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17β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18 F-fluoroestradiol ( 18 F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health., (© 2024. The Author(s).)

Super-resolution and single-molecule microscopies have been increasingly applied to complex biological systems. A major challenge of these approaches is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments of cells and tissue. We present RASP, Radiality Analysis of Single Puncta, a bioimaging-segmentation method that solves this problem. RASP removes false-positive puncta that other analysis methods detect and detects features over a broad range of spatial scales: from single proteins to complex cell phenotypes. RASP outperforms the state-of-the-art methods in precision and speed using image gradients to separate Gaussian-shaped objects from the background. We demonstrate RASP's power by showing that it can extract spatial correlations between microglia, neurons, and α-synuclein oligomers in the human brain. This sensitive, computationally efficient approach enables fluorescent puncta and cellular features to be distinguished in cellular and tissue environments, with sensitivity down to the level of the single protein. Python and MATLAB codes, enabling users to perform this RASP analysis on their own data, are provided as Supporting Information and links to third-party repositories.

All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer's disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.

Objective: To examine in a 3-year brain imaging study the effects of higher vs lower adherence to a Mediterranean-style diet (MeDi) on Alzheimer disease (AD) biomarker changes (brain β-amyloid load via 11 C-Pittsburgh compound B [PiB] PET and neurodegeneration via 18 F-fluorodeoxyglucose [FDG] PET and structural MRI) in midlife., Methods: Seventy 30- to 60-year-old cognitively normal participants with clinical, neuropsychological, and dietary examinations and imaging biomarkers at least 2 years apart were examined. These included 34 participants with higher (MeDi+) and 36 with lower (MeDi-) MeDi adherence. Statistical parametric mapping and volumes of interest were used to compare AD biomarkers between groups at cross section and longitudinally., Results: MeDi groups were comparable for clinical and neuropsychological measures. At baseline, compared to the MeDi+ group, the MeDi- group showed reduced FDG-PET glucose metabolism (CMRglc) and higher PiB-PET deposition in AD-affected regions ( p < 0.001). Longitudinally, the MeDi--group showed CMRglc declines and PiB increases in these regions, which were greater than those in the MeDi+ group ( p interaction < 0.001). No effects were observed on MRI. Higher MeDi adherence was estimated to provide 1.5 to 3.5 years of protection against AD., Conclusion: Lower MeDi adherence was associated with progressive AD biomarker abnormalities in middle-aged adults. These data support further investigation of dietary interventions for protection against brain aging and AD., (© 2018 American Academy of Neurology.)

The possibility that alterations in DNA methylation are mechanistic drivers of development, aging and susceptibility to disease is widely acknowledged, but evidence remains patchy or inconclusive. Of particular interest in this regard is the brain, where it has been reported that DNA methylation impacts on neuronal activity, learning and memory, drug addiction and neurodegeneration. Until recently, however, little was known about the 'landscape' of the human brain methylome. Here we assay 1.9 million CpGs in each of 43 brain samples representing different individuals and brain regions. The cerebellum was a consistent outlier compared to all other regions, and showed over 16 000 differentially methylated regions (DMRs). Unexpectedly, the sequence characteristics of hypo- and hypermethylated domains in cerebellum were distinct. In contrast, very few DMRs distinguished regions of the cortex, limbic system and brain stem. Inter-individual DMRs were readily detectable in these regions. These results lead to the surprising conclusion that, with the exception of cerebellum, DNA methylation patterns are more homogeneous between different brain regions from the same individual, than they are for a single brain region between different individuals. This finding suggests that DNA sequence composition, not developmental status, is the principal determinant of the human brain DNA methylome., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The measurement of Nitric oxide (NO) in real-time has been a major concern due to the involvement of this ubiquitous free radical modulator in several physiological and pathological pathways in tissues. Here we performed a study aiming at evaluating different types of carbon fibers, namely Textron, Amoco, Courtaulds and carbon nanotubes (University of Kentucky) covered with Nafion/o-phenylenediamine (o-PD) for NO measurement in terms of sensitivity, LOD, response time and selectivity against major potential interferents in the brain (ascorbate, nitrite and dopamine). The results indicate that, as compared with the other carbon fibers and nanotubes, Textron carbon fiber microelectrodes coated with two layers of Nafion and o-PD exhibited better characteristics for NO measurement as they are highly selective against ascorbate (>30,000:1), nitrite (>2000:1) and dopamine (>80:1). These coated Textron microelectrodes showed an average sensitivity of 341+/-120pA/microM and a detection limit of 16+/-11nM. The better performance of the Textron fibers is likely related to a stronger adhesion or more uniform coating of the Nafion and o-PD polymers to the fiber surface. In addition, the background current of the Textron carbon fibers is low, contributing to the excellent signal-to-noise for detection of NO.

Although deep brain stimulation (DBS) has recently been shown to be effective for neurological disorders such as Parkinson's disease, there are many limitations of the current technology: the large size of current microelectrodes (approximately 1 mm diameter); the lack of monitoring of local brain electrical activity and neurotransmitters (e.g. dopamine in Parkinson's disease); the open-loop nature of the stimulation (i.e. not guided by brain electrochemical activity). Reducing the size of the monitoring and stimulating electrodes by orders of magnitude (to the size of neural elements) allows remarkable improvements in both monitoring (spatial resolution, temporal resolution, and sensitivity) and stimulation. Carbon nanofiber nanoelectrode technology offers the possibility of trimodal arrays (monitoring electrical activity, monitoring neurotransmitter levels, precise stimulation). DBS can then be guided by changes in brain electrical activity and/or neurotransmitter levels (i.e. closed-loop DBS). Here, we describe the basic manufacture and electrical characteristics of a prototype nanoelectrode array for DBS, as well as preliminary studies with electroconductive polymers necessary to optimize DBS in vivo. An approach such as the nanoelectrode array described here may offer a generic electrical-neural interface for use in various neural prostheses.

Background: One-third of children diagnosed with autism spectrum disorders (ASDs) are reported to have had normal early development followed by an autistic regression between the ages of 2 and 3 years. This clinical profile partly parallels that seen in Landau-Kleffner syndrome (LKS), an acquired language disorder (aphasia) believed to be caused by epileptiform activity. Given the additional observation that one-third of autistic children experience one or more seizures by adolescence, epileptiform activity may play a causal role in some cases of autism., Objective: To compare and contrast patterns of epileptiform activity in children with autistic regressions versus classic LKS to determine if there is neurobiological overlap between these conditions. It was hypothesized that many children with regressive ASDs would show epileptiform activity in a multifocal pattern that includes the same brain regions implicated in LKS., Design: Magnetoencephalography (MEG), a noninvasive method for identifying zones of abnormal brain electrophysiology, was used to evaluate patterns of epileptiform activity during stage III sleep in 6 children with classic LKS and 50 children with regressive ASDs with onset between 20 and 36 months of age (16 with autism and 34 with pervasive developmental disorder-not otherwise specified). Whereas 5 of the 6 children with LKS had been previously diagnosed with complex-partial seizures, a clinical seizure disorder had been diagnosed for only 15 of the 50 ASD children. However, all the children in this study had been reported to occasionally demonstrate unusual behaviors (eg, rapid blinking, holding of the hands to the ears, unprovoked crying episodes, and/or brief staring spells) which, if exhibited by a normal child, might be interpreted as indicative of a subclinical epileptiform condition. MEG data were compared with simultaneously recorded electroencephalography (EEG) data, and with data from previous 1-hour and/or 24-hour clinical EEG, when available. Multiple-dipole, spatiotemporal modeling was used to identify sites of origin and propagation for epileptiform transients., Results: The MEG of all children with LKS showed primary or secondary epileptiform involvement of the left intra/perisylvian region, with all but 1 child showing additional involvement of the right sylvian region. In all cases of LKS, independent epileptiform activity beyond the sylvian region was absent, although propagation of activity to frontal or parietal regions was seen occasionally. MEG identified epileptiform activity in 41 of the 50 (82%) children with ASDs. In contrast, simultaneous EEG revealed epileptiform activity in only 68%. When epileptiform activity was present in the ASDs, the same intra/perisylvian regions seen to be epileptiform in LKS were active in 85% of the cases. Whereas primary activity outside of the sylvian regions was not seen for any of the children with LKS, 75% of the ASD children with epileptiform activity demonstrated additional nonsylvian zones of independent epileptiform activity. Despite the multifocal nature of the epileptiform activity in the ASDs, neurosurgical intervention aimed at control has lead to a reduction of autistic features and improvement in language skills in 12 of 18 cases., Conclusions: This study demonstrates that there is a subset of children with ASDs who demonstrate clinically relevant epileptiform activity during slow-wave sleep, and that this activity may be present even in the absence of a clinical seizure disorder. MEG showed significantly greater sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, and 24-hour clinical EEG. The multifocal epileptiform pattern identified by MEG in the ASDs typically includes the same perisylvian brain regions identified as abnormal in LKS. When epileptiform activity is present in the ASDs, therapeutic strategies (antiepileptic drugs, steroids, and even neurosurgery) aimed at its control can lead to a significa

Real-time tissue identification can benefit procedures such as stereotactic brain biopsy, functional neurosurgery and brain tumor excision. Optical scattering spectroscopy has been shown to be effective at discriminating cancer from noncancerous conditions in the colon, bladder and breast. The NASA Smart Probe extends the concept of 'optical biopsy' by using neural network techniques to combine the output from 3 microsensors contained within a cannula 2. 7 mm in diameter (i.e. the diameter of a stereotactic brain biopsy needle). Experimental data from 5 rats show the clear differentiation between tissues such as brain, nerve, fat, artery and muscle that can be achieved with optical scattering spectroscopy alone. These data and previous findings with other modalities such as (1) analysis of the image from a fiberoptic neuroendoscope and (2) the output from a microstrain gauge suggest the Smart Probe multiple microsensor technique shows promise for real-time tissue identification in neurosurgical procedures., (Copyright 2000 S. Karger AG, Basel)

Real-time identification of tissue would improve procedures such as stereotactic brain biopsy (SBX), functional and implantation neurosurgery, and brain tumor excision. To standard SBX equipment has been added: (1) computer-controlled stepper motors to drive the biopsy needle/probe precisely; (2) multiple microprobes to track tissue density, detect blood vessels and changes in blood flow, and distinguish the various tissues being penetrated; (3) neural net learning programs to allow real-time comparisons of current data with a normative data bank; (4) three-dimensional graphic displays to follow the probe as it traverses brain tissue. The probe can differentiate substances such as pig brain, differing consistencies of the 'brain-like' foodstuff tofu, and gels made to simulate brain, as well as detect blood vessels imbedded in these substances. Multimodality probes should improve the safety, efficacy, and diagnostic accuracy of SBX and other neurosurgical procedures.

Background: Patients with multilobar or bihemispheric seizure foci (MLBHSF) are generally not considered candidates for major resective surgery because of the high risk of complications. A combination of relatively less invasive surgical procedures were used to treat 19 patients with intractable seizures with MLBHSF., Methods: Epileptogenic areas were identified via standard techniques. Locations of the seizure foci were in two lobes of a hemisphere in 11 patients, three lobes of a hemisphere in four patients, four lobes of a hemisphere in one patient, and both hemispheres in three patients. All 19 patients had multiple subpial transections; in addition, seven patients had small topectomies and nine patients had amygdala hippocampotomies., Results: The longest follow-up is 54 months and the median for follow-up is 33 months. Nine patients (47%) are either free of seizures or have only rare seizures; eight patients (41%) have greater than 90% reduction in seizure frequency; one patient (6%) has complete cessation of myoclonic seizures and secondary generalization, and greater than 50% reduction in partial complex seizures; and one patient (6%) has greater than 50% reduction in seizure frequency. There were no permanent operative complications., Conclusion: Though the follow-up is relatively short and the number of patients is small, these results are encouraging, because the majority of patients in this group were poor surgical candidates.

Undue intraoperative brain retraction can cause significant neurosurgical morbidity. By combining brain retractor blade pressure measurement with monitoring of brain electrical activity, one can determine the limits of safe brain retraction and then test systematically various therapeutic interventions. Cortical evoked potential (EP) mapping and laser-Doppler cerebral blood flow (CBF) measurement were undertaken during brain retraction in the miniature swine (Sus scrofa). Forelimb somatosensory EP recording during subtemporal retraction simulated the pterional and subtemporal approaches, respectively. Retraction pressure of 30 mmHg usually resulted in a 50% decrement in EP amplitude after 10 to 20 minutes in normotensive, normocapnic adult animals. Recovery of EP occurred within 5 to 10 minutes of retraction release. The effects of animal age, induced hypotension (nitroprusside, MAP approximately 40), and induced hypocapnia (hyperventilation, PaCO2 approximately 28) on EP preservation during retraction were then investigated, with data reported here from 23 animals (8 to 35 kg). By Spearman rank correlation coefficients, early loss of EP was associated with the following: lower MAP (p approximately 0.0001), lower CBF (p approximately 0.0005), lower PaCO2 (p less than 0.001), and older age (p approximately 0.01). These results indicate (1) retractors should be relaxed every 10-15 minutes whenever possible (for at least 5 minutes), and (2) hypotension, in particular, but also hypocapnia (hyperventilation) should not be used indiscriminately. Details of this new model of retraction ischaemia are presented.

In our miniature swine model simulating operating room brain retraction, we investigated the effects of mannitol plus nimodipine on cerebral blood flow (CBF) and evoked potentials (EP) ipsilateral and contralateral to retraction, in comparison with either agent alone, during both normoventilation and hyperventilation. We here report results in 27 animals with intravenous mannitol (2 g kg-1 over 15 min) and/or nimodipine (1 microgram kg-1 min-1 constant infusion). Mannitol plus nimodipine was superior both to controls and to either mannitol alone or nimodipine alone in preserving EP amplitude ipsilateral to retraction during both normoventilation and hyperventilation. Mannitol alone was effective in normoventilation at preserving EP, while nimodipine alone was effective in hyperventilation. No significant asymmetries in CBF or EP were seen with mannitol plus nimodipine in either normoventilation or hyperventilation. By five minutes postretraction CBF had returned to preretraction values for all groups, and EP amplitude had returned also except for hyperventilated controls. In this model of brain retraction, mannitol plus nimodipine is superior to either agent alone in maintaining both CBF and EP when normoventilation and hyperventilation are employed. The results are discussed in terms of the possible mechanisms for the different and complementary effects of mannitol and nimodipine.

We review here the literature in both animal models and humans concerning electrical activity, blood flow, and metabolism in the hemisphere contralateral to unilateral cerebral ischemia. We analyze the data by periods based on the time from initial injury to emphasize the time course of transhemispheric diaschisis. Contralateral electrical activity, such as evoked potential amplitude, is increased in the late stages after unilateral infarction, with the data from the more acute periods being inconclusive. Contralateral blood flow changes probably depend on the magnitude of the ischemic injury, with a larger insult resulting in a decrease not seen with smaller insults. Some studies have shown a decrease in contralateral blood flow over the first week followed by a gradual return toward baseline. Most measures of contralateral metabolism show a time course similar to blood flow, that is, a decrease followed by gradual recovery. The effects of corpus callosum section on transhemispheric diaschisis are not yet established. We provide examples to show that under certain conditions, diaschisis may represent a loss of remote inhibition rather than a loss of remote facilitation, as von Monakow originally suggested. By following the contralateral changes over time, particularly during the first minutes and hours of ischemia, insight will be gained into the brain's responses remote from the focus of ischemic injury. These responses should bear a relation to the brain's defense mechanisms ipsilaterally to the region of ischemia.

The miniature swine (Sus scrofa) is a desirable model for certain electrophysiological studies because of its large brain, ready availability and low cost. We report our findings regarding the location of the auditory and somatosensory cortices obtained by cortical surface evoked potential mapping. Data were collected from 11 animals under general endotracheal anesthesia. Consistent positive potentials were obtained for both auditory (P24) and median nerve somatosensory (P26) stimulation. The auditory region was centered around the lateral (sylvian) fissure; the somatosensory region was centered around the central (dorsomedial suprasylvian) fissure. In the miniature swine the locations of the auditory and somatosensory cortices are comparable to those found in other species.

The general consensus of opinion in psychopharmacology is that the basic lesion in schizophrenia is a defect of the dopaminergic mechanism in some part or parts of the brain. In this article I wish to show that there is sufficient evidence to indicate that the central lesion involves the polyamines rather than dopamine.