Loss in Executive Functioning Best Explains Changes in Pain Responsiveness in Patients with Dementia-Related Cognitive Decline.

There is ample evidence that dementia changes the processing of pain. However, it is not known whether this change in pain processing is related to the general decline in cognitive functioning or whether it may be related to specific domains of cognitive functioning. With the present study we tried to answer this question. We assessed different cognitive domains (orientation, memory, abstract thinking/executive function, aphasia and apraxia, and information processing speed) in 70 older patients with cognitive impairment (mild cognitive impairment up to moderate degrees of dementia). Pain responsiveness was assessed by measuring the nociceptive flexion reflex (NFR) threshold and facial responses to noxious electrical stimulation. Using regression analyses, we assessed which domain of cognitive functioning best predicted variance in pain responsiveness. Variance in pain responsiveness (NFR and facial expressions) was best explained by those items assessing executive functioning even when controlling for overall cognitive performance and memory functioning. The close association between executive functioning and pain responsiveness suggests that dementia-related neurodegeneration in prefrontal areas might result not only in reduced executive functioning but also in a loss of pain inhibitory potency, rendering the patient more vulnerable to pain. Our findings also suggest that pain assessment in dementia should be regularly completed by tests of cognitive functions.

The effects of oral contraceptives on detection and pain thresholds as well as headache intensity during menstrual cycle in migraine.

BACKGROUND: Clinically, oral contraceptives (OC) can influence pain in both migraine headache and temporomandibular pain disorders. Estrogen as an ingredient of OC might be a responsible factor for these observations. We conducted the present study to test whether OC are able to alter the severity of headache attacks as well as the detection or pain thresholds over the course of the menstrual cycle in patients with migraine. METHODS: Thirteen healthy and regularly menstruating women and 26 migraineurs (13 using OC and 13 not using OC) were studied on the days 1, 4, 14, and 22 of their menstrual cycle. In all participants, saliva was collected first for determination of estrogen on each study day. Then, detection thresholds (warmth, cold, electrical current) and pain thresholds (cold, heat, pressure, electrical current) were assessed. Migraineurs were asked for headache attacks occurring in a period of 24 hours before testing and to estimate pain intensity on a verbal rating scale. RESULTS: On day 4 of the menstrual cycle, migraineurs using OC suffered significantly more from severe migraine attacks than migraineurs not taking OC. With respect to detection and pain thresholds, no effects of OC could be observed as concerning the differences between migraineurs with or without OC medication. On day 22, the severity of migraine headache was significantly related with the pain thresholds for pressure and electrical current, suggesting paradoxically more severe headache attacks in patients presenting with higher pain thresholds. Healthy volunteers disclosed higher salivary estrogen levels than migraineurs and migraineurs not using OC higher concentrations than migraineurs using OC throughout the menstrual cycle. CONCLUSIONS: In this study, the use of OC intensified migraine (however only at the end of menstruation) however had no influence on detection and pain thresholds in migraineurs. Possible reasons for this dissociation will be discussed.

Health-related quality of life in ALS, myasthenia gravis and facioscapulohumeral muscular dystrophy.

Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (n = 37), FSHD (n = 17) or MG (n = 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG.

Socioeconomic burden of amyotrophic lateral sclerosis, myasthenia gravis and facioscapulohumeral muscular dystrophy.

Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (n = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a "bottom-up" approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090-47,970) per patient in ALS, EUR 26,240 (95% CI 17,770-37,940) in FSHD and EUR 14,950 (95% CI 10,470-21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary.

Effects of age and mild cognitive impairment on the pain response system.

BACKGROUND: Both age and dementia have been shown to have an effect on nociception and pain processing. The question arises whether mild cognitive impairment (MCI), which is thought to be a transitional stage between normal ageing and dementia, is also associated with alterations in pain processing. OBJECTIVE: The aim of the present study was to answer this question by investigating the impact of age and MCI on the pain response system. METHODS: Forty young subjects, 45 cognitively unimpaired elderly subjects and 42 subjects with MCI were investigated by use of an experimental multi-method approach. The subjects were tested for their subjective (pain ratings), motor (RIII reflex), facial (Facial Action Coding System) and their autonomic (sympathetic skin response and evoked heart rate response) responses to noxious electrical stimulation of the nervus suralis. RESULTS: We found significant group differences in the autonomic responses to noxious stimulation. The sympathetic skin response amplitude was significantly reduced in the cognitively unimpaired elderly subjects compared to younger subjects and to an even greater degree in subjects with MCI. The evoked heart rate response was reduced to a similar degree in both groups of aged subjects. Regression analyses within the two groups of the elderly subjects revealed that age and, in the MCI group, cognitive status were significant predictors of the decrease in autonomic responsiveness to noxious stimulation. Except for the autonomic parameters, no other pain parameter differed between the three groups. CONCLUSION: The pain response system appeared to be quite unaltered in MCI patients compared to cognitively unimpaired individuals of the same age. Only the sympathetic responsiveness qualified as an indicator of early aging effects as well as of pathophysiology associated with MCI, which both seemed to affect the pain system independently from each other.

Serum concentrations of s100b and NSE in migraine.

BACKGROUND: The protein s100b indicates astrocytal damage as well as dysfunction of the blood-brain barrier (BBB), and neuron-specific enolase (NSE) is regarded as a marker for neuronal cell loss. Recently, s100b was shown to be a potentially useful marker for migraine in children. In this study, we investigated the levels of s100b and NSE in adult migraineurs during and after migraine attacks in order to gain some more insight into migraine pathophysiology. METHODS: Serum levels of s100b and NSE were measured in 21 migraineurs and compared with 21 healthy subjects matched by sex and age. In migraineurs, blood samples were taken during a migraine attack and following a pain-free period of 2-4 days. RESULTS: During migraine attacks elevated s100b levels could be observed. Maximal concentrations were detected in the pain-free period after 2-4 days. Regarding NSE, serum levels were decreased slightly during and after migraine bouts. CONCLUSIONS: Our data suggest a prolonged disruption of BBB during and after migraine attacks. Other possible explanations concerning the detected serum levels of s100b and NSE will be discussed; however, neuronal cell death can be ruled out by the decreased serum concentrations of NSE. With regard to the results of the present study, further research is necessary to evaluate the role of s100b and NSE in migraine.

Effects of ageing on spinal motor and autonomic pain responses.

The course of ageing leads to various changes in the nervous system, which can affect pain processing in the elderly. However, the affection of different components of the nociceptive system remains unclear. To investigate basic nocifensive responses, we compared age-related changes of autonomic and motor reflex responses to noxious electrical stimulation. In 39 healthy young subjects (mean +/- S.D.; 24.1 +/- 3.3 years) and 52 healthy elderly subjects (mean +/- S.D.; 71.9 +/- 5.3 years) the nociceptive flexion reflex (NFR) and the sympathetic skin response (SSR) were determined using noxious electrical stimulation of the sural nerve. Verbal pain ratings were assessed in addition. No ageing effects on the NFR and on verbal pain ratings were found, whereas the SSR amplitude declined significantly with ageing. Since both SSR and NFR share comparable primary afferent pathways and the motor as well as the subjective responses to noxious stimulation were preserved, our data seem to suggest that central or peripheral efferent sympathetic functions are altered by age.

Impact of age on the facial expression of pain.

OBJECTIVE: Old age has traditionally been viewed as being associated with a decline in emotional expressivity. Interestingly, empirical evidence based on analyses of facial expressions contradicts this traditionally view and points to absence of (or only very slight) age-related changes in emotional expressivity. However, this research on emotional expressivity in older persons has neglected one important emotionally colored state-expression of pain. In order to close this gap, we aimed to investigate the influence of age on the facial expression of pain. METHODS: Forty young (mean age, 24.1 years) and 61 elderly (mean age, 72.3 years) subjects were investigated for their facial (Facial Action Coding System) and subjective responses to noxious mechanical and electrical stimuli of various intensities. RESULTS: Young and elderly subjects did not differ with respect to the frequency of facial responses during noxious mechanical and electrical stimulations. Moreover, age had no significant impact on the pain specificity of these facial responses. Furthermore, we found no significant age differences in self-report ratings of pressure and electrical pain, thus indicating that both age groups experienced comparable amounts of pain intensities. CONCLUSION: These findings suggest that the facial expression of pain, like facial expressions of other affective states, remains unchanged in older persons. Consequently, elderly individuals seem to communicate pain through their facial expression as validly as younger individuals do.

The facial expression of pain in patients with dementia.

The facial expression of pain has emerged as an important pain indicator in demented patients, who have difficulties in providing self-report ratings. In a few clinical studies an increase of facial responses to pain was observed in demented patients compared to healthy controls. However, it had to be shown that this increase can be verified when using experimental methods, which also allows for testing whether the facial responses in demented patients are still typical for pain. We investigated facial responses in 42 demented patients and 54 aged-matched healthy controls to mechanically induced pain of various intensities. The face of the subject was videotaped during pressure stimulation and was later analysed using the Facial Action Coding System. Besides facial responses we also assessed self-report ratings. Comparable to previous findings, we found that facial responses to noxious stimulation were significantly increased in demented patients compared to healthy controls. This increase was mainly due to an increase of pain-indicative facial responses in demented patients. Moreover, facial responses were closely related to the intensity of stimulation, especially in demented patients. Regarding self-report ratings, we found no significant group differences; however, the capacity to provide these self-report ratings was diminished in demented patients. The preserved pain typicalness of facial responses to noxious stimulation suggests that pain is reflected as validly in the facial responses of demented patients as it is in healthy individuals. Therefore, the facial expression of pain has the potential to serve as an alternative pain assessment tool in demented patients, even in patients who are verbally compromised.

High-frequency rTMS of the motor cortex does not influence the nociceptive flexion reflex but increases the unpleasantness of electrically induced pain.

The aim of this study was to investigate whether a 10-Hz repetitive transcranial magnetic stimulation (rTMS) applied over the motor cortex, using a stimulus paradigm employed for pain control in chronic pain, affects acute electrically induced pain. We investigated whether rTMS modulates the nociceptive flexion reflex (NFR) in addition to subjective pain perception. Pain threshold, NFR threshold, supra-threshold NFR response, and the concomitant pain intensity and pain unpleasantness visual analogue scale (VAS) scores were compared before and after 20 min of rTMS. Effects of 20 trains of 5 s' duration (55 s intertrain interval) of 10-Hz rTMS at 80% of the resting motor threshold (RMT) applied over the dominant motor cortex were compared to sham rTMS in 12 healthy volunteers. Supra-threshold NFR stimulation significantly increased pain unpleasantness VAS scores with real rTMS compared to sham rTMS (F(1,10)=6.91; P=0.025). There was no significant effect of 10-Hz rTMS on the subjective pain threshold or on the NFR, neither at threshold nor at supra-threshold noxious stimulation. The rTMS paradigm used to control chronic pain is not suitable for controlling Adelta fiber-mediated acute experimentally induced pain since the effects on pain perception were only marginal, with an increase in the VAS unpleasantness scores but with no effect on the NFR. The increased activity of cortico-thalamic projections might modulate the perception of Adelta fiber-mediated pain within the lateral pain pathway. The type of fiber that is stimulated and neuroplastic changes in chronic pain and are thought to be critical for rTMS to have an effect.

Modulation of electrically induced pain by paired pulse transcranial magnetic stimulation of the medial frontal cortex.

OBJECTIVE: Aim of this study was to investigate whether paired pulse transcranial magnetic stimulation (ppTMS) applied over the medial frontal cortex (MFC) affects acute Adelta fiber-mediated electrically induced pain. In addition, we investigated whether this effect depends on the time course of the stimulation, on the noxious stimulus intensity or on the ppTMS intensity. METHODS: For painful stimulation, the electrical stimulus for the nociceptive flexion reflex (NFR) was used. PpTMS (ISI: 50 ms) was applied over the medial frontal cortex at different intervals ranging from 0 to 1,000 ms following the previous elicited NFR in 10 healthy volunteers. Three sequences at 3 different NFR stimulus intensities (at NFR threshold, 1.3 x and 1.6 x NFR threshold) with a ppTMS stimulus intensity at 1.2 x resting motor threshold (RMT) and one sequence with elevated ppTMS at 1.6 x RMT stimulus intensity were performed. Pain intensity and pain unpleasantness were assessed by visual analogue scales. RESULTS: Pain ratings differed in dependence of the interstimulus interval between NFR and ppTMS. Post-hoc t-tests revealed an increased verbal pain report within interstimulus intervals from 25 to 75 ms at NFR threshold as well as for 25 ms at 1.3 x NFR threshold when ppTMS was applied at 1.2 x RMT and from 0 to 75 ms at 1.6 x NFR threshold when ppTMS was applied at 1.6 x RMT. CONCLUSIONS: The present data suggest that ppTMS over MFC-applied in a certain time window-can enhance pain perception of acute Adelta fiber-mediated electrically induced pain. We hypothesize that the increase of pain is due to interference between ppTMS and the incoming nociceptive input. Further pain processing might be modulated by direct effects on MFC or indirect effects on anterior cingulate cortex (ACC) or spinal nociception. SIGNIFICANCE: Brain areas involved in cognitive and emotional adaptation to pain can be used, in place of primary motor areas, as cortical targets in TMS trials of experimental or ongoing pain.

Sex differences in nociceptive withdrawal reflex and pain perception.

Experimentally induced pain often reveals sex differences, with higher pain sensitivity in females. The degree of differences has been shown to depend on the stimulation and assessment methods. Since sex differences in pain develop anywhere along the physiological and psychological components of the nociceptive system, we intended to compare the nociceptive flexion reflex (NFR) as a more physiological (spinal) aspect of pain procession to the verbal pain report of intensity and unpleasantness as the more psychological (cortical) aspect. Twenty female and twenty male healthy university students were investigated by use of nociceptive flexion reflex threshold (staircase method) after electrical stimulation of the N. suralis. Furthermore, we assessed supra-threshold reflex responses (latency, amplitude and area) by applying 10 stimuli 5 mA above reflex threshold. Following each stimulation, the subjects provided pain ratings of intensity and unpleasantness on a visual analogue scale. Females exhibited marked lower nociceptive flexion reflex thresholds than males, while the supra-threshold reflex response tailored to the individual reflex threshold did not show any significant differences. The verbal pain ratings, corrected for NFR threshold, were not found to differ significantly. The large sex differences in nociception that were present in NFR threshold but not in the pain ratings corroborate the hypothesis that spinal processes contribute substantially to sex differences in pain procession.

On the relationship between self-report and facial expression of pain.

UNLABELLED: Several investigators have reported weak or no associations between self-report and facial expression of pain, concluding that both parameters appear to be unrelated. However, studies so far have only focused on an overall association, not considering psychophysical relationships between stimulus intensities and pain responses while computing correlations. In the present study these psychophysical relationships, between stimulus intensity on the one hand and response magnitudes (of self-report and facial expression) on the other hand, were described in terms of intercept and slope. Correlation analyses were conducted between intercept and slope parameters of self-report and facial expression of pain. Forty young, pain-free individuals were investigated for their responses to mechanically and electrically induced pain. Self-report was assessed by Visual Analog Scales. Facial expression was examined by using the Facial Action Coding System. There were significant correlations between the linear slopes of the psychophysical functions of self-report and facial expression in pressure pain. Neither the intercepts nor overall mean responses in the 2 pain-signaling systems were significantly correlated. These findings suggest that the facial expression of pain appears to mirror self-report ratings, when their increases over a range of increasing stimulus intensities are considered in parallel. PERSPECTIVE: In future studies, our psycho-physically derived observation that incremental changes in facial expression during developing pain are more characteristic for individuals than static levels needs further corroboration.

Dysfunction of the pupillary light reflex following migraine headache.

Using pupillometry and sympathetic skin responses we compared the changes in local and systemic autonomic function within one week of a migraine attack. We investigated whether the measurement of the pupillary light reflex provides further information on the pathophysiology of migraine.Forty-two migraine patients and forty-two healthy age-matched controls were included. The parameters that were measured were the amplitude of the pupillary light reflex, the pupil size at the beginning of the measurement, the latency, the velocity of constriction and the velocity at the end of the dilatation. The average pupil size was 6.43 mm in the migraine group and 6.7 mm in the control group (p < 0.01). Reduced velocity of constriction and smaller amplitude of constriction in migraine patients within two days of an attack were signs of a parasympathetic dysfunction (p < 0.05). The sympathetic skin response did not differ significantly between migraine sufferers and controls. These findings indicate that both parasympathetic and sympathetic nerves supplying the eye are involved in migraine headache presumably due to effects on the pericarotid sympathetic fibers and involvement of trigeminal-parasympathetic reflexes.

Responsiveness of slowly conducting articular afferents to bradykinin: effects of an experimental arthritis.

Bradykinin (BK), an important inflammatory mediator and potent algogenic substance, is supposed to contribute to the generation of arthritic hyperalgesia and pain. The present study was undertaken to examine if an experimental kaolin/carrageenan arthritis sensitizes articular afferents to BK in the cat's knee joint using two different approaches. First, the proportion of afferent units activated by BK was assessed in fully inflamed joints and compared with corresponding data of normal knee joints. BK (injected i.a. as a bolus close to the joint) at the dose of 2.6 micrograms activated 60% of the units of groups II-IV in the inflamed state, compared to 71% in normal joints. The proportions of low- and high-threshold afferents activated by BK were similar, but more spontaneously active units than units without ongoing activity responded to BK both in inflamed and normal knee joints. Second, the responsiveness of individual afferent units to BK was examined during the development of inflammation. Units not activated by BK remained unresponsive after inflammation. From 11 units activated by BK, 3 units lost their responsiveness and in 4 other units the response to BK was reduced within 2-6 h after the onset of inflammation. Only in 4 units was the BK response increased in the inflamed joint. It is concluded that desensitizing rather than sensitizing processes are involved to change the response behavior of articular afferents to BK during acute experimental inflammation.