Showing papers in "Brain and behavior in 2018"

Maternal hormonal milieu influence on fetal brain development.

Abstract: An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high-risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short-term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment.

What is the actual prevalence of migraine

Abstract: Objectives: Population prevalence studies of migraine report prevalence rates of between 2.6 and 21.7%, with an average of ~12%. However, migraine prevalence among neurologists is reported to be significantly higher, between 27.6% and 48.6%. Increasing knowledge of the protean manifestations of migraine may explain this difference. Similarly, under-recognition of migraine in control groups may explain the lack of genetic and biomarker findings in this disorder. We therefore sought to determine the prevalence of migraine in an admixed group of individuals with varied knowledge of migraine symptomatology. Methods: Attendees at the Australian and New Zealand Association of Neurologists Annual Scientific Meeting (ANZAN ASM) 2017 were surveyed anonymously. Those surveyed included three groups: neurologists, neurology trainees, and others including nonclinical researchers, members of lay organizations, and representatives of the pharmaceutical industry. Results: In total, 313 of 606 attendees responded (51.7%). 65.9% of neurologist, 57.4% of trainee, and 52.5% of others respondents had a personal history of migraine, with the difference between neurologists and others being statistically significant (p = .03). Migraine in migraineurs and nonmigraine headache in nonmigraineurs were nearly all self-diagnosed. Among neurologist migraineurs, 51.2% experienced migraine with aura and 43% migraine without aura. Conclusions: Migraine prevalence is significantly higher in neurologists compared to non-neurologists and at least 2-3 times higher than reported in population prevalence studies. This may be due to significant under-recognition of migraine in non-neurologists. This under-recognition of migraine may significantly influence the search for genetic predictors and biomarkers of migraine.

Repetitive transcranial magnetic stimulation therapy for motor recovery in Parkinson's disease: A Meta-analysis.

Abstract: INTRODUCTION Therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on motor recovery of Parkinson's disease (PD) have been reported; however, the protocols of these studies varied greatly. The aim of this meta-analysis was to evaluate the optimal rTMS parameters for motor recovery of PD. METHODS Electronic databases were searched for studies investigating the therapeutic effects of rTMS on motor function in patients with PD. The section III of the Unified Parkinson's Disease Rating Scale (UPDRS) was extracted as the primary outcome, and the standardized mean difference (SMD) with 95% confidence interval (CI) was calculated. RESULTS Twenty-three studies with a total of 646 participants were included. The pooled estimates of rTMS revealed significant short-term (SMD, 0.37; p < 0.00001) and long-term (SMD, 0.39; p = 0.005) effects on motor function improvement of PD. Subgroup analysis observed that high-frequency rTMS (HF-rTMS) was significant in improving motor function (SMD, 0.48; p < 0.00001), but low-frequency rTMS (LF-rTMS) was not. In particular, when HF-rTMS targeted over the primary motor cortex (M1), in which the bilateral M1 revealed a larger effect size than unilateral M1. Compared to single-session, multi-session of HF-rTMS over the M1 showed significant effect size. In addition, HF-rTMS over the M1 with a total of 18,000-20,000 stimulation pulses yielded more significant effects (SMD, 0.97; p = 0.01) than other dosages. CONCLUSIONS In conclusion, multi-session of HF-rTMS over the M1 (especially bilateral M1) with a total of 18,000-20,000 pulses appears to be the optimal parameters for motor improvement of PD.

Disability and quality of life 20 years after traumatic brain injury.

Abstract: Objectives The study describes functional outcomes and health-related quality of life (HRQL) in patients with traumatic brain injury (TBI) 20 years postinjury. Materials and methods Forty-four survivors who acquired moderate and severe TBI during 1995-1996 were followed 10 and 20 years postinjury. Outcomes were Glasgow Outcome Scale Extended (GOSE), Community Integration Questionnaire (CIQ), and SF-36 questionnaire (SF-36). Multiple regressions were performed to examine the relationship between follow-up measurements, controlling for baseline demographics and injury severity. Results There were no significant differences in baseline age and civil status between moderate and severe TBI, but patients with severe injury had significantly lower employment rates (p = 0.05). Mean age at 20-years follow-up was 50.8 (SD 11.4) years, and 73% were males. Most patients showed good recovery (52%) or moderate disability (43%). Disability levels remained stable between and within severity groups from 10 to 20 years. Community integration including social integration improved from 10 to 20 years (p = 0.01 and p = 0.005, respectively). HRQL remained stable, except for subscales Bodily Pain and Role Emotional (p = 0.02 and p = 0.06). Depression at 10 years and females were associated with poorer mental health, while productive activity at 10 years indicated better physical and mental health at 20 years postinjury, respectively. Conclusions Functional limitations persist even decades after moderate and severe TBI, with poorer prognosis for females and persons who were depressed at the 10-year follow-up. Development and evaluation of targeted long-term follow-up programs and access to rehabilitation services for these groups should be highlighted. Improved community integration despite stable functional limitations draws attention to long-term adaptation to adversity and illness.

An overview of protective strategies against ischemia/reperfusion injury: The role of hyperbaric oxygen preconditioning

Abstract: Introduction Ischemia/reperfusion (I/R) injury, such as myocardial infarction, stroke, and peripheral vascular disease, has been recognized as the most frequent causes of devastating disorders and death currently. Protective effect of various preconditioning stimuli, including hyperbaric oxygen (HBO), has been proposed in the management of I/R. Methods In this study, we searched and reviewed up-to-date published papers to explore the pathophysiology of I/R injury and to understand the mechanisms underlying the protective effect of HBO as conditioning strategy. Results Animal study and clinic observation support the notion that HBO therapy and conditioning provide beneficial effect against the deleterious effects of postischemic reperfusion. Several explanations have been proposed. The first likely mechanism may be that HBO counteracts hypoxia and reduces I/R injury by improving oxygen delivery to an area with diminished blood flow. Secondly, by reducing hypoxia-ischemia, HBO reduces all the pathological events as a consequence of hypoxia, including tissue edema, increased affective area permeability, postischemia derangement of tissue metabolism, and inflammation. Thirdly, HBO may directly affect cell apoptosis, signal transduction, and gene expression in those that are sensitive to oxygen or hypoxia. HBO provides a reservoir of oxygen at cellular level not only carried by blood, but also by diffusion from the interstitial tissue where it reaches high concentration that may last for several hours, improves endothelial function and rheology, and decreases local inflammation and edema. Conclusion Evidence suggests the benefits of HBO when used as a preconditioning stimulus in the setting of I/R injury. Translating the beneficial effects of HBO into current practice requires, as for the "conditioning strategies", a thorough consideration of risk factors, comorbidities, and comedications that could interfere with HBO-related protection.

Identification of aberrant circulating miRNAs in Parkinson's disease plasma samples

Abstract: Objective To detect the aberrant expression of circulating miRNAs and explore the potential early diagnostic biomarkers in patients with Parkinson's disease (PD). Methods Plasma samples were collected from 25 treatment-naive PD-diagnosed patients and 25 healthy controls followed by a real-time PCR-based miRNA screening analysis of neuron disease-related miRNAs. Results A subset of miRNAs with aberrant expression levels in the plasma of PD-diagnosed patients were identified including upregulation of miR-27a and downregulation of let-7a, let-7f, miR-142-3p, and miR-222 with the AUC values more than 0.8 derived from the receiver operating characteristic curves. Conclusions The high sensitivity and specificity of the circulating miRNAs may enable early diagnosis of PD. The study provides a group of novel miRNA candidates for detecting PD.

Impact of brain-derived neurotrophic factor genetic polymorphism on cognition: A systematic review.

Abstract: Author(s): Toh, Yi Long; Ng, Terence; Tan, Megan; Tan, Azrina; Chan, Alexandre | Abstract: IntroductionBrain-derived neurotrophic factor (BDNF) has an important role in the neurogenesis and neuroplasticity of the brain. This systematic review was designed to examine the association between BDNF Val66Met (rs6265) polymorphism and four cognitive domains-attention and concentration, executive function, verbal fluency, and memory, respectively.MethodologyPrimary literature search was performed using search engines such as PubMed and Scopus. Observational studies that evaluated the neurocognitive performances in relation to BDNF polymorphism within human subjects were included in this review, while animal studies, overlapping studies, and meta-analysis were excluded.ResultsForty of 82 reviewed studies (48.8%) reported an association between Val66Met polymorphism and neurocognitive domains. The proportion of the studies showing positive findings in cognitive performances between Val/Val homozygotes and Met carriers was comparable, at 30.5% and 18.3%, respectively. The highest percentage of positive association between Val66Met polymorphism and neurocognition was reported under the memory domain, with 26 of 63 studies (41.3%), followed by 18 of 47 studies (38.3%) under the executive function domain and four of 23 studies (17.4%) under the attention and concentration domain. There were no studies showing an association between Val66Met polymorphism and verbal fluency. In particular, Val/Val homozygotes performed better in tasks related to the memory domain, while Met carriers performed better in terms of executive function, in both healthy individuals and clinical populations.ConclusionWhile numerous studies report an association between Val66Met polymorphism and neurocognitive changes in executive function and memory domains, the effect of Met allele has not been clearly established.

Curcumin protects neural cells against ischemic injury in N2a cells and mouse brain with ischemic stroke.

Abstract: Background and purpose Curcumin, a natural antioxidant isolated from Curcuma longa, has been reported to exert neuroprotective effect in animal models of ischemic stroke. However, the underlying mechanism is still not fully understood. The purpose of this study was to investigate the effect of curcumin treatment on neuronal apoptosis in the periinfarct cortex after cerebral ischemia/reperfusion (I/R) injury and in mouse N2a cells after oxygen-glucose deprivation/reoxygenation (OGD/R) injury and its underlying mechanism. Methods The cerebral I/R injury was established by 1-hr middle cerebral artery occlusion (MCAO) and reperfusion in mice. Infarct volume was determined by TTC staining, and neurological score was evaluated by mNSS. Cell morphology in the ischemic boundary zone were detected by HE staining. The number and apoptotic rate of neurons in ischemic boundary zone were assayed by immunohistochemistry and TUNEL, respectively. Mouse neuroblastoma N2a cells were subjected to OGD/R. Cell viability was assessed with CCK-8. The mitochondrial membrane potential was measured using JC-1 staining. The expression of Bax, Bcl-2, and caspase-3 was detected using Western blotting. Besides, cellular distribution of Bax was determined by immunofluorescence assays. Results Curcumin treatment reduced infarct volume, improved neurological function, alleviated the morphological damage of neurons, and increased neuronal survival rate after I/R injury in vivo. Moreover, curcumin treatment improved cell viability, reduced cell apoptosis, increased Bcl-2 protein levels while decreased Bax and caspase-3 expressions in mouse N2a cells after OGD/R injury. Besides, curcumin treatment inhibited Bax activation and maintained mitochondrial membrane integrity. Conclusion Curcumin promotes neuron survival in vivo and in vitro to exert neuroprotective effects against ischemia injury. Moreover, our results for the first time demonstrated curcumin inhibited ischemia-induced mitochondrial apoptosis via restricting Bax activation, which may be one of the possible mechanisms underlying the neuroprotective effects of curcumin.

Transcranial DC stimulation modifies functional connectivity of large-scale brain networks in abstinent methamphetamine users.

Abstract: Background Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation tool suited to alter cortical excitability and activity via the application of weak direct electrical currents. An increasing number of studies in the addiction literature suggests that tDCS modulates subjective self-reported craving through stimulation of dorsolateral prefrontal cortex (DLPFC). The major goal of this study was to explore effects of bilateral DLPFC stimulation on resting state networks (RSNs) in association with drug craving modulation. We targeted three large-scale RSNs; the default mode network (DMN), the executive control network (ECN), and the salience network (SN). Methods Fifteen males were recruited after signing written informed consent. We conducted a double-blinded sham-controlled crossover study. Twenty-minute "real" and "sham" tDCS (2 mA) were applied over the DLPFC on two separate days in random order. Each subject received both stimulation conditions with a 1-week washout period. The anode and cathode electrodes were located over the right and left DLPFC, respectively. Resting state fMRI was acquired before and after real and sham stimulation. Subjective craving was assessed before and after each fMRI scan. The RSNs were identified using seed-based analysis and were compared using a generalized linear model. Results Subjective craving decreased significantly after real tDCS compared to sham stimulation (p = .03). Moreover, the analysis shows significant modulation of DMN, ECN, and SN after real tDCS compared to sham stimulation. Additionally, alteration of subjective craving score was correlated with modified activation of the three networks. Discussion Given the observed alteration of the targeted functional brain networks in methamphetamine users, new potentials are highlighted for tDCS as a network intervention strategy and rsfMRI as a suitable monitoring method for these interventions.

The crossed frontal aslant tract: A possible pathway involved in the recovery of supplementary motor area syndrome.

Abstract: Introduction Supplementary motor area (SMA) syndrome is a constellation of temporary symptoms that may occur following tumors of the frontal lobe. Affected patients develop akinesia and mutism but often recover within weeks to months. With our own case examples and with correlations to fiber tracking validated by gross anatomical dissection as ground truth, we describe a white matter pathway through which recovery may occur. Methods Diffusion spectrum imaging from the Human Connectome Project was used for tractography analysis. SMA outflow tracts were mapped in both hemispheres using a predefined seeding region. Postmortem dissections of 10 cadaveric brains were performed using a modified Klingler technique to verify the tractography results. Results Two cases were identified in our clinical records in which patients sustained permanent SMA syndrome after complete disconnection of the SMA and corpus callosum (CC). After investigating the postoperative anatomy of these resections, we identified a pattern of nonhomologous connections through the CC connecting the premotor area to the contralateral premotor and SMAs. The transcallosal fibers have projections from the previously described frontal aslant tract (FAT) and thus, we have termed this path the "crossed FAT." Conclusions We hypothesize that this newly described tract may facilitate recovery from SMA syndrome by maintaining interhemispheric connectivity through the supplementary motor and premotor areas.

POCD in patients receiving total knee replacement under deep vs light anesthesia: A randomized controlled trial.

Abstract: Objectives Clinical observation, as well as randomized controlled trials, indicated an increasing rate of postoperative cognitive dysfunction (POCD) with increasing depth of general anesthesia. However, the findings are subject to bias due to varying degree of analgesia. In this trial, we compared the rate of POCD between patients receiving light versus high anesthesia while holding analgesia comparable using nerve block. Methods Elderly patients (≧60 years) receiving elective total knee replacement were randomized to receive the surgery under general anesthesia at BIS 40-50 (LOBIS group) or BIS 55-65 (HIBIS group). The femoral nerve and the sciatic nerve were blocked under ultrasonic guidance in all patients before induction. Cognitive performance was assessed with Montreal cognitive assessment (MoCA) at the baseline and 1d, 3d, and 7d after the surgery. POCD was defined by Z score of >1.96 using cross-reference. The extubation time and recovery time were also compared. Results A total of 66 patients were randomized; 60 (n = 30 per group) completed trial as the protocol specified. POCD occurred in six patients (20%) in the LOBIS group vs. in one patient (3.3%) in the HIBIS group (Figure 3, p = .04). In all seven cases, the diagnosis of POCD was based on MoCA assessment on 1d after the surgery. Assessment in 3d and 7d after surgery did not reveal POCD in any case. Extubation time was longer in the LOBIS group (12.16 ± 2.58 vs. 5.77 ± 3.01 min in the HIBIS group (p < .001)). The time of comeback of directional ability was 13.47 ± 3.14 and 6.17 ± 3.23 min in the LOBIS and HIBIS groups, respectively (p < .001). Conclusions In elderly patients receiving a total knee replacement, lighter anesthesia could reduce the rate of POCD with complete analgesia during surgery.

Altered functional connectivity in blepharospasm/orofacial dystonia.

Abstract: Introduction Blepharospasm is characterized by involuntary eyelid spasms. It can be associated with perioral dystonia (Meige's syndrome or orofacial dystonia). We aimed at studying resting-state functional brain connectivity in these patients and its potential modulation by therapeutic botulinum toxin injections. Methods We performed resting-state functional MRI and a region of interest-based analysis of functional connectivity in 13 patients with blepharospasm/Meige's syndrome in comparison to 13 healthy controls. Patients were studied before and 4 weeks after botulinum toxin treatment. Simultaneous facial electromyography was applied to control for involuntary facial movements. Results Before botulinum toxin treatment, patients showed reduced functional connectivity between caudate and primary sensorimotor, somatosensory association and visual cortices as well as between putamen and parietal association cortex. Cerebellar areas displayed decreased functional connectivity to somatosensory and visual association cortices. On the cortical level, connectivity was reduced between the cingulate cortex and the primary sensorimotor/premotor and parietal association cortex, between premotor areas and the primary somatosensory cortices, and between the postcentral gyrus and temporoparietal, secondary somatosensory, cingular, and cerebellar regions. Botulinum toxin treatment modulated functional connectivity, especially between cerebellum and visual cortices. Conclusions Patients with blepharospasm/Meige's syndrome show altered functional connectivity at rest in widespread brain regions including basal ganglia, cerebellar, primary/secondary sensorimotor, and visual areas. Functionally, this may reflect a predisposition for defective movement inhibition and sensorimotor integration. Botulinum toxin treatment could modulate brain connectivity in blepharospasm by altering visual and sensory input.

Progressive multiple sclerosis, cognitive function, and quality of life.

Abstract: Background Patients with progressive multiple sclerosis (MS) often have cognitive impairment in addition to physical impairment. The burden of cognitive and physical impairment progresses over time, and may be major determinants of quality of life. The aim of this study was to assess to which degree quality of life correlates with physical and cognitive function in progressive MS. Methods This is a retrospective study of 52 patients with primary progressive (N = 18) and secondary progressive MS (N = 34). Physical disability was assessed using the Expanded Disability Status Scale, Timed 25 Foot Walk (T25FW) test and 9-Hole Peg Test (9HPT). Cognitive function was assessed using Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test, and Trail Making Test B (TRAIL-B). In addition, quality of life was assessed by the Short Form 36 (SF-36) questionnaire. Results Only measures of cognitive function correlated with the overall SF-36 quality of life score and the Mental Component Summary score from the SF-36. The only physical measure that correlated with a measure of quality of life was T25FW test, which correlated with the Physical Component Summary from the SF-36. We found no other significant correlations between the measures of cognitive function and the overall physical measures but interestingly, we found a possible relationship between the 9HPT score for the nondominant hand and the SDMT and TRAIL-B. Conclusion Our findings support inclusion of measures of cognitive function in the assessment of patients with progressive MS as these correlated closer with quality of life than measures of physical impairment.

Altered resting-state hippocampal and caudate functional networks in patients with obstructive sleep apnea.

Abstract: Author(s): Song, Xiaopeng; Roy, Bhaswati; Kang, Daniel W; Aysola, Ravi S; Macey, Paul M; Woo, Mary A; Yan-Go, Frisca L; Harper, Ronald M; Kumar, Rajesh | Abstract: IntroductionBrain structural injury and metabolic deficits in the hippocampus and caudate nuclei may contribute to cognitive and emotional deficits found in obstructive sleep apnea (OSA) patients. If such contributions exist, resting-state interactions of these subcortical sites with cortical areas mediating affective symptoms and cognition should be disturbed. Our aim was to examine resting-state functional connectivity (FC) of the hippocampus and caudate to other brain areas in OSA relative to control subjects, and to relate these changes to mood and neuropsychological scores.MethodsWe acquired resting-state functional magnetic resonance imaging (fMRI) data from 70 OSA and 89 healthy controls using a 3.0-Tesla magnetic resonance imaging scanner, and assessed psychological and behavioral functions, as well as sleep issues. After standard fMRI data preprocessing, FC maps were generated for bilateral hippocampi and caudate nuclei, and compared between groups (ANCOVA; covariates, age and gender).ResultsObstructive sleep apnea subjects showed significantly higher levels of anxiety and depressive symptoms over healthy controls. In OSA subjects, the hippocampus showed disrupted FC with the thalamus, para-hippocampal gyrus, medial and superior temporal gyrus, insula, and posterior cingulate cortex. Left and right caudate nuclei showed impaired FC with the bilateral inferior frontal gyrus and right angular gyrus. In addition, altered limbic-striatal-cortical FC in OSA showed relationships with behavioral and neuropsychological variables.ConclusionsThe compromised hippocampal-cortical FC in OSA may underlie depression and anxious mood levels in OSA, while impaired caudate-cortical FC may indicate deficits in reward processing and cognition. These findings provide insights into the neural mechanisms underlying the comorbidity of mood and cognitive deficits in OSA.

Neural functional architecture and modulation during decision making under uncertainty in individuals with generalized anxiety disorder

Abstract: Background Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) might be effective in treating generalized anxiety disorder (GAD). Cognitive models of GAD highlight the role of intolerance of uncertainty (IU) in precipitating and maintaining worry, and it has been hypothesized that patients with GAD exhibit decision-making deficits under uncertain conditions. Improving understanding of the neural mechanisms underlying cognitive deficits associated with IU may lead to the identification of novel rTMS treatment targets and optimization of treatment parameters. The current report describes two interrelated studies designed to identify and verify a potential neural target for rTMS treatment of GAD. Methods Study I explored the integrity of prefrontal cortex (PFC) and amygdala neural networks, which underlie decision making under conditions of uncertainty, in GAD. Individuals diagnosed with GAD (n = 31) and healthy controls (n = 20) completed a functional magnetic resonance imaging (fMRI) gambling task that manipulated uncertainty using high versus low error rates. In a subsequent randomized-controlled trial (Study II), a subset of the GAD sample (n = 16) completed the fMRI gambling task again after 30 sessions of active versus sham rTMS (1 Hz, right dorsolateral prefrontal cortex) to investigate the modulation of functional networks and symptoms. Results In Study I, participants with GAD demonstrated impairments in PFC-PFC and PFC-amygdala functional connectivity (FC) mostly during the high uncertainty condition. In Study II, one region of interest pair, dorsal anterior cingulate (ACC) - subgenual ACC, showed "normalization" of FC following active, but not sham, rTMS, and neural changes were associated with improvement in worry symptoms. Conclusions These results outline a possible treatment mechanism of rTMS in GAD, and pave the way for future studies of treatment optimization.

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice.

Abstract: INTRODUCTION Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age-related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age-related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways. METHODS Twenty-month-old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins. RESULTS CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin. CONCLUSIONS These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age-related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.

N-back training and transfer effects revealed by behavioral responses and EEG.

Abstract: Introduction Cognitive function performance decreases in older individuals compared to young adults. To curb this decline, cognitive training is applied, but it is not clear whether it improves only the trained task or also other cognitive functions. To investigate this, we considered an N-back working memory (WM) training task and verified whether it improves both trained WM and untrained cognitive functions. Methods As EEG studies have noted task difficulty and age-related changes in time-locked EEG responses, called event-related potentials (ERPs), we focused on the relation between the P300 ERP component, task difficulty level, and behavior response accuracy and reaction time (RT) in young and older healthy adults. We used two groups of young and older healthy participants to assess the effect of N-back training: cognitive training group (CTG) and passive control group (PCG). Before and after training, cognitive tests were administered to both groups to evaluate transfer effects. Results Despite the observed age-related differences in the P300 ERP component and in terms of RT and accuracy, our findings demonstrate a stronger improvement in the trained task for older CTGs compared to younger CTGs, larger near- and far-transfer effect to WM and fluid intelligence for both younger and older CTGs, and a far-transfer effect to attention but only for older adults. Significant differences in response accuracy were shown between young and older subjects in spatial memory and attention tests. Conclusion The application of a WM training is a promising tool for both healthy adults, and in particular for older subjects, as it showed physiological and behavioral differences in cognitive plasticity across life span and evidence of benefits in the trained task and near-/far-transfer effects to other cognitive functions.

Neurodegenerative disease biomarkers Aβ1-40, Aβ1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy.

Abstract: Author(s): Chen, Jason A; Fears, Scott C; Jasinska, Anna J; Huang, Alden; Al-Sharif, Noor B; Scheibel, Kevin E; Dyer, Thomas D; Fagan, Anne M; Blangero, John; Woods, Roger; Jorgensen, Matthew J; Kaplan, Jay R; Freimer, Nelson B; Coppola, Giovanni | Abstract: Background:The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods:To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results:Aβ1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aβ1-40 was heritable. No significant linkage (LOD g 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions:Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aβ1-40 and p-tau181 as potentially valuable biomarkers of these processes.

High expression of the HMGB1-TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging.

Abstract: Objective To detect the expression of high-mobility group box protein 1 (HMGB1) and toll-like receptor 4 (TLR4) and their downstream signaling factors-myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), and tumor necrosis factor alpha (TNF-α)-in the sera of patients with Parkinson's disease (PD) in order to evaluate the relationship of the HMGB1-TLR4 axis with PD development and progression. Methods The serum HMGB1 and TLR4 protein levels of 120 patients with PD and 100 healthy volunteers were measured using double-antibody sandwich ELISA, and their correlations with PD staging, disease duration, drug treatment effectiveness, and clinical classification were analyzed. In addition, their correlations with the key downstream factors of the HMGB1-TLR4 axis (MyD88, NF-κB, and TNF-α) were analyzed. Results HMGB1 and TLR4 expressions were higher in the peripheral blood of patients with PD than in healthy volunteers. PD patients with poor drug treatment outcomes had significantly higher HMGB1 and TLR4 expressions than PD patients with stable drug treatment outcomes. Higher HMGB1 and TLR4 expressions were found in patients at higher PD stages, and patients with >4-year disease duration had significantly higher HMGB1 and TLR4 expressions than patients with <4-year disease duration. No significant difference in HMGB1 and TLR4 expressions was found among patients with tremor-dominant, akinetic-rigid, and mixed subtypes of PD. NF-κB and TNF-α expressions were positively correlated with high expression of the HMGB1-TLR4 axis. Conclusion High expression of the HMGB1-TLR4 axis is closely associated with PD development, progression, drug treatment effectiveness, staging, and disease duration and has great significance for PD diagnosis and treatment.

The association between "Brain-Age Score" (BAS) and traditional neuropsychological screening tools in Alzheimer's disease.

Abstract: Introduction We present the Brain-Age Score (BAS) as a magnetic resonance imaging (MRI)-based index for Alzheimer's disease (AD). We developed a fully automated framework for estimating the BAS in healthy controls (HCs) and individuals with mild cognitive impairment (MCI) or AD, using MRI scans. Methods We trained the proposed framework using 385 HCs from the IXI and OASIS datasets and evaluated 146 HCs, 102 stable-MCI (sMCI), 112 progressive-MCI (pMCI), and 147 AD patients from the J-ADNI dataset. We used a correlation test to determine the association between the BAS and four traditional screening tools of AD: the Mini-Mental State Examination (MMSE), Clinical Dementia Ratio (CDR), Alzheimer's Disease Assessment Score (ADAS), and Functional Assessment Questionnaire (FAQ). Furthermore, we assessed the association between BAS and anatomical MRI measurements: the normalized gray matter (nGM), normalized white matter (nWM), normalized cerebrospinal fluid (nCSF), mean cortical thickness as well as hippocampus volume. Results The correlation results demonstrated that the BAS is in line with traditional screening tools of AD (i.e., the MMSE, CDR, ADAS, and FAQ scores) as well as anatomical MRI measurements (i.e., nGM, nCSF, mean cortical thickness, and hippocampus volume). Discussion The BAS may be useful for diagnosing the brain atrophy level and can be a reliable automated index for clinical applications and neuropsychological screening tools.

Sensor‐based gait analysis in atypical parkinsonian disorders

Abstract: Background and objectives Gait impairment and reduced mobility are typical features of idiopathic Parkinson's disease (iPD) and atypical parkinsonian disorders (APD). Quantitative gait assessment may have value in the diagnostic workup of parkinsonian patients and as endpoint in clinical trials. The study aimed to identify quantitative gait parameter differences in iPD and APD patients using sensor-based gait analysis and to correlate gait parameters with clinical rating scales. Subjects and methods Patients with iPD and APD including Parkinson variant multiple system atrophy and progressive supranuclear palsy matched for age, gender, and Hoehn and Yahr (≤3) were recruited at two Movement Disorder Units and assessed using standardized clinical rating scales (MDS-UPDRS-3, UMSARS, PSP-RS). Gait analysis consisted of inertial sensor units laterally attached to shoes, generating as objective targets spatiotemporal gait parameters from 4 × 10 m walk tests. Results Objective sensor-based gait analysis showed that gait speed and stride length were markedly reduced in APD compared to iPD patients. Moreover, clinical ratings significantly correlated with gait speed and stride length in APD patients. Conclusion Our findings suggest that patients with APD had more severely impaired gait parameters than iPD patients despite similar disease severity. Instrumented gait analysis provides complementary rater independent, quantitative parameters that can be exploited for clinical trials and care.

Sleep disturbances and depression severity in patients with Parkinson's disease.

Abstract: OBJECTIVES Parkinson's disease (PD) is a multisystem movement disorder associated with sleep disturbance and depression. Sleep disturbances and depression severity share a bidirectional association. This association may be greater in individuals who are more vulnerable to the deleterious consequences of sleep disturbance and depression severity. We investigated whether the association between sleep disturbances and depression severity is greater in patients with PD than in matched controls (MC). MATERIALS AND METHODS The study sample (N = 98) included 50 patients with idiopathic PD and 48 age-, race-, sex-, and education-matched controls. Sleep disturbances were assessed using self-reported total sleep time (TST) on the Pittsburgh Sleep Quality Index, the sleep item on the Beck Depression Inventory, 2nd ed. (BDI-II), and the Insomnia Severity Index total score. Depression severity was assessed using the BDI-II total score, excluding the sleep item. Spearman's correlations, chi-squared tests, and multiple regression were used to assess associations between sleep disturbances and depression severity in PD and MC. Fisher's Z transformation was used to test whether the association between sleep disturbances and depression severity was stronger in patients with PD. RESULTS Shorter TST, sleeping less than usual, and insomnia severity were associated with depression severity in the total sample, rs(94) = -0.35, p = .001; rs(71) = 0.51, p < .001; rs(78) = -0.47, p < .001; rs(98) = 0.46, p < .001, respectively. The association between shorter TST and depression severity was greater in patients with PD than it was in MC, p < .05. CONCLUSION Short TST may be an important marker, predictor, or consequence of depression severity in patients with Parkinson's disease.

Timing for cranioplasty to improve neurological outcome: A systematic review

Abstract: INTRODUCTION Cranioplasty is a surgical technique applied for the reconstruction of the skullcap removed during decompressive craniectomy (DC). Cranioplasty improves rehabilitation from a motor and cognitive perspective. However, it may increase the possibility of postoperative complications, such as seizures and infections. Timing of cranioplasty is therefore crucial even though literature is controversial. In this study, we compared motor and cognitive effects of early cranioplasty after DC and assess the optimal timing to perform it. METHODS A literature research was conducted in PubMed, Web of Science, and Cochrane Library databases. We selected studies including at least one of the following test: Mini-Mental State Examination, Rey Auditory Verbal Learning Test immediate and 30-min delayed recall, Digit Span Test, Glasgow Coma Scale, Glasgow Outcome Scale, Coma Recovery Scale-Revised, Level of Cognitive Functioning Scale, Functional Independence Measure, and Barthel Index. RESULTS Six articles and two systematic reviews were included in the present study. Analysis of changes in pre- and postcranioplasty scores showed that an early procedure (within 90 days from decompressive craniectomy) is more effective in improving motor functions (standardized mean difference [SMD] = 0.51 [0.05; 0.97], p-value = 0.03), whereas an early procedure did not significantly improve neither MMSE score (SMD = 0.06 [-0.49; 0.61], p-value = 0.83) nor memory functions (SMD = -0.63 [-0.97; -0.28], p-value < 0.001). No statistical significance emerged when we compared studies according to the timing from DC. CONCLUSIONS It is believed that cranioplasty performed from 3 to 6 months after DC may significantly improve both motor and cognitive recovery.

Maternal separation affects expression of stress response genes and increases vulnerability to ethanol consumption

Abstract: Introduction Maternal separation is an early life stress event associated with behavioral alterations and ethanol consumption. We aimed to expand the current understanding on the molecular mechanisms mediating the impact of postnatal stress on ethanol consumption. Methods In the first experiment (T1), some of the pups were separated from their mothers for 6 hr daily (Maternal Separation group - MS), whereas the other pups remained in the cage with their respective mothers (Control group - C). In the second experiment (T2), mice from both groups were subjected to the model of free-choice between water and sucrose solution or between water and ethanol solution. Maternal behavior was assessed at the end of T1. At the end of both T1 and T2, pups were subjected to the light/dark box behavioral test and blood corticosterone concentrations were analyzed. Results Our maternal separation protocol led to intense maternal care and affected weight gain of the animals. The expression of stress response genes was altered with higher levels of Crh and Pomc being observed in the hypothalamus, and higher levels of Crhr1, Crhr2, Htr2a and lower levels of Nr3c1 and Htr1a being observed in the hippocampus after T1. At the end of T2, we observed higher levels of Avp and Pomc in the hypothalamus, and higher levels of Crhr1, Crhr2, Nr3c1, Slc6a4, Bdnf and lower levels of Htr1a in the hippocampus. Additionally, maternal separation increased vulnerability to ethanol consumption during adolescence and induced changes in anxiety/stress-related behavior after T2. Furthermore, voluntary ethanol consumption attenuated stress response and modified expression of reward system genes: enhancing Drd1 and Drd2, and reducing Gabbr2 in the striatum. Conclusion Maternal separation induced behavioral changes and alterations in the expression of key genes involved in HPA axis and in the serotonergic and reward systems that are likely to increase vulnerability to ethanol consumption in adolescence. We demonstrated, for the first time, that ethanol consumption masked stress response by reducing the activity of the HPA axis and the serotonergic system, therefore, suggesting that adolescent mice from the MS group probably consumed ethanol for stress relieving purposes.

The characteristics of cognitive impairment in subjective chronic tinnitus

Abstract: Introduction Subjective chronic tinnitus is a common medical syndrome with a high frequency of cognitive impairment; however, the characteristics of cognitive impairment in chronic tinnitus are poorly understood. Investigating the scope of cognitive impairment across the severity spectrum of tinnitus patients may shed light on the issue. Methods A consecutive series of 207 subjective chronic tinnitus patients were classified into mild tinnitus group (n = 95) and severe tinnitus group (n = 112) by THI score (the cutoff THI scores were 37/38). These patients were assessed using the Cognitive Abilities Screening Instrument (CASI) and P300 event-related potential. Results Although pure tone averages were not different between mild or severe tinnitus patients, severe tinnitus patients scored lower on the CASI assessment as well as almost all subdomains of CASI, particularly in items such as "short-term memory," "concentration or mental manipulation," "orientation," "abstraction and judgment," "language abilities," and "visual construction." Furthermore, compared to mild tinnitus patients, severe tinnitus patients exhibited longer N2 and P3 latencies. Finally, a correlation analysis revealed that tinnitus severity was negatively correlated with CASI score and positively correlated with N2 and P3 latencies. Conclusions This study reveals that tinnitus patients on the severe end of the spectrum may be at risk for serious cognitive deficits, which may not be a secondary response to disease manifestations but a primary feature of the underlying disease.

Neural bases of enhanced attentional control: Lessons from action video game players

Abstract: Objectives: The ability to resist distraction and focus on-task-relevant information while being responsive to changes in the environment is fundamental to goal-directed behavior. Such attentional control abilities are regulated by a constant interplay between previously characterized bottom-up and top-down attentional networks. Here we ask about the neural changes within these two attentional networks that may mediate enhanced attentional control. Materials and Methods: To address this question, we contrasted action video game players (AVGPs) and nonvideo game players (NVGPs) in a Posner-cueing paradigm, building on studies documenting enhanced attentional control in AVGPs. Results: Behavioral results indicated a trend for more efficient target processing in AVGPs, and better suppression in rare catch trials for which responses had to be withheld. During the cue period, AVGPs recruited the top-down network less than NVGPs, despite showing comparable validity effects, in line with a greater efficiency of that network in AVGPs. During target processing, as previously shown, recruitment of top-down areas correlated with greater processing difficulties, but only in NVGPs. AVGPs showed no such effect, but rather greater activation across the two networks. In particular, the right temporoparietal junction, middle frontal gyrus, and superior parietal cortex predicted better task performance in catch trials. A functional connectivity analysis revealed enhanced correlated activity in AVGPs compared to NVGPs between parietal and visual areas. Conclusions: These results point to dynamic functional reconfigurations of top-down and bottom-up attentional networks in AVGPs as attentional demands vary. Aspects of this functional reconfiguration that may act as key signatures of high attentional control are discussed.

High-definition transcranial direct current stimulation (HD-tDCS) of left dorsolateral prefrontal cortex affects performance in Balloon Analogue Risk Task (BART).

Abstract: Background Studies on risk preferences have long been of great concern and have examined the neural basis underlying risk-based decision making. However, studies using conventional transcranial direct current stimulation (tDCS) revealed that bilateral stimulation could change risk propensity with limited evidence of precisely focalized unilateral high-definition transcranial direct current stimulation (HD-tDCS). The aim of this experiment was to investigate the effect of HD-tDCS focalizing the left dorsal lateral prefrontal cortex (DLPFC) on risk-taking behavior during the Balloon Analogue Risk Task (BART). Methods This study was designed as a between-subject, single-blind, sham-controlled experiment. University students were randomly assigned to three groups: the anodal group (F3 anode, AF3, F1, F5, FC3 returned), the cathodal group (F3 cathodal, AF3, F1, F5, FC3 returned) and the sham group. Subsequently, 1.5-mA 20-min HD-tDCS was applied during the BART, and the Positive Affect and Negative Affect Scale (PANAS), the Sensation Seeking Scale-5 (SSS-5), and the Behavioral Inhibition System and Behavioral Approach System scale (BIS/BAS) were measured as control variables. Results The cathodal group earned less total money than the sham group, and no significant difference was observed between the anodal group and the sham group. Conclusions These results showed that, to some extent, focalized unilateral cathodal HD-tDCS on left DLPFC could change performance during risky tasks and diminish risky decision making. Further studies are needed to investigate the dose effect and electrode distribution of HD-tDCS during risky tasks and examine synchronous brain activity to show the neural basis.

Altered functional networks in long-term unilateral hearing loss: A connectome analysis.

Abstract: Introduction In neuroimaging studies, long-term unilateral hearing loss (UHL) is associated with functional changes in specific brain regions and connections; however, little is known regarding alterations in the topological organization of whole-brain functional networks and whether these alterations are related to hearing behavior in UHL patients. Methods We acquired resting-state fMRI data from 21 patients with UHL caused by acoustic neuromas and 21 matched healthy controls. Whole-brain functional networks were constructed by measuring interregional temporal correlations of 278 brain regions. Alterations in interregional functional connectivity and topological properties (e.g., small-world, efficiency, and nodal centrality) were identified using graph-theory analysis. The subjects also completed a battery of hearing behavior measures. Results Both UHL patients and controls exhibited efficient small-world properties in their functional networks. Compared with controls, UHL patients showed increased and decreased nodal centrality in distributed brain regions. Furthermore, the brain regions with significantly increased and decreased functional connections associated with UHL were components of the following important networks: (1) visual network; (2) higher-order functional networks, including the default-mode and attention networks; and (3) subcortical network and cerebellum. Intriguingly, the changes in intranetwork connections in UHL were significantly correlated with disease duration and hearing level. Conclusions This study revealed connectome-level alterations involved in multiple large-scale networks related to sensory and higher-level cognitive functions in long-term UHL patients. These reorganizations of the brain in UHL patients may depend on the stage of deafness and hearing level. Together, our findings provided empirical evidence for understanding the neuroplastic mechanisms underlying hearing impairment, establishing potential biomarkers for monitoring the progression and further treatment effects for UHL patients.

The importance of hippocampal dynamic connectivity in explaining memory function in multiple sclerosis.

Abstract: Introduction: Brain dynamics (i.e., variable strength of communication between areas), even at the scale of seconds, are thought to underlie complex human behavior, such as learning and memory. In multiple sclerosis (MS), memory problems occur often and have so far only been related to "stationary" brain measures (e.g., atrophy, lesions, activation and stationary (s) functional connectivity (FC) over an entire functional scanning session). However, dynamics in FC (dFC) between the hippocampus and the (neo)cortex may be another important neurobiological substrate of memory impairment in MS that has not yet been explored. Therefore, we investigated hippocampal dFC during a functional (f) magnetic resonance imaging (MRI) episodic memory task and its relationship with verbal and visuospatial memory performance outside the MR scanner. Methods: Thirty-eight MS patients and 29 healthy controls underwent neuropsychological tests to assess memory function. Imaging (1.5T) was obtained during performance of a memory task. We assessed hippocampal volume, functional activation, and sFC (i.e., FC of the hippocampus with the rest of the brain averaged over the entire scan, using an atlas-based approach). Dynamic FC of the hippocampus was calculated using a sliding window approach. Results: No group differences were found in hippocampal activation, sFC, and dFC. However, stepwise forward regression analyses in patients revealed that lower dFC of the left hippocampus (standardized β = -0.30; p = .021) could explain an additional 7% of variance (53% in total) in verbal memory, in addition to female sex and larger left hippocampal volume. For visuospatial memory, lower dFC of the right hippocampus (standardized β = -0.38; p = .013) could explain an additional 13% of variance (24% in total) in addition to higher sFC of the right hippocampus. Conclusion: Low hippocampal dFC is an important indicator for maintained memory performance in MS, in addition to other hippocampal imaging measures. Hence, brain dynamics may offer new insights into the neurobiological mechanisms underlying memory (dys)function.

Functional outcome and survival following spontaneous intracerebral hemorrhage: A retrospective population-based study.

Abstract: BACKGROUND Accurate and reliable clinical and radiological predictors of intracerebral hemorrhage (ICH) outcomes are needed to optimize treatment of ICH. The aim of this study was to investigate functional outcome and identify predictors of severe disability or death following ICH. MATERIALS AND METHODS Retrospective population-based study of spontaneous ICH. Clinical and radiological data were obtained from electronic medical records, and functional outcome estimated using the modified Rankin Scale (mRS) before ICH and at 3 and 12 months after ICH. RESULTS Four hundred and fifty-two patients were included (mean age 74.8 years, 45.6% females). Proportion of fatal outcome at 1 week was 22.1%, at 3 months 39.2%, and at 12 months 44.9%. Median mRS score before the ICH was 1 (interquartile range [IQR] 2); for survivors at 3 months, it was 5 (IQR 3); and at 12 months, it was 3 (IQR 2). Independent predictors of severe disability (mRS of 5) or death (mRS of 6) were use of oral antithrombotic drugs (OR 2.2, 95% CI 1.3-3.8, p = 0.04), mRS score before the ICH (OR 1.8, 95% CI 1.4-2.2, p 60 ml (OR 4.5, 05% CI 2.0-10.2, p < 0.001), and intraventricular hematoma extension (OR 1.8, 95% CI 0.8-4.2, p < 0.001). CONCLUSION Intracerebral hemorrhage is associated with high mortality, and more than one third of survivors end up with severe disability or death 3 months later. Predictors of severe disability or death were use of oral antithrombotic drugs, functional disability prior to ICH, low GCS on admission, larger hematoma volume, and intraventricular hematoma extension.