Preclinical and clinical evidence for a distinct regulation of mu opioid and type 1 cannabinoid receptor genes expression in obesity

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention

Complexity of multi-dimensional spontaneous EEG decreases during propofol induced general anaesthesia

Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct ‘flavours’ of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia

Mechanisms underlying disorders of consciousness: Bridging gaps to move toward an integrated translational science

AIM: In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. METHODS: To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. RESULTS: We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. CONCLUSION: In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a virtuous cycle, leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice

Making things happen : a model of proactive motivation

Being proactive is about making things happen, anticipating and preventing problems, and seizing opportunities. It involves self-initiated efforts to bring about change in the work environment and/or oneself to achieve a different future. The authors develop existing perspectives on this topic by identifying proactivity as a goal-driven process involving both the setting of a proactive goal (proactive goal generation) and striving to achieve that proactive goal (proactive goal striving). The authors identify a range of proactive goals that individuals can pursue in organizations. These vary on two dimensions: the future they aim to bring about (achieving a better personal fit within one’s work environment, improving the organization’s internal functioning, or enhancing the organization’s strategic fit with its environment) and whether the self or situation is being changed. The authors then identify “can do,” “reason to,” and “energized to” motivational states that prompt proactive goal generation and sustain goal striving. Can do motivation arises from perceptions of self-efficacy, control, and (low) cost. Reason to motivation relates to why someone is proactive, including reasons flowing from intrinsic, integrated, and identified motivation. Energized to motivation refers to activated positive affective states that prompt proactive goal processes. The authors suggest more distal antecedents, including individual differences (e.g., personality, values, knowledge and ability) as well as contextual variations in leadership, work design, and interpersonal climate, that influence the proactive motivational states and thereby boost or inhibit proactive goal processes. Finally, the authors summarize priorities for future researc

TMS-Induced Cortical Potentiation during Wakefulness Locally Increases Slow Wave Activity during Sleep

BACKGROUND: Sleep slow wave activity (SWA) is thought to reflect sleep need, increasing in proportion to the length of prior wakefulness and decreasing during sleep. However, the process responsible for SWA regulation is not known. We showed recently that SWA increases locally after a learning task involving a circumscribed brain region, suggesting that SWA may reflect plastic changes triggered by learning. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis directly, we used transcranial magnetic stimulation (TMS) in conjunction with high-density EEG in humans. We show that 5-Hz TMS applied to motor cortex induces a localized potentiation of TMS-evoked cortical EEG responses. We then show that, in the sleep episode following 5-Hz TMS, SWA increases markedly (+39.1±17.4%, p<0.01, n = 10). Electrode coregistration with magnetic resonance images localized the increase in SWA to the same premotor site as the maximum TMS-induced potentiation during wakefulness. Moreover, the magnitude of potentiation during wakefulness predicts the local increase in SWA during sleep. CONCLUSIONS/SIGNIFICANCE: These results provide direct evidence for a link between plastic changes and the local regulation of sleep need

A preliminary investigation of materialism and impulsiveness as predictors of technological addictions among young adults

Background and aims: The primary objective of the present research is to investigate the drivers of technological addiction in college students — heavy users of Information and Communication Technology (ICT). The study places cell phone and instant messaging addiction in the broader context of consumption pathologies, investigating the influence of materialism and impulsiveness on these two technologies. Clearly, cell phones serve more than just a utilitarian purpose. Cell phones are used in public and play a vital role in the lives of young adults. The accessibility of new technologies, like cell phones, which have the advantages of portability and an ever increasing array of functions, makes their over-use increasingly likely. Methods: College undergraduates (N = 191) from two U.S. universities completed a paper and pencil survey instrument during class. The questionnaire took approximately 15–20 minutes to complete and contained scales that measured materialism, impulsiveness, and mobile phone and instant messaging addiction. Results: Factor analysis supported the discriminant validity of Ehrenberg, Juckes, White and Walsh's (2008) Mobile Phone and Instant Messaging Addictive Tendencies Scale. The path model indicates that both materialism and impulsiveness impact the two addictive tendencies, and that materialism's direct impact on these addictions has a noticeably larger effect on cell phone use than instant messaging. Conclusions: The present study finds that materialism and impulsiveness drive both a dependence on cell phones and instant messaging. As Griffiths (2012) rightly warns, however, researchers must be aware that one's addiction may not simply be to the cell phone, but to a particular activity or function of the cell phone. The emergence of multi-function smart phones requires that research must dig beneath the technology being used to the activities that draw the user to the particular technology

Fractionation of parietal function in bistable perception probed with concurrent TMS-EEG

When visual input has conflicting interpretations, conscious perception can alternate spontaneously between these possible interpretations. This is called bistable perception. Previous neuroimaging studies have indicated the involvement of two right parietal areas in resolving perceptual ambiguity (ant-SPLr and post-SPLr). Transcranial magnetic stimulation (TMS) studies that selectively interfered with the normal function of these regions suggest that they play opposing roles in this type of perceptual switch. In the present study, we investigated this fractionation of parietal function by use of combined TMS with electroencephalography (EEG). Specifically, while participants viewed either a bistable stimulus, a replay stimulus, or resting-state fixation, we applied single pulse TMS to either location independently while simultaneously recording EEG. Combined with participant’s individual structural magnetic resonance imaging (MRI) scans, this dataset allows for complex analyses of the effect of TMS on neural time series data, which may further elucidate the causal role of the parietal cortex in ambiguous perception

Integrated Information in Discrete Dynamical Systems: Motivation and Theoretical Framework

This paper introduces a time- and state-dependent measure of integrated information, φ, which captures the repertoire of causal states available to a system as a whole. Specifically, φ quantifies how much information is generated (uncertainty is reduced) when a system enters a particular state through causal interactions among its elements, above and beyond the information generated independently by its parts. Such mathematical characterization is motivated by the observation that integrated information captures two key phenomenological properties of consciousness: (i) there is a large repertoire of conscious experiences so that, when one particular experience occurs, it generates a large amount of information by ruling out all the others; and (ii) this information is integrated, in that each experience appears as a whole that cannot be decomposed into independent parts. This paper extends previous work on stationary systems and applies integrated information to discrete networks as a function of their dynamics and causal architecture. An analysis of basic examples indicates the following: (i) φ varies depending on the state entered by a network, being higher if active and inactive elements are balanced and lower if the network is inactive or hyperactive. (ii) φ varies for systems with identical or similar surface dynamics depending on the underlying causal architecture, being low for systems that merely copy or replay activity states. (iii) φ varies as a function of network architecture. High φ values can be obtained by architectures that conjoin functional specialization with functional integration. Strictly modular and homogeneous systems cannot generate high φ because the former lack integration, whereas the latter lack information. Feedforward and lattice architectures are capable of generating high φ but are inefficient. (iv) In Hopfield networks, φ is low for attractor states and neutral states, but increases if the networks are optimized to achieve tension between local and global interactions. These basic examples appear to match well against neurobiological evidence concerning the neural substrates of consciousness. More generally, φ appears to be a useful metric to characterize the capacity of any physical system to integrate information

Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy

peer reviewedBackground: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. Methods: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time–frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. Results: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha–gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). Conclusions: Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS. © 2018 British Journal of AnaesthesiaARC-06/11-34