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OBJECTIVE: In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) add significantly to both hyperalgesia and maintenance of peripheral inflammation. METHODS: Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNFalpha-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally. RESULTS: Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept. CONCLUSION: Our findings indicate that spinal TNFalpha plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation. [ABSTRACT FROM AUTHOR]

Autonomic cardiac dysfunction is a common complication in patients with anorexia nervosa (AN). Despite its high prevalence, physicians often overlook this clinical condition, and little research has been dedicated so far. To probe the functional role of the neurocircuitry underpinning the poorly understood autonomic cardiac dysfunction, we examined dynamic functional differences in the central autonomic network (CAN) between 21 acute AN individuals and 24 age, sex and heart rate-matched healthy controls (HC). We assessed functional connectivity (FC) changes in CAN using seeds in the ventromedial prefrontal cortex, left and right anterior insular cortex, left and right amygdala and dorsal anterior cingulate cortex. The overall FC between the six investigated seeds is reduced in AN individuals compared to HC, although no changes were observed for single connections. Moreover, AN exhibited higher complexity in the FC time series of such CAN regions. Contrary to HC, we found that the degree of complexity between FC and heart rate (HR) series did not correlate in AN, suggesting a shift from central to peripheral control of the heart in AN individuals. Using dynamic FC analysis, we showed that the CAN transits across five functional states with no preference for any. Strikingly, at the state of weakest connectivity, the entropy significantly diverges between healthy and AN individuals, reaching its minimum and maximum values, respectively. Overall, our findings provide evidence that core regions of the CAN engaged in cardiac regulation are functionally affected in acute AN., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Purpose: To determine alterations in the retina of patients with Alzheimer's disease (AD) by the newly developed technique of fluorescence lifetime imaging ophthalmoscopy (FLIO) in a pilot study., Methods: FLIO set-up uses a scanning laser ophthalmoscope (HRA2, Heidelberg Engineering, Germany), which was modified by the use of an excitation pulse laser BLD440 (Becker&Hickl, Berlin, Germany) and detection of fluorescence lifetime by time-correlated single photon counting (TCSPC; Becker&Hickl) in two spectral channels (channel 1: 490-560 nm, channel 2: 560-700 nm). Least square fit of three exponential functions was used for fluorescence decay analysis. That resulted in three fluorescent components with lifetimes τi , amplitudes αi and relative contributions Qi . 16 patients with AD (mean age 77.2 ± 7.0 years) were investigated. After regular ophthalmic investigation, FLIO examination and OCT examination were performed. Alzheimer-specific clinical data were collected (MMSE, cerebrospinal fluid (CSF) concentration of amyloid-β (1-42), total-tau and phosphorylated tau181 (p-tau181) protein)., Results: The FLIO parameters of the second fluorescent component α2 and Q2 (channel 2) correlated significantly with MMSE score (Q2 , R = -0.757, p = 0.007; α2 , R = -0.618, p = 0.043) as well as p-tau181-protein concentration in CSF (Q2 , R = 0.919, p = 0.009; α2 , R = 0.881, p = 0.020) in patients with AD. OCT measurements of retinal nerve fibre layer thickness, optic disc excavation and macular thickness neither correlated with Alzheimer-specific CSF data nor MMSE score., Conclusions: Unlike conventional techniques, such as OCT, the new technique of FLIO revealed changes in the retina of patients with AD in relation to Alzheimer-specific markers in this pilot study., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: Reduced perception of pain is a well-established phenomenon in patients with anorexia nervosa (AN). We tested the hypothesis that altered processing of pain within the insula might account for reduced perception of pain., Method: Heat pain thresholds were obtained in nineteen patients with AN and matched controls. Thereafter, a thermode was used to deliver thermal painful stimuli to the right arm during functional magnetic resonance imaging (fMRI) measurements. Stimuli were initiated for 10 s from a baseline resting temperature (32°C) to three different levels (37, 42, 45°C)., Results: Significantly increased heat pain thresholds were observed in patients. A stronger activation during heat pain perception was found in the left posterior insula in controls. In contrast, higher levels of activity were shown in the ipsilateral pons in patients when compared to controls. In patients, we found a significant interrelation between the depression score (Beck depression inventory) and heat pain activations., Conclusion: We suggest that reduced activity in the left posterior insula might contribute to increased pain thresholds in patients, while increased activations in the right anterior insula and pons mirror augmented sympathetic modulation putatively related to amplification of adrenergic descending pain inhibition. In addition, pain thresholds and brain activations were influenced by disease-inherent depressed mood., (© 2012 John Wiley & Sons A/S.)

Recent studies applying functional magnetic resonance imaging have focused on the description of cerebral substrates of changes in cardiac function during diverse autonomic maneuvers or stressful cognitive tasks. These studies might be limited by the indistinguishable neuronal activity due to cognitive processes, which are known to influence autonomic function, and the 'baseline' activity in the central autonomic network. We therefore investigated 26 healthy volunteers in the magnetic resonance scanner to simultaneously obtain functional brain images and RR intervals (intervals between ventricular depolarizations) of the high-resolution electrocardiogram. The mean RR interval length within each functional scan was computed, which was finally convolved with the canonical hemodynamic response function to obtain a regressor for the functional time series. The resulting individual contrast image indicated a positive covariation of the blood oxygen level-dependent signal and RR interval length in the ventromedial prefrontal cortex (vmPFC). Furthermore, a reduced mean cross-approximate entropy value was shown for the interaction between the vmPFC and individual RR intervals. This suggests reduced asynchrony between the heart rate and vmPFC activity in contrast to other brain areas. Our findings confirm data obtained in animals describing the vmPFC as an important forebrain structure of the central autonomic network and an influence of the vmPFC in the cortical generation of efferent vagal activity. This finding needs to be investigated in diseases with known suppression of efferent vagal modulation.

Background: Many symptoms of alcohol withdrawal (AW) such as tachycardia or elevated blood pressure might be explained by increased peripheral and central adrenergic activity. In contrast to many neurochemical studies of sympathetic activation during AW, only very few studies investigated autonomic balance using neurophysiological methods., Methods: We investigated heart rate variability (HRV) and sympathetic skin response (SSR) in male patients suffering from mild AW syndrome (n = 20, no treatment required) and in patients with moderate to severe AW syndrome (n = 20, clomethiazole treatment) in the acute stage. Sympathovagal influence was quantified using measures of time and frequency domain of HRV as well as modern nonlinear parameters (compression entropy). Furthermore, we obtained latencies and amplitudes of SSR to quantify isolated sympathetic influence. Measures were obtained during the climax of withdrawal symptomatology before treatment, 1 day after climax, and shortly before discharge from hospital. Alcohol withdrawal scores were obtained and correlated to autonomic measures., Results: Ambulatory blood pressure and AW scores revealed characteristic withdrawal symptoms in both patient groups. Apart from the nonlinear parameter compression entropy, Hc, measures of HRV revealed no sign of autonomic dysfunction in contrast to the significantly increased heart rates at the time of admission. Latencies and amplitudes of SSR did not indicate any increase of sympathetic activity. A negative correlation was found between Hc and mental withdrawal symptoms., Conclusions: We show here that classical measures for autonomic nervous system activity such as HRV and SSR are not suitable for describing the autonomic changes seen in acute AW, although a major role for the sympathetic nervous system has been proposed. This might be due to multiple dysregulation of metabolites in AWS or to subtle alcohol-induced damage to neuronal structures, issues that should be addressed in future studies.