Generative models of neuroimaging and electrophysiological data present new opportunities for accessing hidden or latent brain states. Dynamic causal modeling (DCM) uses Bayesian model inversion and selection to infer the synaptic mechanisms underlying empirically observed brain responses. DCM for electrophysiological data, in particular, aims to estimate the relative strength of synaptic transmission at different cell types and via specific neurotransmitters. Here, we report a DCM validation study concerning inference on excitatory and inhibitory synaptic transmission, using different doses of a volatile anaesthetic agent (isoflurane) to parametrically modify excitatory and inhibitory synaptic processing while recording local field potentials (LFPs) from primary auditory cortex (A1) and the posterior auditory field (PAF) in the auditory belt region in rodents. We test whether DCM can infer, from the LFP measurements, the expected drug-induced changes in synaptic transmission mediated via fast ionotropic receptors; i.e., excitatory (glutamatergic) AMPA and inhibitory GABAA receptors. Cross- and auto-spectra from the two regions were used to optimise three DCMs based on biologically plausible neural mass models and specific network architectures. Consistent with known extrinsic connectivity patterns in sensory hierarchies, we found that a model comprising forward connections from A1 to PAF and backward connections from PAF to A1 outperformed a model with forward connections from PAF to A1 and backward connections from A1 to PAF and a model with reciprocal lateral connections. The parameter estimates from the most plausible model indicated that the amplitude of fast glutamatergic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) behaved as predicted by previous neurophysiological studies. Specifically, with increasing levels of anaesthesia, glutamatergic EPSPs decreased linearly, whereas fast GABAergic IPSPs displayed a nonlinear (saturating) increase. The consistency of our model-based in vivo results with experimental in vitro results lends further validity to the capacity of DCM to infer on synaptic processes using macroscopic neurophysiological data.

Detecting sudden environmental changes is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN), a component of auditory evoked potentials (AEPs), reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potentiality of the MMN for clinical applications, establishing valid animal models that allow for detailed investigation of its neurophysiological mechanisms is important. Rodent studies, so far almost exclusively under anesthesia, have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, including the effect of anesthesia. We therefore used epidural recordings in awake black hooded rats, from two auditory cortical areas in both hemispheres, and with bandpass filtered noise stimuli that were optimized in frequency and duration for eliciting MMN in rats. Using a classical oddball paradigm with frequency deviants, we detected mismatch responses at all four electrodes in primary and secondary auditory cortex, with morphological and functional properties similar to those known in humans, i.e., large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. These mismatch responses significantly diminished in a control condition that removed the predictive context while controlling for presentation rate of the deviants. While our present study does not allow for disambiguating precisely the relative contribution of adaptation and prediction error processing to the observed mismatch responses, it demonstrates that MMN-like potentials can be obtained in awake and unrestrained rats.

We analyzed the metabolic response to cortical spreading depression that drastically increases local energy demand to restore ion homeostasis. During single and multiple cortical spreading depressions in the rat cortex, we simultaneously monitored extracellular levels of glucose and lactate using rapid sampling microdialysis and glucose influx using 18 F-fluorodeoxyglucose positron emission tomography while tracking cortical spreading depression using laser speckle imaging. Combining the acquired data with steady-state requirements we developed a mass-conserving compartment model including neurons and glia that was consistent with the observed data. In summary, our findings are: (1) Early breakdown of glial glycogen provides a major source of energy during increased energy demand and leaves 80% of blood-borne glucose to neurons. (2) Lactate is used solely by neurons and only if extracellular lactate levels are >80% above normal. (3) Although the ratio of oxygen and glucose consumption transiently reaches levels <3, the major part (>90%) of the overall energy supply is from oxidative metabolism. (4) During cortical spreading depression, brain release of lactate exceeds its consumption suggesting that lactate is only a circumstantial energy substrate. Our findings provide a general scenario for the metabolic response to increased cerebral energy demand.

Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth. We used an embolic stroke model that enabled us to investigate inverse coupling of blood flow by laser speckle imaging (CBF LSF ) to CSD as a contributing factor to lesion growth already in the early phase after arterial occlusion. Embolization by macrospheres injected into the left carotid artery of anesthetized rats reduced CBF LSF in the territories of the middle cerebral artery (MCA) (8/14 animals), the posterior cerebral artery (PCA) (2/14) or in less clearly defined regions (4/14). Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex. Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core. In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF LSF responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core. We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories.

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4 hachioji azumacho clinic, hachioji, 5 sapporo Kita clinic, sapporo, 6 Kawakita general hospital, suginami, Japan Study purpose: Whether or not socioeconomic status (SES)-related differences in the health of hemodialysis patients differ by age, period, and birth cohort remains unclear. We examined whether SES-related gaps in physical and mental health change with age, period, and birth cohort for hemodialysis patients. Methods: Data were obtained from repeated cross-sectional surveys conducted in 1996, 2001, 2006, and 2011, with members of a national patients' association as participants. We used raking adjustment to create a database which had similar characteristics to the total sample of dialysis patients in Japan. SES was assessed using family size-adjusted income levels. We divided patients into three groups based on their income levels: below the first quartile, over the second quartile and under the third quartile, and over the fourth quartile. We used the number of dialysis complications as a physical health indicator and depressive symptoms as a mental health indicator. We used a cross-classified random-effects model that estimated fixed effects of age categories and period as level-1 factors, and random effects of birth cohort as level-2 factors. Results: Relative risk of dialysis complications in respondents below the first quartile compared with ones over the fourth quartile was reduced in age categories >60 years. Mean differences in depressive symptoms between respondents below the first quartile and ones over the fourth quartile peaked in the 50-to 59-year-old age group, and were reduced in age groups >60 years. In addition, mean differences varied across periods, widening from 1996 to 2006. There were no significant birth cohort effects on income differences for dialysis complications or depressive symptoms. Conclusion: The number of dialysis complications and depressive symptoms in dialysis patients were affected by income differences, and the degree of these differences changed with age category and period.

The generalizability of differences in dietary restrictions (DRs) as function of socioeconomic status (SES) and the pathways of the associations between SES and DRs remain unclear. Therefore, we aimed to explore SES differences in DRs and psychosocial mediators between SES and DRs in Japanese patients receiving hemodialysis. This study was a cross-sectional survey of 6,644 outpatients (average age = 66.5 years; 65% males) of hemodialysis facilities across Japan. DRs were assessed by self-reported and objective measures, and SES was assessed based on education and income. Three psychosocial mediators were used: self-efficacy, control expectancy, and social support. Indirect influences of SES through the mediators were evaluated with a multiple mediator model. Although higher education was significantly associated with higher self-reported DRs, higher income was significantly associated with lower self-reported DRs. Significant SES differences in objective DRs were not observed. The relationships between education and self-reported DRs and objective DRs were significantly mediated by self-efficacy and/or control expectancy. The influences of income were mediated by social support. It becomes possible to design interventions targeting modifiable psychosocial factors including self-efficacy, control expectancy, and social support in order to reduce SES inequalities in DRs.

Aneurysm at the origin of a duplication of the middle cerebral artery (DMCA) is very rare, and only 29 treated cases have been reported. All of the cases were treated by direct surgery except a ruptured case treated by intentional partial coil embolization. We report the first unruptured case treated by coil embolization and review the previously published cases. Coil embolization can be alternative treatment for an unruptured aneurysm at the origin of the DMCA. Stable framing to spare the origin of it and prevention of thromboembolic complications are keys for safe treatment.