text: Brain Sciences 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/2076-3425/6/4/57 Subthalamic nucleus (STN) local field potentials (LFP) are neural signals that have been shown to reveal motor and language behavior, as well as pathological parkinsonian states. We use a research-grade implantable neurostimulator (INS) with data collection capabilities to record STN-LFP outside the operating room to determine the reliability of the signals over time and assess their dynamics with respect to behavior and dopaminergic medication. Seven subjects were implanted with the recording augmented deep brain stimulation (DBS) system, and bilateral STN-LFP recordings were collected in the clinic over twelve months. Subjects were cued to perform voluntary motor and language behaviors in on and off medication states. The STN-LFP recorded with the INS demonstrated behavior-modulated desynchronization of beta frequency (13–30 Hz) and synchronization of low gamma frequency (35–70 Hz) oscillations. Dopaminergic medication did not diminish the relative beta frequency oscillatory desynchronization with movement. However, movement-related gamma frequency oscillatory synchronization was only observed in the medication on state. We observed significant inter-subject variability, but observed consistent STN-LFP activity across recording systems and over a one-year period for each subject. These findings demonstrate that an INS system can provide robust STN-LFP recordings in ambulatory patients, allowing for these signals to be recorded in settings that better represent natural environments in which patients are in a variety of medication states. Brain Sciences 2016-11-29 6 4 Article 10.3390/brainsci6040057 57 2076-3425 2016-11-29 doi: 10.3390/brainsci6040057 Sara Hanrahan Joshua Nedrud Bradley Davidson Sierra Farris Monique Giroux Aaron Haug Mohammad Mahoor Anne Silverman Jun Zhang Adam Hebb http://www.mdpi.com/2076-3425/6/4/56 Background: There is emerging evidence that cervical dystonia is a neural network disorder with the cerebellum as a key node. The cerebellum may provide a target for neuromodulation as a therapeutic intervention in cervical dystonia. Objective: This study aimed to assess effects of intermittent theta-burst stimulation of the cerebellum on dystonia symptoms, quality of life, hand motor dexterity and cortical neurophysiology using transcranial magnetic stimulation. Methods: Sixteen participants with cervical dystonia were randomised into real or sham stimulation groups. Cerebellar neuromodulation was combined with motor training for the neck and an implicit learning task. The intervention was delivered over 10 working days. Outcome measures included dystonia severity and pain, quality of life, hand dexterity, and motor-evoked potentials and cortical silent periods recorded from upper trapezius muscles. Assessments were taken at baseline and after 5 and 10 days, with quality of life also measured 4 and 12 weeks later. Results: Intermittent theta-burst stimulation improved dystonia severity (Day 5, −5.44 points; p = 0.012; Day 10, −4.6 points; p = 0.025), however, effect sizes were small. Quality of life also improved (Day 5, −10.6 points, p = 0.012; Day 10, −8.6 points, p = 0.036; Week 4, −12.5 points, p = 0.036; Week 12, −12.4 points, p = 0.025), with medium or large effect sizes. There was a reduction in time to complete the pegboard task pre to post intervention (both p < 0.008). Cortical neurophysiology was unchanged by cerebellar neuromodulation. Conclusion: Intermittent theta-burst stimulation of the cerebellum may improve cervical dystonia symptoms, upper limb motor control and quality of life. The mechanism likely involves promoting neuroplasticity in the cerebellum although the neurophysiology remains to be elucidated. Cerebellar neuromodulation may have potential as a novel treatment intervention for cervical dystonia, although larger confirmatory studies are required. Brain Sciences 2016-11-23 6 4 Article 10.3390/brainsci6040056 56 2076-3425 2016-11-23 doi: 10.3390/brainsci6040056 Lynley Bradnam Michelle McDonnell Michael Ridding http://www.mdpi.com/2076-3425/6/4/55 Background: Studies have demonstrated that fear memories can be modified using non-invasive methods. Recently, we demonstrated that anodal transcranial direct current stimulation (tDCS) of the right dorsolateral prefrontal cortex is capable of enhancing fear memories. Here, we examined the effects of cathodal tDCS of the right dorsolateral prefrontal cortex during fear reconsolidation in humans. Methods: Seventeen young, healthy subjects were randomly assigned to two groups, which underwent fear conditioning with mild electric stimuli paired with a visual stimulus. Twenty-four hours later, both groups were shown a reminder of the conditioned fearful stimulus. Shortly thereafter, they received either tDCS (right prefrontal—cathodal, left supraorbital—anodal) for 20 min at 1 mA, or sham stimulation. A day later, fear responses of both groups were compared. Results: On Day 3, during fear response assessment, there were no significant differences between the tDCS and sham group (p > 0.05). Conclusion: We conclude that cathodal tDCS of the right dorsolateral prefrontal cortex (right prefrontal—cathodal, left supraorbital—anodal) did not influence fear memories. Brain Sciences 2016-11-04 6 4 Article 10.3390/brainsci6040055 55 2076-3425 2016-11-04 doi: 10.3390/brainsci6040055 Aditya Mungee Max Burger Malek Bajbouj http://www.mdpi.com/2076-3425/6/4/54 Neural connections remain partially viable after stroke, and access to these residual connections provides a substrate for training-induced plasticity. The objective of this project was to test if reflex excitability could be modified with arm and leg (A & L) cycling training. Nineteen individuals with chronic stroke (more than six months postlesion) performed 30 min of A & L cycling training three times a week for five weeks. Changes in reflex excitability were inferred from modulation of cutaneous and stretch reflexes. A multiple baseline (three pretests) within-subject control design was used. Plasticity in reflex excitability was determined as an increase in the conditioning effect of arm cycling on soleus stretch reflex amplitude on the more affected side, by the index of modulation, and by the modulation ratio between sides for cutaneous reflexes. In general, A & L cycling training induces plasticity and modifies reflex excitability after stroke. Brain Sciences 2016-11-03 6 4 Article 10.3390/brainsci6040054 54 2076-3425 2016-11-03 doi: 10.3390/brainsci6040054 Taryn Klarner Trevor Barss Yao Sun Chelsea Kaupp Pamela Loadman E. Zehr http://www.mdpi.com/2076-3425/6/4/53 Clinicians often base their predictions of walking and arm recovery on multiple predictors. Multivariate prediction models may assist clinicians to make accurate predictions. Several reviews have been published on the prediction of motor recovery after stroke, but none have critically appraised development and validation studies of models for predicting walking and arm recovery. In this review, we highlight some common methodological limitations of models that have been developed and validated. Notable models include the proportional recovery model and the PREP algorithm. We also identify five other models based on clinical predictors that might be ready for further validation. It has been suggested that neurophysiological and neuroimaging data may be used to predict arm recovery. Current evidence suggests, but does not show conclusively, that the addition of neurophysiological and neuroimaging data to models containing clinical predictors yields clinically important increases in predictive accuracy. Brain Sciences 2016-11-02 6 4 Review 10.3390/brainsci6040053 53 2076-3425 2016-11-02 doi: 10.3390/brainsci6040053 Li Kwah Robert Herbert http://www.mdpi.com/2076-3425/6/4/52 Fetal alcohol exposure (FAE) alters hippocampal cell numbers in rodents and primates, and this may be due, in part, to a reduction in the number or migration of neuronal progenitor cells. The olfactory bulb exhibits substantial postnatal cellular proliferation and a rapid turnover of newly formed cells in the rostral migratory pathway, while production and migration of postnatal neurons into the dentate gyrus may be more complex. The relatively small size of the olfactory bulb, compared to the hippocampus, potentially makes this structure ideal for a rapid analysis. This study used the St. Kitts vervet monkey (Chlorocebus sabeus) to (1) investigate the normal developmental sequence of post-natal proliferation in the olfactory bulb and dentate gyrus and (2) determine the effects of naturalistic prenatal ethanol exposure on proliferation at three different ages (neonate, five months and two years). Using design-based stereology, we found an age-related decrease of actively proliferating cells in the olfactory bulb and dentate gyrus for both control and FAE groups. Furthermore, at the neonatal time point, the FAE group had fewer actively proliferating cells as compared to the control group. These data are unique with respect to fetal ethanol effects on progenitor proliferation in the primate brain and suggest that the olfactory bulb may be a useful structure for studies of cellular proliferation. Brain Sciences 2016-10-27 6 4 Article 10.3390/brainsci6040052 52 2076-3425 2016-10-27 doi: 10.3390/brainsci6040052 Mark Burke Alexey Inyatkin Maurice Ptito Frank Ervin Roberta Palmour http://www.mdpi.com/2076-3425/6/4/51 It has been known that both estrogen (E2) and nitric oxide (NO) are critical for proper cardiovascular system (CVS) function. It has also been demonstrated that E2 acts as an upstream effector in the nitric oxide (NO) pathway. Results from this study indicate that the use of a nitric oxide synthase (NOS) inhibitor (NOSI) which targets specifically neuronal NOS (nNOS or NOS1), proadifen hydrochloride, caused a significant depression of fish heart rates (HR) accompanied by increased arrhythmic behavior. However, none of these phenotypes were evident with either the inhibition of endothelial NOS (eNOS) or inducible NOS (iNOS) isoforms. These cardiac arrhythmias could also be mimicked by inhibition of E2 synthesis with the aromatase inhibitor (AI), 4-OH-A, in a manner similar to that of nNOSI. In both scenarios, by using an NO donor (DETA-NO) in either NO + nNOSI or E2 + AI co-treatments, fish could be significantly rescued from decreased HR and increased arrhythmias. However, the addition of an NOS inhibitor (L-NAME) to the E2 + AI co-treatment fish prevented the rescue of low heart rates and arrhythmias, which strongly implicates the NO pathway as a downstream E2 targeted molecule for the maintenance of healthy cardiomyocyte contractile conditions in the developing zebrafish. Cardiac arrhythmias could be mimicked by the S-nitrosylation pathway inhibitor DTT (1,4-dithiothreitol) but not by ODQ (1H-[1–3]oxadiazolo[4,3-a]quinoxalin-1-one), the inhibitor of the NO receptor molecule sGC in the cGMP-dependent pathway. In both the nNOSI and AI-induced arrhythmic conditions, 100% of the fish expressed the phenotype, but could be rapidly rescued with maximum survival by a washout with dantrolene, a ryanodine Ca2+ channel receptor blocker, compared to the time it took for rescue using a control salt solution. In addition, of the three NOS isoforms, eNOS was the one most implicated in the maintenance of an intact developing fish vascular system. In conclusion, results from this study have shown that nNOS is the prominent isoform that is responsible, in part, for maintaining normal heart rates and prevention of arrhythmias in the developing zebrafish heart failure model. These phenomena are related to the upstream stimulatory regulation by E2. On the other hand, eNOS has a minimal effect and iNOS has little to no influence on this phenomenon. Data also suggests that nNOS acts on the zebrafish cardiomyocytes through the S-nitrosylation pathway to influence the SR ryanidine Ca2+ channels in the excitation-coupling phenomena. In contrast, eNOS is the prominent isoform that influences blood vessel development in this model. Brain Sciences 2016-10-26 6 4 Article 10.3390/brainsci6040051 51 2076-3425 2016-10-26 doi: 10.3390/brainsci6040051 Benjamin Sykes Peter Van Steyn Jonathan Vignali John Winalski Julie Lozier Wade Bell James Turner http://www.mdpi.com/2076-3425/6/4/50 Symptoms of inattention and hyperactivity frequently co-occur with language difficulties in both clinical and community samples. We explore the specificity and strength of these associations in a heterogeneous sample of 254 children aged 5 to 15 years identified by education and health professionals as having problems with attention, learning and/or memory. Parents/carers rated pragmatic and structural communication skills and behaviour, and children completed standardised assessments of reading, spelling, vocabulary, and phonological awareness. A single dimension of behavioural difficulties including both hyperactivity and inattention captured behaviour problems. This was strongly and negatively associated with pragmatic communication skills. There was less evidence for a relationship between behaviour and language structure: behaviour ratings were more weakly associated with the use of structural language in communication, and there were no links with direct measures of literacy. These behaviour problems and pragmatic communication difficulties co-occur in this sample, but impairments in the more formal use of language that impact on literacy and structural communication skills are tied less strongly to behavioural difficulties. One interpretation is that impairments in executive function give rise to both behavioural and social communication problems, and additional or alternative deficits in other cognitive abilities impact on the development of structural language skills. Brain Sciences 2016-10-21 6 4 Article 10.3390/brainsci6040050 50 2076-3425 2016-10-21 doi: 10.3390/brainsci6040050 Erin Hawkins Susan Gathercole Duncan Astle The CALM Team Joni Holmes http://www.mdpi.com/2076-3425/6/4/49 Transcranial magnetic stimulation (TMS) can be used as an assessment or intervention to evaluate or influence brain activity in children with hemiparetic cerebral palsy (CP) commonly caused by perinatal stroke. This communication report analyzed data from two clinical trials using TMS to assess corticospinal excitability in children and young adults with hemiparetic CP. The results of this communication revealed a higher probability of finding a motor evoked potential (MEP) on the non-lesioned hemisphere compared to the lesioned hemisphere (p = 0.005). The resting motor threshold (RMT) was lower on the non-lesioned hemisphere than the lesioned hemisphere (p = 0.013). There was a significantly negative correlation between age and RMT (rs = −0.65, p = 0.003). This communication provides information regarding MEP responses, motor thresholds (MTs) and the association with age during TMS assessment in children with hemiparetic CP. Such findings contribute to the development of future pediatric studies in neuroplasticity and neuromodulation to influence motor function and recovery after perinatal stroke. Brain Sciences 2016-10-20 6 4 Communication 10.3390/brainsci6040049 49 2076-3425 2016-10-20 doi: 10.3390/brainsci6040049 Chao-Ying Chen Tonya Rich Jessica Cassidy Bernadette Gillick http://www.mdpi.com/2076-3425/6/4/48 Tremulous voice is characteristically associated with essential tremor, and is referred to as essential vocal tremor (EVT). Current estimates suggest that up to 40% of individuals diagnosed with essential tremor also present with EVT, which is associated with an impaired quality of life. Traditional EVT treatments have demonstrated limited success in long-term management of symptoms. However, voice tremor has been noted to decrease in patients receiving deep brain stimulation (DBS) with the targeting of thalamic nuclei. In this study, we describe our multidisciplinary procedure for awake, frameless DBS with optimal stimulation targets as well as acoustic analysis and laryngoscopic assessment to quantify tremor reduction. Finally, we investigate the most recent clinical evidence regarding the procedure. Brain Sciences 2016-10-10 6 4 Article 10.3390/brainsci6040048 48 2076-3425 2016-10-10 doi: 10.3390/brainsci6040048 Vinod Ravikumar Allen Ho Jonathon Parker Elizabeth Erickson-DiRenzo Casey Halpern http://www.mdpi.com/2076-3425/6/4/47 The experience of pain in disorders of consciousness is still debated. Neuroimaging studies, using functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), multichannel electroencephalography (EEG) and laser-evoked potentials, suggest that the perception of pain increases with the level of consciousness. Brain activation in response to noxious stimuli has been observed in patients with unresponsive wakefulness syndrome (UWS), which is also referred to as a vegetative state (VS), as well as those in a minimally conscious state (MCS). However, all of these techniques suggest that pain-related brain activation patterns of patients in MCS more closely resemble those of healthy subjects. This is further supported by fMRI findings showing a much greater functional connectivity within the structures of the so-called pain matrix in MCS as compared to UWS/VS patients. Nonetheless, when interpreting the results, a distinction is necessary between autonomic responses to potentially harmful stimuli and conscious experience of the unpleasantness of pain. Even more so if we consider that the degree of residual functioning and cortical connectivity necessary for the somatosensory, affective and cognitive-evaluative components of pain processing are not yet clear. Although procedurally challenging, the particular value of the aforementioned techniques in the assessment of pain in disorders of consciousness has been clearly demonstrated. The study of pain-related brain activation and functioning can contribute to a better understanding of the networks underlying pain perception while addressing clinical and ethical questions concerning patient care. Further development of technology and methods should aim to increase the availability of neuroimaging, objective assessment of functional connectivity and analysis at the level of individual cases as well as group comparisons. This will enable neuroimaging to truly become a clinical tool to reliably investigate pain in severely brain-injured patients as well as an asset for research. Brain Sciences 2016-10-08 6 4 Review 10.3390/brainsci6040047 47 2076-3425 2016-10-08 doi: 10.3390/brainsci6040047 Francesca Pistoia Simona Sacco Janet Stewart Marco Sarà Antonio Carolei http://www.mdpi.com/2076-3425/6/4/46 Deep brain stimulation (DBS) is a unique, functional neurosurgical therapy indicated for medication refractory movement disorders as well as some psychiatric diseases. Multicontact electrodes are placed in "deep" structures within the brain with targets varying depending on the surgical indication. An implanted programmable pulse generator supplies the electrodes with a chronic, high frequency electrical current that clinically mimics the effects of ablative lesioning techniques. DBS's efficacy has been well established for its movement disorder indications (Parkinson's disease, essential tremor, and dystonia). However, clinical outcomes are sometimes suboptimal, even in the absence of common, potentially reversible complications such as hardware complications, infection, poor electrode placement, and poor programming parameters. This review highlights some of the rescue procedures that have been explored in suboptimal DBS cases for Parkinson's disease, essential tremor, and dystonia. To date, the data is limited and difficult to generalize, but a large majority of published reports demonstrate positive results. The decision to proceed with such treatments should be made on a case by case basis. Larger studies are needed to clearly establish the benefit of rescue procedures and to establish for which patient populations they may be most appropriate. Brain Sciences 2016-10-08 6 4 Review 10.3390/brainsci6040046 46 2076-3425 2016-10-08 doi: 10.3390/brainsci6040046 Adam Nagy Christopher Tolleson http://www.mdpi.com/2076-3425/6/4/44 Effective Brain–Computer Interfaces (BCIs) require that the time-varying activation patterns of 2-D neural ensembles be modelled. The cluster variation method (CVM) offers a means for the characterization of 2-D local pattern distributions. This paper provides neuroscientists and BCI researchers with a CVM tutorial that will help them to understand how the CVM statistical thermodynamics formulation can model 2-D pattern distributions expressing structural and functional dynamics in the brain. The premise is that local-in-time free energy minimization works alongside neural connectivity adaptation, supporting the development and stabilization of consistent stimulus-specific responsive activation patterns. The equilibrium distribution of local patterns, or configuration variables, is defined in terms of a single interaction enthalpy parameter (h) for the case of an equiprobable distribution of bistate (neural/neural ensemble) units. Thus, either one enthalpy parameter (or two, for the case of non-equiprobable distribution) yields equilibrium configuration variable values. Modeling 2-D neural activation distribution patterns with the representational layer of a computational engine, we can thus correlate variational free energy minimization with specific configuration variable distributions. The CVM triplet configuration variables also map well to the notion of a M = 3 functional motif. This paper addresses the special case of an equiprobable unit distribution, for which an analytic solution can be found. Brain Sciences 2016-09-30 6 4 Article 10.3390/brainsci6040044 44 2076-3425 2016-09-30 doi: 10.3390/brainsci6040044 Alianna Maren http://www.mdpi.com/2076-3425/6/4/45 Sensorimotor integration is altered in people with chronic pain. While there is substantial evidence that pain interferes with neural activity in primary sensory and motor cortices, much less is known about its impact on integrative sensorimotor processes. Here, the short latency afferent inhibition (SAI) paradigm was used to assess sensorimotor integration in the presence and absence of experimental cutaneous heat pain applied to the hand. Ulnar nerve stimulation was combined with transcranial magnetic stimulation to condition motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Four interstimulus intervals (ISI) were tested, based on the latency of the N20 component of the afferent sensory volley (N20−5 ms, N20+2 ms, N20+4 ms, N20+10 ms). In the PAIN condition, MEPs were smaller compared to the NEUTRAL condition (p = 0.005), and were modulated as a function of the ISI (p = 0.012). Post-hoc planned comparisons revealed that MEPs at N20+2 and N20+4 were inhibited compared to unconditioned MEPs. However, the level of inhibition (SAI) was similar in the PAIN and NEUTRAL conditions. This suggests that the interplay between pain and sensorimotor integration is not mediated through direct and rapid pathways as assessed by SAI, but rather might involve higher-order integrative areas. Brain Sciences 2016-09-29 6 4 Article 10.3390/brainsci6040045 45 2076-3425 2016-09-29 doi: 10.3390/brainsci6040045 Catherine Mercier Martin Gagné Karen Reilly Laurent Bouyer http://www.mdpi.com/2076-3425/6/4/43 Prenatal ethanol exposure can result in social deficits in humans and animals, including altered social interaction and poor communication. Rats exposed to ethanol prenatally show reduced play fighting, and a combination of prenatal ethanol exposure and neonatal whisker clipping further reduces play fighting compared with ethanol exposure alone. In this study, we explored whether expression of hedonic ultrasonic vocalizations (USVs) correlated with the number of playful attacks by ethanol-exposed rats, rats subjected to postnatal sensory deprivation by whisker clipping or both compared to control animals. In normally developing rats, hedonic USVs precede such interactions and correlate with the number of play interactions exhibited in dyads. Pregnant Long-Evans rats were fed an ethanol-containing liquid diet or a control diet. After birth, male and female pups from each litter were randomly assigned to the whisker-clipped or non-whisker-clipped condition. Animals underwent a social interaction test with a normally developing play partner during early or late-adolescence. USVs were recorded during play. Prenatal ethanol exposure reduced both play and hedonic USVs in early adolescence compared to control rats and persistently reduced social play. Interestingly, ethanol exposure, whisker clipping and the combination abolished the significant correlation between hedonic USVs and social play detected in control rats in early adolescence. This relationship remained disrupted in late adolescence only in rats subjected to both prenatal ethanol and whisker clipping. Thus, both insults more persistently disrupted the relationship between social communication and social play. Brain Sciences 2016-09-28 6 4 Article 10.3390/brainsci6040043 43 2076-3425 2016-09-28 doi: 10.3390/brainsci6040043 Jaylyn Waddell Tianqi Yang Eric Ho Kristen Wellmann Sandra Mooney http://www.mdpi.com/2076-3425/6/4/42 Loss of hand function after cervical spinal cord injury (SCI) impacts heavily on independence. Multiple nerve transfer surgery has been applied successfully after cervical SCI to restore critical arm and hand functions, and the outcome depends on nerve integrity. Nerve integrity is assessed indirectly using muscle strength testing and intramuscular electromyography, but these measures cannot show the manifestation that SCI has on the peripheral nerves. We directly assessed the morphology of nerves biopsied at the time of surgery, from three patients within 18 months post injury. Our objective was to document their morphologic features. Donor nerves included teres minor, posterior axillary, brachialis, extensor carpi radialis brevis and supinator. Recipient nerves included triceps, posterior interosseus (PIN) and anterior interosseus nerves (AIN). They were fixed in glutaraldehyde, processed and embedded in Araldite Epon for light microscopy. Eighty percent of nerves showed abnormalities. Most common were myelin thickening and folding, demyelination, inflammation and a reduction of large myelinated axon density. Others were a thickened perineurium, oedematous endoneurium and Renaut bodies. Significantly, very thinly myelinated axons and groups of unmyelinated axons were observed indicating regenerative efforts. Abnormalities exist in both donor and recipient nerves and they differ in appearance and aetiology. The abnormalities observed may be preventable or reversible. Brain Sciences 2016-09-27 6 4 Article 10.3390/brainsci6040042 42 2076-3425 2016-09-27 doi: 10.3390/brainsci6040042 Aurora Messina Natasha Van Zyl Michael Weymouth Stephen Flood Andrew Nunn Catherine Cooper Jodie Hahn Mary Galea http://www.mdpi.com/2076-3425/6/4/41 Parkinson's disease (PD) is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of PD, and are implicated in the cell death in this region. Neuroinflammation is evidently involved in PD pathology and mitigating the inflammatory cascade has been a therapeutic strategy. Age is the number one risk factor for PD and thus needs to be considered in the context of disease pathology. Here, we discuss the role of neuroinflammation within the context of aging as it applies to the development of PD, and the potential for two representative compounds, fractalkine and astaxanthin, to attenuate the pathophysiology that modulates neurodegeneration that occurs in Parkinson's disease. Brain Sciences 2016-09-23 6 4 Review 10.3390/brainsci6040041 41 2076-3425 2016-09-23 doi: 10.3390/brainsci6040041 Bethany Grimmig Josh Morganti Kevin Nash Paula Bickford http://www.mdpi.com/2076-3425/6/3/40 During the last 25 years, more than 100,000 patients have been treated with Deep Brain Stimulation (DBS). While human clinical and animal preclinical research has shed light on the complex brain-signaling disturbances that underpin e.g., Parkinson's disease (PD), less information is available when it comes to complex psychosocial changes following DBS interventions. In this contribution, we propose to more thoroughly investigate complex personality-related changes following deep brain stimulation through refined and reliable instruments in order to help patients and their relatives in the post-surgery phase. By pursuing this goal, we first outline the clinical importance DBS has attained followed by discussing problematic and undesired non-motor problems that accompany some DBS interventions. After providing a brief definition of complex changes, we move on by outlining the measurement problem complex changes relating to non-motor symptoms currently are associated with. The latter circumstance substantiates the need for refined instruments that are able to validly assess personality-related changes. After providing a brief paragraph with regard to conceptions of personality, we argue that the latter is significantly influenced by certain competencies which themselves currently play only a tangential role in the clinical DBS-discourse. Increasing awareness of the latter circumstance is crucial in the context of DBS because it could illuminate a link between competencies and the emergence of personality-related changes, such as new-onset impulse control disorders that have relevance for patients and their relatives. Finally, we elaborate on the field of application of instruments that are able to measure personality-related changes. Brain Sciences 2016-09-07 6 3 Opinion 10.3390/brainsci6030040 40 2076-3425 2016-09-07 doi: 10.3390/brainsci6030040 Christian Ineichen Heide Baumann-Vogel Markus Christen http://www.mdpi.com/2076-3425/6/3/39 New deep brain stimulation (DBS) electrode designs offer operation in voltage and current mode and capability to steer the electric field (EF). The aim of the study was to compare the EF distributions of four DBS leads at equivalent amplitudes (3 V and 3.4 mA). Finite element method (FEM) simulations (n = 38) around cylindrical contacts (leads 3389, 6148) or equivalent contact configurations (leads 6180, SureStim1) were performed using homogeneous and patient-specific (heterogeneous) brain tissue models. Steering effects of 6180 and SureStim1 were compared with symmetric stimulation fields. To make relative comparisons between simulations, an EF isolevel of 0.2 V/mm was chosen based on neuron model simulations (n = 832) applied before EF visualization and comparisons. The simulations show that the EF distribution is largely influenced by the heterogeneity of the tissue, and the operating mode. Equivalent contact configurations result in similar EF distributions. In steering configurations, larger EF volumes were achieved in current mode using equivalent amplitudes. The methodology was demonstrated in a patient-specific simulation around the zona incerta and a "virtual" ventral intermediate nucleus target. In conclusion, lead design differences are enhanced when using patient-specific tissue models and current stimulation mode. Brain Sciences 2016-09-07 6 3 Article 10.3390/brainsci6030039 39 2076-3425 2016-09-07 doi: 10.3390/brainsci6030039 Fabiola Alonso Malcolm Latorre Nathanael Göransson Peter Zsigmond Karin Wårdell http://www.mdpi.com/2076-3425/6/3/38 Huntington's disease (HD) is one of the most disabling degenerative movement disorders, as it not only affects the motor system but also leads to cognitive disabilities and psychiatric symptoms. Deep brain stimulation (DBS) of the pallidum is a promising symptomatic treatment targeting the core motor symptom: chorea. This article gives an overview of preliminary evidence on pathophysiology, safety and efficacy of DBS in HD. Brain Sciences 2016-08-30 6 3 Review 10.3390/brainsci6030038 38 2076-3425 2016-08-30 doi: 10.3390/brainsci6030038 Lars Wojtecki Stefan Groiss Christian Hartmann Saskia Elben Sonja Omlor Alfons Schnitzler Jan Vesper http://www.mdpi.com/2076-3425/6/3/37 There is a long-standing debate as to whether recollection is a continuous/graded process or a threshold/all-or-none process. In the current spatial memory functional magnetic resonance imaging (fMRI) study, we examined the hippocampal activity distributions—the magnitude of activity as a function of memory strength—to determine the nature of processing in this region. During encoding, participants viewed abstract shapes in the left or right visual field. During retrieval, old shapes were presented at fixation and participants classified each shape as previously in the "left" or "right" visual field followed by an "unsure"–"sure"–"very sure" confidence rating. The contrast of left-hits and left-misses produced two activations in the hippocampus. The hippocampal activity distributions for left shapes and right shapes were completely overlapping. Critically, the magnitude of activity associated with right-miss-very sure responses was significantly greater than zero. These results support the continuous model of recollection, which predicts overlapping activity distributions, and contradict the threshold model of recollection, which predicts a threshold above which only one distribution exists. Receiver operating characteristic analysis did not distinguish between models. The present results demonstrate that the hippocampus operates in a continuous manner during recollection and highlight the utility of analyzing activity distributions to determine the nature of neural processing. Brain Sciences 2016-08-26 6 3 Article 10.3390/brainsci6030037 37 2076-3425 2016-08-26 doi: 10.3390/brainsci6030037 Brittany Jeye Jessica Karanian Scott Slotnick http://www.mdpi.com/2076-3425/6/3/36 Over the last few decades, brain signals have been significantly exploited for brain-computer interface (BCI) applications. In this paper, we study the extraction of features using event-related desynchronization/synchronization techniques to improve the classification accuracy for three-class motor imagery (MI) BCI. The classification approach is based on combining the features of the phase and amplitude of the brain signals using fast Fourier transform (FFT) and autoregressive (AR) modeling of the reconstructed phase space as well as the modification of the BCI parameters (trial length, trial frequency band, classification method). We report interesting results compared with those present in the literature by utilizing sequential forward floating selection (SFFS) and a multi-class linear discriminant analysis (LDA), our findings showed superior classification results, a classification accuracy of 86.06% and 93% for two BCI competition datasets, with respect to results from previous studies. Brain Sciences 2016-08-23 6 3 Article 10.3390/brainsci6030036 36 2076-3425 2016-08-23 doi: 10.3390/brainsci6030036 Ridha Djemal Ayad Bazyed Kais Belwafi Sofien Gannouni Walid Kaaniche http://www.mdpi.com/2076-3425/6/3/35 Tourette syndrome (TS) is a childhood neurobehavioural disorder, characterised by the presence of motor and vocal tics, typically starting in childhood but persisting in around 20% of patients into adulthood. In those patients who do not respond to pharmacological or behavioural therapy, deep brain stimulation (DBS) may be a suitable option for potential symptom improvement. This manuscript attempts to summarise the outcomes of DBS at different targets, explore the possible mechanisms of action of DBS in TS, as well as the potential of adaptive DBS. There will also be a focus on the future challenges faced in designing optimized trials. Brain Sciences 2016-08-19 6 3 Review 10.3390/brainsci6030035 35 2076-3425 2016-08-19 doi: 10.3390/brainsci6030035 Ladan Akbarian-Tefaghi Ludvic Zrinzo Thomas Foltynie http://www.mdpi.com/2076-3425/6/3/34 The efficacy of Deep Brain Stimulation (DBS) for an expanding array of neurological and psychiatric disorders demonstrates directly that DBS affects the basic electroneurophysiological mechanisms of the brain. The increasing array of active electrode configurations, stimulation currents, pulse widths, frequencies, and pulse patterns provides valuable tools to probe electroneurophysiological mechanisms. The extension of basic electroneurophysiological and anatomical concepts using sophisticated computational modeling and simulation has provided relatively straightforward explanations of all the DBS parameters except frequency. This article summarizes current thought about frequency and relevant observations. Current methodological and conceptual errors are critically examined in the hope that future work will not replicate these errors. One possible alternative theory is presented to provide a contrast to many current theories. DBS, conceptually, is a noisy discrete oscillator interacting with the basal ganglia–thalamic–cortical system of multiple re-entrant, discrete oscillators. Implications for positive and negative resonance, stochastic resonance and coherence, noisy synchronization, and holographic memory (related to movement generation) are presented. The time course of DBS neuronal responses demonstrates evolution of the DBS response consistent with the dynamics of re-entrant mechanisms. Finally, computational modeling demonstrates identical dynamics as seen by neuronal activities recorded from human and nonhuman primates, illustrating the differences of discrete from continuous harmonic oscillators and the power of conceptualizing the nervous system as composed on interacting discrete nonlinear oscillators. Brain Sciences 2016-08-17 6 3 Review 10.3390/brainsci6030034 34 2076-3425 2016-08-17 doi: 10.3390/brainsci6030034 Erwin Montgomery Huang He http://www.mdpi.com/2076-3425/6/3/33 Over the course of the development of deep brain stimulation (DBS) into a well-established therapy for Parkinson's disease, essential tremor, and dystonia, its utility as a potential treatment for autonomic dysfunction has emerged. Dysfunction of autonomic processes is common in neurological diseases. Depending on the specific target in the brain, DBS has been shown to raise or lower blood pressure, normalize the baroreflex, to alter the caliber of bronchioles, and eliminate hyperhidrosis, all through modulation of the sympathetic nervous system. It has also been shown to improve cortical control of the bladder, directly induce or inhibit the micturition reflex, and to improve deglutition and gastric emptying. In this review, we will attempt to summarize the relevant available studies describing these effects of DBS on autonomic function, which vary greatly in character and magnitude with respect to stimulation target. Brain Sciences 2016-08-16 6 3 Review 10.3390/brainsci6030033 33 2076-3425 2016-08-16 doi: 10.3390/brainsci6030033 Adam Basiago Devin Binder http://www.mdpi.com/2076-3425/6/3/32 The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia. This form of neurotoxic insult could cause a major disruption in brain development with the potential to permanently shape behavior and cognitive ability. Evidence does suggest that psychoactive drugs alter neurodevelopment and synaptic plasticity in the animal brain, which, in the human brain, may translate to permanent neurodevelopmental changes associated with long-term intellectual disability. This paper reviews the seminal animal research on drug-induced developmental apoptosis and the subsequent clinical studies that have been conducted thus far. In humans, there is growing evidence that suggests anesthetics have the potential to harm the developing brain, but the long-term outcome is not definitive and causality has not been determined. The consensus is that there is more work to be done using both animal models and human clinical studies. Brain Sciences 2016-08-16 6 3 Review 10.3390/brainsci6030032 32 2076-3425 2016-08-16 doi: 10.3390/brainsci6030032 Catherine Creeley http://www.mdpi.com/2076-3425/6/3/31 Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain. Brain Sciences 2016-08-16 6 3 Review 10.3390/brainsci6030031 31 2076-3425 2016-08-16 doi: 10.3390/brainsci6030031 Mariko Saito Goutam Chakraborty Maria Hui Kurt Masiello Mitsuo Saito http://www.mdpi.com/2076-3425/6/3/30 Medication-overuse headache (MOH) is a challenging neurological disease, which brings frustration for sufferers and treating physicians. The patient's lack of adherence and limited treatment evidence are frequent. The aim of this study was to compare the outcome and treatment strategies between consecutive MOH patients with daily and near-daily headache from a tertiary center. Methods: Every consecutive patient seen between January and December 2014 with the diagnosis of MOH was included. Psychiatric comorbidities, inability to inform baseline headache frequency, current or previous two-month use of preventive medications, and refusal to sign informed consent were exclusion criteria. The patients were evaluated in thorough initial consultations and divided in two groups based on their baseline headache frequency. The diagnosis and treatment strategies were clearly explained. The filling out of a detailed headache diary was requested from all patients. Endpoints compared headache frequency and adherence after two, four, and eight months between the two study groups. Results: One-hundred sixty-eight patients (31 male, 137 female) met the inclusion criteria. Nineteen patients (11.3%) were excluded. All patients had migraine or chronic migraine as primary headaches. Eighty had daily (DH), and 69 near-daily headache (NDH), at baseline consultation. Mean baseline frequency was 24.8 headache days/month (18.9 days/month for the near-daily group), average headache history was 20.6 years and mean time with >15 headache days/month was 4.8 years. Outpatient withdrawal, starting prevention, and enforcing the correct use of rescue therapy was carried out with all patients. After two months, 88% of the DH and 71% of the NDH groups adhered to treatment (p = 0.0002). The HF decreased to 12 and 9 headache days/month, respectively in DH and NDH groups (p > 0.05, non-significant) (Intention-to-treat (ITT) 14 DH; 12 NDH; p > 0.05). After four and eight months, 86.3% and 83.7% of the DH patients, and 59.4% and 55% of the NDH patients were still under treatment (p = 0.0003 and p = 0.0001). The HF decreased, respectively, to nine and nine headache days/month in the DH patients compared to 6 and 7 headache days/month in the NDH group (p > 0.05) (ITT, 12; 12; DH; 10; 11; NDH; p > 0.05). Conclusions: Although open studies provide limited conclusions, withdrawing overused medications and starting prevention may have helped the favorable outcomes. However, daily headache patients had a significantly higher adherence and lower relapse rates than near-daily headache patients, despite a considerable reduced headache frequency in both groups. Additionally, real-world patient studies are scarce and the comparison between these two subsets of patients may be useful to guide clinicians in approaching their patients. Controlled studies are necessary to confirm these observations. Brain Sciences 2016-08-15 6 3 Article 10.3390/brainsci6030030 30 2076-3425 2016-08-15 doi: 10.3390/brainsci6030030 Abouch Krymchantowski Stewart Tepper Carla Jevoux Marcelo Valença http://www.mdpi.com/2076-3425/6/3/29 Increased survival after spinal cord injury (SCI) worldwide has enhanced the need for quality data that can be compared and shared between centers, countries, as well as across research studies, to better understand how best to prevent and treat SCI. Such data should be standardized and be able to be uniformly collected at any SCI center or within any SCI study. Standardization will make it possible to collect information from larger SCI populations for multi-center research studies. With this aim, the international SCI community has obtained consensus regarding the best available data and measures for use in SCI clinical practice and research. Reporting of SCI data is likewise standardized. Data elements are continuously updated and developed using an open and transparent process. There are ongoing internal, as well as external review processes, where all interested parties are encouraged to participate. The purpose of this review paper is to provide an overview of the initiatives to standardize data including the International Spinal Cord Society's International SCI Data Sets and the National Institutes of Health, National Institute of Neurological Disorders and Stroke Common Data Elements Project within SCI and discuss future opportunities. Brain Sciences 2016-08-12 6 3 Review 10.3390/brainsci6030029 29 2076-3425 2016-08-12 doi: 10.3390/brainsci6030029 Fin Biering-Sørensen Vanessa Noonan http://www.mdpi.com/2076-3425/6/3/28 The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety. Brain Sciences 2016-08-10 6 3 Article 10.3390/brainsci6030028 28 2076-3425 2016-08-10 doi: 10.3390/brainsci6030028 Jean-Philippe Langevin James Chen Ralph Koek David Sultzer Mark Mandelkern Holly Schwartz Scott Krahl http://www.mdpi.com/2076-3425/6/3/27 This magnetoencephalography (MEG) study investigated evoked ON and OFF responses to ramped and damped sounds in normal-hearing human adults. Two pairs of stimuli that differed in spectral complexity were used in a passive listening task; each pair contained identical acoustical properties except for the intensity envelope. Behavioral duration judgment was conducted in separate sessions, which replicated the perceptual bias in favour of the ramped sounds and the effect of spectral complexity on perceived duration asymmetry. MEG results showed similar cortical sites for the ON and OFF responses. There was a dominant ON response with stronger phase-locking factor (PLF) in the alpha (8–14 Hz) and theta (4–8 Hz) bands for the damped sounds. In contrast, the OFF response for sounds with rising intensity was associated with stronger PLF in the gamma band (30–70 Hz). Exploratory correlation analysis showed that the OFF response in the left auditory cortex was a good predictor of the perceived temporal asymmetry for the spectrally simpler pair. The results indicate distinct asymmetry in ON and OFF responses and neural oscillation patterns associated with the dynamic intensity changes, which provides important preliminary data for future studies to examine how the auditory system develops such an asymmetry as a function of age and learning experience and whether the absence of asymmetry or abnormal ON and OFF responses can be taken as a biomarker for certain neurological conditions associated with auditory processing deficits. Brain Sciences 2016-08-05 6 3 Article 10.3390/brainsci6030027 27 2076-3425 2016-08-05 doi: 10.3390/brainsci6030027 Yang Zhang Bing Cheng Tess Koerner Robert Schlauch Keita Tanaka Masaki Kawakatsu Iku Nemoto Toshiaki Imada http://www.mdpi.com/2076-3425/6/3/26 Background: Transcranial direct current stimulation (tDCS) is emerging as a promising adjuvant to enhance motor function. However, there has been increasing reservations about the reliability and variability of the neuromodulatory effects evoked by tDCS. Objective/Hypothesis: The main purpose of this study was to explore the test-retest reliability and inter-individual variability of tDCS of the lower limb M1 and the relationship between transcranial magnetic stimulation (TMS)-related measures and tDCS-induced changes. Methods: Fifteen healthy participants received anodal tDCS of the lower limb M1 either when performing a lower limb motor task or when the limb was at rest. Each condition was tested twice. tDCS induced changes in corticomotor excitability of the tibialis anterior muscle were measured using TMS. A repeated measures ANOVA was performed to examine efficacy of tDCS between the two task conditions. Intraclass correlation coefficients (ICC) and variance component analyses were performed to examine reliability and variability respectively. Results: A significant increase in in corticomotor excitability was noted for the tDCS-task condition at 140% active motor threshold (AMT) and when comparing recruitment curve slopes, but not at 120% and 130% AMT. Overall, ICC values between testing days for each stimulation condition ranged from 0.6–0.9. Higher ICCs were seen for higher TMS intensities (140% AMT) and recruitment curve slopes. Inter-individual variability contributed to 34% of the exhibited variance. Conclusions: Our data suggest that the TMS-related measure used to assess neuromodulation after tDCS has an effect on its perceived test-retest reliability and inter-individual variability. Importantly, we noticed that a high reliability and low variability does not necessarily indicate clinical efficacy of tDCS as some participants showed little to no modulation of corticomotor excitability consistently. Brain Sciences 2016-07-27 6 3 Article 10.3390/brainsci6030026 26 2076-3425 2016-07-27 doi: 10.3390/brainsci6030026 Sangeetha Madhavan Aishwarya Sriraman Sally Freels http://www.mdpi.com/2076-3425/6/3/25 Stress is a strong risk factor in alcoholic relapse and may exert effects that mimic aspects of chronic alcohol exposure on neurobiological systems. With the neuroimmune system becoming a prominent focus in the study of the neurobiological consequences of stress, as well as chronic alcohol exposure proving to be a valuable focus in this regard, the present study sought to compare the effects of stress and chronic ethanol exposure on induction of components of the neuroimmune system. Rats were exposed to either 1 h exposure to a mild stressor (restraint) or exposure to withdrawal from 15 days of chronic alcohol exposure (i.e., withdrawal from chronic ethanol, WCE) and assessed for neuroimmune mRNAs in brain. Restraint stress alone elevated chemokine (C–C motif) ligand 2 (CCL2), interleukin-1-beta (IL-1β), tumor necrosis factor alpha (TNFα) and toll-like receptor 4 (TLR4) mRNAs in the cerebral cortex within 4 h with a return to a control level by 24 h. These increases were not accompanied by an increase in corresponding proteins. Withdrawal from WCE also elevated cytokines, but did so to varying degrees across different cytokines and brain regions. In the cortex, stress and WCE induced CCL2, TNFα, IL-1β, and TLR4 mRNAs. In the hypothalamus, only WCE induced cytokines (CCL2 and IL-1β) while in the hippocampus, WCE strongly induced CCL2 while stress and WCE induced IL-1β. In the amygdala, only WCE induced CCL2. Finally—based on the previously demonstrated role of corticotropin-releasing factor 1 (CRF1) receptor inhibition in blocking WCE-induced cytokine mRNAs—the CRF1 receptor antagonist CP154,526 was administered to a subgroup of stressed rats and found to be inactive against induction of CCL2, TNFα, or IL-1β mRNAs. These differential results suggest that stress and WCE manifest broad neuroimmune effects in brain depending on the cytokine and brain region, and that CRF inhibition may not be a relevant mechanism in non-alcohol exposed animals. Overall, these effects are complex in terms of their neuroimmune targets and neuroanatomical specificity. Further investigation of the differential distribution of cytokine induction across neuroanatomical regions, individual cell types (e.g., neuronal phenotypes and glia), severity of chronic alcohol exposure, as well as across differing stress types may prove useful in understanding differential mechanisms of induction and for targeting select systems for pharmacotherapeutic intervention in alcoholism. Brain Sciences 2016-07-27 6 3 Article 10.3390/brainsci6030025 25 2076-3425 2016-07-27 doi: 10.3390/brainsci6030025 Darin Knapp Kathryn Harper Buddy Whitman Zachary Zimomra George Breese http://www.mdpi.com/2076-3425/6/3/24 Evidence from human studies indicates that maternal metabolic state and malnutrition dramatically influence the risk for developing psychiatric complications in later adulthood. In this regard, the central role of polyunsaturated fatty acids (PUFAs), and particularly n-3 PUFAs, is emerging considering that epidemiological evidences have established a negative correlation between n-3 PUFA consumption and development of mood disorders. These findings were supported by clinical studies indicating that low content of n-3 PUFAs in diet is linked to an increased susceptibility to psychiatric disorders. PUFAs regulate membrane fluidity and exert their central action by modulating synaptogenesis and neurotrophic factor expression, neurogenesis, and neurotransmission. Moreover, they are precursors of molecules implicated in modulating immune and inflammatory processes in the brain. Importantly, their tissue concentrations are closely related to diet intake, especially to maternal consumption during embryonal life, considering that their synthesis from essential precursors has been shown to be inefficient in mammals. The scope of this review is to highlight the possible mechanisms of PUFA functions in the brain during pre- and post-natal period and to evaluate their role in the pathogenesis of psychiatric diseases. Brain Sciences 2016-07-27 6 3 Review 10.3390/brainsci6030024 24 2076-3425 2016-07-27 doi: 10.3390/brainsci6030024 Maria Morgese Luigia Trabace http://www.mdpi.com/2076-3425/6/3/23 Oligodendrocytes wrap neuronal axons to form myelin, an insulating sheath which is essential for nervous impulse conduction along axons. Axonal myelination is highly regulated by neuronal and astrocytic signals and the maintenance of myelin sheaths is a very complex process. Oligodendrocyte damage can cause axonal demyelination and neuronal injury, leading to neurological disorders. Demyelination in the cerebrum may produce cognitive impairment in a variety of neurological disorders, including human immunodeficiency virus type one (HIV-1)-associated neurocognitive disorders (HAND). Although the combined antiretroviral therapy has markedly reduced the incidence of HIV-1-associated dementia, a severe form of HAND, milder forms of HAND remain prevalent even when the peripheral viral load is well controlled. HAND manifests as a subcortical dementia with damage in the brain white matter (e.g., corpus callosum), which consists of myelinated axonal fibers. How HIV-1 brain infection causes myelin injury and resultant white matter damage is an interesting area of current HIV research. In this review, we tentatively address recent progress on oligodendrocyte dysregulation and HAND pathogenesis. Brain Sciences 2016-07-22 6 3 Review 10.3390/brainsci6030023 23 2076-3425 2016-07-22 doi: 10.3390/brainsci6030023 Han Liu Enquan Xu Jianuo Liu Huangui Xiong http://www.mdpi.com/2076-3425/6/3/22 This article discusses the special features of odor-evoked memory and the current state-of-the-art in odor-evoked memory research to show how these unique experiences may be able to influence and benefit psychological and physiological health. A review of the literature leads to the conclusion that odors that evoke positive autobiographical memories have the potential to increase positive emotions, decrease negative mood states, disrupt cravings, and reduce physiological indices of stress, including systemic markers of inflammation. Olfactory perception factors and individual difference characteristics that would need to be considered in therapeutic applications of odor-evoked-memory are also discussed. This article illustrates how through the experimentally validated mechanisms of odor-associative learning and the privileged neuroanatomical relationship that exists between olfaction and the neural substrates of emotion, odors can be harnessed to induce emotional and physiological responses that can improve human health and wellbeing. Brain Sciences 2016-07-19 6 3 Review 10.3390/brainsci6030022 22 2076-3425 2016-07-19 doi: 10.3390/brainsci6030022 Rachel Herz http://www.mdpi.com/2076-3425/6/3/21 Obesity is a chronic, progressive and prevalent disorder. Morbid obesity, in particular, is associated with numerous comorbidities and early mortality. In patients with morbid obesity, pharmacological and behavioral approaches often have limited results. Bariatric surgery is quite effective but is associated with operative failures and a non-negligible incidence of side effects. In the last decades, deep brain stimulation (DBS) has been investigated as a neurosurgical modality to treat various neuropsychiatric disorders. In this article we review the rationale for selecting different brain targets, surgical results and future perspectives for the use of DBS in medically refractory obesity. Brain Sciences 2016-07-18 6 3 Review 10.3390/brainsci6030021 21 2076-3425 2016-07-18 doi: 10.3390/brainsci6030021 Ruth Franco Erich Fonoff Pedro Alvarenga Antonio Lopes Euripides Miguel Manoel Teixeira Durval Damiani Clement Hamani http://www.mdpi.com/2076-3425/6/3/20 The Sound of Vision project involves developing a sensory substitution device that is aimed at creating and conveying a rich auditory representation of the surrounding environment to the visually impaired. However, the feasibility of such an approach is strongly constrained by neural flexibility, possibilities of sensory substitution and adaptation to changed sensory input. We review evidence for such flexibility from various perspectives. We discuss neuroplasticity of the adult brain with an emphasis on functional changes in the visually impaired compared to sighted people. We discuss effects of adaptation on brain activity, in particular short-term and long-term effects of repeated exposure to particular stimuli. We then discuss evidence for sensory substitution such as Sound of Vision involves, while finally discussing evidence for adaptation to changes in the auditory environment. We conclude that sensory substitution enterprises such as Sound of Vision are quite feasible in light of the available evidence, which is encouraging regarding such projects. Brain Sciences 2016-06-27 6 3 Review 10.3390/brainsci6030020 20 2076-3425 2016-06-27 doi: 10.3390/brainsci6030020 Ómar Jóhannesson Oana Balan Runar Unnthorsson Alin Moldoveanu Árni Kristjánsson http://www.mdpi.com/2076-3425/6/2/19 An important aspect of CNS disease and injury is the elevated expression of neuroimmune factors. These factors are thought to contribute to processes ranging from recovery and repair to pathology. The complexity of the CNS and the multitude of neuroimmune factors that are expressed in the CNS during disease and injury is a challenge to an understanding of the consequences of the elevated expression relative to CNS function. One approach to address this issue is the use of transgenic mice that express elevated levels of a specific neuroimmune factor in the CNS by a cell type that normally produces it. This approach can provide basic information about the actions of specific neuroimmune factors and can contribute to an understanding of more complex conditions when multiple neuroimmune factors are expressed. This review summarizes studies using transgenic mice that express elevated levels of IL-6, CCL2 or CXCL10 through increased astrocyte expression. The studies focus on the effects of these neuroimmune factors on synaptic function at the Schaffer collateral to CA1 pyramidal neuron synapse of the hippocampus, a brain region that plays a key role in cognitive function. Brain Sciences 2016-06-17 6 2 Review 10.3390/brainsci6020019 19 2076-3425 2016-06-17 doi: 10.3390/brainsci6020019 Donna Gruol http://www.mdpi.com/2076-3425/6/2/18 The cytokines interleukin 13 and 4 share a common heterodimeric receptor and are important modulators of peripheral allergic reactions. Produced primarily by T-helper type 2 lymphocytes, they are typically considered as anti-inflammatory cytokines because they can downregulate the synthesis of T-helper type 1 pro-inflammatory cytokines. Their presence and role in the brain is only beginning to be investigated and the data collected so far shows that these molecules can be produced by microglial cells and possibly by neurons. Attention has so far been given to the possible role of these molecules in neurodegeneration. Both neuroprotective or neurotoxic effects have been proposed based on evidence that interleukin 13 and 4 can reduce inflammation by promoting the M2 microglia phenotype and contributing to the death of microglia M1 phenotype, or by potentiating the effects of oxidative stress on neurons during neuro-inflammation. Remarkably, the heterodimeric subunit IL-13Rα1 of their common receptor was recently demonstrated in dopaminergic neurons of the ventral tegmental area and the substantia nigra pars compacta, suggesting the possibility that both cytokines may affect the activity of these neurons regulating reward, mood, and motor coordination. In mice and man, the gene encoding for IL-13Rα1 is expressed on the X chromosome within the PARK12 region of susceptibility to Parkinson's disease (PD). This, together with finding that IL-13Rα1 contributes to loss of dopaminergic neurons during inflammation, indicates the possibility that these cytokines may contribute to the etiology or the progression of PD. Brain Sciences 2016-06-13 6 2 Article 10.3390/brainsci6020018 18 2076-3425 2016-06-13 doi: 10.3390/brainsci6020018 Simone Mori Pamela Maher Bruno Conti http://www.mdpi.com/2076-3425/6/2/16 Excessive alcohol consumption results in neurodegeneration which some hypothesize is caused by neuroinflammation. One characteristic of neuroinflammation is microglial activation, but it is now well accepted that microglial activation may be pro- or anti-inflammatory. Recent work indicates that the Majchrowicz model of alcohol-induced neurodegeneration results in anti-inflammatory microglia, while intermittent exposure models with lower doses and blood alcohol levels produce microglia with a pro-inflammatory phenotype. To determine the effect of a repeated binge alcohol exposure, rats received two cycles of the four-day Majchrowicz model. One hemisphere was then used to assess microglia via immunohistochemistry and while the other was used for ELISAs of cytokines and growth factors. A single binge ethanol exposure resulted in low-level of microglial activation; however, a second binge potentiated the microglial response. Specifically, double binge rats had greater OX-42 immunoreactivity, increased ionized calcium-binding adapter molecule 1 (Iba-1+) cells, and upregulated tumor necrosis factor-α (TNF-α) compared with the single binge ethanol group. These data indicate that prior ethanol exposure potentiates a subsequent microglia response, which suggests that the initial exposure to alcohol primes microglia. In summary, repeated ethanol exposure, independent of other immune modulatory events, potentiates microglial activity. Brain Sciences 2016-05-26 6 2 Article 10.3390/brainsci6020016 16 2076-3425 2016-05-26 doi: 10.3390/brainsci6020016 Simon Marshall Chelsea Geil Kimberly Nixon http://www.mdpi.com/2076-3425/6/2/17 Parkinson's disease (PD) is a degenerative disorder of the central nervous system, in which a small naturally unfolded protein α-synuclein plays an essential role. α-Synuclein belongs to a synuclein family comprising three members: α, β, and γ-synucleins associated with neurodegenerative and neoplastic diseases and involved in development. Several studies revealed that α-synuclein is present not only in the brain, but also in the skin and other peripheral tissues. This finding open a new approach to PD diagnosis based on the assay of α-synuclein from a biological sample of a living patient. Furthermore, PD is associated with an increased risk of skin melanoma. An important posttranslational modification of α-synuclein is phosphorylation at serine-129, which may convert the protein into pathological species both in PD and melanoma. Thus, analysis of phosphorylated α-synuclein might be an important diagnostic test for both diseases providing additional information about the mechanism of pathology. Brain Sciences 2016-05-26 6 2 Discussion 10.3390/brainsci6020017 17 2076-3425 2016-05-26 doi: 10.3390/brainsci6020017 Andrei Surguchov http://www.mdpi.com/2076-3425/6/2/15 Interleukin-6 (IL-6) is a multifunctional cytokine that not only plays major roles in the immune system, but also serves as a coordinator between the nervous and endocrine systems. IL-6 is produced in multiple cell types in the CNS, and in turn, many cells respond to it. It is therefore important to ascertain which cell type is the key responder to IL-6 during both physiological and pathological conditions. In order to test the role of astrocytic IL-6 in neuroinflammation, we studied an extensively-used animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), in mice with an IL-6 deficiency in astrocytes (Ast-IL-6 KO). Results indicate that lack of astrocytic IL-6 did not cause major changes in EAE symptomatology. However, a delay in the onset of clinical signs was observed in Ast-IL-6 KO females, with fewer inflammatory infiltrates and decreased demyelination and some alterations in gliosis and vasogenesis, compared to floxed mice. These results suggest that astrocyte-secreted IL-6 has some roles in EAE pathogenesis, at least in females. Brain Sciences 2016-05-17 6 2 Article 10.3390/brainsci6020015 15 2076-3425 2016-05-17 doi: 10.3390/brainsci6020015 Maria Erta Mercedes Giralt Silvia Jiménez Amalia Molinero Gemma Comes Juan Hidalgo http://www.mdpi.com/2076-3425/6/2/14 Objective: To assess the neural activity associated with mindfulness-based alterations of pain perception. Methods: The Cochrane Central, EMBASE, Ovid Medline, PsycINFO, Scopus, and Web of Science databases were searched on 2 February 2016. Titles, abstracts, and full-text articles were independently screened by two reviewers. Data were independently extracted from records that included topics of functional neuroimaging, pain, and mindfulness interventions. Results: The literature search produced 946 total records, of which five met the inclusion criteria. Records reported pain in terms of anticipation (n = 2), unpleasantness (n = 5), and intensity (n = 5), and how mindfulness conditions altered the neural activity during noxious stimulation accordingly. Conclusions: Although the studies were inconsistent in relating pain components to neural activity, in general, mindfulness was able to reduce pain anticipation and unpleasantness ratings, as well as alter the corresponding neural activity. The major neural underpinnings of mindfulness-based pain reduction consisted of altered activity in the anterior cingulate cortex, insula, and dorsolateral prefrontal cortex. Brain Sciences 2016-04-19 6 2 Review 10.3390/brainsci6020014 14 2076-3425 2016-04-19 doi: 10.3390/brainsci6020014 Elena Bilevicius Tiffany Kolesar Jennifer Kornelsen http://www.mdpi.com/2076-3425/6/2/13 Perineuronal nets (PNNs) are specialized extracellular matrix molecules that are associated with the closing of the critical period, among other functions. In the adult brain, PNNs surround specific types of neurons, however the expression of PNNs in the auditory system of the mouse, particularly at the level of the midbrain and forebrain, has not been fully described. In addition, the association of PNNs with excitatory and inhibitory cell types in these structures remains unknown. Therefore, we sought to investigate the expression of PNNs in the inferior colliculus (IC), thalamic reticular nucleus (TRN) and primary auditory cortex (A1) of the mouse brain by labeling with wisteria floribunda agglutinin (WFA). To aid in the identification of inhibitory neurons in these structures, we employed the vesicular GABA transporter (VGAT)-Venus transgenic mouse strain, which robustly expresses an enhanced yellow-fluorescent protein (Venus) natively in nearly all gamma-amino butyric acid (GABA)-ergic inhibitory neurons, thus enabling a rapid and unambiguous assessment of inhibitory neurons throughout the nervous system. Our results demonstrate that PNNs are expressed throughout the auditory midbrain and forebrain, but vary in their local distribution. PNNs are most dense in the TRN and least dense in A1. Furthermore, PNNs are preferentially associated with inhibitory neurons in A1 and the TRN, but not in the IC of the mouse. These data suggest regionally specific roles for PNNs in auditory information processing. Brain Sciences 2016-04-13 6 2 Article 10.3390/brainsci6020013 13 2076-3425 2016-04-13 doi: 10.3390/brainsci6020013 Sarah Fader Kazuo Imaizumi Yuchio Yanagawa Charles Lee http://www.mdpi.com/2076-3425/6/2/12 Alcohol consumption during pregnancy and its damaging consequences on the developing infant brain are significant public health, social, and economic issues. The major distinctive features of prenatal alcohol exposure in humans are cognitive and behavioral dysfunction due to damage to the central nervous system (CNS), which results in a continuum of disarray that is collectively called fetal alcohol spectrum disorder (FASD). Many rodent models have been developed to understand the mechanisms of and to reproduce the human FASD phenotypes. These animal FASD studies have provided several molecular pathways that are likely responsible for the neurobehavioral abnormalities that are associated with prenatal alcohol exposure of the developing CNS. Recently, many laboratories have identified several immediate, as well as long-lasting, epigenetic modifications of DNA methylation, DNA-associated histone proteins and microRNA (miRNA) biogenesis by using a variety of epigenetic approaches in rodent FASD models. Because DNA methylation patterns, DNA-associated histone protein modifications and miRNA-regulated gene expression are crucial for synaptic plasticity and learning and memory, they can therefore offer an answer to many of the neurobehavioral abnormalities that are found in FASD. In this review, we briefly discuss the current literature of DNA methylation, DNA-associated histone proteins modification and miRNA and review recent developments concerning epigenetic changes in FASD. Brain Sciences 2016-04-08 6 2 Review 10.3390/brainsci6020012 12 2076-3425 2016-04-08 doi: 10.3390/brainsci6020012 Balapal Basavarajappa Shivakumar Subbanna http://www.mdpi.com/2076-3425/6/2/11 In the past twenty years, evidence of neurotoxicity in the developing brain in animal studies from exposure to several general anesthetics has been accumulating. Propofol, a commonly used general anesthetic medication, administered during synaptogenesis, may trigger widespread apoptotic neurodegeneration in the developing brain and long-term neurobehavioral disturbances in both rodents and non-human primates. Despite the growing evidence of the potential neurotoxicity of different anesthetic agents in animal studies, there is no concrete evidence that humans may be similarly affected. However, given the growing evidence of the neurotoxic effects of anesthetics in laboratory studies, it is prudent to further investigate the mechanisms causing these effects and potential ways to mitigate them. Here, we review multiple studies that investigate the effects of in utero propofol exposure and the developmental agents that may modify these deleterious effects. Brain Sciences 2016-03-28 6 2 Review 10.3390/brainsci6020011 11 2076-3425 2016-03-28 doi: 10.3390/brainsci6020011 Ming Xiong Li Zhang Jing Li Jean Eloy Jiang Ye Alex Bekker http://www.mdpi.com/2076-3425/6/1/10 Visual perception is constructive in nature; that is, a coherent whole is generated from ambiguous fragments that are encountered in dynamic visual scenes. Creating this coherent whole from fragmented sensory inputs requires one to detect, identify, distinguish and organize sensory input. The organization of fragments into a coherent whole is facilitated by the continuous interactions between lower level sensory inputs and higher order processes. However, age-related declines are found in both neural structures and cognitive processes (e.g., attention and inhibition). The impact of these declines on the constructive nature of visual processing was the focus of this study. Here we asked younger adults, young-old (65–79 years), and old-old adults (80+ years) to view a multistable figure (i.e., Necker cube) under four conditions (free, priming, volition, and adaptation) and report, via a button press, when percepts spontaneously changed. The oldest-olds, unlike young-olds and younger adults, were influenced by priming, had less visual stability during volition and showed less ability to adapt to multistable stimuli. These results suggest that the ability to construct a coherent whole from fragments declines with age. More specifically, vision is constructed differently in the old-olds, which might influence environmental interpretations and navigational abilities in this age group. Brain Sciences 2016-03-22 6 1 Article 10.3390/brainsci6010010 10 2076-3425 2016-03-22 doi: 10.3390/brainsci6010010 Khushi Patel Maureen Reed http://www.mdpi.com/2076-3425/6/1/9 (1) Background: Hyperkinetic syndrome of childhood (HKSoC) is an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) category in which the majority of the children are also diagnosed under the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), where the umbrella term is "Attention-Deficit and Disruptive Behavior Disorders". The diagnostic criteria for HKSoC are developmentally inappropriate inattention, hyperactivity, and impulsivity. Some studies have implicated mercury (Hg) exposure as a risk factor. (2) Methods: This hypothesis testing study; using the Vaccine Safety Datalink; assessed the toxicological effects of bolus exposure to organic-Hg from Thimerosal-containing vaccines (TCVs) by examining the relationship between Thimerosal-preserved hepatitis B vaccines (TM-HepB) given at varying levels and at specific intervals in the first six months after birth and the risk of a child being diagnosed with HKSoC. (3) Results: Children diagnosed with HKSoC were significantly more likely to be exposed to increased organic-Hg from TM-HepB doses given within the first month (odds ratio = 1.45; 95% confidence interval (CI) = 1.30–1.62); within the first two months (odds ratio = 1.43; 95% CI = 1.28–1.59); and within the first six months (odds ratio = 4.51; 95% CI = 3.04–6.71) than controls. (4) Conclusion: The results indicate that increasing organic-Hg exposure from TCVs heightens the risk of a HKSoC diagnosis. Brain Sciences 2016-03-15 6 1 Article 10.3390/brainsci6010009 9 2076-3425 2016-03-15 doi: 10.3390/brainsci6010009 David Geier Janet Kern Brian Hooker Lisa Sykes Mark Geier http://www.mdpi.com/2076-3425/6/1/8 To begin to elucidate the mechanisms underlying the benefits of exercise for chronic pain, we assessed the influence of exercise on brain responses to pain in fibromyalgia (FM). Complete data were collected for nine female FM patients and nine pain-free controls (CO) who underwent two functional neuroimaging scans, following exercise (EX) and following quiet rest (QR). Brain responses and pain ratings to noxious heat stimuli were compared within and between groups. For pain ratings, there was a significant (p < 0.05) Condition by Run interaction characterized by moderately lower pain ratings post EX compared to QR (d = 0.39–0.41) for FM but similar to ratings in CO (d = 0.10–0.26), thereby demonstrating that exercise decreased pain sensitivity in FM patients to a level that was analogous to pain-free controls. Brain responses demonstrated a significant within-group difference in FM patients, characterized by less brain activity bilaterally in the anterior insula following QR as compared to EX. There was also a significant Group by Condition interaction with FM patients showing less activity in the left dorsolateral prefrontal cortex following QR as compared to post-EX and CO following both conditions. These results suggest that exercise appeared to stimulate brain regions involved in descending pain inhibition in FM patients, decreasing their sensitivity to pain. Thus, exercise may benefit patients with FM via improving the functional capacity of the pain modulatory system. Brain Sciences 2016-02-26 6 1 Article 10.3390/brainsci6010008 8 2076-3425 2016-02-26 doi: 10.3390/brainsci6010008 Laura Ellingson Aaron Stegner Isaac Schwabacher Kelli Koltyn Dane Cook http://www.mdpi.com/2076-3425/6/1/7 Rumination is a trait response to blocked goals that can have positive or negative outcomes for goal resolution depending on where attention is focused. Whereas "moody brooding" on affective states may be maladaptive, especially for females, "reflective pondering" on concrete strategies for problem solving may be more adaptive. In the context of a challenging general knowledge test, we examined how Brooding and Reflection rumination styles predicted students' subjective and event-related responses (ERPs) to negative feedback, as well as use of this feedback to rebound from failure on a later surprise retest. For females only, Brooding predicted unpleasant feelings after failure as the task progressed. It also predicted enhanced attention to errors through both bottom-up and top-down processes, as indexed by increased early (400–600 ms) and later (600–1000 ms) late positive potentials (LPP), respectively. Reflection, despite increasing females' initial attention to negative feedback (i.e., early LPP), as well as both genders' recurring negative thoughts, did not result in sustained top-down attention (i.e., late LPP) or enhanced negative feelings toward errors. Reflection also facilitated rebound from failure in both genders, although Brooding did not hinder it. Implications of these gender and time-related rumination effects for learning in challenging academic situations are discussed. Brain Sciences 2016-02-17 6 1 Article 10.3390/brainsci6010007 7 2076-3425 2016-02-17 doi: 10.3390/brainsci6010007 Ronald Whiteman Jennifer Mangels http://www.mdpi.com/2076-3425/6/1/6 Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event. Brain Sciences 2016-02-17 6 1 Review 10.3390/brainsci6010006 6 2076-3425 2016-02-17 doi: 10.3390/brainsci6010006 Gatambwa Mukandala Ronan Tynan Sinead Lanigan John O'Connor http://www.mdpi.com/2076-3425/6/1/5 There is a wealth of evidence that disrupted sleep and circadian rhythms, which are common in modern society even during the early stages of life, have unfavorable effects on brain function. Altered brain function can cause problem behaviors later in life, such as truancy from or dropping out of school, quitting employment, and committing suicide. In this review, we discuss findings from several large cohort studies together with recent results of a cohort study using the marshmallow test, which was first introduced in the 1960s. This test assessed the ability of four-year-olds to delay gratification and showed how this ability correlated with success later in life. The role of the serotonergic system in sleep and how this role changes with age are also discussed. The serotonergic system is involved in reward processing and interactions with the dorsal striatum, ventral striatum, and the prefrontal cortex are thought to comprise the neural basis for behavioral patterns that are affected by the quantity, quality, and timing of sleep early in life. Brain Sciences 2016-01-29 6 1 Review 10.3390/brainsci6010005 5 2076-3425 2016-01-29 doi: 10.3390/brainsci6010005 Jun Kohyama http://www.mdpi.com/2076-3425/6/1/4 We review evidence for cross-modal cortical re-organization in clinical populations with hearing loss. Cross-modal plasticity refers to the ability for an intact sensory modality (e.g., vision or somatosensation) to recruit cortical brain regions from a deprived sensory modality (e.g., audition) to carry out sensory processing. We describe evidence for cross-modal changes in hearing loss across the age-spectrum and across different degrees of hearing impairment, including children with profound, bilateral deafness with cochlear implants, single-sided deafness before and after cochlear implantation, and adults with early-stage, mild-moderate, age-related hearing loss. Understanding cross-modal plasticity in the context of auditory deprivation, and the potential for reversal of these changes following intervention, may be vital in directing intervention and rehabilitation options for clinical populations with hearing loss. Brain Sciences 2016-01-26 6 1 Review 10.3390/brainsci6010004 4 2076-3425 2016-01-26 doi: 10.3390/brainsci6010004 Anu Sharma Hannah Glick http://www.mdpi.com/2076-3425/6/1/3 The editors of Brain Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. [...] Brain Sciences 2016-01-22 6 1 Editorial 10.3390/brainsci6010003 3 2076-3425 2016-01-22 doi: 10.3390/brainsci6010003 Brain Sciences Editorial Office http://www.mdpi.com/2076-3425/6/1/2 Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety-associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS− conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding. Brain Sciences 2016-01-06 6 1 Article 10.3390/brainsci6010002 2 2076-3425 2016-01-06 doi: 10.3390/brainsci6010002 Steven Greening Tae-Ho Lee Mara Mather http://www.mdpi.com/2076-3425/6/1/1 Emerging evidence suggests that emotion and affect modulate the relation between sleep and cognition. In the present study, we investigated the role of rapid-eye movement (REM) sleep in mood regulation and memory consolidation for sad stories. In a counterbalanced design, participants (n = 24) listened to either a neutral or a sad story during two sessions, spaced one week apart. After listening to the story, half of the participants had a short (45 min) morning nap. The other half had a long (90 min) morning nap, richer in REM and N2 sleep. Story recall, mood evolution and changes in emotional response to the re-exposure to the story were assessed after the nap. Although recall performance was similar for sad and neutral stories irrespective of nap duration, sleep measures were correlated with recall performance in the sad story condition only. After the long nap, REM sleep density positively correlated with retrieval performance, while re-exposure to the sad story led to diminished mood and increased skin conductance levels. Our results suggest that REM sleep may not only be associated with the consolidation of intrinsically sad material, but also enhances mood reactivity, at least on the short term. Brain Sciences 2015-12-29 6 1 Article 10.3390/brainsci6010001 1 2076-3425 2015-12-29 doi: 10.3390/brainsci6010001 Médhi Gilson Gaétane Deliens Rachel Leproult Alice Bodart Antoine Nonclercq Rudy Ercek Philippe Peigneux http://www.mdpi.com/2076-3425/5/4/546 This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca2+ channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle. Brain Sciences 2015-12-03 5 4 Review 10.3390/brainsci5040546 546 567 2076-3425 2015-12-03 doi: 10.3390/brainsci5040546 Edgar Garcia-Rill Brennon Luster Susan Mahaffey Melanie MacNicol James Hyde Stasia D'Onofrio Cristy Phillips http://www.mdpi.com/2076-3425/5/4/521 Particularly with the fundamental works of the Leipzig school of experimental psychophysiology (between the 1850s and 1880s), the modern neurosciences witnessed an increasing interest in attempts to objectify "pain" as a bodily signal and physiological value. This development has led to refined psychological test repertoires and new clinical measurement techniques, which became progressively paired with imaging approaches and sophisticated theories about neuropathological pain etiology. With the advent of electroencephalography since the middle of the 20th century, and through the use of brain stimulation technologies and modern neuroimaging, the chosen scientific route towards an ever more refined "objectification" of pain phenomena took firm root in Western medicine. This article provides a broad overview of landmark events and key imaging technologies, which represent the long developmental path of a field that could be called "algesiogenic pathology." Brain Sciences 2015-11-17 5 4 Review 10.3390/brainsci5040521 521 545 2076-3425 2015-11-17 doi: 10.3390/brainsci5040521 Frank Stahnisch http://www.mdpi.com/2076-3425/5/4/509 Emotional meta-memory can be defined as the knowledge people have about the strategies and monitoring processes that they can use to remember their emotionally charged memories. Although meta-memory per se has been studied in many cognitive laboratories for many years, fewer studies have explicitly focused on meta-memory for emotionally charged or valenced information. In this brief review, we analyzed a series of behavioral and neuroimaging studies that used different meta-memory tasks with valenced information in order to foster new research in this direction, especially in terms of commonalities/peculiarities of the emotion and meta-memory interaction. In addition, results further support meta-cognitive models that take emotional factors into account when defining meta-memory per se. Brain Sciences 2015-11-09 5 4 Review 10.3390/brainsci5040509 509 520 2076-3425 2015-11-09 doi: 10.3390/brainsci5040509 Beth Fairfield Nicola Mammarella Rocco Palumbo Alberto Di Domenico http://www.mdpi.com/2076-3425/5/4/494 Cognitive development is influenced by maturational changes in processing speed, a construct reflecting the rapidity of executing cognitive operations. Although cognitive ability and processing speed are linked to spindles and sigma power in the sleep electroencephalogram (EEG), little is known about such associations in early childhood, a time of major neuronal refinement. We calculated EEG power for slow (10–13 Hz) and fast (13.25–17 Hz) sigma power from all-night high-density electroencephalography (EEG) in a cross-sectional sample of healthy preschool children (n = 10, 4.3 ± 1.0 years). Processing speed was assessed as simple reaction time. On average, reaction time was 1409 ± 251 ms; slow sigma power was 4.0 ± 1.5 μV2; and fast sigma power was 0.9 ± 0.2 μV2. Both slow and fast sigma power predominated over central areas. Only slow sigma power was correlated with processing speed in a large parietal electrode cluster (p < 0.05, r ranging from −0.6 to −0.8), such that greater power predicted faster reaction time. Our findings indicate regional correlates between sigma power and processing speed that are specific to early childhood and provide novel insights into the neurobiological features of the EEG that may underlie developing cognitive abilities. Brain Sciences 2015-11-04 5 4 Article 10.3390/brainsci5040494 494 508 2076-3425 2015-11-04 doi: 10.3390/brainsci5040494 Margaret Doucette Salome Kurth Nicolas Chevalier Yuko Munakata Monique LeBourgeois http://www.mdpi.com/2076-3425/5/4/456 One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS), which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD). Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD. Brain Sciences 2015-10-29 5 4 Review 10.3390/brainsci5040456 456 493 2076-3425 2015-10-29 doi: 10.3390/brainsci5040456 Balapal Basavarajappa http://www.mdpi.com/2076-3425/5/4/441 Caffeine is the most commonly ingested psychoactive drug worldwide with increasing consumption rates among young individuals. While caffeine leads to decreased sleep quality in adults, studies investigating how caffeine consumption affects children's and adolescents' sleep remain scarce. We explored the effects of regular caffeine consumption on sleep behavior and the sleep electroencephalogram (EEG) in children and adolescents (10–16 years). While later habitual bedtimes (Caffeine 23:14 ± 11.4, Controls 22:17 ± 15.4) and less time in bed were found in caffeine consumers compared to the control group (Caffeine 08:10 ± 13.3, Controls 09:03 ± 16.1), morning tiredness was unaffected. Furthermore, caffeine consumers exhibited reduced sleep EEG slow-wave activity (SWA, 1–4.5 Hz) at the beginning of the night compared to controls (20% ± 9% average reduction across all electrodes and subjects). Comparable reductions were found for alpha activity (8.25–9.75 Hz). These effects, however, disappeared in the morning hours. Our findings suggest that caffeine consumption in adolescents may lead to later bedtimes and reduced SWA, a well-established marker of sleep depth. Because deep sleep is involved in recovery processes during sleep, further research is needed to understand whether a caffeine-induced loss of sleep depth interacts with neuronal network refinement processes that occur during the sensitive period of adolescent development. Brain Sciences 2015-10-15 5 4 Article 10.3390/brainsci5040441 441 455 2076-3425 2015-10-15 doi: 10.3390/brainsci5040441 Andrina Aepli Salome Kurth Noemi Tesler Oskar Jenni Reto Huber http://www.mdpi.com/2076-3425/5/4/419 Ecumenically, the fastest growing segment of Big Data is human biology-related data and the annual data creation is on the order of zetabytes. The implications are global across industries, of which the treatment of brain related illnesses and trauma could see the most significant and immediate effects. The next generation of health care IT and sensory devices are acquiring and storing massive amounts of patient related data. An innovative Brain-Computer Interface (BCI) for interactive 3D visualization is presented utilizing the Hadoop Ecosystem for data analysis and storage. The BCI is an implementation of Bayesian factor analysis algorithms that can distinguish distinct thought actions using magneto encephalographic (MEG) brain signals. We have collected data on five subjects yielding 90% positive performance in MEG mid- and post-movement activity. We describe a driver that substitutes the actions of the BCI as mouse button presses for real-time use in visual simulations. This process has been added into a flight visualization demonstration. By thinking left or right, the user experiences the aircraft turning in the chosen direction. The driver components of the BCI can be compiled into any software and substitute a user's intent for specific keyboard strikes or mouse button presses. The BCI's data analytics OPEN ACCESS Brain. Sci. 2015, 5 420 of a subject's MEG brainwaves and flight visualization performance are stored and analyzed using the Hadoop Ecosystem as a quick retrieval data warehouse. Brain Sciences 2015-09-30 5 4 Article 10.3390/brainsci5040419 419 440 2076-3425 2015-09-30 doi: 10.3390/brainsci5040419 Wilbert McClay Nancy Yadav Yusuf Ozbek Andy Haas Hagaii Attias Srikantan Nagarajan http://www.mdpi.com/2076-3425/5/4/400 Neuroimaging technologies with an exceptional spatial resolution and noninvasiveness have become a powerful tool for assessing neural activity in both animals and humans. However, the effectiveness of neuroimaging for pain remains unclear partly because the neurovascular coupling during pain processing is not completely characterized. Our current work aims to unravel patterns of neurovascular parameters in pain processing. A novel fiber-optic method was used to acquire absolute values of regional oxy- (HbO) and deoxy-hemoglobin concentrations, oxygen saturation rates (SO2), and the light-scattering coefficients from the spinal cord and primary somatosensory cortex (SI) in 10 rats. Brief mechanical and electrical stimuli (ranging from innocuous to noxious intensities) as well as a long-lasting noxious stimulus (formalin injection) were applied to the hindlimb under pentobarbital anesthesia. Interhemispheric comparisons in the spinal cord and SI were used to confirm functional activation during sensory processing. We found that all neurovascular parameters showed stimulation-induced changes; however, patterns of changes varied with regions and stimuli. Particularly, transient increases in HbO and SO2 were more reliably attributed to brief stimuli, whereas a sustained decrease in SO2 was more reliably attributed to formalin. Only the ipsilateral SI showed delayed responses to brief stimuli. In conclusion, innocuous and noxious stimuli induced significant neurovascular responses at critical centers (e.g., the spinal cord and SI) along the somatosensory pathway; however, there was no single response pattern (as measured by amplitude, duration, lateralization, decrease or increase) that was able to consistently differentiate noxious stimuli. Our results strongly suggested that the neurovascular response patterns differ between brief and long-lasting noxious stimuli, and can also differ between the spinal cord and SI. Therefore, a use of multiple-parameter strategy tailored by stimulus modality (brief or long-lasting) as well as region-dependent characteristics may be more effective in detecting pain using neuroimaging technologies. Brain Sciences 2015-09-29 5 4 Article 10.3390/brainsci5040400 400 418 2076-3425 2015-09-29 doi: 10.3390/brainsci5040400 Ji-Wei He Hanli Liu Yuan Peng http://www.mdpi.com/2076-3425/5/4/387 Functional near-infrared imaging (fNIRI) is a non-invasive, low-cost and highly portable technique for assessing brain activity and functions. Both clinical and experimental evidence suggest that fNIRI is able to assess brain activity at associated regions during pain processing, indicating a strong possibility of using fNIRI-derived brain activity pattern as a biomarker for pain. However, it remains unclear how, especially in small animals, the scalp influences fNIRI signal in pain processing. Previously, we have shown that the use of a multi-channel system improves the spatial resolution of fNIRI in rats (without the scalp) during pain processing. Our current work is to investigate a scalp effect by comparing with new data from rats with the scalp during innocuous or noxious stimulation (n = 6). Results showed remarkable stimulus-dependent differences between the no-scalp and intact-scalp groups. In conclusion, the scalp confounded the fNIRI signal in pain processing likely via an autonomic mechanism; the scalp effect should be a critical factor in image reconstruction and data interpretation. Brain Sciences 2015-09-29 5 4 Article 10.3390/brainsci5040387 387 399 2076-3425 2015-09-29 doi: 10.3390/brainsci5040387 Ji-Wei He Hanli Liu Yuan Peng http://www.mdpi.com/2076-3425/5/3/369 Although attention-deficit hyperactivity disorder (ADHD) has been linked to emotion dysregulation, few studies have experimentally investigated this whilst controlling for the effects of comorbid conduct disorder (CD). Economic decision-making games that assess how individuals respond to offers varying in fairness have been used to study emotion regulation. The present study compared adolescent boys with ADHD (n = 90), ADHD + CD (n = 94) and typical controls (n = 47) on the Ultimatum Game and examined the contribution of ADHD and CD symptom scores and callous and unemotional traits to acceptance levels of unfair offers. There were no significant differences in acceptance rates of fair and highly unfair offers between groups, and only boys with ADHD did not significantly differ from the controls. However, the subgroup of boys with ADHD and additional high levels of aggressive CD symptoms rejected significantly more ambiguous (i.e., moderately unfair) offers than any other subgroup, suggesting impaired emotion regulation in those with ADHD and aggressive CD. Correlations within the CD group showed that the rejection rate to moderately unfair offers was predicted by aggressive CD symptom severity, but not callous and unemotional traits. These findings highlight the fact that ADHD is a heterogeneous condition from an emotion regulation point of view. Brain Sciences 2015-09-07 5 3 Article 10.3390/brainsci5030369 369 386 2076-3425 2015-09-07 doi: 10.3390/brainsci5030369 Clare Northover Anita Thapar Kate Langley Stephanie van Goozen http://www.mdpi.com/2076-3425/5/3/357 Motivated by conflicting evidence in the literature, we re-assessed the role of facial feedback when detecting quantitative or qualitative changes in others' emotional expressions. Fifty-three healthy adults observed self-paced morph sequences where the emotional facial expression either changed quantitatively (i.e., sad-to-neutral, neutral-to-sad, happy-to-neutral, neutral-to-happy) or qualitatively (i.e. from sad to happy, or from happy to sad). Observers held a pen in their own mouth to induce smiling or frowning during the detection task. When morph sequences started or ended with neutral expressions we replicated a congruency effect: Happiness was perceived longer and sooner while smiling; sadness was perceived longer and sooner while frowning. Interestingly, no such congruency effects occurred for transitions between emotional expressions. These results suggest that facial feedback is especially useful when evaluating the intensity of a facial expression, but less so when we have to recognize which emotion our counterpart is expressing. Brain Sciences 2015-08-26 5 3 Article 10.3390/brainsci5030357 357 368 2076-3425 2015-08-26 doi: 10.3390/brainsci5030357 Janek Lobmaier Martin Fischer http://www.mdpi.com/2076-3425/5/3/318 Individuals with severe neuromuscular impairments face many challenges in communication and manipulation of the environment. Brain-computer interfaces (BCIs) show promise in presenting real-world applications that can provide such individuals with the means to interact with the world using only brain waves. Although there has been a growing body of research in recent years, much relates only to technology, and not to technology in use—i.e., real-world assistive technology employed by users. This review examined the literature to highlight studies that implicate the human factors and ergonomics (HFE) of P300-based BCIs. We assessed 21 studies on three topics to speak directly to improving the HFE of these systems: (1) alternative signal evocation methods within the oddball paradigm; (2) environmental interventions to improve user performance and satisfaction within the constraints of current BCI systems; and (3) measures and methods of measuring user acceptance. We found that HFE is central to the performance of P300-based BCI systems, although researchers do not often make explicit this connection. Incorporation of measures of user acceptance and rigorous usability evaluations, increased engagement of disabled users as test participants, and greater realism in testing will help progress the advancement of P300-based BCI systems in assistive applications. Brain Sciences 2015-08-10 5 3 Review 10.3390/brainsci5030318 318 356 2076-3425 2015-08-10 doi: 10.3390/brainsci5030318 J. Powers Kateryna Bieliaieva Shuohao Wu Chang Nam http://www.mdpi.com/2076-3425/5/3/299 GABAergic local circuit neurons are critical for the network activity and functional interaction of the amygdala and hippocampus. Previously, we obtained evidence for a GABAergic contribution to the hippocampal projection into the basolateral amygdala. Using fluorogold retrograde labeling, we now demonstrate that this projection indeed has a prominent GABAergic component comprising 17% of the GABAergic neurons in the ventral hippocampus. A majority of the identified GABAergic projection neurons are located in the stratum oriens of area CA1, but cells are also found in the stratum pyramidale and stratum radiatum. We could detect the expression of different markers of interneuron subpopulations, including parvalbumin and calbindin, somatostatin, neuropeptide Y, and cholecystokinin in such retrogradely labeled GABA neurons. Thus GABAergic projection neurons to the amygdala comprise a neurochemically heterogeneous group of cells from different interneuron populations, well situated to control network activity patterns in the amygdalo-hippocampal system. Brain Sciences 2015-07-31 5 3 Article 10.3390/brainsci5030299 299 317 2076-3425 2015-07-31 doi: 10.3390/brainsci5030299 Robert Lübkemann Judith Eberhardt Friedrich-Wilhelm Röhl Kathrin Janitzky Sven Nullmeier Oliver Stork Herbert Schwegler Rüdiger Linke http://www.mdpi.com/2076-3425/5/3/275 Dystrophin-glycoprotein complex (DGC) is an important structural unit in skeletal muscle that connects the cytoskeleton (f-actin) of a muscle fiber to the extracellular matrix (ECM). Several muscular dystrophies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, congenital muscular dystrophies (dystroglycanopathies), and limb-girdle muscular dystrophies (sarcoglycanopathies), are caused by mutations in the different DGC components. Although many early studies indicated DGC plays a crucial mechanical role in maintaining the structural integrity of skeletal muscle, recent studies identified novel roles of DGC. Beyond a mechanical role, these DGC members play important signaling roles and act as a scaffold for various signaling pathways. For example, neuronal nitric oxide synthase (nNOS), which is localized at the muscle membrane by DGC members (dystrophin and syntrophins), plays an important role in the regulation of the blood flow during exercise. DGC also plays important roles at the neuromuscular junction (NMJ) and in the brain. In this review, we will focus on recently identified roles of DGC particularly in exercise and the brain. Brain Sciences 2015-07-29 5 3 Review 10.3390/brainsci5030275 275 298 2076-3425 2015-07-29 doi: 10.3390/brainsci5030275 Bailey Nichols Shin'ichi Takeda Toshifumi Yokota http://www.mdpi.com/2076-3425/5/3/258 Stress is a major driving force in alcohol use disorders (AUDs). It influences how much one consumes, craving intensity and whether an abstinent individual will return to harmful alcohol consumption. We are most vulnerable to the effects of stress during early development, and exposure to multiple traumatic early life events dramatically increases the risk for AUDs. However, not everyone exposed to early life stress will develop an AUD. The mechanisms determining whether an individual's brain adapts and becomes resilient to the effects of stress or succumbs and is unable to cope with stress remain elusive. Emerging evidence suggests that neuroplastic changes in the nucleus accumbens (NAc) following early life stress underlie the development of AUDs. This review discusses the impact of early life stress on NAc structure and function, how these changes affect cholinergic signaling within the mesolimbic reward pathway and the role nicotinic acetylcholine receptors (nAChRs) play in this process. Understanding the neural pathways and mechanism determining stress resilience or susceptibility will improve our ability to identify individuals susceptible to developing AUDs, formulate cognitive interventions to prevent AUDs in susceptible individuals and to elucidate and enhance potential therapeutic targets, such as the nAChRs, for those struggling to overcome an AUD. Brain Sciences 2015-06-30 5 3 Review 10.3390/brainsci5030258 258 274 2076-3425 2015-06-30 doi: 10.3390/brainsci5030258 Joan Holgate Selena Bartlett http://www.mdpi.com/2076-3425/5/2/241 The mechanism by which the hippocampus facilitates declarative memory formation appears to involve, among other things, restructuring of the actin cytoskeleton within neuronal dendrites. One protein involved in this process is cortactin, which is an important link between extracellular signaling and cytoskeletal reorganization. In this paper, we demonstrate that total hippocampal cortactin, as well as Y421-phosphorylated cortactin are transiently reduced following spatial working memory formation in the radial arm maze (RAM). Because cortactin is a substrate of the cysteine protease calpain, we also assessed the effect of chronic calpain inhibition on RAM performance and cortactin expression. Calpain inhibition impaired spatial working memory and blocked the reduction in hippocampal cortactin levels following RAM training. These findings add to a growing body of research implicating cortactin and calpain in hippocampus-dependent memory formation. Brain Sciences 2015-06-19 5 2 Article 10.3390/brainsci5020241 241 257 2076-3425 2015-06-19 doi: 10.3390/brainsci5020241 Mikel Olson Anna Ingebretson Katherine Harmelink http://www.mdpi.com/2076-3425/5/2/220 Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen. Brain Sciences 2015-05-22 5 2 Article 10.3390/brainsci5020220 220 240 2076-3425 2015-05-22 doi: 10.3390/brainsci5020220 Amanda Smith Haley Garbus Ted Rosenkrantz Roslyn Fitch http://www.mdpi.com/2076-3425/5/2/201 Stress can increase emotional vigilance at the cost of a decrease in attention towards non-emotional stimuli. However, the time-dependent effects of acute stress on emotion processing are uncertain. We tested the effects of acute stress on subsequent emotion processing up to 40 min following an acute stressor. Our measure of emotion processing was the late positive potential (LPP) component of the visual event-related potential (ERP), and our measure of non-emotional attention was the sustained attention to response task (SART). We also measured cortisol levels before and after the socially evaluated cold pressor test (SECPT) induction. We found that the effects of stress on the LPP ERP emotion measure were time sensitive. Specifically, the LPP ERP was only altered in the late time-point (30–40 min post-stress) when cortisol was at its highest level. Here, the LPP no longer discriminated between the emotional and non-emotional picture categories, most likely because neutral pictures were perceived as emotional. Moreover, compared to the non-stress condition, the stress-condition showed impaired performance on the SART. Our results support the idea that a limit in attention resources after an emotional stressor is associated with the brain incorrectly processing non-emotional stimuli as emotional and interferes with sustained attention. Brain Sciences 2015-05-20 5 2 Article 10.3390/brainsci5020201 201 219 2076-3425 2015-05-20 doi: 10.3390/brainsci5020201 Rima Alomari Mercedes Fernandez Jonathan Banks Juliana Acosta Jaime Tartar http://www.mdpi.com/2076-3425/5/2/188 CD157, also referred to as bone marrow stromal cell antigen-1 (BST-1), is a glycosylphosphatidylinositol-anchored molecule that promotes pre-B-cell growth. Previous studies have reported associations between single-nucleotide polymorphisms (SNPs) of the CD157/BST1 gene with Parkinson's disease. In an attempt to determine whether SNPs or haplotypes in the CD157/BST1 are associated with other brain disorders, we performed a case-control study including 147 autism spectrum disorder (ASD) patients at Kanazawa University Hospital in Japan and 150 unselected Japanese volunteers by the sequence-specific primer-polymerase chain reaction method combined with fluorescence correlation spectroscopy. Of 93 SNPs examined, two SNPs showed significantly higher allele frequencies in cases with ASDs than in unaffected controls (rs4301112, OR = 6.4, 95% CI = 1.9 to 22, p = 0.0007; and rs28532698, OR = 6.2, 95% CI = 1.8 to 21, p = 0.0012; Fisher's exact test; p < 0.002 was considered significant after multiple testing correction). In addition, CT genotype in rs10001565 was more frequently observed in the ASD group than in the control group (OR = 15, 95% CI = 2.0 to 117, p = 0.0007; Fisher's exact test). The present data indicate that genetic variation of the CD157/BST1 gene might confer susceptibility to ASDs. Brain Sciences 2015-05-20 5 2 Article 10.3390/brainsci5020188 188 200 2076-3425 2015-05-20 doi: 10.3390/brainsci5020188 Shigeru Yokoyama Naila Al Mahmuda Toshio Munesue Kenshi Hayashi Kunimasa Yagi Masakazu Yamagishi Haruhiro Higashida http://www.mdpi.com/2076-3425/5/2/178 Hypoxia induced endoplasmic reticulum stress causes accumulation of unfolded proteins in the endoplasmic reticulum and activates the unfolded protein response, resulting in apoptosis through CCAAT-enhancer-binding protein homologous protein (CHOP) activation. In an in vitro and in vivo model of ischemic stroke, we investigated whether hypothermia regulates the unfolded protein response of CHOP and Endoplasmic reticulum oxidoreductin-α (Ero1-α), because Ero1-α is suggested to be a downstream CHOP target. The gene expression of CHOP and Ero1-α was measured using Quantitative-PCR (Q-PCR) in rat hippocampi following global cerebral ischemia, and in hypoxic pheochromocytoma cells during normothermic (37 °C) and hypothermic (31 °C) conditions. As a result of ischemia, a significant increase in expression of CHOP and Ero1-α was observed after three, six and twelve hours of reperfusion following global ischemia. A stable increase in CHOP expression was observed throughout the time course (p < 0.01, p < 0.0001), whereas Ero1-α expression peaked at three to six hours (p < 0.0001). Induced hypothermia in hypoxia stressed PC12 cells resulted in a decreased expression of CHOP after three, six and twelve hours (p < 0.0001). On the contrary, the gene expression of Ero1-α increased as a result of hypothermia and peaked at twelve hours (p < 0.0001). Hypothermia attenuated the expression of CHOP, supporting that hypothermia suppress endoplasmic reticulum stress induced apoptosis in stroke. As hypothermia further induced up-regulation of Ero1-α, and since CHOP and Ero1-α showed differential regulation as a consequence of both disease (hypoxia) and treatment (hypothermia), we conclude that they are regulated independently. Brain Sciences 2015-05-15 5 2 Article 10.3390/brainsci5020178 178 187 2076-3425 2015-05-15 doi: 10.3390/brainsci5020178 Gagandip Poone Henrik Hasseldam Nina Munkholm Rune Rasmussen Nina Grønberg Flemming Johansen http://www.mdpi.com/2076-3425/5/2/165 In recent years, growth factor therapy has emerged as a potential treatment for ischemic brain injury. The efficacy of therapies that either directly introduce or stimulate local production of growth factors and their receptors in damaged brain tissue has been tested in a multitude of models for different Central Nervous System (CNS) diseases. These growth factors include erythropoietin (EPO), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor (IGF-1), among others. Despite the promise shown in animal models, the particular growth factors that should be used to maximize both brain protection and repair, and the therapeutic critical period, are not well defined. We will review current pre-clinical and clinical evidence for growth factor therapies in treating different causes of brain injury, as well as issues to be addressed prior to application in humans. Brain Sciences 2015-04-30 5 2 Review 10.3390/brainsci5020165 165 177 2076-3425 2015-04-30 doi: 10.3390/brainsci5020165 Amara Larpthaveesarp Donna Ferriero Fernando Gonzalez http://www.mdpi.com/2076-3425/5/2/144 Overgeneral autobiographical memory (AM) manifests in individuals with major depressive disorder (MDD) tested during depressed (dMDD) or remitted phases (rMDD), and healthy individuals at high-risk (HR) for developing MDD. The current study aimed to elucidate differences in hemodynamic correlates of AM recall between rMDDs, HRs, and controls (HCs) to identify neural changes following previous depressive episodes without the confound of current depressed mood. HCs, HRs, and unmedicated rMDDs (n = 20/group) underwent fMRI while recalling AMs in response to emotionally valenced cue words. HRs and rMDDs recalled fewer specific and more categorical AMs relative to HCs. During specific AM recall, HRs had increased activity relative to rMDDs and HCs in left ventrolateral prefrontal cortex (VLPFC) and lateral orbitofrontal cortex. During positive specific AM recall, HRs and HCs had increased activity relative to rMDDs in bilateral dorsomedial prefrontal cortex (DMPFC) and left precuneus. During negative specific AM recall HRs and HCs had increased activity in left VLPFC and right DMPFC, while rMDDs had increased activity relative to HRs and HCs in right DLPFC and precuneus. Differential recruitment of medial prefrontal regions implicated in emotional control suggests experiencing a depressive episode may consequently reduce one's ability to regulate emotional responses during AM recall. Brain Sciences 2015-04-24 5 2 Article 10.3390/brainsci5020144 144 164 2076-3425 2015-04-24 doi: 10.3390/brainsci5020144 Kymberly Young Patrick Bellgowan Jerzy Bodurka Wayne Drevets http://www.mdpi.com/2076-3425/5/2/130 Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity. Brain Sciences 2015-04-21 5 2 Article 10.3390/brainsci5020130 130 143 2076-3425 2015-04-21 doi: 10.3390/brainsci5020130 Tarek Saleh Barry Connell Inan Kucukkaya Alaa Abd-El-Aziz http://www.mdpi.com/2076-3425/5/2/118 Citrus polymethoxylated flavones (PMFs) have recently been shown to suppress inflammation in peripheral tissues. In the present study, we investigated the effects of 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), one of the PMFs, on inflammation in the brain in vivo using mice injected intrahippocampally with lipopolysaccharide (LPS). We demonstrated that subcutaneously injected HMF suppressed: (1) LPS-induced losses in body weight; (2) LPS-induced microglial activation in the hippocampus; and (3) LPS-induced interleukin-1β mRNA expression in the hippocampus. These results suggest that HMF has the ability to reduce neuroinflammation in the brain. Brain Sciences 2015-04-15 5 2 Communication 10.3390/brainsci5020118 118 129 2076-3425 2015-04-15 doi: 10.3390/brainsci5020118 Satoshi Okuyama Kazuhiro Miyoshi Yuichi Tsumura Yoshiaki Amakura Morio Yoshimura Takashi Yoshida Mitsunari Nakajima Yoshiko Furukawa http://www.mdpi.com/2076-3425/5/2/92 Autism Spectrum Disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders with different but potentially related neurobiological underpinnings, which exhibit significant overlap in their behavioural symptoms. FXS is a neurogenetic disorder of known cause whereas ASD is a complex genetic disorder, with both rare and common genetic risk factors and likely genetic and environmental interaction effects. A comparison of the phenotypic presentation of the two disorders may highlight those symptoms that are more likely to be under direct genetic control, for example in FXS as opposed to shared symptoms that are likely to be under the control of multiple mechanisms. This review is focused on the application and analysis of electroencephalography data (EEG) in ASD and FXS. Specifically, Event Related Potentials (ERP) and resting state studies (rEEG) studies investigating ASD and FXS cohorts are compared. This review explores the electrophysiological similarities and differences between the two disorders in addition to the potentially associated neurobiological mechanisms at play. A series of pertinent research questions which are suggested in the literature are also posed within the review. Brain Sciences 2015-03-27 5 2 Review 10.3390/brainsci5020092 92 117 2076-3425 2015-03-27 doi: 10.3390/brainsci5020092 Niamh Devitt Louise Gallagher Richard Reilly http://www.mdpi.com/2076-3425/5/1/69 Capitalizing from neuroscience knowledge on how individuals are affected by the sound environment, we propose to adopt a cybernetic and ecological point of view on the musical aesthetic experience, which includes subprocesses, such as feature extraction and integration, early affective reactions and motor actions, style mastering and conceptualization, emotion and proprioception, evaluation and preference. In this perspective, the role of the listener/composer/performer is seen as that of an active "agent" coping in highly individual ways with the sounds. The findings concerning the neural adaptations in musicians, following long-term exposure to music, are then reviewed by keeping in mind the distinct subprocesses of a musical aesthetic experience. We conclude that these neural adaptations can be conceived of as the immediate and lifelong interactions with multisensorial stimuli (having a predominant auditory component), which result in lasting changes of the internal state of the "agent". In a continuous loop, these changes affect, in turn, the subprocesses involved in a musical aesthetic experience, towards the final goal of achieving better perceptual, motor and proprioceptive responses to the immediate demands of the sounding environment. The resulting neural adaptations in musicians closely depend on the duration of the interactions, the starting age, the involvement of attention, the amount of motor practice and the musical genre played. Brain Sciences 2015-03-23 5 1 Article 10.3390/brainsci5010069 69 91 2076-3425 2015-03-23 doi: 10.3390/brainsci5010069 Mark Reybrouck Elvira Brattico http://www.mdpi.com/2076-3425/5/1/58 Among epigenetic factors leading to increased prevalence of juvenile neuropsychiatric disorders, including autism spectrum disorder, exposure to metals, such as lead (Pb) have led to conflicting results. The aim of the present study was to determine the levels of Pb in the urine of children with autism spectrum disorder (ASD) compared with typically developing children (TD) age- and sex-matched, and to analyze any association between core symptoms of ASD, special diets, supplements intake or prescription drugs and the concentration of Pb. The study was performed in a group of children with ASD (n = 35, average age 7.4 ± 0.5 years) and TD (n = 34, average age 7.7 ± 0.9 years). Measurement of lead in urine was performed by atomic absorption spectrometry; symptoms of ASD were analyzed by diagnostic and statistical manual of mental disorders (DMS-IV) using the questionnary ADI-R. Careful clinical evaluation was also undertaken and statistical analysis was done taking into account any possible confounding factor. Brain Sciences 2015-02-16 5 1 Article 10.3390/brainsci5010058 58 68 2076-3425 2015-02-16 doi: 10.3390/brainsci5010058 Milagros Fuentes-Albero Carmen Puig-Alcaraz Omar Cauli http://www.mdpi.com/2076-3425/5/1/32 A considerable number of cognitive processes depend on the integration of multisensory information. The brain integrates this information, providing a complete representation of our surrounding world and giving us the ability to react optimally to the environment. Infancy is a period of great changes in brain structure and function that are reflected by the increase of processing capacities of the developing child. However, it is unclear if the optimal use of multisensory information is present early in childhood or develops only later, with experience. The first part of this review has focused on the typical development of multisensory integration (MSI). We have described the two hypotheses on the developmental process of MSI in neurotypical infants and children, and have introduced MSI and its neuroanatomic correlates. The second section has discussed the neurodevelopmental trajectory of MSI in cognitively-challenged infants and children. A few studies have brought to light various difficulties to integrate sensory information in children with a neurodevelopmental disorder. Consequently, we have exposed certain possible neurophysiological relationships between MSI deficits and neurodevelopmental disorders, especially dyslexia and attention deficit disorder with/without hyperactivity. Brain Sciences 2015-02-11 5 1 Review 10.3390/brainsci5010032 32 57 2076-3425 2015-02-11 doi: 10.3390/brainsci5010032 Emmanuelle Dionne-Dostie Natacha Paquette Maryse Lassonde Anne Gallagher http://www.mdpi.com/2076-3425/5/1/14 Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development. Brain Sciences 2015-01-26 5 1 Article 10.3390/brainsci5010014 14 31 2076-3425 2015-01-26 doi: 10.3390/brainsci5010014 Subit Barua Salomon Kuizon Kathryn Chadman W. Brown Mohammed Junaid http://www.mdpi.com/2076-3425/5/1/3 Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia. Brain Sciences 2015-01-20 5 1 Article 10.3390/brainsci5010003 3 13 2076-3425 2015-01-20 doi: 10.3390/brainsci5010003 Akira Mizuno Stanislav Cherepanov Yusuke Kikuchi Azam Fakhrul Shirin Akther Kisaburo Deguchi Toru Yoshihara Katsuhiko Ishihara Satoshi Shuto Haruhiro Higashida http://www.mdpi.com/2076-3425/5/1/1 The editors of Brain Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2014:[...] Brain Sciences 2015-01-08 5 1 Editorial 10.3390/brainsci5010001 1 2 2076-3425 2015-01-08 doi: 10.3390/brainsci5010001 Brain Sciences Editorial Office http://www.mdpi.com/2076-3425/4/4/613 Language and face processing develop in similar ways during the first year of life. Early in the first year of life, infants demonstrate broad abilities for discriminating among faces and speech. These discrimination abilities then become tuned to frequently experienced groups of people or languages. This process of perceptual development occurs between approximately 6 and 12 months of age and is largely shaped by experience. However, the mechanisms underlying perceptual development during this time, and whether they are shared across domains, remain largely unknown. Here, we highlight research findings across domains and propose a top-down/bottom-up processing approach as a guide for future research. It is hypothesized that perceptual narrowing and tuning in development is the result of a shift from primarily bottom-up processing to a combination of bottom-up and top-down influences. In addition, we propose word learning as an important top-down factor that shapes tuning in both the speech and face domains, leading to similar observed developmental trajectories across modalities. Importantly, we suggest that perceptual narrowing/tuning is the result of multiple interacting factors and not explained by the development of a single mechanism. Brain Sciences 2014-12-16 4 4 Review 10.3390/brainsci4040613 613 634 2076-3425 2014-12-16 doi: 10.3390/brainsci4040613 Hillary Hadley Gwyneth Rost Eswen Fava Lisa Scott http://www.mdpi.com/2076-3425/4/4/594 Congenital amusia is defined by marked deficits in pitch perception and production. Though historically examined only in otherwise typically developing (TD) populations, amusia has recently been documented in Williams syndrome (WS), a genetic, neurodevelopmental disorder with a unique auditory phenotype including auditory sensitivities and increased emotional responsiveness to music but variable musical skill. The current study used structural T1-weighted magnetic resonance imaging and diffusion tensor imaging to examine neural correlates of amusia in 17 individuals with WS (4 of whom met criteria for amusia). Consistent with findings from TD amusics, amusia in WS was associated with decreased fractional anisotropy (FA) in the right superior longitudinal fasciculus (SLF). The relationship between amusia and FA in the inferior component of the SLF was particularly robust, withstanding corrections for cognitive functioning, auditory sensitivities, or musical training. Though the number of individuals with amusia in the study is small, results add to evidence for the role of fronto-temporal disconnectivity in congenital amusia and suggest that novel populations with developmental differences can provide a window into understanding gene-brain-behavior relationships that underlie musical behaviors. Brain Sciences 2014-11-21 4 4 Article 10.3390/brainsci4040594 594 612 2076-3425 2014-11-21 doi: 10.3390/brainsci4040594 Miriam Lense Nathan Dankner Jennifer Pryweller Tricia Thornton-Wells Elisabeth Dykens http://www.mdpi.com/2076-3425/4/4/575 Musical training during childhood has been linked to more robust encoding of sound later in life. We take this as evidence for an auditory reserve: a mechanism by which individuals capitalize on earlier life experiences to promote auditory processing. We assert that early auditory experiences guide how the reserve develops and is maintained over the lifetime. Experiences that occur after childhood, or which are limited in nature, are theorized to affect the reserve, although their influence on sensory processing may be less long-lasting and may potentially fade over time if not repeated. This auditory reserve may help to explain individual differences in how individuals cope with auditory impoverishment or loss of sensorineural function. Brain Sciences 2014-11-14 4 4 Commentary 10.3390/brainsci4040575 575 593 2076-3425 2014-11-14 doi: 10.3390/brainsci4040575 Erika Skoe Nina Kraus http://www.mdpi.com/2076-3425/4/4/560 When one sense is unavailable, sensory responsibilities shift and processing of the remaining modalities becomes enhanced to compensate for missing information. This shift, referred to as compensatory plasticity, results in a unique sensory experience for individuals who are deaf, including the manner in which music is perceived. This paper evaluates the neural, behavioural and cognitive evidence for compensatory plasticity following auditory deprivation and considers how this manifests in a unique experience of music that emphasizes visual and vibrotactile modalities. Brain Sciences 2014-10-28 4 4 Review 10.3390/brainsci4040560 560 574 2076-3425 2014-10-28 doi: 10.3390/brainsci4040560 Arla Good Maureen Reed Frank Russo http://www.mdpi.com/2076-3425/4/4/532 Recent behavioral and electrophysiological evidence has highlighted the long-term importance for language skills of an early ability to recognize words in continuous speech. We here present further tests of this long-term link in the form of follow-up studies conducted with two (separate) groups of infants who had earlier participated in speech segmentation tasks. Each study extends prior follow-up tests: Study 1 by using a novel follow-up measure that taps into online processing, Study 2 by assessing language performance relationships over a longer time span than previously tested. Results of Study 1 show that brain correlates of speech segmentation ability at 10 months are positively related to 16-month-olds' target fixations in a looking-while-listening task. Results of Study 2 show that infant speech segmentation ability no longer directly predicts language profiles at the age of five. However, a meta-analysis across our results and those of similar studies (Study 3) reveals that age at follow-up does not moderate effect size. Together, the results suggest that infants' ability to recognize words in speech certainly benefits early vocabulary development; further observed relationships of later language skills to early word recognition may be consequent upon this vocabulary size effect. Brain Sciences 2014-10-24 4 4 Article 10.3390/brainsci4040532 532 559 2076-3425 2014-10-24 doi: 10.3390/brainsci4040532 Caroline Junge Anne Cutler http://www.mdpi.com/2076-3425/4/4/509 Given the current focus on anticipation in perception, action and cognition, including language processing, there is a need for a method to tap into predictive processing in situations in which cue and feedback stimuli are not explicitly marked as such. To this aim, event related potentials (ERPs) were obtained while participants viewed alphabetic letter sequences ("A", "B", "C", "D", "E", …), in which the letters were highly predictable, and random sequences ("S", "B", "A", "I", "F", "M", …), without feedback. Occasionally, the presentation of a letter in a sequence was delayed by 300 ms. During this delay period, an increased negativity was observed for predictive versus random sequences. In addition, the early positivity following the delay was larger for predictive compared with random sequences. These results suggest that expectation-sensitive ERP modulations can be elicited in anticipation of stimuli that are not explicit targets, rewards, feedback or instructions, and that a delay can strengthen the prediction for a particular stimulus. Applications to language processing will be discussed. Brain Sciences 2014-10-23 4 4 Article 10.3390/brainsci4040509 509 531 2076-3425 2014-10-23 doi: 10.3390/brainsci4040509 Edith Kaan Evan Carlisle http://www.mdpi.com/2076-3425/4/3/488 The authors wish to make the following correction to this paper (Cecotti, H.; Rivet, B. Subject Combination and Electrode Selection in Cooperative Brain-Computer Interface Based on Event Related Potentials. Brain Sci. 2014, 4, 335–355): Due to an internal error, the reference numbers in the original published paper were not shown, and the error was not due to the authors. The former main text should be replaced as below. Brain Sciences 2014-09-19 4 3 Correction 10.3390/brainsci4030488 488 508 2076-3425 2014-09-19 doi: 10.3390/brainsci4030488 Hubert Cecotti Bertrand Rivet http://www.mdpi.com/2076-3425/4/3/471 Initially, infants are capable of discriminating phonetic contrasts across the world's languages. Starting between seven and ten months of age, they gradually lose this ability through a process of perceptual narrowing. Although traditionally investigated with isolated speech sounds, such narrowing occurs in a variety of perceptual domains (e.g., faces, visual speech). Thus far, tracking the developmental trajectory of this tuning process has been focused primarily on auditory speech alone, and generally using isolated sounds. But infants learn from speech produced by people talking to them, meaning they learn from a complex audiovisual signal. Here, we use near-infrared spectroscopy to measure blood concentration changes in the bilateral temporal cortices of infants in three different age groups: 3-to-6 months, 7-to-10 months, and 11-to-14-months. Critically, all three groups of infants were tested with continuous audiovisual speech in both their native and another, unfamiliar language. We found that at each age range, infants showed different patterns of cortical activity in response to the native and non-native stimuli. Infants in the youngest group showed bilateral cortical activity that was greater overall in response to non-native relative to native speech; the oldest group showed left lateralized activity in response to native relative to non-native speech. These results highlight perceptual tuning as a dynamic process that happens across modalities and at different levels of stimulus complexity. Brain Sciences 2014-08-11 4 3 Article 10.3390/brainsci4030471 471 487 2076-3425 2014-08-11 doi: 10.3390/brainsci4030471 Eswen Fava Rachel Hull Heather Bortfeld http://www.mdpi.com/2076-3425/4/3/453 Sleep has many important biological functions, but how sleep is regulated remains poorly understood. In humans, social isolation and other stressors early in life can disrupt adult sleep. In fruit flies housed at different population densities during early adulthood, social enrichment was shown to increase subsequent sleep, but it is unknown if population density during early development can also influence adult sleep. To answer this question, we maintained Drosophila larvae at a range of population densities throughout larval development, kept them isolated during early adulthood, and then tested their sleep patterns. Our findings reveal that flies that had been isolated as larvae had more fragmented sleep than those that had been raised at higher population densities. This effect was more prominent in females than in males. Larval population density did not affect sleep in female flies that were mutant for amnesiac, which has been shown to be required for normal memory consolidation, adult sleep regulation, and brain development. In contrast, larval population density effects on sleep persisted in female flies lacking the olfactory receptor or83b, suggesting that olfactory signals are not required for the effects of larval population density on adult sleep. These findings show that population density during early development can alter sleep behavior in adulthood, suggesting that genetic and/or structural changes are induced by this developmental manipulation that persist through metamorphosis. Brain Sciences 2014-08-11 4 3 Article 10.3390/brainsci4030453 453 470 2076-3425 2014-08-11 doi: 10.3390/brainsci4030453 Michael Chi Leslie Griffith Christopher Vecsey http://www.mdpi.com/2076-3425/4/2/428 Rhythm as the time structure of music is composed of distinct temporal components such as pattern, meter, and tempo. Each feature requires different computational processes: meter involves representing repeating cycles of strong and weak beats; pattern involves representing intervals at each local time point which vary in length across segments and are linked hierarchically; and tempo requires representing frequency rates of underlying pulse structures. We explored whether distinct rhythmic elements engage different neural mechanisms by recording brain activity of adult musicians and non-musicians with positron emission tomography (PET) as they made covert same-different discriminations of (a) pairs of rhythmic, monotonic tone sequences representing changes in pattern, tempo, and meter, and (b) pairs of isochronous melodies. Common to pattern, meter, and tempo tasks were focal activities in right, or bilateral, areas of frontal, cingulate, parietal, prefrontal, temporal, and cerebellar cortices. Meter processing alone activated areas in right prefrontal and inferior frontal cortex associated with more cognitive and abstract representations. Pattern processing alone recruited right cortical areas involved in different kinds of auditory processing. Tempo processing alone engaged mechanisms subserving somatosensory and premotor information (e.g., posterior insula, postcentral gyrus). Melody produced activity different from the rhythm conditions (e.g., right anterior insula and various cerebellar areas). These exploratory findings suggest the outlines of some distinct neural components underlying the components of rhythmic structure. Brain Sciences 2014-06-17 4 2 Article 10.3390/brainsci4020428 428 452 2076-3425 2014-06-17 doi: 10.3390/brainsci4020428 Michael Thaut Pietro Trimarchi Lawrence Parsons http://www.mdpi.com/2076-3425/4/2/405 In recent years, musicians have been increasingly recruited to investigate grey and white matter neuroplasticity induced by skill acquisition. The development of Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) has allowed more detailed investigation of white matter connections within the brain, addressing questions about the effect of musical training on connectivity between specific brain regions. Here, current DT-MRI analysis techniques are discussed and the available evidence from DT-MRI studies into differences in white matter architecture between musicians and non-musicians is reviewed. Collectively, the existing literature tends to support the hypothesis that musical training can induce changes in cross-hemispheric connections, with significant differences frequently reported in various regions of the corpus callosum of musicians compared with non-musicians. However, differences found in intra-hemispheric fibres have not always been replicated, while findings regarding the internal capsule and corticospinal tracts appear to be contradictory. There is also recent evidence to suggest that variances in white matter structure in non-musicians may correlate with their ability to learn musical skills, offering an alternative explanation for the structural differences observed between musicians and non-musicians. Considering the inconsistencies in the current literature, possible reasons for conflicting results are offered, along with suggestions for future research in this area. Brain Sciences 2014-06-10 4 2 Review 10.3390/brainsci4020405 405 427 2076-3425 2014-06-10 doi: 10.3390/brainsci4020405 Emma Moore Rebecca Schaefer Mark Bastin Neil Roberts Katie Overy http://www.mdpi.com/2076-3425/4/2/396 Patients with conversion disorder generally suffer from a severe neurological deficit which cannot be attributed to a structural neurological damage. In two patients with acute conversion paraplegia, investigation with functional magnetic resonance imaging (fMRI) showed that the insular cortex, a limbic-related cortex involved in body-representation and subjective emotional experience, was activated not only during attempt to move the paralytic body-parts, but also during mental imagery of their movements. In addition, mental rotation of affected body-parts was found to be disturbed, as compared to unaffected body parts or external objects. fMRI during mental rotation of the paralytic body-part showed an activation of another limbic related region, the anterior cingulate cortex. These data suggest that conversion paraplegia is associated with pathological activity in limbic structures involved in body representation and a deficit in mental processing of the affected body-parts. Brain Sciences 2014-05-20 4 2 Project Report 10.3390/brainsci4020396 396 404 2076-3425 2014-05-20 doi: 10.3390/brainsci4020396 Arnaud Saj Noa Raz Netta Levin Tamir Ben-Hur Shahar Arzy