Michael L. Meier

Beta-hydroxybutyric acid--an indicator for an alcoholic ketoacidosis as cause of death in deceased alcohol abusers.

We analyzed the postmortem blood of a total of 100 fatal cases for beta-hydroxybutyric acid (BHBA). In 25 cases of sudden and unexpected death of alcoholics we found pathologically increased levels of BHBA of 1260 to 47200 (median 8000) micromol/L. This led us to the diagnosis of an alcoholic ketoacidosis (AKA) as cause of death in these cases. The control group of 69 postmortem cases revealed that BHBA concentrations below 500 can be regarded as normal, and values up to 2500 micromol/L as elevated. Our study shows that BHBA values over 2500 micromol/L could lead to death, if no medical attention is sought. During storage we did not find any indication of postmortem formation or decomposition of BHBA in blood in vitro or in the corpses. In our opinion, BHBA should be considered the diagnostic marker of choice for the postmortem determination of alcoholic ketoacidosis (AKA) as the cause of death. The classical indications of such deaths are: unexpected death of a chronic alcoholic; none or only traces of ethanol in the blood; increased acetone blood concentration; and neither autopsy, histology, microbiology, nor toxicology reveal the cause of death. In six further cases a diabetic ketoacidosis (DKA) was diagnosed as the cause of death.

Taking Sides with Pain – Lateralization aspects Related to Cerebral Processing of Dental Pain

The current fMRI study investigated cortical processing of electrically induced painful tooth stimulation of both maxillary canines and central incisors in 21 healthy, right-handed volunteers. A constant current, 150% above tooth specific pain perception thresholds was applied and corresponding online ratings of perceived pain intensity were recorded with a computerized visual analog scale during fMRI measurements. Lateralization of cortical activations was investigated by a region of interest analysis. A wide cortical network distributed over several areas, typically described as the pain or nociceptive matrix, was activated on a conservative significance level. Distinct lateralization patterns of analyzed structures allow functional classification of the dental pain processing system. Namely, certain parts are activated independent of the stimulation site, and hence are interpreted to reflect cognitive emotional aspects. Other parts represent somatotopic processing and therefore reflect discriminative perceptive analysis. Of particular interest is the observed amygdala activity depending on the stimulated tooth that might indicate a role in somatotopic encoding.

Tracing Toothache Intensity in the Brain

Identification of brain regions that differentially respond to pain intensity may improve our understanding of trigeminally mediated nociception. This report analyzed cortical responses to painless and painful electrical stimulation of a right human maxillary canine tooth. Functional magnetic resonance images were obtained during the application of five graded stimulus strengths, from below, at, and above the individually determined pain thresholds. Study participants reported each stimulus on a visual rating scale with respect to evoked sensation. Based on hemodynamic responses of all pooled stimuli, a cerebral network was identified that largely corresponds to the known lateral and medial nociceptive system. Further analysis of the five graded stimulus strengths revealed positive linear correlations for the anterior insula bilaterally, the contralateral (left) anterior mid-cingulate, as well as contralateral (left) pregenual cingulate cortices. Cerebral toothache intensity coding on a group level can thus be attributed to specific subregions within the cortical pain network.

Insula-specific responses induced by dental pain. A proton magnetic resonance spectroscopy study.

ObjectivesTo evaluate whether induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex after stimulation of the right maxillary canine and to examine whether these metabolic changes and the subjective pain intensity perception correlate.MethodsTen male volunteers were included in the pain group and compared with a control group of 10 other healthy volunteers. The pain group received a total of 87–92 electrically induced pain stimuli over 15xa0min to the right maxillary canine tooth. Contemporaneously, they evaluated the subjective pain intensity of every stimulus using an analogue scale. Neurotransmitter changes within the left insular cortex were evaluated by MR spectroscopy.ResultsSignificant metabolic changes in glutamine (+55.1%), glutamine/glutamate (+16.4%) and myo-inositol (−9.7%) were documented during pain stimulation. Furthermore, there was a significant negative correlation between the subjective pain intensity perception and the metabolic levels of Glx, Gln, glutamate and N-acetyl aspartate.ConclusionThe insular cortex is a metabolically active region in the processing of acute dental pain. Induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex resulting in significant alterations in metabolites. Negative correlation between subjective pain intensity rating and specific metabolites could be observed.

Neural Correlates of Fear of Movement in Patients with Chronic Low Back Pain vs. Pain-Free Individuals

Fear of movement (FOM) can be acquired by a direct aversive experience such as pain or by social learning through observation and instruction. Excessive FOM results in heightened disability and is an obstacle for recovery from acute, subacute, and chronic low back pain (cLBP). FOM has further been identified as a significant explanatory factor in the Fear Avoidance (FA) model of cLBP that describes how individuals experiencing acute back pain may become trapped into a vicious circle of chronic disability and suffering. Despite a wealth of evidence emphasizing the importance of FOM in cLBP, to date, no related neural correlates in patients were found and this therefore has initiated a debate about the precise contribution of fear in the FA model. In the current fMRI study, we applied a novel approach encompassing: (1) video clips of potentially harmful activities for the back as FOM inducing stimuli; and (2) the assessment of FOM in both, cLBP patients (N = 20) and age- and gender-matched pain-free subjects (N = 20). Derived from the FA model, we hypothesized that FOM differentially affects brain regions involved in fear processing in patients with cLBP compared to pain-free individuals due to the recurrent pain and subsequent avoidance behavior. The results of the whole brain voxel-wise regression analysis revealed that: (1) FOM positively correlated with brain activity in fear-related brain regions such as the amygdala and the insula; and (2) differential effects of FOM between patients with cLBP and pain-free subjects were found in the extended amygdala and in its connectivity to the anterior insula. Current findings support the FOM component of the FA model in cLBP.

Brain activation induced by dentine hypersensitivity pain–an fMRI study

AIMnDentine hypersensitivity (DH) is characterized by a short, sharp pain arising from exposed dentin. Most published literature reports on peripheral neural aspects of this pain condition. The current investigation focused on differential cerebral activity elicited by stimulation of sensitive and insensitive teeth by means of natural air stimuli.nnnMATERIALS AND METHODSnFive graded stimulus strengths were randomly applied by means of a multi-injector air jet delivery system, each followed by an individual rating of perceived stimulus intensity. Brain activity was analysed by functional magnetic resonance imaging (fMRI).nnnRESULTSnStimulation of sensitive teeth induced significant activation in the thalamus, somatosensory cortices (SI & SII), anterior, middle and posterior insular cortices, anterior mid cingulate cortex, perigenual anterior cingulate cortex and frontal regions (BA10 and BA46). Differential responses to DH and painless perceptions were observed in the anterior insula and anterior midcingulate cortex.nnnCONCLUSIONnFor the first time, this fMRI study demonstrates the feasibility of investigating cerebral processes related to DH evoked by natural (air) stimuli. Our neuroimaging data additionally provide evidence that differential activity in the anterior Insula (aIC) and anterior midcingulate cortex (aMCC) may represent clinically relevant pain experienced by DH patients.

Neural responses of posterior to anterior movement on lumbar vertebrae: a functional magnetic resonance imaging study.

OBJECTIVEnThe purpose of this study was to develop and test a clinically relevant method to mechanically stimulate lumbar functional spinal units while recording brain activity by means of functional magnetic resonance imaging (MRI).nnnMETHODSnSubjects were investigated in the prone position with their face lying on a modified stabilization pillow. To minimize head motion, the pillow was fixed to the MRI headrest, and supporting straps were attached around the shoulders. An experienced manual therapist applied controlled, nonpainful pressure stimuli to 10 healthy subjects at 3 different lumbar vertebrae (L1, L3, and L5). Pressure applied to the thumb was used as a control. The stimulation consisted of posterior to anterior (PA) pressure movement. The therapist followed a randomized stimulation protocol projected onto a screen in the MRI room. Blood oxygenation level-dependent responses were analyzed in relation to the lumbar and the thumb stimulations. The study was conducted by the Chiropractic Department, Faculty of Medicine, University of Zürich, Switzerland.nnnRESULTSnNo participant reported any discomfort due to the prone-lying position or use of the pillow. Importantly, PA-induced pressure produced only minimal head movements. Stimulation of the lumbar spinous processes revealed bilateral neural responses in medial parts of the postcentral gyrus (S1). Additional activity was observed in the secondary somatosensory cortex (S2), posterior parts of the insular cortex, different parts of the cingulate cortex, and the cerebellum. Thumb stimulations revealed activation only in lateral parts of the contralateral S1.nnnCONCLUSIONnThe current study demonstrates the feasibility of the application of PA pressure on lumbar spinous processes in an MRI environment. This approach may serve as a promising tool for further investigations regarding neuroplastic changes in chronic low back pain subjects.

Fear avoidance beliefs in back pain-free subjects are reflected by amygdala-cingulate responses

In most individuals suffering from chronic low back pain, psychosocial factors, specifically fear avoidance beliefs (FABs), play central roles in the absence of identifiable organic pathology. On a neurobiological level, encouraging research has shown brain system correlates of somatic and psychological factors during the transition from (sub) acute to chronic low back pain. The characterization of brain imaging signatures in pain-free individuals before any injury will be of high importance regarding the identification of relevant networks for low back pain (LBP) vulnerability. Fear-avoidance beliefs serve as strong predictors of disability and chronification in LBP and current research indicates that back pain related FABs already exist in the general and pain-free population. Therefore, we aimed at investigating possible differential neural functioning between high- and low fear-avoidant individuals in the general population using functional magnetic resonance imaging. Results revealed that pain-free individuals without a history of chronic pain episodes could be differentiated in amygdala activity and connectivity to the pregenual anterior cingulate cortex by their level of back pain related FABs. These results shed new light on brain networks underlying psychological factors that may become relevant for enhanced disability in a future LBP episode.

Physiological effects of mechanical pain stimulation at the lower back measured by functional near-infrared spectroscopy and capnography

The aim was to investigate the effect of mechanical pain stimulation at the lower back on hemodynamic and oxygenation changes in the prefrontal cortex (PFC) assessed by functional near-infrared spectroscopy (fNIRS) and on the partial pressure of end-tidal carbon dioxide ( PetCO 2) measured by capnography. 13 healthy subjects underwent three measurements (M) during pain stimulation using pressure pain threshold (PPT) at three locations, i.e., the processus spinosus at the level of L4 (M1) and the lumbar paravertebral muscles at the level of L1 on the left (M2) and the right (M3) side. Results showed that only in the M2 condition the pain stimulation elicited characteristic patterns consisting of (1) a fNIRS-derived decrease in oxy- and total hemoglobin concentration and tissue oxygen saturation, an increase in deoxy-hemoglobin concentration, (2) a decrease in the PetCO 2 response and (3) a decrease in coherence between fNIRS parameters and PetCO 2 responses in the respiratory frequency band (0.2-0.5 Hz). We discuss the comparison between M2 vs. M1 and M3, suggesting that the non-significant findings in the two latter measurements were most likely subject to effects of the different stimulated tissues, the stimulated locations and the stimulation order. We highlight that PetCO 2 is a crucial parameter for proper interpretation of fNIRS data in experimental protocols involving pain stimulation. Together, our data suggest that the combined fNIRS-capnography approach has potential for further development as pain monitoring method, such as for evaluating clinical pain treatment.

The cortical and cerebellar representation of the lumbar spine.

Eight decades after Penfields discovery of the homunculus only sparse evidence exists on the cortical representation of the lumbar spine. The aim of our investigation was the description of the lumbar spines cortical representation in healthy subjects during the application of measured manual pressure. Twenty participants in the prone position were investigated during functional magnetic resonance imaging (fMRI). An experienced manual therapist applied non‐painful, posterior‐to‐anterior (PA) pressure on three lumbar spinous processes (L1, L3, and L5). The pressure (30 N) was monitored and controlled by sensors. The randomized stimulation protocol consisted of 68 pressure stimuli of 5 s duration. Blood oxygenation level dependent (BOLD) responses were analyzed in relation to the lumbar stimulations. The results demonstrate that controlled PA pressure on the lumbar spine induced significant activation patterns. The major new finding was a strong and consistent activation bilaterally in the somatosensory cortices (S1 and S2). In addition, bilateral activation was located medially in the anterior cerebellum. The activation pattern also included other cortical areas probably related to anticipatory postural adjustments. These revealed stable somatosensory maps of the lumbar spine in healthy subjects can subsequently be used as a baseline to investigate cortical and subcortical reorganization in low back pain patients. Hum Brain Mapp 35:3962–3971, 2014.