrier dysfunction and subsequent small-vessel disease pathology. There are varying causes for hyperhomocysteinemia, including genetic and dietary, among others. We highlight the importance of identifying hyperhomocysteinemia as a potential etiologic and therapeutic target for the most common subtypes of dementia. Full article

Working memory capacity (WMC) varies tremendously among individuals. Here, we investigate the possibility that subjects with high WMC use this limited resource more efficiently by reducing the precision with which they store information in demanding tasks. Task difficulty was increased by (a) presenting more objects to be memorized, (b) informing subjects only after the encoding phase about the relevant objects, and (c) delivering distracting features at retrieval. Precision was assessed by means of a continuous delayed-estimation task, in which object features had to be estimated from memory. High WMC subjects did not show a stronger drop in precision in difficult tasks. Instead, a positive correlation between precision and general WMC emerged. These findings suggest that high WMC subjects do not necessarily trade in quantity for quality when forming working memory (WM) representations under increasing demand. Instead, they seem to be able to devote more cognitive resources to support WM storage. Full article

The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased place conditioning procedure using ethanol doses of 0, 2, or 4 g/kg; all injections were given immediately after 5-min exposure to distinctive tactile cues. There were dose-dependent effects of ethanol on CPA and on the change in pre-injection activity rates between the first and last conditioning trials. Most strains (80%) developed CPA, demonstrating the generalizability of this behavior. Moreover, genotype had significant effects on CPA magnitude and locomotor activity rates. Strain means from this study and previously published studies were then used to examine genetic correlations. These analyses showed significant genetic correlations between CPA and ethanol intake/preference, conditioned taste aversion, and drug withdrawal (but not blood ethanol concentration or conditioned place preference), supporting the idea of commonality in the genes underlying CPA and each of these behaviors. The overall pattern of findings is consistent with previous data suggesting that genetic differences in sensitivity to ethanol’s aversive effects play a role in determining strain differences in ethanol drinking. The broader implication is that individuals who are more sensitive to the aversive effects of ethanol may be protected from developing the excessive drinking behaviors characteristic of alcohol use disorders. Full article

A foundation of medical research is time series analysis—the behavior of variables of interest with respect to time. Time series data are often analyzed using the mean, with statistical tests applied to mean differences, and has the assumption that data are stationary. Although widely practiced, this method has limitations. Here we present an alternative statistical approach with sample analysis that provides a summary statistic accounting for the non-stationary nature of time series data. This work discusses the use of entropy as a measurement of the complexity of time series, in the context of Neuroscience, due to the non-stationary characteristic of the data. To elucidate our argument, we conducted entropy analysis on a sample of electroencephalographic (EEG) data from an interventional study using non-invasive electrical brain stimulation. We demonstrated that entropy analysis could identify intervention-related change in EEG data, supporting that entropy can be a useful “summary” statistic in non-linear dynamical systems. Full article

Intracranial hemorrhage (ICH) is a catastrophic complication in patients with acute myeloid leukemia (AML). AML cells, especially in the acute promyelocytic leukemia subtype, may release microparticles (MPs), tissue factor (TF), and cancer procoagulant (CP) to promote coagulopathy. Hyperfibrinolysis is also triggered via release of annexin II, t-PA, u-PA, and u-PAR. Various inflammatory cytokines from cancer cells, such as IL-1β and TNF-α, activate endothelial cells and promote leukostasis. This condition may increase the ICH risk and lead to poor clinical outcomes. Here, we present a case under a unique situation with acute ICH detected prior to the diagnosis of AML. The patient initially presented with two episodes of syncope. Rapidly progressive ICH was noted in follow-up computed tomography (CT) scans. Therefore, we highlight that AML should be among the differential diagnoses of the etiologies of ICH. Early diagnosis and timely intervention are very important for AML patients. Full article

Anxiety disorders are the most common psychological disorders worldwide resulting in a great demand of adequate and cost-effective treatment. New short-term interventions can be used as an effective adjunct or alternative to pharmaco- and psychotherapy. One of these approaches is therapeutic tapping. It combines somatic stimulation of acupressure points with elements from Cognitive Behavioral Therapy (CBT). Tapping reduces anxiety symptoms after only one session. Anxiety is associated with a deficient emotion regulation for threatening stimuli. These deficits are compensated e.g., by CBT. Whether Tapping can also elicit similar modulations and which dynamic neural correlates are affected was subject to this study. Anxiety patients were assessed listening to pseudowords with a different emotional prosody (happy, angry, fearful, and neutral) prior and after one Tapping session. The emotion-related component Late Positive Potential (LPP) was investigated via electroencephalography. Progressive Muscle Relaxation (PMR) served as control intervention. Results showed LPP reductions for negative stimuli after the interventions. Interestingly, PMR influenced fearful and Tapping altered angry prosody. While PMR generally reduced arousal for fearful prosody, Tapping specifically affected fear-eliciting, angry stimuli, and might thus be able to reduce anxiety symptoms. Findings highlight the efficacy of Tapping and its impact on neural correlates of emotion regulation. Full article

Background: We examined corticospinal and spinal excitability across multiple power outputs during arm cycling using a weak and strong stimulus intensity. Methods: We elicited motor evoked potentials (MEPs) and cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii using magnetic stimulation over the motor cortex and electrical stimulation of corticospinal axons during arm cycling at six different power outputs (i.e., 25, 50, 100, 150, 200 and 250 W) and two stimulation intensities (i.e., weak vs. strong). Results: In general, biceps brachii MEP and CMEP amplitudes (normalized to maximal M-wave (M_max)) followed a similar pattern of modulation with increases in cycling intensity at both stimulation strengths. Specifically, MEP and CMEP amplitudes increased up until ~150 W and ~100 W when the weak and strong stimulations were used, respectively. Further increases in cycling intensity revealed no changes on MEP or CMEP amplitudes for either stimulation strength. Conclusions: In general, MEPs and CMEPs changed in a similar manner, suggesting that increases and subsequent plateaus in overall excitability are likely mediated by spinal factors. Interestingly, however, MEP amplitudes were disproportionately larger than CMEP amplitudes as power output increased, despite being initially matched in amplitude, particularly with strong stimulation. This suggests that supraspinal excitability is enhanced to a larger degree than spinal excitability as the power output of arm cycling increases. Full article

We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75^NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75^NTR receptors. ProNGF is the precursor form of NGF, binds to p75^NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75^NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75^NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75^NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75^NTR expression and activation of RhoA, leading to neuronal cell death. Full article

The auditory steady-state response (ASSR) elicited by a periodic sound stimulus is a neural oscillation recorded by magnetoencephalography (MEG), which is phase-locked to the repeated sound stimuli. This ASSR phase alternates after an abrupt change in the feature of a periodic sound stimulus and returns to its steady-state value. An abrupt change also elicits a MEG component peaking at approximately 100–180 ms (called “Change-N1m”). We investigated whether both the ASSR phase deviation and Change-N1m were affected by the magnitude of change in sound pressure. The ASSR and Change-N1m to 40 Hz click-trains (1000 ms duration, 70 dB), with and without an abrupt change (± 5, ± 10, or ± 15 dB) were recorded in ten healthy subjects. We used the source strength waveforms obtained by a two-dipole model for measurement of the ASSR phase deviation and Change-N1m values (peak amplitude and latency). As the magnitude of change increased, Change-N1m increased in amplitude and decreased in latency. Similarly, ASSR phase deviation depended on the magnitude of sound-pressure change. Thus, we suspect that both Change-N1m and the ASSR phase deviation reflect the sensitivity of the brain’s neural change-detection system. Full article

The classification recognition rate of motor imagery is a key factor to improve the performance of brain–computer interface (BCI). Thus, we propose a feature extraction method based on discrete wavelet transform (DWT), empirical mode decomposition (EMD), and approximate entropy. Firstly, the electroencephalogram (EEG) signal is decomposed into a series of narrow band signals with DWT, then the sub-band signal is decomposed with EMD to get a set of stationary time series, which are called intrinsic mode functions (IMFs). Secondly, the appropriate IMFs for signal reconstruction are selected. Thus, the approximate entropy of the reconstructed signal can be obtained as the corresponding feature vector. Finally, support vector machine (SVM) is used to perform the classification. The proposed method solves the problem of wide frequency band coverage during EMD and further improves the classification accuracy of EEG signal motion imaging. Full article

Background: Cervical myelopathy (CM) is a common cause of morbidity and disability in patients with mucopolysaccharidosis (MPS) and, therefore, early detection is crucial for the best surgical intervention and follow-up. Transcranial magnetic stimulation (TMS) non-invasively evaluates the conduction through the cortico-spinal tract, also allowing preclinical diagnosis and monitoring. Methods: Motor evoked potentials (MEPs) to TMS were recorded in a group of eight patients with MPS-related CM. Responses were obtained during mild tonic muscular activation by means of a circular coil held on the “hot spot” of the first dorsal interosseous and tibialis anterior muscles, bilaterally. The motor latency by cervical or lumbar magnetic stimulation was subtracted from the MEP cortical latency to obtain the central motor conduction time. The MEP amplitude from peak to peak to cortical stimulation and the interside difference of each measure were also calculated. Results: TMS revealed abnormal findings from both upper and lower limbs compatible with axonal damage and demyelination in six of them. Notably, a subclinical cervical spinal disease was detected before the occurrence of an overt CM in two patients, whereas TMS signs compatible with a CM of variable degree persisted despite surgery in all treated subjects. Conclusions: TMS can be viewed as an adjunct diagnostic test pending further rigorous investigations. Full article

Objective: The purpose of this systematic review is to quantitatively estimate (or invest) the impacts of sports-related concussions (SRCs) on cognitive performance among retired athletes more than 10 years after retirement. Methods: Six databases including (MEDLINE, Scopus, Web of Science, SPORTDiscus, CINAHL, and PsycArtilces) were employed to retrieve the related studies. Studies that evaluate the association between cognitive function and the SRC of retired athletes sustaining more than 10 years were included. Results: A total of 11 studies that included 792 participants (534 retired athletes with SRC) were identified. The results indicated that the retired athletes with SRCs, compared to the non-concussion group, had significant cognitive deficits in verbal memory (SMD = −0.29, 95% CI −0.59 to −0.02, I² = 52.8%), delayed recall (SMD = −0.30, 95% CI –0.46 to 0.07, I² = 27.9%), and attention (SMD = −0.33, 95% CI −0.59 to −0.06, I² = 0%). Additionally, meta-regression demonstrated that the period of time between testing and the last concussion is significantly associated with reduced verbal memory (β = −0.03681, p = 0.03), and increasing age is significantly associated with the verbal memory (β = −0.03767, p = 0.01), immediate recall (β = −0.08684, p = 0.02), and delay recall (β = −0.07432, p = 0.02). Conclusion: The retired athletes who suffered from SRCs during their playing career had declined cognitive performance in partial domains (immediate recall, visuospatial ability, and reaction time) later in life. Full article

A significant challenge for fMRI research is statistically controlling for false positives without omitting true effects. Although a number of traditional methods for multiple comparison correction exist, several alternative tools have been developed that do not rely on strict parametric assumptions, but instead implement alternative methods to correct for multiple comparisons. In this study, we evaluated three of these methods, Statistical non-Parametric Mapping (SnPM), 3DClustSim, and Threshold Free Cluster Enhancement (TFCE), by examining which method produced the most consistent outcomes even when spatially-autocorrelated noise was added to the original images. We assessed the false alarm rate and hit rate of each method after noise was applied to the original images. Full article

Complex regional pain syndrome type I (CRPS-I) is a chronic painful condition. We investigated whether manual therapy (MT), in a chronic post-ischemia pain (CPIP) model, is capable of reducing pain behavior and oxidative stress. Male Swiss mice were subjected to ischemia-reperfusion (IR) to mimic CRPS-I. Animals received ankle joint mobilization 48h after the IR procedure, and response to mechanical stimuli was evaluated. For biochemical analyses, mitochondrial function as well as oxidative stress thiobarbituric acid reactive substances (TBARS), protein carbonyls, antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) levels were determined. IR induced mechanical hyperalgesia which was subsequently reduced by acute MT treatment. The concentrations of oxidative stress parameters were increased following IR with MT treatment preventing these increases in malondialdehyde (MDA) and carbonyls protein. IR diminished the levels of SOD and CAT activity and MT treatment prevented this decrease in CAT but not in SOD activity. IR also diminished mitochondrial complex activity, and MT treatment was ineffective in preventing this decrease. In conclusion, repeated sessions of MT resulted in antihyperalgesic effects mediated, at least partially, through the prevention of an increase of MDA and protein carbonyls levels and an improvement in the antioxidant defense system. Full article

Alzheimer’s disease (AD) is the most common form of dementia worldwide. The hallmarks of AD are the extracellular amyloid plaques, which are formed by amyloid β (Aβ) aggregates derived from the processing of the amyloid precursor protein (APP), and the intraneuronal neurofibrillary tangles, which are formed by the hyperphosphorylated tau protein. The aim of this work was to study the effects of α-tocopherol in retinoic acid differentiated SH-SY5Y neuroblastoma cells exposed to Aβ_1-42 evaluating the transcriptional profile by next-generation sequencing. We observed that α-tocopherol was able to reduce the cytotoxicity induced by Aβ treatment, as demonstrated by Thiazolyl Blue Tetrazolium Bromide (MTT) assay. Moreover, the transcriptomic analysis evidenced that α-tocopherol treatment upregulated genes involved in the non-amyloidogenic processing of APP, while it downregulated the amyloidogenic pathway. Moreover, α-tocopherol modulated the expression of the genes involved in autophagy and the cell cycle, which are both known to be altered in AD. The treatment with α-tocopherol was also able to reduce oxidative stress, restoring nuclear factor erythroid-derived 2-like 2 (Nrf2) and decreasing inducible nitric oxide synthase (iNOS) levels, as demonstrated by immunocytochemistry. Full article

Objective: Occult central nervous system (CNS) symptoms not recognized by people living with HIV (PLWH) receiving efavirenz or their clinicians could occur and impact people’s quality of life. The aim of this study was to determine whether CNS parameters improve in PLWH when switching from efavirenz to rilpivirine. Methods: PLWH receiving tenofovir disoproxil fumarate, emtricitabine, efavirenz (Atripla™) with undetectable HIV RNA, and no CNS symptoms were switched cART to tenofovir disoproxil fumarate, emtricitabine, rilpivirine (Eviplera™). CNS parameters including sleep, anxiety, and depressive symptoms were evaluated using patient-reported outcome measures at baseline, 4, 12, and 24 weeks after switching therapy. A median CNS score was derived from the sum of CNS toxicities of all the grades collected in the study questionnaires. Cognitive function was assessed using a computerized test battery. Results: Of 41 participants, median age was 47 years, Interquartile range (IQR) 31, 92% were male and 80% were of white ethnicity. A significant reduction in total CNS score (10 to 7) was observed at 4 weeks (p = 0.028), but not thereafter. Significant improvements in sleep and anxiety were observed 4, 12 and 24 weeks after switching therapy (p < 0.05). No significant change in global cognitive scores was observed. Conclusions: Switching from efavirenz to rilpivirine based regimens in virologically suppressed PLWH without perceived CNS symptoms was well tolerated and slightly improved overall CNS symptoms. Full article