Secondary Hyperalgesia Phenotypes Exhibit Differences in Brain Activation during Noxious Stimulation

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury, and to secondary hyperalgesia in normal skin surrounding the injury. Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic. To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47°C, 7 min, 9 cm²) on the non-dominant lower-leg. Areas of secondary hyperalgesia were assessed 100 min after the injury. We measured neuronal activation by recording blood-oxygen-level-dependent-signals (BOLD-signals) during mechanical noxious stimulation before burn injury and in both primary and secondary hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application of the burn-injury) (p < 0.05). After the burn-injury, we found significant differences between responders during noxious stimulation of both primary (p < 0.01) and secondary hyperalgesia (p ≤ 0.04) skin areas. A decreased volume of the right (p = 0.001) and left caudate nucleus (p = 0.01) was detected in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious stimulation differs according to secondary hyperalgesia phenotype. This indicates differences in central sensitization according to phenotype, which may have predictive value on the susceptibility to development of high-intensity acute and persistent pain.     

Spinal fMRI Reveals Decreased Descending Inhibition during Secondary Mechanical Hyperalgesia

Mechanical hyperalgesia is one distressing symptom of neuropathic pain which is explained by central sensitization of the nociceptive system. This sensitization can be induced experimentally with the heat/capsaicin sensitization model. The aim was to investigate and compare spinal and supraspinal activation patterns of identical mechanical stimulation before and after sensitization using functional spinal magnetic resonance imaging (spinal fMRI). Sixteen healthy subjects (6 female, 10 male, mean age 27.2±4.0 years) were investigated with mechanical stimulation of the C6 dermatome of the right forearm during spinal fMRI. Testing was always performed in the area outside of capsaicin application (i.e. area of secondary mechanical hyperalgesia). During slightly noxious mechanical stimulation before sensitization, activity was observed in ipsilateral dorsolateral pontine tegmentum (DLPT) which correlated with activity in ipsilateral spinal cord dorsal gray matter (dGM) suggesting activation of descending nociceptive inhibition. During secondary mechanical hyperalgesia, decreased activity was observed in bilateral DLPT, ipsilateral/midline rostral ventromedial medulla (RVM), and contralateral subnucleus reticularis dorsalis, which correlated with activity in ipsilateral dGM. Comparison of voxel-based activation patterns during mechanical stimulation before/after sensitization showed deactivations in RVM and activations in superficial ipsilateral dGM. This study revealed increased spinal activity and decreased activity in supraspinal centers involved in pain modulation (SRD, RVM, DLPT) during secondary mechanical hyperalgesia suggesting facilitation of nociception via decreased endogenous inhibition. Results should help prioritize approaches for further in vivo studies on pain processing and modulation in humans.     

Brain Metabolism during Hallucination-Like Auditory Stimulation in Schizophrenia

Auditory verbal hallucinations (AVH) in schizophrenia are typically characterized by rich emotional content. Despite the prominent role of emotion in regulating normal perception, the neural interface between emotion-processing regions such as the amygdala and auditory regions involved in perception remains relatively unexplored in AVH. Here, we studied brain metabolism using FDG-PET in 9 remitted patients with schizophrenia that previously reported severe AVH during an acute psychotic episode and 8 matched healthy controls. Participants were scanned twice: (1) at rest and (2) during the perception of aversive auditory stimuli mimicking the content of AVH. Compared to controls, remitted patients showed an exaggerated response to the AVH-like stimuli in limbic and paralimbic regions, including the left amygdala. Furthermore, patients displayed abnormally strong connections between the amygdala and auditory regions of the cortex and thalamus, along with abnormally weak connections between the amygdala and medial prefrontal cortex. These results suggest that abnormal modulation of the auditory cortex by limbic-thalamic structures might be involved in the pathophysiology of AVH and may potentially account for the emotional features that characterize hallucinatory percepts in schizophrenia.     

Different Brain Activation under Left and Right Ventricular Stimulation: An fMRI Study in Anesthetized Rats

Background

Myocardial ischemia in the anterior wall of the left ventricule (LV) and in the inferior wall and/or right ventricle (RV) shows different manifestations that can be explained by the different innervations of cardiac afferent nerves. However, it remains unclear whether information from different areas of the heart, such as the LV and RV, are differently processed in the brain. In this study, we investigated the brain regions that process information from the LV or RV using cardiac electrical stimulation and functional magnetic resonance imaging (fMRI) in anesthetized rats because the combination of these two approaches cannot be used in humans.

Methodology/Principal Findings

An electrical stimulation catheter was inserted into the LV or RV (n = 12 each). Brain fMRI scans were recorded during LV or RV stimulation (9 Hz and 0.3 ms width) over 10 blocks consisting of alternating periods of 2 mA for 30 sec followed by 0.2 mA for 60 sec. The validity of fMRI signals was confirmed by first and second-level analyses and temporal profiles. Increases in fMRI signals were observed in the anterior cingulate cortex and the right somatosensory cortex under LV stimulation. In contrast, RV stimulation activated the right somatosensory cortex, which was identified more anteriorly compared with LV stimulation but did not activate the anterior cingulate cortex.

Conclusion/Significance

This study provides the first evidence for differences in brain activation under LV and RV stimulation. These different brain processes may be associated with different clinical manifestations between anterior wall and inferoposterior wall and/or RV myocardial ischemia.     

Alterations in Prefrontal-Limbic Functional Activation and Connectivity in Chronic Stress-Induced Visceral Hyperalgesia

Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([¹⁴C]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH.     

Parkinson-Related Changes of Activation in Visuomotor Brain Regions during Perceived Forward Self-Motion

Radial expanding optic flow is a visual consequence of forward locomotion. Presented on screen, it generates illusionary forward self-motion, pointing at a close vision-gait interrelation. As particularly parkinsonian gait is vulnerable to external stimuli, effects of optic flow on motor-related cerebral circuitry were explored with functional magnetic resonance imaging in healthy controls (HC) and patients with Parkinson’s disease (PD). Fifteen HC and 22 PD patients, of which 7 experienced freezing of gait (FOG), watched wide-field flow, interruptions by narrowing or deceleration and equivalent control conditions with static dots. Statistical parametric mapping revealed that wide-field flow interruption evoked activation of the (pre-)supplementary motor area (SMA) in HC, which was decreased in PD. During wide-field flow, dorsal occipito-parietal activations were reduced in PD relative to HC, with stronger functional connectivity between right visual motion area V5, pre-SMA and cerebellum (in PD without FOG). Non-specific ‘changes’ in stimulus patterns activated dorsolateral fronto-parietal regions and the fusiform gyrus. This attention-associated network was stronger activated in HC than in PD. PD patients thus appeared compromised in recruiting medial frontal regions facilitating internally generated virtual locomotion when visual motion support falls away. Reduced dorsal visual and parietal activations during wide-field optic flow in PD were explained by impaired feedforward visual and visuomotor processing within a magnocellular (visual motion) functional chain. Compensation of impaired feedforward processing by distant fronto-cerebellar circuitry in PD is consistent with motor responses to visual motion stimuli being either too strong or too weak. The ‘change’-related activations pointed at covert (stimulus-driven) attention.     

Characterization of Inhibitory GABA-A Receptor Activation during Spreading Depolarization in Brain Slice

Spreading depolarization (SD) is a slowly propagating wave of near complete depolarizations of neurons and glia. Previous studies have reported large GABA releases during SD, but there is limited understanding of how GABA release and receptor activation are regulated and influence the propagating SD wavefront, as well as an excitatory phase immediately following the passage of SD. The present study characterized GABA-A type receptor (GABA_AR) currents during SD generated by KCl microinjection in acute hippocampal slices from adult mice. Spontaneous GABA_AR-mediated currents (sIPSCs) were initially enhanced, and were followed by a large outward current at the wavefront. sIPSC were then transiently supressed during the late SD phase, resulting in a significant reduction of the sIPSC/sEPSC ratio. The large outward current generated during SD was eliminated by the GABA_AR antagonist gabazine, but the channel potentiator/agonist propofol failed to potentiate the current, likely because of a ceiling effect. Extracellular Cl⁻ decreases recorded during SD were reduced by the antagonist but were not increased by the potentiator. Together with effects of GABA_AR modulators on SD propagation rate, these results demonstrate a significant inhibitory role of the initial GABA_AR activation and suggest that intracellular Cl⁻ loading is insufficient to generate excitatory GABA_AR responses during SD propagation. These results provide a mechanistic explanation for facilitating effects of GABA_AR antagonists, and the lack of inhibitory effect of GABA_AR potentiators on SD propagation. In addition, selective suppression of GABA transmission in the late SD period and the lack of effect of GABA_A modulators on the duration of SD suggests that GABA modulation may not be effective approach to protect neurons during the vulnerable phase of SD.     

不同伤害性刺激致大鼠痛感觉与痛情绪的比较

为比较不同伤害性刺激致大鼠痛感觉与痛情绪的差异,对17只麻醉SD大鼠进行痛感觉代表脑区异颗粒区(dysgranular zone,DZ)和痛情绪代表核团基底外侧杏仁核(basolateral amygdala,BLA)电活动,与心电、呼吸肌肌电、皮肤电导、体温的同步心理生理学记录,按顺序均衡法分别给予热、夹尾和电刺激。观察到热和夹尾刺激增强BLA和DZ,而电刺激仅增强DZ的放电活动,且热刺激所诱发的BLA与DZ放电活动均强于夹尾和电刺激所诱发的活动(P<0.05)。BLA与DZ的基础放电频率呈正相关(P<0.05),夹尾刺激后相关性增高(P<0.05)。各刺激诱发的情绪相关生理反应无显著性差异。结果表明不同伤害性刺激所诱发的BLA和DZ放电活动有明显差异,而生理反应是相似的。     

Rat Brain Apotransketolase: Activation and Inactivation

Kinetic analysis of the combination of rat brain apotransketolase with thiamine diphosphate suggested that the enzyme exists in more than one form. One part of the apoenzyme reacted rapidly with thiamine diphosphate to reconstitute the holoenzyme, but another part appeared to combine only relatively slowly. In addition, an apparently irreversible further change took place, the apoenzyme being converted progressively to a form which apparently could not be activated by thiamine diphosphate. The relative proportions of the three forms i.e., that reacting rapidly, slowly, or not at all with thiamine diphosphate, were a function of the duration and conditions of storage, with the proportion of the apoenzyme form which reacted rapidly with thiamine diphosphate decreasing progressively. The findings reported here provide a possible explanation for problems various workers have encountered in attempting to evaluate Michaelis constants for the reaction of thiamine diphosphate with apotransketolase.     

Association of Body Mass and Brain Activation during Gastric Distention: Implications for Obesity

Background

Gastric distention (GD), as it occurs during meal ingestion, signals a full stomach and it is one of the key mechanisms controlling food intake. Previous studies on GD showed lower activation of the amygdala for subjects with higher body mass index (BMI). Since obese subjects have dopaminergic deficits that correlate negatively with BMI and the amygdala is innervated by dopamine neurons, we hypothesized that BMI would correlate negatively with activation not just in the amygdala but also in other dopaminergic brain regions (midbrain and hypothalamus).

Methodology/Principal Findings

We used functional magnetic resonance imaging (fMRI) to evaluate brain activation during GD in 24 healthy subjects with BMI range of 20–39 kg/m². Using multiple regression and cross-correlation analyses based on a family-wise error corrected threshold P = 0.05, we show that during slow GD to maximum volumes of 500 ml and 700 ml subjects with increased BMI had increased activation in cerebellum and left posterior insula, and decreased activation of dopaminergic (amygdala, midbrain, hypothalamus, thalamus) and serotonergic (pons) brain regions and anterior insula, regions that were functionally interconnected with one another.

Conclusions

The negative correlation between BMI and BOLD responses to gastric distention in dopaminergic (midbrain, hypothalamus, amygdala, thalamus) and serotonergic (pons) brain regions is consistent with disruption of dopaminergic and serotonergic signaling in obesity. In contrast the positive correlation between BMI and BOLD responses in posterior insula and cerebellum suggests an opposing mechanism that promotes food intake in obese subjects that may underlie their ability to consume at once large food volumes despite increasing gastric distention.     

Brain Activation of SIRT1: Role in Neuropathology

Sirtuins (SIRTs) are a family of regulatory proteins of genetic information with a high degree of conservation among species. The SIRTs are heavily involved in several physiological functions including control of gene expression, metabolism, and aging. SIRT1 has been the most studied sirtuin and plays important role in the prevention and progression of neurodegenerative diseases acting in different pathways of proteins involved in brain function. SIRT1 activation regulates important genes that also exert neuroprotective actions such as p53, nuclear factor kappa B, peroxisome proliferator-activated receptor-gamma (PPARγ), PPARγ coactivator-1α, liver X receptor, and forkhead box O. It is well established in literature that growing population aging, oxidative stress, inflammation, and genetic factors are important conditions to development of neurodegenerative disorders. However, the exact pathophysiological mechanisms leading to these diseases remain obscure. The sirtuins show strong potential to become valuable predictive and prognostic markers for diseases and as therapeutic targets for the treatment of a variety of neurodegenerative disorders. In this context, the aim of the current review is to present an actual view of the potential role of SIRT1 in modulating the interaction between target genes and neurodegenerative diseases on the brain.