Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.

Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.

Relationship between autonomic neuropathy and thermogenesis in non diabetic and diabetic obese patients.

Autonomic neuropathy is a well known complication of diabetes. Diabetes is often superimposed on obesity. A reduction in the variability of the heart rate in the resting state has been demonstrated in 16 obese diabetic subjects as well as in 34 obese non-diabetic subjects. The coefficient of variation (CV) of the heart rate during 30 minutes of resting was significantly decreased in both obese groups (3.9 +/- 0.2% for the diabetics; 5.2 +/- 0.2%, p less than 0.01 for the non diabetics) as compared to their own controls (4.5 +/- 0.6% and 6.5 +/- 0.4%, respectively). Age also contributes to decreased heart rate variability. Furthermore, this defect of autonomic function has been correlated with the blunted glucose-induced thermogenesis (GIT) seen in both obese groups (r = 0.52, p. less than 0.001): the increase in energy expenditure over basal values following a 100 g oral glucose load was only 4.8 +/- 0.8% for the diabetic obese group (p less than 0.001), and 8.5 +/- 0.7% for the non-diabetic obese group (p less than 0.001) as opposed to their own controls (12.4 +/- 1.3% and 13.3 +/- 0.6% respectively). Measurement of the variability of heart rate in obese individuals may be of predictive value in assessing blunted glucose-induced thermogenesis in non diabetic and diabetic obese patients.

Investigation of high-resolution functional magnetic resonance imaging by means of surface and array radiofrequency coils at 7 T.

In this investigation, high-resolution, 1x1x1-mm(3) functional magnetic resonance imaging (fMRI) at 7 T is performed using a multichannel array head coil and a surface coil approach. Scan geometry was optimized for each coil separately to exploit the strengths of both coils. Acquisitions with the surface coil focused on partial brain coverage, while whole-brain coverage fMRI experiments were performed with the array head coil. BOLD sensitivity in the occipital lobe was found to be higher with the surface coil than with the head array, suggesting that restriction of signal detection to the area of interest may be beneficial for localized activation studies. Performing independent component analysis (ICA) decomposition of the fMRI data, we consistently detected BOLD signal changes and resting state networks. In the surface coil data, a small negative BOLD response could be detected in these resting state network areas. Also in the data acquired with the surface coil, two distinct components of the positive BOLD signal were consistently observed. These two components were tentatively assigned to tissue and venous signal changes.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage. Hum Brain Mapp 36:1609-1619, 2015. © 2014 Wiley Periodicals, Inc.

Metabolic connectivity as index of verbal working memory.

Positron emission tomography (PET) data are commonly analyzed in terms of regional intensity, while covariant information is not taken into account. Here, we searched for network correlates of healthy cognitive function in resting state PET data. PET with [(18)F]-fluorodeoxyglucose and a test of verbal working memory (WM) were administered to 35 young healthy adults. Metabolic connectivity was modeled at a group level using sparse inverse covariance estimation. Among 13 WM-relevant Brodmann areas (BAs), 6 appeared to be robustly connected. Connectivity within this network was significantly stronger in subjects with above-median WM performance. In respect to regional intensity, i.e., metabolism, no difference between groups was found. The results encourage examination of covariant patterns in FDG-PET data from non-neurodegenerative populations.

Weakened functional connectivity in patients with psychogenic non-epileptic seizures (PNES) converges on basal ganglia.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) are involuntary paroxysmal events that are unaccompanied by epileptiform EEG discharges. We hypothesised that PNES are a disorder of distributed brain networks resulting from their functional disconnection.The disconnection may underlie a dissociation mechanism that weakens the influence of unconsciously presented traumatising information but exerts maladaptive effects leading to episodic failures of behavioural control manifested by psychogenic 'seizures'. METHODS: To test this hypothesis, we compared functional connectivity (FC) derived from resting state high-density EEGs of 18 patients with PNES and 18 age-matched and gender-matched controls. To this end, the EEGs were transformed into source space using the local autoregressive average inverse solution. FC was estimated with a multivariate measure of lagged synchronisation in the θ, α and β frequency bands for 66 brain sites clustered into 18 regions. A multiple comparison permutation test was applied to deduce significant between-group differences in inter-regional and intraregional FC. RESULTS: The significant effect of PNES-a decrease in lagged FC between the basal ganglia and limbic, prefrontal, temporal, parietal and occipital regions-was found in the α band. CONCLUSION: We believe that this finding reveals a possible neurobiological substrate of PNES, which explains both attenuation of the effect of potentially disturbing mental representations and the occurrence of PNES episodes. By improving understanding of the aetiology of this condition, our results suggest a potential refinement of diagnostic criteria and management principles.

Études de type structure fonction du couplage électromécanique et de la coopérativité sous-unitaire chez les canaux potassiques dépendants du voltage

Les canaux potassiques voltage-dépendants forment des tétramères dont chaque sous-unité comporte six segments transmembranaires (S1 à S6). Le pore, formé des segments S5-S6 de chaque sous-unité, est entouré de quatre domaines responsables de la sensibilité au potentiel membranaire, les senseurs de voltage (VS; S1-S4). Lors d’une dépolarisation membranaire, le mouvement des résidus chargés situés dans le VS entraine un mouvement de charges détectable en électrophysiologie, le courant de « gating ». L’activation du VS conduit à l'ouverture du pore, qui se traduit par un changement de conformation en C-terminal du segment S6. Pour élucider les principes qui sous-tendent le couplage électromécanique entre ces deux domaines, nous avons étudié deux régions présumées responsables du couplage chez les canaux de type Shaker K+, soit la région carboxy-terminale du segment S6 et le lien peptidique reliant les segments transmembranaire S4-S5 (S4-5L). Avec la technique du « cut-open voltage clamp fluorometry » (COVCF), nous avons pu déterminer que l’interaction inter-sous-unitaire RELY, formée par des acides aminés situés sur le lien S4-5L et S6 de deux sous-unités voisines, est impliquée dans le développement de la composante lente observée lors du retour des charges de « gating » vers leur état de repos, le « OFF-gating ». Nous avons observé que l’introduction de mutations dans la région RELY module la force de ces interactions moléculaires et élimine l’asymétrie observée dans les courants de « gating » de type sauvage. D’ailleurs, nous démontrons que ce couplage inter-sous-unitaire est responsable de la stabilisation du pore dans l’état ouvert. Nous avons également identifié une interaction intra-sous-unitaire entre les résidus I384 situé sur le lien S4-5L et F484 sur le segment S6 d’une même sous-unité. La déstabilisation de cette interaction hydrophobique découple complètement le mouvement des senseurs de voltage et l'ouverture du pore. Sans cette interaction, l’énergie nécessaire pour activer les VS est moindre en raison de l’absence du poids mécanique appliqué par le pore. De plus, l’abolition du couplage électromécanique élimine également le « mode shift », soit le déplacement de la dépendance au voltage des charges de transfert (QV) vers des potentiels hyperpolarisants. Ceci indique que le poids mécanique du pore imposé au VS entraine le « mode shift », en modulant la conformation intrinsèque du VS par un processus allostérique.

Corrélats neuronaux de la mémoire de travail en magnétoencéphalographie à l’état de repos.

Purpose: There are few studies demonstrating the link between neural oscillations in magnetoencephalography (MEG) at rest and cognitive performance. Working memory is one of the most studied cognitive processes and is the ability to manipulate information on items kept in short-term memory. Heister & al. (2013) showed correlation patterns between brain oscillations at rest in MEG and performance in a working memory task (n-back). These authors showed that delta/theta activity in fronto-parietal areas is related to working memory performance. In this study, we use resting state MEG oscillations to validate these correlations with both of verbal (VWM) and spatial (SWM) working memory, and test their specificity in comparison with other cognitive abilities. Methods: We recorded resting state MEG and used clinical neuropsychological tests to assess working memory performance in 18 volunteers (6 males and 12 females). The other neuropsychological tests of the WAIS-IV were used as control tests to assess the specificity of the correlation patterns with working memory. We calculated means of Power Spectrum Density for different frequency bands (delta, 1-4Hz; theta, 4-8Hz; alpha, 8-13Hz; beta, 13-30Hz; gamma1, 30-59Hz; gamma2, 61-90Hz; gamma3, 90-120Hz; large gamma, 30-120Hz) and correlated MEG power normalised for the maximum in each frequency band at the sensor level with working memory performance. We then grouped the sensors showing a significant correlation by using a cluster algorithm. Results: We found positive correlations between both types of working memory performance and clusters in the bilateral posterior and right fronto-temporal regions for the delta band (r2 =0.73), in the fronto-middle line and right temporal regions for the theta band (r2 =0.63) as well as in the parietal regions for the alpha band (r2 =0.78). Verbal working memory and spatial working memory share a common fronto-parietal cluster of sensors but also show specific clusters. These clusters are specific to working memory, as compared to those obtained for other cognitive abilities and right posterior parietal areas, specially in slow frequencies, appear to be specific to working memory process. Conclusions: Slow frequencies (1-13Hz) but more precisely in delta/theta bands (1-8Hz), recorded at rest with magnetoencephalography, predict working memory performance and support the role of a fronto-parietal network in working memory.

Mecanismes cel·lulars en la curació de ferides a Hirudo medicinalis

S'estudia la histologia normal de la paret corporal d'Hirudo medicinalis i els canvis morfogenètics que es donen durant el procés de cicatrització de ferides per incisió, cauterització i nitrat de plata. El procés de curació de ferides a Hirudo medicinalis consta d'una fase de formació d'un tap cel·lular, el pseudoblastema, d'un procés de reepitelització i de la formació d'un teixit cicatricial, com en els altres hirudinis estudiats (Myers, 1935; LeGore i Sparks, 1971; Cornec, 1984). Hem observat també el fenomen de la contracció de la ferida que permet l'acostament dels marges de la ferida. Formació i evolució del pseudoblastema El pseudoblastema, a diferència d'altres espècies estudiades, està format per un sol tipus cel·lular: les cèl·lules vasocentrals, provinents del teixit vasofibrós, una especialització del teixit connectiu. Aquestes cèl·lules estan capacitades per realitzar les diferents funcions que en espècies rincobdèl·lides realitzen diferents tipus cel·lulars. En concret: taponament de la ferida a través de la formació del pseudoblastema, fagocitosi dels teixits necrosats i regeneració, almenys d'una part, de la matriu connectiva cicatricial. També són responsables de la contracció de la ferida. Les cèl·lules vasocentrals en el seu estadi de repòs es troben en el teixit vasofibrós formant agrupacions coherents, però sense mostrar unions intercel·lulars especialitzades visibles en ME. La coherència del grup queda assegurada per les interdigitacions entre les cèl·lules vasocentrals i probablement per unions tipus adherens o especialitzades. Les unions amb la matriu són de tipus adherens. Aquestes cèl·lules vasocentrals presenten feixos de filaments d'actina força conspicus. En produir-se una ferida les cèl·lules vasocentrals s'activen, desconnecten les unions intercel·lulars i amb la matriu i migren cap a la zona afectada, on s'acumulen. El pseudoblastema actua com un tap cel·lular que funciona de forma eficient per tancar la ferida en un plaç de temps relativament curt. El pseudoblastema forma un teixit coherent amb unions intercel·lulars tipus adherens, caracteritzades per material electrodens en la cara intracitoplasmàtica, feixos de filaments d'actina que hi convergeixen i espais intercel·lulars petits, de 17-20 mm, atravessats per petites fibril·les. Un cop finalitzat el procés de reepitelització, es produeix una contracció de la ferida. Es produeix per la retracció del pseudoblastema cap a l'interior de l'animal. El pseudoblastema disminueix la seva amplària i arrossega els teixits contigus provocant un tancament. La força motriu que provoca la retracció i l'arrossegament dels teixits vindria donada per la presència dels filaments d'actina a les cèl·lules del pseudoblastema, els quals durant aquesta fase es tornen mes conspicus. La presència d'unions intercel·lulars especialitzades característiques de la fase de contracció, està relacionada amb la transmissió de la força de tensió. Aquestes unions connecten els feixos de filaments d'actina de les cèl·lules amb la matriu o d'una cèl·lula a altre a través d'espais intercel·lulars força amples en els que s'observa material electrodens. Reepitelització L'epitelització s'inicia quan el pseudoblastema està consolidat i segueix el mateix patró que la reepitelització de ferides en epitelis monoestratificats de vertebrats (Stem i DePalma, 1983, és a dir, per migració de tota la capa per sobre del substrat, segons l'anomenat model de lliscament. Les glàndules unicel·lulars mucoses del tegument degeneren abans de produir-se la migració epitelial i posteriorment, un cop consolidat l'epiteli a sobre de la ferida, es diferencien a partir de les cèl·lules epitelials. Durant l'epitelització es produeixen canvis importants en el citosquelet i les unions basals de les cèl·lules epitelials. En canvi, el complex d'unió lateral es manté durant tot el procés. En iniciar-se la migració els tonofilaments es desconnecten dels hemidesmosomes cuticulars i dèrmics i es reagrupen al voltant del nucli, a la vegada que els hemidesmosomes dèrmics es desconnecten de la làmina basal. Un cop acabada la migració, les cèl·lules epitelials estableixen unions basals amb les cèl·lules del pseudoblastema. Aquestes unions no són hemidesmosomes sinó que presenten el mateix aspecte que les unions intercel·lulars del pseudoblastema. Els hemidesmosomes no es tornen a formar fins que les cèl·lules epitelials han restablert la membrana basal. La regeneració de la membrana basal no s'inicia fins que no s'ha començat a regenerar matriu connectiva a la zona cicatricial. Regeneració de la cicatriu Al mateix temps que es dona el fenomen de contracció, s'observa regeneració de la matriu connectiva entre les cèl·lules del pseudoblastema. Aquestes cèl·lules són responsables almenys del recobriment fibrós que presenten en aquest estadi, durant el qual mostren sàculs del reticle endoplasmàtic rugós molt dilatats, característics de cèl·lules que secreten constituents de la matriu. A més, s'observa infiltració de matriu connectiva i processos citoplasmàtics dels fibròcits en els marges del pseudoblastema. En la matriu del teixit connectiu normal s'observen fibres que estan constituïdes per un còrtex de fibril·les col·làgenes organitzades al voltant dels processos citoplasmàtics dels fibròcits. Les fibres del teixit connectiu peridigestiu, d'uns 1,2-1,9 mm de diàmetre, presenten el còrtex prim, amb les fibril·les organitzades paral·lelament a l'eix de la fibra. En canvi, les fibres de la dermis i teixit connectiu intramuscular, d'uns 2,5-7,1 mm de diàmetre, tenen el còrtex gruixut, amb fibril·les que s'organitzen paral·lelament en la zona proximal a la medul·la i de forma desorganitzada en la part més distal. Als 8 mesos la cicatriu encara és detectable. La matriu cicatricial presenta fibres connectives del tipus prim i força material fibril·lar desorganitzat disposat laxament. S'observa colonització per part de fibròcits, cromatòfors, petites fibres musculars i nervis.

A shift to randomness of brain oscillations in people with autism

BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) enables investigation of the intrinsic functional organization of the brain. Fractal parameters such as the Hurst exponent, H, describe the complexity of endogenous low-frequency fMRI time series on a continuum from random (H = .5) to ordered (H = 1). Shifts in fractal scaling of physiological time series have been associated with neurological and cardiac conditions. METHODS: Resting-state fMRI time series were recorded in 30 male adults with an autism spectrum condition (ASC) and 33 age- and IQ-matched male volunteers. The Hurst exponent was estimated in the wavelet domain and between-group differences were investigated at global and voxel level and in regions known to be involved in autism. RESULTS: Complex fractal scaling of fMRI time series was found in both groups but globally there was a significant shift to randomness in the ASC (mean H = .758, SD = .045) compared with neurotypical volunteers (mean H = .788, SD = .047). Between-group differences in H, which was always reduced in the ASC group, were seen in most regions previously reported to be involved in autism, including cortical midline structures, medial temporal structures, lateral temporal and parietal structures, insula, amygdala, basal ganglia, thalamus, and inferior frontal gyrus. Severity of autistic symptoms was negatively correlated with H in retrosplenial and right anterior insular cortex. CONCLUSIONS: Autism is associated with a small but significant shift to randomness of endogenous brain oscillations. Complexity measures may provide physiological indicators for autism as they have done for other medical conditions.

Associating spontaneous with evoked activity in a neural mass model of cat visual cortex

Spontaneous activity of the brain at rest frequently has been considered a mere backdrop to the salient activity evoked by external stimuli or tasks. However, the resting state of the brain consumes most of its energy budget, which suggests a far more important role. An intriguing hint comes from experimental observations of spontaneous activity patterns, which closely resemble those evoked by visual stimulation with oriented gratings, except that cortex appeared to cycle between different orientation maps. Moreover, patterns similar to those evoked by the behaviorally most relevant horizontal and vertical orientations occurred more often than those corresponding to oblique angles. We hypothesize that this kind of spontaneous activity develops at least to some degree autonomously, providing a dynamical reservoir of cortical states, which are then associated with visual stimuli through learning. To test this hypothesis, we use a biologically inspired neural mass model to simulate a patch of cat visual cortex. Spontaneous transitions between orientation states were induced by modest modifications of the neural connectivity, establishing a stable heteroclinic channel. Significantly, the experimentally observed greater frequency of states representing the behaviorally important horizontal and vertical orientations emerged spontaneously from these simulations. We then applied bar-shaped inputs to the model cortex and used Hebbian learning rules to modify the corresponding synaptic strengths. After unsupervised learning, different bar inputs reliably and exclusively evoked their associated orientation state; whereas in the absence of input, the model cortex resumed its spontaneous cycling. We conclude that the experimentally observed similarities between spontaneous and evoked activity in visual cortex can be explained as the outcome of a learning process that associates external stimuli with a preexisting reservoir of autonomous neural activity states. Our findings hence demonstrate how cortical connectivity can link the maintenance of spontaneous activity in the brain mechanistically to its core cognitive functions.

Amygdala functional connectivity with medial prefrontal cortex at rest predicts the positivity effect in older adults’ memory

As people get older, they tend to remember more positive than negative information. This age-by-valence interaction has been called “positivity effect.” The current study addressed the hypotheses that baseline functional connectivity at rest is predictive of older adults' brain activity when learning emotional information and their positivity effect in memory. Using fMRI, we examined the relationship among resting-state functional connectivity, subsequent brain activity when learning emotional faces, and individual differences in the positivity effect (the relative tendency to remember faces expressing positive vs. negative emotions). Consistent with our hypothesis, older adults with a stronger positivity effect had increased functional coupling between amygdala and medial PFC (MPFC) during rest. In contrast, younger adults did not show the association between resting connectivity and memory positivity. A similar age-by-memory positivity interaction was also found when learning emotional faces. That is, memory positivity in older adults was associated with (a) enhanced MPFC activity when learning emotional faces and (b) increased negative functional coupling between amygdala and MPFC when learning negative faces. In contrast, memory positivity in younger adults was related to neither enhanced MPFC activity to emotional faces, nor MPFC–amygdala connectivity to negative faces. Furthermore, stronger MPFC–amygdala connectivity during rest was predictive of subsequent greater MPFC activity when learning emotional faces. Thus, emotion–memory interaction in older adults depends not only on the task-related brain activity but also on the baseline functional connectivity.

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks

Human minds often wander away from their immediate sensory environment. It remains unknown whether such mind wandering is unsystematic or whether it lawfully relates to an individual’s tendency to attend to salient stimuli such as pain and their associated brain structure/function. Studies of pain–cognition interactions typically examine explicit manipulation of attention rather than spontaneous mind wandering. Here we sought to better represent natural fluctuations in pain in daily life, so we assessed behavioral and neural aspects of spontaneous disengagement of attention from pain. We found that an individual’s tendency to attend to pain related to the disruptive effect of pain on his or her cognitive task performance. Next, we linked behavioral findings to neural networks with strikingly convergent evidence from functional magnetic resonance imaging during pain coupled with thought probes of mind wandering, dynamic resting state activity fluctuations, and diffusion MRI. We found that (i) pain-induced default mode network (DMN) deactivations were attenuated during mind wandering away from pain; (ii) functional connectivity fluctuations between the DMN and periaqueductal gray (PAG) dynamically tracked spontaneous attention away from pain; and (iii) across individuals, stronger PAG–DMN structural connectivity and more dynamic resting state PAG–DMN functional connectivity were associated with the tendency to mind wander away from pain. These data demonstrate that individual tendencies to mind wander away from pain, in the absence of explicit manipulation, are subserved by functional and structural connectivity within and between default mode and antinociceptive descending modulation networks.