Ghrelin, an endogenous ligand for the GHS receptor, stimulates GH secretion and gastrointestinal motility and has orexigenic effects. In this study, the relationships between ghrelin, GH secretion, feeding behavior, and sleep-wake patterns were investigated in adult male rats. The half-life of exogenous ghrelin (10 microg i.v.) in plasma was about 30 min. Repeated administration of ghrelin at 3- to 4-h intervals (one during lights-on and two during lights-off periods) increased GH release and feeding activity, and decreased rapid eye movement sleep duration. Endogenous plasma ghrelin levels exhibited pulsatile variations that were smaller and less regular compared with those of GH. No significant correlation between GH and ghrelin circulating levels was found, although mean interpeak intervals and pulse frequencies were close for the two hormones. In contrast, ghrelin pulse variations were correlated with food intake episodes in the lights off period, and plasma ghrelin concentrations decreased by 26% in the 20 min following the end of the food intake periods. A positive correlation between ghrelin levels and active wake was found during the first 3 h of the dark period only. In conclusion, ghrelin, in addition to affecting GH secretion, gastrointestinal motility, and feeding activity, also modifies sleep-wake patterns. However, a direct action of ghrelin per se or the indirect effects of feeding (and all of its attendant metabolic sequelae) on sleep cannot be differentiated. Moreover, ghrelin secretion is pulsatile and directly related to feeding behavior only.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We did a randomised double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18–75 years with peripheral neuropathic pain were randomly assigned in a 1:1 ratio to M1 or DLPFC-rTMS and re-randomised in a 2:1 ratio to active or sham rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary endpoint was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (group by time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory (BPI), using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified ITT population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self reported pain intensity and fatigue (patients diary), patient and clinician global impression of change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomised and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for group x session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; p = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI:-0.04 to 0.03, p = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimenson of pain, self reported pain intensity and fatigue, PGIC and CGIC. There were no effect on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups respectively (p = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta () oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid ␤ (A␤) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal A␤ injections progressively impaired behavioral performances, the associated hippocampal power, and frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal A␤ treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.