Frontal Cortex Research Articles

Incidental learning of predictive temporal context within cortical representations of visual shape.

Abstract Incidental learning of spatio-temporal regularities and consistencies— also termed ‘statistical learning’— may be important for discovering the causal principles governing the world. We studied statistical learning of temporal structure simultaneously at two time-scales: the presentation of synthetic visual objects (3 s) and predictive temporal context (30 s) in the order of appearance of such objects. Visual objects were complex and rotated in three dimensions about varying axes. Observers viewed fifteen (15) objects recurring many times each, intermixed with other objects that appeared only once, while whole-brain BOLD activity was recorded. Over three successive days, observers grew familiar with the recurring objects and reliably distinguished them from others. As reported elsewhere (Kakaei & Braun, 2023), representational similarity analysis (RSA) of multivariate BOLD activity revealed 124 ‘object-selective’ brain parcels with selectivity for recurring objects, located mostly in the ventral occipitotemporal cortex and the parietal cortex. Here we extend RSA to the representation of predictive temporal context, specifically “temporal communities” formed by objects that tended to follow each other. After controlling for temporal proximity, we observed 27 ‘community-sensitive’ brain parcels, in which pairwise distances between multivariate responses reflected community structure, either positively (smaller distances within than between communities) or negatively (larger distances within). Among object-selective parcels, 11 parcels were positively community-sensitive in the primary visual cortex (2 parcels), the ventral occipital, lingual, or fusiform cortex (8 parcels), and the inferior temporal cortex (1 parcel). Among non-object-selective parcels, 12 parcels were negatively community-sensitive in the superior, middle, and medial frontal cortex (6 parcels), the insula (2 parcels), the putamen (1 parcel), and in the superior temporal or parietal cortex (3 parcels). We conclude that cortical representations of object shape and of predictive temporal context are largely coextensive along the ventral occipitotemporal cortex.

Analysis of functional network asymmetry in major depressive disorder under four fNIRS tasks

BackgroundResearch in functional asymmetry of Major Depressive Disorder (MDD) under different tasks is crucial for clinical diagnose. MethodsFifty individuals with MDD and twenty healthy controls (HCS) were recruited for hemodynamic data collection under four fNIRS tasks (Emotional picture, Verbal fluency, Fingering and Negative emotional picture description task). Integral values and functional connectivity strength were employed to probe neural activation and functional connectivity in frontal and temporal lobes in MDD. Following, asymmetry characteristic of the frontal cortex between MDD and HCS under four tasks were carefully analyzed and compared. ResultsIndividuals with MDD demonstrated heightened connectivity between the frontal and right temporal lobes and reduced connectivity between the frontal and left temporal lobes compared to HCS in all tasks. Additionally, MDD exhibited attenuated activation in the left frontal lobes and exaggerated activation in the right frontal lobes, diverging from HCS. Furthermore, the disparities in left-right asymmetry characteristic of frontal cortex activation between MDD and HCS were more pronounced during the combined task. LimitationsFurther research is required to grasp the neurophysiological mechanisms governing left-right asymmetry across various tasks and the influence of task-induced brain fatigue on cerebral cortex hemodynamics in MDD. ConclusionThe left-right asymmetry feature provides valuable neurophysiological insights for diagnosing MDD clinically. Variations in activation patterns and functional connectivity features between MDD and HCS are closely tied to the task chosen. Thus, in clinical practice, carefully selecting appropriate fNIRS tasks and relevant features can significantly improve the diagnostic accuracy of MDD.

New functional dissociations between prefrontal and parietal cortex during task switching: A combined fMRI and TMS study

Preparatory control in task-switching has been suggested to rely upon a set of distributed regions within a frontoparietal network, with frontal and parietal cortical areas cooperating to implement switch-specific preparation processes. Although recent causal evidence using transcranial magnetic stimulation (TMS) have generally supported this model, alternative results from both functional neuroimaging and neurophysiological studies have questioned the switch-specific role of both frontal and parietal cortices. The aim of the present study was to clarify the involvement of prefrontal and parietal areas in preparatory cognitive control. With this purpose, an fMRI study was conducted to identify the brain areas activated during cue events in a task-switching paradigm, indicating whether to switch or to repeat among numerical tasks. Then, TMS was applied over the specific coordinates previously identified through fMRI, that is, the right inferior frontal gyrus (IFG) and right intraparietal sulcus (IPS). Results revealed that TMS over the right IFG disrupted performance in both switch and repeat trails in terms of delayed responses as compared to Sham condition. In contrast, TMS over the right IPS selectively interfered performance in switch trials. These findings support a multi-component model of executive control with the IFG being involved in more general switch-unspecific process such as the episodic retrieval of goals, and the IPS being related to the implementation of switch-specific preparation mechanisms for activating stimulus-response mappings. The results are discussed within the framework of contemporary hierarchical models of prefrontal cortex organization, suggesting that distinct prefrontal areas may carry out coordinated functions in preparatory control.

Overexpression of the Apoe gene in the frontal cortex of mice causes sex-dependent changes in learning, attention, and anxiety-like behavior.

Apolipoprotein E (ApoE) is a protein that is important for lipid storage, transport, and metabolism. APOE gene variants are associated with Alzheimer's disease (AD), as well as attentional function in healthy humans. Previous research has shown that Apoe transcription is increased following stimulation of the pathway between the locus coeruleus (LC) and frontal cortex (FC) in mice. This result suggests that Apoe may affect attentional function by virtue of its expression in circuits that control attention. Does Apoe causally regulate attention, or is its expression simply a byproduct of neuronal activity in the LC and FC? To answer this question, we synthetically induced Apoe transcription in the FC of male and female mice, and subsequently tested their ability to learn a touchscreen-based rodent version of the continuous performance test of sustained attention (the rCPT). We found that increased Apoe transcription impaired performance when attentional demand was increased in male mice, while in female mice, increased Apoe transcription significantly accelerated rCPT learning. We further found that this increase in Apoe transcription affected subsequent anxiety-like behavior and cellular activity in the FC in a sex-dependent manner. The results of this study provide insight into how Apoe causally regulates translationally relevant behaviors in rodent models.

Brain Glucose Metabolism and COMT Val 158 Met Polymorphism in Female Patients with Work-Related Stress.

Stress is a ubiquitous challenge in modern societies. Symptoms range from mood swings and cognitive impairment to autonomic symptoms. This study explores the link between work-related stress and the neurobiological element of brain processing, testing the hypothesis that patients with occupational stress have altered cerebral glucose consumption compared to healthy controls. The participants' present conditions were evaluated using an adapted WHO SCAN interview. Neural activity at rest was assessed by positron emission tomography (PET) with the glucose analogue [18F]fluorodeoxyglucose. Participants were genotyped for the Val158Met polymorphism of the COMT gene, believed to influence stress resilience. This study included 11 women with work-related stress and 11 demographically comparable healthy controls aged 28-62 years, with an average of 46.2 years. The PET scans indicated clusters of decreased glucose consumption primarily located in the white matter of frontal lobe sub-gyral areas in stress patients. COMT Val158Met polymorphism detection indicated no immediate relation of the homozygous alleles and stress resilience; however, healthy controls mainly had the heterozygous allele. In conclusion, the results support that work-related stress does affect the brain in the form of altered glucose metabolism, suggesting neurobiological effects could be related to white matter abnormalities rather than gray matter deterioration. Genotyping indicates a more complex picture than just that of the one type being more resilient to stress. Further studies recruiting a larger number of participants are needed to confirm our preliminary findings.

TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism.

TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS. The coding regions of TBK1, SOD1, TARDBP, and FUS were genetically analyzed using Sanger sequencing. Repeat-primed PCR was used to survey the GGGGCC repeat in C9ORF72. The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies. We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization. The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.

HIV transcription persists in the brain of virally suppressed people with HIV.

HIV persistence in the brain is a barrier to cure, and potentially contributes to HIV-associated neurocognitive disorders. Whether HIV transcription persists in the brain despite viral suppression with antiretroviral therapy (ART) and is subject to the same blocks to transcription seen in other tissues and blood, is unclear. Here, we quantified the level of HIV transcripts in frontal cortex tissue from virally suppressed or non-virally suppressed people with HIV (PWH). HIV transcriptional profiling of frontal cortex brain tissue (and PBMCs where available) from virally suppressed (n = 11) and non-virally suppressed PWH (n = 13) was performed using digital polymerase chain reaction assays (dPCR). CD68+ myeloid cells or CD3+ T cells expressing HIV p24 protein present in frontal cortex tissue was detected using multiplex immunofluorescence imaging. Frontal cortex brain tissue from PWH had HIV TAR (n = 23/24) and Long-LTR (n = 20/24) transcripts. Completion of HIV transcription was evident in brain tissue from 12/13 non-virally suppressed PWH and from 5/11 virally suppressed PWH, with HIV p24+CD68+ cells detected in these individuals. While a block to proximal elongation was present in frontal cortex tissue from both PWH groups, this block was more extensive in virally suppressed PWH. These findings suggest that the brain is a transcriptionally active HIV reservoir in a subset of virally suppressed PWH.

Functional network characteristics in anxiety- and mania-based subgroups of bipolar I disorder

BackgroundBipolar disorder I (BD-I) is a heterogeneous disorder with a high prevalence of comorbid anxiety. The aim of this study was to investigate whether anxiety and mania symptoms define distinct subgroups within BD-I and to explore potential differences in functional network characteristics between these subgroups. MethodsSubgroups were identified using scores from clinical anxiety and mania scales. After dimension reduction of these scores, data-driven clustering analysis with cross-validation was employed to reveal the existence of subgroups. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were pre-processed using fMRIPrep. After parcellation and network construction, global and regional graph theoretical measures were calculated per subgroup. ResultsClustering results revealed that, based on anxiety symptomatology, subjects fell into two distinct subgroups, whereas mania symptoms divided subjects into four unique subgroups. These subgroups varied notably on several symptom scales. Network assortativity was significantly associated with anxiety subgroups. Post-hoc pairwise comparisons did not reveal significant global functional network differences between the anxiety subgroups or between mania subgroups. Regional network differences between clinical subgroups were especially apparent for strength and degree in the temporal and frontal lobes. LimitationsSmall sample size of some subgroups is a limitation of this study as is the categorical rather than continuous representation of anxiety and mania symptoms. ConclusionsBD-I populations may be stratified into robust subgroups based on anxiety and mania symptoms, showing differences in functional network connectivity. Our findings highlight new avenues of research for investigating heterogeneity in psychiatric populations.

Real-world analysis of brain atrophy in multiple sclerosis patients with an artificial intelligence based software tool

BackgroundAtrophy of white and grey matter volumes occurs early in the brains of people with multiple sclerosis (pwMS) and has great clinical relevance. In clinical trials, brain atrophy can be quantified by magnetic resonance imaging (MRI) with automated software tools.MethodsIn this study, we analyze volumes of various brain regions with the software “md brain” based on routine MRI scans of 53 pwMS in a real-world setting. We compare brain volumes of pwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years to the brain volumes of pwMS with an EDSS < 3.5 and a disease duration < 10 years as well as with or without immunotherapy.ResultspwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years had significantly lower volumes of the total brain, the grey matter and of the frontal, temporal, parietal and occipital lobe regions as compared to pwMS with an EDSS < 3.5 and a disease duration < 10 years. Regional brain volumes were significantly lower in pwMS without immunotherapy.ConclusionsThe study showed that higher EDSS, longer disease duration and absence of immunotherapy was associated with lower volumes in a number of brain regions. Further real-world studies may include larger patient cohorts in longitudinal analyses.

Caffeine and modafinil modulate the effects of sleep deprivation on thalamic resting-state functional connectivity: A double-blind pilot study

BackgroundStudies have found that the use of clinically approved caffeine and modafinil can alleviate cognitive impairment due to sleep deprivation (SD) to some extent. However, the neural mechanisms by which these two cognitive enhancers work to counteract the effects of SD on cognitive impairment remain unclear. MethodsA double-blind within-subjects experiment using resting-state functional magnetic resonance imaging (rs-fMRI) was designed. Participants underwent three 36-h SD trials, each of which involved taking 200 mg of caffeine, modafinil, or placebo at the 28th and 32 nd h of SD. Sixteen subregions of the thalamus were selected as the regions of interest and changes in functional connectivity (FC) between the thalamus and the other brain regions were explored after the participants took caffeine or modafinil. ResultsThe subjective sleepiness of the participants increased with the duration of SD. compared with placebo, modafinil and caffeine had insignificant effects on wakefulness or sleepiness. However, in terms of neural FC, we found varying degrees of attenuation or enhancement of the FC between the thalamus and other regions. Taking caffeine during SD weakened the FC between the right rostral temporal thalamus (rTtha) subregion and the left lingual gyrus compared with placebo. Caffeine enhanced the FC between three subregions of the thalamus, namely the left sensory thalamus, the left rTtha, and the right lateral pre-frontal thalamus, and the right inferior temporal, left orbitofrontal, and right superior occipital gyris. Modafinil weakened the FC between the right posterior parietal thalamus and left middle temporal gyrus, and enhanced the FC between the left medial pre-frontal thalamus, left rTtha, and right occipital thalamus and left middle frontal gyrus. ConclusionsAfter 36 h of total SD, modafinil and caffeine administration enhanced or attenuated the time-domain correlations between various subregions of the thalamus and brain regions of the frontal and temporal lobes in healthy adults, compared with placebo. These results provide valuable evidence for further unraveling the neuropharmacological mechanisms of caffeine and modafinil, as well as important insights for exploring effective pharmacological intervention strategies against SD.

Age-related alterations in human cortical microstructure across the lifespan: Insights from high-gradient diffusion MRI.

The human brain undergoes age-related microstructural alterations across the lifespan. Soma and Neurite Density Imaging (SANDI), a novel biophysical model of diffusion MRI, provides estimates of cell body (soma) radius and density, and neurite density in gray matter. The goal of this cross-sectional study was to assess the sensitivity of high-gradient diffusion MRI toward age-related alterations in cortical microstructure across the adult lifespan using SANDI. Seventy-two cognitively unimpaired healthy subjects (ages 19-85 years; 40 females) were scanned on the 3T Connectome MRI scanner with a maximum gradient strength of 300mT/m using a multi-shell diffusion MRI protocol incorporating 8 b-values and diffusion time of 19 ms. Intra-soma signal fraction obtained from SANDI model-fitting to the data was strongly correlated with age in all major cortical lobes (r = -0.69 to -0.60, FDR-p < 0.001). Intra-soma signal fraction (r = 0.48-0.63, FDR-p < 0.001) and soma radius (r = 0.28-0.40, FDR-p < 0.04) were significantly correlated with cortical volume in the prefrontal cortex, frontal, parietal, and temporal lobes. The strength of the relationship between SANDI metrics and age was greater than or comparable to the relationship between cortical volume and age across the cortical regions, particularly in the occipital lobe and anterior cingulate gyrus. In contrast to the SANDI metrics, all associations between diffusion tensor imaging (DTI) and diffusion kurtosis imaging metrics and age were low to moderate. These results suggest that high-gradient diffusion MRI may be more sensitive to underlying substrates of neurodegeneration in the aging brain than DTI and traditional macroscopic measures of neurodegeneration such as cortical volume and thickness.

Selective attention function impairment in HIV-negative patients with early forms of neurosyphilis

BackgroundThe attentional network test (ANT) is widely used to evaluate the performance of three attentional networks: alerting, orienting and executive attention networks. This study aimed to investigate the characteristics of attention functions in HIV-negative patients with early forms of neurosyphilis (NS) and their correlation with abnormalities in brain magnetic resonance imaging (MRI).MethodsThirty patients with early forms of NS, 31 patients with syphilis but without NS (Non-NS) and 35 healthy controls were recruited from an HIV-negative cohort between September 2020 and November 2022. The participants were evaluated with the ANT and the Mini-Mental State Examination (MMSE). Brain MRI was performed in NS and Non-NS patients.ResultsNo significant differences were observed in the MMSE scores among the three groups. However, patients with early forms of NS showed poorer performance in orienting and alerting functions than Non-NS group (F = 6.952, P = 0.011 and F = 8.794, P = 0.004, respectively); No significant difference was observed in executive function between the two groups (F = 0.001, P = 0.980). Multivariate analysis of variance using the Bonferroni post hoc test indicated that patients with NS exhibited less efficient orienting function (P = 0.023), and alerting function (P = 0.003) but not executive function (P = 0.99), compared to Non-NS patients. Additionally, a significant difference was found in orienting function between patients with NS and healthy controls (P < 0.001) compared to healthy controls. MRI scans revealed that the NS group had a higher prevalence of abnormalities in the frontal lobes and/or the temporoparietal junction compared to the Non-NS group (24/25 vs. 13/19, P = 0.032).ConclusionsThe orienting and alerting functions but not executive function were significantly less efficient in early forms of NS group than in the Non-NS group (P < 0.01). This indicates deficits in selective attention in patients with early forms of NS. Brain MRI scans revealed abnormalities in the frontal and/or parietal lobes, as well as the temporoparietal junction, suggesting potential neuropathological correlates of these attentional deficits.

Usefulness of combined pseudo-continuous arterial spin labelling and spectroscopic analysis in schizophrenic Egyptian population sample

BackgroundSchizophrenia is a prevalent psychiatric disorder that affects 1% of the global population. Schizophrenia frequently begins in late adolescence or early adulthood, causing significant educational, social, and economic costs for people and society. Functional neuroimaging research on schizophrenia physiopathology has been beneficial. Arterial spin labelling (ASL) is one of functional magnetic resonance imaging (fMRI) technologies that assess brain function without radiation. ASL uses magnetic resonance (MR) imaging to quantify tissue-level brain perfusion non-invasively. Arterial spin labelling (ASL) is one of the functional magnetic resonance imaging (fMRI) technologies that assess the brain function without radiation hazards. ASL uses magnetic resonance (MR) imaging to quantify tissue-level brain perfusion non-invasively. Many publications were performed on role of different advanced MRI techniques in schizophrenia, but our study insisted on the added value of combined ASL and MRS over the conventional MRI in schizophrenic Egyptian population sample.Aim of the workThe purpose of this work was to evaluate the added value of combined ASL-perfusion MRI and MRS in schizophrenic patients.MethodsThis prospective case–control study was carried out on two groups: First group was 30 patients who were diagnosed clinically as schizophrenic patients, and second group was 20 healthy volunteers as a control group for comparison in the period from August 2021 till July 2022.ResultsThe majority of newly diagnosed cases had significant higher positive symptoms than chronic cases. According to arterial spin labelling (ASL) data, rCBF was noticed to be reduced in anterior cingulate, frontal lobe, and parietal lobe of both patients’ subgroups but more significant in chronically ill patients. Convergent results of decreased rCBF were also found in the parietal lobe and occipital lobe. Magnetic resonance spectroscopic analysis showed that NAA was decreased in the anterior cingulate cortex, thalami and basal ganglia of the newly diagnosed cases more than chronic cases. The ASL-MRI perfusion accurately detected the hypo-perfusion of different brain regions with sensitivity 100%, specificity 66.67%, positive predictive value 96.43%, negative predictive value 100%, and accuracy 96.67%, while MR spectroscopy showed sensitivity 100%, specificity 33.33%, positive predictive value 93.10%, negative predictive value 100%, and accuracy 93.33% in evaluation of changes of brain metabolites.ConclusionASL is a promising functional MRI technique that can produce together with MRS quantitative information about the metabolites of different brain regions. The ASL-MRI appears as a reliable non-invasive technique to measure cerebral blood flow and identify decreased rCBF without any contrast administration, and it could be repeatable which helps in early diagnosis as well as follow-up of the progression of the disease.

Gradual change of cortical representations with growing visual expertise for synthetic shapes

Abstract Objective: Visual expertise for particular categories of objects (e.g., mushrooms, birds, flowers, minerals, and so on) is known to enhance cortical responses in parts of the ventral occipitotemporal cortex. How is such additional expertise integrated into the prior cortical representation of life-long visual experience? To address this question, we presented synthetic visual objects rotating in three dimensions and recorded multivariate BOLD responses as initially unfamiliar objects gradually became familiar. Main results: An analysis of pairwise distances between multivariate BOLD responses (“representational similarity analysis,” RSA) revealed that visual objects were linearly discriminable in large parts of the ventral occipital cortex, including the primary visual cortex, as well as in certain parts of the parietal and frontal cortex. These cortical representations were present from the start, when objects were still unfamiliar, and even though objects were shown from different sides. As shapes became familiar with repeated viewing, the distribution of responses expanded to fill more of the available space. In contrast, the distribution of responses to novel shapes (which appeared only once) contracted and shifted to the margins of the available space. Conclusion: Our results revealed cortical representations of object shape and gradual changes in these representations with learning and consolidation. The cortical representations of once-viewed shapes that remained novel diverged dramatically from repeatedly viewed shapes that became familiar. This disparity was evident in both the similarity and the diversity of multivariate BOLD responses.

Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome.

We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolatedfrom postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.

Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease

Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

Independent expansion, selection and hypervariability of the TBC1D3 gene family in humans.

TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 non-human primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on Chromosome 17. We find that all human copy number variation maps to two distinct clusters located at Chromosome 17q12 and that humans are highly structurally variable at this locus, differing by as many as 20 copies and ~1 Mbp in length depending on haplotypes. We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Lastly, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.

Combination antiretroviral therapy prevents SIV- induced aging in the hippocampus and neurodegeneration throughout the brain.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated neurocognitive disorders (HAND) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining acute infection, and cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and altered expression of SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions, and treatment with cART reduced GFAP expression in SIV-infected animals and thus likely decreases inflammation in the brain. Importantly, cART reversed SIV-induced accelerated aging (p16 and SIRT1) and neurodegeneration in the frontal lobe and hippocampus. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HAND.

Developmental trajectory and sex differences in auditory processing in a PTEN-deletion model of autism spectrum disorders

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.

Unveiling hierarchy and spatial distribution of O6-methylguanine-DNA methyltransferase promoter methylation in World Health Organization grade 2-3 gliomas.

This study investigated the role of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. Our findings highlighted the critical role of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. In conclusion, our study elucidates the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas, providing insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.