The localization of orexin neuropeptides in the lateral hypothalamus has focused interest on their role in ingestion. The orexigenic neurones in the lateral hypothalamus, however, project widely in the brain, and thus the physiological role of orexins is likely to be complex. Here we describe an investigation of the action of orexin A in modulating the arousal state of rats by using a combination of tissue localization and electrophysiological and behavioral techniques. We show that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of orexin A increases cell firing of intrinsic noradrenergic neurones. Orexin A increases arousal and locomotor activity and modulates neuroendocrine function. The data suggest that orexin A plays an important role in orchestrating the sleep-wake cycle.Since the discovery of the orexins (1) investigations of their functions have been guided by evidence for their hypothalamic distribution (1, 2), focusing on feeding, energy homeostasis (1, 3), and neurocrine functions (3). Our studies now show the presence of orexin A immunoreactive fibers and varicosities in extrahypothalamic areas, particularly the locus coeruleus, and demonstrate that the functions of orexin A extend beyond the hypothalamus.Orexin A and B are derived from a 130-aa precursor, prepro-orexin, which is encoded by a gene localized to human chromosome 17q21 (1). Prepro-orexin, or preprohypocretin (2), was identified in the rat hypothalamus by directional tag PCR subtractive hybridization (2) and has been shown by Northern blot analysis to be abundant in the brain and detectable at low levels in testes but not in a variety of other tissues (1, 2). Hypocretins had been identified as hypothalamic neuropeptides, but their biological role was not described (2). Nucleotide sequence alignment shows that hypocretins 1 and 2 have sequence in common with orexins A and B, respectively, but additional amino acids are present in both hypocretins. In situ hybridization maps confirm dense prepro-orexin mRNA expression in the hypothalamus (1, 2). Immunocytochemical mapping of orexin A has identified a population of mediumsized neurones within the hypothalamus, median eminence (3), and ventral thalamic nuclei of rat brain (1, 3). This distribution has been confirmed in human tissue (4).Orexin A binds with high affinity to the novel G proteincoupled receptors orexin 1 (OX 1 ) (IC 50 20 nM) and orexin 2 (OX 2 ) (IC 50 38 nM). Calcium mobilization assays in transfected HEK293 cells confirm that orexin A is a potent agonist at both OX 1 (EC 50 30 nM) and OX 2 (EC 50 34 nM) (1). Emerging evidence suggests the existence of an extensive extrahypothalamic projection of orexin-immunoreactive neurones. Peyron et al. (5), in addition to confirming the presence of immunoreactive cell somata within the hypothalamus, reported immunolabeled fibers throughout extrahypothalamic regions, including septal nuclei, substantia nigra, and raphe nucle...

Visual hallucinations are common symptoms of seizures affecting primary and association cortices, and can provide vital information about the ictal onset zone. Epileptic kinetopsia, defined as illusionary movement of stationary objects in the visual field, was reported in a patient with a tumor in the temporal-parietal-occipital (TPO) junction. Intracranial stimulation of TPO junction did not evoke kinetopsia and the site of onset of this phenomenon is unknown. 1 We describe a patient with ictal kinetopsia whose seizure onset zone was localized with intracranial EEG.Case report. A 33-year-old right-handed woman had had pharmacoresistant focal epilepsy since age 15 months. Her habitual seizures started at age 16 years, characterized by visual perception of stationary objects located on her right side shift to the center or to the left. During these episodes, she described difficulties differentiating near and far objects, without blurring, double vision, scotomas, headache, or light hypersensitivity. This progressed to forceful blinking, tingling sensation of the left cheek and arm, followed by left arm posturing and left foot-jerking movements with preserved awareness. Postictally, visual field and color vision were normal. Scalp EEG revealed interictal epileptiform spikes or polyspikes over right centroparietal region (CP2, CP4, C4.P4, CZ, F4). Brain MRI showed area of cortical dysplasia in the right superior parietal lobule (SPL) and intraparietal sulcus (IPS) with cortical thickening on T1 and fluidattenuated inversion recovery signal change in the underlying white matter ( figure 1, A and B).Intracranial EEG recording and stimulation. Intracranial EEG was performed to determine the ictal onset zone and map sensory and motor functions. The patient underwent implantation of 8 3 7 contact subdural grid (10-mm spacing, AD-Tech, Watertown, WI) covering the area of cortical dysplasia and precentral and postcentral gyrus. Three depth electrodes were placed targeting the lesion (anteriorly D1, 1 3 6 contacts 5-mm spaced), posteriorly (D2, 1 3 4 contacts 5-mm spaced), and inferiorly (D3, 1 3 4 contacts 10-mm spaced) ( figure 1C). Interictally, frequent spikes were seen in the SPL and IPS. We recorded 51 seizures with kinetopsia at the onset, progressing to bilateral eye blinking and sometimes left hand-tingling sensation. In the postictal period, visual fields, language, and motor skills were normal. Ictal EEG showed stereotypical fast activity in right SPL and IPS (electrode contacts GA12 . GA13 . D2, ;70 Hz) ( figure 1D). Bipolar electrocortical stimulation of contact GA 13 (against distant electrode GA 53) evoked kinetopsia time locked to the electrical stimulus (figure e-1 on the Neurology ® Web site at Neurology.org); following stimulation, habitual interictal spikes returned on GA 12, 13, and D2. Resection was carried out at the posterior parietal cortex and pathology revealed Taylor type IIb focal cortical dysplasia. Postoperatively, there were no visual deficits. Transient difficulties to reach for objects wi...

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