Search

This systematic literature review aims at providing a concise, yet comprehensive overview of the neurophysiology of pain for non-neurophysiologists. In particular, we focused on the neurophysiological processes involved in the transduction, transmission, modulation, and perception of acute pain. A systematic literature search was performed using the PubMed-database on October 30th, 2020. After screening for inclusion/exclusion, we selected 79 articles to be included in this review. The primary intention of this review is to serve as base upon which mathematical and computational models of the pain system can be built. For this purpose, we present the consensus and disagreements in the field in a comprehensive manner. We also hope that it can provide insight for other professionals interested on pain, who do not have a background in neurophysiology.

Background: The impact of renal denervation (RDN) on muscle sympathetic nerve activity (MSNA) at rest remains controversial. Mental stress (MS) induces transient changes in sympathetic nerve activity, heart rate (HR) and blood pressure (BP). It is not known whether RDN modifies these changes.Purpose: The main objective was to assess the effect of RDN on MSNA and BP alterations during MS.Methods: In 14 patients (11 included in analysis) with resistant hypertension multi-unit MSNA, BP (Finometer ®) and HR were assessed at rest and during forced arithmetics at baseline and 6 months after RDN.Results: Systolic office BP decreased significantly 6 months after RDN (185 ± 29 vs.175 ± 33 mmHG; p = 0.04). No significant changes in MSNA at rest (68 ± 5 vs 73 ± 5 bursts/100hb; p = 0.43) were noted and no significant stress-induced change in group averaged sympathetic activity was found pre- (101 ± 24%; p = 0.9) or post-intervention (108 ± 26%; p = 0.37). Stress was associated with significant increases in mean arterial BP (p < 0.01) and HR (p < 0.01) at baseline, reactions which remained unaltered after intervention. We did not note any correlation between sympathetic nerve activity and BP changes after RDN.Conclusion: Thus, in our group of resistant hypertensives we find no support for the hypothesis that the BP-lowering effect of RDN depends on altered neurovascular responses to stress.

Using machine learning in clinical practice poses hard requirements on explainability, reliability, replicability and robustness of these systems. Therefore, developing reliable software for monitoring critically ill patients requires close collaboration between physicians and software engineers. However, these two different disciplines need to find own research perspectives in order to contribute to both the medical and the software engineering domain. In this paper, we address the problem of how to establish a collaboration where software engineering and medicine meets to design robust machine learning systems to be used in patient care. We describe how we designed software systems for monitoring patients under carotid endarterectomy, in particular focusing on the process of knowledge building in the research team. Our results show what to consider when setting up such a collaboration, how it develops over time and what kind of systems can be constructed based on it. We conclude that the main challenge is to find a good research team, where different competences are committed to a common goal.

Abdominal injury is a frequent cause of death for trauma patients, and early recognition is essential to limit fatalities. There is a need for a wearable sensor system for prehospital settings that can detect and monitor bleeding in the abdomen (hemoperitoneum). This study evaluates the potential for microwave technology to fill that gap. A simple prototype of a wearable microwave sensor was constructed using eight antennas. A realistic porcine model of hemoperitoneum was developed using anesthetized pigs. Ten animals were measured at healthy state and at two sizes of bleeding. Statistical tests and a machine learning method were used to evaluate blood detection sensitivity. All subjects presented similar changes due to accumulation of blood, which dampened the microwave signal ($$p < 0.05$$ p < 0.05 ). The machine learning analysis yielded an area under the receiver operating characteristic (ROC) curve (AUC) of 0.93, showing 100% sensitivity at 90% specificity. Large inter-individual variability of the healthy state signal complicated differentiation of bleedings from healthy state. A wearable microwave instrument has potential for accurate detection and monitoring of hemoperitoneum, with automated analysis making the instrument easy-to-use. Future hardware development is necessary to suppress measurement system variability and enable detection of smaller bleedings.

In homeostasis, somatosensory C fibre afferents are hypothesised to mediate input to the brain about interactions with external stimuli and sympathetic efference provides the output that regulates bodily functions. We aimed to test this hypothesis and whether different types of innocuous somatosensory input have differential effects. Healthy volunteers performed a muscle fatigue (hand-grip) task to exhaustion, which produces increased muscle sympathetic nerve activity (MSNA), as measured through microneurography. Participants completed the muscle fatigue task without concurrent cutaneous sensory stimulation (control) or we applied skin warming (heat pack) as a C fibre stimulation, slow brush stroking as C and Aβ fibre stimulation, or vibration as Aβ fibre stimulation, to the participant’s forearm. We also measured heart rate, the duration of the hand-grip task, and ratings of pain at the end of the task. Concurrent skin warming showed increased MSNA compared to the other conditions. Tactile stimuli (brushing, vibration) were not significantly different to the control (no intervention) condition. Warming increased the pain from the muscle contraction, whereas the tactile stimuli did not. We interpret the effect of warming on MSNA as providing relevant afferent information during muscle contraction, which needed to be counteracted via vasoconstriction to maintain homeostasis. Brushing and vibration were less homeostatically relevant stimuli for the muscle contraction and hence had no significant effect. The findings add sensory specificity to our current understanding of homeostatic regulation through somatosensory afferent and sympathetic efferent pathways.

Microwave technology has the potential to revolutionize how, when, and what care can be delivered to patients with acute, life-threatening medical conditions. The prospects are that microwave systems can both improve diagnostic ability and accuracy and enable earlier diagnosis. Early diagnosis is a key factor in acute situations, especially when breathing and circulation are affected. Conventional imaging modalities used for diagnostics, such as magnetic resonance imaging (MRI) and X-ray computed tomography (CT), are powerful but normally available only at hospitals.

Traumatic brain injury (TBI) is the leading cause of death and disability among young persons. A key to improve outcome for patients with TBI is to reduce the time from injury to definitive care by achieving high triage accuracy. Microwave technology (MWT) allows for a portable device to be used in the pre-hospital setting for detection of intracranial hematomas at the scene of injury, thereby enhancing early triage and allowing for more adequate early care. MWT has previously been evaluated for medical applications including the ability to differentiate between hemorrhagic and ischemic stroke. The purpose of this study was to test whether MWT in conjunction with a diagnostic mathematical algorithm could be used as a medical screening tool to differentiate patients with traumatic intracranial hematomas, chronic subdural hematomas (cSDH), from a healthy control (HC) group. Twenty patients with cSDH and 20 HC were measured with a MWT device. The accuracy of the diagnostic algorithm was assessed using a leave-one-out analysis. At 100% sensitivity, the specificity was 75%—i.e., all hematomas were detected at the cost of 25% false positives (patients who would be overtriaged). Considering the need for methods to identify patients with intracranial hematomas in the pre-hospital setting, MWT shows promise as a tool to improve triage accuracy. Further studies are under way to evaluate MWT in patients with other intracranial hemorrhages.

Microneurographic recordings of human muscle sympathetic nerve activity responses to sudden sensory stimuli (ie, arousal) have revealed 2 intraindividually reproducible response profiles in healthy young males that predict different neural and blood pressure responses to more sustained stress. Approximately 50% of subjects inhibit muscle sympathetic nerve activity during arousal, whereas the remaining 50% do not, and the latter group displays a markedly greater blood pressure increase in response to arousal, as well as during and after 3 minutes of mental arithmetic. Studying a group of monozygotic twins (10 pairs, 2 excluded from analysis), the aim of the present study was to evaluate the degree of genetic determination of these sympathetic response profiles. Muscle sympathetic burst incidence at rest was similar in twins, with a within-pair burst incidence ratio of 0.87±0.02 (SEM) compared with 0.73±0.07 found in unrelated pairs ( P =0.002), confirming a previous study from our laboratory. In contrast, the sympathetic responses to arousal showed large twin within-pair variance (arousal inhibition ratio 0.56±0.11), which did not significantly differ ( P =0.939) from the variance in pairs of unrelated subjects (0.46±0.11). The finding that human muscle sympathetic nerve responses to arousal are less determined by genotype than the resting level of corresponding sympathetic nerve activity suggests that the arousal response pattern is more prone to be altered by environmental factors. This raises the possibility that these intraindividually reproducible sympathetic neural response profiles can be modified in a positive direction from a cardiovascular risk perspective.

We used a stepwise process to develop a new paradigm for preoperative cortical mapping of receptive language in children, using temporary functional blocking with transcranial magnetic stimulation (TMS). The method combines short sentences with a lexical decision task in which children are asked to point at a picture that fits a short sentence delivered aurally. This was first tested with 24 healthy children aged 4–16 years. Next, 75 sentences and 25 slides were presented to five healthy children in a clinical setting without TMS. Responses were registered on a separate computer, and facial expressions and hand movements were filmed for later offline review. Technical adjustments were made to combine these elements with the existing TMS equipment. The audio-recorded sentences were presented before the visual stimuli. Sentence lists were constructed to avoid similar stimuli in a row. Two different baseline lists were used before the TMS registration; the second baseline resulted in faster responses and was chosen as the reference for possible response delays induced by TMS. Protocols for offline reviews were constructed. No response, incorrect response, self-correction, delayed response, and perseveration were considered clear stimulation effects, while poor attention, discomfort, and other events were regarded as unclear. Finally, three children (6:2, 14:0, 14:10 years) with epilepsy and expected to undergo neurosurgery were assessed using TMS (left hemisphere in one; both hemispheres in the other two). In the two assessed bilaterally, TMS effects indicated bilateral language processing. Delayed response was the most common error. This is a first attempt to develop a new TMS paradigm for receptive language mapping, and further evaluation is suggested.

Traumatic brain injury is the leading cause of death and severe disability for young people and a major public health problem for elderly. Many patients with intracranial bleeding are treated too late, because they initially show no symptoms of severe injury and are not transported to a trauma center. There is a need for a method to detect intracranial bleedings in the prehospital setting. In this study, we investigate whether broadband microwave technology (MWT) in conjunction with a diagnostic algorithm can detect subdural hematoma (SDH). A human cranium phantom and numerical simulations of SDH are used. Four phantoms with SDH 0, 40, 70 and 110 mL are measured with a MWT instrument. The simulated dataset consists of 1500 observations. Classification accuracy is assessed using fivefold cross-validation, and a validation dataset never used for training. The total accuracy is 100 and 82-96 % for phantom measurements and simulated data, respectively. Sensitivity and specificity for bleeding detection were 100 and 96 %, respectively, for the simulated data. SDH of different sizes is differentiated. The classifier requires training dataset size in order of 150 observations per class to achieve high accuracy. We conclude that the results indicate that MWT can detect and estimate the size of SDH. This is promising for developing MWT to be used for prehospital diagnosis of intracranial bleedings.

Aim Trauma to the thorax is common and can be life-threatening. Prehospital diagnosis of thoracic injuries is challenging. Ultrasound is a promising technology; however, its accuracy is operator dependent. Methods not requiring operator image interpretation would be beneficial. The aim of this study is to evaluate electrical bioimpedance (EBI) and microwave technology (MWT). Both technologies are non-operator dependent, non-invasive, harmless, cost efficient, rapid and portable. Methods Two complementary lines of research are pursued. A clinical study aiming to differentiate EBI measurements of thoracic trauma patients (n=20) and healthy controls (n=20), using diagnostic mathematical algorithms, has been completed. Clinical trials are complemented by experiments on realistic porcine models of pneumothorax (PTX) and hemothorax (HTX).1–2 These experiments enable analysis of EBI and MWT with well-defined injuries. A pilot study on two pigs with unilateral PTX from small (50 mL) to large (2000 mL) sizes, and large HTX, was performed. Diagnostic performance is evaluated using cross-validation to derive the area under the ROC curve (AUC), and confusion matrices. Results The clinical study achieved AUC=0.87. The pilot porcine study showed that EBI parameters evolved as expected with increasing PTX/HTX; EBI theory predicts presence of air should increase resistivity and fluid decrease it. The MWT classification accuracy for predicting size of PTX was 100% and 98% for each pig, respectively. Conclusion EBI and MW are promising technologies for prehospital diagnosis of thoracic injuries. References Buendia, et al. Electrical bioimpedance for diagnosing thoracic injuries: Test on a porcine pneumothorax and hemothorax model. (2016) Short Communications From AAAM’s 60th Annual Scientific Conference, Traffic Injury Prevention, 17:supp 1, 175–218. Oveland, et al.: A wearable microwave detector for diagnosing thoracic injuries-test on a porcine pneumothorax model. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine2015;23(Suppl 2):A20. Conflict of interest None declared. Funding The authors acknowledge funding received from the Swedish research centre MedTech West and Folksam insurance company.

Here, we present two different brain diagnostic devices based on microwave technology and the associated two first proof-of-principle measurements that show that the systems can differentiate hemorrhagic from ischemic stroke in acute stroke patients, as well as differentiate hemorrhagic patients from healthy volunteers. The system was based on microwave scattering measurements with an antenna system worn on the head. Measurement data were analyzed with a machine-learning algorithm that is based on training using data from patients with a known condition. Computer tomography images were used as reference. The detection methodology was evaluated with the leave-one-out validation method combined with a Monte Carlo-based bootstrap step. The clinical motivation for this project is that ischemic stroke patients may receive acute thrombolytic treatment at hospitals, dramatically reducing or abolishing symptoms. A microwave system is suitable for prehospital use, and therefore has the potential to allow significantly earlier diagnosis and treatment than today.

To examine whether cerebrospinal fluid biomarkers for neuroaxonal damage, neuroglial activation, and amyloid β-related processes could characterize the neurochemical response to cranial radiation.Before prophylactic cranial irradiation (PCI) of patients with small cell lung cancer, each patient underwent magnetic resonance imaging of the brain, lumbar puncture, and Mini-Mental State Examination of cognitive function. These examinations were repeated at approximately 3 and 12 months after radiation.The major findings were as follows. (1) Cerebrospinal fluid markers for neuronal and neuroglial injury were elevated during the subacute phase after PCI. Neurofilament and T-tau increased 120% and 50%, respectively, after PCI (P.05). The same was seen for the neuroglial markers YKL-40 and glial fibrillary acidic protein, which increased 144% and 106%, respectively, after PCI (P.05). (2) The levels of secreted amyloid precursor protein-α and -β were reduced 44% and 46%, respectively, 3 months after PCI, and the levels continued to decrease as long as 1 year after treatment (P.05). (3) Mini-Mental State Examination did not reveal any cognitive decline, indicating that a more sensitive test should be used in future studies.In conclusion, we were able to detect radiation therapy-induced changes in several markers reflecting neuronal injury, inflammatory/astroglial activation, and altered amyloid precursor protein/amyloid β metabolism, despite the low number of patients and quite moderate radiation doses (20-30 Gy). These changes are hypothesis generating and could potentially be used to assess the individual risk of developing long-term symptoms of chronic encephalopathy after PCI. This has to be evaluated in large studies with extended clinical follow-up and more detailed neurocognitive assessments.

The baroreceptor reflex controls spontaneous fluctuations in blood pressure. One major control variable of the baroreflex is the sympathetic vasoconstrictor activity to muscles [MSNA; burst frequency (BF) and burst incidence (BI)], which can be quantitatively assessed by microneurography. We aimed to investigate the central regions involved in baroreflex regulation of MSNA. Healthy men (mean age 25 years) participated in three experimental sessions. (i) Microneurography recordings of MSNA from the left peroneal nerve during rest and baroreflex unloading, induced by lower body negative pressure (LBNP; -40 mmHg). If MSNA could be reliably recorded throughout this procedure (n = 15), the subjects entered the positron emission tomography (PET) experiments. The two PET sessions took place in a randomised order. Cerebral glucose metabolism (18-fluorodeoxyglucose) was analysed after: (ii) baroreflex unloading (LBNP); and (iii) control condition (lying in the LBNP chamber without suction). The PET data were analysed employing SPM8. LBNP elicited a significant increase in MSNA in all successfully recorded subjects (BI: P = 0.001; F = 5.54; BF: P < 0.001; F = 36.59). As compared with the control condition, LBNP was associated with increased PET regional glucose metabolism bilaterally in the orbitofrontal cortex (OFC; BA 11, 47). Related to the rise of BF, there was increased activation of the left OFC (BA 11); related to the rise of BI there was increased activation of the brainstem corresponding to the rostral ventrolateral medulla. Our data support a role for the ventrolateral medulla and the OFC in baroreflex-mediated control of MSNA in humans.

Autonomic dysreflexia, a dangerous and sustained increase in blood pressure brought about by widespread, reflexly generated vasoconstriction, can be induced by visceral or somatic sensory inputs originating below the lesion following spinal cord injury (SCI). We assessed whether cutaneous vasoconstriction below the lesion could serve as a proxy marker of incipient autonomic dysreflexia during bladder distension. Skin blood flow (pulse plethysmography), sweat release, blood pressure, heart rate, bladder and rectal pressures were recorded during routine cystometry (urodynamics) in 16 patients with SCI. Eight urological patients without SCI served as control subjects. In all SCI patients, who had sustained injuries 2 months to 44 years previously at levels C3-T3, bladder filling (mean ± SD, 339 ± 132 ml) induced increases in detrusor (bladder-rectal) pressure (52 ± 25 cmH(2)O) and cutaneous vasoconstriction in the fingers, but no consistent increases in sweat release. This occurred irrespective of whether the spinal lesions were complete [American Spinal Injury Association (ASIA) grade A, n = 6] or incomplete (ASIA B-D; n = 10). Group mean blood pressure for the SCI patients increased by 17 ± 15 mmHg, but in four patients the pressure decreased or did not change. Despite similar bladder volumes (423 ± 126 ml) in the control patients, the increases in detrusor pressure (14 ± 8 cmH(2)O) and blood pressure (9 ± 12 mmHg) were significantly smaller than in the SCI patients; moreover, there were no consistent changes in skin blood flow in the control subjects. In all SCI patients, changes in finger pulse amplitudes were inversely correlated to changes in detrusor pressure (mean r = -0.62 ± 0.17). Changes in finger pulse amplitudes correlated inversely to changes in blood pressure in nine of 15 patients. It is concluded that cystometry in SCI patients is associated with detrusor and cardiovascular reflex effects that are exaggerated compared with those in intact subjects and that measurement of skin blood flow from the fingers in patients with a high spinal lesion provides a supplementary, clinically useful, non-invasive and continuous marker of spinally mediated viscerosympathetic reflex activity below the lesion in such patients.

Background When using transcranial magnetic stimulation, a stimulation intensity defined as a certain level above the threshold for activation of a hand muscle is commonly used, disregarding the fact that the areas of activation for different muscles may have varying response characteristics intra- and interindividually. Objective To study the response characteristics of different muscles and compare them within and between individuals. Also to investigate the effect of varying stimulation intensity (defined in two different ways) and amplitude criterion for response, on the sizes of the activation areas for different muscles. Methods A system of transcranial magnetic stimulation with navigation capacity where the stimulation intensity can be defined in terms of the electric field strength in the tissue was used. Four different muscles were investigated in healthy adults. The threshold for activation at rest (RMT) of the different muscles and their respective areas of activation were quantified using three different stimulus intensities (100, 110 and 120% RMT) and two criteria for response amplitude (20 and 50 μV). Results Responses could readily be determined using 20 μV as response limit. The RMTs for different muscles varied within and between individuals. The degree to which the area depended on stimulation intensity differed between muscles intra- and interindividually. All results were statistically significant (P Conclusions The response characteristics vary between muscles within an individual and between individuals for a certain muscle. Thus, for optimal accuracy when delineating the activation area, the investigation should be adapted to each particular muscle.

Human muscle sympathetic activity (MSA) is modulated by arterial baroreflex mechanisms: the sympathetic impulses are grouped in pulse synchronous bursts occurring preferentially during transient reductions of blood pressure (Delius et al. 1972), and changes in arterial baroreceptor firing induce reciprocal changes in the strength of the MSA (Wallin et al. 1975; Wallin & Eckberg, 1982). In each subject an approximately constant baroreflex latency can be defined, i.e. a given sympathetic burst can always be related to a given cardiac cycle (Delius et al. 1972). This basic relationship is similar in all subjects despite the fact that some subjects have few, and others many, sympathetic bursts. Such interindividual differences in the amount of activity are highly reproducible over several years (Sundlof & Wallin, 1977; Fagius & Wallin, 1993). Different methods have been used to quantify the arterial baroreflex influence on MSA. In an early study, Sundlof & Wallin (1978) described the relationship between spontaneous variations of blood pressure and nerve traffic in terms of (1) threshold (i.e. whether or not a sympathetic burst is generated) and (2) baroreflex sensitivity (i.e. the slope of the relationship between the strength of a burst and the diastolic pressure in the corresponding heart beat). The same approach has been used to study baroreflex sensitivity during sleep (Nakazato et al. 1998) and to compare groups of normotensive and hypertensive subjects (Wallin & Sundlof, 1979). More commonly, baroreflex effects on MSA have been quantified by measuring the relationship between changes in MSA and blood pressure induced by injections of vasoactive drugs. This approach has been used to study baroreflex sensitivity in healthy subjects at different ages (e.g. Ebert et al. 1992; Matsukawa et al. 1996), in association with manoeuvres (e.g. Halliwill et al. 1996), in cardiovascular diseases (e.g. Ferguson et al. 1992; Grassi et al. 1995; Carlson et al. 1996; Meyrelles et al. 1997) or after administration of anaesthetic drugs (e.g. Sellgren et al. 1994; Muzi & Ebert, 1995). Surprisingly, neither method has been used to quantify arterial baroreflex characteristics in individual subjects. Thus, it is not known whether significant arterial baroreflex thresholds and sensitivites in MSA can be defined for all subjects, and whether, in a given subject, such measures of arterial baroreflex function are reproducible. It is also unknown whether baroreflex characteristics in MSA differ between subjects with few and many MSA bursts at rest. The aim of the present study was to answer these questions. Baroreflex threshold and sensitivity were determined from spontaneous variations of blood pressure/cardiac interval and sympathetic nerve traffic (Sundlof & Wallin, 1978). To minimize random variations in the results, a study of the method of analysis was also included.

OBJECTIVE: To test whether sympathetic nerve hyperactivity associated with adult hypopituitarism and untreated growth hormone (GH) deficiency is affected by GH treatment. DESIGN AND METHODS: Sympathetic nerve activity to the muscle vascular bed (MSA) expressed as burst frequency (bursts/min) and incidence (bursts/100 heartbeats) was recorded in 10 hypopituitary patients (aged 48-69 years), before and after acute (1 week) randomized, double-blind, crossover treatment with a 1-month washout period and chronic (1 year) GH replacement treatment. RESULTS: MSA burst frequency and incidence remained unchanged from baseline values after the short-term treatment, but exhibited decreases in median values [from 53 to 47 bursts/min (P = 0.02) and from 85 to 70 bursts/100 heartbeats (P = 0.03), respectively] after 12 months of replacement therapy. Twenty-four-hour urinary excretion of nitrate increased after the short-term cross-over treatment and the long-term treatment (P = 0.04). Diastolic blood pressure and waist circumference decreased after the 12-month treatment (P = 0.02 and P = 0.04, respectively). No correlation was found between the reduction in MSA and the increase in 24-h urinary nitrate excretion, the decrease in diastolic blood pressure and waist circumference. CONCLUSIONS: The sympathoexcitation in adult GH deficiency and the modest decline in MSA seen after long-term GH replacement treatment may suggest that the somatotropic axis is involved in the regulation of central sympathetic outflow.

Mental stress often begins with a sudden sensory (or internal) stimulus causing a brief arousal reaction, and is followed by a more long lasting stress phase. Both arousal and stress regularly induce blood pressure (BP) increases whereas effects on muscle sympathetic nerve activity (MSNA) are variable. Here we have compared responses of MSNA and BP during arousal induced by an electrical skin stimulus and mental stress evoked by a 3 min paced auditory serial arithmetic test (PASAT) in 30 healthy males aged 33 ± 10 years. In addition, recordings were made of ECG, respiratory movements, electrodermal activity and perceived stress. We also monitored corresponding effects of a cold test (CT: 2 min immersion of a hand in ice water). The arousal stimulus evoked significant inhibition of one or two MSNA bursts in 16 subjects, who were classified as responders; the remaining 14 subjects were non-responders. During mental stress responders showed a significant decrease of MSNA and a lesser BP increase compared to non-responders. In non-responders MSNA was unchanged or increased. Perceived stress was higher in non-responders (P = 0.056), but other measures were similar in the two groups. In non-responders mental stress and the cold test induced increases of BP that lasted throughout the subsequent rest period. During the cold test MSNA and BP increased equally in responders and non-responders. In the whole group of subjects, there was a significant correlation (r = 0.80, P 0.6). Additionally arousal-induced MSNA change was positively correlated with blood pressure changes during MS (systolic BP: r = 0.48; P < 0.01; diastolic BP: r = 0.42; P < 0.05) but not with blood pressure changes during CT. We conclude that in males the MSNA response to arousal predicts the MSNA and BP responses to mental stress.

Non-technical summary Recent work has demonstrated differences in the firing pattern of sympathetic nerves in a variety of patient groups. The significance or consequences of this firing pattern remain unknown. We examined whether the nerve firing pattern was associated with increased noradrenaline release from the heart. The activity and pattern of the nerve firing was recorded in the peroneal nerve and subjects were divided into two groups according to the firing pattern as ‘low firing rate’ or ‘high firing rate’. In those with a high firing rate, the noradrenaline released by the heart was two times higher than that of subjects with a low firing rate. This study indicates that the nerve firing pattern may dictate the amount of noradrenaline released by the heart. Abstract Recent work using single-unit sympathetic nerve recording techniques has demonstrated aberrations in the firing pattern of sympathetic nerves in a variety of patient groups. We sought to examine whether nerve firing pattern is associated with increased noradrenaline release. Using single-unit muscle sympathetic nerve recording techniques coupled with direct cardiac catheterisation and noradrenaline isotope dilution methodology we examined the relationship between single-unit firing patterns and cardiac and whole body noradrenaline spillover to plasma. Participants comprised patients with hypertension (n= 6), depression (n= 7) and panic disorder (n= 9) who were drawn from our ongoing studies. The patient groups examined did not differ in their single-unit muscle sympathetic nerve firing characteristics nor in the rate of spillover of noradrenaline to plasma from the heart. The median incidence of multiple spikes per beat was 9%. Patients were stratified according to the firing pattern: low level of incidence (less than 9% incidence of multiple spikes per beat) and high level of incidence (greater than 9% incidence of multiple spikes per beat). High incidence of multiple spikes within a cardiac cycle was associated with higher firing rates (P < 0.0001) and increased probability of firing (P < 0.0001). Whole body noradrenaline spillover to plasma and (multi-unit) muscle sympathetic nerve activity in subjects with low incidence of multiple spikes was not different to that of those with high incidence of multiple spikes. In those with high incidence of multiple spikes there occurred a parallel activation of the sympathetic outflow to the heart, with cardiac noradrenaline spillover to plasma being two times that of subjects with low nerve firing rates (11.0 ± 1.5 vs. 22.0 ± 4.5 ng min−1, P < 0.05). This study indicates that multiple within-burst firing and increased single-unit firing rates of the sympathetic outflow to the skeletal muscle vasculature is associated with high cardiac noradrenaline spillover.

Scalp-recorded EEG activity reflects a number of oscillatory phenomena, many of which are generated by coupled brain sources or behave as travelling waves. Decomposition of EEG oscillations into sets of coherent processes may help investigation of the underlying functional brain networks. Traditional decomposition methods, such as ICA and PCA, cannot satisfactorily characterize coherent EEG oscillations. Moreover, these methods impose non-physiological constraints (orthogonality, maximal time independence) on the solutions. We introduce the C 3 R-MDD method, that is based on recursive multi-dimensional decomposition (R-MDD). The method allows separation of ongoing EEG into a predefined number of coherent oscillatory processes. Applied to a multichannel complex cross-correlation array (C 3 ), the method extracts oscillatory processes characterized by a dominant frequency, spatial amplitude-phase distribution, and stability in time. Introduction of an additional dimension of experimental conditions allows characterization of condition-related dynamics of the processes. In this study, we first used C 3 R-MDD to decompose a simulated signal created by superposition of components with known properties. Meaningful solutions were obtained even with a suboptimal number of components in the model. Second, we applied the method to decompose rhythmic processes in ongoing low- and high-frequency EEG records of two subjects and demonstrated good reproducibility of the components obtained with different solutions, two halves of the EEG record, and different experimental sessions. The C 3 R-MDD method is compared with other types of signal decomposition: real-numbers ICA and real-numbers MDD.

Loken LS, Lundblad LC, Elam M, Olausson HW. Tactile direction discrimination and vibration detection in diabetic neuropathy. Acta Neurol Scand: 2010: 121: 302–308. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To evaluate the clinical usefulness of quantitative testing of tactile direction discrimination (TDD) in patients with diabetic neuropathy. Materials and methods – TDD and vibration detection were examined on the dorsum of the feet in 43 patients with type 1 diabetes mellitus and clinical signs and symptoms indicating mild neuropathy, and abnormal results for neurography, temperature detection, or heart rate variability. Test–retest examination of TDD was performed in nine of the patients. Results – Twenty-six of the patients had abnormal TDD (sensitivity 0.60) and 20 had abnormal vibration detection (sensitivity 0.46). Ten of the patients had abnormal TDD and normal vibration detection. Four of the patients had abnormal vibration detection and normal TDD. Test–retest examination of TDD showed a high degree of reproducibility (r = 0.87). Conclusion – TDD seems more useful than vibration detection in examination of diabetic neuropathy.

Objective This study aimed to investigate electrophysiological correlates of initial attention orienting to temporally novel sound in children with autism (CWA). Methods Twenty-one CWA (4–8 years) and 21 age-matched typically developing children (TDC) were presented with pairs of clicks separated by a 0.5 s intra-pair interval, with longer (7–9 s) intervals between pairs. Children watched a silent movie during click presentation. We assessed EEG perturbations and event-related potentials (ERP) in response to sounds of different temporal novelty – first (S1) and second (S2) clicks in the pair. Results In TDC, the early attention-modulated midtemporal N1c wave evoked by S1 and corresponding EEG phase locking and power increase were right-lateralized and were bilaterally higher than those evoked by S2. CWA demonstrated abnormal S1 responses, characterized by reduced N1c amplitude and EEG phase locking in the right midtemporal region, reversed leftward lateralization of the phase locking, and diminished later frontal N2 wave. Their brain responses to S2 were essentially normal. Conclusions The impaired right hemispheric processing of temporary and contextually novel information and suboptimal lateralization of normally right-lateralized attention networks may be important features of autistic disorder. Significance Results of this study contribute to the understanding of autism neurobiology.

While sudden (startling) sensory stimuli are generally thought of as inducing sympathetic excitation, in humans there is a short-lasting inhibition of limb muscle sympathetic nerve activity (MSNA). This study is the first to examine and contrast the effects of acoustic startle and the prepulse inhibition of startle (PPI) on MSNA, blood pressure, heart rate, and eye blinks. Startle elicited a two-component withdrawal of MSNA: an early inhibition of one sympathetic burst followed by a second inhibition. PPI abolished the early, but not the late MSNA inhibition. Prepulse stimuli alone had no early inhibitory effects on MSNA. Early MSNA inhibition, which may occur at latencies of approximately 100 ms, appears to be part of a CNS-generated startle reflex which subserves automatic defensive responses to potential threats. The late MSNA inhibition coincided with the stimulus-induced blood pressure increase and is probably an inhibitory reflex response.

A previous functional magnetic resonance imaging (fMRI) study of an A-beta deafferented subject (GL) showed that stimulation of tactile C afferents (CT) activates insular cortex whereas no activation was seen in somatosensory cortices. Psychophysical studies suggested that CT afferents contribute to affective but not to discriminative aspects of tactile stimulation. We have now examined cortical processing following CT stimulation in a second similarly deafferented subject (IW), as well as revisited the data from GL. The results in IW showed similar activation of posterior insular cortex following CT stimulation as in GL and so strengthen the view that CT afferents underpin emotional aspects of touch. In addition, CT stimulation evoked significant fMRI deactivation in somatosensory cortex in both subjects supporting the notion that CT is not a system for discriminative touch.

Anhidrosis occurs in the majority of multiple system atrophy (MSA) patients but the underlying site of lesion is not well established. We describe three patients with long-standing MSA and anhidrosis diagnosed on the basis of a thermoregulatory sweating test. In biopsies of anhidrotic skin, immunofluorescence analysis disclosed a well preserved postganglionic sudomotor innervation in all three patients supporting the hypothesis of a preganglionic nerve fiber lesion underlying their anhidrosis. Postganglionic sudomotor fiber integrity was also confirmed by normal electrodermal responses in one patient, whereas such responses and microneurographically detectable skin sympathetic nerve activity were absent in the other two MSA patients, suggesting a functional inactivity of structurally intact postganglionic sympathetic skin fibers.

Unusual reactions to auditory stimuli are often observed in autism and may relate to ineffective inhibitory modulation of sensory input (sensory gating). A previous study of P50 sensory gating did not reveal abnormalities in high-functioning school age children [C. Kemner, B. Oranje, M.N. Verbaten, H. van Engeland, Normal P50 gating in children with autism, J. Clin. Psychiatry 63 (2002) 214-217]. Sensory gating deficit may, however, characterize younger children with autism or be a feature of retarded children with autism, reflecting imbalance of neuronal excitation/inhibition in these cohorts. We applied a paired clicks paradigm to study P50 sensory gating, and its relation to IQ and EEG gamma spectral power (as a putative marker of cortical excitability), in young (3-8 years) children with autism (N=21) and age-matched typically developing children (N=21). P50 suppression in response to the second click was normal in high-functioning children with autism, but significantly (p

In addition to A-beta fibres the human hairy skin has unmyelinated (C) fibres responsive to light touch. Previous functional magnetic resonance imaging (fMRI) studies in a subject with a neuronopathy who specifically lacks A-beta afferents indicated that tactile C afferents (CT) activate insular cortex, whereas no response was seen in somatosensory areas 1 and 2. Psychophysical tests suggested that CT afferents give rise to an inconsistent perception of weak and pleasant touch. By examining two neuronopathy subjects as well as control subjects we have now demonstrated that CT stimulation can elicit a sympathetic skin response. Further, the neuronopathy subjects' ability to localize stimuli which activate CT afferents was very poor but above chance level. The findings support the interpretation that the CT system is well suited to underpin affective rather than discriminative functions of tactile sensations.

Study design Measurement of cutaneous sympathetic reflexes and hemodynamic responses to brief electrical stimuli applied above (forehead) and below (abdominal wall) a spinal lesion. Objective To assess the validity of using cutaneous vasoconstriction as a sensitive indicator of increases in sympathetic activity in spinal cord injury. Setting Prince of Wales Medical Research Institute, Australia. Subjects Twenty spinal cord injured subjects with injuries ranging from C3–T11 and nine able-bodied controls. Method Cutaneous electrical stimulation was applied to the forehead and abdominal wall to subjects at unexpected times. Sudomotor and vasomotor responses, as well as continuous arterial pressure, heart rate and respiration were monitored. Results Sudomotor (electrodermal) responses to forehead stimulation were scarce in spinal cord injured subjects, whereas cutaneous vasoconstrictor responses (photoelectric pulse plethysmography) provided a sensitive indicator of any remaining central control of sympathetic function below the lesion. Electrical stimulation applied to the abdominal wall evoked vasoconstrictor reflexes below the lesion in the majority of spinal cord injured subjects, whereas only a limited number of electrodermal responses were observed. That these cutaneous vasoconstrictor responses could reflect parallel increases in muscle and splanchnic vasoconstrictor activity was indicated by the increases in blood pressure; patients lacking vasoconstrictor responses rarely showed stimulus-induced blood pressure increases. Conclusion Our findings show that skin vasomotor responses to somatosensory stimulation provide a more sensitive tool than electrodermal responses for evaluation of sympathetic function below a spinal cord lesion. Statement of ethics We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research, and all experiments were conducted with the understanding and consent of each subject.

There is a great need for novel diagnostics and treatment tools in today's healthcare. In this paper we describe our development and progress in novel microwave based diagnostics and treatment applications. The target applications are stroke diagnostics, breast cancer detection and microwave hyperthermia.

The interaction between sympathetic vasoconstrictor activity to muscles [muscle sympathetic nerve activity (MSNA), burst frequency (BF) and burst incidence (BI)] and different stress and somatosensory stimuli is still unclear. Eighteen healthy men (median age 28 years) underwent microneurography recordings from the peroneal nerve. MSNA was recorded during heat pain (HP) and cold pain (CP) alone as well as combined with different stress tasks (mental arithmetic, singing, giving a speech). An additional nine healthy men (median age 26 years) underwent the stimulation protocol with an additional control task (thermal pain combined with listening to music) to evaluate possible attentional confounders. MSNA was significantly increased by CP and HP. CP-evoked responses were smaller. The diastolic blood pressure followed the time course of MSNA while heart rate remained unchanged. The mental stress tasks further increased MSNA and were sufficient to reduce pain while the control task had no effect. MSNA activity correlated negatively with pain intensity and positively with analgesia. High blood pressure values were associated with lower pain intensity. Our study indicates an impact of central sympathetic drive on pain and pain control.

The present study aimed to evaluate adipose tissue blood flow (ATBF) by means of laser-Doppler flowmetry (LDF) in humans. Lower body negative pressure (LBNP) and straining known to affect epidermal blood flow through the autonomic nervous system were performed in 11 lean and 11 obese female volunteers. ATBF changes were compared between both groups and also discriminated from skin blood flow (SBF) responses of the immediate vicinity. Additionally, LDF measurements were compared with flow measurements using 133xenon washout in 10 lean subjects during whole body cooling. LDF estimations of SBF and ATBF showed a positive correlation to 133Xe during cooling. SBF and ATBF were reduced to the same extent in both lean and obese subjects during LBNP. Straining induced divergent changes in SBF and ATBF: initially SBF decreased while ATBF increased, but toward the end of straining SBF increased above baseline and ATBF returned down to baseline level. Those changes were similar in both weight groups. Interestingly, only in obese subjects, both LBNP and straining were followed by ATBF augmentation, while SBF levels remained stable. In conclusion, LDF compares with 133Xe washout in monitoring ATBF during tonic perfusion changes. Its strength, however, lies in the detection of rapid flow alterations within the subcutaneous tissue, allowing the evaluation of reflex responses of the subcutaneous microcirculation. Interestingly, those rapid changes in SBF and ATBF can be both concordant and discordant. With regard to ATBF, vasoconstrictor components of the reflex responses were similar in lean and obese subjects, whereas vasodilatory responses were more pronounced in obese volunteers.

Objective To study behavioral correlates of theta oscillations in infants and preschool children. Methods EEG was recorded during baseline (visual attention) and two test conditions—exploration of toys and attention to ‘social’ stimulation. Age specific frequency boundaries of theta and mu rhythms were assessed using narrow bin analysis of EEG spectra. Results Theta spectral power increased whereas mu power decreased under test conditions in both age groups. In preschoolers theta rhythm increased predominantly over anterior regions during exploratory behavior and over posterior regions during attention to social stimulation. Theta frequency range changed with age from 3.6 to 5.6 Hz in infants to 4–8 Hz in children, and mu range from 6.4–8.4 Hz to 8.4–10.4 Hz. Conclusions In early life, theta oscillations are strongly related to behavioral states with substantial attentional and emotional load. The scalp distribution of theta spectral power depends on age and behavioral condition and may reflect engagement of different brain networks in control of behavior. Significance The findings contribute to the scanty knowledge about the developmental course of theta rhythm. Data on behavioral correlates of theta rhythm in early life may improve our understanding of cognitive and mental processes in healthy and neuropsychiatrically diseased children.

Continuous intracisternal infusion of bupivacaine for the management of intractable pain of the head and neck is effective in controlling pain in this patient group. With the catheter tip being located at the height of the C1 vertebral body, autonomic regulatory information may also be influenced by the infusion of bupivacaine. By combining direct sampling of cerebrospinal fluid (CSF), via a percutaneously placed catheter in the cisterna magna, with a noradrenaline and adrenaline isotope dilution method for examining sympathetic and adrenal medullary activity, we were able to quantify the release of brain neurotransmitters and examine efferent sympathetic nervous outflow in patients following intracisternal administration of bupivacaine. Despite severe pain, sympathetic and adrenal medullary activities were well within normal range (4.2 +/- 0.6 and 0.7 +/- 0.2 nmol min(-1), respectively, mean +/-S.E.M.). Intracisternal bupivacaine administration caused an almost instantaneous elevation in mean arterial blood pressure, increasing by 17 +/- 7 mmHg after 10 min (P < 0.01). Heart rate increased in parallel (17 +/- 5 beats min(-1)), and these changes coincided with an increase in sympathetic nervous activity, peaking with an approximately 50% increase over resting level 10 min after injection (P < 0.01). CSF levels of GABA were reduced following bupivacaine (P < 0.05). CSF catecholamines and serotonin, and EEG, remained unaffected. These results show that acutely administered bupivacaine in the cisterna magna of chronic pain sufferers leads to an activation of the sympathetic nervous system. The results suggest that the haemodynamic consequences occur as a result of interference with the neuronal circuitry in the brainstem. Although these effects are transient, they warrant caution at the induction of intracisternal local anaesthesia.

It is not known whether bilateral stimulation of the subthalamic nucleus, performed to improve skeletal motor control in advanced Parkinson's disease, also affects central autonomic regulation of cardiovascular motor function. Furthermore, reduced treatment with dopaminergic and other drugs after bilateral stimulation of the subthalamic nucleus could affect cardiovascular autonomic reflexes and/or other factors controlling blood pressure level. The primary aim of this study was to investigate putative effects of bilateral stimulation of the subthalamic nucleus on the autonomic nervous system, using respiratory heart rate variability and blood pressure responses to tilt as indices. Baseline autonomic tests were performed in 19 patients with Parkinson's disease and 10 matched healthy subjects. Patients were divided in two groups and re-investigated after 1 year of optimized pharmacological treatment (n = 8) or 1 year of bilateral subthalamic nucleus stimulation (n = 11). Both skeletal motor dysfunction and dopaminergic drug treatment were significantly reduced after 1 year of bilateral subthalamic nucleus stimulation. However, heart rate variability as well as blood pressure during tilt was reduced compared to baseline to a similar extent in both patient groups. The number of individual patients showing pathological autonomic test results at 1-year follow-up increased only in the subthalamic nucleus stimulation group. Despite reduced pharmacological treatment and reduced motor disability, bilateral subthalamic nucleus stimulation does not improve cardiovascular autonomic reflex function or protect against development of cardiovascular autonomic failure in Parkinson's disease. Preoperative cardiovascular autonomic reflex dysfunction, conversely, does not exclude an excellent stimulation effect. © 2005 Movement Disorder Society

In clinical practise, the notion that some complex regional pain syndromes (CRPS) are associated with sympathetic facilitation of nociceptive transmission is widespread. However, physiological increases in cutaneous sympathetic nerve activity have not been found to influence the firing properties of cutaneous polymodal nociceptive (high-threshold mechano-heat sensitive) fibers in human subjects. Whether the same applies to low-threshold cutaneous mechanoreceptors is not known. Such an effect could be relevant for sympathetic facilitation of nociception, given that tactile afferents are implicated in the allodynia associated with CRPS. This issue was addressed by recording the responses of single cutaneous mechanoreceptors in the glabrous skin of the finger pads to constant mechanical stimuli, at rest and during physiological increases in cutaneous sympathetic activity produced by arousal stimuli. Unitary recordings were made from 17 rapidly adapting (15 FAI and 2 FAII) and 20 slowly adapting (9 SAI and 11 SAII) afferents located in the finger pads via tungsten microelectrodes inserted percutaneously into the median nerve at the wrist in nine subjects. A servomotor applied 1 s constant-displacement ramp-and-hold indentations to the receptor-bearing digit every 3 s. Displacement and compression force were recorded. Blood flow in the finger pad and sweating in the palm were measured contralaterally. Increases in cutaneous sympathetic outflow caused only modest changes in the spontaneous and compression-evoked firing of tactile afferents. These changes were usually (for 26/37 afferents) related to the associated decreases in skin blood flow. The latency from the start of the ramp stimulus to the onset of firing was inversely correlated to flow (i.e. unit response was delayed during vasoconstriction) for 11/31 units (7/15 FAI, 1/2 FAII, 2/9 SAI, 1/5 SAII), whereas no units showed a positive correlation. Compression-evoked firing rates were positively correlated to flow (i.e. vasoconstriction reduced firing rates) for 14/31 units (2/15 FAI, 1/2 FAII, 7/9 SAI, 4/5 SAII), whereas no units showed a negative correlation. 10/11 SAII afferents exhibited spontaneous background firing, which increased for 4 and decreased for 4 in response to arousal stimuli, presumably reflecting their sensitivity to changes in skin stretch associated with sympathetically mediated reductions in blood volume in the finger pad. Two afferents showed no change, but nor was there significant vasoconstriction in these recordings. Thus, arousal stimuli reduced rather than augmented tactile afferent firing. The close relation to blood flow for all types of afferents, and the different responses among SAII afferents, suggest that sympathetically mediated changes in afferent firing properties are indirect, i.e. secondary to changes in the mechanoreceptors' tissue environment rather than to a direct sympathetic effect on the endings.

Essential hypertension (EH) has been associated with abnormal sympathetic outflow particularly during mental stress. However data were unclear because of associated pharmacological drugs often taken by patients. The aim of this study is to ascertain abnormalities of sympathetic during mental stress in patients with untreated EH. We studied 7 untreated patients with established criteria for EH, and 10 sex and age matched healthy subjects. Patients with EH underwent an extensive laboratory screening excluding secondary causes of hypertension. Subjects underwent sitting microneurographic recording of muscle sympathetic activity (MSNA) from peroneal nerve, heart rate (HR) and blood pressure (BP) during resting state and mental stress (3-min of paced auditory serial arithmetic test -PASAT) and a cold test (two minutes immersion of a hand in ice water). The pharmacological treatment for EH was usually started after the microneurographby evaluation. As expected EH patients showed increased resting BP compared to controls but MSNA was not significantly increased although showed a tendency toward the increase. During mental stress BP was increased compared to controls but HR and MSNA did not show a significant difference. Sympathetic and cardiovascular parameters did not differ during cold test. Our data confirmed the higher BP reactivity in EH patients but this was not due to increased MSNA. However these data are preliminary and a larger cohort of patients must be recruited before drawing a definite conclusion.