A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.

/pdf/a-default-mode-of-brain-function-zwenkbmjw7.pdf

A default mode of brain function.

The alpha- and beta-subunits of membrane-bound ATP synthase complex bind ATP and ADP: beta contributes to catalytic sites, and alpha may be involved in regulation of ATP synthase activity. The sequences of beta-subunits are highly conserved in Escherichia coli and bovine mitochondria. Also alpha and beta are weakly homologous to each other throughout most of their amino acid sequences, suggesting that they have common functions in catalysis. Related sequences in both alpha and beta and in other enzymes that bind ATP or ADP in catalysis, notably myosin, phosphofructokinase, and adenylate kinase, help to identify regions contributing to an adenine nucleotide binding fold in both ATP synthase subunits.

Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.

Neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation. Magnetic resonance imaging (MRI) techniques sensitive to changes in cerebral blood flow and blood oxygenation were developed by high-speed echo planar imaging. These techniques were used to obtain completely noninvasive tomographic maps of human brain activity, by using visual and motor stimulus paradigms. Changes in blood oxygenation were detected by using a gradient echo (GE) imaging sequence sensitive to the paramagnetic state of deoxygenated hemoglobin. Blood flow changes were evaluated by a spin-echo inversion recovery (IR), tissue relaxation parameter T1-sensitive pulse sequence. A series of images were acquired continuously with the same imaging pulse sequence (either GE or IR) during task activation. Cine display of subtraction images (activated minus baseline) directly demonstrates activity-induced changes in brain MR signal observed at a temporal resolution of seconds. During 8-Hz patterned-flash photic stimulation, a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.8% (GE) and 1.8% +/- 0.9% (IR) was observed in the primary visual cortex (V1) of seven normal volunteers. The mean rise-time constant of the signal change was 4.4 +/- 2.2 s for the GE images and 8.9 +/- 2.8 s for the IR images. The stimulation frequency dependence of visual activation agrees with previous positron emission tomography observations, with the largest MR signal response occurring at 8 Hz. Similar signal changes were observed within the human primary motor cortex (M1) during a hand squeezing task and in animal models of increased blood flow by hypercapnia. By using intrinsic blood-tissue contrast, functional MRI opens a spatial-temporal window onto individual brain physiology.

https://www.pnas.org/content/pnas/89/12/5675.full.pdf

Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation.

Functional magnetic resonance imaging (fMRI) is currently the mainstay of neuroimaging in cognitive neuroscience. Advances in scanner technology, image acquisition protocols, experimental design, and analysis methods promise to push forward fMRI from mere cartography to the true study of brain organization. However, fundamental questions concerning the interpretation of fMRI data abound, as the conclusions drawn often ignore the actual limitations of the methodology. Here I give an overview of the current state of fMRI, and draw on neuroimaging and physiological data to present the current understanding of the haemodynamic signals and the constraints they impose on neuroimaging data interpretation.

What we can do and what we cannot do with fMRI

The purpose of this report is to provide revised standards and guidelines for the exercise testing and training of individuals who are free from clinical manifestations of cardiovascular disease and those with known cardiovascular disease. These guidelines are intended for physicians, nurses, exercise physiologists, specialists, technologists, and other healthcare professionals involved in exercise testing and training of these populations. This report is in accord with the “Statement on Exercise” published by the American Heart Association (AHA).1

These guidelines are a revision of the 1995 standards of the AHA that addressed the issues of exercise testing and training.2 An update of background, scientific rationale, and selected references is provided, and current issues of practical importance in the clinical use of these standards are considered. These guidelines are in accord with the American College of Cardiology (ACC)/AHA Guidelines for Exercise Testing.3

### The Cardiovascular Response to Exercise

Exercise, a common physiological stress, can elicit cardiovascular abnormalities that are not present at rest, and it can be used to determine the adequacy of cardiac function. Because exercise is only one of many stresses to which humans can be exposed, it is more appropriate to call an exercise test exactly that and not a “stress test.” This is particularly relevant considering the increased use of nonexercise stress tests.

### Types of Exercise

Three types of muscular contraction or exercise can be applied as a stress to the cardiovascular system: isometric (static), isotonic (dynamic or locomotory), and resistance (a combination of isometric and isotonic).4,5 Isotonic exercise, which is defined as a muscular contraction resulting in movement, primarily provides a volume load to the left ventricle, and the response is proportional to the size of the working muscle mass and the intensity of exercise. Isometric exercise is defined as a muscular contraction without movement (eg, handgrip) and imposes greater pressure than volume …

Exercise Standards for Testing and Training A Scientific Statement From the American Heart Association

Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field

The metabolic state of skeletal muscle and brain within intact rats is monitored using high resolution phosphorus nuclear magnetic resonance. Regional disturbances in metabolism (for example, localised ischaemia) are easily observed, indicating the diagnostic possibilities of the method. Measurements are made using 'surface' radiofrequency coils, which we discuss in detail.

Mapping of metabolites in whole animals by 31P NMR using surface coils.

31P NMR spectra of intact biological tissues can now be observed. The use of the spectra to study the course of reactions within the tissues is illustrated by experiments on muscle and its glycogen particle fraction.

Observation of tissue metabolites using 31P nuclear magnetic resonance.

The metabolic state of human muscle in various functional states has been investigated by the non-invasive technique of 31P nuclear magnetic resonance. The concentrations of phosphocreatine, ATP and inorganic phosphate as well as intracellular pH in the flexor digitorum superficialis have been measured during rest, dynamic exercise and recovery from exercise. The observed relationship between phosphocreatine utilization and decrease in intracellular pH during aerobic exercise indicates that lactate production only becomes significant after more than 60% of the phosphocreatine is used up. Surprisingly intracellular pH may reach as low a value as 5.9 to 6.1, indicating that phosphofructokinase is still partially active at pH 6.0. There is no metabolic recovery if the muscle is made ischaemic following exercise, implying that glycolysis is switched off as soon as exercise is stopped. Lactic acidosis is not the cause of this and presumably Ca2+ is needed to maintain the activation of phosphorylase kinase. The time-course of phosphocreatine recovery after exercise reflects the rate of oxidative metabolism, while pH recovery probably represents H+ ion export from the muscle cell. The dynamics of metabolic changes can now be observed with a time resolution of 10 to 60 seconds and thus disturbances in energy metabolism can be readily detected in several pathological states.

Bioenergetics of intact human muscle. A 31P nuclear magnetic resonance study.

Background— It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high-energy phosphate metabolism. Methods and Results— We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age-, sex-, and body mass index-matched control subjects. Cardiac high-energy phosphate metabolites were measured at rest using 31P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high-energy phosphate metabolites, intracellular pH, and oxygenation were measured using 31P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50±0.11, than the healthy volunteers, at 2.30±0.12. The...

George K. Radda

Papers

Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field

Mapping of metabolites in whole animals by 31P NMR using surface coils.

Observation of tissue metabolites using 31P nuclear magnetic resonance.

Bioenergetics of intact human muscle. A 31P nuclear magnetic resonance study.

Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes.