Brain Sciences

Online ISSN: 2076-3425
Publications
Gradient Program. 
Cont.
(A) Representative photomicrographs of 2,3,5-triphenol tetrazolium chloride (TTC)-stained, 1 mm thick coronal sections through the rat brain. Lack of staining (white regions) in the tissue from both vehicle and UPEI-104-treated rats indicates areas of infarct; (B) Bar graph demonstrating the effect of UPEI-104 treatment on infarct volume as a function of dose in Sprague-Dawley rats that were treated with the compound (0.001-0.1 mg/kg) 30 min prior to the middle cerebral artery (MCA) was occluded to induce a stroke. Numbers inside bars indicate the number of animals/dose group. (* Asterisk indicates significantly different from vehicle group; p < 0.05; ANOVA). 
Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.
 
Coherence was derived from inter-hemispheric ( left panel ), central (C4A1-C3A2) and occipital (O2A1-O1A2) EEG derivations and from intra-hemispheric derivations ( right panel ) in the left (C3A2-O1A2) and right (C4A1-O2A1) hemisphere. 
Sleep has beneficial effects on brain function and learning, which are reflected in plastic changes in the cortex. Early childhood is a time of rapid maturation in fundamental skills-e.g., language, cognitive control, working memory-that are predictive of future functioning. Little is currently known about the interactions between sleep and brain maturation during this developmental period. We propose coherent electroencephalogram (EEG) activity during sleep may provide unique insight into maturational processes of functional brain connectivity. Longitudinal sleep EEG assessments were performed in eight healthy subjects at ages 2, 3 and 5 years. Sleep EEG coherence increased across development in a region- and frequency-specific manner. Moreover, although connectivity primarily decreased intra-hemispherically across a night of sleep, an inter-hemispheric overnight increase occurred in the frequency range of slow waves (0.8-2 Hz), theta (4.8-7.8 Hz) and sleep spindles (10-14 Hz), with connectivity changes of up to 20% across a night of sleep. These findings indicate sleep EEG coherence reflects processes of brain maturation-i.e., programmed unfolding of neuronal networks-and moreover, sleep-related alterations of brain connectivity during the sensitive maturational window of early childhood.
 
Demographic characteristics at 3-year follow-up unless otherwise noted. 
Characterizing the effects of alcohol and marijuana use on adolescent brain development is important for understanding potential alterations in neurodevelopment. Several cross sectional studies have identified group differences in white matter integrity after initiation of heavy alcohol and marijuana use, however none have explored white matter trajectories in adolescents pre- and post initiation of use, particularly for marijuana users. This study followed 16 adolescents with minimal alcohol and marijuana use at ages 16-18 over three years. At follow-up, teens were 19-22 years old; half of the participants initiated heavy alcohol use and half initiated heavy alcohol and marijuana use. Repeated-measures ANOVA revealed 20 clusters in association and projection fibers tracts (p < 0.01) in which a group by time interaction was found. Most consistently, white matter integrity (i.e., fractional anisotropy) decreased for those who initiated both heavy alcohol and marijuana use over the follow-up interval. No effect of time or change in white matter integrity was seen for those who initiated alcohol use only in the majority of clusters. In most regions, at the baseline time point, teens who would later initiate both alcohol and marijuana use demonstrated white matter integrity greater than or equal to teens that initiated alcohol use only. Findings suggest poorer tissue integrity associated with combined initiation of heavy alcohol and marijuana use in late adolescence. While OPEN ACCESS pre-existing differences may also be related to likelihood of substance use, the present data suggest an effect on tissue integrity for these teens transitioning to combined alcohol and marijuana use in later adolescence.
 
Sleep changes were studied in mice (n = 59) from early adolescence to adulthood (postnatal days P19-111). REM sleep declined steeply in early adolescence, while total sleep remained constant and NREM sleep increased slightly. Four hours of sleep deprivation starting at light onset were performed from ages P26 through adulthood (>P60). Following this acute sleep deprivation all mice slept longer and with more consolidated sleep bouts, while NREM slow wave activity (SWA) showed high interindividual variability in the younger groups, and increased consistently only after P42. Three parameters together explained up to 67% of the variance in SWA rebound in frontal cortex, including weight-adjusted age and increase in alpha power during sleep deprivation, both of which positively correlated with the SWA response. The third, and strongest predictor was the SWA decline during the light phase in baseline: mice with high peak SWA at light onset, resulting in a large SWA decline, were more likely to show no SWA rebound after sleep deprivation, a result that was also confirmed in parietal cortex. During baseline, however, SWA showed the same homeostatic changes in adolescents and adults, declining in the course of sleep and increasing across periods of spontaneous wake. Thus, we hypothesize that, in young adolescent mice, a ceiling effect and not the immaturity of the cellular mechanisms underlying sleep homeostasis may prevent the SWA rebound when wake is extended beyond its physiological duration.
 
Mean ± SEM number of horizontal beam breaks in 5 min bins on day 1 and day 10 during 90 min activity trials. Saline (SAL n = 8) or 15 mg/kg cocaine (COC n = 9) injection were given IP at 30 min. * Indicates a significant difference between COC day 1 and COC day 10 ( p < 0.05). 
Median activated voxels in the PAG of saline and cocaine treated females presented with an empty stage, stage with pups, and pups with a male intruder rat on days 2 and 8 of pup sensitization ( A ), and composite activation maps showing areas of increased BOLD activation in rats presented with stage, stage with pups and pups and male intruder ( B ). Insets at the bottom highlight the area of the periaqueductal grey. Data are shown for control and cocaine treated rats on day 2 following initial exposure to pups and on day 8 after repeated sessions of exposure in their home cage. Color scale hue indicates percent change in signal intensity. 
Although data from both animals and humans suggests that adult cocaine use can have long term effects on behavior, it is unknown if prior cocaine use affects future maternal behavior in nulliparous females. In the current study, cocaine or saline was administered to adult female rats for 10 days, the animals were withdrawn from cocaine for 7 days, and the females were then exposed to donor pups to induce the expression of maternal behavior. Nulliparous females sensitized to cocaine were more likely to retrieve pups, spent more time caring for the pups, and were more likely to express full maternal behavior on day 8 of pup exposure. The fMRI data revealed significant effects of pup exposure in the hippocampal CA1 region, and effects of cocaine in the anterior thalamus and periaqueductal gray. Prior adult cocaine use may have lasting effects on offspring care, and this effect is not dependent on pup mediated effects or the endocrine changes of gestation and lactation. The present findings provide support for the hypothesis that maternal motivation to exhibit maternal behavior is enhanced by prior cocaine sensitization, possibly due to cross sensitization between cocaine and the natural reward of maternal behavior.
 
Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I2 (PGI2). The present study investigated whether the PGI2 IP receptor plays an important role in brain injury after global cerebral ischemia in aged mice. Adult young (2-3 months) and aged (12-15 months) male C57Bl/6 wild-type (WT) or IP receptor knockout (IP KO) mice underwent a 12 min bilateral common carotid artery occlusion (BCCAO) or a sham surgery. Behavior tests (neurologic deficit and T-maze) were performed 3 and 7 days after BCCAO. After seven days of reperfusion, the numbers of cells positive for markers of neurons, astrocytes, microglia, myeloperoxidase (MPO) and phosphorylated CREB (p-CREB) were evaluated immunohistochemically. Interestingly, in young and aged IP KO ischemic mice, there was a significant increase (p < 0.01) in cognitive deficit, hippocampal CA1 pyramidal neuron death, microglia and MPO activation, while p-CREB was reduced as compared to their corresponding WT controls. These data suggest that following ischemia, IP receptor deletion contributes to memory and cognitive deficits regulated by the CREB pathway and that treatment with IP receptor agonists could be a useful target to prevent harmful consequences.
 
Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects.
 
Computer plots showing laminar degeneration of layer II and V neurons in the primary visual cortex of neonatal rhesus monkeys following exposure to GABA agonists, and absence of a similar pattern in control or ketamine-exposed neonatal monkey brain.  
Cellular degeneration induced by alcohol in the caudate/putamen of fetal rhesus monkey brain as detected by activated caspase 3 (AC3) immunohistochemistry. There is a marked increase in AC3-positive neuronal profiles in the alcohol-exposed caudate (A) and putamen (C), compared to the sparse display of apoptotic profiles in control caudate (B) or control putamen (not shown).  
These panels are computer plots of sections cut through the basal ganglia [caudate (Ca) and putamen (Pu)] of the fetal rhesus monkey brain following exposure to an NMDA antagonist anesthetic (ketamine), or to GABA agonist anesthetics (propofol or isoflurane). Apoptotic neurons (red dots) are sparsely distributed in the basal ganglia region of the control brain, and are much more heavily concentrated in the basal ganglia region following exposure to any of the three anesthetic agents. In the anesthesia-exposed brains, apoptotic OLs (white dots) are densely and diffusely distributed throughout all white matter areas, including the corpus callosum (CC), Corona Radiata (CR), Centrum Semi-Ovale (CSO) and Internal capsule (IC).  
These panels depict the cingulate cortex and corpus callosum of a 10-day-old mouse brain, 72 h after treatment with saline (left) or a single high dose (5 g/kg) of alcohol (right). Both brain sections are shown at the same magnification and are cut from the same rostrocaudal level. Note the decreased cortical mass and also the decreased size of the corpus callosum of the alcohol brain. The number of neuronal profiles within the demarcated area of the saline vs. ethanol brain is 881 vs. 488, which represents a 45% cell loss within the cingulate region. Adapted from Olney et al. [7].  
These histological sections depict the parietal cortex (PC), cingulate cortex (Cing), rostral hippocampus (HC) and corpus callosum (CC) of a 7-day-old C57BL/6 mouse 8 h following subcutaneous treatment with saline (left) or ethanol (right). Both sections have been stained immunocytochemically with antibodies to activated caspase-3. The saline control brain shows a pattern of caspase-3 activation that occurs normally in the 7-day-old mouse brain, and is attributable to physiological cell death. The pattern of caspase-3 activation closely resembles the pattern of silver staining shown in Figure 4C, but the density of caspase staining is not as great as the density of silver staining, because the silver stain marks all neurons and fragments thereof that have degenerated over a 24 h period, and caspase-3 marks only those neurons that are undergoing caspase-3 activation at a given survival interval, in this case the 8 h interval. Adapted from Olney et al. [7].  
Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities.
 
Schematic diagram of the study design illustrating main experimental approach. 
Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development.
 
Cortical parcellation of the target regions of interest. (1) Transverse temporal gyrus; (2) Superior temporal gyrus; (3) Pars orbitalis. 
Superior longitudinal fasciculus (SLF) regions of interest (ROIs) selected in Reproducible Objective Quantification Scheme (ROQS), shown on fractional anisotropy (FA) map of representative Williams syndrome participant. White matter fiber tract directionality is given by the FA map: red (right-left), green (anterior-posterior), blue (superior-inferior). (A) Right and left superior SLF ROIs; (B) Right and left inferior SLF ROIs. 
Correlations of Distorted Tunes Test (DTT) scores with brain volume and fractional anisotropy (FA). DTT scores ≤ 18 are considered amusic. ♦ = Non-amusia; = Amusia. (A) DTT scores and white matter volume of right pars orbitalis (r = 0.507, p = 0.038); (B) DTT scores and gray matter volume of right pars orbitalis (r = 0.479, p = 0.052); (C) DTT scores and FA of right inferior SLF (r = 0.694, p = 0.002); (D) DTT scores and FA of right superior SLF (r = 0.506, p = 0.038). 
Congenital amusia is defined by marked deficits in pitch perception and production. Though historically examined only in otherwise typically developing (TD) populations, amusia has recently been documented in Williams syndrome (WS), a genetic, neurodevelopmental disorder with a unique auditory phenotype including auditory sensitivities and increased emotional responsiveness to music but variable musical skill. The current study used structural T1-weighted magnetic resonance imaging and diffusion tensor imaging to examine neural correlates of amusia in 17 individuals with WS (4 of whom met criteria for amusia). Consistent with findings from TD amusics, amusia in WS was associated with decreased fractional anisotropy (FA) in the right superior longitudinal fasciculus (SLF). The relationship between amusia and FA in the inferior component of the SLF was particularly robust, withstanding corrections for cognitive functioning, auditory sensitivities, or musical training. Though the number of individuals with amusia in the study is small, results add to evidence for the role of fronto-temporal disconnectivity in congenital amusia and suggest that novel populations with developmental differences can provide a window into understanding gene-brain-behavior relationships that underlie musical behaviors.
 
Chemical structures of oxytocin (OT) and its analog, lipo-oxytocin-1 (LOT-1). 
Anxiety and social preference tests 30 min after injection of OT or LOT-1. ( A ) Representative traces show movement tracks of the CD157 +/+ and CD157 − / − mice over a 
Anxiety and social preference tests 24 h after injection of OT or LOT-1. ( A ) Representative traces show movement tracks of the CD157 − / − mice over a 20-min period 
Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.
 
Mean + SEM duration values for pup retrieval, pup grooming and total maternal care (sum of pup grooming and nursing) on day 10 of lactation during a 30 min maternal care observation test of chronic social stressed dams treated with either saline or AVP. * indicates a significant difference between treatments ( p ≤ 0.05). 
Mean + SEM duration values for nursing latency and total maternal care (sum of pup grooming and nursing) on day 3 of lactation during a 30 min maternal aggression observation test of chronic social stressed dams treated with either saline or AVP. * indicates a significant difference between treatments ( p ≤ 0.05). 
Means ± SEM behavioral data during 30-min maternal aggression tests on lactation days 3, 10 and 17. Data in bold represent significant differences between saline and AVP treated animals.
Mean + SEM duration values for pinning and total aggression (sum of attacks, pinning, kicking and biting) on day 3 of lactation during a 30 min maternal aggression observation test of chronic social stressed dams treated with either saline or AVP. * indicates a significant difference between treatments ( p < 0.05). 
Exposure of mothers to chronic stressors during pregnancy or the postpartum period often leads to the development of depression, anxiety, or other related mood disorders. The adverse effects of mood disorders are often mediated through maternal behavior and recent work has identified arginine vasopressin (AVP) as a key neuropeptide hormone in the expression of maternal behavior in both rats and humans. Using an established rodent model that elicits behavioral and physiological responses similar to human mood disorders, this study tested the effectiveness of chronic AVP infusion as a novel treatment for the adverse effects of exposure to chronic social stress during lactation in rats. During early (day 3) and mid (day 10) lactation, AVP treatment significantly decreased the latency to initiate nursing and time spent retrieving pups, and increased pup grooming and total maternal care (sum of pup grooming and nursing). AVP treatment was also effective in decreasing maternal aggression and the average duration of aggressive bouts on day 3 of lactation. Central AVP may be an effective target for the development of treatments for enhancing maternal behavior in individuals exposed to chronic social stress.
 
Young adults benefit from music practice during childhood. For adults with no past musical experience (black), the auditory brainstem frequency-following response is less robust (i.e., smaller signal to noise ratios) relative to adults who started playing music around age 9 and who continued to play for either 1-5 (blue) or 6-11 (red) years. (A) Frequency-following responses (FFR) were recorded to 8 musical notes, varying in frequency from 262 Hz to 440 Hz (inset). The FFR was analyzed by calculating the amplitude of the response to each note relative to the physiological baseline (noise), producing a signal-to-noise ratio (SNR) for each note. (B) Bar graph depicting average SNR for each group (mean ± 1 SEM), ** p < 0.01. (C) Correlations between neural SNR and the number of years since music lessons occurred. In the group with 1-5 years of training (right panel), the SNR decreased in as a function of how long it has been since lessons occurred (r = −0.522, p = 0.046), whereas in the group with more training (left panel) this fading effect (i.e., decrease) is not observed (r = 0.090, p = 0.747). Modified from Skoe and Kraus [32]. 
A model of processing speech in noise in middle-age and older adults. The structural equation model [93] includes variables relating to cognition, central auditory processing, musical background, and life experiences (i.e., socioeconomic status and fitness level). This model, as schematized here, suggests that the neural networks that contribute to understanding speech in noise differ depending on whether the participant received musical training in their past or not. The group of older adults with past music training (blue arrows) was found to rely more on cognitive factors, whereas the group without musical training (black arrows) are shown to rely more on other life experiences. For each comparison, the wider arrow refers to the stronger contributor. Modified from Anderson et al., 2013 [93]. 
Musical training during childhood has been linked to more robust encoding of sound later in life. We take this as evidence for an auditory reserve: a mechanism by which individuals capitalize on earlier life experiences to promote auditory processing. We assert that early auditory experiences guide how the reserve develops and is maintained over the lifetime. Experiences that occur after childhood, or which are limited in nature, are theorized to affect the reserve, although their influence on sensory processing may be less long-lasting and may potentially fade over time if not repeated. This auditory reserve may help to explain individual differences in how individuals cope with auditory impoverishment or loss of sensorineural function.
 
Among epigenetic factors leading to increased prevalence of juvenile neuropsychiatric disorders, including autism spectrum disorder, exposure to metals, such as lead (Pb) have led to conflicting results. The aim of the present study was to determine the levels of Pb in the urine of children with autism spectrum disorder (ASD) compared with typically developing children (TD) age- and sex-matched, and to analyze any association between core symptoms of ASD, special diets, supplements intake or prescription drugs and the concentration of Pb. The study was performed in a group of children with ASD (n = 35, average age 7.4 ± 0.5 years) and TD (n = 34, average age 7.7 ± 0.9 years). Measurement of lead in urine was performed by atomic absorption spectrometry; symptoms of ASD were analyzed by diagnostic and statistical manual of mental disorders (DMS-IV) using the questionnary ADI-R. Careful clinical evaluation was also undertaken and statistical analysis was done taking into account any possible confounding factor.
 
( A ) Magnetic resonance spectroscopy acquisition: white squares represent the spectroscopic voxels selected in the trunk representation in each primary motor cortex; ( B ) LCModel output showing N -acetylaspartate (NAA) and myo-inositol (mI) peaks from right M1 in one representative control and low back pain subject. Lower NAA (8.5 mM vs . 9.8 mM) is visible in patient compared to control; ppm, parts per million; R, right; L, left. 
Clinical scores (mean ± SD) in low back pain (LBP) group.
Mean (+SD) concentrations of N -acetylaspartate ( A ) and myo-inositol ( B ) in control (grey bars) and low back pain (LBP, black bars) groups in right and left M1. Significantly lower NAA has been observed in right M1 in LBP; * p < 0.05. 
The involvement of the primary motor cortex (M1) in chronic low back pain (LBP) is a relatively new concept. Decreased M1 excitability and an analgesic effect after M1 stimulation have been recently reported. However, the neurochemical changes underlying these functional M1 changes are unknown. The current study investigated whether neurochemicals specific to neurons and glial cells in both right and left M1 are altered. N-Acetylaspartate (NAA) and myo-inositol (mI) were measured with proton magnetic resonance spectroscopy in 19 subjects with chronic LBP and 14 healthy controls. We also examined correlations among neurochemicals within and between M1 and relationships between neurochemical concentrations and clinical features of pain. Right M1 NAA was lower in subjects with LBP compared to controls (p = 0.008). Left M1 NAA and mI were not significantly different between LBP and control groups. Correlations between neurochemical concentrations across M1s were different between groups (p = 0.008). There were no significant correlations between M1 neurochemicals and pain characteristics. These findings provide preliminary evidence of neuronal depression and altered neuronalglial interactions across M1 in chronic LBP.
 
Physiological measurement of neural change in the olfacto-hippocampal pathway of adult mice treated with binge-like ethanol at postnatal day 7. (A) Diagram of primary information flow through the olfacto-hippocampal regional circuit. (B) Expansion of the piriform cortex (dotted box region in A) with basic local circuit feedback loop detail, including general modes of local connectivity existing between major cell types (green arrows = excitatory, red knobs = inhibitory). Stimulation from the olfactory bulb (OB) transmits to the piriform cortex (PCX) via the lateral olfactory tract (LOT). As pyramidal cells (grey triangle) are depolarized, associated feedback interneurons (FB) are activated to provide rapid inhibition of subsequent pyramidal cell activity, thus establishing temporally organized PCX processing and distribution of odorant information. (C) Idealized LOT-PCX paired-pulse analysis results (adapted from Sadrian et al. 2012 [23] and Wilson et al. 2011 [35]). Adults exposed to saline at P7 exhibit paired-pulse depression with reduced responses to the second test pulse at shorter inter-pulse intervals between the preceding condition pulse. In strong contrast, paired-pulse depression shifts to facilitation in adult mice exposed to ethanol at P7, suggesting dysfunctional local inhibition that is long-lasting. (D) Odor-evoked field potentials in the hippocampus were found to be enhanced in P7 ethanol-treated adult mice. Hyperexcitability or inhibitory deficits may also contribute to this type of interregional communication change along the olfacto-hippocampal pathway. Additional abbreviations: EC = entorhinal cortex, Hipp = Hippocampus, FF = feed-forward interneuron. 
Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances in our understanding of the nature of early alcohol-induced disorders toward human therapies. Research findings over the last decade have developed a model where ethanol-induced neurodegeneration impacts early neural circuit development, thereby perpetuating subsequent integration and plasticity in vulnerable brain regions. Here we review our current knowledge of FASD neuropathology based on discoveries of long-lasting neurophysiological effects of acute developmental ethanol exposure in animal models. We discuss the important balance between synaptic excitation and inhibition in normal neural network function, and relate the significance of that balance to human FASD as well as related disease states. Finally, we postulate that excitation/inhibition imbalance caused by early ethanol-induced neurodegeneration results in perturbed local and regional network signaling and therefore neurobehavioral pathology.
 
Language and face processing develop in similar ways during the first year of life. Early in the first year of life, infants demonstrate broad abilities for discriminating among faces and speech. These discrimination abilities then become tuned to frequently experienced groups of people or languages. This process of perceptual development occurs between approximately 6 and 12 months of age and is largely shaped by experience. However, the mechanisms underlying perceptual development during this time, and whether they are shared across domains, remain largely unknown. Here, we highlight research findings across domains and propose a top-down/bottom-up processing approach as a guide for future research. It is hypothesized that perceptual narrowing and tuning in development is the result of a shift from primarily bottom-up processing to a combination of bottom-up and top-down influences. In addition, we propose word learning as an important top-down factor that shapes tuning in both the speech and face domains, leading to similar observed developmental trajectories across modalities. Importantly, we suggest that perceptual narrowing/tuning is the result of multiple interacting factors and not explained by the development of a single mechanism.
 
We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI-CTR), and tandem insult pups from dams administered a low-dose, non-hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35-49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences.
 
Given the current focus on anticipation in perception, action and cognition, including language processing, there is a need for a method to tap into predictive processing in situations in which cue and feedback stimuli are not explicitly marked as such. To this aim, event related potentials (ERPs) were obtained while participants viewed alphabetic letter sequences ("A", "B", "C", "D", "E", …), in which the letters were highly predictable, and random sequences ("S", "B", "A", "I", "F", "M", …), without feedback. Occasionally, the presentation of a letter in a sequence was delayed by 300 ms. During this delay period, an increased negativity was observed for predictive versus random sequences. In addition, the early positivity following the delay was larger for predictive compared with random sequences. These results suggest that expectation-sensitive ERP modulations can be elicited in anticipation of stimuli that are not explicit targets, rewards, feedback or instructions, and that a delay can strengthen the prediction for a particular stimulus. Applications to language processing will be discussed.
 
Although activation of the innate and adaptive arms of the immune system are undoubtedly involved in the pathophysiology of neurodegenerative diseases, it is unclear whether immune system activation is a primary or secondary event. Increasingly, published studies link primary metabolic stress to secondary inflammatory responses inside and outside of the nervous system. In this study, we show that the metabolic stress pathway known as the unfolded protein response (UPR) leads to secondary activation of the immune system. First, we observe innate immune system activation in autopsy specimens from Pelizaeus-Merzbacher disease (PMD) patients and mouse models stemming from PLP1 gene mutations. Second, missense mutations in mildly- and severely-affected Plp1-mutant mice exhibit immune-associated expression profiles with greater disease severity causing an increasingly proinflammatory environment. Third and unexpectedly, we find little evidence for dysregulated expression of major antioxidant pathways, suggesting that the unfolded protein and oxidative stress responses are separable. Together, these data show that UPR activation can precede innate and/or adaptive immune system activation and that neuroinflammation can be titrated by metabolic stress in oligodendrocytes. Whether-or-not such activation leads to autoimmune disease in humans is unclear, but the case report of steroid-mitigated symptoms in a PMD patient initially diagnosed with multiple sclerosis lends support.
 
Overview of studies that reports infant speech segmentation ability to predict future language scores. 
Results of the meta-analysis, with each line summarizing a study that describes links between early segmentation ability and future language scores. Studies are indicated by first author, journal and year of publication; * indicates studies presented in the current paper. "Total" gives the number of observations per study (averaged when multiple effect sizes could be calculated). The forest plot presents the weighted mean coefficient of the correlation effect sizes ("COR"; its sign corrected for hypothesized relationship), with lines spanning the 95%-confidence intervals ("95%-CI"). The scale of the forest plot is given at the bottom. "W(random)" reflects the relative weight of this study in the random effects model fit. This model is summarized in the bottom row. 
Scatterplots with correlation coefficients between infant speech segmentation ability and future language profiles plotted on Y-axis as a function of infant age (left), and of age at follow up (right). Labels next to data points refer to the studies from which they were obtained; some studies reported multiple effect sizes. Note that for event-related potentials (ERP) studies, the polarity of the correlation coefficient has been reversed to allow for comparison with the head turn preference (HTP) studies: a positive correlation indicates that the observed correlation conforms to the hypothesis. 
Recent behavioral and electrophysiological evidence has highlighted the long-term importance for language skills of an early ability to recognize words in continuous speech. We here present further tests of this long-term link in the form of follow-up studies conducted with two (separate) groups of infants who had earlier participated in speech segmentation tasks. Each study extends prior follow-up tests: Study 1 by using a novel follow-up measure that taps into online processing, Study 2 by assessing language performance relationships over a longer time span than previously tested. Results of Study 1 show that brain correlates of speech segmentation ability at 10 months are positively related to 16-month-olds' target fixations in a looking-while-listening task. Results of Study 2 show that infant speech segmentation ability no longer directly predicts language profiles at the age of five. However, a meta-analysis across our results and those of similar studies (Study 3) reveals that age at follow-up does not moderate effect size. Together, the results suggest that infants' ability to recognize words in speech certainly benefits early vocabulary development; further observed relationships of later language skills to early word recognition may be consequent upon this vocabulary size effect.
 
Stem cell-based therapies for stroke have expanded substantially over the last decade. The diversity of embryonic and adult tissue sources provides researchers with the ability to harvest an ample supply of stem cells. However, the optimal conditions of stem cell use are still being determined. Along this line of the need for optimization studies, we discuss studies that demonstrate effective dose, timing, and route of stem cells. We recognize that stem cell derivations also provide uniquely individual difficulties and limitations in their therapeutic applications. This review will outline the current knowledge, including benefits and challenges, of the many current sources of stem cells for stroke therapy.
 
Average of % of power spectral density in wild-type and HIP14 knockout mice. 
Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, impairs information processing in the striatum, which, as part of the basal ganglia, modulates motor output. Growing evidence suggests that huntingtin interacting protein 14 (HIP14) contributes to HD neuropathology. Here, we recorded local field potentials (LFPs) in the striatum as HIP14 knockout mice and wild-type controls freely navigated a plus-shaped maze. Upon entering the choice point of the maze, HIP14 knockouts tend to continue in a straight line, turning left or right significantly less often than wild-types, a sign of motor inflexibility that also occurs in HD mice. Striatal LFP activity anticipates this difference. In wild-types, the power spectral density pattern associated with entry into the choice point differs significantly from the pattern immediately before entry, especially at low frequencies (≤13 Hz), whereas HIP14 knockouts show no change in LFP activity as they enter the choice point. The lack of change in striatal activity may explain the turning deficit in the plus maze. Our results suggest that HIP14 plays a critical role in the aberrant behavioral modulation of striatal neuronal activity underlying motor inflexibility, including the motor signs of HD.
 
Cooperative BCI based on the detection of ERPs.  
Detection results based on the AUC and the accuracy (ACC). (a,b) AUC for single-event detection as a function of the number of subjects, and AUC for a single subject as a function of the number of trials, respectively. (c,d) Accuracy for single-event detection as a function of the number of subjects, and accuracy for a single subject as a function of the number of trials, respectively.
Detection results based on the ITR and ITRP f . (a,b) theoretical ITR as a function of the number of subjects and the number of trials, respectively. (c) theoretical ITRP f as a function of the number of subjects and the number of trials, respectively.  
Electrode scores after electrode selection based on the maximization of the mean SSNR across subjects (SS common ).  
Electrode scores after electrode selection based on the maximization of the SSNR for each subject (SS individual ). (A low gray level represents a high score for the electrode.)
The authors wish to make the following correction to this paper (Cecotti, H.; Rivet, B. Subject Combination and Electrode Selection in Cooperative Brain-Computer Interface Based on Event Related Potentials. Brain Sci. 2014, 4, 335-355). Dut to an error the reference number in the original published paper were not shown. The former main text should be replaced as below.
 
Fluorescence imaging studies of isoflurane's effects on ROS levels in HEK 293 Cells. The green fluorescence image shows the of ROS levels in cells. (1) shows the ROS images in the cells treated with control condition; (2) shows the ROS images in the cells treated with 2% isoflurane for 15 min; (3) shows the ROS images in the cells treated with 2% isoflurane for 30 min; (4) shows the ROS image in the cells treated with 2% isoflurane for 60 min; (5) shows the ROS images in the cells treated with 2% isoflurane for 90 min. The treatments with 2% isoflurane for 15 and 30 min (2,3) do not induce visible increases in ROS levels inside the cells as compared to the control condition (1). The treatments with 2% isoflurane for 60 and 90 min (4,5) lead to accumulation of ROS inside the cells as compared to the control condition (1).  
Fluorescence reading studies of isoflurane's effects on ROS levels in HEK 293 Cells. (A) A fluorescence assay shows that the treatment with 2% isoflurane for 15 min (black bar) does not increase ROS levels compared with the control condition (white bar); (B) A fluorescence assay shows that treatment with 2% isoflurane for 30 min (black bar) does not increase ROS levels compared with the control condition (white bar); (C) Treatment with 2% isoflurane for 60 min (black bar) increases ROS levels compared with the control condition (white bar) (** p = 0.001); (D) Treatment with 2% isoflurane for 90 min (black bar) increases ROS levels compared with the control condition (white bar) (** p = 0.0001).  
The inhalation anesthetic isoflurane has been reported to induce caspase activation and apoptosis, which may lead to learning and memory impairment. However, the underlying mechanisms of these effects are largely unknown. Isoflurane has been shown to induce elevation of cytosol calcium levels, accumulation of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore, reduction in mitochondria membrane potential, and release of cytochrome c. The time course of these effects, however, remains to be determined. Therefore, we performed a pilot study to determine the effects of treatment with isoflurane for various times on ROS levels in HEK-293 cells. The cells were treated with 2% isoflurane plus 21% O2 and 5% CO2 for 15, 30, 60, or 90 min. We then used fluorescence imaging and microplate fluorometer to detect ROS levels. We show that 2% isoflurane for 60 or 90 min, but not 15 or 30 min, induced ROS accumulation in the cells. These data illustrated that isoflurane could cause time-dependent effects on ROS levels. These findings have established a system to further determine the time course effects of isoflurane on cellular and mitochondria function. Ultimately, the studies would elucidate, at least partially, the underlying mechanisms of isoflurane-induced cellular toxicity.
 
Consumption of ethanol (g/kg/day) during different phases of the experiment. 
Concentrations of monoamines in different brain areas of young control, old control, and old ethanol-exposed AA rats. 
The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and lifelong ethanol consumption in alcohol-preferring AA (Alko Alcohol) line of rats, selected for high voluntary consumption of ethanol. Intake of ethanol on the level of 4.5-5 g/kg/day for about 20 months induced only limited changes in the neurotransmitter levels; the concentration of noradrenaline was significantly reduced in the frontal cortex. There was also a trend towards lower levels of dopamine and 5-hydroxytryptamine (5-HT) in the frontal cortex, and towards a lower noradrenaline level in the dorsal cortex. Aging was associated with a decreased concentration of dopamine in the dorsal cortex and with a declining trend in the striatum. The levels of 5-HT in the limbic forebrain were higher in the aged than in the young animals, and in the striatum, there was a trend towards higher levels in older animals. The data suggest that a continuous intake of moderate amounts of ethanol does not enhance the age-related alterations in brain monoamine neurotransmission, while the decline in the brain level of dopamine associated with aging may be a factor contributing to age-related neurological disorders.
 
Absolute pitch (AP) is a form of sound recognition in which musical note names are associated with discrete musical pitch categories. The accuracy of pitch matching by non-AP musicians for chords has recently been shown to depend on stimulus familiarity, pointing to a role of spectral recognition mechanisms in the early stages of pitch processing. Here we show that pitch matching accuracy by AP musicians was also dependent on their familiarity with the chord stimulus. This suggests that the pitch matching abilities of both AP and non-AP musicians for concurrently presented pitches are dependent on initial recognition of the chord. The dual mechanism model of pitch perception previously proposed by the authors suggests that spectral processing associated with sound recognition primes waveform processing to extract stimulus periodicity and refine pitch perception. The findings presented in this paper are consistent with the dual mechanism model of pitch, and in the case of AP musicians, the formation of nominal pitch categories based on both spectral and periodicity information.
 
Total locomotor activity in response to (A) saline and (B) heroin peripheral challenges in opiate abstinent rats. Challenges were performed at 3, 6, 9 and 18 weeks of abstinence in animals abstinent from morphine pellets (MP), morphine injections (MI), heroin injections (HI), and in control animals (Control). ANOVA with repeated measures show no significant statistical interaction. Bar graph (A) represents mean ± SEM total number of beam breaks over 60 min in response to a saline challenge (1mL/kg s.c.). Bar graph (B) represents mean ± SEM total number of beam breaks over 180 min in response to a heroin challenge (0.25 mg/kg s.c.). Abstinent rats with previous history of heroin injections show longer lasting sensitivity to heroin challenges (Fisher’s PLSD post-hoc vs. control group, * p < 0.05, ** p < 0.01).
Circadian locomotor activity during spontaneous heroin withdrawal in rats: (A) during daytime and (B) during nighttime. Activity measures were performed from the first day of treatment cessation to the 21st day of abstinence in animals with a history of single heroin dependence (1Dep), 2 heroin dependence episodes (2Dep) and in control animals (Control). Points represent mean ± SEM. (A) Total number of beam breaks during the diurnal part of the circadian cycle. (B) Total number of beam breaks during the nocturnal part of the circadian cycle. Spontaneous withdrawal in 1Dep rats disrupts both diurnal and nocturnal activities for couple of days (Fisher’s PLSD post-hoc vs. control group, # p < 0.05). Abstinent rats with 2 episodes of dependence show longer lasting sensitivity disruption of both activities when compared to control animals (Fisher’s PLSD post-hoc, * p < 0.05).
Spontaneous circadian activity at several time-points of heroin protracted abstinence. (A) Daytime activity and (B) nighttime activity at 4, 12, 16 and 20 weeks in animals with a history of single heroin dependence (1Dep), 2 heroin dependence episodes (2Dep), and in control animals (Control). Points represent mean ± SEM (n = 5–7/group). (A) Total number of beam breaks during the diurnal part of the circadian cycle. (B) Total number of beam breaks during the nocturnal part of the circadian cycle. 2Dep animals show persistent diurnal hyperactivity (Fisher’s PLSD 2Dep vs. control group, * p < 0.05). Moreover, 2Dep animals show a global increase of nocturnal activity (main effect Dependence, # p < 0.001).
Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats. Here, we first compared the effects of several protocols for the induction of opiate dependence (morphine pellets, repeated morphine or heroin injections) on the subsequent response to heroin challenges (0.25 mg/kg) at different time points during abstinence (3, 6, 9 and 18 weeks). In a second set of experiments, rats were exposed to increasing doses of heroin and subsequently monitored for general circadian activity up to 20 weeks of abstinence. Results show that heroin injections rather than the other methods of opiate administration have long-term consequences on rats' sensitivity to heroin with its psychostimulant effects persisting up to 18 weeks of abstinence. Moreover, intermittent episodes of heroin dependence rather than a single exposure produce enduring alteration of the basal circadian activity both upon heroin cessation and protracted abstinence. Altogether, these findings suggest that the induction of heroin dependence through intermittent increasing heroin injections is the optimal method to model long-term behavioral alterations during protracted abstinence in rats. This animal model would be useful in further characterizing long-lasting changes in post-dependent subjects to help understand the prolonged vulnerability to relapse.
 
Relationships between ( a ) accumbens volume and past 3-month drinking frequency and ( b ) OFC volume and past 3-month drinking frequency. Volumes are reported as region to intracranial volume ratios. 
Overall follow-up hierarchical regression models of frequency of alcohol use.
Cont.
Differential neural development of structures associated with reward and control systems may underlie risky behavior in adolescence. The nucleus accumbens and orbitofrontal cortex (OFC) have been implicated in substance use behavior, although structural studies have yet to explore specific relationships between nucleus accumbens and OFC volumes and alcohol use in adolescence. High resolution structural MRI scans and assessments of recent alcohol use and lifetime substance use were collected in a sample of 168 juvenile justice-involved adolescents to explore whether gray matter volumes were associated with past 3-month quantity and frequency of alcohol use. Gray matter volumes were not associated with average quantity of alcohol use. Accumbens volume was positively associated with past 3-month frequency of drinking, and OFC volume was negatively associated with drinking frequency. Results may suggest that structural differences in regions related to reward and control processing may contribute to risk behavior in adolescence.
 
Microdialysis probes were located in the medial NAc shell. 
Evidence links dopamine (DA) in the nucleus accumbens (NAc) shell to the ingestion of palatable diets. Less is known, however, about the specific relation of DA to dietary fat and circulating triglycerides (TG), which are stimulated by fat intake and promote overeating. The present experiments tested in Sprague-Dawley rats whether extracellular levels of NAc DA increase in response to acute access to fat-rich food or peripheral injection of a fat emulsion and, if so, whether this is related to caloric intake or elevated circulating lipids. When rats consumed more calories of a high-fat meal compared with a low-fat meal, there was a significant increase in extracellular accumbens DA (155% vs. 119%). Systemic injection of a fat emulsion, which like a high-fat diet raises circulating TG but eliminates the factor of taste and allows for the control of caloric intake, also significantly increased extracellular levels of DA (127%) compared to an equicaloric glucose solution (70%) and saline (85%). Together, this suggests that a rise in circulating TG may contribute to the stimulatory effect of a high-fat diet on NAc DA.
 
Functional activation t-maps (thresholded at t > 4), superimposed onto proton-density anatomical images, subjects 1 through 5, for three visits in two conditions (Russ-Rest, Eng-Rest).
Percentage of nonzero voxels (PctNZ) for five subjects by ROI and hemisphere over three scans (time), for conditions (Russ-Rest, Eng-Rest).
BOLD fMRI is often used for the study of human language. However, there are still very few attempts to conduct longitudinal fMRI studies in the study of language acquisition by measuring auditory comprehension and reading. The following paper is the first in a series concerning a unique longitudinal study devoted to the analysis of bi- and multilingual subjects who are: (1) already proficient in at least two languages; or (2) are acquiring Russian as a second/third language. The focus of the current analysis is to present data from the auditory sections of a set of three scans acquired from April, 2011 through April, 2012 on a five-person subject pool who are learning Russian during the study. All subjects were scanned using the same protocol for auditory comprehension on the same General Electric LX 3T Signa scanner in Duke University Hospital. Using a multivariate analysis of covariance (MANCOVA) for statistical analysis, proficiency measurements are shown to correlate significantly with scan results in the Russian conditions over time. The importance of both the left and right hemispheres in language processing is discussed. Special attention is devoted to the importance of contextualizing imaging data with corresponding behavioral and empirical testing data using a multivariate analysis of variance. This is the only study to date that includes: (1) longitudinal fMRI data with subject-based proficiency and behavioral data acquired in the same time frame; and (2) statistical modeling that demonstrates the importance of covariate language proficiency data for understanding imaging results of language acquisition.
 
Example of the common coding theory. Thinking about “drinking coffee” activates associated codes, which frequently occur together, such as objects (e.g., coffee cup, coffee beans), motor plans (e.g., the way we like to hold our cup), and sensory states (e.g., the colour, smell, taste of coffee), biasing subsequent processing of any of these associated states.
Example of the direct matching hypothesis. While observing a motor act we automatically map the kinematics of the observed action onto our own motor plans. By retrieving the goals and intentions (in this example “drinking”) behind those motor plans, based on our own prior experience, we understand others’ actions or goals.
Example of predictive coding or forward models. We are constantly making predictions about the future state of our sensory system based on previous associations. Predictions are also quickly updated based on incoming sensory information to minimize prediction error. For example we predict that our friend will take sip from her coffee but when her hand grabs the sugar bowl we quickly alter our prediction.
The Ebbinghaus illusion. This illusion leads to the misperception of the size of the central circle; however the effect decreases significantly if there is a grasping or pointing action directed to the central circle.
Relationship between sensory information and concurrent motor plans and their consequent perceptual effects.
We spend much of our life predicting the future. This involves developing theories and making predictions about others' intentions, goals and about the consequences of the actions we are observing. Adapting our actions and behaviours to the environment is required for achieving our goals, and to do this the motor system relies on input from sensory modalities. However, recent theories suggest that the link between motor and perceptual areas is bidirectional, and that predictions based on planned or intended actions can unconsciously influence and modify our perception. In the following review we describe current theories on the link between action and perception, and examine the ways in which the motor system can unconsciously alter our perception.
 
Degree of recanalization stratified by type of device used.
Endovascular treatment modalities used by year (as a percentage of all endovascular interventions for acute ischemic stroke (AIS)). 
Acute ischemic stroke (AIS) due to thrombo-embolic occlusion in the cerebral vasculature is a major cause of morbidity and mortality in the United States and throughout the world. Although the prognosis is poor for many patients with AIS, a variety of strategies and devices are now available for achieving recanalization in patients with this disease. Here, we review the treatment options for cerebrovascular thromboembolic occlusion with a focus on the evolution of strategies and devices that are utilized for achieving endovascular clot extraction. In order to demonstrate the progression of this treatment strategy over the past decade, we will also present a single-center case series of AIS patients treated with endovascular thrombectomy.
 
When cessation is attempted, the Withdrawal-Related Adaptations (WRA) and Tolerance-Related Adaptations (TRA) continue to stimulate the Craving Generation System (CGS) resulting in withdrawal-related craving in the absence of any cues. Now the stimulation of the CGS provided by the WRA and TRA is no longer restoring homeostasis but is disrupting homeostasis. To restore homeostasis the brain removes the WRA.  
After smoking cessation, the brain dismantles the Withdrawal-Related Adaptations but is unable to dismantle the Tolerance-Related Adaptations (TRA). Unless something is done to re-establish homeostasis, craving would continue forever. To restore homeostasis, Abstinence-Related Adaptations (ARA) develop to provide inhibitory input to the Craving Generation System (CGS) counter-balancing the stimulatory input from the TRA. At this point, withdrawal-related craving ends, but craving could still be stimulated by smoking or emotional cues.  
When an ex-smoker lapses and smokes a cigarette, nicotine stimulates the Craving Inhibition System (CIS) which delivers super-physiologic inhibition to the Craving Generation System (CGS), once again disrupting homeostasis in the CGS. The Abstinence-Related Adaptations (ARA) that provide inhibition to the CGS are now adding to the disruption of homeostasis rather than restoring it. The ARA are rapidly dismantled.  
With the Abstinence-Related Adaptations (ARA) gone, when the down-stream effects of nicotine wear off, the Tolerance-Related Adaptations (TRA) provide un-opposed stimulation to the Craving Generation System (CGS) and this restores craving to its original intensity. Because the Tolerance-Related Adaptations set the latency to the onset of withdrawal craving, relapsed smokers find that they need to smoke at nearly the same frequency as when they had quit smoking no matter how long they had been abstinent.  
The role of neuronal plasticity in supporting the addictive state has generated much research and some conceptual theories. One such theory, the sensitization-homeostasis (SH) model, postulates that nicotine suppresses craving circuits, and this triggers the development of homeostatic adaptations that autonomously support craving. Based on clinical studies, the SH model predicts the existence of three distinct forms of neuroplasticity that are responsible for withdrawal, tolerance and the resolution of withdrawal. Over the past decade, many controversial aspects of the SH model have become well established by the literature, while some details have been disproven. Here we update the model based on new studies showing that nicotine dependence develops through a set sequence of symptoms in all smokers, and that the latency to withdrawal, the time it takes for withdrawal symptoms to appear during abstinence, is initially very long but shortens by several orders of magnitude over time. We conclude by outlining directions for future research based on the updated model, and commenting on how new experimental studies can gain from the framework put forth in the SH model.
 
( a ) Effects of MS on overall D1R density in the plPFC. White bars: CON; Black bars: MS. Averages ± SEM are presented. n = 5–6. * p < 0.05 difference between stress groups, @ p < 0.05 difference from juveniles using post-hoc Bonferroni t -tests after Age × 
Early adverse experience is a well-known risk factor for addictive behaviors later in life. Drug addiction typically manifests during adolescence in parallel with the later-developing prefrontal cortex (PFC). While it has been shown that dopaminergic modulation within the PFC is involved in addiction-like behaviors, little is known about how early adversity modulates its development. Here, we report that maternal separation stress (4 h per day between postnatal days 2-20) alters the development of the prelimbic PFC. Immunofluorescence and confocal microscopy revealed differences between maternally-separated and control rats in dopamine D1 and D2 receptor expression during adolescence, and specifically the expression of these receptors on projection neurons. In control animals, D1 and D2 receptors were transiently increased on all glutamatergic projection neurons, as well as specifically on PFC→nucleus accumbens projection neurons (identified with retrograde tracer). Maternal separation exacerbated the adolescent peak in D1 expression and blunted the adolescent peak in D2 expression on projection neurons overall. However, neurons retrogradely traced from the accumbens expressed lower levels of D1 during adolescence after maternal separation, compared to controls. Our findings reveal microcircuitry-specific changes caused by early life adversity that could help explain heightened vulnerability to drug addiction during adolescence.
 
Medical management of newborn infants often necessitates recurrent painful procedures, which may alter nociceptive pathways during a critical developmental period and adversely effect neuropsychological outcomes. To mitigate the effects of repeated painful stimuli, opioid administration for peri-procedural analgesia and ICU (intensive care unit) sedation is common in the NICU (neonatal intensive care unit). A growing body of basic and animal evidence suggests potential long-term harm associated with neonatal opioid therapy. Morphine increases apoptosis in human microglial cells, and animal studies demonstrate long-term changes in behavior, brain function, and spatial recognition memory following morphine exposure. This comprehensive review examines existing preclinical and clinical evidence on the long-term impacts of neonatal pain and opioid therapy.
 
It is commonly believed that consciousness is a higher brain function. Here we consider the likelihood, based on abundant neuroevolutionary data that lower brain affective phenomenal experiences provide the "energy" for the developmental construction of higher forms of cognitive consciousness. This view is concordant with many of the theoretical formulations of Sigmund Freud. In this reconceptualization, all of consciousness may be dependent on the original evolution of affective phenomenal experiences that coded survival values. These subcortical energies provided a foundation that could be used for the epigenetic construction of perceptual and other higher forms of consciousness. From this perspective, perceptual experiences were initially affective at the primary-process brainstem level, but capable of being elaborated by secondary learning and memory processes into tertiary-cognitive forms of consciousness. Within this view, although all individual neural activities are unconscious, perhaps along with secondary-process learning and memory mechanisms, the primal sub-neocortical networks of emotions and other primal affects may have served as the sentient scaffolding for the construction of resolved perceptual and higher mental activities within the neocortex. The data supporting this neuro-psycho-evolutionary vision of the emergence of mind is discussed in relation to classical psychoanalytical models.
 
Increasing larval population density causes greater sleep consolidation in adult female fruit flies. ( A ) Minutes of sleep per 30-min bin, across an average day consisting of 12 h of light followed by 12 h of darkness (LD). Time after lights-on is indicated by zeitgeber time (ZT) on the X -axis. ( B – F ) Quantification of sleep parameters for the same average LD day, across all 24 h, across the light period (LP), or across the dark period (DP). Error bars represent the standard error of the mean. n represents the number of flies in each group. Letters above columns are present in cases where a significant effect of population density was observed, and indicate significance groups from post-hoc analysis. Columns within each group of four that do not have any letter in common are significantly different from each other. ( B ) Total sleep duration. ( C ) Number of sleep episodes. ( D ) Mean sleep episode duration. ( E ) A metric for relative stability of wake and sleep states, calculated by subtracting the duration of the longest sleep episode from the duration of the longest wake episode. Thus, positive values indicate that wakefulness was more consolidated than sleep, and vice versa . ( F ) Total number of beam crosses, or activity counts, per minute of wakefulness. Increasing larval population density had several effects on female sleep characteristics, tending to decrease the number of sleep episodes while increasing their duration, resulting in more consolidated sleep. 
Increasing larval population density has modest effects on sleep characteristics in adult male fruit flies. ( A ) Minutes of sleep per 30-min bin, across an average day consisting of 12 h of light followed by 12 h of darkness (LD). Time after lights-on is indicated by zeitgeber time (ZT) on the X -axis. ( B – F ) Quantification of sleep parameters for the same average LD day, across all 24 h, across the light period (LP), or across the dark period (DP). Error bars represent the standard error of the mean. n represents the number of flies in each group. Letters above columns are present in cases where a significant effect of population density was observed, and indicate significance groups from post-hoc analysis. Columns within each group of four that do not have any letter in common are significantly different from each other. ( B ) Total sleep duration. ( C ) Number of sleep episodes. ( D ) Mean sleep episode duration. ( E ) A metric for relative stability of wake and sleep states, calculated by subtracting the duration of the longest sleep episode from the duration of the longest wake episode. Thus, positive values indicate that wakefulness was more consolidated than sleep, and vice versa . ( F ) Total number of beam crosses, or activity counts, per minute of wakefulness. There were no significant effects of larval population density in male flies across the 24-period. 
Mutation of the gene amnesiac blocked the effects of larval population density on adult sleep in female flies. ( A ) Minutes of sleep per 30-min bin, across an average day consisting of 12 h of light followed by 12 h of darkness (LD). Time after lights-on is indicated by zeitgeber time (ZT) on the X -axis. ( B – F ) Quantification of sleep parameters for the same average LD day, across all 24 h, across the light period (LP), or across the dark period (DP). Error bars represent the standard error of the mean. n represents the number of flies in each group. * Indicates p < 0.05 for a comparison of the two bars under the line. # Indicates 0.05< p < 0.10. ( B ) Total sleep duration. ( C ) Number of sleep episodes. ( D ) Mean sleep episode duration. ( E ) A metric for relative stability of wake and sleep states, calculated by subtracting the duration of the longest sleep episode from the duration of the longest wake episode. Thus, positive values indicate that wakefulness was more consolidated than sleep, and vice versa . ( F ) Total number of beam crosses, or activity counts, per minute of wakefulness. The promotion of sleep consolidation seen with increased larval population density in CS flies was inhibited in amn 1 flies. In contrast, 
Increasing larval population density causes greater sleep consolidation in adult female fruit flies that lack the olfactory receptor or83b . ( A ) Minutes of sleep per 30-min bin, across an average day consisting of 12 h of light followed by 12 h of darkness (LD). Time after lights-on is indicated by zeitgeber time (ZT) on the X -axis. ( B – F ) Quantification of sleep parameters for the same average LD day, across all 24 h, across the light period (LP), or across the dark period (DP). Error bars represent the standard error of the mean. n represents the number of flies in each group. ( B ) Total sleep duration. ( C ) Number of sleep episodes. ( D ) Mean sleep episode duration. ( E ) A metric for relative stability of wake and sleep states, calculated by subtracting the duration of the longest sleep episode from the duration of the longest wake episode. Thus, positive values indicate that wakefulness was more consolidated than sleep, and vice versa . ( F ) Total number of beam crosses, or activity counts, per minute of wakefulness. As in wild-type CS flies, increases in larval population density were associated with greater sleep consolidation during adulthood in Or83b 2 flies. 
Sleep has many important biological functions, but how sleep is regulated remains poorly understood. In humans, social isolation and other stressors early in life can disrupt adult sleep. In fruit flies housed at different population densities during early adulthood, social enrichment was shown to increase subsequent sleep, but it is unknown if population density during early development can also influence adult sleep. To answer this question, we maintained Drosophila larvae at a range of population densities throughout larval development, kept them isolated during early adulthood, and then tested their sleep patterns. Our findings reveal that flies that had been isolated as larvae had more fragmented sleep than those that had been raised at higher population densities. This effect was more prominent in females than in males. Larval population density did not affect sleep in female flies that were mutant for amnesiac, which has been shown to be required for normal memory consolidation, adult sleep regulation, and brain development. In contrast, larval population density effects on sleep persisted in female flies lacking the olfactory receptor or83b, suggesting that olfactory signals are not required for the effects of larval population density on adult sleep. These findings show that population density during early development can alter sleep behavior in adulthood, suggesting that genetic and/or structural changes are induced by this developmental manipulation that persist through metamorphosis.
 
Total physical activity (blue and red bars) and sports activities (black, superimposed bars) in hours per week across time points separately for participants with high fitness (red) vs . low fitness (blue) at t2. Mean with standard error bars. 
A few months of physical exercise have been shown to increase cognition and to modulate brain functions in previously sedentary, mainly older adults. However, whether the preservation of newly gained cognitive capacities requires an active maintenance of the achieved fitness level during the intervention is not yet known. The aim of the present study was to test whether cardiovascular fitness one year after an exercise intervention was linked to cognitive variables. Twenty-five healthy participants (42-57 years of age) took part in a follow-up assessment one year after the end of a supervised exercise intervention. Measurements included a cardiovascular fitness test, psychometric tests of verbal learning and memory and selective attention as well as questionnaires assessing physical activity and self-efficacy beliefs. Recognition scores of participants with higher cardiovascular fitness at follow-up did not change significantly during the follow-up period; however, the scores of participants with lower cardiovascular fitness decreased. One year after the end of the physical training intervention, previously sedentary participants spent more hours exercising than prior to the intervention. The time participants spent exercising correlated with their self-efficacy beliefs. These results demonstrate a direct link between verbal learning and cardiovascular fitness and show that positive effects of physical interventions on learning and memory do need an active maintenance of cardiovascular fitness.
 
BOLD responses in the insular cortex during movement and mental-imagery conditions. Significant BOLD responses are superimposed on axial and coronal slices in the movement (A,B) and mental imagery (C,D) conditions for both patients. Percent signal change are shown on the right (leg: red; arm: blue). Note the similar patterns for the two patients as well as between movement and mental imagery conditions (error bars represent the standard error of estimate).
Mental rotation of legs, arms and letters. ( A ) Illustration of the stimuli used for tasks, including legs, arms and objects (letters), presented in right, normal view (R) or in false, inverse view (F). The stimuli were presented in five different angles (0°, 45°, 90°, 135°, 180°). Patients and control subjects were requested to determine as quickly as possible whether the stimulus was the normal one or the inversed one. ( B ) Mean reaction-times ( left ) and error-rates ( right ) for legs (red), arms (blue) and letters (green) are plotted separately for patient 1 (plain bars), patient 2 (points) and control subjects (strips). Note the significantly higher reaction times for the legs in the patients with respect to control subjects. Error bars represent the standard deviation. ( C ) BOLD responses in the anterior cingulate and left parietal cortex during mental rotation of legs with respect to arms ( upper row ) and letters ( lower row ). Percent signal changes are shown on the right (red: leg; blue: arm; green: letter). 
Patients with conversion disorder generally suffer from a severe neurological deficit which cannot be attributed to a structural neurological damage. In two patients with acute conversion paraplegia, investigation with functional magnetic resonance imaging (fMRI) showed that the insular cortex, a limbic-related cortex involved in body-representation and subjective emotional experience, was activated not only during attempt to move the paralytic body-parts, but also during mental imagery of their movements. In addition, mental rotation of affected body-parts was found to be disturbed, as compared to unaffected body parts or external objects. fMRI during mental rotation of the paralytic body-part showed an activation of another limbic related region, the anterior cingulate cortex. These data suggest that conversion paraplegia is associated with pathological activity in limbic structures involved in body representation and a deficit in mental processing of the affected body-parts.
 
Demographic information of participants, split per age category. 
Mean scores (and SDs) on the English and Dutch C-test, split per age category. 
Mean WM scores (and SDs) on the L1 and L2 Reading Span Tasks, split per age category. 
Paired-samples t-test statistics for the Dutch versus English Stroop test. 
Independent samples t-test statistics for the bilinguals versus English monolinguals. 
This paper examines the intricate relationship between working memory (WM) capacity and inhibitory control as a function of both L2 proficiency and age. In both its design and research questions, this study closely follows Gass & Lee's work, where both L1 and L2 Reading Span Tasks (as measures of WM capacity) and L1 and L2 Stroop interference tasks (to measure inhibitory control) were administered. In this study, the test battery is augmented by both an L1 and L2 C-test of overall language proficiency. Participants were 63 L1 Dutch speakers of L2 English, who had been immersed in an L2 environment for a considerable amount of time. Their data were set off against those of 54 monolingual Dutch speakers and 56 monolingual English speakers. At the time of testing, all the bilingual participants had a near-native command of English and their L1 and L2 WM scores were not found to be significantly different. However, discrepancies did occur in Stroop test scores of inhibition, where the bilinguals performed better in their L2 English than L1 Dutch. These main effects often contradicted the results found in Gass & Lee's study, who examined less proficient L2 learners. An aging effect was furthermore found: older subjects consistently performed more poorly on WM and inhibition tasks than their younger peers. These results can shed light on how individual factors like WM capacity and inhibitory control interact in successful late bilinguals and how these dynamics shift with advanced age.
 
Over the past decade, much progress has been made regarding our understanding of neurogenesis in both young and old animals and where it occurs throughout the lifespan, although the growth of new neurons declines with increasing age. In addition, physical activity can reverse this age-dependent decline in neurogenesis. Highly correlated with this decline is the degree of inter and intracellular Wnt signaling, the molecular mechanisms of which have only recently started to be elucidated. So far, most of what we know about intracellular signaling during/following exercise centers around the CREB/CRE initiated transcriptional events. Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway. Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals. Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity.
 
Potential abnormalities in the structure and function of the temporal lobes have been studied much less in bipolar disorder than in schizophrenia. This may not be justified because language-related symptoms, such as pressured speech and flight of ideas, and cognitive deficits in the domain of verbal memory are amongst the hallmark of bipolar disorder (BD), and contribution of temporal lobe dysfunction is therefore likely. In the current study, we examined resting-state functional connectivity (FC) between the auditory cortex (Heschl's gyrus [HG], planum temporale [PT]) and whole brain using seed correlation analysis in n = 21 BD euthymic patients and n = 20 matched healthy controls and associated it with verbal memory performance. In comparison to controls BD patients showed decreased functional connectivity between Heschl's gyrus and planum temporale and the left superior and middle temporal gyrus. Additionally, fronto-temporal functional connectivity with the right inferior frontal/precentral gyrus and the insula was increased in patients. Verbal episodic memory deficits in the investigated sample of BD patients and language-related symptoms might therefore be associated with a diminished FC within the auditory/temporal gyrus and a compensatory fronto-temporal pathway.
 
Cont. 
Although amnesic H.M. typically could not recall where or when he met someone, he could recall their topics of conversation after long interference-filled delays, suggesting impaired encoding for some categories of novel events but not others. Similarly, H.M. successfully encoded into internal representations (sentence plans) some novel linguistic structures but not others in the present language production studies. For example, on the Test of Language Competence (TLC), H.M. produced uncorrected errors when encoding a wide range of novel linguistic structures, e.g., violating reliably more gender constraints than memory-normal controls when encoding referent-noun, pronoun-antecedent, and referent-pronoun anaphora, as when he erroneously and without correction used the gender-inappropriate pronoun "her" to refer to a man. In contrast, H.M. never violated corresponding referent-gender constraints for proper names, suggesting that his mechanisms for encoding proper name gender-agreement were intact. However, H.M. produced no more dysfluencies, off-topic comments, false starts, neologisms, or word and phonological sequencing errors than controls on the TLC. Present results suggest that: (a) frontal mechanisms for retrieving and sequencing word, phrase, and phonological categories are intact in H.M., unlike in category-specific aphasia; (b) encoding mechanisms in the hippocampal region are category-specific rather than item-specific, applying to, e.g., proper names rather than words; (c) H.M.'s category-specific mechanisms for encoding referents into words, phrases, and propositions are impaired, with the exception of referent gender, person, and number for encoding proper names; and (d) H.M. overuses his intact proper name encoding mechanisms to compensate for his impaired mechanisms for encoding other functionally equivalent linguistic information.
 
Sketch of the five long-term memory systems. Note that it is assumed that they develop both phylo- and ontogenetically from left to right.
Memory is not a unity, but is divided along a content axis and a time axis, respectively. Along the content dimension, five long-term memory systems are described, according to their hierarchical ontogenetic and phylogenetic organization. These memory systems are assumed to be accompanied by different levels of consciousness. While encoding is based on a hierarchical arrangement of memory systems from procedural to episodic-autobiographical memory, retrieval allows independence in the sense that no matter how information is encoded, it can be retrieved in any memory system. Thus, we illustrate the relations between various long-term memory systems by reviewing the spectrum of abnormalities in mnemonic processing that may arise in the dissociative amnesia-a condition that is usually characterized by a retrieval blockade of episodic-autobiographical memories and occurs in the context of psychological trauma, without evidence of brain damage on conventional structural imaging. Furthermore, we comment on the functions of implicit memories in guiding and even adaptively molding the behavior of patients with dissociative amnesia and preserving, in the absence of autonoetic consciousness, the so-called "internal coherence of life".
 
Absolute and relative use frequency of lexical categories for all words in Study 1.
Absolute and relative use frequency of Study 1 lexical categories, excluding target words.
Three studies examined amnesic H.M.'s use of words, phrases, and propositions on the Test of Language Competence (TLC). In Study 1, H.M. used 19 lexical categories (e.g., common nouns, verbs) and one syntactic category (noun phrases) with the same relative frequency as memory-normal controls, he used no lexical or syntactic category with less-than-normal frequency, and he used proper names (e.g., Melanie) and coordinative conjunctions (e.g., and) with reliably greater-than-normal frequency. In Study 2, H.M. overused proper names relative to controls when answering episodic memory questions about childhood experiences in speech and writing, replicating and extending Study 1 results for proper names. Based on detailed analyses of the use (and misuse) of coordinating conjunctions on the TLC, Study 3 developed a syntax-level "compensation hypothesis" for explaining why H.M. overused coordinating conjunctions relative to controls in Study 1. Present results suggested that (a) frontal mechanisms for retrieving word-, phrase-, and propositional-categories are intact in H.M., unlike in category-specific aphasia, (b) using his intact retrieval mechanisms, H.M. has developed a never-previously-observed proposition-level free association strategy to compensate for the hippocampal region damage that has impaired his mechanisms for encoding novel linguistic structures, and (c) H.M.'s overuse of proper names warrants further research.
 
Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in common clinical use can be neurotoxic to the developing brain and lead to long-term neurological sequelae. These findings have seriously questioned the safe use of general anaesthetics in obstetric and paediatric patients. The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. The aim is to summarise recently available laboratory data, especially those being published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function. In addition, we will discuss recent findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.
 
Anesthetic neurotoxicity has been a hot topic in anesthesia for the past decade. It is of special interest to pediatric anesthesiologists. A subgroup of children potentially at greater risk for anesthetic neurotoxicity, based on a prolonged anesthetic exposure early in development, are those children receiving anesthesia for surgical repair of congenital heart disease. These children have a known risk of neurologic deficit after cardiopulmonary bypass for surgical repair of congenital heart disease. Yet, the type of anesthesia used has not been considered as a potential etiology for their neurologic deficits. These children not only receive prolonged anesthetic exposure during surgical repair, but also receive repeated anesthetic exposures during a critical period of brain development. Their propensity to abnormal brain development, as a result of congenital heart disease, may modify their risk of anesthetic neurotoxicity. This review article provides an overview of anesthetic neurotoxicity from the perspective of a pediatric cardiac anesthesiologist and provides insight into basic science and clinical investigations as it relates to this unique group of children who have been studied over several decades for their risk of neurologic injury.
 
Schematic of the neuroprotective and neurotoxic effects induced by volatile anesthetics. 
The use of volatile anesthetics, a group of general anesthetics, is an exceedingly common practice. These anesthetics may have neuroprotective effects. Over the last decade, anesthetic induced neurotoxicity in pediatric populations has gained a certain notoriety based on pre-clinical cell and animal studies demonstrating that general anesthetics may induce neurotoxicity, including neuroapoptosis, neurodegeneration, and long-term neurocognitive and behavioral deficits. With hundreds of millions of people having surgery under general anesthesia worldwide, and roughly six million children annually in the U.S. alone, the importance of clearly defining toxic or protective effects of general anesthetics cannot be overstated. Yet, with our expanding body of knowledge, we have come to learn that perhaps not all volatile anesthetics have the same pharmacological profiles; certain ones may have a more favorable neurotoxic profile and may actually exhibit neuroprotection in specific populations and situations. Thus far, very few clinical studies exist, and have not yet been convincing enough to alter our practice. This review will provide an update on current data regarding volatile anesthetic induced neurotoxicity and neuroprotection in neonatal and infant populations. In addition, this paper will discuss ongoing studies and the trajectory of further research over the coming years.
 
NADPH oxidases contribute to brain injury, yet they may also have a role in brain repair, particularly in vascular signaling and angiogenesis. This study determined the temporal and spatial profile of NADPH oxidase subunit expression/activity concurrently with angiogenesis in the brain following transient ischemic stroke induced by prolonged constriction of the middle cerebral artery by perivascular injection of endothelin-1 in conscious Hooded Wistar rats (n = 47). VEGF mRNA expression was increased in the ipsilateral cortex and striatum between 6 h and 28 days post-stroke concurrently with a marked increase in Nox2 mRNA expression up to 7 days, and increased Nox4 mRNA expression detected between 7 and 28 days. Point counting of blood vessels using Metamorph imaging software showed increased vascular sprouting between 3 and 7 days after stroke with new vascular networks detected in the core infarct region by 14 days. Angiogenic blood vessels 3 and 7 days post-stroke were observed to co-localise with both Nox2 antibody and dihydroethidium fluorescence suggesting a role for Nox2 generated superoxide during the phase of vascular remodeling, whilst Nox4 expression was detected once new cerebral vessels had formed. These results indicate for the first time that ROS signaling through a cerebrovascular Nox2 NADPH oxidase may be important in initiating brain angiogenesis.
 
Top-cited authors
Shervin Assari
  • Charles R. Drew University of Medicine and Science
Daria Kuss
  • Nottingham Trent University
Mark D Griffiths
  • Nottingham Trent University
Marco Colizzi
  • University of Udine
Leonardo Zoccante
  • Azienda Ospedaliera Universitaria Integrata Verona