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1.  Intravenous injection of neural progenitor cells facilitates angiogenesis after cerebral ischemia 
Brain and Behavior  2012;3(2):43-53.
Earlier we demonstrated that the injection of neural progenitor cells (NPCs) has therapeutic potential for the improvement of learning dysfunction after cerebral ischemia. However, it remained to be clarified how transplantation of NPCs can improve ischemia-induced dysfunction. In this study, we examined whether intravenous injection of NPCs after cerebral ischemia could enhance angiogenesis by affecting the expression of angiogenic factors. The injection of NPCs on day 7 after cerebral ischemia enhanced angiogenesis on day 28. Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 were increased in expression by the NPC injection. The level of angiopoietin-1 (Ang-1), an angiogenic factor, but not that of Ang-2, which acts as an antagonist for the Ang-1 receptor, was also increased on day 28. In addition, the expression of Ang-1 receptor Tie2 was enhanced in brain capillaries. Furthermore, the amounts of tight junctional proteins, which are in the blood–brain barrier and whose expression occurs downstream of Ang-1/Tie2 signaling, were increased by the NPC injection. These results suggest that the NPC injection promoted angiogenesis through Ang-1/Tie2 and/or VEGF/VEGFR2 signaling in brain capillaries after cerebral ischemia. Such signaling might have the potential for causing vascular stabilization and maturation for a long period after cerebral ischemia.
doi:10.1002/brb3.113
PMCID: PMC3607146  PMID: 23532762
Angiopoietin; cerebral ischemia; neural progenitor cells; tight junctional protein; VEGF
2.  High-resolution MRI of basilar atherosclerosis: three-dimensional acquisition and FLAIR sequences 
Brain and Behavior  2012;3(1):1-3.
This case report describes the use of high-resolution magnetic resonance imaging (HRMRI) to visualize basilar artery atherosclerotic plaque in a patient with a pontine stroke. HRMRI with three-dimensional image acquisition was used to visualize plaque in several planes to localize arterial wall pathology. Fluid attenuated inversion recovery (FLAIR) sequences of the basilar artery showed wall thickening throughout the basilar artery wall and good contrast between the artery wall and cerebrospinal fluid.
doi:10.1002/brb3.103
PMCID: PMC3568782  PMID: 23408667
Basilar artery; cerebral infarction; intracranial atherosclerosis; magnetic resonance imaging; plaque; pontine stroke
3.  Comparative study of environmental factors influencing motor task learning and memory retention in sighted and blind crayfish 
Brain and Behavior  2012;3(1):4-13.
In classical conditioning, an alteration in response occurs when two stimuli are regularly paired in close succession. An area of particular research interest is classical conditioning with a chemical signal and visual and/or tactile stimuli as the unconditional stimuli, to test manipulative and motor behaviors in a learning paradigm. A classical learning task chamber was developed to examine learning trends in a sighted surface-dwelling crayfish, Procambarus clarkii, and in a blind cave-dwelling crayfish, Orconectes australis packardi. We examined whether learning is influenced by environmental factors and/or reliance on different primary sensory modalities. Crayfish were trained to manipulate a large, cumbersome cheliped through a small access point to obtain a food reward. In both species, acquisition of the learning task was rapid when they were in nonstressed conditions. The blind crayfish tested in low white light did not successfully complete the task, suggesting a stress response.
doi:10.1002/brb3.106
PMCID: PMC3568783  PMID: 23408733
Cardiac; central nervous system; crustaceans; instrumental; respiratory
4.  Social exclusion, infant behavior, social isolation, and maternal expectations independently predict maternal depressive symptoms 
Brain and Behavior  2012;3(1):14-23.
The objective of the study was to identify latent variables that can be used to inform theoretical models of perinatal influences on postnatal depressed mood and maternal–infant attachment. A routine survey of mothers with newborn infants was commenced in South Western Sydney in 2000. The survey included the Edinburgh Postnatal Depression Scale (EPDS) and 46 psychosocial and health-related variables. Mothers (n = 15,389) delivering in 2002 and 2003 were surveyed at 2–3 weeks for depressive symptoms. Nonlinear principal components analysis was undertaken to identify dimensions that might represent latent variables. Correlations between latent variables and EPDS >12 were assessed by logistic regression. A five-dimension solution was identified, which accounted for 51% of the variance among the items studied. The five dimensions identified were maternal responsiveness, social exclusion, infant behavior, migrant social isolation, and family size. In addition, the variable maternal expectation contributed significantly to total variance and was included in the regression analysis. Regression on EPDS >12 was predictive for all variables except for maternal responsiveness, which was considered an outcome variable. The findings are consistent with the proposition that social exclusion, infant behavior, social isolation among migrant mothers, and maternal expectations are determinants of maternal mood.
doi:10.1002/brb3.107
PMCID: PMC3568785  PMID: 23408743
Immigrants; postpartum depression; social isolation; social support; temperament
5.  Sensory deprivation during early development causes an increased exploratory behavior in a whisker-dependent decision task 
Brain and Behavior  2012;3(1):24-34.
Stimulation of sensory pathways is important for the normal development of cortical sensory areas, and impairments in the normal development can have long-lasting effect on animal's behavior. In particular, disturbances that occur early in development can cause permanent changes in brain structure and function. The behavioral effect of early sensory deprivation was studied in the mouse whisker system using a protocol to induce a 1-week sensory deprivation immediately after birth. Only two rows of whiskers were spared (C and D rows), and the rest were deprived, to create a situation where an unbalanced sensory input, rather than a complete loss of input, causes a reorganization of the sensory map. Sensory deprivation increased the barrel size ratio of the spared CD rows compared with the deprived AB rows; thus, the map reorganization is likely due, at least in part, to a rewiring of thalamocortical projections. The behavioral effect of such a map reorganization was investigated in the gap-crossing task, where the animals used a whisker that was spared during the sensory deprivation. Animals that had been sensory deprived performed equally well with the control animals in the gap-crossing task, but were more active in exploring the gap area and consequently made more approaches to the gap – approaches that on average were of shorter duration. A restricted sensory deprivation of only some whiskers, although it does not seem to affect the overall performance of the animals, does have an effect on their behavioral strategy on executing the gap-crossing task.
doi:10.1002/brb3.102
PMCID: PMC3568787  PMID: 23408764
Barrel cortex; development; gap-cross; sensory deprivation; whisker tracking
6.  Development of sensory neuropathy in streptozotocin-induced diabetic mice 
Brain and Behavior  2012;3(1):35-41.
Diabetic polyneuropathy is a major complication of diabetes and the most common cause of peripheral neuropathy. Sensory-dominant neuropathy is the most common type. We previously used streptozotocin (STZ)-induced diabetic ddY mice with sensory neuropathy to evaluate the therapeutic effects of vascular endothelial growth factor and placental growth factor isoforms. In this study, to characterize the development of diabetic sensory neuropathy, electrophysiological, behavioral, and histopathological studies were performed in these diabetic mice. A significant difference in sensory conduction velocity in the tail nerve was observed between healthy and diabetic mice at 1 week after STZ injection. Diabetic mice developed hypoalgesia at 5 weeks after STZ injection. Axon area and myelin thickness of the myelinated fibers were increased in 17-week-old healthy mice compared with those in 8-week-old healthy mice. However, these increases were retarded in 17-week-old diabetic mice. In unmyelinated fibers, axon area was significantly reduced in 17-week-old diabetic mice compared with 8- and 17-week-old healthy mice. These findings suggest that both impaired maturation of myelinated fibers and atrophy of unmyelinated fibers simultaneously occur in the early stage of diabetes in these mice. Our mouse model may be useful for studying the pathogenesis of and therapies for diabetic sensory neuropathy.
doi:10.1002/brb3.111
PMCID: PMC3568788  PMID: 23407314
Diabetic sensory neuropathy; impaired maturation; sensory conduction velocity; STZ-induced diabetic mice; unmyelinated fiber atrophy
7.  The effects of linguistic relationships among paired associates on verbal self-generation and recognition memory 
Brain and Behavior  2012;2(6):789-795.
Previous studies have shown that self-generated information is better remembered than information that has been read passively. To further examine this subsequent memory effect, we investigated the effect of five different linguistic relationships on memory encoding. Ninety subjects were administered 60 paired associates during an encoding condition: 30 of the second words from each pair were to be read aloud and 30 were to be self-generated from clues as to the correct word. Word pairs were composed of five linguistic relationships: category, rhyme, opposite, synonym, and association. Subsequently, subjects were presented with the words that were read or generated in a forced recognition memory task. Overall, reading accuracy was higher than generation accuracy during the encoding phase (all P < 0.001). During the recognition phase, subjects' performance was better on the generate than on the read conditions for opposite, synonym, category, and association relationships (all P < 0.05), with no difference in the rhyme relationship. These results confirm previous findings that self-generated information is better remembered than read information and suggest that this advantage may be mediated by using opposite, synonym, category, and association relationships, while rhyme relationship may not extend such an advantage. These findings may have implications for future studies of memory interventions in healthy controls and subjects with cognitive impairments.
doi:10.1002/brb3.98
PMCID: PMC3500465  PMID: 23170241
Encoding; recognition memory; self-generation; word associations; word pairs
8.  Issue Information 
Brain and Behavior  2012;2(6):i.
doi:10.1002/brb3.108
PMCID: PMC3500457  PMID: 23170247
9.  Cellular basis for singing motor pattern generation in the field cricket (Gryllus bimaculatus DeGeer) 
Brain and Behavior  2012;2(6):707-725.
The singing behavior of male crickets allows analyzing a central pattern generator (CPG) that was shaped by sexual selection for reliable production of species-specific communication signals. After localizing the essential ganglia for singing in Gryllus bimaculatus, we now studied the calling song CPG at the cellular level. Fictive singing was initiated by pharmacological brain stimulation. The motor pattern underlying syllables and chirps was recorded as alternating spike bursts of wing-opener and wing-closer motoneurons in a truncated wing nerve; it precisely reflected the natural calling song. During fictive singing, we intracellularly recorded and stained interneurons in thoracic and abdominal ganglia and tested their impact on the song pattern by intracellular current injections. We identified three interneurons of the metathoracic and first unfused abdominal ganglion that rhythmically de- and hyperpolarized in phase with the syllable pattern and spiked strictly before the wing-opener motoneurons. Depolarizing current injection in two of these opener interneurons caused additional rhythmic singing activity, which reliably reset the ongoing chirp rhythm. The closely intermeshing arborizations of the singing interneurons revealed the dorsal midline neuropiles of the metathoracic and three most anterior abdominal neuromeres as the anatomical location of singing pattern generation. In the same neuropiles, we also recorded several closer interneurons that rhythmically hyper- and depolarized in the syllable rhythm and spiked strictly before the wing-closer motoneurons. Some of them received pronounced inhibition at the beginning of each chirp. Hyperpolarizing current injection in the dendrite revealed postinhibitory rebound depolarization as one functional mechanism of central pattern generation in singing crickets.
doi:10.1002/brb3.89
PMCID: PMC3500458  PMID: 23170234
Acoustic communication; central pattern generator; identified interneuron; insect; species-specific motor pattern; stridulation
10.  BDNF Val66Met polymorphism interacts with sex to influence bimanual motor control in healthy humans 
Brain and Behavior  2012;2(6):726-731.
Brain-derived neurotrophic factor (BDNF) plays a critical role in brain development. A common single nucleotide polymorphism in the gene encoding BDNF (rs6265, Val66Met) affects BDNF release and has been associated with altered learning and memory performance, and with structural changes in brain morphology and corpus callosum integrity. BDNF Val66Met has more recently been shown to influence motor learning and performance. Some of the BDNF effects seem to be modulated by an individual's sex, but currently the relationship between BDNF and sex in the motor domain remains elusive. Here, we investigate the relationship between BDNF Val66Met genotype and an individual's sex in the motor system. Seventy-six healthy, previously genotyped, individuals performed a task in which the participant drew lines at different angles of varying difficulty. Subjects controlled the horizontal and vertical movement of the line on a computer screen by rotating two cylinders. We used this bimanual motor control task to measure contributions from both current motor function and the pre-existing interhemispheric connectivity. We report that BDNF genotype interacts with sex to influence the motor performance of healthy participants in this bimanual motor control task. We further report that the BDNF genotype by sex interaction was present in the more difficult trials only, which is in line with earlier findings that genetic effects may become apparent only when a system is challenged. Our results emphasize the importance of taking sex into account when investigating the role of BDNF genotype in the motor system.
doi:10.1002/brb3.83
PMCID: PMC3500459  PMID: 23170235
BDNF; bimanual; genetics; motor; Preilowski's task; rs6265; single nucleotide polymorphism; Val66Met
11.  Overexpression of cyclic GMP-dependent protein kinase reduces MeCP2 and HDAC2 expression 
Brain and Behavior  2012;2(6):732-740.
Nitric oxide (NO) and the C-type natriuretic peptide (CNP) exert their action via stimulation of the cyclic GMP (cGMP)-signaling pathway, which includes the activation of cGMP-dependent protein kinases (PKG). The present report shows that the activation of PKG by local application of 8-bromo-cGMP in the caudate–putamen reduced the expression of the epigenetic markers, methyl-CpG-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2), in dopaminergic projection areas of cocaine-treated rats. An effect of lesser amplitude was observed when rats were not injected with cocaine. We also studied the effect of PKG overexpression by injecting a plasmid vector containing the human PKG-Iα cDNA in either the caudate–putamen or the ventral tegmental area. Injection in the caudate–putamen reduced the epigenetic parameters with higher amplitude than the cGMP analog. The effect was abolished by the injection of a selective PKG inhibitor, confirming that it was due to PKG-dependent phosphorylation. As MeCP2 and HDAC2 modulate dynamic functions in the adult brain such as memory formation and synaptic plasticity, the downregulation of expression by PKG suggests that the cGMP pathway affects cognitive processes through a mechanism that comprises the MeCP2/HDAC2 complex and the subsequent control of gene silencing.
doi:10.1002/brb3.92
PMCID: PMC3500460  PMID: 23170236
cGMP-dependent protein kinase; cocaine; cyclic GMP; DNA methylation; histone deacetylase; methyl-CpG-binding protein MeCP2
12.  Effects of motivation on reward and attentional networks: an fMRI study 
Brain and Behavior  2012;2(6):741-753.
Existing evidence suggests that reward and attentional networks function in concert and that activation in one system influences the other in a reciprocal fashion; however, the nature of these influences remains poorly understood. We therefore developed a three-component task to assess the interaction effects of reward anticipation and conflict resolution on the behavioral performance and the activation of brain reward and attentional systems. Sixteen healthy adult volunteers aged 21–45 years were scanned with functional magnetic resonance imaging (fMRI) while performing the task. A two-way repeated measures analysis of variance (ANOVA) with cue (reward vs. non-reward) and target (congruent vs. incongruent) as within-subjects factors was used to test for main and interaction effects. Neural responses to anticipation, conflict, and reward outcomes were tested. Behaviorally there were main effects of both reward cue and target congruency on reaction time. Neuroimaging results showed that reward anticipation and expected reward outcomes activated components of the attentional networks, including the inferior parietal and occipital cortices, whereas surprising non-rewards activated the frontoinsular cortex bilaterally and deactivated the ventral striatum. In turn, conflict activated a broad network associated with cognitive control and motor functions. Interaction effects showed decreased activity in the thalamus, anterior cingulated gyrus, and middle frontal gyrus bilaterally when difficult conflict trials (e.g., incongruent targets) were preceded by reward cues; in contrast, the ventral striatum and orbitofrontal cortex showed greater activation during congruent targets preceded by reward cues. These results suggest that reward anticipation is associated with lower activation in attentional networks, possibly due to increased processing efficiency, whereas more difficult, conflict trials are associated with lower activity in regions of the reward system, possibly because such trials are experienced as less rewarding.
doi:10.1002/brb3.80
PMCID: PMC3500461  PMID: 23170237
Attention; brain reward system; fMRI; motivation; neuroimaging; neuroscience
13.  Age- and disease-related features of task-related brain oscillations by using mutual information 
Brain and Behavior  2012;2(6):754-762.
The aim of this study was to investigate changes in task-related brain oscillations and corticocortical connections in patients with mild cognitive impairment (MCI) and those with normal aging using cross-mutual information (CMI) analysis. We hypothesized that task-related brain oscillations and corticocortical connections were affected by age- and disease-related changes, which could be reflected in the CMI analysis. Electroencephalogram (EEG) recordings were measured in 16 MCI patients, 15 healthy age-matched controls, and 16 healthy younger individuals. The frequencies and interhemispheric CMI data were estimated in all groups. The specific EEG rhythms measured were delta (δ), theta (θ), alpha (α), beta (β), and gamma (γ) bands. Significant differences in δ, θ, α, and β bands were observed between the younger and elderly groups. However, only the θ band was significantly different between the elderly and MCI groups. Moreover, this study used EEG recordings to investigate age- and disease-related changes in the corticocortical connections of the brain. This study proves that the θ-band frequency of the connection between the parietal and occipital lobes for the age- and disease-related changes can be depicted using the CMI analysis.
doi:10.1002/brb3.93
PMCID: PMC3500462  PMID: 23170238
Aging; cross-mutual information; electroencephalogram; mild cognitive impairment; theta band
14.  Two critical periods in early visual cortex during figure–ground segregation 
Brain and Behavior  2012;2(6):763-777.
The ability to distinguish a figure from its background is crucial for visual perception. To date, it remains unresolved where and how in the visual system different stages of figure–ground segregation emerge. Neural correlates of figure border detection have consistently been found in early visual cortex (V1/V2). However, areas V1/V2 have also been frequently associated with later stages of figure–ground segregation (such as border ownership or surface segregation). To causally link activity in early visual cortex to different stages of figure–ground segregation, we briefly disrupted activity in areas V1/V2 at various moments in time using transcranial magnetic stimulation (TMS). Prior to stimulation we presented stimuli that made it possible to differentiate between figure border detection and surface segregation. We concurrently recorded electroencephalographic (EEG) signals to examine how neural correlates of figure–ground segregation were affected by TMS. Results show that disruption of V1/V2 in an early time window (96–119 msec) affected detection of figure stimuli and affected neural correlates of figure border detection, border ownership, and surface segregation. TMS applied in a relatively late time window (236–259 msec) selectively deteriorated performance associated with surface segregation. We conclude that areas V1/V2 are not only essential in an early stage of figure–ground segregation when figure borders are detected, but subsequently causally contribute to more sophisticated stages of figure–ground segregation such as surface segregation.
doi:10.1002/brb3.91
PMCID: PMC3500463  PMID: 23170239
EEG; scene segmentation; TMS; V1/V2; visual perception
15.  The functional epistasis of 5-HTTLPR and BDNF Val66Met on emotion processing: a preliminary study 
Brain and Behavior  2012;2(6):778-788.
An epistatic interaction of 5-HTTLPR and BDNF Val66Met polymorphisms has been implicated in the structure of rostral anterior cingulate cortex (rACC) and amygdala (AMY): key regions associated with emotion processing. However, a functional epistasis of 5-HTTLPR and BDNF Val66Met on overt emotion processing has yet to be determined. Twenty-eight healthy, Caucasian female participants provided saliva samples for genotyping and underwent functional magnetic resonance imaging (fMRI) during which an emotion processing protocol were presented. Confirming the validity of this protocol, we observed blood oxygen level–dependent (BOLD) activity consistent with fMRI meta-analyses on emotion processing. Region-of-interest analysis of the rACC and AMY revealed main effects of 5-HTTLPR and BDNF Val66Met, and an interaction of 5-HTTLPR and BDNF Val66Met. The effect of the BDNF Met66 allele was dependent on 5-HTTLPR alleles, such that participants with S and Met alleles had the greatest rACC and AMY activation during the presentation of emotional images relative to other genetic groupings. Increased activity in these regions was interpreted as increased reactivity to emotional stimuli, suggesting that those with S and Met alleles are more reactive to emotional stimuli relative to other groups. Although limited by a small sample, this study contributes novel and preliminary findings relating to a functional epistasis of the 5-HTTLPR and BDNF Val66Met genes in emotion processing and provides guidance on appropriate methods to determine genetic epistasis in fMRI.
doi:10.1002/brb3.99
PMCID: PMC3500464  PMID: 23170240
5-HTTLPR; BDNF Val66Met; emotion processing; epistasis; fMRI; healthy subjects
16.  Theta event-related synchronization is a biomarker for a morbid effect of alcoholism on the brain that may partially resolve with extended abstinence 
Brain and Behavior  2012;2(6):796-805.
Analyzing the induced (non-stimulus-phase-locked) EEG activity elicited by targets in a three-condition visual oddball task, Fein and colleagues have shown increased theta band event-related synchronization (ERS) in two different samples of long-term abstinent alcoholics (LTAA) compared with age- and gender-comparable controls. The theta ERS effect in alcoholics was also shown to be independent of, and opposite in direction to, the reduced amplitude evoked (stimulus-phase-locked) activity typically found in alcoholics and those at genetic risk of developing alcoholism. This study extends these findings by applying time-frequency analysis to target stimulus event-related EEG to compare evoked and induced theta activity in 43 LTAA and 72 nonalcoholic controls with a group of 31 alcoholics who just recently initiated abstinence from alcohol (between 6- and 15-week abstinent; referred to as short-term abstinent alcoholics, STAA). Results demonstrated that (1) evoked theta power was reduced to the same degree in STAA and LTAA compared with nonalcoholic control participants, while (2) induced theta activity, measured by theta ERS, was increased in both STAA and LTAA relative to controls, but was also increased in STAA relative to LTAA. The STAA and LTAA groups did not differ on measures of alcohol use severity or family history of alcohol problems. These results, coupled with previous findings that show a relationship between stronger theta ERS and increased memory load and attention allocation, suggest that increased theta ERS may be a biomarker for a detrimental effect of chronic alcohol abuse on the brain – a detriment that may recover, at least partially, with extended abstinence.
doi:10.1002/brb3.95
PMCID: PMC3500466  PMID: 23170242
Abstinent; alcoholism; biomarker; EEG; event-related synchronization; theta; time-frequency
17.  The effects of MAOA genotype, childhood trauma, and sex on trait and state-dependent aggression 
Brain and Behavior  2012;2(6):806-813.
Monoamine oxidase A (MAOA) genotypic variation has been associated with variation in aggression, especially in interaction with childhood trauma or other early adverse events. Male carriers of the low-expressing variant (MAOA-L) with childhood trauma or other early adverse events seem to be more aggressive, whereas female carriers with the high-expressing variant (MAOA-H) with childhood trauma or other early adverse events may be more aggressive. We further investigated the effects of MAOA genotype and its interaction with sex and childhood trauma or other early adverse events on aggression in a young adult sample. We hypothesized that the association between genotype, childhood trauma, and aggression would be different for men and women. We also explored whether this association is different for dispositional (trait) aggression versus aggression in the context of dysphoric mood. In all, 432 Western European students (332 women, 100 men; mean age 20.2) were genotyped for the MAOA gene. They completed measures of childhood trauma, state and trait measures of aggression-related behaviors (STAXI), and cognitive reactivity to sad mood (LEIDS-R), including aggression reactivity. Women with the MAOA-H had higher aggression reactivity scores than women with the MAOA-L. This effect was not observed in men, although the nonsignificant findings in men may be a result of low power. Effects on the STAXI were not observed, nor were there gene by environment interactions on any of the aggression measures. A protective effect of the low-expression variant in women on aggression reactivity is consistent with previous observations in adolescent girls. In females, the MAOA-H may predispose to aggression-related problems during sad mood.
doi:10.1002/brb3.96
PMCID: PMC3500467  PMID: 23170243
Aggression; cognitive reactivity; depression; MAOA; sex; trauma
18.  Open label, randomized, crossover pilot trial of high-resolution, relational, resonance-based, electroencephalic mirroring to relieve insomnia 
Brain and Behavior  2012;2(6):814-824.
Effective noninvasive interventions for insomnia are needed. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM™) is a noninvasive, electroencephalography (EEG)-based method to facilitate greater client-unique, autocalibrated improvements of balance and harmony in cortical neural oscillations. This study explores using HIRREM for insomnia. Twenty subjects, with an Insomnia Severity Index (ISI) score of ≥15 (14 women, mean age 45.4, mean ISI 18.6), were enrolled in this randomized, unblinded, wait-list control, crossover, superiority study. Subjects were randomized to receive 8–12 HIRREM sessions over 3 weeks, plus usual care (HUC), or usual care alone (UC). Pre- and post-HIRREM data collection included ISI (primary outcome), and many secondary, exploratory measures (CES-D, SF-36, HR, BP, neurocognitive testing, and VAS scales). The UC group later crossed over to receive HIRREM. ISI was also repeated 4–6 weeks post-HIRREM. All subjects completed the primary intervention period. Analysis for differential change of ISI in the initial intervention period for HUC versus UC showed a drop of 10.3 points (95% CI: −13.7 to −6.9, P < 0.0001, standardized effect size of 2.68). Key secondary outcomes included statistically identical differential change for the crossed-over UC group, and persistence of the effect on the ISI up to > 4 weeks post-HIRREM. Differential change in the HUC group was also statistically significant for CES-D (−8.8, 95% CI: −17.5 to −0.1, P = 0.047), but other exploratory outcomes were not statistically significant. For all receiving HIRREM (n = 19), decreased high-frequency total power was seen in the bilateral temporal lobes. No adverse events were seen. This pilot clinical trial, the first using HIRREM as an intervention, suggests that HIRREM is feasible and effective for individuals having moderate-to-severe insomnia, with clinically relevant, statistically significant benefits based on differential change in the ISI. Effects persisted for 4 weeks after completion of HIRREM. Larger controlled clinical trials are warranted.
doi:10.1002/brb3.101
PMCID: PMC3500468  PMID: 23170244
Biofeedback; EEG; HIRREM; insomnia; neural oscillations
19.  Functional near-infrared spectroscopy for the assessment of overt reading 
Brain and Behavior  2012;2(6):825-837.
Functional near-infrared spectroscopy (fNIRS) has become increasingly established as a promising technique for monitoring functional brain activity. To our knowledge, no study has yet used fNIRS to investigate overt reading of irregular words and nonwords with a full coverage of the cerebral regions involved in reading processes. The aim of our study was to design and validate a protocol using fNIRS for the assessment of overt reading. Twelve healthy French-speaking adults underwent one session of fNIRS recording while performing an overt reading of 13 blocks of irregular words and nonwords. Reading blocks were separated by baseline periods during which participants were instructed to fixate a cross. Sources (n = 55) and detectors (n = 16) were placed bilaterally over frontal, temporal, parietal, and occipital regions. Two wavelengths were used: 690 nm, more sensitive to deoxyhemoglobin (HbR) concentration changes, and 830 nm, more sensitive to oxyhemoglobin (HbO) concentration changes. For all participants, total hemoglobin (HbT) concentrations (HbO + HbR) were significantly higher than baseline for both irregular word and nonword reading in the inferior frontal gyri, the middle and superior temporal gyri, and the occipital cortices bilaterally. In the temporal gyri, although the difference was not significant, [HbT] values were higher in the left hemisphere. In the bilateral inferior frontal gyri, higher [HbT] values were found in nonword than in irregular word reading. This activation could be related to the grapheme-to-phoneme conversion characterizing the phonological pathway of reading. Our findings confirm that fNIRS is an appropriate technique to assess the neural correlates of overt reading.
doi:10.1002/brb3.100
PMCID: PMC3500469  PMID: 23170245
Adults; irregular words; lexical reading; nonwords; optical imaging; phonological reading; reading aloud
20.  Isolated CNS Whipple disease with normal brain MRI and false-positive CSF 14-3-3 protein: a case report and review of the literature 
Brain and Behavior  2012;2(6):838-843.
Whipple disease (WD) is usually a systemic infectious disease that can have central nervous system (CNS) involvement. WD confined to the CNS is extremely rare and difficult to diagnose, but can be fatal if not treated in a timely fashion. We present the case of a 42-year-old man with a subacute dementia accompanied by a movement disorder consisting of progressive supranuclear gaze palsy, myoclonus, and ataxia. Our patient lacked the typical magnetic resonance imaging (MRI) findings reported with isolated CNS WD and had a false-positive cerebrospinal fluid (CSF) 14-3-3 protein. The patient expired, and definitive diagnosis of isolated CNS WD was made by autopsy with characteristic macrophage accumulations found in the brain but not in the gastrointestinal tract. We examine the literature on isolated CNS WD and discuss how these previously unreported findings make a rare diagnosis even more challenging. The reported patient is the first in the literature with tissue diagnosis of isolated CNS WD in the setting of normal brain MRI and positive CSF 14-3-3 protein. Isolated CNS WD should be added to the list of considerations for a false-positive CSF 14-3-3 protein. Even in the absence of typical MRI lesions, a patient with subacute progressive dementia, supranuclear gaze palsy, and other various neurologic abnormalities should have the diagnosis of isolated CNS WD considered.
doi:10.1002/brb3.97
PMCID: PMC3500470  PMID: 23170246
Infectious disease; MRI; neuroimaging; neurology; Whipple disease
21.  Issue Information 
Brain and Behavior  2012;2(5):i.
doi:10.1002/brb3.94
PMCID: PMC3489804  PMID: 23139914
22.  Gene expression profiles associated with depression in patients with chronic hepatitis C (CH-C) 
Brain and Behavior  2012;2(5):525-531.
The standard treatment for CH-C, pegylated interferon-α and ribavirin (PEG-IFN + RBV), is associated with depression. Recent studies have proposed a new role for cytokines in the pathogenesis of depression. We aimed to assess differential gene expression related to depression in CH-C patients treated with PEG-IFN + RBV. We included 67 CH-C patients being treated with PEG-IFN+RBV. Of the entire study cohort, 22% had pre-existing depression, while another 37% developed new depression in course of the treatment. Pretreatment blood samples were collected into PAXgene™ RNA tubes, the RNAs extracted from peripheral blood mononuclear cells (PBMCs) were used for one step RT-PCR to profile 160 mRNAs. Differentially expressed genes were separated into up- and down-regulated genes according to presence or absence of depression at baseline (pre-existing depression) or following the initiation of treatment (treatment-related depression). The mRNA expression profile associated with any depression and with treatment-related depression included four and six genes, respectively. Our data demonstrate a significant down-regulation of TGF-β1 and the shift of Th1-Th2 cytokine balance in the depression associated with IFN-based treatment of HCV infection. We propose that TGF-β1 plays an important role in the imbalance of Th1/Th2 in patients with CH-C and depression. With further validation, TGF-β1 and other components of Th1/Th2 regulation pathway may provide a future marker for CH-C patients predisposed to depression.
doi:10.1002/brb3.72
PMCID: PMC3489805  PMID: 23139898
Depression; hepatitis C; interferon; ribavirin; TGFβ1; Th1/Th2 cytokines; treatment
23.  The effects of acute responsive high frequency stimulation of the subiculum on the intra-hippocampal kainic acid seizure model in rats 
Brain and Behavior  2012;2(5):532-540.
The effects of acute responsive high frequency stimulation (HFS) to the subiculum on seizures and interictal spikes were investigated in a semi-acute kainic acid (KA) induced seizure model in rats. Wistar rats (n = 15) were implanted with an electrode-cannula complex in the CA3 area, stimulation and recording electrodes in the subiculum and another recording electrode at the contralateral motor cortex. Two weeks later rats were injected repeatedly with KA (0.05 μg/0.1 μL) for 3 days with an interval of 48 h. HFS (125 Hz, 100 μsec) was delivered to the subiculum at a predetermined intensity range (100–500 μA) in the HFS group (n = 7) when seizures were visually detected, while no stimulation was delivered in the sham control group (n = 8). Various severities of seizures were obtained (Stage I–V) and all rats of both groups reached Stage V (Racine's scale) on Day 1. The HFS group had less focal seizures and a longer inter-focal seizure interval on Day 1. Interictal spike rate was also lower in the HFS group and decreased with injection days. Significant day effects were found for the latency, number of focal seizures, and duration of focal seizures and generalized seizures while differences between groups were no longer present. Responsive HFS did not disrupt ongoing seizures. However, focal seizures and interictal spikes were suppressed by HFS. Such anticonvulsant effects of acute subicular stimulation indicate that the subiculum is involved in seizure generation. The reduction of seizure sensitivity over the injection day reflects an intrinsic anticonvulsant mechanism.
doi:10.1002/brb3.70
PMCID: PMC3489806  PMID: 23139899
High frequency stimulation; responsive; stimulation; subiculum; temporal lobe epilepsy
24.  Characterization of recovered walking patterns and motor control after contusive spinal cord injury in rats 
Brain and Behavior  2012;2(5):541-552.
Currently, complete recovery is unattainable for most individuals with spinal cord injury (SCI). Instead, recovery is typically accompanied by persistent sensory and motor deficits. Restoration of preinjury function will likely depend on improving plasticity and integration of these impaired systems. Eccentric muscle actions require precise integration of sensorimotor signals and are predominant during the yield (E2) phase of locomotion. Motor neuron activation and control during eccentric contractions is impaired across a number of central nervous system (CNS) disorders, but remains unexamined after SCI. Therefore, we characterized locomotor recovery after contusive SCI using hindlimb (HL) kinematics and electromyographic (EMG) recordings with specific consideration of eccentric phases of treadmill (TM) walking. Deficits in E2 and a caudal shift of locomotor subphases persisted throughout the 3-week recovery period. EMG records showed notable deficits in the semitendinosus (ST) during yield. Unlike other HL muscles, recruitment of ST changed with recovery. At 7 days, the typical dual-burst pattern of ST was lost and the second burst (ST2) was indistinct. By 21 days, the dual-burst pattern returned, but latencies remained impaired. We show that ST2 burst duration is highly predictive of open field Basso, Beattie, Bresnahan (BBB) scores. Moreover, we found that simple changes in locomotor specificity which enhance eccentric actions result in new motor patterns after SCI. Our findings identify a caudal shift in stepping kinematics, irregularities in E2, and aberrant ST2 bursting as markers of incomplete recovery. These residual impairments may provide opportunities for targeted rehabilitation.
doi:10.1002/brb3.71
PMCID: PMC3489807  PMID: 23139900
Kinematics; locomotion; rehabilitation; spinal cord injury
25.  The association between cingulate cortex glutamate concentration and delay discounting is mediated by resting state functional connectivity 
Brain and Behavior  2012;2(5):553-562.
Humans vary in their ability to delay gratification and impulsive decision making is a common feature in various psychiatric disorders. The level of delay discounting is a relatively stable psychological trait, and therefore neural processes implicated in delay discounting are likely to be based on the overall functional organization of the brain (under task-free conditions) in which state-dependent shifts from baseline levels occur. The current study investigated whether delay discounting can be predicted by intrinsic properties of brain functioning. Fourteen healthy male subjects performed a delay discounting task. In addition, resting state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (¹H MRS) were used to investigate the relationship between individual differences in delay discounting and molecular and regional measures of resting state (baseline) activity of dorsal anterior cingulate cortex (dACC). Results showed that delay discounting was associated with both dACC glutamate concentrations and resting state functional connectivity of the dACC with a midbrain region including ventral tegmental area and substantia nigra. In addition, a neural pathway was established, showing that the effect of glutamate concentrations in the dACC on delay discounting is mediated by functional connectivity of the dACC with the midbrain. The current findings are important to acknowledge because spontaneous intrinsic brain processes have been proposed to be a potential promising biomarker of disease and impulsive decision making is associated with several psychiatric disorders.
doi:10.1002/brb3.74
PMCID: PMC3489808  PMID: 23139901
Anterior cingulate cortex; delay discounting; glutamate; impulsive decision making; magnetic resonance spectroscopy; resting state fMRI

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