Simultaneous stereo-EEG and high-density scalp EEG recordings to study the effects of intracerebral stimulation parameters.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) recorded by stereo-electroencephalography (SEEG) are a valuable tool to investigate brain reactivity and effective connectivity. However, invasive recordings are spatially sparse since they depend on clinical needs. This sparsity hampers systematic comparisons across-subjects, the detection of the whole-brain effects of intracortical stimulation, as well as their relationships to the EEG responses evoked by non-invasive stimuli. OBJECTIVE: To demonstrate that CCEPs recorded by high-density electroencephalography (hd-EEG) provide additional information with respect SEEG alone and to provide an open, curated dataset to allow for further exploration of their potential. METHODS: The dataset encompasses SEEG and hd-EEG recordings simultaneously acquired during Single Pulse Electrical Stimulation (SPES) in drug-resistant epileptic patients (N = 36) in whom stimulations were delivered with different physical, geometrical, and topological parameters. Differences in CCEPs were assessed by amplitude, latency, and spectral measures. RESULTS: While invasively and non-invasively recorded CCEPs were generally correlated, differences in pulse duration, angle and stimulated cortical area were better captured by hd-EEG. Further, intracranial stimulation evoked site-specific hd-EEG responses that reproduced the spectral features of EEG responses to transcranial magnetic stimulation (TMS). Notably, SPES, albeit unperceived by subjects, elicited scalp responses that were up to one order of magnitude larger than the responses typically evoked by sensory stimulation in awake humans. CONCLUSIONS: CCEPs can be simultaneously recorded with SEEG and hd-EEG and the latter provides a reliable descriptor of the effects of SPES as well as a common reference to compare the whole-brain effects of intracortical stimulation to those of non-invasive transcranial or sensory stimulations in humans.

Recording cortico-cortical evoked potentials of the human arcuate fasciculus under general anaesthesia.

OBJECTIVE: We examined the feasibility of using cortico-cortical evoked potentials (CCEPs) to monitor the major cortical white matter tract involved in language, the arcuate fasciculus (AF), during surgery under general anaesthesia. METHODS: We prospectively recruited nine patients undergoing surgery for lesions in the left peri-sylvian cortex, for whom awake surgery was not indicated. High angular resolution diffusion imaging (HARDI) tractography was used to localise frontal and temporal AF terminations, which guided intraoperative cortical strip placement. RESULTS: CCEPs were successfully evoked in 5/9 patients, showing a positive potential (P1) at 12 ms and a negative component (N1) at 21 ms when stimulating from the frontal lobe and recording in the temporal lobe. CCEP responses peaked in the posterior middle temporal gyrus. No CCEPs were evoked when stimulating temporal sites and recording from frontal contacts. CONCLUSION: For the first time, we show that CCEPs can be evoked from the peri-sylvian cortices also in adult patients who are not candidates for awake procedures. Our results are akin to those described in the awake setting and suggest the recorded activity is conveyed by the arcuate fasciculus. SIGNIFICANCE: This intraoperative approach may have promising implications in reducing deficits in patients that require surgery in language areas under general anesthesia.

Focal lesions induce large-scale percolation of sleep-like intracerebral activity in awake humans.

Focal cortical lesions are known to result in large-scale functional alterations involving distant areas; however, little is known about the electrophysiological mechanisms underlying these network effects. Here, we addressed this issue by analysing the short and long distance intracranial effects of controlled structural lesions in humans. The changes in Stereo-Electroencephalographic (SEEG) activity after Radiofrequency-Thermocoagulation (RFTC) recorded in 21 epileptic subjects were assessed with respect to baseline resting wakefulness and sleep activity. In addition, Cortico-Cortical Evoked Potentials (CCEPs) recorded before the lesion were employed to interpret these changes with respect to individual long-range connectivity patterns. We found that small structural ablations lead to the generation and large-scale propagation of sleep-like slow waves within the awake brain. These slow waves match those recorded in the same subjects during sleep, are prevalent in perilesional areas, but can percolate up to distances of 60 mm through specific long-range connections, as predicted by CCEPs. Given the known impact of slow waves on information processing and cortical plasticity, demonstrating their intrusion and percolation within the awake brain add key elements to our understanding of network dysfunction after cortical injuries.

Behavioral and hormonal effects of prolonged Sildenafil treatment in a mouse model of chronic social stress.

Chronic social defeat can inhibit the reproductive system of subordinate males and causes behavioral deficits. Sildenafil treatment increases mice testosterone levels through its effects on Leydig cells of mice and it has been found to work as an antidepressant drug both in humans and in animal models. Since previous findings showed that sildenafil can counteract the inhibitory effects of chronic social defeat on agonistic, reproductive and anxiety-like behaviors of subordinate male mice, we investigated whether these behavioral outcomes can be explained by Sildenafil stimulation of testosterone. CD1 mice underwent an intruder-resident paradigm. After the fifth day of test, subordinate mice were injected with either a 10 mg/kg Sildenafil or a saline solution for 4 weeks. The results of the present study showed that Sildenafil treatment increased counterattacking behaviors and sexual motivation of subordinate males in addition to limiting the increase in body weight often observed in subordinate mice following chronic psychosocial stress. Moreover, sildenafil treated mice showed a pattern of behaviors reflecting lower anxiety. In agreement with previous studies, Sildenafil also increased testosterone levels. These data demonstrate that sildenafil can counteract the effects of chronic stress, possibly through its stimulatory effects on Leydig cells. These data demonstrate that sildenafil might counteract the effects of chronic psychosocial stress through centrally and peripherally mediated mechanisms.

Repeated and chronic administration of Vardenafil or Sildenafil differentially affects emotional and socio-sexual behavior in mice.

Selective phosphodiesterases (PDEs) inhibitors have been widely studied as therapeutic agents for treatment of various human diseases, including cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, antithrombotics, antiasthmatics, and agents for improving learning and memory. Although Sildenafil(®) and Vardenafil(®) have similar chemical formulae, the same target and interact with many of the same residues at the active site of phosphodiesterse-5 (PDE-5), they exhibit both in vitro and in vivo some important functional differences that could differentially affect behavior. Therefore we assessed whether repeated and chronic administration of Vardenafil and Sildenafil at a dose based upon human treatment can differentially affect aggressive, social, emotional and sexual behavior. To this aim, the effects of Sildenafil (10mg/kg) or Vardenafil (2mg/kg) (t.i.w., for 5 weeks) were observed in CD1 subordinate male mice in a low aggression and social subordination context. The results show that Sildenafil increased competitive aggression, environmental and social exploration, and reduced anxiety like behaviors as compared to controls, whereas Vardenafil had a significant major effect on appetitive and consummatory aspect of sexual behavior. This demonstrates that Sildenafil and Vardenafil, although being structurally and functionally similar, are characterized by different neuro-behavioral actions and can have differential therapeutic potentials.

Implication of the VGF-derived peptide TLQP-21 in mouse acute and chronic stress responses.

The impact of stress is widely recognized in the etiology of multiple disorders. In particular, psychological stress may increase the risk of cardiovascular, metabolic, immune, and mood disorders. Several genes are considered potential candidates to account for the deleterious consequences of stress and recent data point to role of Vgf. VGF mRNA is abundantly expressed in the hypothalamus, where it has been involved in metabolism and energy homeostasis; more recently a link between VGF-derived peptides and mood disorders has been highlighted. The following experiments were performed to address the contribution of the VGF-system to stress induced changes in mice: the distribution of VGF immuno-reactivity in hypothalamic nuclei and its modulation by social stress; the role of VGF-derived peptide TLQP-21 in plasma catecholamine release induced by acute restraint stress (RS); the efficacy of chronic TLQP-21 in a mouse model of chronic subordination stress (CSS). VGF fibers were found in high density in arcuate, dorsomedial, and suprachiasmatic and, at lower density, in lateral, paraventricular, and ventromedial hypothalamic nuclei. Central administration of either 2 or 4 mM TLQP-21 acutely altered the biphasic serum epinephrine release and decreased norepinephrine serum levels in response to RS. Finally, 28-day of 40 µg/day TLQP-21 treatment increased CSS-induced social avoidance of an unfamiliar conspecific. Overall these data support a role for TLQP-21 in stress responses providing a promising starting point to further elucidate its role as a player in stress-related human pathologies.

Evaluation of normal values of reactive oxygen species and total antioxidant defenses on cord blood of full-term healthy infants with a bedside method.

AIM: We measured in parallel and with a bedside equipment, the reference values of reactive oxygen species (ROS) and of total antioxidant defenses (TAD) in healthy full-term infants at birth on cord blood. TYPE OF STUDY: Population study of consecutive patients. PATIENTS AND METHODS: One hundred infants with gestational age 37-42 wks without signs of fetal distress or perinatal asphyxia. ROS and TAD were measured on cord blood - together with blood gas analysis - immediately after birth with a bedside equipment (FORM plus, Callegari 1930, Italy). RESULTS: The average time to the end of the exams was 19 min (5-55 min). After outliers' exclusion, ROS resulted meanly 117  ±â€Š 58.2 U.F. and TAD 1.31  ±  0.45 mmol/l Trol.eq., being the ROS' value lower and that of TAD in the same range than those of adult people. No relationship was found between cesarean and vaginal delivery and between male and female sex. CONCLUSION: The normal full-term infants present low values of ROS but normal values of TAD when compared to adult people. We speculate this is a defensive mechanism, a sort of preparation of the fetus to face the partial pressure of oxygen of the room-air, increased with respect to that present in the womb.

Current concepts on the pulmonary surfactant in infants.

Surfactant has been a main topic of neonatology in the last 20 years. Many studies have been conducted since the discovery of its role in the pathogenesis of respiratory distress syndrome and the knowledge on its composition and metabolism has become complex. In this article we review the current concepts of its metabolism, ways of acting, properties of its proteins and activities other than the ability of reducing surface tension within the lung as a basis to understand the development of disease in case of its deficiency.

The 5 W's of surfactant for respiratory distress syndrome of the premature infant.

The main points of the recommendations on use of surfactant for respiratory distress syndrome are reported in the article. In particular the aspects of why to administer it, when to give it and what kind of surfactant to use as well as who should inject it and where are analysed in agreement with the data of literature and the experience of the author.

The web survey network of sudden infant death syndrome and apparent life-threatening events in the Emilia-Romagna region.

To survey epidemiology and to study the etiology of sudden infant death syndrome (SIDS) and apparent life threatening events (ALTE) in Emilia-Romagna, a web network was constituted. A regional supervisor and a steering committee plan the action of district and local co-ordinators. They keep contact with the Regional Office of Health Services. District and local co-ordinators collect clinical and laboratory and, in case of SIDS, also autopsy data. Records are communicated to the Regional Supervising Center by on-line software. From these data, future planning of care and of mass information as well as auditing of their efficacy can be carried out. The characteristics of the network that has just started to collect data, as well its future developmental aspects, are discussed.

Neonatal seizures in preterm infants: clinical outcome and relationship with subsequent epilepsy.

OBJECTIVE: Neonatal seizures are considered an acute manifestation of disturbance of the neonatal brain. Some of them can be considered as neonatal epilepsy. Our goal was to evaluate perinatal risk factors, electroencephalogram (EEG) findings and ictal semeiological characteristics of our newborns with neonatal seizures in order to identify which clinical variables were the most early predictive factors of poor neurodevelopmental outcome and of epilepsy. METHODS: Among all preterm infants consecutively admitted to the neonatal intensive care unit (NICU) of the University Hospital of Parma in the period between January 1999 and June 2003, 28 preterm infants with gestational age

A rare case of multiple congenital epulis.

We report a case in a female newborn infant of multiple congenital epulis, i.e. granular cell tumor, that was undetected during regular pregnancy ultrasound monitoring. At birth the neoplasms appeared as two voluminous lesions protruding from the newborn's mouth. The greater of them (5.5 cm x4 cm x3 cm) was pedunculated and attached to the external superior gingiva, shifting the alae nasi and making it difficult to enter the coanae. The second mass was somewhat smaller (3 cm x4 cm x2.5 cm), pedunculated and attached to the external inferior gum. A third smaller mass was less evident, unpedunculated and attached to the rim of the lower gingiva. Histologically the lesions were characterized by large cells, which had abundant pale acidophilic granular cytoplasm. A round-oval nucleus was located centrally. The cell membranes were distinct. Neither mitosis nor necrosis was found. Staining for cytoplasmic granules was intensely periodic acid-Schiff (PAS) positive and diastase resistant. Immunohistochemical negativity for S100 protein, positivity for lysozyme and numerous phagolysosomes in the cytoplasm of neoplastic elements, observed on ultrastructural examination, supported the hypothesis that the congenital type of granular cell tumor cannot have a Schwannian origin like that of the adult type, but is probably a mesenchymal lesion which, for unknown cause, regresses by a degenerative process.

Cross fostering in mice: behavioral and physiological carry-over effects in adulthood.

Cross fostering is a widely used laboratory practice. However, relatively few studies have directly investigated the carry-over effects of this procedure in adult animals. The aim of the present study is to investigate the late effects of cross fostering (CF) at birth (in litters composed of no siblings) on adult mice. When adults, cross-fostered male and female mice were examined for intrasex aggression, and levels of emotionality, exploration and anxiety. In addition, body weight was monitored, several internal organs were weighed and plasma corticosterone levels were measured. When compared to controls, body weight of CF male and female mice was increased, at least after early puberty. CF males showed smaller preputial glands, while basal corticosterone level was not affected by cross fostering. In the free-exploratory test, CF males, but not females, showed a behavioral profile suggestive of lower anxiety. These effects in adulthood cannot be ascribed to differences in the maternal care received, which was not affected by cross fostering. In conclusion, cross fostering at birth induced a number of behavioral and physiological alterations in mice, particularly in males. These findings should be carefully evaluated when applying cross fostering procedure to laboratory animals.

An observational study of surfactant treatment in infants of 23-30 weeks' gestation: comparison of prophylaxis and early rescue.

OBJECTIVE: To test the clinical efficacy of exogenous surfactant for treatment of neonatal respiratory distress syndrome (RDS). METHODS: In a retrospective multicenter observational study, data were collected on 987 infants of 23-30 weeks' gestation given surfactant for respiratory problems within 3 h of birth. Obstetric, neonatal and short-term outcome data were retrieved from recording charts and analyzed after subdivision of the sample into two treatment groups: prophylaxis (surfactant within 15 min) and early rescue (surfactant at 16-180 min). RESULTS: A total of 965 infants were eligible for the study: 244 receiving prophylaxis and 721 receiving early rescue. The prophylaxis group had lower gestational ages and birth weights than the early rescue group (p = 0.0001), but were otherwise comparable. Natural surfactants were used in > 90% of infants in both groups. The rates of retreatments and the mean total doses of surfactant were similar in both groups. Babies receiving prophylaxis presented less grade 3-4 RDS than those receiving early rescue (32.4% vs. 53.8%, p = 0.0001). Those requiring prophylaxis also needed lower peak inspiratory pressure and had a shorter duration of oxygen therapy. Mortality and complications were similar between the groups, but babies receiving prophylaxis had less pulmonary interstitial emphysema (p = 0.0006) and periventricular leukomalacia (p = 0.0113) than infants receiving early rescue. CONCLUSIONS: In clinical practice, prophylaxis was preferred in babies with lower birth weights and gestational ages compared to early rescue treatment. Not surprisingly, infants treated with prophylactic surfactant had a lower rate of RDS than the infants treated by early rescue, even though they did not need less surfactant overall.

Individual housing induces altered immuno-endocrine responses to psychological stress in male mice.

Social isolation and lack of social support have deleterious effects on health, thus being regarded as one of the most relevant causes of diseases in human and other mammalian species. However, only few are the studies aimed at evaluating the psychoneuroimmunological functions of individually housed subjects. The present study was designed to understand how the behavior and the physiology of male house mice might be affected by individual housing. We first analyzed whether individual housing of different duration (1-42 days) would result in immuno-endocrine dysfunction (experiment 1). Then we investigated whether housing conditions would affect the reaction to an acute mild psychological stress (experiments 2 and 3). There were three main findings: first, individually housing mice for increasing time periods did not induce any major immuno-endocrine effects compared to a stable sibling group housing. Therefore, prolonged isolation does not seem to dramatically impair mice immuno-endocrine functions. Second, when exposed to a mild acute stress, i.e. forced exposure to a novel environment, isolated mice showed higher basal corticosterone and lower type 1 (IL-2) and type 2 (IL-4) cytokines as well as splenocytes proliferation compared to group housed male mice. Finally, when faced with a free choice between a novel environment and their home cage, individually housed mice showed reduced neophobic responses resulting in increased exploration of the novel environment, thus suggesting a low anxiety profile. Altogether, our findings suggest that individual housing in itself does not change immunocompetence and corticosterone level, but does affect reactivity to a stressor. In fact, individually housed mice showed high behavioral arousal, as well as altered immuno-endocrine parameters, when challenged with mild psychological novelty-stress.

Ethological methods to study the effects of maternal exposure to estrogenic endocrine disrupters: a study with methoxychlor.

There has been increasing interest, both at the scientific and regulatory level, in the use of ethological methods for evaluating neural effects of endocrine disrupters. We present a series of ethological studies on the effects of maternal exposure to low, environmentally relevant doses (0.02, 0.2, and 2 microg/g mother bw/day) of the estrogenic pesticide methoxychlor (MXC) on behavior. From gestation day 11 to 17, female mice spontaneously drank oil with or without MXC; their maternal behavior was examined from postpartum days 2 to 15. MXC treatment during pregnancy produced slight changes in the expression of maternal behavior: females fed the lower MXC dose spent less time nursing the pups as compared to control dams. Their maternally exposed offspring were subjected to a series of behavioral tests at different ages. Maternal exposure to MXC affected behavioral responses to novelty in both sexes at periadolescence. The onset of male intrasex aggression was delayed in males prenatally exposed to low doses of MXC, since exposed males showed low levels of aggressive interactions during early adolescence but not after they reached adulthood. When adults, MXC-exposed females, but not males showed increased exploration in an unfamiliar open-field. While a sex difference was observed in the control group, with males being significantly more active in the open field than females, prenatal treatment with some MXC doses tended to decrease the sexual dimorphism in activity levels in the novel environment. Ethology, as the evolutionary study of behavior, may provide a framework for integrating a functional perspective (i.e., evolutionary significance) to studies on proximate mechanisms that can account for behavioral alterations induced by developmental exposure to endocrine disrupters.

Effects of prenatal exposure to low doses of diethylstilbestrol, o,p'DDT, and methoxychlor on postnatal growth and neurobehavioral development in male and female mice.

We examined effects of a wide range of doses of three man-made estrogenic chemicals during fetal life on neurobehavioral changes during early postnatal life in mice. Pregnant mice were fed a 4-log range of o,p'DDT, methoxychlor (MXC), and the drug diethystilbestrol (DES) from gestation days 11 to 17. Offspring were examined for changes in postnatal growth and the development of neuromuscular reflexes. Fetal exposure to the estrogenic chemicals altered the number of live pups per litter, the sex ratio of the litters, the anogenital distance of male and female offspring at birth (a bioassay for fetal androgen action), and the body weight of offspring at birth and during the first 5 days of postnatal life. In most cases, however, the dose-response relationships were complex (non-monotonic), with effects at the highest dose examined being opposite to effects seen at lower doses. The two markers of neurobehavioral development, righting and cliff avoidance reflexes, were not sensitive indicators of prenatal estrogen exposure. Only maternal exposure to the lowest MXC dose produced an increase in reactivity in righting and cliff avoidance tests in offspring.

Social status in mice: behavioral, endocrine and immune changes are context dependent.

The aim of the present study was to investigate the effect of social status on the endocrine, immune and behavior response of male mice. We found that in mice reared in a group of siblings since weaning, no difference exists between dominants and subordinates in basal corticosterone level, in behavior in the open-field test (OFT) and in a series of immune parameters. These results suggest that living with siblings is not a stressful condition for either dominant or subordinate mice. Therefore, group-housed siblings can be regarded as a valid control group in social stress studies. When mice were subjected to chronic psychosocial stress for 21 days, four types of social outcome occurred: residents becoming dominants, intruders becoming subordinates, residents becoming subordinates and intruders becoming dominants. Interestingly, the behavioral profile in the OFT revealed a status-dependent effect, with resident dominants (RD) and intruder dominants (InD) showing the highest locomotor and exploratory activity, whereas the corticosterone level was higher than control for all four categories. In addition, a context-dependent effect emerged at the immune level: resident subordinates (RS) had a reduced splenocyte proliferation and IL-4 and IL-10 production. Mice in all the other three social ranks showed no immune alterations. Therefore, the loss of an individual's social rank position seems a promising field of study to investigate the psychological impact of stressful events.

Social stress in mice: gender differences and effects of estrous cycle and social dominance.

A large discrepancy in the possibility of inducing social stress in the two genders exists. Since generalizations of findings from one sex to the other appear not to be valid, reliable models of social stress in females are needed. We examined the effects of social context in the housing environment, as a possible source of stress, on exploration and anxiety in male and female mice, taking into account the estrous phase for females and the social status for males as additional variables. Mice housed individually or with siblings were tested in a free-exploratory paradigm of anxiety (where test animals have a choice to stay in their home cage or to explore an open field, OF). Individually housed females did not leave their home cage for long periods, explored less the unfamiliar area and displayed higher risk assessment, a behavioral profile suggestive of lower propensity for exploration and higher level of anxiety compared with group-housed females. Individually housed males tended to show an opposite profile. Proestrus mice were less sensitive to the decrease of exploratory propensity induced by individually housing compared to estrus and diestrus mice. Social dominants and social subordinates in sibling groups did not differ in their exploratory responses to the OF. Different housing procedures, as means to provide different social environment, may differentially induce mild social stress in male and female mice.