Electrical low-frequency stimulation (LFS) of spinal afferents induces long-term depression (LTD) of nociceptive processing in rodents. LTD and its parameters in man are largely unknown. This study addresses the hypothesis that LTD of spinal nociception and pain in man depends on LFS frequency (0.5, 1, 2 Hz), number of electrical pulses (300, 600, 1200), intensity (relating to pain threshold I(P): 1 x I(P), 2 x I(P), 4 x I(P)), and on LFS repetition. One hundred and twenty electrophysiological and psychophysical experiments were performed in 29 healthy volunteers. Painful electrical test stimulation (0.125 Hz) and conditioning LFS were applied to right hand dorsum by a concentric electrode. Somatosensory evoked cortical potentials (SEP) were recorded and volunteers rated stimulus intensity. LFS with 0.5, 1, and 2 Hz induced significant reduction of SEP and pain ratings as compared to Control group. Effect on SEP amplitude after 1 Hz LFS preponderated that of 2 Hz stimulation. LTD of SEP and pain perception was induced by noxious LFS with 300-1200 pulses. SEP suppression augmented with increasing number of pulses. LFS with intensities 2 x I(P) and 4 x I(P) evoked sustained depression of SEP and pain perception in comparison to Control and 1 x I(P) LFS. Established LTD after single LFS was amplified by an additional second LFS. Hence this study provides electrophysiological and psychophysical evidence for LTD of spinal nociceptive processing and pain perception in man and indicates appropriate LFS parameters 1 Hz, 1200 pulses and 4 x I(P) for future studies on human LTD.

The superior colliculus (SC) in primates plays an important role in orienting gaze and arms toward novel stimuli. Here we ask whether neurons in the intermediate and deep layers of the SC are also involved in the interaction with objects. In two trained monkeys we found a large number of SC units that were specifically activated when the monkeys contacted and pushed a target that had been reached with either hand. These neurons, however, were silent when the monkeys simply looked at or reached for the target but did not touch it. The activity related to interacting with objects was spatially tuned and increased with push strength. Neurons in the SC with this type of activity may be involved in a somatosensory-motor feedback loop that monitors the force of the active muscles together with the spatial position of the limb required for proper interaction with an object.

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Electrical low-frequency stimulation (LFS) of cutaneous afferents reliably induces long-term depression (LTD) of nociception and pain in man. In this study LFS effects on cerebral activation were investigated by functional magnetic resonance imaging (fMRI). In 17 healthy volunteers, nociceptive fibers of right hand dorsum were electrically stimulated via a concentric electrode. Test stimulation sessions consisted of three alternating stimulation periods and rest periods. They were performed before (Pre) and after (Post) conditioning LFS (1200 stimuli, 1Hz) or 20 min break (Control). Volunteers rated sensory and affective pain perception. Before LFS, test stimulation produced activation in bilateral primary and secondary somatosensory cortex (S1,S2), insula, anterior cingulate cortex (ACC), superior temporal cortex (STG), prefrontal cortex and right inferior parietal lobule (IPL). After LFS, exclusively right IPL was activated. Contrast between Pre and Post LFS indicated significant activity decrease in bilateral S1,S2, and ACC and right insula, IPL, and STG. Pre Control and Pre LFS were not different. Activity in Control experiments remained unchanged. Sensory and affective pain rating solely decreased after LFS. Subsequent regression analysis showed significant correlation between pain relief and increased activity after LFS in ACC, anterior insula, striatum, frontal and temporal cortex. The study revealed LTD of pain-related cerebral activation, involving sensory, affective, cognitive, and attentional processes. Positive correlation between pain relief and increased brain activation after LFS may indicate involvement of endogenous pain control mechanisms in LTD. These experiments may help to judge the potency of LTD for future chronic pain treatment.

Electrical low-frequency stimulation (LFS) of nociceptive skin afferents reliably induces long-term depression (LTD) of pain. Recent experiments have assessed the effects of LTD on pain perception by using a simple one-dimensional rating scale. The psychophysical study investigated the impact of noxious LFS on the sensory and affective aspects of pain perception by multidimensional rating scales. In 20 healthy volunteers, nociceptive fibers of the left hand dorsum were electrically stimulated by a concentric electrode. Test stimulation series (15 stimuli each, 0.125Hz) were performed before (Pre) and after (Post) a conditioning LFS (1Hz, 20min) or no stimulation period (Control). Pain ratings concerning test stimulation and LFS were obtained by multidimensional assessment including Verbal rating scale of perceived stimulus intensity (VRS-I) and unpleasantness (VRS-U) and pain perception scale with sensory (SES-S) and affective items (SES-A). After the conditioning LFS, VRS-I, VRS-U, SES-S, and SES-A decreased as compared to Pre series and Control. During conditioning LFS, ratings decreased. Factor analysis of SES-S revealed sole reduction of superficial sharp pain perception after conditioning LFS in contrast to Control experiment. Perception of deep rhythmic pain decreased over time. Deep constant pain and superficial heat pain were not affected. Electrical test stimulation via concentric electrode evokes sensory as well as affective pain perception. Both components decrease during noxious, conditioning LFS and remain depressed for at least one hour. Reduction of sharp pain points to Adelta fiber mediated LTD. These results stress the analgesic potency of LTD and its possible impact on future therapy in chronic pain.

Electrical low-frequency stimulation (LFS) inhibits pain perception and nociceptive processing as shown by psychophysical and electrophysiological means (long-term depression, LTD). Information regarding central mechanisms involved in LTD induction and maintenance are still missing. This study hypothesizes that electrical LFS induces changes in activation pattern of pain-related brain areas. Thirty-two electrophysiological and psychophysical experiments were performed in 16 healthy volunteers. Painful electrical test stimulation (0.125 Hz, 60 pulses) and conditioning LFS (1 Hz, 1200 pulses) were applied by a concentric electrode to the right hand. Test stimulation series were performed before (Pre) and after LFS (Post) or no stimulation period (Control). Volunteers rated pain perception according to a verbal rating scale (0-100). Somatosensory evoked cortical potentials were recorded with 64-channel electroencephalography. Individual dipole source modeling using CURRY software (Compumedics, Hamburg, Germany) yielded information about dipole location and strength. The strongest decrease in LFS-induced pain perception was shown after LFS (p < 0.01). Topographic distribution of cortical potentials revealed reproducible negative (N1, N2) and positive (P2) components. Dipole magnitude analysis showed a significant difference between Post LFS and Post Control for P2 (p < 0.01). P2 dipole location analysis yielded a significant posterior (p < 0.05) shift following LTD induction. Thus, data reveal central changes of pain processing after LTD induction. These experiments may help judging the potency of LTD as model for electrostimulation in future analgesic therapy.

Electrical low-frequency stimulation (LFS) evokes long-term depression (LTD) of nociception. Human studies suggested a strictly homotopic organization. This study hypothesizes that even heterotopic LFS evokes LTD within the same receptive field (RF). In 33 healthy volunteers, painful electrical test stimulation and LFS were applied to the low back by a concentric electrode (ExpBack) and to the forearm by a multiarray electrode (ExpArm). Volunteers rated pain perception during test stimulation that was applied before and after LFS. In ExpBack, test stimuli were administered within the right T12 dermatome. LFS was applied heterotopically within the same RF or remote in dermatome T8. In ExpArm, test stimulation was carried out in the center of the RF whereas LFS was applied to the center, margin, or outside the RF. In ExpBack (n = 20), pain ratings decreased significantly stronger in T12 than in T8 dermatome (P < 0.01). In ExpArm (n = 20), LFS to the center of the RF induced a stronger pain reduction than LFS applied outside the RF (P < 0.001). This study demonstrates a heterosynaptic organization of LTD within the same RF. Profound knowledge about RF involvement on LTD seems crucial in order to judge the quality of LFS as a possible neuromodulatory treatment of pain.

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