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Results for “Resting-state”

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PubMed1999

Functional brain imaging in the resting state and during activation in Alzheimer's disease. Implications for disease mechanisms involving oxidative phosphorylation.

In vivo brain imaging of patients with Alzheimer's disease (AD) using positron emission tomography (PET) demonstrates progressive reductions in resting-state brain glucose metabolism and blood flow in relation to dementia severity, more so in association than primary cortical regions. During cognitive or psychophysical stimulation, blood flow and metabolism in the affected regions can increase to the same extent in mildly demented AD patients as in age-matched controls, suggesting that energy delivery is not rate limiting. Activation declines with dementia severity, and is markedly reduced in severely demented patients. These results suggest that there is an initial "normal" functionally-responsive stage in AD, followed by a late less responsive stage. Studies of biopsied and postmortem brain indicate that the initial stage is accompanied by selective and potentially reversible down-regulation of the brain enzymes, including cytochrome oxidase, which mediate mitochondrial oxidative-phosphorylation.

Alzheimer Disease↗

PubMed1997

Is resting state HCO3- secretion in frog gastric fundus mucosa mediated by apical Cl(-)-HCO3- exchange?

1. We have tested the widely accepted hypothesis that resting-state bicarbonate secretion of gastric fundus mucosa is mediated by Cl(-)-HCO3- exchange in the apical membrane of surface epithelial cells (SECs). To this end, SECs of isolated fundus mucosa of Rana esculenta were punctured with double-barrelled microelectrodes to measure intracellular pH (pHi). 2. No significant pHi changes were observed in response to changing luminal HCO3- and/or Cl- concentrations. The change in pHi (delta pHi) in response to luminal chloride substitution averaged 0.00 +/- 0.01 pH units (mean +/- S.E.M.; n = 48), and did not change after blocking putative basolateral acid/base transporters which could have masked the pHi response. 3. On the other hand, pHi responded readily and reversibly to luminal perfusion with either low-pH (pH 2.5) solution (delta pHi = -0.36 +/- 0.05; n = 4; P < 0.01) or CO2-free HCO3- Ringer solution (delta pHi = +0.10 +/- 0.01; n = 29; P < 0.001). These observations demonstrate that the solution change was effective and complete within 1 min and show that the apical membrane of SECs is permeable to CO2. 4. The apical membrane of frog SECs could not be stained with an antibody against the C-terminal end of the mouse Cl(-)-HCO3- exchanger isoform AE2, although this antibody readily stained the basolateral membrane of the oxyntopeptic cells (OCs). 5. In conclusion, the presence of a Cl(-)-HCO3- exchanger in the apical membrane of SECs of frog gastric fundus mucosa in the resting state could not be confirmed, but other models of HCO3- secretion cannot be fully excluded. Observations from electrical measurements, favouring a model of conductive HCO3- secretion, point to the OCs rather than the SECs as a site of origin of HCO3- secretion.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2003

Mexiletine block of wild-type and inactivation-deficient human skeletal muscle hNav1.4 Na+ channels.

Mexiletine is a class 1b antiarrhythmic drug used for ventricular arrhythmias but is also found to be effective for paramyotonia congenita, potassium-aggravated myotonia, long QT-3 syndrome, and neuropathic pain. This drug elicits tonic block of Na(+) channels when cells are stimulated infrequently and produces additional use-dependent block during repetitive pulses. We examined the state-dependent block by mexiletine in human skeletal muscle hNav1.4 wild-type and inactivation-deficient mutant Na(+) channels (hNav1.4-L443C/A444W) expressed in HEK293t cells with a beta1 subunit. The 50% inhibitory concentrations (IC(50)) for the inactivated-state block and the resting-state block of wild-type Na(+) channels by mexiletine were measured as 67.8 +/- 7.0 microm and 431.2 +/- 9.4 microm, respectively (n= 5). In contrast, the IC(50) for the block of open inactivation-deficient mutant channels at +30 mV by mexiletine was 3.3 +/- 0.1 microm (n= 5), which was within the therapeutic plasma concentration range (2.8-11 microm). Estimated on- and off-rates for the open-state block by mexiletine at +30 mV were 10.4 microm(-1) s(-1) and 54.4 s(-1), respectively. Use-dependent block by mexiletine was greater in inactivation-deficient mutant channels than in wild-type channels during repetitive pulses. Furthermore, the IC(50) values for the block of persistent late hNav1.4 currents in chloramine-T-pretreated cells by mexiletine was 7.5 +/- 0.8 microm (n= 5) at +30 mV. Our results together support the hypothesis that the in vivo efficacy of mexiletine is primarily due to the open-channel block of persistent late Na(+) currents, which may arise during various pathological conditions.

Anti-Arrhythmia Agents↗

PubMed1988

Nonoxidative glucose consumption during focal physiologic neural activity.

Brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with positron emission tomography, and a resting-state molar ratio of oxygen to glucose consumption of 4.1:1 was obtained. Physiological neural activity, however, increased glucose uptake and blood flow much more (51 and 50 percent, respectively) than oxygen consumption (5 percent) and produced a molar ratio for the increases of 0.4:1. Transient increases in neural activity cause a tissue uptake of glucose in excess of that consumed by oxidative metabolism, acutely consume much less energy than previously believed, and regulate local blood flow for purposes other than oxidative metabolism.

Brain↗

PubMed2025

Glaucoma and brain functional networks: a bidirectional Mendelian randomisation study.

OBJECTIVE: Glaucoma is a complex neurodegenerative ocular disorder accompanied by brain functional abnormalities that extend beyond the visual system. However, the causal association between the two remains unclear at present. This study aimed to investigate the potential causal relationships between glaucoma and brain functional networks in order to provide novel insights into the neuropathic mechanism of glaucoma. METHODS AND ANALYSIS: Based on the genome-wide association studies data of glaucoma and resting-state functional MRI (Rs-fMRI), a bidirectional Mendelian randomisation (MR) analysis was conducted between glaucoma and brain functional networks. Inverse variance weighting was applied as the primary method to estimate causality with false discovery rate correction. Additional sensitivity analyses were conducted to evaluate the robustness of the results. RESULTS: Forward MR analysis suggested that glaucoma was causally associated with two brain networks between the subcortical cerebellum and the attention or visual network (p=0.022), as well as the default mode and central executive network (p=0.008), but without significance after false discovery rate correction (q>0.1). Reverse MR analysis revealed 19 Rs-fMRI traits related to glaucoma risk, including the salience or central executive network in the frontal region (p=0.0005, q=0.08) and the motor network (p=0.0009, q=0.08) with significant causality. CONCLUSIONS: This MR study revealed potentially causal relationships between glaucoma and brain functional networks. Especially, the functional connectivity of the motor network between the postcentral or precentral areas may potentially lead to increased risk of glaucoma.

Humans↗

PubMed1989

X-ray absorption spectroscopic investigations of cytochrome c oxidase structure and function.

Although the low sensitivity of the XAS technique imposes difficulties upon the study of an enzyme that is often heterogeneous, significant progress has been made in elucidation of the structures of the functional metal sites of cytochrome c oxidase. Figure 8 summarizes interpretations of the resting-state enzyme based on the XAS results obtained over the past decade by the two main groups involved. Aside from several persisting minor differences in distances and precise ligand compositions of the metal sites, the biggest difference between the two interpretations involves the binuclear O2 interaction site, especially the nature of the bridging ligand and its precise attachments to Fea3 and CuB. However, the structural models presented by the two groups have been converging recently, and there is hope that the next few years will see a resolution of the remaining differences. Other XAS approaches (e.g. studies on oriented multilayers) and other techniques will doubtless contribute to this resolution.

Animals↗

PubMed2002

Alzheimer Disease: evaluation of a functional MR imaging index as a marker.

PURPOSE: To measure changes in functional synchrony in the hippocampus in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). MATERIALS AND METHODS: Three subject groups (nine cognitively healthy elderly control subjects, 10 patients with probable AD, and five subjects with MCI) underwent resting-state functional magnetic resonance (MR) imaging for measurement of functional synchrony in the hippocampus. Functional synchrony was defined and quantified as the mean of the cross-correlation coefficients of spontaneous low frequency (COSLOF) components between possible pairs of voxel time courses in a brain region, or the COSLOF index. The two-tailed Student t test was used to determine differences in the COSLOF index between the control group, the probable AD group, and the MCI group. An operating characteristic curve was calculated to graphically depict the tradeoff between sensitivity and specificity of the COSLOF index. RESULTS: Functional synchrony quantified with the COSLOF index was obtained in AD, MCI, and control subjects. COSLOF index values were significantly lower in AD patients than in control subjects (t = 4.32, P <.0012). For MCI subjects, COSLOF index values were significantly higher than those of AD patients (t = -2.4052, P <.047) but significantly lower than those of control subjects (t = 2.257, P <.043). The exponential-class curve significantly fits the relationship between the COSLOF index and the Mini-Mental Status Examination score (chi(2) = 20.4), indicating the rapid decrease in cognitive capacity below a threshold of the COSLOF index. CONCLUSION: Our results suggest that the COSLOF index could be used as a noninvasive quantitative marker for the preclinical stage of AD.

Aged↗

PubMed1990

Left prefrontal glucose hypometabolism in the depressed state: a confirmation.

The resting-state cerebral metabolic rates for glucose of 10 severely depressed patients (seven bipolar and three unipolar) were compared, before and after treatment with tricyclic antidepressants, to those of 10 control subjects of similar age by means of positron emission tomography and the fluorodeoxyglucose method. Significant left-right prefrontal asymmetry was present in the patients before but not after successful treatment, suggesting that medication can reduce this asymmetry. Also, significant hypofrontality and whole-cortex hypometabolism were found in the patients in the depressed state and persisted in the treated state, despite clinical improvement, suggesting that these abnormalities are not state dependent.

Adult↗

PubMed1987

Mapping human somatosensory cortex with positron emission tomography.

Positron emission tomography measurements of regional cerebral blood flow were used to detect focal neuronal activation in the first somatosensory cortex (SI) of humans induced by cutaneous vibratory stimulation. Intravenously administered water labeled with oxygen-15 (H2(15)O) was used as a blood flow tracer to obtain five stimulated-state and two resting-state blood flow images in each of eight normal volunteers. Three cutaneous surfaces were tested: lips, fingers, and toes. Intense, highly focal SI responses were seen during all 39 stimulated-state trials. The SI responses from the three stimulation sites were anatomically distinct and formed a medial-to-lateral homonculus in every subject. Response magnitudes (increase in local blood flow) and response locales (expressed as proportionately measured bicommissural stereotaxic coordinates) were highly consistent among subjects and on repeated trials for each subject. These findings suggest that eliciting cerebral blood flow responses by cutaneous vibration provides a safe, rapid, and reproducible tool for locating and assessing the functional status of somatosensory cortex, and offers potential clinical and research utility. This study has established normative values for future applications of this experimental paradigm.

Brain Mapping↗

PubMed2026

Genetic Correlation Between Brain Imaging Phenotypes and Externalizing Behavior: A Large-Scale LDSC Analysis of UK Biobank IDPs.

Externalizing has been associated with differences in brain structure and function; however, it remains unclear whether these associations reflect shared common-variant genetic influences. Cross-trait linkage disequilibrium score regression was used to estimate genome-wide genetic correlations between externalizing genome-wide association study (GWAS) results and 3,935 brain imaging-derived phenotypes from the UK Biobank BIG40 resource. The imaging phenotypes covered structural magnetic resonance imaging (MRI), diffusion MRI, susceptibility-weighted imaging, resting-state functional MRI, and task-based functional MRI. Results were included in the primary analysis when the imaging phenotype had positive single-nucleotide polymorphism (SNP) heritability, a heritability Z statistic of at least 1.96, a mean GWAS chi-square statistic of at least 1.02, at least 200,000 regression SNPs, and a complete LDSC result without a fatal error. Technical imaging quality-control phenotypes were excluded from biological inference. Individual results were corrected using the Benjamini-Hochberg false discovery rate procedure. Aggregated Cauchy association tests (ACATs) were used to evaluate evidence across all imaging phenotypes and within predefined imaging categories. Statistical power, simultaneous confidence bounds, and alternative quality-control definitions were examined in sensitivity analyses. Of the 3,935 imaging phenotypes, 3,716 produced estimable genetic correlations, 2,980 met the primary LDSC quality-control criteria, and 2,967 were classified as biological imaging phenotypes. No individual phenotype survived false discovery rate correction. The smallest unadjusted P value was 0.0005, and the minimum adjusted q value was 0.486. The distribution of genetic correlations was centered near zero, with a median genetic correlation of 0.0014 and a median absolute genetic correlation of 0.0338. ACAT provided no evidence of an aggregate association across all biological imaging phenotypes (P = 0.302), and no predefined imaging category survived multiple-testing correction. The median minimum detectable genetic correlation at 80% power was 0.216. Bonferroni-adjusted simultaneous confidence intervals were fully contained within the interval [-0.30, 0.30] for 80.0% of phenotypes in the primary analysis and 88.0% under the stringent heritability quality-control definition. Broad and stringent sensitivity analyses produced the same overall conclusions. In this study, no statistically robust evidence of genome-wide genetic correlations between externalizing and individual UK Biobank brain imaging phenotypes was found. Nevertheless, small, localized, mixed-direction, or developmentally specific genetic effects remain possible.

Journal Article↗

PubMed2002

Simulation of the effects of global normalization procedures in functional MRI.

We report on differences in sensitivity and false-positive rate across five methods of global normalization using resting-state fMRI data embedded with simulated activation. These methods were grand mean session scaling, proportional scaling, ANCOVA, a masking method, and an orthogonalization method. We found that global normalization by proportional scaling and ANCOVA decreased the sensitivity of the statistical analysis and induced artifactual deactivation even when the correlation between the global signal and the experimental paradigm was relatively low. The masking method and the orthogonalization method performed better from this perspective but are both restricted to certain experimental conditions. Based on the results of these simulations, we offer practical guidelines for the choice of global normalization method least likely to bias the experimental results.

Algorithms↗

PubMed2002

The metabolic substrates of bradykinesia and tremor in uncomplicated Parkinson's disease.

The pathophysiological mechanisms of bradykinesia and resting tremor, i.e., two major features of Parkinson's disease (PD), remain incompletely understood despite extensive studies, including functional imaging investigations. Using high-resolution positron emission tomography (PET) and [(18)F]fluoro-2-deoxyglucose (FDG) in 17 nondemented patients with uncomplicated PD on a stable therapeutic regimen, we measured the resting-state cerebral metabolic rate of glucose (CMRGlc), a validated marker of synaptic density/activity. Following formulation of distinct a priori hypotheses about potentially involved brain regions based on previous experimental and clinical literature, correlations between CMRGlc and objective scores of bradykinesia and tremor were searched in a voxel-based fashion using SPM99. Bradykinesia scores were significantly positively correlated with bilateral putamen and globus pallidum CMRGlc, while tremor scores were negatively correlated with bilateral putamen and cerebellar vermis CMRGlc. There was a large overlap of putamenal voxels significantly but inversely correlated with both extrapyramidal features. For both bradykinesia and tremor, the observed patterns of subcortical correlations largely concurred with our a priori hypotheses, and point to the major role of disruption of the striatofrontal and corticocerebellar pathways in the genesis of these extrapyramidal features. The direction of these correlations was not entirely expected, however, which may be due to the patients' being studied on medication, contrary to most studies performed to date. The observation that overlapping portions of the putamen inversely correlated with bradykinesia and tremor was a novel and striking finding which points to the complexity of the underlying pathophysiology of PD. Because it allows greater control of the neurological status, studying patients on medication may partly explain our findings. Voxel-based analysis of resting FDG-PET holds considerable potential for assessing the neural substrates of motor impairment in PD.

Aged↗

PubMed2002

The impact of moderate sleep loss on neurophysiologic signals during working-memory task performance.

STUDY OBJECTIVES: This study examined how sleep loss affects neurophysiologic signals related to attention and working memory. DESIGN: Subjective sleepiness, resting-state electroencephalogram, and behavior and electroencephalogram during performance of working-memory tasks were recorded in a within-subject, repeated-measures design. SETTING: Data collection occurred in a computerized laboratory setting. PARTICIPANTS: Sixteen healthy adults (mean age, 26 years; 8 female) INTERVENTIONS: Data from alert daytime baseline tests were compared with data from tests during a late-night, extended-wakefulness session that spanned up to 21 hours of sleep deprivation. MEASUREMENTS AND RESULTS: Alertness measured both subjectively and electrophysiologically decreased monotonically with increasing sleep deprivation. A lack of alertness-related changes in electroencephalographic measures of the overall mental effort exerted during task execution indicated that participants attempted to maintain high levels of performance throughout the late-night tests. Despite such continued effort, responses became slower, more variable, and more error prone within 1 hour after participants' normal time of sleep onset. This behavior failure was accompanied by significant degradation of event-related brain potentials related to the transient focusing of attention. CONCLUSIONS: Moderate sleep loss compromises the function of neural circuits critical to subsecond attention allocation during working-memory tasks, even when an effort is made to maintain wakefulness and performance. Multivariate analyses indicate that combinations of working-memory-related behavior and neurophysiologic measures can be sensitive enough to permit reliable detection of such effects of sleep loss in individuals. Similar methods might prove useful for assessment of functional alertness in patients with sleep disorders.

Adult↗

PubMed1987

[The timing of crisis and day-night distribution of paroxysmal EEG activities: a study on 197 epileptic patients].

The purpose of the present study was to determine whether paroxysmal EEG activity (PA) occurs randomly over time and whether seizures arise at time of maximum PA. 204 ambulatory recordings (A/EEG) in 197 adult epileptic outpatients have been were included. The patients' seizures were grouped according to ILAE classification: Simple partial seizures; complex partial seizures (CPS), isolated or secondarily generalized; idiopathic generalized seizures: epilepsy with myoclonic absences, generalized tonic-clonic seizures (GTCS) on awakening, GTCS with photo-sensitivity; undetermined epilepsies: "grand mal morpheique", epilepsies with generalized PA without photosensitivity or with All recordings were performed with a 8-channel 24 h cassette recorder system (Medilog 9,000). The video play-back speed used was 20 times the recording speed to allow good detection, characterization and localization of PA. Counting was accomplished by visual analysis. No PA during A/EEG was noted in 24.5 p. 100 of all cases. A diurnal distribution in wakefulness was found in 59 p. 100 of idiopathic generalized epilepsies, PA usually occurring on awakening whatever the specific time of day; in 27 p. 100 of CPS and 20 p. 100 of undetermined epilepsies, with peak PA occurrence at late morning and 6 pm. During resting-state and afternoon-naps, PA occurrence was mainly seen in CPS. PA occurring only in overnight sleep was observed in 17 p. 100 of CPS and 20 p. 100 of undetermined epilepsies. PA distribution pattern in both CPS and undetermined epilepsies suggests an ultradian rhythm (time-dependent). On the other hand, PA pattern in idiopathic generalized epilepsies support the hypothesis of a circadian rhythm linked to sleep/wake--or light/dark--cycle (state-dependent).

Adolescent↗

PubMed1987

Respiratory function of rat brain mitochondria after hypobaric hypoxia and piracetam treatment.

After an acute hypobaric hypoxia the mitochondrial respiratory control index is reduced in consequence of a decreased active-state respiration. The finding is paralleled by decreased uncoupled respiration and a not significantly changed resting-state respiration. Long term hypoxic exposures show adaptive traits of this criterion of mitochondrial energy metabolism. The antihypoxic effect of piracetam may be reflected in a delayed normothermic in vitro aging of mitochondrial suspension.

Animals↗

PubMed1985

Mitochondrial respiratory function as indicator of the ischemic injury of the rat kidney.

The function of mitochondria was considered to be an indicator of ischemic injury of the rat kidney, and the respiration of isolated mitochondria was measured in different metabolic states. The respiratory control index (RCI) was chosen as a parameter of mitochondrial intactness. The results indicate that normothermic in vitro ischemia leads to a rapid decrease of RCI and an almost complete loss of respiratory control within 45 min. Hypothermia during ischemic exposure proved to be an effective protection against mitochondrial injury as indicated by a prolonged coupled respiration and an RCI of about 2, even after 24 h of ischemic kidney storage. The ischemia-induced decrease of RCI was mainly due to a progressive decrease of active-state respiration, whereas the alterations of resting-state respiration were only small. The decline of active-state respiration was paralleled by a decrease of an uncoupled respiration rate. After termination of in vivo ischemia the RCI increased very slowly. Normal RCI values were not obtained until 7 days after onset of blood reflow, which supports the assumption of long-term damage due to ischemia.

Adenosine Triphosphate↗

PubMed1995

Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress.

The long-term consequences of neonatal endotoxin exposure on hypothalamic-pituitary-adrenal axis (HPA) function were assessed in adult female and male Long-Evans rats. At 3 and 5 d of age, pups were administered endotoxin (Salmonella enteritidis, 0.05 mg/kg, i.p.) at a dose that provokes a rapid and sustained physiological response, but with no mortality. As adults, neonatally endotoxin-treated animals exhibited significantly greater adrenocorticotrophic hormone (ACTH) and corticosterone responses to restraint stress than controls. In addition, dexamethasone pretreatment was less effective in suppressing ACTH responses to restraint stress in endotoxin-treated animals than in controls, suggesting decreased negative-feedback sensitivity to glucocorticoids. Neonatal endotoxin treatment elevated resting-state median eminence levels of corticotropin-releasing hormone (CRH) and arginine vasopressin in adult male animals, and arginine vasopressin in both adult males and females. Neonatal exposure to endotoxin also increased CRH mRNA expression in the paraventricular nucleus of the hypothalamus of adult males, with no difference in females. Finally, glucocorticoid receptor density was reduced across a wide range of brain regions in the neonatal endotoxin-treated, adult animals. These data illustrate the interactive nature of immune and endocrine systems during development. It appears that endotoxin exposure during critical stages of development decreases glucocorticoid negative-feedback inhibition of ACTH secretagogue synthesis, thus increasing HPA responsiveness to stress. The implication of these findings is that exposure to gram-negative LPS in early life can alter the development of neural systems which govern endocrine responses to stress and may thereby predispose individuals to stress-related pathology.

Adrenocorticotropic Hormone↗

PubMed2026

Functional neuroimaging subtypes of obsessive-compulsive disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) exhibits substantial clinical heterogeneity that may reflect underlying neurobiological diversity. Neuroimaging-based subtyping may advance precision psychiatry by identifying biologically distinct subgroups with differential treatment responses. This study systematically synthesized evidence from functional neuroimaging subtyping studies in OCD to identify reproducible neurobiological subtypes, characterize their clinical profiles, and establish a consensus-based classification framework. We reviewed 40 original studies employing machine learning, clustering, normative modeling, or classification approaches, encompassing approximately 8,150 patients. Consensus clustering identified three reproducible neurobiological subtypes. The Limbic-Hyperactive subtype, comprising approximately 40% of patients, exhibited amygdala and insula hyperconnectivity, elevated anxiety levels, predominant contamination and washing symptoms, and favorable response to cognitive-behavioral therapy. The Fronto-Striatal-Hypoconnected subtype, comprising approximately 35% of patients, demonstrated reduced orbitofrontal-striatal connectivity, cognitive inflexibility, predominant checking and ordering symptoms, and a favorable response to selective serotonin reuptake inhibitors. The Global-Disrupted subtype, comprising approximately 25% of patients, exhibited widespread connectivity disruption, greater symptom severity, and poor treatment response. Support vector machine classification achieved 81.5% accuracy for subtype assignment, though classification of OCD versus healthy controls showed limited generalizability in multisite settings (AUC 0.567-0.673). These findings support a neuroimaging-based framework for personalized treatment selection but require prospective validation.

Humans↗