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• Auditory and frontal cortex responses were recorded after hearing loss. • Mice show recovery of evoked responses and temporal processing in the absence of ABR. • Temporal processing recovery is cortical region-specific after hearing loss. • Poor recovery in frontal cortex may link hearing loss and cognitive decline. Noise-induced hearing loss (NIHL) studies have focused on the lemniscal auditory pathway, but little is known about how NIHL impacts different cortical regions. Here we compared response recovery trajectories in the auditory and frontal cortices (AC, FC) of mice following NIHL. We recorded EEG responses from awake mice (male n = 15, female n = 14) before and following NIHL (longitudinal design) to quantify event related potentials and gap-in-noise temporal processing. Hearing loss was verified by measuring the auditory brainstem response (ABR) before and at 1-, 10-, 23–, and 45-days after noise-exposure. Resting EEG, event related potentials (ERP) and auditory steady state responses (ASSR) were recorded at the same time-points after NIHL. The inter-trial phase coherence (ITPC) of the ASSR was measured to quantify the ability of AC and FC to synchronize responses to short gaps embedded in noise. Despite the absence of click-evoked ABRs up to 90 dB SPL and up to 45-days post-exposure, ERPs from the AC and FC showed full recovery in ∼ 50 % of the mice to pre-NIHL levels in both AC and FC. The ASSR ITPC was reduced following NIHL in AC and FC in all the mice on day 1 after NIHL. The AC showed full recovery of ITPC over 45-days. Despite ERP amplitude recovery, the FC does not show recovery of ASSR ITPC. These results indicate post-NIHL plasticity with similar response amplitude recovery across AC and FC, but cortical region-specific trajectories in temporal processing recovery. [ABSTRACT FROM AUTHOR]

The neural mechanisms of motor planning have been extensively studied in rodents. Preparatory activity in the frontal cortex predicts upcoming choice, but limitations of typical tasks have made it challenging to determine whether the spatial information is in a selfcentered direction reference frame or a world-centered position reference frame. Here, we trained male rats to make delayed visually guided orienting movements to six different directions, with four different target positions for each direction, which allowed us to disentangle direction versus position tuning in neural activity. We recorded single unit activity from the rat frontal orienting field (FOF) in the secondary motor cortex, a region involved in planning orienting movements. Population analyses revealed that the FOF encodes two separate 2D maps of space. First, a 2D map of the planned and ongoing movement in a self-centered direction reference frame. Second, a 2Dmap of the animal's current position on the port wall in a world-centered reference frame. Thus, preparatory activity in the FOF represents self-centered upcoming movement directions, but FOF neurons multiplex both self- and world-reference frame variables at the level of single neurons. Neural network model comparison supports the view that despite the presence of world-centered representations, the FOF receives the target information as self-centered input and generates self-centered planning signals. [ABSTRACT FROM AUTHOR]

Aims: Anxiety often coexists with migraine, and both conditions share a commonality in oxidative/nitrosative stress and mitochondrial dysfunction contributing to their pathogenesis. β‐Sitosterol, a plant sterol, has shown promise in mitigating oxidative/nitrosative stress, enhancing mitochondrial function, and exerting neuroprotective effects. In this study, we investigated the impact of β‐sitosterol on migraine‐associated anxiety and whether this effect was associated with alleviation of oxidative/nitrosative stress and improvement in mitochondrial function. Methods: Nitroglycerin was used to induce migraine in adult male Wistar rats. β‐Sitosterol treatment consisted of daily intraperitoneal injections (10 mg/kg) for 10 days following migraine induction. Anxiety levels were evaluated using open‐field test (OFT) and hole‐board test (HBT). Frontal cortex samples were analyzed for malondialdehyde (MDA), glutathione (GSH), reactive oxygen/nitrogen species, nitric oxide (NO) (markers of oxidative/nitrosative stress), and ATP (indicator of mitochondrial function). Results: Migraine induction led to impaired performance in both the OFT and the HBT. Concurrently, it elevated MDA, reactive oxygen/nitrogen species, and NO levels while diminishing GSH levels in the frontal cortex, signifying heightened oxidative/nitrosative stress. Moreover, ATP levels decreased, indicating mitochondrial dysfunction. Treatment with β‐sitosterol significantly restored performance in both behavioral assays and normalized the levels of MDA, GSH, reactive oxygen/nitrogen species, NO, and ATP. Conclusion: β‐Sitosterol exerted anxiolytic effects in migraine, which can be attributed to its ability to ameliorate oxidative/nitrosative stress and enhance mitochondrial function. [ABSTRACT FROM AUTHOR]

Aromatase inhibitors (AIs) are associated with sleep difficulties in breast cancer (BC) patients. Sleep is known to favor memory consolidation through the occurrence of specific oscillations, i.e., slow waves (SW) and sleep spindles, allowing a dialogue between prefrontal cortex and the hippocampus. Interestingly, neuroimaging studies in BC patients have consistently shown structural and functional modifications in these two brain regions. With the aim to evaluate sleep oscillations related to memory consolidation during AIs, we collected polysomnography data in BC patients treated (AI+, n = 17) or not (AI-, n = 17) with AIs compared to healthy controls (HC, n = 21). None of the patients had received chemotherapy and radiotherapy was finished since at least 6 months, that limit the confounding effects of other treatments than AIs. Fast and slow spindles were detected during sleep stage 2 at centro-parietal and frontal electrodes respectively. SW were detected at frontal electrodes during stage 3. Here, we show lower frontal SW densities in AI + patients compared to HC. These results concord with previous reports about frontal cortical alterations in cancer following AIs administration. Moreover, AI + patients tended to have lower spindle density at C4 electrode. Regression analyses showed that, in both patient groups, spindle density at C4 electrode explained a large variance of memory performances. Slow spindle characteristics did not differ between groups and sleep oscillations characteristics of AI- patients did not differ significantly from those of both AI + patients and HC. Overall, our results add to the compelling evidence of the systemic effects of AIs previously reported in animals, with deleterious effects on cortical activity during sleep and associated memory consolidation in the current study. There is thus a need to further investigate sleep modifications during AIs administration. Longitudinal studies are needed to confirm these findings and investigation in other cancers on this topic should be conducted. • Frontal slow wave density is lower during aromatase inhibitors treatment. • Seemly, centro-parietal spindle density tend to be lower. • Spindle density is related to memory performance. • Aromatase inhibitors for breast cancer modify sleep-related memory consolidation. • Current patients' results confirm previous reports in animal models. [ABSTRACT FROM AUTHOR]

The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making. [ABSTRACT FROM AUTHOR]

Subjective cognitive decline (SCD) is a high‐risk population in the preclinical stage of Alzheimer's disease (AD), and olfactory dysfunction is a risk factor for dementia progression. The present study aimed to explore the patterns of functional connectivity (FC) changes in the olfactory neural circuits during olfactory stimulation in SCD subjects. A total of 56 SCD subjects and 56 normal controls (NCs) were included. All subjects were assessed with a cognitive scale, an olfactory behavior test, and olfactory task‐based functional magnetic resonance imaging scanning. The FC differences in olfactory neural circuits between the two groups were analyzed by the generalized psychophysiological interaction. Additionally, we calculated and compared the activation of brain regions within the olfactory neural circuits during odor stimulation, the volumetric differences in brain regions showing FC differences between groups, and the correlations between neuroimaging indicators and olfactory behavioral and cognitive scale scores. During odor stimulation, the FC between the bilateral primary olfactory cortex (bPOC) and the right hippocampus in the SCD group was significantly reduced; while the FC between the right hippocampus and the right frontal cortex was significantly increased in the SCD group. The bPOC of all subjects showed significant activation, but no significant difference in activation between groups was found. No significant differences were observed in the volume of the brain regions within the olfactory neural circuits or in olfactory behavior between groups. The volume of the bPOC and right frontal cortex was significantly positively correlated with olfactory identification, and the volume of the right frontal cortex and right hippocampus was significantly correlated with cognitive functions. Furthermore, a significant correlation between the activation of bPOC and the olfactory threshold was found in the whole cohort. These results suggested that while the structure of the olfactory neural circuits and olfactory behavior in SCD subjects remained stable, there were significant changes observed in the FC of the olfactory neural circuits (specifically, the POC‐hippocampus‐frontal cortex neural circuits) during odor stimulation. These findings highlight the potential of FC alterations as sensitive imaging markers for identifying high‐risk individuals in the early stage of AD. [ABSTRACT FROM AUTHOR]

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 microisolated from 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. [ABSTRACT FROM AUTHOR]

• hAPOEε4 rats made more errors and used a non-spatial cognitive strategy. • Primiparous hAPOEε4 rats increased use of a non-spatial cognitive strategy. • Parity increased neurogenesis in wildtype rats, but decreased it in hAPOEε4 rats. • Primiparous hAPOEε4 rats had less active new neurons following memory retrieval. • Parity and hAPOEε4 affect the neuroimmune milieu in a region-specific manner. Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer's disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate inflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscore the importance of considering female-specific factors and genotype in health research. [ABSTRACT FROM AUTHOR]

Stress-induced alterations in central neuron metabolism and function are crucial contributors to depression onset. However, the metabolic dysfunctions of the neurons associated with depression and specific molecular mechanisms remain unclear. This study initially analyzed the relationship between cholesterol and depression using the NHANES database. We then induced depressive-like behaviors in mice via restraint stress. Applying bioinformatics, pathology, and molecular biology, we observed the pathological characteristics of brain cholesterol homeostasis and investigated the regulatory mechanisms of brain cholesterol metabolism disorders. Through the NHANES database, we initially confirmed a significant correlation between cholesterol metabolism abnormalities and depression. Furthermore, based on successful stress mouse model establishment, we discovered the number of cholesterol-related DEGs significantly increased in the brain due to stress, and exhibited regional heterogeneity. Further investigation of the frontal cortex, a brain region closely related to depression, revealed stress caused significant disruption to key genes related to cholesterol metabolism, including HMGCR, CYP46A1, ACAT1, APOE, ABCA1, and LDLR, leading to an increase in total cholesterol content and a significant decrease in synaptic proteins PSD-95 and SYN. This indicates cholesterol metabolism affects neuronal synaptic plasticity and is associated with stress-induced depressive-like behavior in mice. Adeno-associated virus interference with NR3C1 in the prefrontal cortex of mice subjected to short-term stress resulted in reduced protein levels of NRIP1, NR1H2, ABCA1, and total cholesterol content. At the same time, it increased synaptic proteins PSD95 and SYN, effectively alleviating depressive-like behavior. Therefore, these results suggest that short-term stress may induce cholesterol metabolism disorders by activating the NR3C1/NRIP1/NR1H2 signaling pathway. This impairs neuronal synaptic plasticity and consequently participates in depressive-like behavior in mice. These findings suggest that abnormal cholesterol metabolism in the brain induced by stress is a significant contributor to depression onset. [ABSTRACT FROM AUTHOR]

Background: Since the introduction of combination antiretroviral therapy (cART) the brain has become an important human immunodeficiency virus (HIV) reservoir due to the relatively low penetration of many drugs utilized in cART into the central nervous system (CNS). Given the inherent limitations of directly assessing acute HIV infection in the brains of people living with HIV (PLWH), animal models, such as humanized mouse models, offer the most effective means of studying the effects of different viral strains and their impact on HIV infection in the CNS. To evaluate CNS pathology during HIV-1 infection in the humanized bone marrow/liver/thymus (BLT) mouse model, a histological analysis was conducted on five CNS regions, including the frontal cortex, hippocampus, striatum, cerebellum, and spinal cord, to delineate the neuronal (MAP2ab, NeuN) and neuroinflammatory (GFAP, Iba-1) changes induced by two viral strains after 2 weeks and 8 weeks post-infection. Results: Findings reveal HIV-infected human cells in the brain of HIV-infected BLT mice, demonstrating HIV neuroinvasion. Further, both viral strains, HIV-1JR-CSF and HIV-1CH040, induced neuronal injury and astrogliosis across all CNS regions following HIV infection at both time points, as demonstrated by decreases in MAP2ab and increases in GFAP fluorescence signal, respectively. Importantly, infection with HIV-1JR-CSF had more prominent effects on neuronal health in specific CNS regions compared to HIV-1CH040 infection, with decreasing number of NeuN+ neurons, specifically in the frontal cortex. On the other hand, infection with HIV-1CH040 demonstrated more prominent effects on neuroinflammation, assessed by an increase in GFAP signal and/or an increase in number of Iba-1+ microglia, across CNS regions. Conclusion: These findings demonstrate that CNS pathology is widespread during acute HIV infection. However, neuronal loss and the magnitude of neuroinflammation in the CNS is strain dependent indicating that strains of HIV cause differential CNS pathologies. [ABSTRACT FROM AUTHOR]

Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25–57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration. [ABSTRACT FROM AUTHOR]

The aging of attentional and emotional functions has been extensively studied but relatively independently. Therefore, the relationships between aging and the interactions of attentional and emotional processes remain elusive. This study aimed to determine how age affected the interactions between attentional and emotional processes during adulthood. One-hundred forty adults aged 18–79 performed the emotional variant of the Attention Network Test, which probed alerting, orienting, and executive control in the presence and absence of threatening faces. During this task, contexts with varying levels of task preparatory processes were created to modulate the effect of threatening faces on attention, and functional near-infrared spectroscopy (fNIRS) was used to examine the neural underpinnings of the behavioural effects. The behavioural results showed that aging was associated with a significant decline in alerting efficiency, and there was a statistical trend for age-related deficits in executive control. Despite these age differences, age did not significantly moderate the interactions among attentional networks or between attention and emotion. Additionally, the fNIRS results showed that decreased frontal cortex functioning might underlie the age-related decline in executive control. Therefore, while aging has varying effects on different attentional networks, the interactions of attentional and emotional processes remain relatively unaffected by age. [ABSTRACT FROM AUTHOR]

Converging evidence has revealed disturbances in the corticostriatolimic system are associated with suicidal behaviors in adults with major depressive disorder. However, the neurobiological mechanism that confers suicidal vulnerability in depressed adolescents is largely unknown. A total of 86 depressed adolescents with and without prior suicide attempts (SA) and 47 healthy controls underwent resting-state functional imaging (R-fMRI) scans. The dynamic amplitude of low-frequency fluctuations (dALFF) was measured using sliding window approach. We identified SA-related alterations in dALFF variability primarily in the left middle temporal gyrus, inferior frontal gyrus, middle frontal gyrus (MFG), superior frontal gyrus (SFG), right SFG, supplementary motor area (SMA) and insula in depressed adolescents. Notably, dALFF variability in the left MFG and SMA was higher in depressed adolescents with recurrent suicide attempts than in those with a single suicide attempt. Moreover, dALFF variability was capable of generating better diagnostic and prediction models for suicidality than static ALFF. Our findings suggest that alterations in brain dynamics in regions involved in emotional processing, decision-making and response inhibition are associated with an increased risk of suicidal behaviors in depressed adolescents. Furthermore, dALFF variability could serve as a sensitive biomarker for revealing the neurobiological mechanisms underlying suicidal vulnerability. [ABSTRACT FROM AUTHOR]

Neural oscillations are associated with diverse computations in the mammalian brain. The waveform shape of oscillatory activity measured in the cortex relates to local physiology and can be informative about aberrant or dynamically changing states. However, how waveform shape differs across distant yet functionally and anatomically related cortical regions is largely unknown. In this study, we capitalize on simultaneous recordings of local field potentials (LFPs) in the auditory and frontal cortices of awake, male Carollia perspicillata bats to examine, on a cycle-by-cycle basis, waveform shape differences across cortical regions. We find that waveform shape differs markedly in the fronto-auditory circuit even for temporally correlated rhythmic activity in comparable frequency ranges (i.e., in the delta and gamma bands) during spontaneous activity. In addition, we report consistent differences between areas in the variability of waveform shape across individual cycles. A conceptual model predicts higher spike-spike and spike-LFP correlations in regions with more asymmetric shapes, a phenomenon that was observed in the data: spike-spike and spike-LFP correlations were higher in the frontal cortex. The model suggests a relationship between waveform shape differences and differences in spike correlations across cortical areas. Altogether, these results indicate that oscillatory activity in the frontal and auditory cortex possesses distinct dynamics related to the anatomical and functional diversity of the fronto-auditory circuit. [ABSTRACT FROM AUTHOR]

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 (β standardized = 0.02, 95%CI = 0.01–0.04), CDS (β standardized = 0.02, 95%CI = 0.01–0.04), and FAQ (β 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 (β sstandardized = 0.17–0.29, ps < 0.01) and FAQ (β sstandardized = 0.21–0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI (β sstandardized = 0.21–0.29, ps < 0.05); frontal cortex was associated with higher BRI (β 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. Conclusion: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE. [ABSTRACT FROM AUTHOR]

The disconnection of neuronal circuitry through synaptic loss is presumed to be a major driver of age‐related cognitive decline. Age‐related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through maintenance or vulnerability of synaptic connections remains unknown. Previous work using rodent and primate models leveraged various techniques to imply that age‐related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus. Here, we examined the effect of aging on synapses on projection neurons forming a hippocampal‐cortico‐thalamic circuit important for spatial working memory tasks from two genetically distinct mouse strains that exhibit susceptibility (C57BL/6J) or resistance (PWK/PhJ) to cognitive decline during aging. Across both strains, synapse density on CA1‐to‐PFC projection neurons appeared completely intact with age. In contrast, we found synapse loss on PFC‐to‐nucleus reuniens (RE) projection neurons from aged C57BL/6J but not PWK/PhJ mice. Moreover, synapses from aged PWK/PhJ mice but not from C57BL/6J exhibited altered morphologies that suggest increased efficiency to drive depolarization in the parent dendrite. Our findings suggest resistance to age‐related cognitive decline results in part by age‐related synaptic adaptations, and identification of these mechanisms in PWK/PhJ mice could uncover new therapeutic targets for promoting successful cognitive aging and extending human health span. [ABSTRACT FROM AUTHOR]

• Focal transcranial direct current stimulation (tDCS) of auditory cortex changes cerebral blood flow and connectivity in tinnitus. • Tinnitus loudness ratings decreased on average after five sessions of active focal tDCS. • Acute changes in auditory, thalamic, and prefrontal function may predict quieter tinnitus after five sessions. The goal of this pilot study was to understand how focal transcranial direct current stimulation (tDCS) targeting auditory cortex changes brain function in chronic tinnitus using magnetic resonance imaging (MRI). People with chronic tinnitus were randomized to active or sham tDCS on five consecutive days in this mechanistic trial (n = 10/group). Focal 4x1 tDCS (central anode, surround cathodes) targeted left auditory cortex, with single-blind 2 mA current during twenty-minute sessions. Arterial spin-labeled and blood oxygenation level dependent MRI occurred immediately before and after the first tDCS session, and tinnitus symptoms were measured starting one week before the first tDCS session and through four weeks after the final session. Acute increases in cerebral blood flow and functional connectivity were noted in auditory cortex after the first active tDCS session. Reduced tinnitus loudness ratings after the final tDCS session correlated with acute change in functional connectivity between an auditory network and mediodorsal thalamus and prefrontal cortex. Reduced tinnitus intrusiveness also correlated with acute change in connectivity between precuneus and an auditory network. Focal auditory-cortex tDCS can influence function in thalamus, auditory, and prefrontal cortex, which may associate with improved tinnitus. With future refinement, tDCS targeting auditory cortex could become a viable intervention for tinnitus. [ABSTRACT FROM AUTHOR]

HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer's disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in relation to the pathology of Alzheimer's disease has not yet been studied in detail. Here, we investigated whether HMGB1 protein levels in brain tissue homogenates (frontal cortex and striatum) and sera from Tg-APP/PS1 mice, along with its cellular and subcellular localization in those regions, differed. Total HMGB1 levels were increased in the frontal cortices of aged wildtype (7.5 M) mice compared to young (3.5 M) mice, whereas total HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice (7.5 M) were significantly lower than those in age-matched wildtype mice. In contrast, total serum HMGB1 levels were enhanced in aged wildtype (7.5 M) mice and Tg-APP/PS1 mice (7.5 M). Further analysis indicated that nuclear HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice were significantly reduced compared to those in age-matched wildtype controls, and cytosolic HMGB1 levels were also significantly decreased. Triple-fluorescence immunohistochemical analysis indicated that HMGB1 appeared as a ring shape in the cytoplasm of most neurons and microglia in the frontal cortices of 9.5 M Tg-APP/PS1 mice, indicating that nuclear HMGB1 is reduced by aging and in Tg-APP/PS1 mice. Consistent with these observations, Aβ treatment of both primary cortical neuron and primary microglial cultures increased HMGB1 secretion in the media, in an Aβ-dose-dependent manner. Our results indicate that nuclear HMGB1 might be translocated from the nucleus to the cytoplasm in both neurons and microglia in the brains of Tg-APP/PS1 mice, and that it may subsequently be secreted extracellularly. [ABSTRACT FROM AUTHOR]

Performance monitoring that supports ongoing behavioral adjustments is often examined in the context of either choice confidence for perceptual decisions (i.e., "did I get it right?") or reward expectation for reward-based decisions (i.e., "what reward will I receive?"). However, our understanding of how the brain encodes these distinct evaluative signals remains limited because they are easily conflated, particularly in commonly used two-alternative tasks with symmetric rewards for correct choices. Previously we used a motion-discrimination task with asymmetric rewards to identify neural substrates of forming reward-biased perceptual decisions in the caudate nucleus (part of the striatum in the basal ganglia) and the frontal eye field (FEF, in prefrontal cortex). Here we leveraged this task design to partially decouple estimates of accuracy and reward expectation and examine their impacts on subsequent decisions and their representations in those two brain areas. We identified distinguishable representations of these two evaluative signals in individual caudate and FEF neurons, with regional differences in their distribution patterns and time courses. We observed that well-trained monkeys (both sexes) used both evaluative signals, infrequently but consistently, to adjust their subsequent decisions. We found further that these behavioral adjustments had reliable relationships with the neural representations of both evaluative signals in caudate, but not FEF. These results suggest that the cortico-striatal decision network may use diverse evaluative signals to monitor and adjust decision-making behaviors, adding to our understanding of the different roles that the FEF and caudate nucleus play in a diversity of decision-related computations. [ABSTRACT FROM AUTHOR]

Schizophrenia is a serious cognitive disorder characterized by disruptions in neurotransmission, a process requiring the coordination of multiple kinase-mediated signaling events. Evidence suggests that the observed deficits in schizophrenia may be due to imbalances in kinase activity that propagate through an intracellular signaling network. Specifically, 3′-5′-cyclic adenosine monophosphate (cAMP)-associated signaling pathways are coupled to the activation of neurotransmitter receptors and modulate cellular functions through the activation of protein kinase A (PKA), an enzyme whose function is altered in the frontal cortex in schizophrenia. In this study, we measured the activity of PKA in human postmortem anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) tissue from schizophrenia and age- and sex-matched control subjects. No significant differences in PKA activity were observed in male and female individuals in either brain region; however, correlation analyses indicated that PKA activity in the ACC may be influenced by tissue pH in all subjects and by age and tissue pH in females. Our data provide novel insights into the function of PKA in the ACC and DLPFC in schizophrenia. [ABSTRACT FROM AUTHOR]

Recent morphometric magnetic resonance imaging (MRI) studies suggested the possibility that valproate (VPA) use is associated with parieto‐occipital cortical thinning in patients with heterogeneous epilepsy syndromes. In this study, we examined the effect of VPA on the brain volume using a large number of homogenous patients with idiopathic generalized epilepsy. Voxel‐based morphometry was used to compare regional gray matter (GM) volume between 112 patients currently taking VPA (VPA+ group), 81 patients not currently taking VPA (VPA– group), and 120 healthy subjects (control group). The VPA+ group showed a significant GM volume reduction in the bilateral cerebellum, hippocampus, insula, caudate nucleus, medial frontal cortex/anterior cingulate cortex, primary motor/premotor cortex, medial occipital cortex, and anteromedial thalamus, as compared to the control group. The VPA– group showed a significant GM volume reduction in the anteromedial thalamus and right hippocampus/temporal cortex, as compared to the control group. Compared to the VPA– group, the VPA+ group had a significant GM volume reduction in the bilateral cerebellum, primary motor/premotor cortex, and medial frontal cortex/anterior cingulate cortex. We have provided evidence that VPA use could result in GM volume reductions in the frontal cortex and cerebellum. Our findings should be acknowledged as a potential confounding factor in morphometric MRI studies that include subjects taking VPA. [ABSTRACT FROM AUTHOR]

It has been suggested that the neuro-visceral integration works asymmetrically and that this asymmetry is dynamic and modifiable by physio-pathological influences. Aminopeptidases of the renin–angiotensin system (angiotensinases) have been shown to be modifiable under such conditions. This article analyzes the interactions of these angiotensinases between the left or right frontal cortex (FC) and the same enzymes in the hypothalamus (HT), pituitary (PT), adrenal (AD) axis (HPA) in control spontaneously hypertensive rats (SHR), in SHR treated with a hypotensive agent in the form of captopril (an angiotensin-converting enzyme inhibitor), and in SHR treated with a hypertensive agent in the form of the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). In the control SHR, there were significant negative correlations between the right FC with HPA and positive correlations between the left FC and HPA. In the captopril group, the predominance of negative correlations between the right FC and HPA and positive correlations between the HPA and left FC was maintained. In the L-NAME group, a radical change in all types of interactions was observed; particularly, there was an inversion in the predominance of negative correlations between the HPA and left FC. These results indicated a better balance of neuro-visceral interactions after captopril treatment and an increase in these interactions in the hypertensive animals, especially in those treated with L-NAME. [ABSTRACT FROM AUTHOR]

The amygdala contains androgen receptors and is involved in various affective and social functions. An interaction between testosterone and the amygdala's functioning is likely. We investigated the amygdala's resting-state functional connectivity (rsFC) network in association with testosterone in 94 healthy young adult women and men (final data available for analysis from 42 women and 39 men). Across the whole sample, testosterone was positively associated with the rsFC between the right amygdala and the right middle occipital gyrus, and it further predicted lower agreeableness scores. Significant sex differences appeared for testosterone and the functional connectivity between the right amygdala and the right superior frontal gyrus (SFG), showing higher testosterone levels with lower connectivity in women. Sex further predicted the openness and agreeableness scores. Our results show that testosterone modulates the rsFC between brain areas involved in affective processing and executive functions. The data indicate that the cognitive control of the amygdala via the frontal cortex is dependent on the testosterone levels in a sex-specific manner. Testosterone seems to express sex-specific patterns (1) in networks processing affect and cognition, and (2) in the frontal down-regulation of the amygdala. The sex-specific coupling between the amygdala and the frontal cortex in interaction with the hormone levels may drive sex-specific differences in a variety of behavioral phenomena that are further associated with psychiatric illnesses that show sex-specific prevalence rates. [ABSTRACT FROM AUTHOR]

(1) Objective: Narcissism is characterized by emotional regulation deficits, a lack of empathy for others, and extreme self-focus. Narcissism has also been linked to an increased desire for fame and celebrity worship. Here, the neuroscience underlying narcissism is examined in order to determine what regions and networks of the brain are altered when non-narcissistic individuals are compared to participants with both grandiose and vulnerable narcissism. (2) Methods: The behavioral relationships between grandiose narcissism and desire for fame and vulnerable narcissism and celebrity worship are explored, along with a possible relationship at the neural level between these constructs. In this paper, we review research demonstrating that increased levels of grandiose narcissism are associated with an increase in obsession with fame, while vulnerable narcissism is associated with celebrity worship. (3) Results: Based on current data, the frontal regions underlie narcissism and also likely underlie celebrity worship and desire for fame. This tenuous conclusion is based on a limited number of studies. (4) Conclusions: The brain areas associated with grandiose narcissism may be associated with an intense desire for fame as well, while brain regions associated with vulnerable narcissism may be similar in celebrity worshipers. Future research studies on the brain that are specifically designed to test these relationships at a neurological level are needed. [ABSTRACT FROM AUTHOR]

The activity in the open field, short- and long-term memory in the novel object recognition test, and gait features were evaluated in 6- and 12-month-old male C57BL/6 mice. The levels of norepinephrine, dopamine, serotonin, and their metabolites were determined in the cerebellum and frontal cortex. In the observed age range, a decrease in locomotion speed, impairment of gait initiation and stability, and long-term memory deficit were revealed. In the cerebral cortex, reduced levels of dopamine and its metabolites and accelerated metabolism of all neurotransmitters under study were found. In the cerebellum, the content of all studied monoamines was elevated, while dopamine metabolism was decelerated. Analysis of correlations between the neurochemical and behavioral parameters showed that the mechanisms of compensation of brain functions during the early aging may be associated with an increase in activity of the monoaminergic systems in the cerebellum. [ABSTRACT FROM AUTHOR]

Histological and biochemical analyses in postmortem tissues have demonstrated neurodegenerative changes in the cerebral cortex in patients with Alzheimer's disease (AD), and it has been suggested that this represents a loss of synapses. PET imaging of the (pre)synaptic vesicular glycoprotein 2A (SV2A) has demonstrated a reduction in synapse density in AD in the hippocampus but not consistently in the neocortex. This investigation examines the level of [3H]UCB-J binding in postmortem cortical tissue from patients with AD and matched healthy controls using autoradiography. Among the neocortical areas examined, the binding was significantly lower only in the middle frontal gyrus in AD compared to matched controls. No differences were observed in the parietal, temporal, or occipital cortex. The binding levels in the frontal cortex in the AD cohort displayed large variability among subjects, and this revealed a highly significant negative association with the age of the patient. These results demonstrate low UCB-J binding in the frontal cortex of patients with AD, and this biomarker correlates negatively with age, which may further indicate that SV2A could be an important biomarker in AD patients. [ABSTRACT FROM AUTHOR]

Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS. [ABSTRACT FROM AUTHOR]

Learning and recognition can be improved by sorting novel items into categories and subcategories. Such hierarchical categorization is easy when it can be performed according to learned rules (e.g., "if car, then automatic or stick shift" or "if boat, then motor or sail"). Here, we present results showing that human participants acquire categorization rules for new visual hierarchies rapidly, and that, as they do, corresponding hierarchical representations of the categorized stimuli emerge in patterns of neural activation in the dorsal striatum and in posterior frontal and parietal cortex. Participants learned to categorize novel visual objects into a hierarchy with superordinate and subordinate levels based on the objects' shape features, without having been told the categorization rules for doing so. On each trial, participants were asked to report the category and subcategory of the object, after which they received feedback about the correctness of their categorization responses. Participants trained over the course of a one-hour-long session while their brain activation was measured using functional magnetic resonance imaging. Over the course of training, significant hierarchy learning took place as participants discovered the nested categorization rules, as evidenced by the occurrence of a learning trial, after which performance suddenly increased. This learning was associated with increased representational strength of the newly acquired hierarchical rules in a corticostriatal network including the posterior frontal and parietal cortex and the dorsal striatum. We also found evidence suggesting that reinforcement learning in the dorsal striatum contributed to hierarchical rule learning. [ABSTRACT FROM AUTHOR]

The zona incerta (ZI) is involved in mediating survival behaviors and is connected to a wide range of cortical and subcortical structures, including key basal ganglia nuclei. Based on these connections and their links to behavioral modulation, we propose that the ZI is a connectional hub for mediating between top-down and bottom-up control and a possible target for deep brain stimulation for obsessive-compulsive disorder. We analyzed the trajectory of cortical fibers to the ZI in nonhuman and human primates based on tracer injections in monkeys and high-resolution diffusion magnetic resonance imaging in humans. The organization of cortical and subcortical connections within the ZI were identified in the nonhuman primate studies. Monkey anatomical data and human diffusion magnetic resonance imaging data showed a similar trajectory of fibers/streamlines to the ZI. Prefrontal cortex/anterior cingulate cortex terminals all converged within the rostral ZI, with dorsal and lateral areas being most prominent. Motor areas terminated caudally. Dense subcortical reciprocal connections included the thalamus, medial hypothalamus, substantia nigra/ventral tegmental area, reticular formation, and pedunculopontine nucleus and a dense nonreciprocal projection to the lateral habenula. Additional connections included the amygdala, dorsal raphe nucleus, and periaqueductal gray. Dense connections with dorsal and lateral prefrontal cortex/anterior cingulate cortex cognitive control areas and the lateral habenula and the substantia nigra/ventral tegmental area, coupled with inputs from the amygdala, hypothalamus, and brainstem, suggest that the rostral ZI is a subcortical hub positioned to modulate between top-down and bottom-up control. A deep brain stimulation electrode placed in the rostral ZI would not only involve connections common to other deep brain stimulation sites but also capture several critically distinctive connections. [ABSTRACT FROM AUTHOR]

• Examined cross-sectional, age-related volumetric changes in the nonhuman primate brain. • Magnetic resonance imaging analysis revealed several sex differences in normalized brain regions. • Negative trajectories in cortical and subcortical gray matter varied regionally. • Change in white matter volume varied regionally, but many with a middle-age peak and decline. • Frontal cortex is particularly susceptible, with volumetric loss in both gray and white matter. The rhesus macaque is a long-lived nonhuman primate (NHP) with a brain structure similar to humans, which may represent a valuable translational animal model in which to study human brain aging. Previous magnetic resonance imaging (MRI) studies of age in rhesus macaque brains have been prone to low statistical power, unbalanced sex ratio and lack of a complete age range. To overcome these problems, the current study surveyed structural T1-weighted magnetic resonance imaging scans of 66 animals, 34 females (aged 6-31 years) and 32 males (aged 5-27 years). Differences observed in older animals, included enlargement of the lateral ventricles and a smaller volume in the frontal cortex, caudate, putamen, hypothalamus, and thalamus. Unexpected, greater volume, were measured in older animals in the hippocampus, amygdala, and globus pallidus. There were also numerous differences between males and females with respect to age in both white and gray matter regions. As an apparent model of normative human aging, the macaque is ideal for studying induction and mitigation of neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Anaesthesia combined with functional neuroimaging provides a powerful approach for understanding the brain mechanisms of consciousness. Although propofol is used ubiquitously in clinical interventions that reversibly suppress consciousness, it shows large inter‐individual variability, and the brain bases of this variability remain poorly understood. We asked whether three networks key to conscious cognition—the dorsal attention (DAN), executive control (ECN), and default mode (DMN)—underlie responsiveness variability under anaesthesia. Healthy participants (N = 17) were moderately anaesthetized during narrative understanding and resting‐state conditions inside the Magnetic Resonance Imaging scanner. A target detection task measured behavioural responsiveness. An independent behavioural study (N = 25) qualified the attention demands of narrative understanding. Then, 30% of participants were unaffected in their response times, thus thwarting a key aim of anaesthesia—the suppression of behavioural responsiveness. Individuals with stronger functional connectivity within the DAN and ECN, between them, and to the DMN, and with larger grey matter volume in frontal regions were more resilient to anaesthesia. For the first time, we show that responsiveness variability during propofol anaesthesia relates to inherent differences in brain structure and function of the frontoparietal networks, which can be predicted prior to sedation. Results highlight novel markers for improving awareness monitoring during clinical anaesthesia. [ABSTRACT FROM AUTHOR]

Suicide prevention is limited by the frequent non-planned or impulsive nature of suicidal behavior. For instance, 25–62 % of suicide attempts, occur within 30 min of the onset of suicidal ideation. We aimed to examine frontal brain activity in depressed patients following a suicide attempt and its relationship with the duration of the suicidal process. We recruited 35 adult patients within three days of a suicide attempt of at least moderate lethality. Duration of the suicidal process was recorded in a semi-structured interview, including suicide contemplation (time from onset of suicidal ideation to decision to kill oneself) and suicide action intervals (time from the decision to kill oneself to suicide attempt). Resting state EEG data from AF7, AF8, TP9 and TP10 leads was collected with a portable MUSE 2 headband system. The average frequency values throughout a 5-minute portable EEG recording were extracted for delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), and beta (13–30 Hz) waves. Delta (r = 0.450, p = 0.021) and theta power (r = 0.395, p = 0.044) were positively correlated with the duration of the suicide action interval. There were no significant correlations of the suicide contemplation interval with clinical or EEG measures. Patients with suicide action interval shorter than 30 min showed lower delta power (U = 113, p = 0.049) compared with those with longer duration. Lower theta and delta activity may reflect hindered cognitive control and inhibition in impulsive suicide attempters. Portable EEG may provide a valuable tool for clinical research and in the management of acutely suicidal patients. • Delta and theta power were correlated with the duration of the suicide action interval. • Patients with shorter suicide action interval showed lower delta and beta power. • Portable EEG may provide a valuable tool for clinical research of suicidal patients. [ABSTRACT FROM AUTHOR]

Paracetamol (acetaminophen, APAP) is known as a safe pain reliever; however, its negative effects on the central nervous system have gradually been reported. We examined alterations in learning and memory, and brain-derived neurotrophic factor (BDNF) expression in the frontal cortex and hippocampus at different durations of APAP treatment in rats. Novel object recognition (NOR) and Morris water maze (MWM) paradigms were used to assess learning and memory in rats fed with 200 mg/kg APAP at single-dose, 15-day or 30-day treatments. BDNF expression was evaluated through immunohistochemistry and Western blotting. The single-dose APAP treatment did not alter the NOR performance. However, deficits in the NOR and MWM capacities were detected in the rats with longer durations of APAP treatment. An analysis of BDNF expression revealed no significant change in BDNF expression in the single-dose APAP treatment, while rats given APAP for extended periods as treatment showed a significant decrement in this protein in the frontal cortex and hippocampus. Short-term APAP treatment has no effect on learning and memory, or BDNF expression; however, long-term APAP exposure causes cognitive impairment. The diminishment of the BDNF level in the frontal cortex and hippocampus due to the long period of treatment with APAP may at least in part be involved in altered learning and memory in rats. [ABSTRACT FROM AUTHOR]

Habits allow environmental and interoceptive cues to trigger behavior in an automatized fashion, making them liable to deployment in inappropriate or outdated contexts. Over the long term, repeated failure of a once-adaptive habit to satisfy current goals produces extinction learning that suppresses the habit’s execution. Less attention has been afforded to the mechanisms underlying real-time habit suppression: the capacity to stop the execution of a cued habit that is goal conflicting. Here, I first posit a model by which goal-relevant stimuli can (a) bring unfolding habits and their projected outcomes into awareness, (b) prompt evaluation of the habit outcome with respect to current goals, and (c) trigger cessation of the habit response if it is determined to be goal conflicting. Second, I propose a modified stop-signal task to test this model of goal-directed stopping of habit execution. Finally, I marshal evidence indicating that the ventrolateral prefrontal cortex, situated at the nexus of salience detection, action-plan assessment, and motor inhibition networks, is uniquely positioned to coordinate the overriding of habitual behaviors in real time. In sum, this perspective presents a testable model and candidate neurobiological substrate for our capacity to “snap out of autopilot” and override goal-conflicting habits in real time. [ABSTRACT FROM AUTHOR]

Background: This study sought to determine whether (1) evidence is available of interactions between anodal tDCS and oscillated tDCS stimulation patterns to increase the power of endogenous brain oscillations and (2) the frequency matching the applied anodal otDCS's frequency and the brain's dominant intrinsic frequency influence power shifting during stimulation pattern sessions by both anodal DCS and anodal oscillated DCS. Method: Rats received different anodal tDCS and otDCS stimulation patterns using 8.5 Hz and 13 Hz state-related dominant intrinsic frequencies of anodal otDCS. The rats were divided into groups with specific stimulation patterns: group A: tDCS–otDCS (8.5 Hz)–otDCS (13 Hz); group B: otDCS (8.5 Hz)–tDCS–otDCS (13 Hz); group C: otDCS (13 Hz)–tDCS–otDCS (8.5 Hz). Acute relative power changes (i.e., following 10 min stimulation sessions) in six frequency bands—delta (1.5–4 Hz), theta (4–7 Hz), alpha-1 (7–10 Hz), alpha-2 (10–12 Hz), beta-1 (12–15 Hz) and beta-2 (15–20 Hz)—were compared using three factors and repeated ANOVA measurement. Results: For each stimulation, tDCS increased theta power band and, above bands alpha and beta, a drop in delta power was observed. Anodal otDCS had a mild increasing power effect in both matched intrinsic and delta bands. In group pattern stimulations, increased power of endogenous frequencies matched exogenous otDCS frequencies—8.5 Hz or 13 Hz—with more potent effects in upper bands. The power was markedly more potent with the otDCS–tDCS stimulation pattern than the tDCS–otDCS pattern. Significance: The findings suggest that the otDCS–tDCS pattern stimulation increased the power in matched intrinsic oscillations and, significantly, in the above bands in an ascending order. We provide evidence for the successful corporation between otDCS (as frequency-matched guidance) and tDCS (as a power generator) rather than tDCS alone when stimulating a desired brain intrinsic band (herein, tES specificity). [ABSTRACT FROM AUTHOR]

Neonatal exposure to general anesthetics has been associated with neurotoxicity and morphologic changes in the developing brain. Isoflurane is a volatile anesthetic widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated the effects of a single neonatal isoflurane (3% in oxygen, 2 h) exposure in rats at postnatal day (PND) 7, in short-term (24 h — PND8) and long-term (adulthood) protocols. In PND8, ex vivo analysis of hippocampal and frontal cortex slices evaluated cell viability and susceptibility to in vitro glutamate challenge. In adult rats, behavioral parameters related to anxiety-like behavior, short-term memory, and locomotor activity (PND60-62) and ex vivo analysis of cell viability, membrane permeability, glutamate uptake, and susceptibility to in vitro glutamate challenge in hippocampal and cortical slices from PND65. A single isoflurane (3%, 2 h) exposure at PND7 did not acutely alter cell viability in cortical and hippocampal slices of infant rats (PND8) per se and did not alter slice susceptibility to in vitro glutamate challenge. In rat's adulthood, behavioral analysis revealed that the neonatal isoflurane exposure did not alter anxiety-like behavior and locomotor activity (open field and rotarod tests). However, isoflurane exposure impaired short-term memory evaluated in the novel object recognition task. Ex vivo analysis of brain slices showed isoflurane neonatal exposure selectively decreased cell viability and glutamate uptake in cortical slices, but it did not alter hippocampal slice viability or glutamate uptake (PND65). Isoflurane exposure did not alter in vitro glutamate-induced neurotoxicity to slices, and isoflurane exposure caused no significant long-term damage to cell membranes in hippocampal or cortical slices. These findings indicate that a single neonatal isoflurane exposure did not promote acute damage; however, it reduced cortical, but not hippocampal, slice viability and glutamate uptake in the adulthood. Additionally, behavioral analysis showed neonatal isoflurane exposure induces short-term recognition memory impairment, consolidating that neonatal exposure to volatile anesthetics may lead to behavioral impairment in the adulthood, although it may damage brain regions differentially. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease. We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females). Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions. This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology. [Display omitted] • Behavioral and molecular phenotyping of a new Thy1-hSNCA mouse strain (SNCA mice). • SNCA mice produce pSyn129 in frontal cortex, hippocampus and amygdala. • SNCA mice show cognitive deficits related to frontal cortex, no motor dysfunction. • SNCA mice show increased inflammation and decreased plasticity in frontal cortex. • The SNCA model could stand as a model of early stage DLB (prodromal DLB). [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) is characterized by pathology prominently in the basal ganglia, the tegmentum of the brainstem, and the frontal cortex. However, pathology varies according to clinical features. This study aimed to statistically verify the correspondence between the clinical and pathological subtypes of PSP. We identified patients with a pathological diagnosis of PSP and classified the eight clinical subtypes of the Movement Disorders Society criteria for the clinical diagnosis of PSP (MDS-PSP criteria) into the Richardson, Akinesia, and Cognitive groups. We used anti-phosphorylated tau antibody immunostaining to semi-quantitatively evaluate neurofibrillary tangles (NFTs) and coiled bodies/threads (CB/Ths) in the globus pallidus, subthalamic nucleus, and midbrain tegmentum. In the frontal cortex, tufted astrocytes (TAs) and CB/Ths were assessed on a 3-point scale. We compared the pathology among the three groups, recorded the phenotypes ranked the second and lower in the multiple allocation extinction rule and examined whether the pathology changed depending on applying each phenotype. The Richardson group exhibited severe NFTs and CB/Ths in the midbrain tegmentum. The Akinesia group showed severe NFTs in the globus pallidus. The Cognitive group had severe TAs and CB/Ths in the frontal cortex. TAs and CB/Ths in the frontal cortex correspond to behavioral variant frontotemporal dementia, and supranuclear vertical oculomotor palsy. These clinical symptoms may reflect the distribution of tau pathologies in PSP. • Severe pathology the frontal cortex may correspond to vertical oculomotor palsy. • Pathology are relatively confined to the basal ganglia in PSP-P, and -PGF patients. • PSP-SL, and –F patients have severe tufted astrocytes in the frontal cortex. • Strength of this study is large autopsy cohort of PSP from a single brain bank. • Clinical symptoms may reflect the distribution of tau pathologies in PSP. [ABSTRACT FROM AUTHOR]

As the functional properties of a cortical area partly reflect its thalamic inputs, the present study compared collateral projections arising from various rostral thalamic nuclei that terminate across prefrontal (including anterior cingulate) and retrosplenial areas in the rat brain. Two retrograde tracers, fast blue and cholera toxin B, were injected in pairs to different combinations of cortical areas. The research focused on the individual anterior thalamic nuclei, including the interanteromedial nucleus, nucleus reuniens and the laterodorsal nucleus. Of the principal anterior thalamic nuclei, only the anteromedial nucleus contained neurons reaching both the anterior cingulate cortex and adjacent cortical areas (prefrontal or retrosplenial), though the numbers were modest. For these same cortical pairings (medial prefrontal/anterior cingulate and anterior cingulate/retrosplenial), the interanteromedial nucleus and nucleus reuniens contained slightly higher proportions of bifurcating neurons (up to 11% of labelled cells). A contrasting picture was seen for collaterals reaching different areas within retrosplenial cortex. Here, the anterodorsal nucleus, typically provided the greatest proportion of bifurcating neurons (up to 15% of labelled cells). While individual neurons that terminate in different retrosplenial areas were also found in the other thalamic nuclei, they were infrequent. Consequently, these thalamo‐cortical projections predominantly arise from separate populations of neurons with discrete cortical termination zones, consistent with the transmission of segregated information and influence. Overall, two contrasting medial‐lateral patterns of collateral projections emerged, with more midline nuclei, for example, nucleus reuniens and the interoanteromedial nucleus innervating prefrontal areas, while more dorsal and lateral anterior thalamic collaterals innervated retrosplenial cortex. [ABSTRACT FROM AUTHOR]

The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression. [ABSTRACT FROM AUTHOR]

• EEG alpha power increased in the frontal regions when generating creative ideas. • Task-related alpha coherence enhanced between frontal and parietal/temporal sites. • Everyday creativity influenced EEG alpha activity during creative ideation. • The higher the everyday creativity, the stronger increases in alpha power. • Highly creative individuals showed greater increases in alpha coherence. Everyday creativity is the basic ability of human survival and penetrates every aspect of life. Nevertheless, the neural mechanisms underlying everyday creativity was largely unexplored. In this study, seventy-five participants completed the creative behaviour inventory, a tool for assessing creative behaviour in daily life. The participants also completed the alternate uses task (AUT) during an electroencephalography (EEG) assessment to evaluate creative thinking. Alpha power was used to quantify neural oscillations during the creative process, while alpha coherence was used to quantify information communication between frontal regions and other sites during creative ideation. Moreover, these two task-related quantitative measures were combined to investigate the relationship between individual differences in everyday creativity and EEG alpha activity during creative idea generation. Compared with the reference period, increased alpha power was observed in the frontal cortex of the right hemisphere and increased functional coupling was observed between frontal and parietal/temporal regions during the activation period. Interestingly, individual differences in everyday creativity were associated with distinct patterns of EEG alpha activity. Specifically, individuals with higher everyday creativity had increased alpha power in the frontal cortex, and increased changes in coherence in frontal-temporal regions of the right hemisphere while performing the AUT. It might indicate that individuals with higher everyday creativity had an enhanced ability to focus on internal information processing and control bottom-up stimuli, as well as better selection of novel semantic information when performing creative ideation tasks. [ABSTRACT FROM AUTHOR]

Based on numerous imaging and electrophysiological studies, the presupplementary motor area (pre-SMA) and the rostral cingulate motor area are cortical regions considered to be essential to voluntary movement initiation and behavioral control. However, their respective roles and functional interactions remain a long-standing and still debated question. Here, we trained 2 rhesus monkeys (Macaca mulatta) in a complex cognitive task to compare the neuronal activity of these 2 regions on the medial wall during both perceptual and internally guided decisions. We confirmed the implication of both areas throughout the decision process. Critically, we demonstrate that instead of a stable invariant role, the pre-SMA and rostral cingulate motor area manifested a versatile hierarchical relationship depending on the mode of movement initiation. Whereas pre-SMA neurons were primarily engaged in decisions based on perceptual information, rostral cingulate motor area neurons preempted the decision process in case of an internally doubt-driven checking behavior, withholding pre-SMA recruitment during the time spent inhibiting the habitual action. We identified a versatile hierarchical organization of the mediofrontal area that may substantially affect normal and pathological decision processes because adaptive behaviors, such as doubt-checking and its compulsive counterpart, rely on this subtle equilibrium in controlling action initiation. [ABSTRACT FROM AUTHOR]

The administration of the adrenal hormone corticosterone by injection or subcutaneous implantation of its modified-release dosage forms is often used to model situations associated with the effects of various stressors on the brain. The present methodological study investigated the possibility of using Alzet osmotic pumps (OPs) with a capacity of 200 µL and a release rate of 1 µL/h, loaded with corticosterone solutions of 25, 50 and 100 mg/mL or a vehicle (dimethyl sulfoxide/polyethylene glycol-400). The objective was to determine the optimal concentration of corticosterone solution loaded into osmotic pumps to create an increased level of the hormone in the rat blood and brain regions. An increase in blood corticosterone levels was only observed on mg/mL (OP-100). Corticosterone accumulation in the frontal cortex, neocortex and hippocampus increased significantly by day 3 after implantation in the OP-100 group. Thus, OPs with a corticosterone solution in DMSO/PEG-400, at a hormone concentration of 100 mg/mL and release rate of 1 µL/h, can be used to create elevated corticosterone levels in the blood and brain regions of rats. [ABSTRACT FROM AUTHOR]

Integrating behavioral and neurophysiological measures has created new and advanced ways to understand the development of self‐regulation. Electroencephalography (EEG) has been used to examine how self‐regulatory processes are related to frontal alpha power during infancy and early childhood. However, findings across previous studies have been inconsistent. To address this issue, the current meta‐analysis synthesized all prior literature examining associations between individual differences in self‐regulation and frontal EEG alpha power (baseline and/or task). In total, 23 studies consisting of 1275 participants between 1 month and 6 years of age were included, which yielded 149 effect sizes. Findings of the three‐level meta‐analytic model demonstrated a non‐significant overall association between self‐regulation and frontal alpha power. Yet, significant moderating effects were found for self‐regulation construct (emotion regulation, effortful control, executive function), self‐regulation measurement (behavioral task, computer assessment, lab observation, questionnaire), and children's mean age. Self‐regulation was only significantly correlated with frontal alpha power when studies focused on the executive functioning construct. Moreover, the use of behavioral tasks or questionnaires and a higher mean age of the children resulted in small but significant effect size estimates. Higher frontal alpha power values were related to higher order top‐down mechanisms of self‐regulation, indicating that these mechanisms might become stronger when the frontal cortex is sufficiently developed. The findings of the current meta‐analysis highlight the importance of longitudinal analyses and multimethod approaches in future work to reach a more comprehensive understanding of the role of frontal EEG alpha activity in the etiology of individual differences in early self‐regulation. Research Highlights: The first meta‐analysis of individual differences in self‐regulation and frontal EEG alpha power during infancy and early childhood demonstrated a non‐significant overall association.Moderation analyses revealed that variations in frontal alpha power were significantly associated with executive function, but not with effortful control and emotion regulation.Frontal alpha power was related to variations in self‐regulation when measured by behavioral tasks and questionnaires, but not via computer assessments and lab observations.The association between individual differences in self‐regulation and frontal alpha power becomes significantly stronger with age. [ABSTRACT FROM AUTHOR]

In nonhuman primates, major input to the striatum originates from ipsilateral cortex and thalamus. The striatum is a target also of crossed corticostriatal (CSt) projections from the contralateral hemisphere, which have been so far somewhat neglected. In the present study, based on neural tracer injections in different parts of the striatum in macaques of either sex, we analyzed and compared qualitatively and quantitatively the distribution of labeled CSt cells in the two hemispheres. The results showed that crossed CSt projections to the caudate and the putamen can be relatively robust (up to 30% of total labeled cells). The origin of the direct and the crossed CSt projections was not symmetrical as the crossed ones originated almost exclusively from motor, prefrontal, and cingulate areas and not from parietal and temporal areas. Furthermore, there were several cases in which the contribution of contralateral areas tended to equal that of the ipsilateral ones. The present study is the first detailed description of this anatomic pathway of the macaque brain and provides the substrate for bilateral distribution of motor, motivational, and cognitive signals for reinforcement learning and selection of actions or action sequences, and for learning compensatory motor strategies after cortical stroke. [ABSTRACT FROM AUTHOR]

Self-enhancement (SE) is often overlooked as a fundamental cognitive ability mediated via the Prefrontal Cortex (PFC). Here, we present research that establishes the relationship between the PFC, SE, and the potential evolved beneficial mechanisms. Specifically, we believe there is now enough evidence to speculate that SE exists to provide significant benefits and should be considered a normal aspect of the self. Whatever the metabolic or social cost, the upside of SE is great enough that it is a core and fundamental psychological construct. Furthermore, though entirely theoretical, we suggest that a critical reason the PFC has evolved so significantly in Homo sapiens is to, in part, sustain SE. We, therefore, elaborate on its proximate and ultimate mechanisms. [ABSTRACT FROM AUTHOR]

The rodent homolog of the primate pulvinar, the lateral posterior (LP) thalamus, is extensively interconnected with multiple cortical areas. While these cortical interactions can span the entire LP, subdivisions of the LP are characterized by differential connections with specific cortical regions. In particular, the medial LP has reciprocal connections with frontoparietal cortical areas, including the anterior cingulate cortex (ACC). The ACC plays an integral role in top‐down sensory processing and attentional regulation, likely exerting some of these functions via the LP. However, little is known about how ACC and LP interact, and about the information potentially integrated in this reciprocal network. Here, we address this gap by employing a projection‐specific monosynaptic rabies tracing strategy to delineate brain‐wide inputs to bottom‐up LP→ACC and top‐down ACC→LP neurons. We find that LP→ACC neurons receive inputs from widespread cortical regions, including primary and higher order sensory and motor cortical areas. LP→ACC neurons also receive extensive subcortical inputs, particularly from the intermediate and deep layers of the superior colliculus (SC). Sensory inputs to ACC→LP neurons largely arise from visual cortical areas. In addition, ACC→LP neurons integrate cross‐hemispheric prefrontal cortex inputs as well as inputs from higher order medial cortex. Our brain‐wide anatomical mapping of inputs to the reciprocal LP‐ACC pathways provides a roadmap for understanding how LP and ACC communicate different sources of information to mediate attentional control and visuomotor functions. [ABSTRACT FROM AUTHOR]

While conflict between incompatible goals has well-known effects on actions, in many situations the same action may produce harmful or beneficial consequences during different periods in a nonconflicting manner, e.g., crossing the street during a red or green light. To avoid harm, subjects must be cautious to inhibit the action specifically when it is punished, as in passive avoidance, but act when it is beneficial, as in active avoidance or active approach. In mice of both sexes performing a signaled action to avoid harm or obtain reward, we found that addition of a new rule that punishes the action when it occurs unsignaled delays the timing of the signaled action in an apparent sign of increased caution. Caution depended on task signaling, contingency, and reinforcement type. Interestingly, caution became persistent when the signaled action was avoidance motivated by danger but was only transient when it was approach motivated by reward. Although caution is represented by the activity of neurons in the midbrain, it developed independent of frontal cortex or basal ganglia output circuits. These results indicate that caution disrupts actions in different ways depending on the motivational state and may develop from unforeseen brain circuits. [ABSTRACT FROM AUTHOR]

Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as β-amyloid (APP/Aβ and Aβ1–42) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aβ immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS. [ABSTRACT FROM AUTHOR]

Neural oscillations are at the core of important computations in the mammalian brain. Interactions between oscillatory activities in different frequency bands, such as delta (1–4 Hz), theta (4–8 Hz) or gamma (>30 Hz), are a powerful mechanism for binding fundamentally distinct spatiotemporal scales of neural processing. Phase‐amplitude coupling (PAC) is one such plausible and well‐described interaction, but much is yet to be uncovered regarding how PAC dynamics contribute to sensory representations. In particular, although PAC appears to have a major role in audition, the characteristics of coupling profiles in sensory and integration (i.e. frontal) cortical areas remain obscure. Here, we address this question by studying PAC dynamics in the frontal‐auditory field (FAF; an auditory area in the bat frontal cortex) and the auditory cortex (AC) of the bat Carollia perspicillata. By means of simultaneous electrophysiological recordings in frontal and auditory cortices examining local‐field potentials (LFPs), we show that the amplitude of gamma‐band activity couples with the phase of low‐frequency LFPs in both structures. Our results demonstrate that the coupling in FAF occurs most prominently in delta/high‐gamma frequencies (1‐4/75‐100 Hz), whereas in the AC the coupling is strongest in the delta‐theta/low‐gamma (2‐8/25‐55 Hz) range. We argue that distinct PAC profiles may represent different mechanisms for neuronal processing in frontal and auditory cortices, and might complement oscillatory interactions for sensory processing in the frontal‐auditory cortex network. [ABSTRACT FROM AUTHOR]