Intracortical modulation, and not spinal inhibition, mediates placebo analgesia

Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI during placebo analgesia, which is therefore increasingly considered a phenomenon caused by descending inhibition of spinal activity. However, spinal fMRI is technically challenging and prone to false-positive results. Here we recorded laser-evoked potentials (LEPs) during placebo analgesia in humans. LEPs allow neural activity to be measured directly and with high enough temporal resolution to capture the sequence of cortical areas activated by nociceptive stimuli. If placebo analgesia is mediated by inhibition at spinal level, this would result in a general suppression of LEPs rather than in a selective reduction of their late components. LEPs and subjective pain ratings were obtained in two groups of healthy volunteers - one was conditioned for placebo analgesia while the other served as unconditioned control. Laser stimuli at three suprathreshold energies were delivered to the right hand dorsum. Placebo analgesia was associated with a significant reduction of the amplitude of the late P2 component. In contrast, the early N1 component, reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI), was only affected by stimulus energy. This selective suppression of late LEPs indicates that placebo analgesia is mediated by direct intracortical modulation rather than inhibition of the nociceptive input at spinal level. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia

Intracortical modulation, and not spinal inhibition, mediates placebo analgesia

Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI (sfMRI) during placebo analgesia, which is increasingly considered a phenomenon caused by descending inhibition. However, the sfMRI is technically challenging and prone to falsepositive results. We employed EEG and recorded laser‐evoked potentials (LEPs), which allows neural activity to be measured directly and with high enough temporal resolution to capture the ensemble of cortical areas that are activated by nociceptive stimuli. The hypothesis is that inhibition at the spinal level during placebo analgesia should be evidenced by a general suppression of LEPs, rather than by a selective reduction of late LEP components. LEPs and subjective ratings of pain were obtained in two groups of healthy volunteers: one was conditioned for placebo analgesia, while the other served as unconditioned control. Three different supra‐threshold laser stimulus energies (3, 3.5 and 4 Joules) were delivered to the right hand dorsum. Placebo analgesia was associated with a selective reduction of late components of LEPs (P2 wave). In contrast, early component (N1 wave) reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI) were affected by the magnitude of laser stimulus energies only. The selective suppression of late LEPs during placebo analgesia suggests an underlying mechanism of direct intra‐cortical modulation, rather than inhibition at the spinal level of afferent nociceptive input. Furthermore, cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia

Peri-ictal and inter-ictal headache in children and adolescents with idiopathic epilepsy: a multicenter cross-sectional study.

PURPOSE: Headache in epileptic population ranges from 8% to 15%. The aim of this paper was to study the clinical and temporal characteristics of primary headache comorbidity in idiopathic epileptic children. METHODS: From June 2006 to June 2009, a cross-sectional multi-center study involving five Italian Child Neurology University Centers (two in Rome, one in Chieti, one in Naples, and one in L'Aquila) was conducted. Among 1,264 consecutively newly diagnosed, idiopathic, partial, or generalized, epileptic children, according to ILAE diagnostic criteria (aged between 5 and 15 years of age), we selected 142 children (11.2%) (130 of whom completed the study) who showed an associated peri-ictal and/or inter-ictal headache diagnosed according to the International Headache Society Criteria. Rare cases of "ictal epileptic headache", in which headache represents the sole ictal epileptic manifestation, were excluded from this study. RESULTS AND CONCLUSIONS: Post-ictal headaches were most frequent (62%). Pre-ictal headaches were less common (30%). Inter-ictal headaches were described in 57.6%. Clear migrainous features were present in 93% of pre-ictal and 81.4% of post-ictal headaches. Inter-ictal headaches meet criteria for migraines in 87%. The association between partial epilepsy and migraine without aura is most common and reported in 82% of our patients with peri-ictal headache and in 76.5% of patients with post-ictal headache

Should "migralepsy" be considered an obsolete concept? A multicenter retrospective clinical/EEG study and review of the literature.

The few reports that have been published on the current International Classification of Headache Disorders, Second Edition (ICHD-II), criteria for migralepsy and hemicrania epileptica have highlighted the considerable confusion regarding this "hot topic" within both headache and epilepsy classifications (ICHD-II and International League Against Epilepsy [ILAE]). Indeed, the ICHD-II describes a migraine-triggered seizure as a rare event in which a seizure occurs during migraine aura; on the other hand, hemicrania epileptica is described as an "ictal headache" that occurs "synchronously" with a partial seizure. To confuse matters even further, neither the term migralepsy nor the term hemicrania epileptica is included in the currently used ILAE classification. On the basis of both a review of "migralepsy" cases in the literature and 16 additional retrospective multicenter cases, we suggest that the term migraine-triggered seizure or migralepsy be deleted from the ICHD-II classification until unequivocal evidence is provided of its existence, and that the term ictal epileptic headache be introduced into the ILAE classification

Long term outcome in children affected by absence epilepsy with onset before the age of three years.

OBJECTIVE: The goal of this study was to define the long-term outcome of absence epilepsy presenting before the age of 3 years. METHODS: We retrospectively studied the medical records of 40 children from eight neuropediatric centers in Italy with respect to the personal and family histories of epilepsy or febrile seizures, time of follow-up, cognitive functions, treatment, and outcome. RESULTS: Forty patients were enrolled in this study. They all fulfilled the criteria for absence epilepsy with 3-Hz spike-wave complexes on the EEG, normal neurological examination, and no other seizures types. Seizure onset occurred between 24.1 and 36.0 months. There was a family history of epilepsy in 28%, and of febrile seizures in 13%. Thirty-three patients were treated with valproic acid (VPA), mostly used in monotherapy (26 patients) or in association with ethosuximide. At final follow-up, 33 patients were seizure free and 29 had normal EEGs. Thirty-four patients had a normal intelligence quotient (IQ), whereas 6 had a decreased IQ, mainly associated with poor control of seizures. CONCLUSION: In our series, absence seizures presenting before the age of 3 appeared to have quite a good long-term clinical prognosis; the neuropsychological outcome was comparable to that of childhood epilepsy presenting after 3 years of age

Thoughts of Death Modulate Psychophysical and Cortical Responses to Threatening Stimuli

Existential social psychology studies show that awareness of one's eventual death profoundly influences human cognition and behaviour by inducing defensive reactions against end-of-life related anxiety. Much less is known about the impact of reminders of mortality on brain activity. Therefore we explored whether reminders of mortality influence subjective ratings of intensity and threat of auditory and painful thermal stimuli and the associated electroencephalographic activity. Moreover, we explored whether personality and demographics modulate psychophysical and neural changes related to mortality salience (MS). Following MS induction, a specific increase in ratings of intensity and threat was found for both nociceptive and auditory stimuli. While MS did not have any specific effect on nociceptive and auditory evoked potentials, larger amplitude of theta oscillatory activity related to thermal nociceptive activity was found after thoughts of death were induced. MS thus exerted a top-down modulation on theta electroencephalographic oscillatory amplitude, specifically for brain activity triggered by painful thermal stimuli. This effect was higher in participants reporting higher threat perception, suggesting that inducing a death-related mind-set may have an influence on body-defence related somatosensory representations

SK channel-mediated metabolic escape to glycolysis inhibits ferroptosis and supports stress resistance in C. elegans

Metabolic flexibility is an essential characteristic of eukaryotic cells in order to adapt to physiological and environmental changes. Especially in mammalian cells, the metabolic switch from mitochondrial respiration to aerobic glycolysis provides flexibility to sustain cellular energy in pathophysiological conditions. For example, attenuation of mitochondrial respiration and/or metabolic shifts to glycolysis result in a metabolic rewiring that provide beneficial effects in neurodegenerative processes. Ferroptosis, a non-apoptotic form of cell death triggered by an impaired redox balance is gaining attention in the field of neurodegeneration. We showed recently that activation of small-conductance calcium-activated K+ (SK) channels modulated mitochondrial respiration and protected neuronal cells from oxidative death. Here, we investigated whether SK channel activation with CyPPA induces a glycolytic shift thereby increasing resilience of neuronal cells against ferroptosis, induced by erastin in vitro and in the nematode C. elegans exposed to mitochondrial poisons in vivo. High-resolution respirometry and extracellular flux analysis revealed that CyPPA, a positive modulator of SK channels, slightly reduced mitochondrial complex I activity, while increasing glycolysis and lactate production. Concomitantly, CyPPA rescued the neuronal cells from ferroptosis, while scavenging mitochondrial ROS and inhibiting glycolysis reduced its protection. Furthermore, SK channel activation increased survival of C. elegans challenged with mitochondrial toxins. Our findings shed light on metabolic mechanisms promoted through SK channel activation through mitohormesis, which enhances neuronal resilience against ferroptosis in vitro and promotes longevity in vivo

Contact heat evoked potentials using simultaneous EEG and fMRI and their correlation with evoked pain

BACKGROUND: The Contact Heat Evoked Potential Stimulator (CHEPS) utilises rapidly delivered heat pulses with adjustable peak temperatures to stimulate the differential warm/heat thresholds of receptors expressed by Adelta and C fibres. The resulting evoked potentials can be recorded and measured, providing a useful clinical tool for the study of thermal and nociceptive pathways. Concurrent recording of contact heat evoked potentials using electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) has not previously been reported with CHEPS. Developing simultaneous EEG and fMRI with CHEPS is highly desirable, as it provides an opportunity to exploit the high temporal resolution of EEG and the high spatial resolution of fMRI to study the reaction of the human brain to thermal and nociceptive stimuli. METHODS: In this study we have recorded evoked potentials stimulated by 51° C contact heat pulses from CHEPS using EEG, under normal conditions (baseline), and during continuous and simultaneous acquisition of fMRI images in ten healthy volunteers, during two sessions. The pain evoked by CHEPS was recorded on a Visual Analogue Scale (VAS). RESULTS: Analysis of EEG data revealed that the latencies and amplitudes of evoked potentials recorded during continuous fMRI did not differ significantly from baseline recordings. fMRI results were consistent with previous thermal pain studies, and showed Blood Oxygen Level Dependent (BOLD) changes in the insula, post-central gyrus, supplementary motor area (SMA), middle cingulate cortex and pre-central gyrus. There was a significant positive correlation between the evoked potential amplitude (EEG) and the psychophysical perception of pain on the VAS. CONCLUSION: The results of this study demonstrate the feasibility of recording contact heat evoked potentials with EEG during continuous and simultaneous fMRI. The combined use of the two methods can lead to identification of distinct patterns of brain activity indicative of pain and pro-nociceptive sensitisation in healthy subjects and chronic pain patients. Further studies are required for the technique to progress as a useful tool in clinical trials of novel analgesics

Clinical and morphological characteristics of head-facial haemangiomas

BACKGROUND: Haemangiomas of the head or face are a frequent vascular pathology, consisting in an embryonic dysplasia that involves the cranial-facial vascular network. Haemangiomas show clinical, morphological, developmental and structural changes during their course. METHODS: The clinical characteristics of head-facial haemagiomas were studied in 28 individuals (9 males and 19 females) admitted in our Hospital. Sixteen of these patients(n = 16) underwent surgery for the removal of the haemangiomas. All the removed tissues were transferred in experimental laboratories for the staining of microanatomical details, somatic and visceral nerve fibres, adrenergic and catecholaminergic nerve fibres. Beta-adrenergic receptors were died with a fluorescent method. All results were submitted to the quantitative analysis of images and statistical evaluation of the data. RESULTS: The morphological results revealed numerous micro-anatomical characteristics of the haemangiomatous vessels. The somatic and visceral nerve fibres were poor and located exclusively in the adventitial layer. There was a marked decrease of adrenergic nerve fibres in the haemangiomatous vessels. The fluorescence of catecholaminergic nerve fibres and the overall area of fluorescent structures were also decreased in haemangiomatous vessels. Beta adrenergic receptors are strongly decreased in haemangiomatous vessels. The morphometrical analysis of images and statistical evaluation of the data confirmed all our experimental results. CONCLUSION: The catecholaminergic innervation of the human haemangiomatous vessels comprises nerve fibres containing the main catecholaminergic neurotransmitters that are sympathetic in nature. These neurotransmitters are closely related to beta-adrenergic receptors. The sympathetic nervous system plays a key role in the control of the vascular bed flow and vascular motility in both normal and haemangiomatous vessels