Mechano- and thermosensitivity of injured muscle afferents 20 to 80 days after nerve injury.

Chronic injury of limb nerves leading to neuropathic pain affects deep somatic nerves. Here the functional properties of injured afferent fibers in the lateral gastrocnemius-soleus nerve were investigated 20 and 80 days after suturing the central stump of this muscle nerve to the distal stump of the sural nerve in anesthetized rats. Neurophysiological recordings were made from afferent axons identified in either the sciatic nerve (87 A-, 63 C-fibers) or the dorsal root L4/L5 (52 A-, 26 C-fibers) by electrical stimulation of the injured nerve. About 70% of the functionally identified A-fibers had regenerated into skin by 80 days after nerve suture; the remaining A-fibers could be activated only from the injured nerve. In contrast, 93% of the functionally identified C-fibers could only be activated from the injured sural nerve after 80 days. Nearly half of the injured A- (45%) and C-fibers (44%) exhibited ongoing and/or mechanically or thermally evoked activity. Because ~50% of the A- and C-fibers are somatomotor or sympathetic postganglionic axons, respectively, probably all injured muscle afferent A- and C-fibers developed ectopic activity. Ongoing activity was present in 17% of the A- and 46% of the C-fibers. Mechanosensitivity was present in most injured A- (99%) and C-fibers (85%), whereas thermosensitivity was more common in C-fibers (cold 46%, heat 47%) than in A-fibers (cold 18%, heat 12%). Practically all thermosensitive A-fibers and C-fibers were also mechanosensitive. Thus, unlike cutaneous axons, almost all A- and C-fibers afferents in injured muscle nerves demonstrate ectopic activity, even chronically after nerve injury. NEW & NOTEWORTHY After chronic injury of a muscle nerve, allowing the nerve fibers to regenerate to the target tissue, 1) most afferent A-fibers are mechanosensitive and regenerate to the target tissue; 2) ectopic ongoing activity, cold sensitivity, and heat sensitivity significantly decrease with time after injury in A-afferents; 3) most afferent C-fibers do not regenerate to the target tissue; and 4) injured C-afferents maintain the patterns of ectopic discharge properties they already show soon after nerve injury.

White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging.

Pain anticipation recruits the mesolimbic system and differentially modulates subsequent recognition memory.

The ability to encode information into long-term memory is not a passive process but can be influenced by motivational factors. While the mesolimbic system has long been associated with reward-driven memory enhancement, the precise neurobiology of processing aversive events and their effects on declarative learning remain unclear. To address this issue, human subjects encoded a series of scene images, which was combined with cues predicting an aversive electric shock with different probabilities (0.2, 0.5, 0.8). Subsequently, recognition memory for the scenes was tested using a remember/know procedure. In a behavioral experiment, shock probability had linear effects on familiarity and inverted u-shaped effects on recollection. While the behavioral effect was absent in experiment 2 (fMRI), at the neural level encoding-related activity in the hippocampus mimicked the recollection specific quadratic effect, whereas activity in the anterior parahippocampal gyrus mirrored the familiarity specific linear relationship that was evident in experiment 1. Importantly, the probability of upcoming shocks was linearly coded in the substantia nigra / ventral tegmental area, and pain associated brain regions, such as the insula, responded to shock delivery. Our results demonstrate that anticipating primary aversive events recruits the human mesolimbic system and differentially modulates declarative memory functions via medial temporal lobe structures.

Mechano- and thermosensitivity of injured muscle afferents.

Injury of limb nerves leading to neuropathic pain mostly affects deep somatic nerves including muscle nerves. Here, we investigated the functional properties of injured afferent fibers innervating the lateral gastrocnemius-soleus muscle 4-13 h [time period (TP) I] and 4-7 days (TP II) after nerve crush in anesthetized rats using neurophysiological recordings from either the sciatic nerve (165 A-, 137 C-fibers) or the dorsal root L(5) (43 A-, 28 C-fibers). Ongoing activity and responses to mechanical or thermal stimulation of the injury site of the nerve were studied quantitatively. Of the electrically identified A- and C-fibers, 5 and 38% exhibited ectopic activity, respectively, in TP I and 51 and 61%, respectively, in TP II. Thus all afferent fibers in an injured muscle nerve developed ectopic activity since ∼ 50% of the fibers in a muscle nerve are somatomotor or sympathetic postganglionic. Ongoing activity was present in 50% of the afferent A-fibers (TP II) and in 53-56% of the afferent C-fibers (TP I and II). In TP II, mechanical, cold, and heat sensitivity were present in 91, 63, and 52% of the afferent A-fibers and in 50, 40, and 66% of the afferent C-fibers. The cold and heat activation thresholds were 5-27 and 35-48°C, respectively, covering the noxious and innocuous range. Most afferent fibers showed combinations of these sensitivities. Mechano- and cold sensitivity had a significantly higher representation in A- than in C-fibers, but heat sensitivity had a significantly higher representation in C- than in A-fibers. These functional differences between A- and C-fibers applied to large- as well as small-diameter A-fibers. Comparing the functional properties of injured muscle A- and C-afferents with those of injured cutaneous A- and C-afferents shows that both populations of injured afferent neurons behave differently in several aspects.

Neural Habituation to Painful Stimuli Is Modulated by Dopamine: Evidence from a Pharmacological fMRI Study.

In constantly changing environments, it is crucial to adaptively respond to threatening events. In particular, painful stimuli are not only processed in terms of their absolute intensity, but also with respect to their context. While contextual pain processing can simply entail the repeated processing of information (i.e., habituation), it can, in a more complex form, be expressed through predictions of magnitude before the delivery of nociceptive information (i.e., adaptive coding). Here, we investigated the brain regions involved in the adaptation to nociceptive electrical stimulation as well as their link to dopaminergic neurotransmission (placebo/haloperidol). The main finding is that haloperidol changed the habituation to the absolute pain intensity over time. More precisely, in the placebo condition, activity in left postcentral gyrus and midcingulate cortex increased linearly with pain intensity only in the beginning of the experiment and subsequently habituated. In contrast, when the dopaminergic system was blocked by haloperidol, a linear increase with pain intensity was present throughout the entire experiment. Finally, there were no adaptive coding effects in any brain regions. Together, our findings provide novel insights into the nature of pain processing by suggesting that dopaminergic neurotransmission plays a specific role for the habituation to painful stimuli over time.

Effect of local and intravenous lidocaine on ongoing activity in injured afferent nerve fibers.

Lidocaine applied systemically or locally attenuates neuropathic pain in patients. Here we tested the hypothesis that ectopic activity in injured afferent A- or C-fibers is suppressed by lidocaine. In rats the sural nerve (skin nerve) or lateral gastrocnemius-soleus nerve (muscle nerve) was crushed. Four to 11 days after crush lesion afferent fibers were isolated from the lesioned nerves in bundles rostral to the injury site. Ongoing ectopic activity was recorded from 75 A-fibers (muscle N=43, skin N=32) and 69 C-fibers (muscle N=30, skin N=39). Most afferent fibers were functionally characterized by their responses to mechanical and thermal (mostly heat) stimuli applied at or distal to the nerve injury site. Low-threshold cold-sensitive cutaneous C-fibers were excluded from the analysis. Lidocaine was either applied to the nerve at or distal to the injury site in concentrations of 1 to 1000 µg/mL or injected i.v. in doses of 0.09 to 9 mg/kg (skin) or 0.047 to 4.7 mg/kg (muscle). Local application of lidocaine depressed ectopic activity in A- and C-fibers dose-dependently. Depression was weaker in C- than in A-fibers. Intravenous application of lidocaine depressed ongoing ectopic activity in A- and C-fibers dose-dependently. Responses to heat or mechanical stimulation of the injured nerve were not suppressed at the highest concentrations of lidocaine. The results support the hypothesis that decrease of neuropathic pain following local or systemic application of a local anesthetic is related to decrease of ectopic ongoing activity in injured afferent nerve fibers.