John Hansen

Imaging acetylcholinesterase density in peripheral organs in Parkinson's disease with 11C-donepezil PET

Parkinsons disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinsons disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinsons disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinsons disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed.

Sensitivity and Distensibility of the Rectum and Sigmoid Colon in Patients with Irritable Bowel Syndrome

BACKGROUND Hyperalgesia to visceral stimuli is a biological marker of the irritable bowel syndrome (IBS). Abnormal pain processing is probably of most importance, but biomechanical abnormalities of the gut wall may also contribute to the findings. In the current study, we investigated the sensation of the gut to electrical stimuli as well as the distensibility of the rectum and sigmoid colon in IBS patients and a control group. METHODS Nine patients with IBS and 11 controls entered the study. The pain threshold to electrical stimuli at the rectosigmoid junction was determined with bipolar electrodes integrated on the biopsy forceps for the endoscope. Subsequently, controlled distensions of the sigmoid colon and rectum were performed with a balloon integrated on a probe for impedance planimetry, providing the possibility to measure the cross-sectional area (CSA), wall tension and strain to different pressures together with the sensation ratings. RESULTS The pain detection thresholds to electrical stimuli at the rectosigmoid junction were 12.5 (range 7-39) mA in controls and 7.5 (range 0.75-12) mA in IBS patients (P = 0.03). The calculated pressures at the pain detection threshold in the sigmoid colon were lower in the IBS patients (31.5 (range 5-58) versus 5 cm (range 5-25) water; P = 0.03), otherwise no differences were seen in sensation rating to the different distension pressures. The CSA was slightly higher in controls to the different pressures, whereas no differences between the groups were seen in strain and tension of the rectum and sigmoid colon. CONCLUSION The visceral hypersensitivity in IBS seems to be related to alterations in the nervous system rather than biomechanical parameters such as the tension and strain of the gut wall. Treatment of pain in IBS should therefore be based on drugs with documented action on the nociceptive pathways in the central nervous system.Background: Hyperalgesia to visceral stimuli is a biological marker of the irritable bowel syndrome (IBS). Abnormal pain processing is probably of most importance, but biomechanical abnormalities of the gut wall may also contribute to the findings. In the current study, we investigated the sensation of the gut to electrical stimuli as well as the distensibility of the rectum and sigmoid colon in IBS patients and a control group. Methods: Nine patients with IBS and 11 controls entered the study. The pain threshold to electrical stimuli at the rectosigmoid junction was determined with bipolar electrodes integrated on the biopsy forceps for the endoscope. Subsequently, controlled distensions of the sigmoid colon and rectum were performed with a balloon integrated on a probe for impedance planimetry, providing the possibility to measure the cross-sectional area (CSA), wall tension and strain to different pressures together with the sensation ratings. Results: The pain detection thresholds to electrical stimuli at the rectosigmoid junction were 12.5 (range 7-39) mA in controls and 7.5 (range 0.75-12) mA in IBS patients (P = 0.03). The calculated pressures at the pain detection threshold in the sigmoid colon were lower in the IBS patients (31.5 (range 5-58) versus 5 cm (range 5-25) water; P = 0.03), otherwise no differences were seen in sensation rating to the different distension pressures. The CSA was slightly higher in controls to the different pressures, whereas no differences between the groups were seen in strain and tension of the rectum and sigmoid colon. Conclusion: The visceral hypersensitivity in IBS seems to be related to alterations in the nervous system rather than biomechanical parameters such as the tension and strain of the gut wall. Treatment of pain in IBS should therefore be based on drugs with documented action on the nociceptive pathways in the central nervous system.

Acute pain increases heart rate : Differential mechanisms during rest and mental stress

The main aim was to investigate if acutely stressed subjects have abnormal heart rate variability responses to acute pain. Efferent cardiac autonomic activity was assessed by analyzing RR interval variation in 26 male volunteers. Heart rate variability was measured as mean and standard deviation of normal RR intervals (mean RR, SDNN) and by power spectral analysis where high frequency (HF) and low frequency (LF) power were used as indexes of vagal function and of sympatho-vagal interaction, respectively. Coefficient of component variance in the LF and HF bands (CCV-LF, CCV-HF) was estimated to adjust for possible influences of different mean RR levels on power amplitude. Subjects received painful and non-painful sural nerve stimulations during rest, during attention to pain, and during mental stress. Our results show that pain significantly decreased mean RR and increased LF power and CCV-LF during rest and during attention to pain. SDNN, HF power, and total power were not affected by pain. During mental stress, pain significantly decreased mean RR but failed to affect other heart rate variability parameters. We conclude that acute pain induced efferent cardiac sympathetic activation during rest and during attention to pain as LF power and CCV-LF increased without alterations of pure vagal heart rate variability measures. During mental stress, pain inhibited mean RR without changing heart rate variability measures suggesting that pain does not increase efferent cardiac sympathetic activity during mental stress. Pain induced decrease of mean RR during mental stress may be caused by the release of catecholamines into the systemic circulation.

Heart Rate Variability in Complex Regional Pain Syndrome during Rest and Mental and Orthostatic Stress

Background: Complex regional pain syndrome (CRPS) is a pain condition with regional sensory and autonomic abnormalities in the affected limb. The authors studied systemic autonomic and hemodynamic function in CRPS patients during rest, and during orthostatic and mental arithmetic stress. Methods: Twenty patients with CRPS and 20 age-, sex-, and body mass index-matched control subjects participated. Mean values of heart rate variability, baroreceptor sensitivity, blood pressure, stroke volume, cardiac output, and total peripheral resistance were estimated during supine rest and 60° tilt-table testing. On a separate day, heart rate variability was also measured during mental arithmetic stress testing induced by a paced auditory serial addition task. Results: Heart rate was increased and heart rate variability reduced in patients with CRPS patients compared with control subjects during rest and mental and orthostatic stress, whereas baroreceptor sensitivity was unaffected. When tilted from supine to upright position, patients with CRPS were not able to preserve cardiac output in comparison with control subjects, and they exhibited an exaggerated increase in the total peripheral resistance. The hemodynamic changes correlated to pain duration but not to pain intensity. Conclusion: The increased heart rate and decreased heart rate variability in CRPS suggest a general autonomic imbalance, which is an independent predictor for increased mortality and sudden death. The inability of the patients to protect their cardiac output during orthostatic stress was aggravated with the chronicity of the disease.

Experimental pain in the stomach: a model based on electrical stimulation guided by gastroscopy

Background—Abdominal pain is often variable in intensity and difficult to characterise due to its referred pain pattern. Clinical pain is furthermore confounded by various emotional and cognitive factors. Aims—To develop and apply an experimental model to induce localised gastric pain. Subjects—Twelve healthy male volunteers. Methods—Stimulating electrodes were mounted on a biopsy forceps and electric stimuli were delivered during gastroscopy. Single, five repeated, and continuous stimuli were given at four locations in the stomach. Pain detection thresholds and pain intensities were assessed together with localisation of the referred pain area. Results—Pain detection thresholds were higher in the prepyloric region compared with those obtained at the lesser and greater curvature. Increasing stimulus intensity resulted in augmented pain perception and repeated stimuli elicited pain at a lower stimulus intensity than single stimuli. Continuous stimuli evoked constant (33%), increasing (33%), or decreasing (33%) pain. The localisation of referred pain varied considerably in the subjects. Conclusions—The model seems relevant to study basic pain mechanisms elicited by localised stimuli in the stomach. The experimental data support the premise that a gastric focus should always be suspected in patients referred with different kinds of abdominal pain.

Patient controlled versus automatic stimulation of pudendal nerve afferents to treat neurogenic detrusor overactivity.

PURPOSE We investigated whether patients with neurogenic detrusor overactivity can sense the onset of bladder contraction and in turn suppress the contraction by electrical stimulation of the dorsal penile-clitoral nerve. MATERIALS AND METHODS A total of 67 patients with different neurological disorders were recruited to undergo 3 filling cystometries. The first cystometry was done without stimulation. The second cystometry was performed with automatic controlled stimulation based on detrusor pressure. The third cystometry was done with patient controlled stimulation using a push button. RESULTS Four females and 13 males underwent all 3 fillings. Compared to cystometry 1 average bladder capacity for cystometries 2 and 3 was 60% higher. Compared to peak pressure for cystometry 1 average peak pressure during suppressed contractions for cystometries 2 and 3 was 49% and 26% lower, respectively. The average delay of the onset of stimulation during cystometry 3 with respect to cystometry 2 was 5.7 seconds. CONCLUSIONS The study shows that patient controlled genital nerve stimulation is as effective as automatic controlled stimulation to treat neurogenic detrusor overactivity. Thus, patient controlled stimulation is feasible in select patients, although patients must be trained in the technique.

Urethral Sphincter EMG as Event Detector for Neurogenic Detrusor Overactivity

The aim of this study was to investigate the feasibility of using external urethral sphincter electromyogram (EMG) (EUSEMG) to detect the onset of detrusor contractions in patients with both neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia (DSD). Detrusor pressure (Pdet) and EUSEMG was recorded in 23 neurogenic patients during slow artificial bladder filling. The time delay between the onset of EUSEMG detrusor contraction and the onset of activity was calculated together with the detrusor pressure increase related to this delay. Of 23 patients enrolled, 12 patients showed both NDO and DSD. Of these 12 patients, 10 had a strong correlation between detrusor pressure and EUSEMG . One patient in this group was excluded due to a storage pressure above 30 cmH2O . Two detection methods were applied on the remaining 9 patients. Method 1 was a root mean square (RMS)-integrator with simple thresholding. This approach had a good sensitivity but also a poor specificity (many false-positive detections). Detection method 2 included a kurtosis-based scaling function, which was multiplied to a similar RMS-integrator as used in method 1. Onset detection occurred before Pdet exceeded 18 cmH2O with both methods. However, method 1 resulted in 14.1plusmn12.8 false-positive detections during one bladder filling.Pdet at onset detection was on average 1.0plusmn1.1 cmH2O higher with detection method 2 but the number of false-positives was reduced by 95.8%. This paper demonstrates the feasibility of using EUSEMG to estimate the onset of a detrusor contraction in selected patients.

A portable device for experimental treatment of neurogenic detrusor overactivity.

The objective of this study was to evaluate the effect of automatic event‐driven electrical stimulation on the dorsal penile/clitoral nerve for management of neurogenic detrusor overactivity in spinal cord injured subjects. In order to reach the objectives it was necessary to design and realize a portable device for ambulatory urodynamic studies which was able to activate an electrical stimulator when the detrusor pressure exceeded a certain threshold. The developed device was repeatedly tested in a healthy subject and subsequently tested in a spinal cord injured subject. In testing the automatic event‐driven system in the spinal cord injured subject, detrusor contractions were successfully inhibited until a certain bladder volume was reached and no incontinence episodes were observed prior to disabling the system. The preliminary results indicate that automatic event‐driven electrical stimulation on the dorsal penile/clitoral nerve can inhibit involuntary detrusor contractions in spinal cord injured subjects and hereby restore continence and increase bladder capacity.

Cardiac Patients’ Walking Activity Determined by a Step Counter in Cardiac Telerehabilitation: Data From the Intervention Arm of a Randomized Controlled Trial

Background Walking represents a large part of daily physical activity. It reduces both overall and cardiovascular diseases and mortality and is suitable for cardiac patients. A step counter measures walking activity and might be a motivational tool to increase and maintain physical activity. There is a lack of knowledge about both cardiac patients’ adherence to step counter use in a cardiac telerehabilitation program and how many steps cardiac patients walk up to 1 year after a cardiac event. Objective The purpose of this substudy was to explore cardiac patients’ walking activity. The walking activity was analyzed in relation to duration of pedometer use to determine correlations between walking activity, demographics, and medical and rehabilitation data. Methods A total of 64 patients from a randomized controlled telerehabilitation trial (Teledi@log) from Aalborg University Hospital and Hjoerring Hospital, Denmark, from December 2012 to March 2014 were included in this study. Inclusion criteria were patients hospitalized with acute coronary syndrome, heart failure, and coronary artery bypass grafting or valve surgery. In Teledi@log, the patients received telerehabilitation technology and selected one of three telerehabilitation settings: a call center, a community health care center, or a hospital. Monitoring of steps continued for 12 months and a step counter (Fitbit Zip) was used to monitor daily steps. Results Cardiac patients walked a mean 5899 (SD 3274) steps per day, increasing from mean 5191 (SD 3198) steps per day in the first week to mean 7890 (SD 2629) steps per day after 1 year. Adherence to step counter use lasted for a mean 160 (SD 100) days. The patients who walked significantly more were younger (P=.01) and continued to use the pedometer for a longer period (P=.04). Furthermore, less physically active patients weighed more. There were no significant differences in mean steps per day for patients in the three rehabilitation settings or in the disease groups. Conclusions This study indicates that cardiac telerehabilitation at a call center can support walking activity just as effectively as telerehabilitation at either a hospital or a health care center. In this study, the patients tended to walk fewer steps per day than cardiac patients in comparable studies, but our study may represent a more realistic picture of walking activity due to the continuation of step counter use. Qualitative studies on patients’ behavior and motivation regarding step counter use are needed to shed light on adherence to and motivation to use step counters. Trial Registration ClinicalTrails.gov NCT01752192; https://clinicaltrials.gov/ct2/show/NCT01752192 (Archived by WebCite at http://www.webcitation.org/6fgigfUyV)

Acoustic Features for the Identification of Coronary Artery Disease

Goal: Earlier studies have documented that coronary artery disease (CAD) produces weak murmurs, which might be detected through analysis of heart sounds. An electronic stethoscope with a digital signal processing unit could be a low cost and easily applied method for diagnosis of CAD. The current study is a search for heart sound features which might identify CAD. Methods: Nine different types of features from five overlapping frequency bands were obtained and analyzed using 435 recordings from 133 subjects. Results: New features describing an increase in low-frequency power in CAD patients were identified. The features of the different types were relatively strongly correlated. Using a quadratic discriminant function, multiple features were combined into a CAD-score. The area under the receiving operating characteristic for the CAD score was 0.73 (95% CI: 0.69-0.78). Conclusion: The result confirms that there is a potential in heart sounds for the diagnosis of CAD, but that further improvements are necessary to gain clinical relevance.