Brain Metabolic Activity Research Articles

Special Issue on Biomedical Big Data: Understanding, Learning and Applications

The papers in this special issue focus on biomedical Big Data. Biomedical imaging is an essential component in various fields of biomedical research and clinical practice. The study of biologists requires continuous monitoring of cell behavior under microscope. Neuroscientists detect regional metabolic brain activity from positron emission tomography (PET), functional magnetic resonance imaging (MRI), and magnetic resonance spectrum imaging (MRSI) scans. During these researching process, large amount of biomedical data will be produced for processing. The development of advanced imaging equipment and diverse applications also have driven the generation of biomedical big data. The main challenge and bottleneck for the related research is the conversion of “biomedical big data” into interpretable information and hence discoveries. Computer vision theory has a huge potential in many aspects for automated understanding of biomedical data and has been used successfully to speed up and improve applications such as large-scale cell image analysis (image preconditioning, cell segmentation and detection, cell tracking, and cell behavior identification), image reconstruction and registration, organ segmentation and disease classification. Considering the recent advance in machine learning technique, deep learning has revolutionized multiple fields of computer vision, significantly pushing the state of arts of computer vision systems in a broad array of high-level tasks. Hopefully these technique advance will help to deal problems in biomedical big data.

Brain metabolism in patients with freezing of gait after hypoxic-ischemic brain injury: A pilot study.

Movement disorders are 1 of the long-term neurological complications that can occur after hypoxic-ischemic brain injury (HIBI). However, freezing of gait (FOG) after HIBI is rare. The aim of this study was to examine the brain metabolism of patients with FOG after HIBI using F-18 fluoro-2-deoxy-D-glucose positron emission tomography (F-18 FDG PET).We consecutively enrolled 11 patients with FOG after HIBI. The patients’ overall brain metabolism was measured by F-18 FDG PET, and we compared their regional brain metabolic activity with that from 15 healthy controls using a voxel-by-voxel-based statistical mapping analysis. Additionally, we correlated each patient's FOG severity with the brain metabolism using a covariance analysis.Patients with FOG had significantly decreased brain glucose metabolism in the midbrain, bilateral thalamus, bilateral cingulate gyri, right supramarginal gyrus, right angular gyrus, right paracentral lobule, and left precentral gyrus (PFDR-corrected < .01, k = 50). No significant increases in brain metabolism were noted in patients with FOG. The covariance analysis identified significant correlations between the FOG severity and the brain metabolism in the right lingual gyrus, left fusiform gyrus, and bilateral cerebellar crus I (Puncorrected < 0.001, k = 50).Our data suggest that brain regions in the gait-related neural network, including the cerebral cortex, subcortical structures, brainstem, and cerebellum, may significantly contribute to the development of FOG in HIBI. Moreover, the FOG severity may be associated with the visual cortex and cerebellar regions.

Cerebral metabolic correlates of attention networks in Alzheimer's Disease: A study of the Stroop

Patients with Alzheimer's Disease (AD) show difficulties with attention. Cognitive neuroscience models posit that attention can be broken down into alerting, orienting, and executive networks. We used the Stroop Color-Word test to interrogate the neural correlates of attention deficits in AD. We hypothesized that the Word, Color, and Color-Word conditions of the Stroop would all tap into the alerting and orienting networks. The Color-Word condition would additionally tap into the executive network. A ratio of Color-Word to Color naming performance would isolate the executive network from the others. To identify the neural underpinnings of attention in AD we correlated performance on the Stroop with brain metabolic activity. Sixty-six patients with probable AD completed [18F] fluorodeoxyglucose PET scanning and neuropsychological testing. Analysis was conducted with SPM12 (p<0.001 uncorrected, extent threshold 50 voxels). Performance on the Word, Color, and Color-Word conditions directly correlated with metabolic rate in right inferior parietal lobules/intraparietal sulci. The Color-Word/Color ratio revealed associations with metabolic rate in right medial prefrontal cortex and insula/operculum. Overall findings were largely consistent with the hypothesized neuroanatomical substrates of the alerting, orienting, and executive networks. As such, attention deficits in AD reflect compromise to multiple large-scale networks.

Fentanyl-Induced Brain Hypoxia Triggers Brain Hyperglycemia and Biphasic Changes in Brain Temperature.

Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as a drug of abuse are largely unknown. We used high-speed amperometry in freely moving rats to examine the effects of intravenous fentanyl at doses within the range of possible human intake (3-40 μg/kg) on oxygen and glucose levels in nucleus accumbens (NAc). Fentanyl induced a rapid, dose-dependent decrease in NAc oxygen followed by a more delayed and prolonged increase in NAc glucose. Fentanyl induced similar oxygen decreases in the basolateral amygdala, indicating that brain hypoxia could be a generalized phenomenon. We used oxygen recordings in the subcutaneous space to confirm that fentanyl-induced brain hypoxia results from decreases in blood oxygen levels caused by drug-induced respiratory depression. Temperature recordings in the NAc, muscle, and skin showed that fentanyl induces biphasic changes in brain temperature, with an initial decrease that results primarily from peripheral vasodilation, and a subsequent increase driven by metabolic brain activation. The initial vasodilation appears caused by respiratory depression-induced hypoxia and a subsequent rise in CO2 that drives fentanyl-induced increases in NAc glucose. Together, these data suggest that fentanyl-induced respiratory depression triggers brain hypoxia and subsequent hyperglycemia, both of which precede slower changes in brain temperature and metabolic brain activity.

Thiol/disulfide homeostasis as a novel indicator of oxidative stress in children with simple febrile seizures.

Simple febrile seizures are generally benign, but during the seizure, elevated levels of glutamate and high levels of oxygen use due to the high metabolic brain activity result in oxidative stress. However, the relationship between febrile seizures and oxidative stress remains unclear. In this study, we investigated thiol/disulfide homeostasis as a new oxidative stress parameter in patients with simple febrile seizures. This study was performed between February 2016 and May 2016 at the Pediatric Emergency Unit. The study population consisted of 40 patients with a diagnosis of simple febrile seizure and 30 control participants aged 8-59months. Total thiol, native thiol and disulfide levels, disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios were used as thiol/disulfide homeostasis parameters and were quantified in patient and control groups. Furthermore, correlations with seizure duration were investigated. In the patient group, native and total thiol levels and native thiol/total thiol ratios were low, and disulfide levels, disulfide/native thiol, and disulfide/total thiol ratios were significantly higher than in the control group. Negative correlations were observed between seizure duration, total and native thiol levels, and native thiol/total thiol ratio, whereas positive correlations were observed between seizure duration and disulfide/native thiol and disulfide/total thiol ratio. The sensitivities of both disulfide/native thiol and disulfide/total thiol ratios were high for simple febrile seizures. Simple febrile seizures may cause impairment in favor of disulfide bonds in thiol/disulfide homeostasis. Overall, these changes may contribute to neuronal cell damage after simple febrile seizures.

Brain PET and functional MRI: why simultaneously using hybrid PET/MR systems?

In the last 20 years growing attention has been devoted to multimodal imaging. The recent literature is rich of clinical and research studies that have been performed using different imaging modalities on both separate and integrated positron emission tomography (PET) and magnetic resonance (MR) scanners. However, today, hybrid PET/MR systems measure signals related to brain structure, metabolism, neurochemistry, perfusion, and neuronal activity simultaneously, i.e. in the same physiological conditions. A frequently raised question at meeting and symposia is: "Do we really need a hybrid PET/MR system? Are there any advantages over acquiring sequential and separate PET and MR scans?" The present paper is an attempt to answer these questions specifically in relation to PET combined with functional magnetic resonance imaging (fMRI) and arterial spin labeling. We searched (last update: June 2017) the databases PubMed, PMC, Google Scholar and Medline. We also included additional studies if they were cited in the selected articles. No language restriction was applied to the search, but the reviewed articles were all in English. Among all the retrieved articles, we selected only those performed using a hybrid PET/MR system. We found a total of 17 papers that were selected and discussed in three main groups according to the main radiopharmaceutical used: 18F-fluorodeoxyglucose (18F-FDG) (N.=8), 15O-water (15O-H2O) (N.=3) and neuroreceptors (N.=6). Concerning studies using 18F-FDG, simultaneous PET/fMRI revealed that global aspects of functional organization (e.g. graph properties of functional connections) are partially associated with energy consumption. There are remarkable spatial and functional similarities across modalities, but also discrepant findings. More work is needed on this point. There are only a handful of papers comparing blood flow measurements with PET 15O-H2O and MR arterial spin label (ASL) measures, and they show significant regional CBF differences between these two modalities. However, at least in one study the correlation at the level of gray, white matter, and whole brain is rather good (r=0.94, 0.8, 0.81 respectively). Finally, receptor studies show that simultaneous PET/fMRI could be a useful tool to characterize functional connectivity along with dynamic neuroreceptor adaptation in several physiological (e.g. working memory) or pathological (e.g. pain) conditions, with or without drug administrations. The simultaneous acquisition of PET (using a number of radiotracers) and functional MRI (using a number of sequences) offers exciting opportunities that we are just beginning to explore. The results thus far are promising in the evaluation of cerebral metabolism/flow, neuroreceptor adaptation, and network's energetic demand.

DEVELOPMENT OF AN IPSC-BASED BIOMARKER STRATEGY TO IDENTIFY NEUROREGENERATIVE RESPONDERS TO ALLOPREGNANOLONE

Alzheimer's disease (AD) is a national and global epidemic with complex pathoetiology including compromised brain metabolic activity and decreased regenerative capacity. Allopregnanolone (Allo) is an investigational neuroregenerative therapeutic, currently in Phase 1b clinical trial for AD (NCT02221622, https://clinicaltrials.gov/ct2/show/NCT02221622?term=NCT02221622&rank=1). In rodent preclinical models, Allo promotes neural stem cell (NSC) proliferation and neural differentiation and improves mitochondrial function. To develop biomarkers to predict regenerative response to Allo, we have initiated proof of concept analyses to determine the impact of Allo on human induced pluripotent stem cells (iPSCs) and iPSC-derived neural cells. T-cells from Allo clinical trial participants were reprogrammed via a non-integrating, non-viral method, to iPSCs. Additional iPSCs were provided by the University of California Irvine Alzheimer's Disease Research Center (UCI-ADRC) and the Institute for Memory Impairments and Neurological Disorders. Using dual inhibition of SMAD signaling, iPSCs were differentiated to NSCs. Mitochondrial respiration and regenerative capacity were determined by metabolic analyzer and FACS. Analyses were conducted to determine the regenerative and bioenergetic effect of Allo on clinical trial participant iPS-derived NSCs. Within the cell lines of the first cohort of participants, after Allo treatment, 40% had increased NSC proliferation (mean increase 14% versus vehicle) and also bioenergetic capacity (mean increase 13% versus vehicle). These participant cell lines have been labeled ‘responders’, while those that did not have increased NSC proliferation or metabolic capacity are ‘non-responders’. These data demonstrate that Allo promotes regeneration and mitochondrial function of iPSC-derived NSCs in a subset of clinical trial participants. In order to translate these in vitro data to be clinically relevant, the next step is to analyze this cell data for correlations with the clinical trial cognitive and imaging data. These data form the foundation for developing the first biomarker of regenerative potential in brain to determine and monitor response to allopregnanolone as a regenerative therapeutic. Research supported by NIH/NIA U01AG031115 and UF1AG046148 to RDB; NIH/NINDS R00-NS07743 and the Donald E. and Delia B. Baxter Foundation to JKI; NIH/NIA AG005142 to HCC; UCI-ADRC funded by NIH/NIA Grant P50 AG16573; USC Provost Fellowship, CIRM Predoctoral Research Traineeship, and American Foundation for Pharmaceutical Education Fellowship to CMS.

Gender differences in healthy aging and Alzheimer's Dementia: A 18 F-FDG-PET study of brain and cognitive reserve.

Cognitive reserve (CR) and brain reserve (BR) are protective factors against age-associated cognitive decline and neurodegenerative disorders. Very limited evidence exists about gender effects on brain aging and on the effect of CR on brain modulation in healthy aging and Alzheimer's Dementia (AD). We investigated gender differences in brain metabolic activity and resting-state network connectivity, as measured by 18 F-FDG-PET, in healthy aging and AD, also considering the effects of education and occupation. The clinical and imaging data were retrieved from large datasets of healthy elderly subjects (HE) (225) and AD patients (282). In HE, males showed more extended age-related reduction of brain metabolism than females in frontal medial cortex. We also found differences in brain modulation as metabolic increases induced by education and occupation, namely in posterior associative cortices in HE males and in the anterior limbic-affective and executive networks in HE females. In AD patients, the correlations between education and occupation levels and brain hypometabolism showed gender differences, namely a posterior temporo-parietal association in males and a frontal and limbic association in females, indicating the involvement of different networks. Finally, the metabolic connectivity in both HE and AD aligned with these results, suggesting greater efficiency in the posterior default mode network for males, and in the anterior frontal executive network for females. The basis of these brain gender differences in both aging and AD, obtained exploring cerebral metabolism, metabolic connectivity and the effects of education and occupation, is likely at the intersection between biological and sociodemographic factors. Hum Brain Mapp 38:4212-4227, 2017. © 2017 Wiley Periodicals, Inc.

Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration.

The chronic and relapsing nature of addiction suggests that drugs produce persistent adaptations in the brain that make individuals with drug addiction particularly sensitive to drug-related cues and stress and incapable of controlling drug-seeking and drug-taking behavior. In animal models, several long-lasting neuroadaptations have been described. However, few studies have used brain-imaging techniques to provide a complete picture of brain functioning in the course of withdrawal from cocaine. In this study, we allowed rats to self-administer cocaine under short-access (1-h/day) or long-access (6-h/day) conditions and used 2-deoxy-2-(18F)fluoro-d-glucose (18FDG) positron emission tomography scanning to investigate the longitudinal changes in metabolic activity 1 and 4 weeks after discontinuation of cocaine self-administration. We found that compared to naive rats, both long-access and short-access rats showed significant disruptions in basal brain metabolic activity. However, compared to short-access, long-access rats showed more intense, and long-lasting neuroadaptations in a network of brain areas. In particular, abstinence from extended access to cocaine was associated with decreased metabolic activity in the anterior cingulate cortex, the insular cortex, and the dorsolateral striatum, and increased metabolic activity in the mesencephalon, amygdala, and hippocampus. This pattern is strikingly similar to that described in humans that has led to the proposal of the Impaired Response Inhibition and Salience Attribution model of addiction. These results demonstrate that extended access to cocaine leads to persistent neuroadaptations in brain regions involved in motivation, salience attribution, memory, stress, and inhibitory control that may underlie increased risks of relapse.

Intravenous Heroin Induces Rapid Brain Hypoxia and Hyperglycemia that Precede Brain Metabolic Response.

Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 μg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO2 levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra-brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity.

Rapid Physiological Fluctuations in Nucleus Accumbens Oxygen Levels Induced by Arousing Stimuli: Relationships with Changes in Brain Glucose and Metabolic Neural Activation.

Proper entry of oxygen from arterial blood into the brain is essential for maintaining brain metabolism under normal conditions and during functional neural activation. However, little is known about physiological fluctuations in brain oxygen and their underlying mechanisms. To address this issue, we employed high-speed amperometry with platinum oxygen sensors in freely moving male rats. Recordings were conducted in the nucleus accumbens (NAc), a critical structure for sensorimotor integration. Rats were exposed to arousing stimuli of different nature (brief auditory tone, a 1-min novel object presentation, a 3-min social interaction with a conspecific, and a 3-min tail-pinch). We found that all arousing stimuli increased NAc oxygen levels. Increases were rapid (4–10-s onset latencies), modest in magnitude (1–3 μM or 5%–15% over baseline) and duration (5–20 min), and generally correlated with the arousing potential of each stimulus. Two strategies were used to determine the mechanisms underlying the observed increases in NAc oxygen levels. First, we showed that NAc oxygen levels phasically increase following intra-NAc microinjections of glutamate (GLU) that excite accumbal neurons. Therefore, local neural activation with subsequent local vasodilation is involved in mediating physiological increases in NAc oxygen induced by arousing stimuli. Second, by employing oxygen monitoring in the subcutaneous space, a highly-vascularized area with no metabolic activity, we determined that physiological increases in NAc oxygen also depend on the rise in blood oxygen levels caused by respiratory activation. Due to the co-existence of different mechanisms governing oxygen entry into brain tissue, NAc oxygen responses differ from fluctuations in NAc glucose, which, within a normal behavioral continuum, are regulated exclusively by neuro-vascular coupling due to glucose’s highly stable levels in the blood. Finally, we discuss the relationships between physiological fluctuations in NAc oxygen, glucose and metabolic brain activation assessed by intra-brain heat production.

Pathophysiology of Alzheimer Disease

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein

Pathophysiology of Alzheimer Disease

Genetic discoveries coupled with neuropathologic investigations initially established the central role for β-amyloidosis in Alzheimer disease (AD). Three dominantly inherited genes (APP, PSEN1, and PSEN2) and one common allelic variant with lower penetrance (APOE) account for the majority of the genetic basis for AD. PET biomarkers for AD have been developed in the past decade and are fundamentally altering our view of the disease. The availability of PET tracers, first for amyloid and now for tau, has enabled researchers to develop a model of AD that begins long before people become symptomatic. In persons destined to develop dementia due to AD, brain β-amyloid levels begin to rise 10 to 20 years earlier. Other imaging changes that might precede symptomatic disease include (1) reductions in brain metabolic activity in a group of temporal and parietal cortical association areas that can be demonstrated by [18F]fluorodeoxyglucose-PET scanning; (2) losses of hippocampal volume as measured on structural magnetic resonance imaging; and (3) loss of cortical thickness or cortical volume in temporal and parietal cortical association areas. All of these changes are greatly accentuated once people become symptomatic. Although mild elevations in tau PET abnormalities can also be seen in presymptomatic individuals, it is only when persons become symptomatic that marked elevations in these abnormalities begin to occur in those same temporal and parietal cortical association areas. Cerebrospinal fluid (CSF) biomarkers provide a complementary view, with CSF β-amyloid levels falling (presumably due to aggregation within the cortex) even before amyloid PET abnormalities are visible. CSF total tau and phospho-tau levels begin to rise when persons are much closer to being symptomatic. The sum of these observations has allowed researchers to gain a far more insightful antemortem view of the pathophysiology of AD in humans than had previously been available from neuropathologic investigations. Keywords: β-amyloid, cerebrospinal fluid β-amyloid, cerebrospinal fluid phospho-tau, cortical thickness, [18F]fluorodeoxyglucose–positron emission tomography, hippocampal atrophy, preclinical Alzheimer disease, tau protein

Diagnosis of Vascular Cognitive Impairment Using EEG

Dementia or Major Neurocognitive disorder is the second most burdensome chronic condition in which 11.9 percent live with disability and 1.1 percent lost their lives, and their numbers will be doubling every 20 years to 65.7 million by 2030, and 115.4 million by 2050. Dementia due to vascular diseases is the second most common cause of dementia after Alzheimer's disease and 28 to 36 million people worldwide with dementia are undiagnosed1. Vascular Dementia is characterized by distinct aspects of impaired consciousness and such an impairment is indexed by declined performances at controlled cognitive tasks. It is related to reduced brain metabolic activity in a network of frontal, posterior associative, and limbic regions due to the occurrence of multiple mini/major strokes or other conditions that affect blood vessels and nerve fibres deep inside the brain. Diagnosis of Vascular dementia in its preliminary stages is a very complex task as it requires screening, Neuro-cognitive testing, and brain imaging evidence usually CT Scan or MRI. Sometimes cause of mild impairment cannot be diagnosed by brain Imaging. EEG based diagnostic approaches are promising tool in case of differentiating diverse types of dementia. Portable EEG with its high temporal resolution property is an economical solution for the many undiagnosed people with dementia in the low and middle income countries. This paper reviews EEG analysis approaches to diagnose vascular mild impairment and dementia as a future diagnostic tool in the healthcare sector.

Abstract 12605: Brain Metabolic Activity Within Regions Involved in Stress Perception Associates Directly With Arterial Inflammation and Inversely With Aortic Distensibility in Psoriasis

Introduction: Psychological stress and depression are linked to increased cardiovascular (CV) events in the general population and in psoriasis (PSO), a chronic inflammatory disease that increases CV risk. 18-FDG-PET/CT enables quantification of metabolic activity of the amygdala, a neural tissue critically involved in the pathobiology of stress and depression. In individuals without chronic inflammatory diseases, amygdalar activity (AmygAct) associates with greater vascular inflammation (VI) and CV events. However, it is not known whether PSO maintains this relationship with VI and whether AmygAct associates with other measures of subclinical CVD. Hypothesis: In PSO, AmygAct: 1) is higher in individuals who report depression/anxiety, and 2) associates with greater VI and decreased aortic distensibility. Methods: Subjects with PSO (n=82) completed a questionnaire at baseline, reporting psychiatric history and were placed into two groups accordingly: patients with depression/anxiety and age and sex matched controls with no psychiatric diagnoses. AmygAct was quantified using 18-FDG PET/CT by an analyst blinded to clinical data. Mean standardized uptake values (SUV) for the left amygdala were corrected for background brain activity. VI was quantified as a ratio of aortic to blood background SUV. Aortic distensibility was measured using phase contrast MRI. Results: Subjects had a mean age of 49.2 years, were 49% males, and had a median Framingham risk score of 3. Patients with a history of depression and/or anxiety had significantly higher AmygAct than those without (mean±SEM 0.85±0.01 vs. 0.81±0.01; p=0.01). AmygAct correlated with VI (β= 0.26, p=0.02) as well as aortic distensibility (β= -0.50, p&lt;0.001). Moreover, AmygAct remained associated with aortic distensibility after adjustment for Framingham risk score and hypertension (β= -0.37, p=0.007). Conclusions: Metabolic activity within neural tissues involved in stress perception significantly associates with indices of atherosclerotic disease in PSO. Future studies should further evaluate the mechanisms linking neural and atherosclerotic tissues in chronic inflammatory conditions such as PSO, and probe whether perturbing this mechanism may reduce the burden of atherosclerosis.

Non-thermal microwave radiation-induced brain tissue dehydration as a potential factor for brain functional impairment

Based on our previous finding that metabolically controlled cell hydration is sensitive to the changes of physicochemical properties of cell aqua medium, which take place upon the effect of weak physical signals, including microwaves with non-thermal intensity (NT MW), it has been hypothesized that cell aqua medium serves as a primary target for NT MW effect on brain tissue. To elucidate the nature of the metabolic pathway through which the effect of NT MW-induced changes of physicochemical properties of cell aqua medium modulate cell hydration, the effects of intraperitoneal (IP) injection of PS treated by NT MW on brain tissue hydration, 45Ca2+ uptake, [3H]-ouabain binding with cell membrane and intracellular cyclic nucleotides have been studied. The obtained data indicate that PS treated by NT MW through the activation of high affinity ouabain receptors in membrane stimulates cAMP-dependent Na+/Ca2+ exchange in reverse mode (R), which leads to brain tissue hydration in healthy (young) and dehydration in non-healthy (old) rats.As NT MW radiation-induced activation of R Na+/Ca2+ exchange leads to the increase of intracellular Ca2+ ([Ca2+]i), it is considered as a potential factor leading to the brain functional impairment, especially when brain metabolic activity is depressed (e.g. during aging).

Distinctive time-lagged resting-state networks revealed by simultaneous EEG-fMRI

Functional activation as evidenced by blood oxygen level-dependent (BOLD) functional MRI changes or event-related EEG is known to closely follow patterns of stimulation or self-paced action. Any lags are compatible with axonal conduction velocities and neural integration times. The important analysis of resting state networks is generally based on the assumption that these principles also hold for spontaneous fluctuations in brain activity. Previous observations using simultaneous EEG and fMRI indicate that slower processes, with delays in the seconds range, determine at least part of the relationship between spontaneous EEG and fMRI. To assess this relationship systematically, we used deconvolution analysis of EEG-fMRI during the resting state, assessing the relationship between EEG frequency bands and fMRI BOLD across the whole brain while allowing for time lags of up to 10.5s. Cluster analysis, identifying similar BOLD time courses in relation to EEG band power peaks, showed a clear segregation of functional subsystems of the brain. Our analysis shows that fMRI BOLD increases commonly precede EEG power increases by seconds. Most zero-lag correlations, on the other hand, were negative. This indicates two main distinct neuromodulatory mechanisms: an “idling” mechanism of simultaneous electric and metabolic network anticorrelation and a “regulatory” mechanism in which metabolic network activity precedes increased EEG power by some seconds. This has to be taken into consideration in further studies which address the causal and functional relationship of metabolic and electric brain activity patterns.

Metabolic activation of amygdala, lateral septum and accumbens circuits during food anticipatory behavior

When food is restricted to a brief fixed period every day, animals show an increase in temperature, corticosterone concentration and locomotor activity for 2–3h before feeding time, termed food anticipatory activity. Mechanisms and neuroanatomical circuits responsible for food anticipatory activity remain unclear, and may involve both oscillators and networks related to temporal conditioning. Rabbit pups are nursed once-a-day so they represent a natural model of circadian food anticipatory activity. Food anticipatory behavior in pups may be associated with neural circuits that temporally anticipate feeding, while the nursing event may produce consummatory effects. Therefore, we used New Zealand white rabbit pups entrained to circadian feeding to investigate the hypothesis that structures related to reward expectation and conditioned emotional responses would show a metabolic rhythm anticipatory of the nursing event, different from that shown by structures related to reward delivery. Quantitative cytochrome oxidase histochemistry was used to measure regional brain metabolic activity at eight different times during the day. We found that neural metabolism peaked before nursing, during food anticipatory behavior, in nuclei of the extended amygdala (basolateral, medial and central nuclei, bed nucleus of the stria terminalis), lateral septum and accumbens core. After pups were fed, however, maximal metabolic activity was expressed in the accumbens shell, caudate, putamen and cortical amygdala. Neural and behavioral activation persisted when animals were fasted by two cycles, at the time of expected nursing. These findings suggest that metabolic activation of amygdala-septal-accumbens circuits involved in temporal conditioning may contribute to food anticipatory activity.

Targeted α-Based Treatment of Metastatic Castration-Resistant Prostate Cancer: Revolutionizing Systemic Radiotherapy?

1838 Objectives In this study, we aimed to first cross-validate the reproducibility of disease-specific brain networks and metabolic activity associated with progressive supranuclear palsy (PSP) by comparing clinically-confirmed patients in the USA and China. Methods The US cohort of 10 patients with PSP and 10 age-matched healthy controls was scanned on a GE Advance PET camera. The Chinese cohort of the same sample size was scanned on a Siemens Biogragh PET/CT system in China. We first identified a PSP-related pattern (PSPRP) in each cohort and computed network scores prospectively in the other cohort. We then localized brain regions with common or different metabolic abnormalities in the same data using statistical parametric mapping analysis. Results Both cohorts produced analogous PSPRPs characterized by metabolic decreases in the middle prefrontal cortex/cingulate, ventrolateral prefrontal cortex, striatum, thalamus and midbrain, covarying with metabolic increases in the hippocampus and parieto-temporal regions. PSPRP scores were similarly elevated (P < 0.0001; post-hoc tests following one-way analysis of variance across the two cohorts) in the patients relative to the controls in the derivation cohort in the USA and in the validation cohort in China or vice versa. PSPRP scores of each pattern correlated strongly (r 蠅 0.96; P < 0.001) in the two corresponding cohorts from the USA and China, respectively. Moreover, the two cohorts of patients shared a large number of overlapping areas with regional metabolic abnormalities (P < 0.0001) in the same cortical and subcortical regions as in both PSPRPs. Conclusions This dual-center collaborative study demonstrated the high comparability and reproducibility of PSP-related metabolic activities at network and regional levels across patient populations, PET instruments and analytical techniques. These results suggest that metabolic brain network activity may serve as a reliable and objective marker of PSP and is worthy of wide applications in clinical diagnosis and translational research.

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease.

Neuropsychiatric symptoms (NPSs) often occur in early-age-of-onset Alzheimer's disease (EOAD) and cluster into sub-syndromes (SSy). The aim of this study was to investigate the association between 18 F-FDG-PET regional and connectivity-based brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were assessed in 27 EOAD using the Neuropsychiatric Inventory and further clustered into four SSy (apathetic, hyperactivity, affective, and psychotic SSy). Eighty-five percent of EOAD showed at least one NPS. Voxel-wise correlations between SSy scores and brain glucose metabolism (assessed with 18 F-FDG positron emission tomography) were studied. Interregional correlation analysis was used to explore metabolic connectivity in the salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, hyperactivity, and affective SSy were highly prevalent (>60%) as compared to the psychotic SSy (33%). The hyperactivity SSy scores were associated with increase of glucose metabolism in frontal and limbic structures, implicated in behavioral control. A comparable positive correlation with part of the same network was found for the affective SSy scores. On the other hand, the apathetic SSy scores were negatively correlated with metabolism in the bilateral orbitofrontal and dorsolateral frontal cortex known to be involved in motivation and decision-making processes. Consistent with these SSy regional correlations with brain metabolic dysfunction, the connectivity analysis showed increases in the aSN and decreases in the DMN. Behavioral abnormalities in EOAD are associated with specific dysfunctional changes in brain metabolic activity, in particular in the aSN that seems to play a crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. © 2016 Wiley Periodicals, Inc.