Thomas Sycha

On the origin of respiratory artifacts in BOLD-EPI of the human brain

BOLD-based functional MRI (fMRI) can be used to explicitly measure hemodynamic aspects and functions of human neuro-physiology. As fMRI measures changes in regional cerebral blood flow and volume as well as blood oxygenation, rather than neuronal brain activity directly, other processes that may change the above parameters have to be examined closely to assess sensitivity and specificity of fMRI results. Physiological processes that can cause artifacts include cardiac action, breathing and vasomotion. Although there has been substantial research on physiological artifacts and appropriate compensation methods, controversy still remains on the mechanisms that cause the fMRI signal fluctuations. Respiratory-correlated fluctuations may either be induced by changes of the magnetic field homogeneity due to moving organs, intra-thoracic pressure differences, respiration-dependent vasodilation or oxygenation differences. The aim of this study was to characterize the impact of different breathing patterns by varying respiration frequency and/or tidal volume on EPI time courses of the resting human brain. The amount of respiration-related oscillations during three respiration patterns was quantified, and statistically significant differences were obtained in white matter only: p < 0.03 between 6 vs. 12 ml/kg body weight end tidal volume at a respiration frequency of 15/min, p < 0.03 between 12 vs. 6 ml/kg body weight and 15 vs. 10 respiration cycles/min. There was no significant difference between 15 vs. 10 respiration cycles/min at an end tidal volume of 6 ml/kg body weight (p = 0.917). In addition, the respiration-affected brain regions were very similar with EPI readout in the a-p and l-r direction. Based on our results and published literature we hypothesize that venous oxygenation oscillations due to changing intra-thoracic pressure represent a major factor for respiration-related signal fluctuations and increase significantly with increasing end tidal volume in white matter only.

The sunburn pain model: the stability of primary and secondary hyperalgesia over 10 hours in a crossover setting.

It was our aim to study the within-day stability and between-day repeatability of ultraviolet B (UVB) light-induced primary and secondary hyperalgesia over 10 h. Twenty hours after UVB irradiation of a skin spot (r = 2.5 cm) on the upper leg of 8 healthy volunteers the areas of secondary hyperalgesia to pinprick and pain tolerance thresholds to heat (HPTT) and electrical stimuli (5 and 250 Hz, electrical pain tolerance thresholds [EPTT]) were assessed. Measurements were repeated for 10 h at 2-h intervals and in 2 different sessions. Large areas of secondary hyperalgesia to pin prick were observed (5995 mm2; sd, 1645). Primary hyperalgesia was evidenced by significant decreases of HPTT (mean difference, 6.5°C; 95% confidence interval, 6.1–6.8; P < 0.001) and EPTT at 250 Hz (mean difference, 0.45 mA; 95% confidence interval, 0.13–0.78; P < 0.05) compared to normal skin. There was no trend within one session of either primary (P = 0.14 for HPTT) or secondary hyperalgesia (P = 0.95) and no difference between the two sessions (primary hyperalgesia, P = 0.28; secondary hyperalgesia, P = 0.07). The sunburn pain model provides a long time course of stable hyperalgesia with a high within-day stability and between-day repeatability for primary and secondary hyperalgesia

Botulinum toxin in the treatment of Raynaud's phenomenon: a pilot study.

Sir, Raynaud’s phenomenon (RP) is defined as an episodic digital asphyxia caused by arterial insufficiency. Although RP aetiology remains incompletely understood, abnormal central sympathetic control via vascular innervation has been discussed. This concept is supported by the clinical observation that emotional stress is a trigger in up to a third of vasospastic attacks in primary RP [1], and studies demonstrating the beneficial effects of sympatholytic drugs [2] and the use of sympathectomy [3]. The use of Botulinum toxin A (BTX-A) is an established treatment for focal dystonic and spastic syndromes. Additionally, clear beneficial effects of BTX-A have been shown in various types of focal hyperhidrosis [4]. In general, the effect of BTX-A is based on the anticholinergic effects at the neuromuscular endplate and the eccrine sweat glands. Recently, differential effects of BTX-A on vasoconstriction and vasodilation have been studied in vitro [5]. Botulinum toxin type A reduced the amplitude of arterial isometric contractions in response to repeated electrical stimulation of sympathetic axons by 70–80%. Furthermore, the presynaptic cholinergic inhibition of neurogenic relaxation was abolished by BTX-A. As a pilot to a randomized, double-blinded, placebocontrolled trial we treated primary and secondary RP patients with intradigital BTX-A injections. The clinical response was measured using a visual analogue scale (VAS range 0–10) for clinical symptoms (pain, stiffness, numbness, cold sensation), and the superficial skin blood flow was assessed with laser Doppler interferometry (LDI). A 19-year-old female patient with a 2-year history of MCTD refractory to any other treatment was randomly injected on fingers 2 and 5 of the right and on fingers 2 and 3 of the left hand at six injection sites per finger (1 MU per site of BOTOX ® , Allergen Pharmaceuticals Ltd, Westport, Ireland). After 1 week the patient reported relief from pain (VAS pre: 8, post: 5), stiffness (VAS pre: 7, post: 4) and numbness (VAS pre: 6, post: 4). After 6 weeks the LDI scan showed a significant difference between the treated and untreated fingers (102·2 ± 12·1 aU vs. 718 ± 5·6 aU, P < 0·004, Fig. 1). After 9 weeks the patient also reported an improvement in the noninjected fingers.

Rofecoxib attenuates both primary and secondary inflammatory hyperalgesia: a randomized, double blinded, placebo controlled crossover trial in the UV-B pain model

The analysis of drugs influence on peripheral and central sensitisation can give useful information about its mode of action and can lead to more efficacy in the treatment of pain. Peripheral inflammation is associated with peripheral expression and up‐regulation of cyclooxygenase 2 (COX‐2) in the CNS. The relative contribution of COX‐2 mediated central sensitisation may be prominent under inflammatory conditions. In this randomized, double blinded, placebo controlled cross‐over trial the effects of multidoses of the COX‐2 selective inhibitor rofecoxib on primary and secondary hyperalgesia were evaluated in the UVB pain model. Twenty‐four hours after local UVB irradiation at the upper leg of 42 healthy volunteers heat pain perception (HPPT) and heat pain tolerance thresholds (HPTT) were assessed within the inflammation. The area of secondary hyperalgesia was determined by pin prick test. Subjects received oral rofecoxib 50, 250, 500 mg or placebo. Pain testing was repeated after 3 and 6 h. Compared to placebo, rofecoxib significantly increased HPPT (1.55 and 1.08 °C, P<0.0001 and P=0.0333), HPTT (1.74 and 1.58 °C, P<0.0001 and P<0.0001), and reduced the mean area of secondary hyperalgesia by 15.6% (P=0.007) and 16.8% (P<0.001) after 3 and 6 h. No significant difference between the three dosage groups was observed. These data confirm peripheral effects of rofecoxib in a human inflammatory UV‐B pain model and provide circumstantial evidence that even a standard clinical dose of rofecoxib reduces central hyperalgesia in inflammatory pain. We confirm that the effect of single oral dose of rofecoxib plateaus at 50 mg.

A Lack of Antinociceptive or Antiinflammatory Effect of Botulinum Toxin A in an Inflammatory Human Pain Model

Several in vitro and in vivo investigations have shown that botulinum toxin A (BoNT/A) can inhibit the release of substance P and excitatory amino acids. Recently, a marked antinociceptive effect of BoNT/A and inhibition of glutamate release was observed in an animal pain model with inflammatory sensitization. In the present study, we tested the antiinflammatory and antihyperalgetic effect of BoNT/A in a well-characterized human inflammatory pain model. Using a randomized, double-blind, paired study design, we compared the effects of 100 mouse units of BoNT/A versus pure saline. Thermal and mechanical pain testings and superficial skin blood flow measurements were performed at baseline, at 48 h (in normal skin), and at 72 h (in inflamed skin) thereafter. Ultraviolet B irradiation resulted in a local inflammation with significant primary and secondary hyperalgesia. However, despite the evidence of efficacy on sudomotor function, BoNT/A had no effect on pain measures in either normal or inflamed skin. Signs of inflammation and primary and secondary hyperalgesia were found to be unaffected by BoNT. We have confirmed that BoNT/A has no direct effect on acute, noninflammatory pain. Furthermore, despite highly promising data from animal research, we have not observed antiinflammatory or antinociceptive effects of BoNT/A in human inflammatory pain.

Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature.

Abstract.Background:Botulinum neurotoxin (BoNT) is used to treat various neurological disorders associated with pathologically increased muscle tone. Botulinum toxin inhibits the release of the neurotransmitter acetylcholine at the neuromuscular junction thereby inhibiting striatal muscle contractions. Besides the reduction in muscle tone BoNT tends to reduce pain in pain syndromes associated with muscle spasm. In addition, BoNT has been proposed as an analgesic, suggesting alternative non-cholinergic mechanisms of action.Surprisingly, BoNT was reported as a potential treatment for tensiontype headache and migraine—both primary headache syndromes without an apparent muscular component—however, varying responses to BoNT have been found, overall without sufficient evidence for a general treatment.In this systematic review we set out to clarify the efficacy and safety of BoNT in the treatment of rare head and neck pain syndromes (e. g. cervicogenic headache, chronic paroxysmal hemicrania, cluster headache, trigeminal neuralgia, temporomandibular disorders, cervical dystonia and whiplash injuries).Objectives:To assess the analgesic efficacy and safety of botulinum toxins versus other medicines, placebo or no treatment in rare head and neck pain syndromes.Search strategy:We searched the bibliographic databases MEDLINE, EMBASE and PASCAL Biomed to May 2003. We also reviewed the reference lists from identified articles including reviews and meta-analyses of treatment studies. Furthermore we searched booklets of scientific congresses in the field of neurology for potentially relevant studies. Additional reports were identified from the reference list of the retrieved papers, and by contacting experts in the field.Selection criteria:Randomized controlled trials (RCTs) with any dose of BoNT for rare head and neck pain syndromes, describing subjective pain assessment as either the primary or a secondary outcome, were included in this review.Data collection and analysis:All trials were quality scored and two independent reviewers extracted data. Results were compared for differences, and discrepancies were resolved by discussion.Main results:Fourteen RCTs of BoNT in cervical dystonia were included in this review. All except one showed significant pain relief following BoNT treatment compared to placebo. Studies providing dichotomous outcome data were pooled using the Peto method. The overall effect was found to be highly significant (OR 4.795 [95% CI 5.551–6.473]). For cervicogenic headache, two RCTs—one positive study and one negative study—were included. Two studies addressing chronic neck pain were included in this review. Both studies did not reveal significant effects. Furthermore, one small trial (N = 15 patients) focussing BoNT in temporomandibular disorders was included,without demonstrating significant effectiveness but a high proportion of patients lost to follow-up and a high rate of adverse effects. For the use of BoNT in cluster headache, chronic paroxysmal hemicrania and trigeminal neuralgia no RCTs were identified.Adverse effects (AEs) were found to be mild to moderate and dose-dependent. They were summarized where possible, irrespective of the formulation used and condition treated (OR = 5.066 [95% CI 2.770–9.265], number-needed-to-harm (NNH) = 5.5 [range 4.4–17]).Reviewers’ conclusions:There is convincing evidence for the effectiveness of BoNT in the treatment of pain associated with cervical dystonia. Due to the frequent adverse effects predominantly observed with higher doses, the trade off in risk and benefit should be carefully considered in each case. For all other rare head and neck pain syndromes we found no RCTs (cluster headache, chronic paroxysmal hemicrania, trigeminal neuralgia) and only a few small sized trials (cervicogenic headache, chronic neck pain, temporomandibular disorders). We were therefore unable to draw any definite conclusions.

Respective Potencies of Botox® and Dysport® in a Human Skin Model : A Randomized, Double-blind Study

Mouse units used to quantify the activity of botulinum A toxin preparations are not equivalent and issues concerning efficacy and safety remain with regard to their respective potencies and diffusion qualities in human tissue. We compared the effects of Botox® (BOT) and Dysport® (DYS) in different doses and dilutions in a human skin model. Eighteen (8 women, 10 men) healthy volunteers, aged 28.4 years ± 5.7 years were injected intradermally with pure saline, BOT and DYS at 16 points in the abdomen in random order and in a double‐blind condition, using two conversion ratios (1:3 and 1:4) and three different dilution schemes. For an objective outcome, the Ninhydrin sweat test was used to compare the anhidrotic areas. Both preparations showed a linear dose and dilution relationship with similar variances of responses for anhidrosis and hypohidrosis, indicating the same reliability of response. The dose equivalence conversion ratios (BOT: DYS) were 1:1.3 for anhidrosis and 1:1.6 for hypohidrosis (1:1.1‐1.5 and 1:1.4‐1.8 95% confidence intervals). The diffusion characteristics of both products were similar. A dose equivalence factor of more than 1:2 (BOT:DYS) is not supported by these objective and reproducible data.

Dose equivalence of two commercial preparations of botulinum neurotoxin type A: time for a reassessment?

ABSTRACT Background: The units of different preparations of botulinum neurotoxin type A (BoNT-A) have different potencies, and dosing recommendations for each product are not interchangeable. Historically, there has been debate concerning the dose-equivalence ratio that should be used in clinical practice. Methods: Published evidence was considered to establish an appropriate dose-conversion ratio for the two main commercially available preparations of BoNT-A – Dysport (Dp) and Botox (Bx). Results: Four key areas of evidence were identified: nonclinical and preclinical studies; studies exploring the diffusion characteristics and effects of complexing proteins; comparative experimental data from human studies; and clinical studies. Nonclinical data indicate that the principal reasons for differences in unit potency between the two products are dilution artefacts in the mouse assay. Use of saline as a diluent, at high dilutions, results in significant loss of potency in the Bx assay, whereas use of gelatin phosphate buffer in the Dp assay procedure protects the toxin during dilution. The published data on mouse assays show a Dp : Bx unit ratio range of 2.3–2.5 : 1 in saline and 1.8–3.2 : 1 in gelatin phosphate buffer. Data indicate that complexing proteins or size of the complex, which is highly pH sensitive, play no role in toxin diffusion and that Dp and Bx have similar diffusion characteristics when used at comparable doses. Randomized, controlled clinical studies indicate that 3 : 1 is more appropriate than 4 : 1, but the two products are not equivalent at this ratio. Comparative human experimental studies using the extensor digitorum brevis test, facial lines and anhidrotic action halo tests support dose-conversion ratios less than 3 : 1. Limitations: Data comparing dose equivalence ratios from the non-clinical setting should be extrapolated into the clinical setting with some caution. Conclusions: Dose-conversion ratios between Dp and Bx of 4 : 1 and greater are not supported by the recent literature.

Apomorphine in idiopathic restless legs syndrome: an exploratory study

Background: Dopaminergic and opioidergic drugs have been found to be effective in patients with restless legs syndrome (RLS). Objectives: To test the effect of apomorphine—a combined opioidergic and dopaminergic agonist—and subsequent selective antagonism by naloxone and metoclopramide on subjective and objective symptoms in patients with idiopathic RLS. Methods: Nine patients with RLS were pretreated with oral domperidone for three days. A modified suggested immobilisation test (SIT) was carried out between 8 pm and 1 am under the following conditions of intravenous drug administration: baseline–apomorphine–apomorphine plus naloxone–apomorphine plus metoclopramide. Outcome variables were a visual analogue scale (VAS) of subjective RLS symptoms and EMG documented periodic leg movements while awake (PLMW). Results: Compared with baseline, apomorphine resulted in a rapid and significant improvement in subjective RLS symptoms as measured by VAS (54.5% improvement; p = 0.011), and an almost immediate cessation of PLMW, measured by PLMW index (98.0% improvement; p = 0.012). Neither additional naloxone nor metoclopramide blocked this effect significantly. While given apomorphine with metoclopramide, there was a trend to reappearance of PLMW. Conclusions: Apomorphine may be an effective treatment for idiopathic RLS. Its effectiveness may reflect both to its dopaminergic and its opioidergic activity, and is not diminished significantly by blocking only one of these pathways. The trend to a worsening of the PLMW index with metoclopramide hints at a primarily dopaminergic effect of apomorphine in idiopathic RLS.

The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization.

Summary Ultraviolet B irradiation induces generalized hyperalgesia to all pain modalities primarily on the basis of multiple mechanisms of peripheral sensitization, but also involves central sensitization (secondary hyperalgesia and dynamic mechanical allodynia). Abstract The ultraviolet B (UVB) sunburn model was characterized with a comprehensive battery of quantitative sensory testing (QST). Primary hyperalgesia in UVB‐irradiated skin and secondary hyperalgesia in adjacent nonirradiated skin were studied in 22 healthy subjects 24 h after irradiation with UVB at 3‐fold minimal erythema dose of a skin area 5 cm in diameter at the thigh and compared to mirror‐image contralateral control areas. The time course of hyperalgesia over 96 h was studied in a subgroup of 12 subjects. Within the sunburn area, cold hyperesthesia (P = .01), profound generalized hyperalgesia to heat (P < .001), cold (P < .05), pinprick and pressure (P < .001), and mild dynamic mechanical allodynia (P < .001) were present. The finding of cold hyperalgesia and cold hyperesthesia is new in this model. The sunburn was surrounded by large areas of pinprick hyperalgesia (mean ± SEM, 218 ± 32 cm2) and a small rim of dynamic mechanical allodynia but no other sensory changes. Although of smaller magnitude, secondary hyperalgesia and dynamic mechanical allodynia adjacent to the UVB‐irradiated area were statistically highly significant. Primary and secondary hyperalgesia developed in parallel within hours, peaked after 24–32 h, and lasted for more than 96 h. These data reveal that the UVB sunburn model activates a broad spectrum of peripheral and central sensitization mechanisms and hence is a useful human surrogate model to be used as a screening tool for target engagement in phases 1 and 2a of drug development.