Functional and structural studies investigating macroscopic connectivity in the human cerebral cortex suggest that high-order associative regions exhibit greater connectivity compared to primary ones. However, the synaptic organization of these brain regions remains unexplored. In the present work, we conducted volume electron microscopy to investigate the synaptic organization of the human brain obtained at autopsy. Specifically, we examined layer III of Brodmann areas 17, 3b, and 4, as representative areas of primary visual, somatosensorial, and motor cortex. Additionally, we conducted comparative analyses with our previous datasets of layer III from temporopolar and anterior cingulate associative cortical regions (Brodmann areas 24, 38, and 21). 9,690 synaptic junctions were 3D reconstructed, showing that certain synaptic characteristics are specific to particular regions. The number of synapses per volume, the proportion of the postsynaptic targets, and the synaptic size may distinguish one region from another, regardless of whether they are associative or primary cortex. By contrast, other synaptic characteristics were common to all analyzed regions, such as the proportion of excitatory and inhibitory synapses, their shapes, their spatial distribution, and a higher proportion of synapses located on dendritic spines. The present results provide further insights into the synaptic organization of the human cerebral cortex.

Noninvasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS), are emerging as promising tools for enhancing cognitive functions by modulating brain activity and enhancing cognitive functions. Despite their potential, the specific and combined effects of tDCS and tRNS on brain functions, especially regarding functional connectivity, cortical inhibition, and memory performance, are not well-understood. This study aims to explore the distinct and combined impacts of tDCS and tRNS on these neural and cognitive parameters. Using a within-subject design, ten participants underwent four stimulation conditions: sham, tDCS, tRNS, and combined tDCS + tRNS. We assessed the impact on resting-state functional connectivity, cortical inhibition via Cortical Silent Period (CSP), and visuospatial memory performance using the Corsi Block-tapping Test (CBT). Our results indicate that while tDCS appears to induce brain lateralization, tRNS has more generalized and dispersive effects. Interestingly, the combined application of tDCS and tRNS did not amplify these effects but rather suggested a non-synergistic interaction, possibly due to divergent mechanistic pathways, as observed across fMRI, CSP, and CBT measures. These findings illuminate the complex interplay between tDCS and tRNS, highlighting their non-additive effects when used concurrently and underscoring the necessity for further research to optimize their application for cognitive enhancement.

The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB), in maintaining Adenosine triphosphate (ATP) levels. Alzheimer\'s disease (AD) has been linked to increased CKB oxidation and loss of its regulatory function, although specific pathological processes and affected cell types remain unclear. In our study, cerebral cortex samples from individuals with AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Combining immunofluorescence (IF) and mass spectrometry (MS), we explored CKB availability in AD and DLB cases. IF and Western blot analysis demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology. However, transcriptomics data and targeted MS demonstrated unaltered total CKB levels, suggesting posttranslational modifications (PTMs) affecting antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment. These findings highlight that the proper function of astrocytes, understudied in the brain compared with neurons, is highly affected by PTMs. Reduction in ATP levels within astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. As CKB and the creatine-phosphocreatine cycle are important in securing constant ATP availability, PTMs in CKB, and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity could be promising biomarkers for monitoring early-stage energy deficits in AD.

UNASSIGNED: There are well-established relationships between aging and neurodegenerative changes, and between aging and hearing loss. The goal of this study was to determine how structural brain aging is influenced by hearing loss.
UNASSIGNED: Human Connectome Project Aging (HCP-A) data were analyzed, including T1-weighted MRI and Words in Noise (WIN) thresholds (n=623). Freesurfer extracted gray and white matter volume, and cortical thickness, area, and curvature. Linear regression models targeted (1) interactions between age and WIN threshold and (2) correlations with WIN threshold adjusted for age, both corrected for false discovery rate (pFDR<0.05).
UNASSIGNED: WIN threshold moderated age-related increase in volume in bilateral inferior lateral ventricles, with higher threshold associated with increased age-related ventricle expansion. Age-related deterioration in occipital cortex was also increased with higher WIN thresholds. When controlling for age, high WIN threshold was correlated with reduced cortical thickness in Heschl\'s gyrus, calcarine sulcus, and other sensory regions, and reduced temporal lobe white matter. Older volunteers with poorer hearing and cognitive scores had the lowest volume in left parahippocampal white matter.
UNASSIGNED: Preserved hearing abilities in aging associated with a reduction of age-related changes to medial temporal lobe, and preserved hearing at any age associated with preserved cortical tissue in auditory and other sensory regions. Future longitudinal studies are needed to assess the causal nature of these relationships, but these results indicate interventions which preserve hearing function may combat some neurodegenerative changes in aging.

Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., \"lunatic fringe\" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms.
METHODS: In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0-30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects.
RESULTS: The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] standardized = 0.03, 95%CI = 0.01-0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ([Formula: see text] sstandardized = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] sstandardized = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] sstandardized = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] standardized = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13-49% of variance in cognitive and functional scales and 6-14% of variance in neuropsychiatric scales.
CONCLUSIONS: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.

UNASSIGNED: Major depressive disorder (MDD) is highly prevalent, affecting more than 300 million individuals worldwide, and its occurrence may be related to the abnormality of the prefrontal cortex and bilateral temporal cortex. Acupuncture, rooted in the theories of acupoints and meridians, has demonstrated its efficacy in regulating cortical blood flow (CBF) in the brains of MDD patients. As one form of acupuncture, intradermal acupuncture (IA) can alleviate clinical symptoms such as depressive mood and insomnia in MDD patients. However, it remains unknown whether IA will have a specific effect on the prefrontal cortex and bilateral temporal cortex in MDD patients.
UNASSIGNED: In total, 60 participants will be recruited: 20 healthy control participants and 40 MDD patients. All healthy control participants will be allocated to the control group, whereas the 40 MDD patients will be randomly divided into two groups: the gallbladder meridian acupoint (GBA) group and the non-acupoint (NA) group, at a 1:1 allocation ratio. All groups will undergo a one-time IA intervention while their cortical activity is monitored using functional near-infrared spectroscopy (fNIRS). Total hemoglobin, oxygenated hemoglobin, and deoxygenated hemoglobin of the prefrontal and bilateral temporal cortices will be measured by fNIRS during the test procedure.
UNASSIGNED: This trial aims to use fNIRS to compare real-time hemodynamic changes in the prefrontal and bilateral temporal cortices of healthy individuals and MDD patients during IA. The primary objective is to investigate whether MDD patients exhibit specific real-time responses to IA stimulation in these brain regions. The findings from this study will provide clinical data and a possible theoretical basis for the assumption that stimulation of IA may treat MDD by modulating the relevant brain regions.
UNASSIGNED: The study protocol has been registered in the clinicaltrials.gov with the code NCT05707299.

BACKGROUND: This study aimed to delineate the association between menopausal-related symptoms and brain cortical hemodynamics in peri-postmenopause women.
METHODS: Cross-sectional data from a total of 358 Han-Chinese women who visited the Menopause Clinic in the Shanghai Sixth People\'s Hospital from August 2019 to August 2022. Menopausal-related symptoms were analyzed through Kupperman index (KMI) scale and PSQI scale, while cerebral blood flow was measured using a functional near-infrared spectroscopy (fNIRS). Multiple linear regression model was used to assess the risk factors for subregions of brain hemodynamic response.
RESULTS: After adjusting for confounding factors, we identified that menopausal symptom (B = -1.575, 95 % CI (-2.661, -0.488), p = 0.005) and duration of menopause (B = -14.583, 95 % CI (-26.753, -4.192), p = 0.007) were independently associated with the lower brain hemodynamic response in the prefrontal lobe, while in the temporal lobe, overweight (BMI ≥ 24 kg/m2) was negatively associated with the lower brain cortical activity (B = -36.882, 95 % CI (-72.708, -1.056), p = 0.044) after adjusting for other confounding variables.
CONCLUSIONS: Our findings proposed that menopausal symptom and overweight should be attached great importance to the postmenopausal women, which provides clinical evidence for the feasible early detection and effective prevention such as menopausal hormone therapy (MHT) of brain health in postmenopausal women.

Aged rhesus monkeys, like aged humans, show declines in cognitive function. We present cognitive test data from a large sample of male and female rhesus monkeys, 34 young (aged 3.5-13.6 years) and 71 aged (aged 19.9-32.5 years at the start of cognitive testing). Monkeys were tested on spatiotemporal working memory (delayed response), visual recognition memory (delayed nonmatching to sample), and stimulus-reward association learning (object discrimination), tasks with an extensive evidence base in nonhuman primate neuropsychology. On average, aged monkeys performed worse than young on all 3 tasks. Acquisition of delayed response and delayed nonmatching to sample was more variable in aged monkeys than in young. Performance scores on delayed nonmatching to sample and object discrimination were associated with each other, but neither was associated with performance on delayed response. Sex and chronological age were not reliable predictors of individual differences in cognitive outcome among the aged monkeys. These data establish population norms for multiple cognitive tests in young and aged rhesus monkeys in the largest sample reported to date. They also illustrate independence of cognitive aging in task domains dependent on the prefrontal cortex and medial temporal lobe.

Visual processing in the brain has been understood as the ventral and dorsal pathways processing \"what\" and \"where\" information, respectively. Mocz et al. (Mocz V, Vaziri-Pashkam M, Chun M, Xu Y. J Cogn Neurosci 34: 2406-2435, 2022), however, report that the two pathways code object features in a parallel manner. These results support that information processing in the dorsal pathway is not strictly limited to \"where\" and that the two pathways work in parallel to process task-relevant information (\"what we do with it\").