http://www.mdpi.com/journal/brainsci Latest open access articles published in Brain Sci. at http://www.mdpi.com/journal/brainsci http://www.mdpi.com/2076-3425/3/2/790 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. Brain Sciences 2013-05-15 3 2 Article 10.3390/brainsci3020790 790 799 2076-3425 2013-05-15 doi: 10.3390/brainsci3020790 Pia Jaatinen Maija Sarviharju Noora Raivio C. Eriksson Antti Hervonen Kalervo Kiianmaa http://www.mdpi.com/2076-3425/3/2/781 Purpose: To compare neurovascular coupling in the posterior cerebral artery (PCA) between those with spinal cord injury (SCI) and able bodied (AB) individuals. Methods: A total of seven SCI and seven AB were matched for age and sex. Measures included PCA velocity (PCAv), beat-by-beat blood pressure and end-tidal carbon dioxide. Posterior cerebral cortex activation was achieved by 10 cycles of (1) 30 s eyes closed (pre-stimulation), (2) 30 s reading (stimulation). Results: Blood pressure was significantly reduced in those with SCI (SBP: 100 ± 13 mmHg; DBP: 58 ± 13 mmHg) vs. AB (SBP: 121 ± 12 mmHg; DBP: 74 ± 9 mmHg) during both pre-stimulation and stimulation, but the relative increase was similar during the stimulation period. Changes in PCAv during stimulation were mitigated in the SCI group (6% ± 6%) vs. AB (29% ± 12%, P < 0.001). Heart rate and end-tidal carbon dioxide responded similarly between groups. Conclusions: Clearly, NVC is impaired in those with SCI. This study may provide a link between poor perfusion of the posterior cerebral region (containing the medullary autonomic centres) and autonomic dysfunction after SCI. Brain Sciences 2013-05-08 3 2 Article 10.3390/brainsci3020781 781 789 2076-3425 2013-05-08 doi: 10.3390/brainsci3020781 Aaron Phillips Andrei Krassioukov Mei Zheng Darren Warburton http://www.mdpi.com/2076-3425/3/2/757 Learning foreign speech contrasts involves creating new representations of sound categories in memory. This formation of new memory representations is likely to involve changes in neural networks as reflected by oscillatory brain activity. To explore this, we conducted time-frequency analyses of electro-encephalography (EEG) data recorded in a passive auditory oddball paradigm using Thai language tones. We compared native speakers of English (a non-tone language) and native speakers of Mandarin Chinese (a tone language), before and after a two-day laboratory training. Native English speakers showed a larger gamma-band power and stronger alpha-band synchrony across EEG channels than the native Chinese speakers, especially after training. This is compatible with the view that forming new speech categories on the basis of unfamiliar perceptual dimensions involves stronger gamma activity and more coherent activity in alpha-band networks than forming new categories on the basis of familiar dimensions. Brain Sciences 2013-05-03 3 2 Article 10.3390/brainsci3020757 757 780 2076-3425 2013-05-03 doi: 10.3390/brainsci3020757 Edith Kaan Ratree Wayland Andreas Keil http://www.mdpi.com/2076-3425/3/2/744 Chronic and excessive alcohol misuse results in changes in the expression of selected miRNAs and their mRNA targets in specific regions of the human brain. These expression changes likely underlie the cellular adaptations to long term alcohol misuse. In order to delineate the mechanism by which these expression changes occur, we have measured the expression of six miRNAs including miR-7, miR-153, miR-152, miR-15B, miR-203 and miR-144 in HEK293T, SH SY5Y and 1321 N1 cells following exposure to ethanol. These miRNAs are predicted to target key genes involved in the pathophysiology of alcoholism. Chronic and chronic-intermittent exposure to ethanol, and its removal, resulted in specific changes in miRNA expression in each cell line suggesting that different expression patterns can be elicited with different exposure paradigms and that the mechanism of ethanol’s effects is dependent on cell type. Specifically, chronic exposure to ethanol for five days followed by a five day withdrawal period resulted in up-regulation of several miRNAs in each of these cell lines similar to expression changes identified in post mortem human brain. Thus, this model can be used to elucidate the role of miRNAs in regulating gene expression changes that occur in response to ethanol exposure. Brain Sciences 2013-05-03 3 2 Article 10.3390/brainsci3020744 744 756 2076-3425 2013-05-03 doi: 10.3390/brainsci3020744 Gretchen van Steenwyk Paulina Janeczek Joanne Lewohl http://www.mdpi.com/2076-3425/3/2/728 Several cross-sectional functional Magnetic Resonance Imaging (fMRI) studies reported a negative correlation between auditory verbal hallucination (AVH) severity and amplitude of the activations during language tasks. The present study assessed the time course of this correlation and its possible structural underpinnings by combining structural, functional MRI and repetitive Transcranial Magnetic Stimulation (rTMS). Methods: Nine schizophrenia patients with AVH (evaluated with the Auditory Hallucination Rating scale; AHRS) and nine healthy participants underwent two sessions of an fMRI speech listening paradigm. Meanwhile, patients received high frequency (20 Hz) rTMS. Results: Before rTMS, activations were negatively correlated with AHRS in a left posterior superior temporal sulcus (pSTS) cluster, considered henceforward as a functional region of interest (fROI). After rTMS, activations in this fROI no longer correlated with AHRS. This decoupling was explained by a significant decrease of AHRS scores after rTMS that contrasted with a relative stability of cerebral activations. A voxel-based-morphometry analysis evidenced a cluster of the left pSTS where grey matter volume negatively correlated with AHRS before rTMS and positively correlated with activations in the fROI at both sessions. Conclusion: rTMS decreases the severity of AVH leading to modify the functional correlate of AVH underlain by grey matter abnormalities. Brain Sciences 2013-04-29 3 2 Article 10.3390/brainsci3020728 728 743 2076-3425 2013-04-29 doi: 10.3390/brainsci3020728 Olivier Maïza Pierre-Yve Hervé Olivier Etard Annick Razafimandimby Aurélie Montagne-Larmurier Sonia Dollfus http://www.mdpi.com/2076-3425/3/2/704 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. Brain Sciences 2013-04-29 3 2 Review 10.3390/brainsci3020704 704 727 2076-3425 2013-04-29 doi: 10.3390/brainsci3020704 Benjamin Sadrian Donald Wilson Mariko Saito http://www.mdpi.com/2076-3425/3/2/670 Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of fetal alcohol spectrum disorders (FASD). In rodent models, ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The ethanol-induced apoptosis is mitochondria-dependent, involving Bax and caspase-3 activation. Such apoptotic pathways are often mediated by sphingolipids, a class of bioactive lipids ubiquitously present in eukaryotic cellular membranes. While the central role of lipids in ethanol liver toxicity is well recognized, the involvement of sphingolipids in ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that ethanol-induced neuronal apoptosis in animal models of FASD is mediated or regulated by cellular sphingolipids, including via the pro-apoptotic action of ceramide and through the neuroprotective action of GM1 ganglioside. Such sphingolipid involvement in ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against FASD. Here we summarize findings describing the involvement of sphingolipids in ethanol-induced apoptosis and discuss the possibility that the combined action of various sphingolipids in mitochondria may control neuronal cell fate. Brain Sciences 2013-04-26 3 2 Review 10.3390/brainsci3020670 670 703 2076-3425 2013-04-26 doi: 10.3390/brainsci3020670 Mariko Saito Mitsuo Saito http://www.mdpi.com/2076-3425/3/2/642 Auditory verbal hallucinations (AVH) are a common phenomenon, occurring in the “healthy” population as well as in several mental illnesses, most notably schizophrenia. Current thinking supports a spectrum conceptualisation of AVH: several neurocognitive hypotheses of AVH have been proposed, including the “feed-forward” model of failure to provide appropriate information to somatosensory cortices so that stimuli appear unbidden, and an “aberrant memory model” implicating deficient memory processes. Neuroimaging and connectivity studies are in broad agreement with these with a general dysconnectivity between frontotemporal regions involved in language, memory and salience properties. Disappointingly many AVH remain resistant to standard treatments and persist for many years. There is a need to develop novel therapies to augment existing pharmacological and psychological therapies: transcranial magnetic stimulation has emerged as a potential treatment, though more recent clinical data has been less encouraging. Our understanding of AVH remains incomplete though much progress has been made in recent years. We herein provide a broad overview and review of this. Brain Sciences 2013-04-26 3 2 Review 10.3390/brainsci3020642 642 669 2076-3425 2013-04-26 doi: 10.3390/brainsci3020642 Derek Tracy Sukhwinder Shergill http://www.mdpi.com/2076-3425/3/2/627 Findings from recordings of human temporal cortical single neuron activity during several measures of language, including object naming and word reading are reviewed and related to changes in activity in the same neurons during recent verbal memory and verbal associative learning measures, in studies conducted during awake neurosurgery for the treatment of epilepsy. The proportion of neurons changing activity with language tasks was similar in either hemisphere. Dominant hemisphere activity was characterized by relative inhibition, some of which occurred during overt speech, possibly to block perception of one’s own voice. However, the majority seems to represent a dynamic network becoming active with verbal memory encoding and especially verbal learning, but inhibited during performance of overlearned language tasks. Individual neurons are involved in different networks for different aspects of language, including naming or reading and naming in different languages. The majority of the changes in activity were tonic sustained shifts in firing. Patterned phasic activity for specific language items was very infrequently recorded. Human single neuron recordings provide a unique perspective on the biologic substrate for language, for these findings are in contrast to many of the findings from other techniques for investigating this. Brain Sciences 2013-04-26 3 2 Review 10.3390/brainsci3020627 627 641 2076-3425 2013-04-26 doi: 10.3390/brainsci3020627 George Ojemann http://www.mdpi.com/2076-3425/3/2/615 In developing neurons the frequency of long duration, spontaneous, transient calcium (Ca2+) elevations localized to the growth cone, is inversely related to the rate of axon elongation and increases several fold when axons pause. Here we report that these spontaneous Ca2+ transients with slow kinetics, called Ca2+ waves, are modulated by conditions of ethanol exposure that alter axonal growth dynamics. Using time-series fluorescence calcium imaging we found that acute treatment of fetal rat hippocampal neurons with 43 or 87 mM ethanol at an early stage of development in culture decreased the percent of axon growth cones showing at least one Ca2+ wave during 10 min of recording, from 18% in controls to 5% in cultures exposed to ethanol. Chronic exposure to 43 mM ethanol also reduced the incidence of Ca2+ waves to 8%, but exposure to 87 mM ethanol increased their incidence to 31%. Neither chronic nor acute ethanol affected the peak amplitude, time to peak or total duration of Ca2+ waves. In some experiments, we determined the temporal correlation between Ca2+ waves and growth and non-growth phases of axonal growth dynamics. As expected, waves were most prevalent in stationary or retracting growth cones in all treatment groups, except in cultures exposed chronically to 87 mM ethanol. Thus, the relationship between growth cone Ca2+ waves and axon growth dynamics is disrupted by ethanol. Brain Sciences 2013-04-23 3 2 Article 10.3390/brainsci3020615 615 626 2076-3425 2013-04-23 doi: 10.3390/brainsci3020615 Tara Lindsley Joseph Mazurkiewicz http://www.mdpi.com/2076-3425/3/2/599 Stem cells have been touted as a potential source of cells for repair in regenerative medicine. When transplanted into the central nervous system, stem cells have been shown to differentiate into neurons and glia. Recent studies, however, have also revealed neuroprotective properties of stem cells. These studies suggest that various types of stem cells are able to protect against the loss of neurons in conditions of ischemic brain injury. In this article, we discuss the use of stem cells for ischemic stroke and the parameters under which neuroprotection can occur in the translation of stem cell therapy to the clinical setting. Brain Sciences 2013-04-23 3 2 Review 10.3390/brainsci3020599 599 614 2076-3425 2013-04-23 doi: 10.3390/brainsci3020599 Laura Stone Andy Grande Walter Low http://www.mdpi.com/2076-3425/3/2/561 Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation. Brain Sciences 2013-04-22 3 2 Review 10.3390/brainsci3020561 561 598 2076-3425 2013-04-22 doi: 10.3390/brainsci3020561 Sarah McCann Carli Roulston http://www.mdpi.com/2076-3425/3/2/540 Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies. The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA). However, this treatment is limited to within 4.5 h of stroke onset in a small subset of patients. The goal of this review is to focus on mitochondrial-dependent therapeutic agents that could provide neuroprotection following stroke. Dysfunctional mitochondria are linked to neurodegeneration in many disease processes including stroke. The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke. Brain Sciences 2013-04-19 3 2 Review 10.3390/brainsci3020540 540 560 2076-3425 2013-04-19 doi: 10.3390/brainsci3020540 Lora Watts Reginald Lloyd Richard Garling Timothy Duong http://www.mdpi.com/2076-3425/3/2/521 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. Brain Sciences 2013-04-12 3 2 Review 10.3390/brainsci3020521 521 539 2076-3425 2013-04-12 doi: 10.3390/brainsci3020521 Eric Sussman Christopher Kellner Michael McDowell Peter Yang Eric Nelson Sophie Greenberg Daniel Sahlein Sean Lavine Philip Meyers E. Connolly http://www.mdpi.com/2076-3425/3/2/504 Cocaine is a psychostimulant in the pharmacological class of drugs called Local Anesthetics. Interestingly, cocaine is the only drug in this class that has a chemical formula comprised of a tropane ring and is, moreover, addictive. The correlation between tropane and addiction is well-studied. Another well-studied correlation is that between psychosis induced by cocaine and that psychosis endogenously present in the schizophrenic patient. Indeed, both of these psychoses exhibit much the same behavioral as well as neurochemical properties across species. Therefore, in order to study the link between schizophrenia and cocaine addiction, we used a behavioral paradigm called Acoustic Startle. We used this acoustic startle paradigm in female versus male Sprague-Dawley animals to discriminate possible sex differences in responses to startle. The startle method operates through auditory pathways in brain via a network of sensorimotor gating processes within auditory cortex, cochlear nuclei, inferior and superior colliculi, pontine reticular nuclei, in addition to mesocorticolimbic brain reward and nigrostriatal motor circuitries. This paper is the first to report sex differences to acoustic stimuli in Sprague-Dawley animals (Rattus norvegicus) although such gender responses to acoustic startle have been reported in humans (Swerdlow et al. 1997 [1]). The startle method monitors pre-pulse inhibition (PPI) as a measure of the loss of sensorimotor gating in the brain's neuronal auditory network; auditory deficiencies can lead to sensory overload and subsequently cognitive dysfunction. Cocaine addicts and schizophrenic patients as well as cocaine treated animals are reported to exhibit symptoms of defective PPI (Geyer et al., 2001 [2]). Key findings are: (a) Cocaine significantly reduced PPI in both sexes. (b) Females were significantly more sensitive than males; reduced PPI was greater in females than in males. (c) Physiological saline had no effect on startle in either sex. Thus, the data elucidate gender-specificity to the startle response in animals. Finally, preliminary studies show the effect of cocaine on acoustic startle in tandem with effects on estrous cycle. The data further suggest that hormones may play a role in these sex differences to acoustic startle reported herein. Brain Sciences 2013-04-10 3 2 Article 10.3390/brainsci3020504 504 520 2076-3425 2013-04-10 doi: 10.3390/brainsci3020504 Patricia Broderick Taylor Rosenbaum http://www.mdpi.com/2076-3425/3/2/460 Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of “master bifurcation diagrams” that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection. Brain Sciences 2013-04-08 3 2 Concept Paper 10.3390/brainsci3020460 460 503 2076-3425 2013-04-08 doi: 10.3390/brainsci3020460 Donald DeGracia http://www.mdpi.com/2076-3425/3/2/415 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. Brain Sciences 2013-03-27 3 2 Article 10.3390/brainsci3020415 415 459 2076-3425 2013-03-27 doi: 10.3390/brainsci3020415 Donald MacKay Laura Johnson Chris Hadley http://www.mdpi.com/2076-3425/3/1/396 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 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. Brain Sciences 2013-03-22 3 1 Article 10.3390/brainsci3010396 396 414 2076-3425 2013-03-22 doi: 10.3390/brainsci3010396 Joanna Jacobus Lindsay Squeglia M. Infante Sunita Bava Susan Tapert http://www.mdpi.com/2076-3425/3/1/360 Over the past decade, scientific discoveries have highlighted new roles for a unique class of non-coding RNAs. Transcribed from the genome, these non-coding RNAs have been implicated in determining the biological complexity seen in mammals by acting as transcriptional and translational regulators. Non-coding RNAs, which can be sub-classified into long non-coding RNAs, microRNAs, PIWI-interacting RNAs and several others, are widely expressed in the nervous system with roles in neurogenesis, development and maintenance of the neuronal phenotype. Perturbations of these non-coding transcripts have been observed in ischemic preconditioning as well as ischemic brain injury with characterization of the mechanisms by which they confer toxicity. Their dysregulation may also confer pathogenic conditions in neurovascular diseases. A better understanding of their expression patterns and functions has uncovered the potential use of these riboregulators as neuroprotectants to antagonize the detrimental molecular events taking place upon ischemic-reperfusion injury. In this review, we discuss the various roles of non-coding RNAs in brain development and their mechanisms of gene regulation in relation to ischemic brain injury. We will also address the future directions and open questions for identifying promising non-coding RNAs that could eventually serve as potential neuroprotectants against ischemic brain injury. Brain Sciences 2013-03-20 3 1 Review 10.3390/brainsci3010360 360 395 2076-3425 2013-03-20 doi: 10.3390/brainsci3010360 Prameet Kaur Fujia Liu Jun Tan Kai Lim Sugunavathi Sepramaniam Dwi Karolina Arunmozhiarasi Armugam Kandiah Jeyaseelan http://www.mdpi.com/2076-3425/3/1/344 Ghrelin, a gastrointestinal peptide with a major role in regulating feeding and metabolism, has recently been investigated for its neuroprotective effects. In this review we discuss pre-clinical evidence suggesting ghrelin may be a useful therapeutic in protecting the brain against injury after ischemic stroke. Specifically, we will discuss evidence showing ghrelin administration can improve neuronal cell survival in animal models of focal cerebral ischemia, as well as rescue memory deficits. We will also discuss its proposed mechanisms of action, including anti-apoptotic and anti-inflammatory effects, and suggest ghrelin treatment may be a useful intervention after stroke in the clinic. Brain Sciences 2013-03-19 3 1 Review 10.3390/brainsci3010344 344 359 2076-3425 2013-03-19 doi: 10.3390/brainsci3010344 Sarah Spencer Alyson Miller Zane Andrews http://www.mdpi.com/2076-3425/3/1/318 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. Brain Sciences 2013-03-19 3 1 Article 10.3390/brainsci3010318 318 343 2076-3425 2013-03-19 doi: 10.3390/brainsci3010318 Aaron Nelson Ugo Faraguna Jeffrey Zoltan Giulio Tononi Chiara Cirelli http://www.mdpi.com/2076-3425/3/1/294 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. Brain Sciences 2013-03-19 3 1 Article 10.3390/brainsci3010294 294 317 2076-3425 2013-03-19 doi: 10.3390/brainsci3010294 Caroline Taylor Robert Weston Gregory Dusting Carli Roulston http://www.mdpi.com/2076-3425/3/1/262 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. Brain Sciences 2013-03-14 3 1 Article 10.3390/brainsci3010262 262 293 2076-3425 2013-03-14 doi: 10.3390/brainsci3010262 Donald MacKay Laura Johnson Vedad Fazel Lori James http://www.mdpi.com/2076-3425/3/1/239 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. Brain Sciences 2013-03-07 3 1 Review 10.3390/brainsci3010239 239 261 2076-3425 2013-03-07 doi: 10.3390/brainsci3010239 Kazutaka Shinozuka Travis Dailey Naoki Tajiri Hiroto Ishikawa Yuji Kaneko Cesar Borlongan http://www.mdpi.com/2076-3425/3/1/215 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. Brain Sciences 2013-03-07 3 1 Article 10.3390/brainsci3010215 215 238 2076-3425 2013-03-07 doi: 10.3390/brainsci3010215 Cigdem Tosun Michael Koltz David Kurland Hina Ijaz Melda Gurakar Gary Schwartzbauer Turhan Coksaygan Svetlana Ivanova Volodymyr Gerzanich J. Simard http://www.mdpi.com/2076-3425/3/1/191 Hypoxic-ischemic (HI) brain injury is one of the main causes of disabilities in term-born infants. It is the result of a deprivation of oxygen and glucose in the neural tissue. As one of the most important causes of brain damage in the newborn period, the neonatal HI event is a devastating condition that can lead to long-term neurological deficits or even death. The pattern of this injury occurs in two phases, the first one is a primary energy failure related to the HI event and the second phase is an energy failure that takes place some hours later. Injuries that occur in response to these events are often manifested as severe cognitive and motor disturbances over time. Due to difficulties regarding the early diagnosis and treatment of HI injury, there is an increasing need to find effective therapies as new opportunities for the reduction of brain damage and its long term effects. Some of these therapies are focused on prevention of the production of reactive oxygen species, anti-inflammatory effects, anti-apoptotic interventions and in a later stage, the stimulation of neurotrophic properties in the neonatal brain which could be targeted to promote neuronal and oligodendrocyte regeneration. Brain Sciences 2013-03-05 3 1 Review 10.3390/brainsci3010191 191 214 2076-3425 2013-03-05 doi: 10.3390/brainsci3010191 Felipe Cerio Idoia Lara-Celador Antonia Alvarez Enrique Hilario http://www.mdpi.com/2076-3425/3/1/177 Hypoxia Ischemia (HI) refers to the disruption of blood and/or oxygen delivery to the brain. Term infants suffering perinatal complications that result in decreased blood flow and/or oxygen delivery to the brain are at risk for HI. Among a variety of developmental delays in this population, HI injured infants demonstrate subsequent memory deficits. The Rice-Vannucci rodent HI model can be used to explore behavioral deficits following early HI events, as well as possible therapeutic agents to help reduce deleterious outcomes. Caffeine is an adenosine receptor antagonist that has recently shown promising results as a therapeutic agent following HI injury. The current study sought to investigate the therapeutic benefit of caffeine following early HI injury in male rats. On post-natal day (P) 7, HI injury was induced (cauterization of the right common carotid artery, followed by two hours of 8% oxygen). Male sham animals received only a midline incision with no manipulation of the artery followed by room air exposure for two hours. Subsets of HI and sham animals then received either an intraperitoneal (i.p.) injection of caffeine (10 mg/kg), or vehicle (sterile saline) immediately following hypoxia. All animals later underwent testing on the Morris Water Maze (MWM) from P90 to P95. Results show that HI injured animals (with no caffeine treatment) displayed significant deficits on the MWM task relative to shams. These deficits were attenuated by caffeine treatment when given immediately following the induction of HI. We also found a reduction in right cortical volume (ipsilateral to injury) in HI saline animals as compared to shams, while right cortical volume in the HI caffeine treated animals was intermediate. These findings suggest that caffeine is a potential therapeutic agent that could be used in HI injured infants to reduce brain injury and preserve subsequent cognitive function. Brain Sciences 2013-03-05 3 1 Article 10.3390/brainsci3010177 177 190 2076-3425 2013-03-05 doi: 10.3390/brainsci3010177 Michelle Alexander Amanda Smith Ted Rosenkrantz R. Fitch http://www.mdpi.com/2076-3425/3/1/159 Tobacco smoking is the most frequent form of substance abuse. We provide a review of the neuroadaptive changes evidenced in human smokers with regard to the current neurobiological models of addiction. Addiction is thought to result from an interplay between positive and negative reinforcement. Positive reinforcing effects of the drugs are mediated by striatal dopamine release, while negative reinforcement involves the relief of withdrawal symptoms and neurobiological stress systems. In addition, drug-related stimuli are attributed with excessive motivational value and are thought to exert a control on the behavior. This mechanism plays a central role in drug maintenance and relapse. Further neuroadaptive changes associated with chronic use of the drug consist of reduced responses to natural rewards and in the activation of an antireward system, related to neurobiological stress systems. Reduced inhibitory cognitive control is believed to support the development and the maintenance of addiction. The findings observed in human nicotine dependence are generally in line with these models. The current state of the research indicates specific neuroadaptive changes associated with nicotine addiction that need to be further elucidated with regard to their role in the treatment of nicotine dependence. Brain Sciences 2013-02-15 3 1 Review 10.3390/brainsci3010159 159 176 2076-3425 2013-02-15 doi: 10.3390/brainsci3010159 Chantal Martin-Soelch http://www.mdpi.com/2076-3425/3/1/143 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. Brain Sciences 2013-02-04 3 1 Article 10.3390/brainsci3010143 143 158 2076-3425 2013-02-04 doi: 10.3390/brainsci3010143 Heather Brenhouse Jodi Lukkes Susan Andersen http://www.mdpi.com/2076-3425/3/1/123 Stroke is a leading cause of death, disability and dementia worldwide. Despite extensive pre-clinical investigation, few therapeutic treatment options are available to patients, meaning that death, severe disability and the requirement for long-term rehabilitation are common outcomes. Cell loss and tissue injury following stroke occurs through a number of diverse secondary injury pathways, whose delayed nature provides an opportunity for pharmacological intervention. Amongst these secondary injury factors, increased blood-brain barrier permeability and cerebral oedema are well-documented complications of cerebral ischaemia, whose severity has been shown to be associated with final outcome. Whilst the mechanisms of increased blood-brain barrier permeability and cerebral oedema are largely unknown, recent evidence suggests that the neuropeptide substance P (SP) plays a central role. The aim of this review is to examine the role of SP in ischaemic stroke and report on the potential utility of NK1 tachykinin receptor antagonists as therapeutic agents. Brain Sciences 2013-01-30 3 1 Review 10.3390/brainsci3010123 123 142 2076-3425 2013-01-30 doi: 10.3390/brainsci3010123 Renée Turner Robert Vink http://www.mdpi.com/2076-3425/3/1/101 Exercise represents a behavioral intervention that enhances brain health and motor function. The increase in cerebral blood volume in response to physical activity may be responsible for improving brain function. Among the various neuroimaging techniques used to monitor brain hemodynamic response during exercise, functional near-infrared spectroscopy could facilitate the measurement of task-related cortical responses noninvasively and is relatively robust with regard to the subjects’ motion. Although the components of optimal exercise interventions have not been determined, evidence from animal and human studies suggests that aerobic exercise with sufficiently high intensity has neuroprotective properties and promotes motor function. This review provides an insight into the effect of physical activity (based on endurance and resistance exercises) on brain function for producing movement. Since most progress in the study of brain function has come from patients with neurological disorders (e.g., stroke and Parkinson’s patients), this review presents some findings emphasizing training paradigms for restoring motor function. Brain Sciences 2013-01-25 3 1 Review 10.3390/brainsci3010101 101 122 2076-3425 2013-01-25 doi: 10.3390/brainsci3010101 Stephane Perrey http://www.mdpi.com/2076-3425/3/1/87 Parkinson’s disease (PD) is a neurological disorder that is manifested in the form of both motor and non-motor symptoms such as resting tremor, bradykinesia, muscular rigidity, depression, and cognitive impairment. PD is progressive in nature, ultimately leading to debilitating disruption of activities of daily living. Recently, a myriad of research has been focused on non-pharmacological interventions to alleviate the motor and non-motor symptoms of the disease. However, while there is a growing body of evidence supporting exercise as a viable therapy option for the treatment of Parkinson’s disease, there is a lack of literature enumerating a specific exercise sequence for patients with PD. In this literature review, we analyze the success of specific modalities of exercise in order to suggest an optimal exercise regimen for Parkinson’s disease patients. Brain Sciences 2013-01-16 3 1 Review 10.3390/brainsci3010087 87 100 2076-3425 2013-01-16 doi: 10.3390/brainsci3010087 Sanjay Salgado Nori Williams Rima Kotian Miran Salgado http://www.mdpi.com/2076-3425/3/1/84 The first book to consider atypical development across multiple levels (genes, brain, behavior, environment), encouraging readers to think dynamically and developmentally, rather than examining static snapshots of neurodevelopmental disorders.Provides the most comprehensive review of development across cognitive domains (and their interactions), making clinicians more sensitive to looking for underlying cognitive and neural differences even when behavioral scores are in the normal range.Considers development from infancy to adulthood, encouraging the reader to think about the importance of development in understanding neurodevelopmental disorders, for example, by considering the impact that differences in low-level processes in infancy can have on later developing cognitive processes. Brain Sciences 2013-01-15 3 1 New Book Received 10.3390/brainsci3010084 84 86 2076-3425 2013-01-15 doi: 10.3390/brainsci3010084 Shu-Kun Lin http://www.mdpi.com/2076-3425/3/1/54 Leisure-time physical activity (PA) and exercise training are known to help maintain cognitive function in healthy older adults. However, relatively little is known about the effects of PA on cognitive function or brain function in those at increased risk for Alzheimer’s disease through the presence of the apolipoproteinE epsilon4 (APOE-ε4) allele, diagnosis of mild cognitive impairment (MCI), or the presence of metabolic disease. Here, we examine the question of whether PA and exercise interventions may differentially impact cognitive trajectory, clinical outcomes, and brain structure and function among individuals at the greatest risk for AD. The literature suggests that the protective effects of PA on risk for future dementia appear to be larger in those at increased genetic risk for AD. Exercise training is also effective at helping to promote stable cognitive function in MCI patients, and greater cardiorespiratory fitness is associated with greater brain volume in early-stage AD patients. In APOE-ε4 allele carriers compared to non-carriers, greater levels of PA may be more effective in reducing amyloid burden and are associated with greater activation of semantic memory-related neural circuits. A greater research emphasis should be placed on randomized clinical trials for exercise, with clinical, behavioral, and neuroimaging outcomes in people at increased risk for AD. Brain Sciences 2013-01-14 3 1 Review 10.3390/brainsci3010054 54 83 2076-3425 2013-01-14 doi: 10.3390/brainsci3010054 J. Smith Kristy Nielson John Woodard Michael Seidenberg Stephen Rao http://www.mdpi.com/2076-3425/3/1/39 The beneficial effects of exercise on brain function have been demonstrated in animal models and in a growing number of clinical studies on humans. There are multiple mechanisms that account for the brain-enhancing effects of exercise, including neuroinflammation, vascularization, antioxidation, energy adaptation, and regulations on neurotrophic factors and neurotransmitters. Dopamine (DA), noradrenaline (NE), and serotonin (5-HT) are the three major monoamine neurotransmitters that are known to be modulated by exercise. This review focuses on how these three neurotransmitters contribute to exercise affecting brain function and how it can work against neurological disorders. Brain Sciences 2013-01-11 3 1 Review 10.3390/brainsci3010039 39 53 2076-3425 2013-01-11 doi: 10.3390/brainsci3010039 Tzu-Wei Lin Yu-Min Kuo http://www.mdpi.com/2076-3425/3/1/1 Developmental alcohol exposure both early in life and during adolescence can have a devastating impact on normal brain structure and functioning, leading to behavioral and cognitive impairments that persist throughout the lifespan. This review discusses human work as well as animal models used to investigate the effect of alcohol exposure at various time points during development, as well as specific behavioral and neuroanatomical deficits caused by alcohol exposure. Further, cellular and molecular mediators contributing to these alcohol-induced changes are examined, such as neurotrophic factors and apoptotic markers. Next, this review seeks to support the use of aerobic exercise as a potential therapeutic intervention for alcohol-related impairments. To date, few interventions, behavioral or pharmacological, have been proven effective in mitigating some alcohol-related deficits. Exercise is a simple therapy that can be used across species and also across socioeconomic status. It has a profoundly positive influence on many measures of learning and neuroplasticity; in particular, those measures damaged by alcohol exposure. This review discusses current evidence that exercise may mitigate damage caused by developmental alcohol exposure and is a promising therapeutic target for future research and intervention strategies. Brain Sciences 2012-12-21 3 1 Review 10.3390/brainsci3010001 1 38 2076-3425 2012-12-21 doi: 10.3390/brainsci3010001 Anna Klintsova Gillian Hamilton Karen Boschen http://www.mdpi.com/2076-3425/2/4/790 Conscious and unconscious brain mechanisms, including cognition, emotions and language are considered in this review. The fundamental mechanisms of cognition include interactions between bottom-up and top-down signals. The modeling of these interactions since the 1960s is briefly reviewed, analyzing the ubiquitous difficulty: incomputable combinatorial complexity (CC). Fundamental reasons for CC are related to the Gödel’s difficulties of logic, a most fundamental mathematical result of the 20th century. Many scientists still “believed” in logic because, as the review discusses, logic is related to consciousness; non-logical processes in the brain are unconscious. CC difficulty is overcome in the brain by processes “from vague-unconscious to crisp-conscious” (representations, plans, models, concepts). These processes are modeled by dynamic logic, evolving from vague and unconscious representations toward crisp and conscious thoughts. We discuss experimental proofs and relate dynamic logic to simulators of the perceptual symbol system. “From vague to crisp” explains interactions between cognition and language. Language is mostly conscious, whereas cognition is only rarely so; this clarifies much about the mind that might seem mysterious. All of the above involve emotions of a special kind, aesthetic emotions related to knowledge and to cognitive dissonances. Cognition-language-emotional mechanisms operate throughout the hierarchy of the mind and create all higher mental abilities. The review discusses cognitive functions of the beautiful, sublime, music. Brain Sciences 2012-12-18 2 4 Review 10.3390/brainsci2040790 790 834 2076-3425 2012-12-18 doi: 10.3390/brainsci2040790 Leonid Perlovsky Roman Ilin http://www.mdpi.com/2076-3425/2/4/769 There is ongoing debate about the contribution of explicit processes to incidental learning, particularly attention, working memory and control mechanisms. Studies generally measure explicit process contributions to incidental learning by comparing dual- to single-task sequence learning on some variant of a Serial Reaction Time (SRT), usually adopting an auditory tone counting task as the secondary task/memory load. Few studies have used secondary working memory stimuli with the SRT task, those that have typically presented secondary stimuli, before, after or between primary task stimuli. Arguably, this design is problematic because participants may potentially “switch” attention between sequential stimulus sources limiting the potential of both tasks to simultaneously index shared cognitive resources. In the present study secondary Visual and Verbal, memory tasks were temporally synchronous and spatially embedded with the primary SRT task for Visual and Verbal dual-task conditions and temporally synchronous but spatially displaced for Visual-Spatial and Verbal-Spatial Above/Below conditions, to investigate modality specific contributions of visual, verbal and spatial memory to incidental and explicit sequence learning. Incidental learning scores were not different as an effect of condition but explicit scores were. Explicit scores significantly and incrementally diminished from the Single-task through Visual-Spatial Below conditions; percentage accuracy scores on secondary tasks followed a significant corresponding pattern suggesting an explicit learning/secondary memory task trade-off as memory demands of tasks increased across condition. Incidental learning boundary conditions are unlikely to substantially comprise working memory processes. Brain Sciences 2012-12-17 2 4 Article 10.3390/brainsci2040769 769 789 2076-3425 2012-12-17 doi: 10.3390/brainsci2040769 Lynne Barker http://www.mdpi.com/2076-3425/2/4/745 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. Brain Sciences 2012-12-14 2 4 Review 10.3390/brainsci2040745 745 768 2076-3425 2012-12-14 doi: 10.3390/brainsci2040745 Michael Chen Huong Do http://www.mdpi.com/2076-3425/2/4/709 Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging. Brain Sciences 2012-11-29 2 4 Review 10.3390/brainsci2040709 709 744 2076-3425 2012-11-29 doi: 10.3390/brainsci2040709 Rodney Swain Kiersten Berggren Abigail Kerr Ami Patel Caitlin Peplinski Angela Sikorski http://www.mdpi.com/2076-3425/2/4/684 Tor preventive measures are necessary to attenuate the increased economic and social burden of dementia. This review will focus on the potential for physical activity and exercise training to promote brain health and improve cognitive function via neurophysiological changes. We will review pertinent animal and human research examining the effects of physical activity on cognitive function and neurophysiology. We will discuss cross-sectional and longitudinal studies addressing the relationship between neurocognitive health and cardiorespiratory fitness or habitual activity level. We will then present and discuss longitudinal investigations examining the effects of exercise training on cognitive function and neurophysiology. We will conclude by summarizing our current understanding of the relationship between physical activity and brain health, and present areas for future research given the current gaps in our understanding of this issue. Brain Sciences 2012-11-29 2 4 Review 10.3390/brainsci2040684 684 708 2076-3425 2012-11-29 doi: 10.3390/brainsci2040684 Sara Gregory Beth Parker Paul Thompson http://www.mdpi.com/2076-3425/2/4/667 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. Brain Sciences 2012-11-27 2 4 Article 10.3390/brainsci2040667 667 683 2076-3425 2012-11-27 doi: 10.3390/brainsci2040667 Benjamin Nephew Martha Caffrey Ada Felix-Ortiz Marcelo Febo http://www.mdpi.com/2076-3425/2/4/649 Cortical activity is thought to reflect the biomechanical properties of movement (e.g., force or velocity of movement), but fatigue and movement familiarity are important factors that require additional consideration in electrophysiological research. The purpose of this within-group quantitative electroencephalogram (EEG) investigation was to examine changes in cortical activity amplitude and location during four resistance exercise movement protocols emphasizing rate (PWR), magnitude (FOR), or volume (VOL) of force production, while accounting for movement familiarity and fatigue. EEG signals were recorded during each complete repetition and were then grouped by functional region, processed to eliminate artifacts, and averaged to compare overall differences in the magnitude and location of cortical activity between protocols over the course of six sets. Biomechanical, biochemical, and exertional data were collected to contextualize electrophysiological data. The most fatiguing protocols were accompanied by the greatest increases in cortical activity. Furthermore, despite non-incremental loading and lower force levels, VOL displayed the largest increases in cortical activity over time and greatest motor and sensory activity overall. Our findings suggest that cortical activity is strongly related to aspects of fatigue during a high intensity resistance exercise movement. Brain Sciences 2012-11-20 2 4 Article 10.3390/brainsci2040649 649 666 2076-3425 2012-11-20 doi: 10.3390/brainsci2040649 Shawn Flanagan Courtenay Dunn-Lewis Brett Comstock Carl Maresh Jeff Volek Craig Denegar William Kraemer http://www.mdpi.com/2076-3425/2/4/634 Recent studies have shown that during unimanual motor tasks, aging adults show bilateral recruitment of primary motor cortex (M1), while younger adults show a suppression of the ipsilateral motor cortex. Additional work has indicated that increased bilateral M1 recruitment in older adults may be deleterious when performing some motor tasks. However, higher levels of physical fitness are associated with improved dexterity and fitness may mitigate the loss of both inhibitory and excitatory communication in aging adults. The goal of this study was to assess dexterity and interhemispheric motor communication in physically fit and sedentary middle-age (40–60 years) right handed participants using tests of hand deftness and transcranial magnetic stimulation (TMS). To behaviorally assess the influence of interhemispheric communication on motor performance, participants also perform the coin rotation deftness task while maintaining pinch force with the opposite hand (bimanual condition). We correlated these behavioral measures with the ipsilateral silent period using TMS to assess interhemispheric inhibition. Our results show that the middle-aged adults who were physically fit had better dexterity of their right hand (finger tapping and peg-board). When performing the coin rotation task the fit group had no between hand differences, but the sedentary group’s left hand performance was inferior to the their right hand. We found that better dexterity correlated with ipsilateral silent period duration (greater inhibition) thereby supporting the postulate that fitness improves interhemispheric motor communication. Brain Sciences 2012-11-16 2 4 Article 10.3390/brainsci2040634 634 648 2076-3425 2012-11-16 doi: 10.3390/brainsci2040634 Keith McGregor Kenneth Heilman Joe Nocera Carolynn Patten Todd Manini Bruce Crosson Andrew Butler http://www.mdpi.com/2076-3425/2/4/619 Medications that target norepinephrine (NE) neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX), a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8) were administered saline, cocaine (COC, 10 mg/kg) or DOX (0.3 or 1.0 mg/kg) alone or in combination for 5 consecutive days (development). Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression). COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg), but not the low dose (0.3 mg/kg) of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans. Brain Sciences 2012-11-13 2 4 Article 10.3390/brainsci2040619 619 633 2076-3425 2012-11-13 doi: 10.3390/brainsci2040619 Colin N. Haile Yanli Hao Patrick W. O'Malley Thomas F. Newton Therese A. Kosten http://www.mdpi.com/2076-3425/2/4/605 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. Brain Sciences 2012-11-12 2 4 Article 10.3390/brainsci2040605 605 618 2076-3425 2012-11-12 doi: 10.3390/brainsci2040605 Rachel E. Thayer Shirley M. Crotwell Tiffany J. Callahan Kent E. Hutchison Angela D. Bryan http://www.mdpi.com/2076-3425/2/4/589 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. Brain Sciences 2012-11-07 2 4 Article 10.3390/brainsci2040589 589 604 2076-3425 2012-11-07 doi: 10.3390/brainsci2040589 Alexander Coverdill Megan McCarthy Robert Bridges Benjamin Nephew http://www.mdpi.com/2076-3425/2/4/573 Reinstatement of conditioned place preferences have been used to investigate physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuron communication and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The present study determined whether the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) dopamine (DA) D2 receptor antagonist infusions would block (or potentiate) cocaine-induced reinstatement of conditioned place preferences. Adolescent rats (postnatal day (PND 28–39)) were trained to express a cocaine place preference. The involvement of D2 receptors on cocaine-induced reinstatement was determined by intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 μM) during a cocaine-primed reinstatement test (10 mg/kg cocaine, i.p.). Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of conditioned place preference. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate responsivity to cocaine-induced reinstatement of a conditioned place preference during development. Brain Sciences 2012-10-31 2 4 Article 10.3390/brainsci2040573 573 588 2076-3425 2012-10-31 doi: 10.3390/brainsci2040573 Kimberly Badanich Cheryl Kirstein http://www.mdpi.com/2076-3425/2/4/553 The effect of methamphetamine (MA) dependence on the structure of the human brain has not been extensively studied, especially in active users. Previous studies reported cortical deficits and striatal gains in grey matter (GM) volume of abstinent MA abusers compared with control participants. This study aimed to investigate structural GM changes in the brains of 17 active MA-dependent participants compared with 20 control participants aged 18–46 years using voxel-based morphometry and region of interest volumetric analysis of structural magnetic resonance imaging data, and whether these changes might be associated with cognitive performance. Significant volume increases were observed in the right and left putamen and left nucleus accumbens of MA-dependent compared to control participants. The volumetric gain in the right putamen remained significant after Bonferroni correction, and was inversely correlated with the number of errors (standardised z-scores) on the Go/No-go task. MA-dependent participants exhibited cortical GM deficits in the left superior frontal and precentral gyri in comparison to control participants, although these findings did not survive correction for multiple comparisons. In conclusion, consistent with findings from previous studies of abstinent users, active chronic MA-dependent participants showed significant striatal enlargement which was associated with improved performance on the Go/No-go, a cognitive task of response inhibition and impulsivity. Striatal enlargement may reflect the involvement of neurotrophic effects, inflammation or microgliosis. However, since it was associated with improved cognitive function, it is likely to reflect a compensatory response to MA-induced neurotoxicity in the striatum, in order to maintain cognitive function. Follow-up studies are recommended to ascertain whether this effect continues to be present following abstinence. Several factors may have contributed to the lack of more substantial cortical and subcortical GM changes amongst MA-dependent participants, including variability in MA exposure variables and difference in abstinence status from previous studies. Brain Sciences 2012-10-30 2 4 Article 10.3390/brainsci2040553 553 572 2076-3425 2012-10-30 doi: 10.3390/brainsci2040553 Reem Jan Joanne Lin Sylvester Miles Rob Kydd Bruce Russell http://www.mdpi.com/2076-3425/2/4/523 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. Brain Sciences 2012-10-17 2 4 Review 10.3390/brainsci2040523 523 552 2076-3425 2012-10-17 doi: 10.3390/brainsci2040523 Joseph R. DiFranza Wei Huang Jean King http://www.mdpi.com/2076-3425/2/4/504 Whether or not affect can be unconscious remains controversial. Research claiming to demonstrate unconscious affect fails to establish clearly unconscious stimulus conditions. The few investigations that have established unconscious conditions fail to rule out conscious affect changes. We report two studies in which unconscious stimulus conditions were met and conscious mood changes measured. The subliminal stimuli were positive and negative affect words presented at the objective detection threshold; conscious mood changes were measured with standard manikin valence, potency, and arousal scales. We found and replicated that unconscious emotional stimuli produced conscious mood changes on the potency scale but not on the valence scale. Were positive and negative affects aroused unconsciously, but reflected consciously in potency changes? Or were the valence words unconscious cognitive causes of conscious mood changes being activated without unconscious affect? A thought experiment is offered as a way to resolve this dilemma. Brain Sciences 2012-10-17 2 4 Article 10.3390/brainsci2040504 504 522 2076-3425 2012-10-17 doi: 10.3390/brainsci2040504 Howard Shevrin Jaak Panksepp Linda A. W. Brakel Michael Snodgrass http://www.mdpi.com/2076-3425/2/4/483 Caveolin is the principal protein of caveolae and has been implicated in the pathogenesis of cerebral ischemia. To investigate whether changed expression of caveolins has a pivotal role in focal cerebral ischemia, we induced middle cerebral artery occlusion (MCAo)-reperfusion and examined expression of caveolins, inflammatory activation markers, and mediators of autophagic cell death. We also treated MCAo rats with forced exercise to determine its effects on neurological outcome. Particularly, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used to compare the effects of hypertension on focal cerebral ischemia. All MCAo groups showed neurological deficiencies, motor dysfunction, and disruption of balancing ability; however, these pathological changes were more severe in SHR than WKY rats. Expression of caveolins was decreased in MCAo brain tissue, whereas the levels of iNOS and glial fibrillary acidic protein (GFAP) increased. Additionally, LC3-II and beclin-1 levels were elevated in the MCAo groups. Forced exercise attenuated both molecular and behavioral changes in MCAo animals, but SHR rats showed delayed functional recovery and residual molecular changes when compared to WKY rats. These results suggest that forced exercise may be beneficial for promoting functional recovery following cerebral ischemia through caveolin-dependent mechanisms or interactions between caveolins and these signaling molecules in ischemic brain regions. Brain Sciences 2012-10-16 2 4 Article 10.3390/brainsci2040483 483 503 2076-3425 2012-10-16 doi: 10.3390/brainsci2040483 Sookyoung Park Jinhee Shin Yunkyung Hong Sunmi Kim Seunghoon Lee Kanghui Park Tserentogtokh Lkhagvasuren Sang-Rae Lee Kyu-Tae Chang Yonggeun Hong http://www.mdpi.com/2076-3425/2/4/434 Methamphetamine (MA) is a potent psychostimulant drug whose abuse has become a global epidemic in recent years. Firstly, this review article briefly discusses the epidemiology and clinical pharmacology of methamphetamine dependence. Secondly, the article reviews relevant animal literature modeling methamphetamine dependence and discusses possible mechanisms of methamphetamine-induced neurotoxicity. Thirdly, it provides a critical review of functional and structural neuroimaging studies in human MA abusers; including positron emission tomography (PET) and functional and structural magnetic resonance imaging (MRI). The effect of abstinence from methamphetamine, both short- and long-term within the context of these studies is also reviewed. Brain Sciences 2012-10-01 2 4 Review 10.3390/brainsci2040434 434 482 2076-3425 2012-10-01 doi: 10.3390/brainsci2040434 Reem K. Jan Rob R. Kydd Bruce R. Russell http://www.mdpi.com/2076-3425/2/3/421 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. Brain Sciences 2012-09-20 2 3 Article 10.3390/brainsci2030421 421 433 2076-3425 2012-09-20 doi: 10.3390/brainsci2030421 Luis Stinus Martine Cador Stephanie Caille http://www.mdpi.com/2076-3425/2/3/405 I have been asked to write a few words on consciousness in this editorial issue. My thoughts on consciousness will focus on the relation between consciousness and will. Consciousness is not an epiphenomenon as some people believe—it is not a psychological construct either. Consciousness is a brain function. With deeper thought it is even more than that—a brain state. Writing this, I am in a conscious state, I hope at least. In every day philosophy, a close connection of consciousness with will is ventured, and is expressed in the term “conscious free will”. However, this does not mean that our will is totally determined and not free, be it conscious or unconscious. Total determinists postulate total freedom from nature in order to speak of free will. Absolute freedom from nature is an a priori impossibility; there is no way to escape from nature. However, we have relative freedom, graded freedom, freedom in degrees, enabling us to make responsible decisions and be captains of our own destiny. We are not totally determined. We can upregulate our degrees of freedom by self-management or we can downregulate them by self-mismanagement. In the present communication consciousness and the unconscious are discussed in their various aspects and interactions. Brain Sciences 2012-09-18 2 3 Communication 10.3390/brainsci2030405 405 420 2076-3425 2012-09-18 doi: 10.3390/brainsci2030405 Lüder Deecke http://www.mdpi.com/2076-3425/2/3/375 The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin®). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed “normal” (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin® (2 × 2 mg/kg/day) or distilled water (dH2O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH2O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in “normal” WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls. Brain Sciences 2012-09-12 2 3 Article 10.3390/brainsci2030375 375 404 2076-3425 2012-09-12 doi: 10.3390/brainsci2030375 Margery C. Pardey Natasha N. Kumar Ann K. Goodchild Kelly J. Clemens Judi Homewood Jennifer L. Cornish http://www.mdpi.com/2076-3425/2/3/347 In the past decade, research has accumulated suggesting that excessive Internet use can lead to the development of a behavioral addiction. Internet addiction has been considered as a serious threat to mental health and the excessive use of the Internet has been linked to a variety of negative psychosocial consequences. The aim of this review is to identify all empirical studies to date that used neuroimaging techniques to shed light upon the emerging mental health problem of Internet and gaming addiction from a neuroscientific perspective. Neuroimaging studies offer an advantage over traditional survey and behavioral research because with this method, it is possible to distinguish particular brain areas that are involved in the development and maintenance of addiction. A systematic literature search was conducted, identifying 18 studies. These studies provide compelling evidence for the similarities between different types of addictions, notably substance-related addictions and Internet and gaming addiction, on a variety of levels. On the molecular level, Internet addiction is characterized by an overall reward deficiency that entails decreased dopaminergic activity. On the level of neural circuitry, Internet and gaming addiction led to neuroadaptation and structural changes that occur as a consequence of prolonged increased activity in brain areas associated with addiction. On a behavioral level, Internet and gaming addicts appear to be constricted with regards to their cognitive functioning in various domains. The paper shows that understanding the neuronal correlates associated with the development of Internet and gaming addiction will promote future research and will pave the way for the development of addiction treatment approaches. Brain Sciences 2012-09-05 2 3 Review 10.3390/brainsci2030347 347 374 2076-3425 2012-09-05 doi: 10.3390/brainsci2030347 Daria J. Kuss Mark D. Griffiths http://www.mdpi.com/2076-3425/2/3/332 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. Brain Sciences 2012-08-27 2 3 Article 10.3390/brainsci2030332 332 346 2076-3425 2012-08-27 doi: 10.3390/brainsci2030332 Kirsten Hötting Gesche Schauenburg Brigitte Röder http://www.mdpi.com/2076-3425/2/3/319 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 neuronal-glial interactions across M1 in chronic LBP. Brain Sciences 2012-08-21 2 3 Article 10.3390/brainsci2030319 319 331 2076-3425 2012-08-21 doi: 10.3390/brainsci2030319 Neena K. Sharma William M. Brooks Anda E. Popescu Linda VanDillen Steven Z. George Kenneth E. McCarson Byron J. Gajewski Patrick Gorman Carmen M. Cirstea http://www.mdpi.com/2076-3425/2/3/298 The use of methamphetamine (MA) is increasing in the U.S. and elsewhere around the world. MA’s capacity to cause addiction significantly exceeds other psychostimulant drugs, and its use negatively impacts learning and memory. Recently, attempts have been made to interfere with the presumed mechanism(s) underlying the establishment of drug-induced memory consolidation. The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists. The present investigation utilized an angiotensin IV (AngIV) analogue, Divalinal-AngIV (divalinal), to disrupt acquisition of MA-induced dependence in rats as measured using the conditioned place preference paradigm. Results indicate that both acute and chronic intracerebroventricular infusion of divalinal prior to each daily subcutaneous injection of MA prevented acquisition. However, divalinal was unable to prevent MA-induced reinstatement after prior acquisition followed by extinction trials. These results indicate that prevention of MA dependence can be accomplished by blockade of the brain AT4 receptor subtype. On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective. Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference. Brain Sciences 2012-08-20 2 3 Article 10.3390/brainsci2030298 298 318 2076-3425 2012-08-20 doi: 10.3390/brainsci2030298 John W. Wright Wendy L. Wilson Vanessa Wakeling Alan S. Boydstun Audrey Jensen Leen Kawas Joseph W. Harding http://www.mdpi.com/2076-3425/2/3/267 This study compared automatic and controlled cognitive processes that underlie event-related potentials (ERPs) effects during speech perception. Sentences were presented to French native speakers, and the final word could be congruent or incongruent, and presented at one of four levels of degradation (using a modulation with pink noise): no degradation, mild degradation (2 levels), or strong degradation. We assumed that degradation impairs controlled more than automatic processes. The N400 and Late Positive Complex (LPC) effects were defined as the differences between the corresponding wave amplitudes to incongruent words minus congruent words. Under mild degradation, where controlled sentence-level processing could still occur (as indicated by behavioral data), both N400 and LPC effects were delayed and the latter effect was reduced. Under strong degradation, where sentence processing was rather automatic (as indicated by behavioral data), no ERP effect remained. These results suggest that ERP effects elicited in complex contexts, such as sentences, reflect controlled rather than automatic mechanisms of speech processing. These results differ from the results of experiments that used word-pair or word-list paradigms. Brain Sciences 2012-08-14 2 3 Article 10.3390/brainsci2030267 267 297 2076-3425 2012-08-14 doi: 10.3390/brainsci2030267 Jérôme Daltrozzo Norma Wioland Boris Kotchoubey http://www.mdpi.com/2076-3425/2/2/254 Prefrontal cortex function has traditionally been associated with explicit executive function. Recently, however, evidence has been presented that lateral prefrontal cortex is also involved in high-level cognitive processes such as task set selection or inhibition in the absence of awareness. Here, we discuss evidence that not only lateral prefrontal cortex, but also rostral prefrontal cortex is involved in such kinds of implicit control processes. Specifically, rostral prefrontal cortex activation changes have been observed when implicitly learned spatial contingencies in a search display become invalid, requiring a change of attentional settings for optimal guidance of visual search. Brain Sciences 2012-06-15 2 2 Review 10.3390/brainsci2020254 254 266 2076-3425 2012-06-15 doi: 10.3390/brainsci2020254 Stefan Pollmann http://www.mdpi.com/2076-3425/2/2/242 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. Brain Sciences 2012-06-11 2 2 Article 10.3390/brainsci2020242 242 253 2076-3425 2012-06-11 doi: 10.3390/brainsci2020242 Pedro Rada Nicole M. Avena Jessica R. Barson Bartley G. Hoebel Sarah F. Leibowitz http://www.mdpi.com/2076-3425/2/2/225 Subliminal priming refers to behavioral modulation by an unconscious stimulus, and can thus be regarded as a form of unconscious visual processing. Theories on recurrent processing have suggested that the neural correlate of consciousness (NCC) comprises of the non-hierarchical transfer of stimulus-related information. According to these models, the neural correlate of subliminal priming (NCSP) corresponds to the visual processing within the feedforward sweep. Research from cognitive neuroscience on these two concepts and the relationship between them is discussed here. Evidence favoring the necessity of recurrent connectivity for visual awareness is accumulating, although some questions, such as the need for global versus local recurrent processing, are not clarified yet. However, this is not to say that recurrent processing is sufficient for consciousness, as a neural definition of consciousness in terms of recurrent connectivity would imply. We argue that the limited interest cognitive neuroscience currently has for the NCSP is undeserved, because the discovery of the NCSP can give insight into why people do (and do not) express certain behavior. Brain Sciences 2012-05-29 2 2 Review 10.3390/brainsci2020225 225 241 2076-3425 2012-05-29 doi: 10.3390/brainsci2020225 Christianne Jacobs Alexander T. Sack http://www.mdpi.com/2076-3425/2/2/203 The mammalian brain varies in size by a factor of 100,000 and is composed of anatomically and functionally distinct structures. Theoretically, the manner in which brain composition can evolve is limited, ranging from highly modular (“mosaic evolution”) to coordinated changes in brain structure size (“concerted evolution”) or anything between these two extremes. There is a debate about the relative importance of these distinct evolutionary trends. It is shown here that the presence of taxa-specific allometric relationships between brain structures makes a taxa-specific approach obligatory. In some taxa, the evolution of the size of brain structures follows a unique, coordinated pattern, which, in addition to other characteristics at different anatomical levels, defines what has been called here a “taxon cerebrotype”. In other taxa, no clear pattern is found, reflecting heterogeneity of the species’ lifestyles. These results suggest that the evolution of brain size and composition depends on the complex interplay between selection pressures and constraints that have changed constantly during mammalian evolution. Therefore the variability in brain composition between species should not be considered as deviations from the normal, concerted mammalian trend, but in taxa and species-specific versions of the mammalian brain. Because it forms homogenous groups of species within this complex “space” of constraints and selection pressures, the cerebrotype approach developed here could constitute an adequate level of analysis for evo-devo studies, and by extension, for a wide range of disciplines related to brain evolution. Brain Sciences 2012-05-18 2 2 Article 10.3390/brainsci2020203 203 224 2076-3425 2012-05-18 doi: 10.3390/brainsci2020203 Romain Willemet http://www.mdpi.com/2076-3425/2/2/176 Considerable evidence has argued in favor of multiple neural systems supporting human category learning, one based on conscious rule inference and one based on implicit information integration. However, there have been few attempts to study potential system interactions during category learning. The PINNACLE (Parallel Interactive Neural Networks Active in Category Learning) model incorporates multiple categorization systems that compete to provide categorization judgments about visual stimuli. Incorporating competing systems requires inclusion of cognitive mechanisms associated with resolving this competition and creates a potential credit assignment problem in handling feedback. The hypothesized mechanisms make predictions about internal mental states that are not always reflected in choice behavior, but may be reflected in neural activity. Two prior functional magnetic resonance imaging (fMRI) studies of category learning were re-analyzed using PINNACLE to identify neural correlates of internal cognitive states on each trial. These analyses identified additional brain regions supporting the two types of category learning, regions particularly active when the systems are hypothesized to be in maximal competition, and found evidence of covert learning activity in the “off system” (the category learning system not currently driving behavior). These results suggest that PINNACLE provides a plausible framework for how competing multiple category learning systems are organized in the brain and shows how computational modeling approaches and fMRI can be used synergistically to gain access to cognitive processes that support complex decision-making machinery. Brain Sciences 2012-04-23 2 2 Article 10.3390/brainsci2020176 176 202 2076-3425 2012-04-23 doi: 10.3390/brainsci2020176 Emi M. Nomura Paul J. Reber http://www.mdpi.com/2076-3425/2/2/147 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. Brain Sciences 2012-04-17 2 2 Review 10.3390/brainsci2020147 147 175 2076-3425 2012-04-17 doi: 10.3390/brainsci2020147 Mark Solms Jaak Panksepp http://www.mdpi.com/2076-3425/2/2/130 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. Brain Sciences 2012-04-16 2 2 Review 10.3390/brainsci2020130 130 146 2076-3425 2012-04-16 doi: 10.3390/brainsci2020130 Veronika Halász Ross Cunnington http://www.mdpi.com/2076-3425/2/2/101 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”. Brain Sciences 2012-04-10 2 2 Review 10.3390/brainsci2020101 101 129 2076-3425 2012-04-10 doi: 10.3390/brainsci2020101 Angelica Staniloiu Hans J. Markowitsch http://www.mdpi.com/2076-3425/2/2/85 The unconscious effects of an emotional stimulus have been highlighted by a vast amount of research, whereover it remains questionable whether it is possible to assign a specific function to cortical brain oscillations in the unconscious perception of facial expressions of emotions. Alpha band variation was monitored within the right- and left-cortical side when subjects consciously (supraliminal stimulation) or unconsciously (subliminal stimulation) processed facial patterns. Twenty subjects looked at six facial expressions of emotions (anger, fear, surprise, disgust, happiness, sadness, and neutral) under two different conditions: supraliminal (200 ms) vs. subliminal (30 ms) stimulation (140 target-mask pairs for each condition). The results showed that conscious/unconscious processing and the significance of the stimulus can modulate the alpha power. Moreover, it was found that there was an increased right frontal activity for negative emotions vs. an increased left response for positive emotion. The significance of facial expressions was adduced to elucidate cortical different responses to emotional types. Brain Sciences 2012-03-26 2 2 Article 10.3390/brainsci2020085 85 100 2076-3425 2012-03-26 doi: 10.3390/brainsci2020085 Michela Balconi Chiara Ferrari http://www.mdpi.com/2076-3425/2/1/61 The latency of startle reflex potentiation may shed light on the aware and unaware processes underlying associative learning, especially associative fear learning. We review research suggesting that single-cue delay classical conditioning is independent of awareness of the contingency between the conditioned stimulus (CS) and the unconditioned stimulus (US). Moreover, we discuss research that argues that conditioning independent of awareness has not been proven. Subsequently, three studies from our lab are presented that have investigated the role of awareness in classical conditioning, by measuring the minimum latency from CS onset to observed changes in reflexive behavior. In sum, research using this method shows that startle is potentiated 30 to 100 ms after CS onset following delay conditioning. Following trace fear conditioning, startle is potentiated 1500 ms after CS presentation. These results indicate that the process underlying delay conditioned responding is independent of awareness, and that trace fear conditioned responding is dependent on awareness. Finally, this method of investigating the role of awareness is discussed and future research possibilities are proposed. Brain Sciences 2012-02-16 2 1 Review 10.3390/brainsci2010061 61 84 2076-3425 2012-02-16 doi: 10.3390/brainsci2010061 Ole Åsli Magne A. Flaten http://www.mdpi.com/2076-3425/2/1/33 According to the bottom-up theory of attention, unconscious abrupt onsets are highly salient and capture attention via the Superior Colliculi (SC). Crucially, abrupt onsets increase the perceived contrast. In line with the SC hypothesis, unconscious abrupt-onset cues capture attention regardless of the cue color when participants search for abrupt-onset targets (Experiment 1). Also, stronger cueing effects occur for higher than lower contrast cues (Experiment 2) and for temporally, rather than nasally, presented stimuli (Experiment 3). However, in line with the known color-insensitivity of the SC, the SC pathway is shunted and unconscious abrupt-onset cues no longer capture attention when the participants have to search for color-defined targets (Experiment 4) or color-singleton targets (Experiment 5). When using color change cues instead of abrupt-onset cues, the cueing effect also vanishes (Experiment 6). Together the results support the assumption that unconscious cues can capture attention in different ways, depending on the exact task of the participants, but that one way is attentional capture via the SC. The present findings also offer a reconciliation of conflicting results in the domain of unconscious attention. Brain Sciences 2012-02-15 2 1 Article 10.3390/brainsci2010033 33 60 2076-3425 2012-02-15 doi: 10.3390/brainsci2010033 Isabella Fuchs Ulrich Ansorge http://www.mdpi.com/2076-3425/2/1/22 In some circumstances, accurate recognition of repeated images in an explicit memory test is driven by implicit memory. We propose that this “implicit recognition” results from perceptual fluency that influences responding without awareness of memory retrieval. Here we examined whether recognition would vary if images appeared in the same or different visual hemifield during learning and testing. Kaleidoscope images were briefly presented left or right of fixation during divided-attention encoding. Presentation in the same visual hemifield at test produced higher recognition accuracy than presentation in the opposite visual hemifield, but only for guess responses. These correct guesses likely reflect a contribution from implicit recognition, given that when the stimulated visual hemifield was the same at study and test, recognition accuracy was higher for guess responses than for responses with any level of confidence. The dramatic difference in guessing accuracy as a function of lateralized perceptual overlap between study and test suggests that implicit recognition arises from memory storage in visual cortical networks that mediate repetition-induced fluency increments. Brain Sciences 2012-02-06 2 1 Article 10.3390/brainsci2010022 22 32 2076-3425 2012-02-06 doi: 10.3390/brainsci2010022 Iliana M. Vargas Joel L. Voss Ken A. Paller http://www.mdpi.com/2076-3425/2/1/1 Scientific studies have shown that non-conscious stimuli and representations influence information processing during conscious experience. In the light of such evidence, questions about potential functional links between non-conscious brain representations and conscious experience arise. This article discusses neural model capable of explaining how statistical learning mechanisms in dedicated resonant circuits could generate specific temporal activity traces of non-conscious representations in the brain. How reentrant signaling, top-down matching, and statistical coincidence of such activity traces may lead to the progressive consolidation of temporal patterns that constitute the neural signatures of conscious experience in networks extending across large distances beyond functionally specialized brain regions is then explained. Brain Sciences 2011-12-27 2 1 Review 10.3390/brainsci2010001 1 21 2076-3425 2011-12-27 doi: 10.3390/brainsci2010001 Birgitta Dresp-Langley http://www.mdpi.com/2076-3425/1/1/3 Our study provides evidence that Mild Cognitive Impairment (MCI) is associated with olfactory dysfunction on both conscious and non-conscious levels. MCI patients and age-matched controls underwent a face processing task during which sympathy decisions had to be made via button presses. Incidentally, some of the faces were associated with a simultaneously presented odour. Although attention was paid to faces, brain activities were analysed with respect to odour versus no-odour conditions. Behavioural differences were found related to overall face recognition performance, but these were not statistically significant. However, odour-related neurophysiology differed between both groups. Normal controls demonstrated brain activity differences between odour and no-odour conditions that resemble difference activity patterns in healthy young participants as described in a previous magnetoencephalography (MEG) study [1]. They showed odour-related activity patterns between about 160 ms and 320 ms after stimulus onset and between about 640 ms and 720 ms. On the other hand, the patient group did not show any such difference activities. Based on previous research we interpret the early odour-related brain activity pattern in controls as being associated with subliminal olfaction and the later activity pattern with conscious olfaction. None of these were found in MCI patients, although it has to be emphasised that our sample size was rather small. We confirm previous findings about olfactory related dysfunction in patients with MCI and conclude from our findings that even subliminal odour-related information processing is impaired. Brain Sciences 2011-10-28 1 1 Article 10.3390/brainsci1010003 3 15 2076-3425 2011-10-28 doi: 10.3390/brainsci1010003 Peter Walla Cornelia Duregger Lüder Deecke Peter Dal-Bianco http://www.mdpi.com/2076-3425/1/1/1 During the first ten years that followed “The Decade of the Brain”, the quest of neuroscience for understanding brain function in health and disease has greatly expanded to include molecular, developmental, cognitive and evolutionary aspects of the nervous system. This increased multidisciplinary effort has been complemented by the spectacular development of highly sophisticated experimental methods. Neuroscientists can now perform studies ranging from molecular and imaging analysis of single pre- and postsynaptic neuronal processes to imaging of neural activity in the whole brain during perceptual and motor behavioral tasks. At the same time, theoretical advances in neuroscience have been aided by the rapid development of mathematical and computational simulations of biologically and functionally realistic single cells and complex neural networks across multiple spatiotemporal scales. Therefore, neuroscientists are more than ever in a position to deliver answers to basic, medical and biotechnological questions related to brain function and dysfunction. [...] Brain Sciences 2010-07-15 1 1 Editorial 10.3390/brainsci1010001 1 2 2076-3425 2010-07-15 doi: 10.3390/brainsci1010001 Germán Barrionuevo