H. C. Hopf

Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 × 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for >3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 μm diameter) in skin adjacent to the HFS–LFS conditioning skin site revealed a marked twofold to threefold increase in pain sensitivity (secondary hyperalgesia, undiminished for >3 hr) after HFS but also a moderate secondary hyperalgesia (30% above baseline) after strong LFS. Additionally, HFS but not LFS caused pain to light tactile stimuli in adjacent skin (allodynia). In summary, HFS and LFS stimulus protocols that induce LTP or LTD in spinal nociceptive pathways in animal experiments led to similar LTP- and LTD-like changes in human pain perception (long-term hyperalgesia or hypoalgesia) mediated by the conditioned pathway. Additionally, secondary hyperalgesia and allodynia in adjacent skin induced by the HFS protocol and, to a minor extent, also by the LFS protocol, suggested that these perceptual changes encompassed an LTP-like heterosynaptic facilitation of adjacent nociceptive pathways by a hitherto unknown mechanism.

Changes of sensory conduction velocity and refractory periods with decreasing tissue temperature in man

SummaryChanges with temperature of maximum sensory nerve conduction velocity as well as absolute and relative refractory periods were tested in 14 human subjects. Corresponding to previously published findings maximum conduction velocity decreased with cooling following a Q10 of +1.4. The absolute and relative refractory periods were increased by cooling, the Q10 being −3.1 and −3.35 respectively. There was a tendency showing a more pronounced temperature effect at low temperatures. The Q10 and the steepness of the regressionline changed at the level of 26.9°C, but were significant for the relative refractory period only.ZusammenfassungAn 14 gesunden jugendlichen Probanden wurde die sensible Nervenleitgeschwindigkeit sowie die absolute und relative Refraktärperiode des N. ulnaris bei Temperaturen zwischen 35°C und 20°C bestimmt.Die Gewebstemperatur wurde durch eisgekühlte Gelkissen bis auf 20°C gesenkt und subkutan dicht am Nerven bestimmt.Für die Bereiche 35°C bis 25°C und 30°C bis 20°C wurden die Q10-Werte für die sensible NLG mit 1,36 bzw. 1,44, für die absolute Refraktärperiode mit −3,18 bzw. −3,01 und für die relative Refraktärperiode mit −3,21 bzw. −3,49 bestimmt.Die Unterschiede der Q10-Werte für die NLG und die Refraktärperioden sowie die Zunahme des Q10 unterhalb einer Temperatur von 27°C werden anhand der bisher veröffentlichten Literaturbefunde diskutiert.Unter Berücksichtigung dieser Befunde ergibt sich bei Extrapolation klinisch-neurophysiologischer Meßwerte auf 35°C für die NLG eine Korrektur von 1,3 m/s pro °C und für die relative Refraktärperiode von 0,5 ms/°C.

Diffusion weighted magnetic resonance imaging in the diagnosis of reversible ischaemic deficits of the brainstem

Objectives: To evaluate the sensitivity of diffusion weighted magnetic resonance imaging (MRI) for the diagnosis of clinically suspected reversible ischaemic deficits of the brainstem. Methods: A total of 158 consecutive patients presenting with acute signs of brainstem dysfunction were investigated using EPI diffusion weighted MRI within 24 hours of the onset of symptoms. High resolution T1 and T2 weighted imaging was performed as a follow up after a median of six days Results: Fourteen of the 158 patients had a complete clinical recovery within 24 hours (transitory ischaemic attack (TIA)), and 19 patients recovered in less than one week (prolonged reversible neurological deficit (RIND)). Diffusion weighted MRI showed acute ischaemic deficits in 39% of patients with transient neurological deficits. The detection rate seemed to be higher in patients with longer lasting symptoms, but the difference between patients with TIA (29%) and RIND (47%) was not significant. Conclusions: Diffusion weighted MRI is a sensitive indicator of acute ischaemic brainstem deficits even in patients with reversible neurological deficit. Early identification of patients with TIA and increased risk of stroke may influence acute management and improve patient outcome.

Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system

We recently reported perceptual correlates of long-term potentiation (LTP) of synaptic strength within the nociceptive system demonstrating the functional relevance of LTP for human pain sensation. LTP is generally classified as NMDA-receptor dependent or independent. Here we show that low doses of the NMDA-receptor antagonist ketamine (0.25 mg/kg) prevented the long-term increase in perceived pain to electrical test stimuli, which was induced by high-frequency electrical stimulation (HFS) of nociceptive afferents. Whereas in a control experiment HFS led to a stable increase in perceived pain by 51% for the entire observation period of 1h HFS given 4 min after i.v. ketamine was ineffective. In contrast, HFS induced a two-fold increase of pinprick-evoked pain surrounding the HFS site (secondary neurogenic hyperalgesia) in both experiments. Pain evoked by light tactile stimuli (allodynia) was also unaffected by ketamine. These data support the concept that homotopic hyperalgesia to electrical stimulation of the conditioned pathway is a perceptual correlate of NMDA-receptor sensitive homosynaptic LTP in the nociceptive system, e.g. in the spinal cord. Although secondary neurogenic hyperalgesia and allodynia are induced by the same HFS protocol, they involve additional NMDA-receptor insensitive mechanisms of heterosynaptic facilitation.

The location by early auditory evoked potentials (EAEP) of acoustic nerve and brainstem demyelination in multiple sclerosis (MS)

SummaryTone pips of suprathreshold intensities elicit an acoustic nerve response (I) and six low amplitude brainstem potentials (II–VII) during the initial 10 ms. Seven waves were studied in 40 control subjects and 5 waves (I–V) in 47 patients with MS. The results suggest involvement of the auditory pathway of 24 of 27 patients in the clinically “definite”, of 5 of 9 cases in the “probable” and in none of 5 patients in the “possible” MS groups. EAEPs were normal in 6 cases with a spinal form with one exception where changes of potential were indicative of a midbrain lesion. Dysfunction within the acoustic pathway was observed at the level of the acoustic nerve and in the medulla oblongata, pons and midbrain. The significance of the bilateral EAEP abnormalities found in some patients at different levels is discussed with regard to a polytopic location of the underlying lesion.ZusammenfassungNach einem kurzen Tonimpuls (tone pip) lassen sich in den ersten 10 ms eine Antwort vom N. acusticus und 6 im Nanovoltbereich liegende Hirnstammpotentiale auslösen. 7 Komponenten wurden bei 40 Normalpersonen und 5 Komponenten (I–V) bei 47 MS-Patienten untersucht. Bei „eindeutiger“ MS war in 24 von 27 Fällen ein Befall der Hörbahn nachweisbar. Bei der „wahrscheinlichen“ Form sahen wir in 5 von 9 Fällen und bei der „fraglichen“ MS bei keinem der Patienten Veränderungen. Bei der „spinalen“ Form waren die frühen akustisch evozierten Potentiale (FAEP) bis auf einen Fall mit Hinweis auf eine Mittelhirnschädigung normal. Schädigungen konnten in allen Hirnstammbereichen (Medulla oblongata, Pons und Mittelhirn) nachgewiesen werden. Ein Befall von peripheren Anteilen der Hörbahn (N. acusticus) mit intermittierenden und bleibenden Veränderungen der 1. Reizantwort ließ in 7 Fällen an eine extramedulläre Dissemination denken. Bei Patienten mit Befall beider Hörbahnen aber in verschiedenen Höhen wird die Möglichkeit einer Aussage in Richtung einer polytopischen Lokalisation in Aussicht gestellt.

Blink reflex R2 changes and localisation of lesions in the lower brainstem (Wallenberg’s syndrome): an electrophysiological and MRI study

OBJECTIVES Pathways of late blink reflexes are detected by high resolution MRI. Electronically matched stroke lesions superimposed to an anatomical atlas show the suspected course. METHODS Fifteen patients with infarction of the lower brainstem, MRI lesions and electrically elicited blink reflexes were examined. The involved structures in patients with R2 and R2c blink reflex changes were identified by biplane high resolution MRI with individual slices matched to an anatomical atlas at 10 different levels using digital postprocessing methods. RESULTS The blink reflexes were normal in five of 15 patients (33%) and showed loss or delay of R2 and R2c to stimulation ipsilaterally to lesion (R2-i and R2c-i) in eight (53%). Loss or delay of R2-i/R2c-i was seen in lesions covering the entire trigeminal spinal tract and nucleus (TSTN) at at least one level. These infarctions were located more dorsally within the medulla. Patients with normal blink reflexes showed lesions sparing or involving the TSTN only partially. They more often had incomplete Wallenberg’s syndromes and MRI lesions were located more ventrally. CONCLUSIONS Using digital postprocessing MRI methods it was possible to identify central pathways of late blink reflex in patients with Wallenberg’s syndrome. This method is suggested as a new approach to identify incompletely understood functional structures of the brainstem.

Differentiation of recent and old cerebral infarcts by diffusion-weighted MRI

Abstract We performed MRI, including diffusion-weighted imaging, in 15 patients with recurrent strokes with acute ischaemia and at least one old lesion according to the clinical history and/or CT. Routine MRI showed similar signal intensity changes in both situations. Diffusion-weighted images, however, were positive in all acute or subacute infarcts. The high signal of acutely disturbed diffusion due to intracellular oedema could also be identified in small brain stem lesions. Spatial resolution was increased by applying separate gradients in each axis instead of creating anisotropy-independent trace images.

Topodiagnostic investigations on the sympathoexcitatory brain stem pathway using a new method of three dimensional brain stem mapping

Objectives: To study the incompletely understood sympathoexcitatory pathway through the human brain stem, using a new method of three dimensional brain stem mapping on the basis of digitally postprocessed magnetic resonance imaging (MRI). Methods: 258 consecutive patients presenting with acute signs of brain stem ischaemia underwent biplane T2 and EPI diffusion weighted MRI, with slice orientation parallel and perpendicular to a transversal slice selection of the stereotactic anatomical atlas of Schaltenbrand and Wahren, 1977. The individual slices were digitally normalised and projected onto the appropriate slices of the anatomical atlas. For correlation analysis lesions were imported into a three dimensional model of the human brain stem. Results: 31 of the 258 patients had Horner’s syndrome caused by acute brain stem ischaemia. Only four of the patients with Horner’s syndrome had pontine infarctions, 12 had pontomedullary lesions, and 15 had medullary lesions. Correlation analysis showed significantly affected voxels in the dorsolateral medulla but not in the pons. A statistical comparison with infarct topology in patients with medullary lesions but without Horner’s syndrome indicated that involvement of the medial and ventral part of affected voxels located in the ventrolateral medullary tegmentum was specific for Horner’s syndrome. Conclusions: Based on this first in vivo topodiagnostic study, the central sympathoexcitatory pathway probably descends through the dorsal pons before converging on specific generators in the ventrolateral medullary tegmentum at a level below the IX and X nerve exits.

Electrophysiological brainstem investigations in obstructive sleep apnoea syndrome.

Phasic inspiratory genioglossus activity prevents pharyngeal airway collapse in healthy subjects during sleep and is diminished or absent in obstructive sleep apnoea syndrome (OSAS), thus leading to pharyngeal obstruction. Case reports of OSAS after pontomedullary lesions indicate that impaired inspiratory genioglossal activity may result from brainstem lesions. We therefore investigated brainstem functions in 18 awake patients with OSAS using brainstem auditory evoked potentials, blink reflex, masseter reflex, masseter inhibitory reflex (in 11 of 18 patients), magnetic evoked potentials of the tongue and electrooculography with vestibular testing. Fifteen of 18 patients showed no electrophysiological abnormalities. One patient had a left pontine and two patients a bilateral pontomesencephalic lesion, although a causal connection with OSAS was not conclusively confirmed. Our results do not support the assumption of a relevant structural brainstem lesion in OSAS patients with normal neurological findings.

Abolished laser-evoked potentials and normal blink reflex in midlateral medullary infarction

Abstract We investigated two patients presenting with the rare finding of almost isolated hemianalgesia with a sensory level on the contralateral side sparing the face. Clinical findings, electrophysiological studies (absent laser-evoked pain-related somatosensory potentials, normal electrically evoked somatosensory potentials, magnetically evoked potentials, and blink reflexes), and magnetic resonance imaging showed the ventrolateral medullar tegmentum containing the spinothalamic tract to be affected by lacunar infarction. The blink reflex R2 component was unimpaired in both patients.