The principle of 'brain energy on demand' and its predictive power for stress, sleep, stroke, obesity and diabetes.

Does the brain actively draw energy from the body when needed? There are different schools of thought regarding energy metabolism. In this study, the various theoretical models are classified into one of two categories: (1) conceptualizations of the brain as being purely passively supplied, which we call 'P-models,' and (2) models understanding the brain as not only passively receiving energy but also actively procuring energy for itself on demand, which we call 'A-models.' One prominent example of such theories making use of an A-model is the selfish-brain theory. The ability to make predictions was compared between the A- and P-models. A-models were able to predict and coherently explain all data examined, which included stress, sleep, caloric restriction, stroke, type-1-diabetes mellitus, obesity, and type-2-diabetes, whereas the predictions of P-models failed in most cases. The strength of the evidence supporting A-models is based on the coherence of accurate predictions across a spectrum of metabolic states. The theory test conducted here speaks to a brain that pulls its energy from the body on-demand.

Obesity and Type 2 Diabetes Mellitus Explained by the Free Energy Principle.

According to the free energy principle, all sentient beings strive to minimize surprise or, in other words, an information-theoretical quantity called variational free energy. Consequently, psychosocial "stress" can be redefined as a state of "heightened expected free energy," that is, a state of "expected surprise" or "uncertainty." Individuals experiencing stress primarily attempt to reduce uncertainty, or expected free energy, with the help of what is called an uncertainty resolution program (URP). The URP consists of three subroutines: First, an arousal state is induced that increases cerebral information transmission and processing to reduce uncertainty as quickly as possible. Second, these additional computations cost the brain additional energy, which it demands from the body. Third, the program controls which stress reduction measures are learned for future use and which are not. We refer to an episode as "good" stress, when the URP has successfully reduced uncertainty. Failure of the URP to adequately reduce uncertainty results in either stress habituation or prolonged toxic stress. Stress habituation reduces uncertainty by flattening/broadening individual goal beliefs so that outcomes previously considered as untenable become acceptable. Habituated individuals experience so-called "tolerable" stress. Referring to the Selfish Brain theory and the experimental evidence supporting it, we show that habituated people, who lack stress arousals and therefore have decreased average brain energy consumption, tend to develop an obese type 2 diabetes mellitus phenotype. People, for whom habituation is not the free-energy-optimal solution, do not reduce their uncertainty by changing their goal preferences, and are left with nothing but "toxic" stress. Toxic stress leads to recurrent or persistent arousal states and thus increased average brain energy consumption, which in turn promotes the development of a lean type 2 diabetes mellitus phenotype. In conclusion, we anchor the psychosomatic concept of stress in the information-theoretical concept of uncertainty as defined by the free energy principle. In addition, we detail the neurobiological mechanisms underlying uncertainty reduction and illustrate how uncertainty can lead to psychosomatic illness.

How Stress Can Change Our Deepest Preferences: Stress Habituation Explained Using the Free Energy Principle.

People who habituate to stress show a repetition-induced response attenuation-neuroendocrine, cardiovascular, neuroenergetic, and emotional-when exposed to a threatening environment. But the exact dynamics underlying stress habituation remain obscure. The free energy principle offers a unifying account of self-organising systems such as the human brain. In this paper, we elaborate on how stress habituation can be explained and modelled using the free energy principle. We introduce habituation priors that encode the agent's tendency for stress habituation and incorporate them in the agent's decision-making process. Using differently shaped goal priors-that encode the agent's goal preferences-we illustrate, in two examples, the optimising (and thus habituating) behaviour of agents. We show that habituation minimises free energy by reducing the precision (inverse variance) of goal preferences. Reducing the precision of goal priors means that the agent accepts adverse (previously unconscionable) states (e.g., lower social status and poverty). Acceptance or tolerance of adverse outcomes may explain why habituation causes people to exhibit an attenuation of the stress response. Given that stress habituation occurs in brain regions where goal priors are encoded, i.e., in the ventromedial prefrontal cortex and that these priors are encoded as sufficient statistics of probability distributions, our approach seems plausible from an anatomical-functional and neuro-statistical point of view. The ensuing formal and generalisable account-based on the free energy principle-further motivate our novel treatment of stress habituation. Our analysis suggests that stress habituation has far-reaching consequences, protecting against the harmful effects of toxic stress, but on the other hand making the acceptability of precarious living conditions and the development of the obese type 2 diabetes mellitus phenotype more likely.

Psychological stress, body shape and cardiovascular events: Results from the Whitehall II study.

BACKGROUND AND AIM: It is known that persistent psychological stress predicts changes in body shape in two different ways: some stressed people lose weight, others gain weight. It is also known that persistent psychological stress predicts adverse health events. But it is unknown what role the body shape plays in this particular network of relationships. We therefore analyzed the Whitehall II dataset to relate body shape to stress and health risk. METHODS: Data of 4969 men and 2138 women from the Whitehall II cohort were analyzed. Psychological stress (General Health Questionnaire) was measured three times in the years 1991 till 2001. Body shape (BMI, waist and hip circumferences) was measured in the years 1991 till 1994. Childhood adversities were retrospectively assessed by questionnaire. Outcomes included the incidence of non-fatal or fatal CHD events (coronary heart disease) collected up to the years 2012 and 2013 and all-cause mortality collected up to July 2015. Cox proportional hazard models were conducted to estimate the relation between psychological stress and CHD events or all-cause mortality. RESULTS: There was an increase in the expected hazard to develop CHD with high psychological stress (men: Exp (B) = 1.25 (1.06-1.47); P = 0.008; women: Exp (B) = 1.34 (1.05-1.70); P = 0.017). We found a clear dose-response relationship for the association between psychological stress and CHD events in both genders. That is, subjects with consistently high psychological stress in all assessments had a 2.4-fold (men) or 2.3-fold (women) higher risk for later CHD events compared to never-stressed subjects. Moreover, subjects with a high sum score of all 13 childhood experiences had a 10% increased hazard to develop fatal or non-fatal CHD events in adulthood. Although we could not find stress or BMI linked to all-cause mortality, the waist-to-hip ratio contributed to the risk of all-cause mortality in both genders (Exp (B) = 34.66 (6.43-186.92); P < 0.001 for men; Exp (B) = 60.65 (9.33-394.22); P < 0.001 for women). CONCLUSION: This analysis supports the notion that psychological stress and childhood adversities are associated with the risk of fatal or non-fatal CHD events. When this relationship is analyzed in more detail, the Whitehall II dataset provides further insights into the role of body shape. That is, stress is also related to changes in body shape, with waist size in particular predicting higher all-cause mortality.

Brain Mass (Energy) Resistant to Hyperglycaemic Oversupply: A Systematic Review.

Cerebral energy supply is determined by the energy content of the blood. Accordingly, the brain is undersupplied during hypoglycaemia. Whether or not there is an additional cerebral energy demand that depends upon the energy content of the brain is considered differently in two opposing theoretical approaches. The Selfish-Brain theory postulates that the brain actively demands energy from the body when needed, while long-held theories, the gluco-lipostatic theory and its variants, deny such active brain involvement and view the brain as purely passively supplied. Here we put the competing theories to the test. We conducted a systematic review of a condition in which the rival theories make opposite predictions, i.e., experimental T1DM. The Selfish-Brain theory predicts that induction of experimental type 1 diabetes causes minor mass (energy) changes in the brain as opposed to major glucose changes in the blood. This prediction becomes our hypothesis to be tested here. A total of 608 works were screened by title and abstract, and 64 were analysed in full text. According to strict selection criteria defined in our PROSPERO preannouncement and complying with PRISMA guidelines, 18 studies met all inclusion criteria. Thirteen studies provided sufficient data to test our hypothesis. The 13 evaluable studies (15 experiments) showed that the diabetic groups had blood glucose concentrations that differed from controls by +294 ± 96% (mean ± standard deviation) and brain mass (energy) that differed from controls by -4 ± 13%, such that blood changes were an order of magnitude greater than brain changes (T = 11.5, df = 14, p < 0.001). This finding confirms not only our hypothesis but also the prediction of the Selfish-Brain theory, while the predictions of the gluco-lipostatic theory and its variants were violated. The current paper completes a three-part series of systematic reviews, the two previous papers deal with a distal and a proximal bottleneck in the cerebral brain supply, i.e., caloric restriction and cerebral artery occlusion. All three papers demonstrate that accurate predictions are only possible if one regards the brain as an organ that regulates its energy concentrations independently and occupies a primary position in a hierarchically organised energy metabolism. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=156816, PROSPERO, identifier: CRD42020156816.

Collective-Mode Enhanced Matter-Wave Optics.

In contrast to light, matter-wave optics of quantum gases deals with interactions even in free space and for ensembles comprising millions of atoms. We exploit these interactions in a quantum degenerate gas as an adjustable lens for coherent atom optics. By combining an interaction-driven quadrupole-mode excitation of a Bose-Einstein condensate (BEC) with a magnetic lens, we form a time-domain matter-wave lens system. The focus is tuned by the strength of the lensing potential and the oscillatory phase of the quadrupole mode. By placing the focus at infinity, we lower the total internal kinetic energy of a BEC comprising 101(37) thousand atoms in three dimensions to 3/2 k_{B}·38_{-7}^{+6} pK. Our method paves the way for free-fall experiments lasting ten or more seconds as envisioned for tests of fundamental physics and high-precision BEC interferometry, as well as opens up a new kinetic energy regime.

Proximal Disruption of Brain Energy Supply Raises Systemic Blood Glucose: A Systematic Review.

This work joins a series that methodically tests the predictions of the Selfish-Brain theory. The theory postulates a vital ability of the mammalian brain, namely to give priority to its own energy metabolism. The brain behaves "selfishly" in this respect. For the cerebral artery occlusion studied here, the theory predicts an increase in blood glucose concentration, what becomes the hypothesis to be tested. We conducted a systematic review of cerebral-artery-occlusion papers to test whether or not the included studies could confirm this hypothesis. We identified 239 records, screened 231 works by title or abstract, and analyzed 89 by full text. According to strict selection criteria (set out in our PROSPERO preregistration, complying with PRISMA guidelines), 7 papers provided enough information to decide on the hypothesis. Our hypothesis could be fully confirmed for the 3 to 24 h after the onset of a transient 2 h or permanent occlusion. As for the mechanism, the theory predicts that the energy-deprived brain suppresses insulin secretion via the sympathoadrenal system, thereby preventing insulin-mediated glucose uptake into muscle and fat and, as a result, enhancing insulin-independent glucose uptake via the blood-brain barrier. Evidence from our included studies actually demonstrated cerebral insulin suppression. In all, the current work confirms the second major prediction of the Selfish-Brain theory that relates to a proximal bottleneck of the cerebral supply chain, cerebral artery occlusion. Its first major prediction relates to a distal supply bottleneck, caloric restriction, and is fulfilled as shown by our previous work, whereas the prediction of the long held gluco-lipostatic theory, which sees the brain as only passively supplied, is violated (Sprengell et al., 2021). The crucial point was that caloric restriction elicits smaller changes in mass (energy) in the brain than in the body. Taken together, the evidence from the current and previous work clearly shows that the most accurate predictions are possible with a theory that views the brain as an independently self-regulating energy compartment occupying a primary position in energy metabolism.

Brain More Resistant to Energy Restriction Than Body: A Systematic Review.

The gluco-lipostatic theory and its modern variants assume that blood glucose and energy stores are controlled in closed-loop feedback processes. The Selfish Brain theory is based on the same assumptions, but additionally postulates that the brain, as an independent energy compartment, self-regulates its energy concentration with the highest priority. In some clinical situations these two theories make opposite predictions. To investigate one of these situations, namely caloric restriction, we formulated a hypothesis which, if confirmed, would match the predictions of the Selfish Brain theory-but not those of the gluco-lipostatic theory. Hypothesis: Calorie restriction causes minor mass (energy) changes in the brain as opposed to major changes in the body. We conducted a systematic review of caloric-restriction studies to test whether or not the evaluated studies confirmed this hypothesis. We identified 3,157 records, screened 2,804 works by title or abstract, and analyzed 232 by full text. According to strict selection criteria (set out in our PROSPERO preregistration, complying with PRISMA guidelines, and the pre-defined hypothesis-decision algorithm), 8 papers provided enough information to decide on the hypothesis: In animals, high-energy phosphates were measured by 31P-nuclear magnetic resonance, and organ and total body weights were measured by scales, while in humans organ sizes were determined by magnetic resonance imaging. All 8 decidable papers confirmed the hypothesis, none spoke against it. The evidence presented here clearly shows that the most accurate predictions are possible with a theory that regards the brain as independently self-regulating and as occupying a primary position in a hierarchically organized energy metabolism.

Ultracold atom interferometry in space.

Bose-Einstein condensates (BECs) in free fall constitute a promising source for space-borne interferometry. Indeed, BECs enjoy a slowly expanding wave function, display a large spatial coherence and can be engineered and probed by optical techniques. Here we explore matter-wave fringes of multiple spinor components of a BEC released in free fall employing light-pulses to drive Bragg processes and induce phase imprinting on a sounding rocket. The prevailing microgravity played a crucial role in the observation of these interferences which not only reveal the spatial coherence of the condensates but also allow us to measure differential forces. Our work marks the beginning of matter-wave interferometry in space with future applications in fundamental physics, navigation and earth observation.

Cooperation and Social Rules Emerging From the Principle of Surprise Minimization.

The surprise minimization principle has been applied to explain various cognitive processes in humans. Originally describing perceptual and active inference, the framework has been applied to different types of decision making including long-term policies, utility maximization and exploration. This analysis extends the application of surprise minimization (also known as free energy principle) to a multi-agent setup and shows how it can explain the emergence of social rules and cooperation. We further show that in social decision-making and political policy design, surprise minimization is superior in many aspects to the classical approach of maximizing utility. Surprise minimization shows directly what value freedom of choice can have for social agents and why, depending on the context, they enter into cooperation, agree on social rules, or do nothing of the kind.

Compact and robust diode laser system technology for dual-species ultracold atom experiments with rubidium and potassium in microgravity.

We present a compact and robust distributed-feedback diode laser system architecture for ultracold atom experiments with K41 and Rb87 in a mobile setup operating at the ZARM drop tower in Bremen. Our system withstands DC accelerations of up to 43 g in operation with only minor adjustments over several drop campaigns. Micro-integrated master-oscillator-power-amplifier modules in conjunction with miniaturized, free-space opto-mechanics are integrated on a platform with a volume of 43 L. With compact control and driver electronics, this laser system features output power and spectral characteristics suitable for 2D+ and 3D magneto-optical trapping operation, atomic state preparation, Bragg-diffraction-based atom interferometry, and detection.

Space-borne Bose-Einstein condensation for precision interferometry.

Owing to the low-gravity conditions in space, space-borne laboratories enable experiments with extended free-fall times. Because Bose-Einstein condensates have an extremely low expansion energy, space-borne atom interferometers based on Bose-Einstein condensation have the potential to have much greater sensitivity to inertial forces than do similar ground-based interferometers. On 23 January 2017, as part of the sounding-rocket mission MAIUS-1, we created Bose-Einstein condensates in space and conducted 110 experiments central to matter-wave interferometry, including laser cooling and trapping of atoms in the presence of the large accelerations experienced during launch. Here we report on experiments conducted during the six minutes of in-space flight in which we studied the phase transition from a thermal ensemble to a Bose-Einstein condensate and the collective dynamics of the resulting condensate. Our results provide insights into conducting cold-atom experiments in space, such as precision interferometry, and pave the way to miniaturizing cold-atom and photon-based quantum information concepts for satellite-based implementation. In addition, space-borne Bose-Einstein condensation opens up the possibility of quantum gas experiments in low-gravity conditions1,2.

LTP or LTD? Modeling the Influence of Stress on Synaptic Plasticity.

In cognitive memory, long-term potentiation (LTP) has been shown to occur when presynaptic and postsynaptic activities are highly correlated and glucocorticoid concentrations are in an optimal (i.e., low normal) range. In all other conditions, LTP is attenuated or even long-term depression (LTD) occurs. In this paper, we focus on NMDA receptor (NMDA-R)-dependent LTP and LTD, two processes involving various molecular mechanisms. To understand which of these mechanisms are indispensable for explaining the experimental evidence reported in the literature, we here propose a parsimonious model of NMDA-R-dependent synaptic plasticity. Central to this model are two processes. First, AMPA receptor-subunit trafficking; and second, glucocorticoid-dependent modifications of the brain-derived neurotrophic factor (BDNF)-receptor system. In 2008, we have published a core model, which contained the first process, while in the current paper we present an extended model, which also includes the second process. Using the extended model, we could show that stress attenuates LTP, while it enhances LTD. These simulation results are in agreement with experimental findings from other labs. In 2013, surprising experimental evidence showed that the GluA1 C-tail is unnecessary for LTP. When using our core model in its original form, our simulations already predicted that there would be no requirement for the GluA1 C-tail for LTP, allowing to eliminate a redundant mechanism from our model. In summary, we present a mathematical model that displays reduced complexity and is useful for explaining when and how LTP or LTD occurs at synapses during cognitive memory formation.

Effects of blood glucose on delay discounting, food intake and counterregulation in lean and obese men.

BACKGROUND: Delay discounting as a measure of impulsivity has been shown to be higher in obesity with an association of increased food intake. Moreover, obese humans showed a higher wanting for high-calorie food than lean men when blood glucose concentrations were low. First studies linking blood glucose levels to delay discounting yielded mixed results. We hypothesized that obese people - in comparison to lean men - have a relative lack of energy, especially when blood glucose levels are low, that results in higher levels of delay discounting, food intake and hormonal counterregulation. METHODS: We investigated 20 lean and 20 obese healthy young men in a single-blind balanced cross-over design. With a standardized glucose clamp technique, subjects underwent a hypoglycemic state in one condition and a euglycemic state in the control condition. Regularly, blood was sampled for assessment of hormonal status, and questionnaires were filled out to assess delay discounting and symptom awareness. After normalizing blood glucose concentrations, subjects were free to eat from a standardized test buffet, followed by a snack test. RESULTS: Delay discounting was higher in obese than in lean men throughout experiments (p < 0.03). However, we did not observe significant discounting differences between glucose conditions (p > 0.1). Furthermore, the discounting performance did not correlate with food intake from the test buffet or snack test (p > 0.3). As a response to hypoglycemia, hormonal counterregulation was pronounced in both weight groups (p < 0.03), but responses of ACTH, norepinephrine and glucagon were stronger in obese compared to lean men (p < 0.03). Also, intake from the high-calorie buffet after hypoglycemia compared to euglycemia was higher in obese subjects (p < 0.02) but comparable in lean men (p > 0.5). CONCLUSIONS: Our data suggest that augmented delay discounting is a robust feature in obesity that is not linked to glucose levels or actual food intake. With our systematically controlled approach, combining performance in delay discounting with regard to distinct blood glucose levels, different weight groups, counterregulatory behavior and food intake, our results imply that delay discounting is not susceptible to fluctuations of blood glucose and do not support the assumption that a low body's energy content leads to increased impulsivity. Further replications including women and larger sample sizes are needed to corroborate our data.

Comparison of symmetric and asymmetric double quantum well extended-cavity diode lasers for broadband passive mode-locking at 780 nm.

We present a compact, mode-locked diode laser system designed to emit a frequency comb in the wavelength range around 780 nm. We compare the mode-locking performance of symmetric and asymmetric double quantum well ridge-waveguide diode laser chips in an extended-cavity diode laser configuration. By reverse biasing a short section of the diode laser chip, passive mode-locking at 3.4 GHz is achieved. Employing an asymmetric double quantum well allows for generation of a mode-locked optical spectrum spanning more than 15 nm (full width at -20 dB) while the symmetric double quantum well device only provides a bandwidth of ∼2.7 nm (full width at -20 dB). Analysis of the RF noise characteristics of the pulse repetition rate shows an RF linewidth of about 7 kHz (full width at half-maximum) and of at most 530 Hz (full width at half-maximum) for the asymmetric and symmetric double quantum well devices, respectively. Investigation of the frequency noise power spectral density at the pulse repetition rate shows a white noise floor of approximately 2100 Hz2/Hz and of at most 170 Hz2/Hz for the diode laser employing the asymmetric and symmetric double quantum well structures, respectively. The pulse width is less than 10 ps for both devices.

Stress-Related Changes in Body Form: Results from the Whitehall II Study.

OBJECTIVE: Stress is associated with body mass gain in some people but with body mass loss in others. When the stressor persists, some people adapt with their stress responses, whereas others do not. Heart rate variability (HRV) reflects autonomic variability and is related to stress responses to psychosocial challenges. It was hypothesized that the combined effects of stress exposure and autonomic variability predict long-term changes in body form. METHODS: Data of 1,369 men and 612 women from the Whitehall II cohort were analyzed. BMI, hip-to-height ratio, and waist-to-height ratio were measured at three time points over a 10-year period. HRV and psychological distress (General Health Questionnaire) were assessed. RESULTS: Men with high psychological distress were at risk of developing an increased waist-to-height ratio (F = 3.4, P = 0.038). Men with high psychological distress and low HRV were prone to develop an increased body mass and hip-to-height ratio (psychological distress: F = 4.3, P = 0.016; HRV: F = 5.0, P = 0.008). Statistical trends showed that women displayed similar patterns of stress-related changes in body form (P = 0.061; P = 0.063). CONCLUSIONS: Assessing psychological distress and autonomic variability predicts changes in body form. Psychological distress was found to be associated with an increased risk of developing the wide-waisted phenotype, while psychological distress combined with low autonomic variability was associated with an increased risk of developing the corpulent phenotype.

Uncertainty and stress: Why it causes diseases and how it is mastered by the brain.

The term 'stress' - coined in 1936 - has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach - based on the 'free energy principle' - defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources to master it? Mathematically speaking, uncertainty is entropy or 'expected surprise'. The 'free energy principle' rests upon the fact that self-organizing biological agents resist a tendency to disorder and must therefore minimize the entropy of their sensory states. Applied to our everyday life, this means that we feel uncertain, when we anticipate that outcomes will turn out to be something other than expected - and that we are unable to avoid surprise. As all cognitive systems strive to reduce their uncertainty about future outcomes, they face a critical constraint: Reducing uncertainty requires cerebral energy. The characteristic of the vertebrate brain to prioritize its own high energy is captured by the notion of the 'selfish brain'. Accordingly, in times of uncertainty, the selfish brain demands extra energy from the body. If, despite all this, the brain cannot reduce uncertainty, a persistent cerebral energy crisis may develop, burdening the individual by 'allostatic load' that contributes to systemic and brain malfunction (impaired memory, atherogenesis, diabetes and subsequent cardio- and cerebrovascular events). Based on the basic tenet that stress originates from uncertainty, we discuss the strategies our brain uses to avoid surprise and thereby resolve uncertainty.

Development of a compact optical absolute frequency reference for space with 10-15 instability.

We report on a compact and ruggedized setup for laser frequency stabilization employing Doppler-free spectroscopy of molecular iodine near 532 nm. Using a 30 cm long iodine cell in a triple-pass configuration in combination with noise-canceling detection and residual amplitude modulation control, a frequency instability of 6×10-15 at 1 s integration time and a Flicker noise floor below 3×10-15 for integration times between 100 and 1000 s was found. A specific assembly-integration technology was applied for the realization of the spectroscopy setup, ensuring high beam pointing stability and high thermal and mechanical rigidity. The setup was developed with respect to future applications in space, including high-sensitivity interspacecraft interferometry, tests of fundamental physics, and navigation and ranging.

Method for in-depth characterization of electro-optic phase modulators.

A flexible method to measure the modulation efficiency and residual amplitude modulation, including non-linearities, of phase modulators is presented. The method is based on demodulation of the modulated optical field in the optical domain by means of a heterodyne interferometer and subsequent analysis of the I&Q quadrature components of the corresponding RF beat note signal. As an example, we determine the phase modulation efficiency and residual amplitude modulation for both the TE and TM modes of a GaAs chip-based phase modulator at the wavelength of 1064 nm. From the results of these measurements, we estimate the linear and quadratic electro-optic coefficients for a P-p-n-N GaAs/AlGaAs double heterostructure.