Electrical stimulation of primary sensory afferents is known to have an antinociceptive effect. Animal and functional imaging studies suggest a role for supraspinal structures in this response. Eight patients with chronic migraine (≥15 days per month of attacks of migraine without aura), who had shown a marked beneficial response to implanted bilateral suboccipital stimulators, were studied. Stimulation evoked local paraesthesia, the presence of which was a criterion of pain relief. On stimulation, the headache began to improve instantaneously and was completely suppressed within 30 min. On switching off the stimulation, the headache recurred instantly and peaked within 20 min. PET scans were performed using regional cerebral blood flow (rCBF) as a marker of neuronal activity. Each patient was scanned in the following three states: (1) stimulator at optimum settings: patient pain‐free but with paraesthesia; (2) stimulator off: patient in pain and no paraesthesia; (3) stimulator partially activated: patient with intermediate levels of pain and paraesthesia. All scans were processed and analysed using Statistical Parametric Mapping (SPM) 99. There were significant changes in rCBF in the dorsal rostral pons, anterior cingulate cortex (ACC) and cuneus, correlated to pain scores, and in the ACC and left pulvinar, correlated to stimulation‐induced paraesthesia scores. The activation pattern in the dorsal rostral pons is highly suggestive of a role for this structure in the pathophysiology of chronic migraine. The localization and persistence of activity during stimulation is exactly consistent with a region activated in episodic migraine, and with the persistence of activation of that area after successful treatment. The dorsal rostral pons may be a locus of neuromodulation by suboccipital stimulation. In addition, suboccipital stimulation modulated activity in the left pulvinar.

Patients with primary headaches often report pain that involves not only the front of the head, innervated by the first (ophthalmic) division of the trigeminal nerve, but also the back of the head, innervated by the greater occipital nerve (GON) that is a branch of the C₂ spinal root. The aim of this work was to study the physiology of trigeminocervical input in a model of cranial nociception by describing a population of nociceptive neurones that receive convergent input from the supratentorial dura and the GON. Rats were anaesthetized with pentobarbital, paralysed and ventilated. The parietal dura above the middle meningeal artery was stimulated through a closed cranial window. The GON was exposed in the neck and stimulated. Recordings were made from 67 neurones (52 wide dynamic range neurones/15 nociceptive‐specific‐neurones) in the C₂ spinal dorsal horn, which responded to stimulation of the dura and the GON. Most neurones showed receptive fields corresponding to the first trigeminal division as well as input from C₂ skin and muscle. Neurones were recorded in superficial and deep layers of the dorsal horn. All neurones tested received input from the ipsilateral and contralateral GON (n = 5). The responses to dural stimulation were analysed before and after stimulation of the GON. Supramaximal electrical stimulation of the GON (20 s to 5 min) enhanced afferent dural input in 8/20 neurones. Application of the C‐fibre activator mustard oil (MO) to the cutaneous receptive field or suboccipital muscles innervated by the GON induced an increased excitability of dural responses in 8/12 and 9/10 neurones, respectively. Stimulation of muscle afferents had a significant longer facilitatory effect than cutaneous stimulation (P < 0.05). These results show that a considerable population of neurones show convergent input from both dura as well as cervical cutaneous and muscle territories, which supports the view of a functional continuum between the caudal trigeminal nucleus and upper cervical segments involved in cranial nociception. The facilitatory effect of GON stimulation on dural stimulation suggests a central mechanism at the second order neurone level. This mechanism may be important in pain referral from cervical structures to the head and therefore have implications for most forms of primary headache.

Pain referral and spread in headache patients may be attributed to a sensitization of central nociceptive neurons with an increased excitability to afferent input. We investigated if noxious dural stimulation evokes sensitization of second‐order neurons that leads to an increased responsiveness to stimulation of cervical afferents. Recordings were made from 29 nociceptive neurons in the C₂ dorsal horn of the rat that received convergent synaptic input from trigeminal and cervical afferents. Trigeminal afferents of the supratentorial dura mater were activated by mustard oil (MO) and the responses of second‐order neurons to stimulation of the greater occipital nerve (GON) were studied before and after dural stimulation. Projection sites to the contralateral thalamus were determined by antidromic stimulation. After dural application with MO, mechanical thresholds of the dura significantly decreased (P < 0.05) and an enlargement of the trigeminal and cervical cutaneous mechanoreceptive fields was observed in 71% of neurons. The responses to noxious mechanical stimulation of deep paraspinal muscles increased after MO application (P < 0.001). Similarly, an increase in the excitability to electrical stimulation of the GON was observed in C‐fibre responses (P < 0.001). These results suggest that stimulation of nociceptive afferent C‐fibres of the dura mater leads to a sensitization of second‐order neurons receiving cervical input. This mechanism might be involved in the referral of pain from trigeminal to cervical structures and might contribute to the clinical phenomena of cervical hypersensitivity in migraine and cluster headache. Understanding this interaction is likely to be pivotal in characterizing the physiology of treatment with manipulations involving cervical input, such as GON injection.

Limbic encephalitis with leucine-rich, glioma-inactivated 1 (LGI1) antibodies is one of the most frequent variants of autoimmune encephalitis with antibodies targeting neuronal surface antigens. However, the neuroimaging pattern and long-term cognitive outcome are not well understood. To study cognitive outcome and structural magnetic resonance imaging (MRI) alterations in patients with anti-LGI1 encephalitis. A cross-sectional study was conducted at the Departments of Neurology at Charité-Universitätsmedizin Berlin and University Hospital Schleswig-Holstein, Kiel, Germany. Data on 30 patients with anti-LGI1 encephalitis and 27 healthy control individuals matched for age, sex, and educational level were collected from June 1, 2013, through February 28, 2015. Clinical assessment, cognitive testing, and high-resolution MRI data, including whole-brain, hippocampal and basal ganglia volumetry; white matter integrity (diffusion tensor imaging); gray matter density (voxel-based morphometry); and hippocampal microstructural integrity (mean diffusivity and fractional anisotropy). Of the 30 patients included in the study, 19 were male (63%); mean (SD) age was 65.7 (12.3) years. Patients with anti-LGI1 encephalitis had incomplete recovery with significant and persisting verbal (mean [SE] Rey Auditory Verbal Learning Test [RAVLT], delayed recall: patients, 6.52 [1.05]; controls, 11.78 [0.56], P < .001) and visuospatial (Rey-Osterrieth Complex Figure Test [ROCF], delayed recall: patients, 16.0 [1.96]; controls, 25.86 [1.24]; P < .001) memory deficits. These deficits were accompanied by pronounced hippocampal atrophy, including subfields cornu ammonis 2/3 (CA2/3) and CA4/dentate gyrus (DG), as well as impaired hippocampal microstructural integrity. Higher disease severity correlated with larger verbal memory deficits (RAVLT delayed recall, r = -0.40; P = .049), decreased volumes of left hippocampus (r = -0.47; P = .02) and left CA2/3 (r = -0.41; P = .04) and CA4/DG (r = -0.43; P = .03) subfields, and impaired left hippocampal microstructural integrity (r = 0.47; P = .01). In turn, decreased volume of the left CA2/3 subfield (RAVLT delayed recall, r = 0.40; P = .047) and impaired left hippocampal microstructural integrity (RAVLT recognition, r = -0.41; P = .04) correlated with verbal memory deficits. Basal ganglia MRI signal abnormalities were observed in only 1 patient, but a longer duration of faciobrachial dystonic seizures correlated with a reduction of pallidum volume (r = -0.71; P = .03). In contrast, no abnormalities of cortical gray matter or white matter were found. The latency between disease onset and initiation of immunotherapy was significantly correlated with verbal (RAVLT recall after interference, r = -0.48; P = .02) and visuospatial (ROCF delayed recall, r = -0.46; P = .03) memory deficits. Anti-LGI1 encephalitis is associated with cognitive deficits and disability as a result of structural damage to the hippocampal memory system. This damage might be prevented by early immunotherapy.

Autobiographical memories in our lives are critically dependent on temporal lobe structures. However, the contribution of CA1 neurons in the human hippocampus to the retrieval of episodic autobiographical memory remains elusive. In patients with a rare acute transient global amnesia, highly focal lesions confined to the CA1 field of the hippocampus can be detected on MRI. We studied the effect of these lesions on autobiographical memory using a detailed autobiographical interview including the remember/know procedure. In 14 of 16 patients, focal lesions in the CA1 sector of the hippocampal cornu ammonis were detected. Autobiographical memory was significantly affected over all time periods, including memory for remote periods. Impairment of episodic memory and autonoetic consciousness exhibited a strong temporal gradient extending 30 to 40 y into the past. These results highlight the distinct and critical role of human hippocampal CA1 neurons in autobiographical memory retrieval and for re-experiencing detailed episodic memories.