Spinal Excitability in Patients with Painful Chronic Pancreatitis.

Purpose: Abdominal pain is common in patients with chronic pancreatitis (CP), but management is challenging - possibly due to altered pain processing within the central nervous system rendering conventional treatments ineffective. We hypothesized that many patients with painful CP have generalized hyperalgesia correlating with central neuronal hyperexcitability. Patients and Methods: Seventeen CP patients with pain and 20 matched healthy controls underwent experimental pain testing, including repeated pain stimuli (temporal summation), pressure algometry performed in dermatomes with same spinal innervation as the pancreatic gland (pancreatic areas) and remote dermatomes (control areas), a cold pressor test and a conditioned pain modulation paradigm. To probe central neuronal excitability, the nociceptive withdrawal reflex was elicited by electrical stimulation of the plantar skin, and electromyography was obtained from the ipsilateral anterior tibial muscle together with somatosensory evoked brain potentials. Results: Compared to healthy controls, patients with painful CP had generalized hyperalgesia as evidenced by 45% lower pressure pain detection thresholds (P<0.05) and decreased cold pressor endurance time (120 vs 180 seconds, P<0.001). In patients, reflex thresholds were lower (14 vs 23 mA, P=0.02), and electromyographic responses were increased (16.4 vs 9.7, P=0.04) during the withdrawal reflex, reflecting predominantly spinal hyperexcitability. Evoked brain potentials did not differ between groups. A positive correlation was found between reflex thresholds and cold pressor endurance time (ρ=0.71, P=0.004). Conclusion: We demonstrated somatic hyperalgesia in patients with painful CP associated with spinal hyperexcitability. This highlights that management should be directed at central mechanisms using, eg, gabapentinoids or serotonin-noradrenaline reuptake inhibitors.

Features characterising cardiac autonomic neuropathy in diabetes using ensembled classification.

OBJECTIVE: Using supervised machine learning to classify the severity of cardiovascular autonomic neuropathy (CAN). The aims were 1) to investigate which features contribute to characterising CAN 2) to generate an ensembled set of features that best describes the variation in CAN classification. METHODS: Eighty-two features from demographic, beat-to-beat, biochemical, and inflammation were obtained from 204 people with diabetes and used in three machine-learning-classifiers, these are: support vector machine, decision tree, and random forest. All data were ensembled using a weighted mean of the features from each classifier. RESULTS: The 10 most important features derived from the domains: Beat-to-beat, inflammation markers, disease-duration, and age. CONCLUSIONS: Beat-to-beat measures associate with CAN as diagnosis is mainly based on cardiac reflex responses, disease-duration and age are also related to CAN development throughout disease progression. The inflammation markers may reflect the underlying disease process, and therefore, new treatment modalities targeting systemic low-grade inflammation should potentially be tested to prevent the development of CAN. SIGNIFICANCE: Cardiac reflex responses should be monitored closely to diagnose and classify severity levels of CAN accurately. Standard clinical biochemical analytes, such as glycaemic level, lipidic level, or kidney function were not included in the ten most important features. Beat-to-beat measures accounted for approximately 60% of the features in the ensembled data.

The PanGut-study: Evoked potentials following rectal balloon distention, a way of evaluating diabetic autonomic neuropathy in the gut?

AIM: There is a lack of methods for investigating the autonomic nerves of the gastrointestinal tract. Our aim was to explore a novel test measuring visceral sensory evoked potentials (EPs) in response to rapid balloon distention in the rectum and compare it to established tests for diabetic neuropathy. METHOD: Participants with longstanding type 2 diabetes, newly onset, untreated diabetes <1 year, and matched controls, were included. Tests included cardiovascular reflex tests, orthostatic blood pressure, electrical skin conductance assessment, sural nerve testing and monofilament test. The rectal balloon distention pressure at earliest sensation and threshold of unpleasantness were identified and used to elicit mechanical EPs. RESULTS: The pressure at earliest sensation was higher in people with diabetes, 0.038 (0.012) bar vs. controls 0.030 (0.009) bar, p = 0.002, and in people with signs of peripheral neuropathy, 0.045 (0.014) bar, p < 0.01. Clinical correlations between EP amplitude and latency, and other tests were found. CONCLUSIONS: Rectal hyposensitivity was associated with both longstanding and early diabetes, indicating enteric sensory dysfunction already in early stages of diabetes. Correlation analyses may indicate that central afferent processing is affected in parallel with peripheral neuronal function.

Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial.

Opioids change gut motility, and opium tincture has been used for treatment of chronic diarrhoea for centuries. However, the effects have never been documented in controlled trials. We aimed to investigate the effects of opium tincture on gastrointestinal transit and motility, frequency of bowel movements, stool consistency, gastrointestinal symptoms and sedation. Twenty healthy subjects were included in this randomized controlled trial. Opium tincture or placebo was each applied for 9 days. Gastrointestinal transit and motility were investigated with the 3D-transit system. Bowel movements and gastrointestinal symptoms were recorded daily. General cognition, reaction time, memory and electroencephalography were used to assess effects on the central nervous system. Opium tincture doubled colonic transit (49 vs. 23 h, p < 0.001), decreased antegrade colonic movements (p < 0.05), reduced daily bowel movements (0.7 vs. 1.2, p < 0.001) and increased stool consistency (Type 3 vs. Type 4, p < 0.001). No changes in general cognition, reaction time or memory were observed, and minor changes of power observed by electroencephalography did not indicate sedation. This study is the first to show that opium tincture has anti-propulsive properties in the healthy gut, while no sedative effects were seen. This indicates that opium tincture is a relevant and safe treatment option in chronic diarrhoea.

Indentation of a pressurized silicon stomach model - A non-invasive study of gastric wall stiffness and pressurized gastric content stiffness.

BACKGROUND AND AIMS: Evaluation of gastric wall stiffness and intragastric pressure is essential for detailed assessments of gastric accommodation. However, non-invasive assessments are needed for large scale clinical studies and none of the existing methods takes abdominal wall effect into the calculation. This study aimed to assess gastric wall stiffness and gastric content stiffness as a proxy for intragastric pressure using novel mechanical modeling and non-invasive indentation tests on a silicon stomach model. METHODS: A silicon stomach model (scaling 1:1 with the human stomach) was indented using a pressure algometer at intragastric pressures from 0 to 0.8 kPa. Wall thicknesses and luminal cross-sectional areas along the stomach were measured with ultrasound images. The gastric wall stiffness was compared between measurements from tensile tests on strips cut from the silicon stomach and estimations from a shell indentation model. The pressurized gastric content stiffness was predicted from a bonded two-layer axisymmetric half-space indentation model. RESULTS: The gastric wall stiffness estimated from the shell indentation model showed no difference to measurements from the mechanical tests on the cutting strips (p = 0.14). The predicted gastric content stiffness was strongly associated with the intragastric pressure (r > 0.83, p < 0.001). CONCLUSIONS: The mechanical model developed in this study can simultaneously predict the gastric wall stiffness and the pressurized gastric content stiffness. In future studies, the method can be applied to reveal intragastric pressure conditions non-invasively via the pressurized gastric content stiffness during gastric accommodation and emptying such as with magnetic resonance imaging.

Influence of tapentadol and oxycodone on the spinal cord and brain using electrophysiology: a randomized, placebo-controlled trial.

AIMS: The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. METHODS: Twenty-one healthy volunteers completed a cross-over trial with oxycodone (10 mg), tapentadol (50 mg) extended-release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post-interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory-evoked potential. RESULTS: Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by -0.89 (P = .001, 95% confidence interval [CI] -1.46, -0.32), whereas oxycodone increased the latency of the N1 component of the sensory-evoked potential at the vertex by 12.5 ms (P = .003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P < .02), and the insula components moved caudally in both the oxycodone and tapentadol arms (all P < .03). CONCLUSION: A decrease in the number of nociceptive withdrawal reflex was observed during tapentadol treatment, possibly relating to the noradrenaline reuptake inhibition effects on the spinal cord. Both oxycodone and tapentadol affected cortical measures possible due to µ-opioid receptor agonistic effects evident in the dipole sources, with the strongest effect being mediated by oxycodone. These findings could support the dual effect analgesic mechanisms of tapentadol in humans as previously shown in preclinical studies.

Central neuronal transmission in response to tonic cold pain is modulated in people with type 1 diabetes and severe polyneuropathy.

AIMS: This study aimed to investigate cortical source activity and identify source generators in people with type 1 diabetes during rest and tonic cold pain. METHODS: Forty-eight participants with type 1 diabetes and neuropathy, and 21 healthy controls were investigated with electroencephalography (EEG) during 5-minutes resting and 2-minutes tonic cold pain (immersing the hand into water at 2 °C). EEG power was assessed in eight frequency bands, and EEG source generators were analyzed using standardized low-resolution electromagnetic tomography (sLORETA). RESULTS: Compared to resting EEG, cold pain EEG power differed in all bands in the diabetes group (all p < 0.001) and six bands in the controls (all p < 0.05). Source generator activity in the diabetes group was increased in delta, beta2, beta3, and gamma bands and decreased in alpha1 (all p < 0.006) with changes mainly seen in the frontal and limbic lobe. Compared to controls, people with diabetes had decreased source generator activity during cold pain in the beta2 and beta3 bands (all p < 0.05), mainly in the frontal lobe. CONCLUSIONS: Participants with type 1 diabetes had altered EEG power and source generator activity predominantly in the frontal and limbic lobe during tonic cold pain. The results may indicate modulated central transmission and neuronal impairment.

Contractility patterns and gastrointestinal movements monitored by a combined magnetic tracking and motility testing unit.

BACKGROUND: Ingestible wireless capsules, including the 3D-transit magnetic capsule and the wireless motility capsule (WMC), describe gastrointestinal (GI) motility from changes in position or pressure. This study aimed to combine information on contractile events in terms of position (assessed with the 3D-transit) and change in pressure (assessed with the WMC) throughout the entire GI tract. METHODS: The 3D-transit capsule and WMC were combined into a single-wireless unit system. Three-dimensional space-time coordinates, pressure, and pH data from a pilot case were analyzed as the combined unit passed the GI tract. Two single and three continuous contraction patterns were defined according to pressure changes and quantified through the GI tract. KEY RESULTS: The combined unit was well tolerated and provided information on contractions throughout the gut. Single contraction patterns with no significant progressive movement of the unit were most prevalent in the stomach and the rectosigmoid colon. During the continuous contraction patterns, the unit moved in an antegrade or retrograde direction. Longer distance and higher velocity were seen during antegrade than during retrograde movements. The motility indices (as measured with WMC) in combined ascending, transverse and descending colon showed a positive linear association (r = 0.7) to the capsule movements (as measured with 3D-transit). CONCLUSIONS & INFERENCES: The combined system provides synchronous information about movements and gut contractions. These measurements can be used to extract more information from existing recordings and may enhance our understanding of GI motility in health and disease.

The effects of tapentadol and oxycodone on central processing of tonic pain.

OBJECTIVE: The present study investigated differences between opioids to experimental tonic pain in healthy men. METHODS: Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. RESULTS: A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. CONCLUSION: Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. SIGNIFICANCE: Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol.

Tapentadol results in less deterioration of gastrointestinal function and symptoms than standard opioid therapy in healthy male volunteers.

BACKGROUND: Tapentadol is a combined opioid agonist and norepinephrine reuptake inhibitor with fewer gastrointestinal side effects at equianalgesic doses compared with classical strong opioids. Previous studies on tapentadol have included multi-morbid patients in whom confounders exclude detailed assessment of the mechanistic effects and strict comparison with other opioids or placebo. This study aimed at investigating the effects of tapentadol and oxycodone on gastrointestinal motility and gastrointestinal side effects. METHODS: 21 healthy males participated in a randomized, double-blind, placebo-controlled, crossover study. Tapentadol (50 mg twice daily), oxycodone (10 mg twice daily), or placebo tablets were administered for 14 days. Segmental gastrointestinal transit times and colonic motility parameters were measured with electromagnetic capsules. Gastrointestinal side effects were assessed using questionnaires. KEY RESULTS: During dosing with tapentadol, gastrointestinal side effects and motility parameters were on placebo level. Compared with tapentadol, oxycodone increased whole gut transit time by 17.9 hours (p = .015) and rectosigmoid transit time by 6.5 hours (p = .005). Compared with tapentadol, oxycodone also reduced long, fast antegrade colonic movements (p = .001). In comparison with placebo, oxycodone prolonged whole gut transit time by 31.6 hours, (p < .001). Moreover, less long, fast antegrade colonic movements (p = .002) were observed during oxycodone. For oxycodone only, slow colonic movements were associated with gastrointestinal side effects. CONCLUSIONS & INFERENCES: In this mechanistic study, tapentadol caused significantly less colonic dysmotility and gastrointestinal side effects as compared with oxycodone in equianalgesic doses.

Reliability of Tibialis Anterior Muscle Voluntary Activation Using the Interpolated Twitch Technique and the Central Activation Ratio in People with Stroke.

Voluntary activation (VA) is measured by applying supramaximal electrical stimulation to a muscle during a maximal voluntary contraction (MVC). The amplitude of the evoked muscle twitch is used to determine any VA deficit, and indicates incomplete central neural drive to the motor units. People with stroke experience VA deficits and greater levels of central fatigue, which is the decrease in VA that occurs following exercise. This study investigated the between-session reliability of VA and central fatigue of the tibialis anterior muscle (TA) in people with chronic stroke (n = 12), using the interpolated twitch technique (ITT), adjusted-ITT, and central activation ratio (CAR) methods. On two separate sessions, supramaximal electrical stimulation was applied to the TA when it was at rest and maximally activated, at the start and end of a 30-s isometric dorsiflexor MVC. The most reliable measures of VA were obtained using the CAR calculation on transformed data, which produced an ICC of 0.92, and a lower bound confidence interval in the good range (95% CI 0.77 to 0.98). Reliability was lower for the CAR calculation on non-transformed data (ICC 0.82, 95% CI 0.63 to 0.91) and the ITT and adjusted-ITT calculations on transformed data (ICCs 0.82, 95% CIs 0.51 to 0.94), which had lower bound confidence intervals in the moderate range. The two ITT calculations on non-transformed data demonstrated the poorest reliability (ICCs 0.62, 95% CI 0.25 to 0.74). Central fatigue measures demonstrated very poor reliability. Thus, the reliability for VA in people with chronic stroke ranged from good to poor, depending on the calculation method and statistical analysis method, whereas the reliability for central fatigue was very poor.

Although tapentadol and oxycodone both increase colonic volume, tapentadol treatment resulted in softer stools and less constipation: a mechanistic study in healthy volunteers.

OBJECTIVES: Opioids are often used in treatment of severe pain, although many patients experience gastrointestinal side-effects like constipation. The aim of the current study was to investigate changes in colonic volume, as the result of both colonic motility and fluid transport, in healthy volunteers during opioid treatment with tapentadol as compared with oxycodone and placebo. METHODS: In a randomized, double-blind, cross-over study, 21 healthy male volunteers were administered equianalgesic dosages of oral tapentadol (50 mg bid), oxycodone (10 mg bid) or corresponding placebo for 14 days. Segmental colonic volumes were quantified using T2-weighted magnetic resonance images, and gastrointestinal side-effects were assessed with questionnaires. RESULTS: Total colonic volume increase during treatment was higher during tapentadol and oxycodone treatment (median 48 and 58 mL) compared to placebo (median -14 mL, both p≤0.003). Tapentadol (and placebo) treatment resulted in more bowel movements (both p<0.05) and softer stool consistency as compared with oxycodone (both p<0.01). Only oxycodone treatment was associated with increased constipation, straining during defecation, and tiredness (all p≤0.01). The colonic volume increase during treatment was directly associated with softer stools during tapentadol treatment (p=0.019). CONCLUSIONS: Tapentadol treatment increased colonic volume without leading to harder stools, likely as the opioid sparing effects result in less water absorption from the gut lumen. Oxycodone treatment also increased colonic volume, but with a simultaneous increase in stool dryness and gastrointestinal and central nervous system side-effects. The results confirm that tapentadol treatment may be advantageous to oxycodone regarding tolerability to pain treatment.

Diabetic Neuropathy Influences Control of Spinal Mechanisms.

PURPOSE: Comprehensive evaluation of the upstream sensory processing in diabetic symmetrical polyneuropathy (DSPN) is sparse. The authors investigated the spinal nociceptive withdrawal reflex and the related elicited somatosensory evoked cortical potentials. They hypothesized that DSPN induces alterations in spinal and supraspinal sensory-motor processing compared with age- and gender-matched healthy controls. METHODS: In this study, 48 patients with type 1 diabetes and DSPN were compared with 21 healthy controls. Perception and reflex thresholds were determined and subjects received electrical stimulations on the plantar site of the foot at three stimulation intensities to evoke a nociceptive withdrawal reflex. Electromyogram and EEG were recorded for analysis. RESULTS: Patients with DSPN had higher perception (P < 0.001) and reflex (P = 0.012) thresholds. Fewer patients completed the recording session compared with healthy controls (34/48 vs. 21/21; P = 0.004). Diabetic symmetrical polyneuropathy reduced the odds ratio of a successful elicited nociceptive withdrawal reflex (odds ratio = 0.045; P = 0.014). Diabetic symmetrical polyneuropathy changed the evoked potentials (F = 2.86; P = 0.025), and post hoc test revealed reduction of amplitude (-3.72 mV; P = 0.021) and prolonged latencies (15.1 ms; P = 0.013) of the N1 peak. CONCLUSIONS: The study revealed that patients with type 1 diabetes and DSPN have significantly changed spinal and supraspinal processing of the somatosensory input. This implies that DSPN induces widespread differences in the central nervous system processing of afferent A-δ and A-ß fiber input. These differences in processing may potentially lead to identification of subgroups with different stages of small fiber neuropathy and ultimately differentiated treatments.

Acute Effects of Aerobic Exercise on Somatosensory-Evoked Potentials in Patients with Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is becoming a serious problem for developing countries as the lifespan of populations increases. Exercise is known to be clinically beneficial for MCI patients. Somatosensory-evoked potentials (SEPs) may be a potential diagnostic and prognostic marker for this population. The objective of this study was to determine the acute effects of aerobic exercise on SEPs in patients with MCI, to test whether SEPs are sensitive enough to detect improvements in early somatosensory processing. The study had a randomized parallel-group design and included 28 MCI subjects (14 in the experimental group and 14 in the control group). The experimental intervention was 20 min of aerobic exercise using a stationary bicycle. The control intervention involved 20 min of movements and stretches. Subjects were assessed before and after a single intervention session. SEPs were recorded by stimulating the median nerve of the dominant hand. Analysis of normalized SEP peak amplitudes showed that a single session of aerobic activity significantly reduced the N30 peak at the F3 channel (p = 0.03). There were no significant effects of aerobic exercise on SEP peak latencies. The results indicate that 20 min of aerobic exercise has a significant effect on the N30 SEP peak amplitude in MCI patients. The results suggest that aerobic exercise is likely to provide sensory-enriching inputs that enhance sensorimotor integration. Future studies should assess the effects of aerobic exercise on somatosensory processing in progressive stages of Alzheimer's disease, longer exercise durations, and multiple exercise sessions.

Investigating the Effects of Chiropractic Spinal Manipulation on EEG in Stroke Patients.

: Objective: The purpose of this study was to evaluate the impact of chiropractic spinal manipulation on the early somatosensory evoked potentials (SEPs) and resting-state electroencephalography (EEG) recorded from chronic stroke patients. Methods: Seventeen male patients (53 ± 12 years old) participated in this randomized cross-over study. The patients received chiropractic spinal manipulation and control intervention, in random order, separated by at least 24 hours. EEG was recorded before and after each intervention during rest and stimulation of the non-paretic median nerve. For resting-state EEG, the delta-alpha ratio, brain-symmetry index, and power-spectra were calculated. For SEPs, the amplitudes and latencies of N20 and N30 peaks were assessed. Source localization was performed on the power-spectra of resting-state EEG and the N30 SEP peak. Results: Following spinal manipulation, the N30 amplitude increased by 39%, which was a significant increase compared to the control intervention (p < 0.01). The latency and changes to the strength of the cortical sources underlying the N30 peak were not significant. The N20 peak, the resting-state power-spectra, delta-alpha ratio, brain-symmetry index, and resting-state source localization showed no significant changes after either intervention. Conclusion: A single session of chiropractic spinal manipulation increased the amplitude of the N30 SEP peak in a group of chronic stroke patients, which may reflect changes to early sensorimotor function. More research is required to investigate the long-term effects of chiropractic spinal manipulation, to better understand what impact it may have on the neurological function of stroke survivors.