Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction.

The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized

Bimodal coupling of ripples and slower oscillations during sleep in patients with focal epilepsy.

OBJECTIVE: Differentiating pathologic and physiologic high-frequency oscillations (HFOs) is challenging. In patients with focal epilepsy, HFOs occur during the transitional periods between the up and down state of slow waves. The preferred phase angles of this form of phase-event amplitude coupling are bimodally distributed, and the ripples (80-150 Hz) that occur during the up-down transition more often occur in the seizure-onset zone (SOZ). We investigated if bimodal ripple coupling was also evident for faster sleep oscillations, and could identify the SOZ. METHODS: Using an automated ripple detector, we identified ripple events in 40-60 min intracranial electroencephalography (iEEG) recordings from 23 patients with medically refractory mesial temporal lobe or neocortical epilepsy. The detector quantified epochs of sleep oscillations and computed instantaneous phase. We utilized a ripple phasor transform, ripple-triggered averaging, and circular statistics to investigate phase event-amplitude coupling. RESULTS: We found that at some individual recording sites, ripple event amplitude was coupled with the sleep oscillatory phase and the preferred phase angles exhibited two distinct clusters (p \u3c 0.05). The distribution of the pooled mean preferred phase angle, defined by combining the means from each cluster at each individual recording site, also exhibited two distinct clusters (p \u3c 0.05). Based on the range of preferred phase angles defined by these two clusters, we partitioned each ripple event at each recording site into two groups: depth iEEG peak-trough and trough-peak. The mean ripple rates of the two groups in the SOZ and non-SOZ (NSOZ) were compared. We found that in the frontal (spindle, p = 0.009; theta, p = 0.006, slow, p = 0.004) and parietal lobe (theta, p = 0.007, delta, p = 0.002, slow, p = 0.001) the SOZ incidence rate for the ripples occurring during the trough-peak transition was significantly increased. SIGNIFICANCE: Phase-event amplitude coupling between ripples and sleep oscillations may be useful to distinguish pathologic and physiologic events in patients with frontal and parietal SOZ

Getting the best outcomes from epilepsy surgery

Neurosurgery is an under-utilised treatment that can potentially cure drug-refractory epilepsy. Careful, multidisciplinary pre-surgical evaluation is vital for selecting patients and ensure optimal outcomes. Advances in neuroimaging have improved diagnosis and guide surgical intervention. Invasive electroencephalography allows the evaluation of complex patients who would otherwise not be candidates for neurosurgery. We review the current state of the assessment and selection of patients and consider established and novel surgical procedures, and associated outcome data. We aim to dispel myths that may inhibit physicians from referring and patients from considering neurosurgical intervention for drug-refractory focal epilepsies

A Simple Statistical Method for the Automatic Detection of Ripples in Human Intracranial EEG

High frequency oscillations (HFOs) are a promising biomarker of epileptic tissue, but detection of these electrographic events remains a challenge. Automatic detectors show encouraging results, but they typically require optimization of multiple parameters, which is a barrier to good performance and broad applicability. We therefore propose a new automatic HFO detection algorithm, focusing on simplicity and ease of implementation. It requires tuning of only an amplitude threshold, which can be determined by an iterative process or directly calculated from statistics of the rectified filtered data (i.e. mean plus standard deviation). The iterative approach uses an estimate of the amplitude probability distribution of the background activity to calculate the optimum threshold for identification of transient high amplitude events. We tested both the iterative and non-iterative approaches using a dataset of visually marked HFOs, and we compared the performance to a commonly used detector based on the root-mean-square. When the threshold was optimized for individual channels via ROC curve, all three methods were comparable. The iterative detector achieved a sensitivity of 99.6%, false positive rate (FPR) of 1.1%, and false detection rate (FDR) of 37.3%. However, in an eight-fold cross-validation test, the iterative method had better sensitivity than the other two methods (80.0% compared to 64.4 and 65.8%), with FPR and FDR of 1.3, and 49.4%, respectively. The simplicity of this algorithm, with only a single parameter, will enable consistent application of automatic detection across research centers and recording modalities, and it may therefore be a powerful tool for the assessment and localization of epileptic activity

Fast Ripples Reflect Increased Excitability That Primes Epileptiform Spikes

The neuronal circuit disturbances that drive inter-ictal and ictal epileptiform discharges remain elusive. Using a combination of extra-operative macro-electrode and micro-electrode inter-ictal recordings in six pre-surgical patients during non-rapid eye movement sleep, we found that, exclusively in the seizure onset zone, fast ripples (200–600 Hz), but not ripples (80–200 Hz), frequently occur \u3c300 ms before an inter-ictal intra-cranial EEG spike with a probability exceeding chance (bootstrapping, P \u3c 1e−5). Such fast ripple events are associated with higher spectral power (P \u3c 1e−10) and correlated with more vigorous neuronal firing than solitary fast ripple (generalized linear mixed-effects model, P \u3c 1e−9). During the intra-cranial EEG spike that follows a fast ripple, action potential firing is lower than during an intra-cranial EEG spike alone (generalized linear mixed-effects model, P \u3c 0.05), reflecting an inhibitory restraint of intra-cranial EEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike fast ripple in a separate cohort of 23 patients implanted with stereo EEG electrodes, who underwent resections. In non-rapid eye movement sleep recordings, sites containing a high proportion of fast ripple preceding intra-cranial EEG spikes correlate with brain areas where seizures begin more than solitary fast ripple (P \u3c 1e−5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that fast ripple preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating inter-ictal epileptiform discharges

Graph Theoretical Measures of Fast Ripple Networks Improve the Accuracy of Post-operative Seizure Outcome Prediction

Fast ripples (FR) are a biomarker of epileptogenic brain, but when larger portions of FR generating regions are resected seizure freedom is not always achieved. To evaluate and improve the diagnostic accuracy of FR resection for predicting seizure freedom we compared the FR resection ratio (RR) with FR network graph theoretical measures. In 23 patients FR were semi-automatically detected and quantified in stereo EEG recordings during sleep. MRI normalization and co-registration localized contacts and relation to resection margins. The number of FR, and graph theoretical measures, which were spatial (i.e., FR rate-distance radius) or temporal correlational (i.e., FR mutual information), were compared with the resection margins and with seizure outcome We found that the FR RR did not correlate with seizure-outcome (p \u3e 0.05). In contrast, the FR rate-distance radius resected difference and the FR MI mean characteristic path length RR did correlate with seizure-outcome (p \u3c 0.05). Retesting of positive FR RR patients using either FR rate-distance radius resected difference or the FR MI mean characteristic path length RR reduced seizure-free misclassifications from 44 to 22% and 17%, respectively. These results indicate that graph theoretical measures of FR networks can improve the diagnostic accuracy of the resection of FR events for predicting seizure freedom

Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases

Output-Mode Transitions Are Controlled by Prolonged Inactivation of Sodium Channels in Pyramidal Neurons of Subiculum

Transitions between different behavioral states, such as sleep or wakefulness, quiescence or attentiveness, occur in part through transitions from action potential bursting to single spiking. Cortical activity, for example, is determined in large part by the spike output mode from the thalamus, which is controlled by the gating of low-voltage–activated calcium channels. In the subiculum—the major output of the hippocampus—transitions occur from bursting in the delta-frequency band to single spiking in the theta-frequency band. We show here that these transitions are influenced strongly by the inactivation kinetics of voltage-gated sodium channels. Prolonged inactivation of sodium channels is responsible for an activity-dependent switch from bursting to single spiking, constituting a novel mechanism through which network dynamics are controlled by ion channel gating

Delta oscillation coupled propagating fast ripples precede epileptiform discharges in patients with focal epilepsy.

Epileptiform spikes are used to localize epileptogenic brain tissue. The mechanisms that spontaneously trigger epileptiform discharges are not yet elucidated. Pathological fast ripple (FR, 200-600 Hz) are biomarkers of epileptogenic brain, and we postulated that FR network interactions are involved in generating epileptiform spikes. Using macroelectrode stereo intracranial EEG (iEEG) recordings from a cohort of 46 patients we found that, in the seizure onset zone (SOZ), propagating FR were more often followed by an epileptiform spike, as compared with non-propagating FR (p \u3c 0.05). Propagating FR had a distinct frequency and larger power (p \u3c 1e-10) and were more strongly phase coupled to the peak of iEEG delta oscillation, which likely correspond with the DOWN states during non-REM sleep (p \u3c 1e-8), than non-propagating FR. While FR propagation was rare, all FR occurred with the highest probability within +/- 400 msec of epileptiform spikes with superimposed high-frequency oscillations (p \u3c 0.05). Thus, a sub-population of epileptiform spikes in the SOZ, are preceded by propagating FR that are coordinated by the DOWN state during non-REM sleep

Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world

Background Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world.Methods Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n=118) compared with patients from the rest of the world [ROW (n=727)].Results Phenotype distribution differed among patients in Latin America compared to ROW(Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). the frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%.Conclusion These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.MPS I Registry team at Genzyme CorporationHosp Nacl Pediat JP Garrahan, Unidad Errores Congenitos Metab, Buenos Aires, DF, ArgentinaHosp Especialidades UMAE 25, Monterrey, MexicoGenzyme Corp, Latin Amer Grp, Registry Program, Rio de Janeiro, BrazilUniv Rosario, Fdn Univ Ciencias Salud, Bogota, ColombiaUniv Valparaiso, Fac Med, Neurol Infantil Programa Formac Neuropediat, Valparaiso, ChileUniv Chile, INTA, Lab Genet & Enfermedades Metab, Santiago, ChileUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilGenzyme Corp, Latin Amer Grp, Compassionate Use Program, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilWeb of Scienc