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Benign paroxysmal positional vertigo is the most frequent cause of recurrent vertigo and according to the canalo- and cupulolithiasis theory it is caused by detached otoconia which accumulate in the semicircular canals. However, the mechanisms leading to detachment of otoconia from the matrix are still poorly understood. Head trauma, inner ear diseases, advanced age, migraine and bed rest are known predisposing factors. We report a case of a healthy 44-year-old female, who developed left sided benign paroxysmal positional vertigo 10 hours following standard bilateral diagnostic transcranial magnetic stimulation. As our patient did not innate any established predisposing factor and has a relatively young age, we conclude that diagnostic transcranial magnetic stimulation to elicit motor evoked potentials might be an iatrogenic cause of benign paroxysmal positional vertigo.

The anticonvulsant drug lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and has been shown to be an effective add-on treatment for partial-onset seizures. Common adverse events (frequency 10%) of lacosamide doses up to 600 mg/day include nonspecific central nervous system effects (e.g., dizziness, ataxia, diplopia, and somnolence). There are no human data regarding the safety of very high dosages of lacosamide. We report the clinical course of a patient with bitemporal epilepsy who ingested 12 g of lacosamide, 56 g of gabapentin, 2g of topiramate, and 2.8 g of zonisamide during a suicide attempt. The patient was found comatose and experienced repeated generalized tonic-clonic seizures, aspiration with subsequent pneumonia, hypotension, and an increase in PR interval. Complete physical recovery occurred after several days of supportive treatment. We conclude that intoxication with lacosamide, in combination with overdoses of multiple AEDs, can be survived without sequelae, even after ingestion of 12 g lacosamide.

The catechol-O-methyltransferase (COMT) val158met polymorphism, which codes for the substitution of valine (val) by methionine (met) leading to a reduced COMT activity in homo- or heterozygous individuals, is associated with individual pain sensitivity and dopaminergic responses in Parkinson's disease as well as with various chronic painful diseases. Recent investigations support the notion of an alteration of the medial pain pathway as well as of the descending inhibitory control system in restless legs syndrome (RLS), that both involve dopaminergic transmission as well. Thus, the distribution of the COMT val158met polymorphism was assessed in 298 RLS patients and compared with 135 healthy controls in relation to sex, age of onset and family history. The data revealed no significant differences in the distribution of the COMT val158met polymorphism in RLS patients compared with the control group, also when the heterozygous and the homozygous group containing the 158met allele were combined. In addition, sex, age of onset and family history were not associated with the COMT val158met polymorphism in this German population of RLS patients. The present study adds to previous mostly negative investigations on the genetic determination of dopaminergic transmission in RLS, which have – so far – only detected an association of the MAO-A activity and RLS in females in a French-Canadian population. Further investigations assessing the different COMT haplotypes and experimental and clinical parameters are nevertheless warranted.

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.

Summary Introduction Pantothenate kinase-associated neurodegenerative disease (PKAN) is a secondary generalized dystonia associated with an accumulation of iron in the basal ganglia and increased motor cortex excitability. A pilot study in three patients with secondary generalized dystonia had reported a reduced frequency of painful axial spasms following inhibitory 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied over the premotor cortex. Patient and methods We compared the effects of real versus sham rTMS on the frequency of the complex movement pattern and the need for additional benzodiazepine medication in a 6-year-old male patient with PKAN. A 20-minute session of left premotor 1-Hz rTMS was performed daily on 5 consecutive days. Results The occurrence of the complex movement pattern was gradually reduced from three to two attacks daily to one attack daily by real rTMS while sham rTMS had no effect. This reduction was obtained concomitantly with a similar reduction of additional benzodiazepines for both real and sham rTMS sessions. Conclusion Inhibitory rTMS of the premotor cortex may be used to temporarily control motor symptoms in PKAN.

High-frequency repetitive transcranial magnetic stimulation (rTMS) increases and low-frequency rTMS decreases neural excitability. Clinically, rTMS shows beneficial effects in the treatment of neurological and psychiatric disorders. Furthermore, chronic and neuropathic pain has been shown to respond to rTMS treatment. A small pilot study revealed prophylactic effects of high-frequency rTMS in migraine. As there is evidence of neuronal hyperexcitability in migraine, we conducted a placebo-controlled, blinded study to evaluate the therapeutic effects of low-frequency rTMS in migraine. The primary end-point was defined as a reduction of migraine attacks compared with placebo, secondary outcomes were a reduction in the total number of days with headache, hours with headache, pain intensity and a decrease of analgesic intake for migraine. Twenty-seven migraineurs completed the study and were treated with rTMS on five consecutive days. For the verum group, two trains of 500 pulses with a frequency of 1 Hz were applied over vertex with a round coil. For the treatment of the placebo group, a figure-of-eight sham coil was used. A significant decrease of migraine attacks could be observed in the verum group. However, when comparing these effects with placebo, no significance was evident. The same was true concerning secondary outcome measures with regard to days with migraine and total hours with migraine. No effects were evident for pain intensity and use of analgesics. The rTMS treatment was tolerated well. rTMS stimulation over vertex with 1 Hz was not effective in migraine prophylaxis when compared with placebo. The positive effects regarding migraine attacks, days and total hours with migraine in the verum group are encouraging and indicate that further research on this topic is warranted.

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.

Experimental findings on the influence of dementia on pain have so far been conflicting. There is evidence for a decreased, an unchanged and even for an increased pain processing in patients with dementia. The present study was conducted to add on the description of the impact of dementia on pain processing by assessing multiple components of pain (subjective, facial, motor reflex and autonomic responses) in parallel in one group of demented patients. Subjective (rating scale), facial (FACS), motor reflex (NFR) and autonomic (SSR, heart rate) responses to noxious electrical stimulation were assessed in 35 demented patients and 46 aged-matched healthy controls. Stimulus intensities were tailored to the individual NFR threshold. Demented patients rated the stimuli similarly painful as healthy controls did; however, the ability to provide these self-report ratings was markedly diminished in demented patients. Facial responses to noxious stimulation were significantly increased in demented patients. In line with this the NFR threshold was markedly decreased in the patient group. Autonomic responses on the other hand tended to be diminished in patients with dementia. In conclusion, dementia tends to affect different pain components in different ways. Therefore, the assessment of pain in patients with dementia should be based on the measurement of multiple components of pain and not solely on subjective self-report ratings. Furthermore, taking into account our findings on facial responses and the NFR, we think that there is sufficient evidence suggesting a rather intensified processing of noxious stimulation in this patient group.

Einleitung: In der vorliegenden Studie wurde untersucht ob die Modulation von elektrisch induzierten akuten Schmerzen durch transcranielle Doppelstimulation (paired-pulse TMS=ppTMS) uber dem Motorkortex (M1) vom Intervall zwischen den Stimulationen abhangt. Durch die Untersuchung des spinalen nozizeptiven Flexorreflexes (NFR) wurde zusatzlich untersucht, ob sich diese Veranderungen schon auf spinaler Ebene ereignen. Dabei wird durch die elektrische Stimulation des N. suralis eine ipsilaterale Kontraktion von Unterschenkelflexoren, die uber dem M. biceps femoris abgeleitet wird, ausgelost. Da der NFR hoch mit der subjektiven Schmerzschwelle korreliert wird er als objektives Mas fur die spinale Nozizeption verwendet. Methoden: Die ppTMS (ISI: 50ms, 1,2-facher Ruhemotorschwelle (RMT)) wurde uber dem motorischen Areal des M. abductor hallucis appliziert. In verschiedenen Intervallen (–400 (ppTMS zuerst) bis +400ms (NFR zuerst)) dazu wurde contra lateral der NFR (1,3-fache Schwellenintensitat) bei 10 gesunden Freiwilligen ausgelost. Funf Reflexantworten wurden gemittelt und deren Parameter fur die Intervalle –400, –75 und Kontrolle (Latenz, Amplitude und Flache) ausgewertet. Schmerzintensitat und Aversivitat wurden mit einer visuellen Analogskala gemessen. Ergebnisse: Eine ANOVA mit Messwiederholung und den Faktoren 'Intervall' and 'VAS (Intensitat und Aversivitat)' zeigte einen signifikanten Einfluss von 'Intervall' (F(6,36)=3,337; P=0,01). Bei Intervallen von –75, –25, +25 and +400ms waren die VAS Ratings hoher und bei einem Intervall von –400ms waren die VAS Ratings im Vergleich zur Kontrolle niedriger. Die ppTMS hatte keinen signifikanten Einfluss auf die Parameter des NFR. Diskussion: Die Daten zeigen, dass ppTMS uber M1 die Schmerzwahrnehmung verstarken kann, wenn sie wahrend der Verarbeitung von A delta Faser-induziertem Schmerz im lateralen schmerzverabeitenden System appliziert wird. Wenn ppTMS vor dem Einsetzen der noxischen Stimulation verabreicht wird, kann die weitere Schmerzverarbeitung inhibiert werden. Da kein Effekt auf den NFR festgestellt wurde, vermuten wir, dass die Schmerzmodulation eher durch eine Veranderung korticothalamischer Bahnen bewirkt wird, als durch einen Einfluss auf die spinale Nozizeption. Erganzend stellen wir vorherige Studien zum Effekt von TMS auf experimentell induzierte Schmerzen vor (Mylius et al., Clin Neurophysiol 2006;117:1814–1820).

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 Aδ 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 Aδ 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.

Objective Aim of this study was to investigate whether paired pulse transcranial magnetic stimulation (ppTMS) applied over the medial frontal cortex (MFC) affects acute Aδ 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: 50ms) was applied over the medial frontal cortex at different intervals ranging from 0 to 1000ms following the previous elicited NFR in 10 healthy volunteers. Three sequences at 3 different NFR stimulus intensities (at NFR threshold, 1.3× and 1.6×NFR threshold) with a ppTMS stimulus intensity at 1.2×resting motor threshold (RMT) and one sequence with elevated ppTMS at 1.6×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 75ms at NFR threshold as well as for 25ms at 1.3×NFR threshold when ppTMS was applied at 1.2×RMT and from 0 to 75ms at 1.6×NFR threshold when ppTMS was applied at 1.6×RMT. Conclusions The present data suggest that ppTMS over MFC—applied in a certain time window—can enhance pain perception of acute Aδ 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.

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.

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.

Question Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive way to modulate brain neural activities, able to modify cortical functions for clinical and therapeutic purposes. Neuromodulation induced by rTMS notably depends on the frequency of stimulation, equal or less than 1 Hz (low-frequency (LF) rTMS) or equal or more than 5 Hz (high-frequency (HF) rTMS). In patients with unilateral or asymmetric chronic neuropathic pain, HF-rTMS is known to be able to produce analgesic effects when applied to the motor cortex (precentral gyrus) contralateral to pain side. Analgesic effects of HF-rTMS have been also reported when applied to the left dominant motor cortex (M1) in patients with generalized non-neuropathic pain (fibromyalgia). Conversely, motor cortex LF-rTMS was found to be inefficacious in the same conditions. A therapeutic impact on pain syndromes was also observed following HF-rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC), but LF-rTMS of the right DLPFC showed a similar efficacy, according to the theory of interhemispheric balance. In contrast, the potential analgesic effect of LF-rTMS of the right M1 has never been investigated. Methods In a randomized placebo-controlled and double-blinded study, the effects of robotized-navigated LF-TMS applied for two weeks over a target grid of the non-dominant right M1 or DLPFC were assessed in 24 right-handed patients with macrophagic myofasciitis (MFM). Symptomatic MFM represents a rare generalized pain syndrome induced by aluminium oxyhydroxide from vaccine injections. Assessments included measures of pain, fibromyalgia symptoms, quality of life, depression, anxiety, fatigue and cortical excitability. Results LF-rTMS of the right M1 but not of the right DLPFC reduced pain level for at least 4 weeks. Both M1 and DLPFC stimulation yielded significant effects on fibromyalgia symptom severity scale as well as on the cognitive and social components of fatigue. Conclusion For the first time we showed that LF-rTMS may have therapeutic effects in generalized pain, when applied to the non-dominant cortex. We also demonstrated the eligibility of a robotized-navigated rTMS procedure, allowing a precise stimulation over M1 or DLPFC regions, based on individual anatomical targeting.