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1.  Issue Information 
Brain and Behavior  2014;4(3):i-iii.
doi:10.1002/brb3.166
PMCID: PMC4055182  PMID: 24944874
2.  Characterization of NO-producing neurons in the rat corpus callosum 
Brain and Behavior  2014;4(3):317-336.
Introduction
The aim of this study was to determine the presence and distribution of nitric oxide (NO)-producing neurons in the rat corpus callosum (cc).
Material and methods
To investigate this aspect of cc organization we used nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and neuronal NO synthase (nNOS) immunocytochemistry.
Results
Intense NADPH-d-positive (NADPH-d+) neurons were found along the rostrocaudal extension of the cc (sagittal sections). They were more numerous in the lateral cc and gradually decreased in the more medial regions, where they were very few or absent. The Golgi-like appearance of NADPH-d+ intracallosal neurons allowed dividing them into five morphological types: (1) bipolar; (2) fusiform; (3) round; (4) polygonal; and (5) pyramidal. The number of NADPH-d+ neurons (both hemispheres) was counted in two brains using 50-μm thick sections. In the first brain, counts involved 145 sections and neurons were 2959; in the second, 2227 neurons were counted in 130 sections. The distribution and morphology of nNOS-immunopositive (nNOSIP) neurons was identical to that of NADPH-d+neurons. Some of these neurons were observed in the cc ependymal region, where they might be in contact with cerebrospinal fluid (CSF), monitoring its composition, pH, and osmolality changes, or playing a role in regulating the synthesis and release of several peptides. The somatic, dendritic, and axonal processes of many NADPH-d+/nNOSIP neurons were closely associated with intracallosal blood vessels.
Conclusions
Such close relationship raises the possibility that these neurons are a major source of NO during neural activity. As NO is a potent vasodilator, these findings strongly suggest that NO-positive neurons transduce neuronal signals into vascular responses in selected cc regions, thus giving rise to hemodynamic changes detectable by neuroimaging.
doi:10.1002/brb3.218
PMCID: PMC4055183  PMID: 24944862
Colocalization; GFAP; immunocytochemistry; NADPH-d; nitric oxide; nNOS
3.  BOLD signal and functional connectivity associated with loving kindness meditation 
Brain and Behavior  2014;4(3):337-347.
Loving kindness is a form of meditation involving directed well-wishing, typically supported by the silent repetition of phrases such as “may all beings be happy,” to foster a feeling of selfless love. Here we used functional magnetic resonance imaging to assess the neural substrate of loving kindness meditation in experienced meditators and novices. We first assessed group differences in blood oxygen level-dependent (BOLD) signal during loving kindness meditation. We next used a relatively novel approach, the intrinsic connectivity distribution of functional connectivity, to identify regions that differ in intrinsic connectivity between groups, and then used a data-driven approach to seed-based connectivity analysis to identify which connections differ between groups. Our findings suggest group differences in brain regions involved in self-related processing and mind wandering, emotional processing, inner speech, and memory. Meditators showed overall reduced BOLD signal and intrinsic connectivity during loving kindness as compared to novices, more specifically in the posterior cingulate cortex/precuneus (PCC/PCu), a finding that is consistent with our prior work and other recent neuroimaging studies of meditation. Furthermore, meditators showed greater functional connectivity during loving kindness between the PCC/PCu and the left inferior frontal gyrus, whereas novices showed greater functional connectivity during loving kindness between the PCC/PCu and other cortical midline regions of the default mode network, the bilateral posterior insula lobe, and the bilateral parahippocampus/hippocampus. These novel findings suggest that loving kindness meditation involves a present-centered, selfless focus for meditators as compared to novices.
doi:10.1002/brb3.219
PMCID: PMC4055184  PMID: 24944863
Connectivity; default mode network; fMRI; loving kindness; meditation; metta
4.  Reducing anxiety and enhancing physical performance by using an advanced version of EMDR: a pilot study 
Brain and Behavior  2014;4(3):348-355.
Background
The main aim of this pilot study was to investigate an advanced version of eye movement desensitization and reprocessing (EMDR) for reducing anxiety.
Methods
Fifty participants were asked at two times of measurement (T1 and T2 with a rest of 4 weeks) to generate anxiety via the recall of autobiographical memories according to their anxiety. Furthermore, the participants were randomly assigned to an experimental group and a control group, and the experimental group received an intervention of 1–2 h with the advanced version of EMDR in order to their anxiety 2 weeks after T1. At T1 as well as T2, we measured the intensity of participants' anxiety with a Likert scale (LS) and collected participants' state (temporary) and trait (chronic) anxiety with the State-Trait Anxiety Inventory (STAI). In addition, we measured participants' physical performance in a test for the finger musculature under the induction of their anxiety.
Results
The results showed that participant's ratings of their perceived intensity of anxiety (measured by a 9-point LS) and the state and trait anxiety decreased significantly in the experimental group but not in the control group from T1 to T2. Moreover, the physical performance under the induction of participants' anxiety increased significantly in the experimental group from T1 to T2 and there were no significant changes in the control group.
Conclusions
The study could show that the advanced version of EMDR is an appropriate method to reduce anxiety.
doi:10.1002/brb3.221
PMCID: PMC4055185  PMID: 24944864
Anxiety; EMDR; physical performance; treatment of anxiety; wingwave
5.  The role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking in rats 
Brain and Behavior  2014;4(3):356-367.
Introduction
Stress is related to heavy alcohol use and relapse in alcoholics. Using the reinstatement model, we have shown that corticotropin-releasing factor (CRF) underlies stress-induced relapse to alcohol seeking in laboratory rodents. Little is known about how other neurotransmitters interact with CRF in these effects. Dynorphin and its receptor (kappa opioid receptor, KOR) are involved in stress responses and in alcohol seeking. KOR and CRF receptors (CRF R) may interact in the production of stress-related behaviors but it is not known whether this interaction is involved in reinstatement of alcohol seeking.
Methods
Male Long Evans rats were trained to self-administer alcohol (12% w/v). After extinction of responding, we determined the effects of the KOR agonist, U50,488 (2.5, 5 mg/kg) on reinstatement of alcohol seeking, and their sensitivity to the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) (10 mg/kg) administered at different times before U50,488. We then examined the effects of nor-BNI on reinstatement induced by the stressor yohimbine (1.25 mg/kg) and on reinstatement induced by exposure to alcohol-associated cues. Finally, we determined whether CRF R1 blockade with antalarmin (10, 20 mg/kg) attenuates alcohol seeking induced by U50,488.
Results
U50,488 reinstated alcohol seeking. Prior treatment with nor-BNI 2, but not 24 h before administration of U50,488 or yohimbine blocked reinstatement induced by these drugs. Cue-induced reinstatement was blocked by nor-BNI administered 2 h prior to testing. Finally, U50,488-induced reinstatement was blocked by antalarmin.
Conclusions
These data further support a role for KOR in reinstatement of alcohol seeking under nonstress and stressful conditions and that KOR and CRF R interact in these effects.
doi:10.1002/brb3.222
PMCID: PMC4055186  PMID: 24944865
Alcohol self-administration; conditioned cue; CRF receptors; kappa opioid receptors; reinstatement; stress
6.  Lesion of the dopaminergic nigrostriatal pathway induces trigeminal dynamic mechanical allodynia 
Brain and Behavior  2014;4(3):368-380.
Background
Pain constitutes the major non motor syndrome in Parkinson's disease (PD) and includes neuropathic pain; however current drug therapies used to alleviate it have only limited efficacy. This is probably due to poor understanding of the mechanisms underlying it.
Aims
We investigated a major class of trigeminal neuropathic pain, dynamic mechanical allodynia (DMA), in a rat model of PD and in which a bilateral 6-hydroxy dopamine (6-OHDA) injection was administered to produce a lesion of the nigrostriatal dopaminergic pathway.
Results and discussion
Lesioned animals presented significant DMA in the orofacial area that occurred from 4 days to 5 weeks post-injury. To investigate a segmental implication in the neuropathic pain induced by dopamine depletion, the expression of the isoform gamma of the protein kinase C (PKCg) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) was explored in the medullary dorsal horn (MDH). There was a high increase in PKCg expression in the III and IIi laminae of the MDH of lesioned-animals compared to shams. pERK1/2 expression was also significantly high in the ipsilateral MDH of lesioned rats in response to non-noxious tactile stimulus of the orofacial region. Since pERK1/2 is expressed only in response to nociceptive stimuli in the dorsal spinal horn, the current study demonstrates that non-noxious stimuli evoke allodynic response. Intraperitoneal and intracisternal administrations of bromocriptine, a dopamine 2 receptor (D2R) agonist, significantly decreased DMA compared to control rats injected with saline. These data demonstrate for the first time that nigrostriatal dopaminergic depletion produces trigeminal neuropathic pain that at least involves a segmental mechanism. In addition, bromocriptine was shown to have a remarkable analgesic effect on this neuropathic pain symptom.
doi:10.1002/brb3.214
PMCID: PMC4055187  PMID: 24944866
Atypical facial algia; basal ganglia; burning mouth syndrome; orofacial pain; Parkinson disease; trigeminal subnucleus caudalis (Sp5C)
7.  Alterations in empathic responding among women with posttraumatic stress disorder associated with childhood trauma 
Brain and Behavior  2014;4(3):381-389.
Objective
Although studies increasingly point toward problems with social cognition among individuals with posttraumatic stress disorder (PTSD), few studies have assessed empathic responding. The aim of the current study was to investigate empathic responding in women with PTSD related to childhood trauma, and the contribution of parental bonding to empathic abilities in this sample.
Methods
Participants with PTSD (n = 29) and sex- and age-matched healthy controls (n = 20) completed two self-report empathy measures, the Interpersonal Reactivity Index (IRI) and the Toronto Empathy Questionnaire (TEQ), and a self-report measure of attachment, the Parental Bonding Instrument (PBI).
Results
Women with PTSD, relative to controls, reported significantly lower levels of empathic concern (r = 0.29) and perspective taking (r = 0.30), yet significantly higher levels of personal distress (r = 0.45) on the IRI. Women with PTSD also reported elevated scores on the TEQ (η2 = 0.13). Levels of paternal care on the PBI, rather than childhood trauma severity or PTSD symptom severity best predicted perspective taking scores on the IRI in the PTSD sample (R2 = 0.20).
Conclusion
Women with PTSD associated with childhood trauma reported alterations among different domains of empathic functioning that may be related to low levels of paternal care.
doi:10.1002/brb3.215
PMCID: PMC4055188  PMID: 24944867
Adult survivors of child abuse; empathy; posttraumatic; stress disorders
8.  Noncontinuous use of antidepressant in adults with major depressive disorders – a retrospective cohort study 
Brain and Behavior  2014;4(3):390-397.
Background
Noncontinuous antidepressant use is frequently observed in clinical practice despite the standard recommendation of at least 6–9 months of continuous treatment. The problem may be more serious in Chinese populations where stigmatization is common. This retrospective cohort study investigated the rate of noncontinuous antidepressant use and subsequent rate of relapse and recurrence in psychiatric Chinese outpatients by examining the prescription records, electronic medical records, and written medical records. Factors associated with noncontinuous antidepressant use were also identified.
Methods
We reviewed the medical records of 189 patients newly dispensed with an antidepressant in the psychiatric outpatient clinic during year 2006 and 2007. Primary outcome was the rate of noncontinuous antidepressant use within 6 months of therapy. Secondary outcomes included the factors associated with noncontinuous antidepressant use and the rate of subsequent depression relapse and recurrence within 1 year of starting treatment.
Results
Among the 189 subjects included in this study, 46% were noncontinuous users of the newly prescribed antidepressant therapy. The noncontinuous users were found to have an eightfold increase (OR: 8.42, 95% CI: 3.30–21.47) in the risks of relapse/recurrence depressive episodes within 1 year after treatment initiation. Younger age (P = 0.008), female, (P = 0.029), residency in public housing estate (P = 0.029), experiencing side effects (P = 0.024), infrequent follow-ups (P = 0.006), and earlier onset of diagnosis (P = 0.034) were factors significantly associated with noncontinuous antidepressant use.
Conclusions
Noncontinuous antidepressant use is common in the local Chinese depressive patients and associated with a high rate of relapse and recurrence. Collaborative multidisciplinary approaches that target patient education and enhancement of follow-up adherence are needed.
doi:10.1002/brb3.224
PMCID: PMC4055189  PMID: 24944868
Adherence; antidepressant; depression; pharmacotherapy; treatment
9.  The left inferior frontal gyrus is involved in adjusting response bias during a perceptual decision-making task 
Brain and Behavior  2014;4(3):398-407.
Introduction
Changing the way we make decisions from one environment to another allows us to maintain optimal decision-making. One way decision-making may change is how biased one is toward one option or another. Identifying the regions of the brain that underlie the change in bias will allow for a better understanding of flexible decision-making.
Methods
An event-related, perceptual decision-making task where participants had to detect a picture of an animal amongst distractors was used during functional magnetic resonance imaging. Positive and negative financial motivation were used to affect a change in response bias, and changes in decision-making behavior were quantified using signal detection theory.
Results
Response bias became relatively more liberal during both positive and negative motivated trials compared to neutral trials. For both motivational conditions, the larger the liberal shift in bias, the greater the left inferior frontal gyrus (IFG) activity. There was no relationship between individuals' belief that they used a different strategy and their actual change in response bias.
Conclusions
The present findings suggest that the left IFG plays a role in adjusting response bias across different decision environments. This suggests a potential role for the left IFG in flexible decision-making.
doi:10.1002/brb3.223
PMCID: PMC4055190  PMID: 24944869
fMRI; inferior frontal gyrus; motivation; perceptual decision-making; signal detection theory
10.  The development and expression of physical nicotine dependence corresponds to structural and functional alterations in the anterior cingulate-precuneus pathway 
Brain and Behavior  2014;4(3):408-417.
Introduction
Perturbations in neural function provoked by a drug are thought to induce neural adaptations, which, in the absence of the drug, give rise to withdrawal symptoms. Previously published structural data from this study indicated that the progressive development of physical dependence is associated with increasing density of white matter tracts between the anterior cingulum bundle and the precuneus.
Methods
Using functional magnetic resonance imaging, we compared 11 smokers after 11 h of abstinence from nicotine and after satiation, with 10 nonsmoking controls, using independent component analysis for brain network comparisons as well as a whole brain resting-state functional connectivity analysis using the anterior cingulate cortex as a seed.
Results
Independent component analysis demonstrated increased functional connectivity in brain networks such as the default mode network associated with the withdrawal state in multiple brain regions. In seed-based analysis, smokers in the withdrawal state showed stronger functional connectivity than nonsmoking controls between the anterior cingulate cortex and the precuneus, caudate, putamen, and frontal cortex (P < 0.05). Among smokers, compared to the satiated state, nicotine withdrawal was associated with increased connectivity between the anterior cingulate cortex and the precuneus, insula, orbital frontal gyrus, superior frontal gyrus, posterior cingulate cortex, superior temporal, and inferior temporal lobe (P < 0.02). The intensity of withdrawal-induced craving correlated with the strength of connectivity between the anterior cingulate cortex and the precuneus, insula, caudate, putamen, middle cingulate gyrus, and precentral gyrus (r = 0.60–0.76; P < 0.05).
Conclusions
In concordance with our previous report that structural neural connectivity between the anterior cingulate area and the precuneus increased in proportion to the progression of physical dependence, resting-state functional connectivity in this pathway increases during nicotine withdrawal in correlation with the intensity of withdrawal-induced craving. These findings suggest that smoking triggers structural and functional neural adaptations in the brain that support withdrawal-induced craving.
doi:10.1002/brb3.227
PMCID: PMC4055191  PMID: 24944870
Addiction; nicotine; resting-state functional connectivity
11.  Candidate gene associations with mood disorder, cognitive vulnerability, and fronto-limbic volumes 
Brain and Behavior  2014;4(3):418-430.
Background
Four of the most consistently replicated variants associated with mood disorder occur in genes important for synaptic function: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and DGKH (rs1170191).
Aims
The present study examined associations between these candidates, mood disorder diagnoses, cognition, and fronto-limbic regions implicated in affect regulation.
Methods and materials
Participants included 128 individuals with bipolar disorder (33% male, Mean age = 38.5), 48 with major depressive disorder (29% male, Mean age = 40.4), and 149 healthy controls (35% male, Mean age = 36.5). Genotypes were determined by 5′-fluorogenic exonuclease assays (TaqMan®). Fronto-limbic volumes were obtained from high resolution brain images using Freesurfer. Chi-square analyses, bivariate correlations, and mediational models examined relationships between genetic variants, mood diagnoses, cognitive measures, and brain volumes.
Results
Carriers of the minor BDNF and ANK3 alleles showed nonsignificant trends toward protective association in controls relative to mood disorder patients (P = 0.047). CACNA1C minor allele carriers had larger bilateral caudate, insula, globus pallidus, frontal pole, and nucleus accumbens volumes (smallest r = 0.13, P = 0.043), and increased IQ (r = 0.18, P < 0.001). CACNA1C associations with brain volumes and IQ were independent; larger fronto-limbic volumes did not mediate increased IQ. Other candidate variants were not significantly associated with diagnoses, cognition, or fronto-limbic volumes.
Discussion and conclusions
CACNA1C may be associated with biological systems altered in mood disorder. Increases in fronto-limbic volumes and cognitive ability associated with CACNA1C minor allele genotypes are congruent with findings in healthy samples and may be a marker for increased risk for neuropsychiatric phenotypes. Even larger multimodal studies are needed to quantify the magnitude and specificity of genetic-imaging-cognition-symptom relationships.
doi:10.1002/brb3.226
PMCID: PMC4055192  PMID: 24944871
ANK3; BDNF; bipolar disorder; CACNA1C; candidate gene; DGKH; major depression; mediation; mood disorder; structural neuroimaging
12.  Muscarinic acetylcholine receptors are expressed by most parvalbumin-immunoreactive neurons in area MT of the macaque 
Brain and Behavior  2014;4(3):431-445.
Background
In the mammalian neocortex, cells that express parvalbumin (PV neurons) comprise a dominant class of inhibitory neuron that substantially overlaps with the fast/narrow-spiking physiological phenotype. Attention has pronounced effects on narrow-spiking neurons in the extrastriate cortex of macaques, and more consistently so than on their broad-spiking neighbors. Cortical neuromodulation by acetylcholine (ACh) is a candidate mechanism for aspects of attention and in the primary visual cortex (V1) of the macaque, receptors for ACh (AChRs) are strongly expressed by inhibitory neurons. In particular, most PV neurons in macaque V1 express m1 muscarinic AChRs and exogenously applied ACh can cause the release of γ-aminobutyric acid. In contrast, few PV neurons in rat V1 express m1 AChRs. While this could be a species difference, it has also been argued that macaque V1 is anatomically unique when compared with other cortical areas in macaques.
Aims
The aim of this study was to better understand the extent to which V1 offers a suitable model circuit for cholinergic anatomy in the macaque occipital lobe, and to explore cholinergic modulation as a biological basis for the changes in circuit behavior seen with attention.
Materials and methods
We compared expression of m1 AChRs by PV neurons between area V1 and the middle temporal visual area (MT) in macaque monkeys using dual-immunofluorescence confocal microscopy.
Results and conclusion
We find that, as in V1, most PV neurons in MT express m1 AChRs but, unlike in V1, it appears that so do most excitatory neurons. This provides support for V1 as a model of cholinergic modulation of inhibition in macaque visual cortex, but not of cholinergic modulation of visual cortical circuits in general. We also propose that ACh acting via m1 AChRs is a candidate underlying mechanism for the strong effects of attention on narrow-spiking neurons observed in behaving animals.
doi:10.1002/brb3.225
PMCID: PMC4055193  PMID: 24944872
Anatomy; calcium-binding proteins; immunofluorescence; neuromodulation; parvalbumin; quantitative; visual cortex
13.  Morbidity in early Parkinson's disease and prior to diagnosis 
Brain and Behavior  2014;4(3):446-452.
Background
Nonmotor symptoms are probably present prior to, early on, and following, a diagnosis of Parkinson's disease. Nonmotor symptoms may hold important information about the progression of Parkinson's disease.
Objective
To evaluated the total early and prediagnostic morbidities in the 3 years before a hospital contact leading to a diagnosis of Parkinson's disease.
Methods
Retrospective morbidity data from Danish National Patient Registry records (1997–2007) of 10,490 adult patients with a secondary care diagnosis of Parkinson's disease were compared with 42,505 control cases.
Results
Parkinson's disease was associated with significantly higher morbidity rates associated with conditions in the following categories: mental and psychiatric, nervous system, gastrointestinal, musculoskeletal system and connective tissue, genitourinary, abnormal clinical and laboratory findings, injury, poisoning and certain other external causes, and other factors influencing health status and contact with health services. It was negatively associated with neoplasm, cardiovascular, and respiratory diseases.
Conclusions
Patients with a diagnosis of Parkinson's disease present significant differences in morbidities early on, following, and prior to, their diagnosis, compared with healthy controls.
doi:10.1002/brb3.228
PMCID: PMC4055194  PMID: 24944873
Morbidities; National Patient Registry; Parkinson's disease; prediagnostic
14.  Brain and Behavior 
Brain and Behavior  2014;4(2):i-iii.
doi:10.1002/brb3.165
PMCID: PMC3967527  PMID: 24683523
15.  The role of FGF2 in spinal cord trauma and regeneration research 
Brain and Behavior  2014;4(2):105-107.
doi:10.1002/brb3.207
PMCID: PMC3967528  PMID: 24683505
16.  N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities 
Brain and Behavior  2014;4(2):108-122.
Background
There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.
Aim and discussion
Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.
Conclusion
Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.
doi:10.1002/brb3.208
PMCID: PMC3967529  PMID: 24683506
N-acetylcysteine; neurological disorder; treatment
17.  Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection 
Brain and Behavior  2013;4(2):123-142.
Background
The purpose of this study was to characterize hepatitis C virus (HCV)-associated differences in the expression of 47 inflammatory factors and to evaluate the potential role of peripheral immune activation in HCV-associated neuropsychiatric symptoms—depression, anxiety, fatigue, and pain. An additional objective was to evaluate the role of immune factor dysregulation in the expression of specific neuropsychiatric symptoms to identify biomarkers that may be relevant to the treatment of these neuropsychiatric symptoms in adults with or without HCV.
Methods
Blood samples and neuropsychiatric symptom severity scales were collected from HCV-infected adults (HCV+, n = 39) and demographically similar noninfected controls (HCV−, n = 40). Multi-analyte profile analysis was used to evaluate plasma biomarkers.
Results
Compared with HCV− controls, HCV+ adults reported significantly (P < 0.050) greater depression, anxiety, fatigue, and pain, and they were more likely to present with an increased inflammatory profile as indicated by significantly higher plasma levels of 40% (19/47) of the factors assessed (21%, after correcting for multiple comparisons). Within the HCV+ group, but not within the HCV− group, an increased inflammatory profile (indicated by the number of immune factors > the LDC) significantly correlated with depression, anxiety, and pain. Within the total sample, neuropsychiatric symptom severity was significantly predicted by protein signatures consisting of 4–10 plasma immune factors; protein signatures significantly accounted for 19–40% of the variance in depression, anxiety, fatigue, and pain.
Conclusions
Overall, the results demonstrate that altered expression of a network of plasma immune factors contributes to neuropsychiatric symptom severity. These findings offer new biomarkers to potentially facilitate pharmacotherapeutic development and to increase our understanding of the molecular pathways associated with neuropsychiatric symptoms in adults with or without HCV.
doi:10.1002/brb3.200
PMCID: PMC3967530  PMID: 24683507
Anxiety; biological markers; chronic infection; cytokines; depression; fatigue; pain
18.  Unilateral disruptions in the default network with aging in native space 
Brain and Behavior  2013;4(2):143-157.
Background
Disruption of the default-mode network (DMN) in healthy elders has been reported in many studies.
Methods
In a group of 51 participants (25 young, 26 elder) we examined DMN connectivity in subjects' native space. In the native space method, subject-specific regional masks (obtained independently for each subject) are used to extract regional fMRI times series. This approach substitutes the spatial normalization and subsequent smoothing used in prevailing methods, affords more accurate spatial localization, and provides the power to examine connectivity separately in the two hemispheres instead of averaging regions across hemispheres.
Results
The native space method yielded new findings which were not detectable by the prevailing methods. The most reliable and robust disruption in elders' DMN connectivity were found between supramarginal gyrus and superior-frontal cortex in the right hemisphere only. The mean correlation between these two regions in young participants was about 0.5, and dropped significantly to 0.04 in elders (P = 2.1 × 10−5). In addition, the magnitude of functional connectivity between these regions in the right hemisphere correlated with memory (P = 0.05) and general fluid ability (P = 0.01) in elder participants and with speed of processing in young participants (P = 0.008). These relationships were not observed in the left hemisphere.
Conclusion
These findings suggest that analysis of DMN connectivity in subjects' native space can improve localization and power and that it is important to examine connectivity separately in each hemisphere.
doi:10.1002/brb3.202
PMCID: PMC3967531  PMID: 24683508
Age-related brain change; cognitive performance; fMRI analysis; interhemispheric averaging; resting-state BOLD fMRI; spatial normalization; SPM
19.  White matter integrity is associated with alcohol cue reactivity in heavy drinkers 
Brain and Behavior  2013;4(2):158-170.
Neuroimaging studies have shown that white matter damage accompanies excessive alcohol use, but the functional correlates of alcohol-related white matter disruption remain unknown. This study applied tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) data from 332 heavy drinkers (mean age = 31.2 ± 9.4; 31% female) to obtain averaged fractional anisotropy (FA) values of 18 white matter tracts. Statistical analyses examined correlations of FA values with blood-oxygenation-level-dependent (BOLD) response to an alcohol taste cue, measured with functional magnetic resonance imaging (fMRI). FA values of nine white matter tracts (anterior corona radiata, body of corpus callosum, cingulate gyrus, external capsule, fornix, inferior frontooccipital fasciculus, posterior corona radiata, retrolenticular limb of internal capsule, and superior longitudinal fasciculus) were significantly, negatively correlated with BOLD activation in medial frontal gyrus, parahippocampal gyrus, fusiform gyrus, cingulum, thalamus, caudate, putamen, insula, and cerebellum. The inverse relation between white matter integrity and functional activation during the alcohol taste cue provides support for the hypothesis that lower white matter integrity in frontoparietal and corticolimbic networks is a factor in loss of control over alcohol consumption.
doi:10.1002/brb3.204
PMCID: PMC3967532  PMID: 24683509
Alcohol use disorders; diffusion tensor imaging; functional magnetic resonance imaging; tract-based spatial statistics; white matter
20.  Brain training: rationale, methods, and pilot data for a specific visuomotor/visuospatial activity program to change progressive cognitive decline 
Brain and Behavior  2013;4(2):171-179.
Introduction
Research in the field of the aging brain has evolved to the extent that it is now commonly understood that actively engaging in cognitive tasks provides the potential of being beneficial in affecting the trajectory of age-related cognitive decline. What remains to be examined is the extent, and type, of program required to effect change in aging cognitively impaired individuals.
Methods
To address this issue, a cognitive program focusing on the use of visuospatial (VS)/visuomotor (VM) elements was applied to a group of six older individuals with identified progressive cognitive impairments. It was hypothesized that using tasks with VS and VM components may be beneficial in supporting overall brain performance, and subsequently assist individuals to perform well in various cognitive and behavioral tasks.
Results
Results showed that on many evaluative measures individuals remained stable, or improved in performance with medium-to-large effect sizes (e.g., 0.3–1.0). Thus, in a cognitively impaired population sample where decline would be the norm, our participants improved or remained stable.
Conclusion
The novel application of a VS/VM training program shows promise in addressing global cognitive decline, by targeting a brain area susceptible to early disruptions and providing it with additional and ongoing stimulative tasks in an effort to bolster its functioning and subsequently overall brain functioning.
doi:10.1002/brb3.196
PMCID: PMC3967533  PMID: 24683510
Cognitive impairment; cognitive training; visuospatial/visuomotor
21.  Neural differences in processing of case particles in Japanese: an fMRI study 
Brain and Behavior  2013;4(2):180-186.
Introduction
In subject–object–verb (SOV) languages, such as Japanese, sentence processing proceeds incrementally to the late presentation of the head (verb). Japanese case particles play a crucial role in sentence processing; however, little is known about how these particles are processed. In particular, it is still unclear how the functional difference between case particles is represented in the human brain.
Methods
In this study, we conducted an fMRI experiment using an event-related design to directly compare brain activity during Japanese case particle processing among the nominative case ga, accusative case o, and dative case ni. Twenty five native Japanese speakers were asked to judge whether the presented character was a particle in a particle judgment task and whether the character ended with a specific vowel in a phonological judgment task, which was used as a control condition.
Results
A particle comparison demonstrated that the processing of ni was associated with significantly weaker brain activity than that of ga and o in the left middle frontal gyrus (MFG) and the inferior frontal gyrus (IFG). Significantly greater brain activity associated with ni relative to ga in the right IFG was also observed.
Conclusion
These results suggest that the Japanese case particles ga, ni, and o are represented differently in the brain.
doi:10.1002/brb3.201
PMCID: PMC3967534  PMID: 24683511
Comprehension; functional MRI; language; neuroimaging; syntax
22.  Fgf2 improves functional recovery—decreasing gliosis and increasing radial glia and neural progenitor cells after spinal cord injury 
Brain and Behavior  2014;4(2):187-200.
Objectives
A major impediment for recovery after mammalian spinal cord injury (SCI) is the glial scar formed by proliferating reactive astrocytes. Finding factors that may reduce glial scarring, increase neuronal survival, and promote neurite outgrowth are of major importance for improving the outcome after SCI. Exogenous fibroblast growth factor (Fgf) has been shown to decrease injury volume and improve functional outcome; however, the mechanisms by which this is mediated are still largely unknown.
Methods
In this study, Fgf2 was administered for 2 weeks in mice subcutaneously, starting 30 min after spinal cord hemisection.
Results
Fgf2 treatment decreased the expression of TNF-a at the lesion site, decreased monocyte/macrophage infiltration, and decreased gliosis. Fgf2 induced astrocytes to adopt a polarized morphology and increased expression of radial markers such as Pax6 and nestin. In addition, the levels of chondroitin sulfate proteoglycans (CSPGs), expressed by glia, were markedly decreased. Furthermore, Fgf2 treatment promotes the formation of parallel glial processes, “bridges,” at the lesion site that enable regenerating axons through the injury site. Additionally, Fgf2 treatment increased Sox2-expressing cells in the gray matter and neurogenesis around and at the lesion site. Importantly, these effects were correlated with enhanced functional recovery of the left paretic hind limb.
Conclusions
Thus, early pharmacological intervention with Fgf2 following SCI is neuroprotective and creates a proregenerative environment by the modulation of the glia response.
doi:10.1002/brb3.172
PMCID: PMC3967535  PMID: 24683512
Astroglia; GFAP; nestin; Pax6; progenitors; regeneration; Sox2; spinal cord injury
23.  Neural substrates of socioemotional self-awareness in neurodegenerative disease 
Brain and Behavior  2014;4(2):201-214.
Background
Neuroimaging studies examining neural substrates of impaired self-awareness in patients with neurodegenerative diseases have shown divergent results depending on the modality (cognitive, emotional, behavioral) of awareness. Evidence is accumulating to suggest that self-awareness arises from a combination of modality-specific and large-scale supramodal neural networks.
Methods
We investigated the structural substrates of patients' tendency to overestimate or underestimate their own capacity to demonstrate empathic concern for others. Subjects' level of empathic concern was measured using the Interpersonal Reactivity Index, and subject-informant discrepancy scores were used to predict regional atrophy pattern, using voxel-based morphometry analysis. Of the 102 subjects, 83 were patients with neurodegenerative diseases such as behavioral variant frontotemporal dementia (bvFTD) or semantic variant primary progressive aphasia (svPPA); the other 19 were healthy older adults.
Results
bvFTD and svPPA patients typically overestimated their level of empathic concern compared to controls, and overestimating one's empathic concern predicted damage to predominantly right-hemispheric anterior infero-lateral temporal regions, whereas underestimating one's empathic concern showed no neuroanatomical basis.
Conclusions
These findings suggest that overestimation and underestimation of one's capacity for empathic concern cannot be interpreted as varying degrees of the same phenomenon, but may arise from different pathophysiological processes. Damage to anterior infero-lateral temporal regions has been associated with semantic self-knowledge, emotion processing, and social perspective taking; neuropsychological functions partly associated with empathic concern itself. These findings support the hypothesis that—at least in the socioemotional domain—neural substrates of self-awareness are partly modality-specific.
doi:10.1002/brb3.211
PMCID: PMC3967536  PMID: 24683513
Affective perspective taking; dementia; empathy; infero-lateral temporal cortex; neurodegeneration; semantic self-knowledge; unawareness; voxel-based morphometry
24.  A Neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects 
Brain and Behavior  2014;4(2):215-226.
Background: Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis. Methods: We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n = 31) for rs35753505 or homozygous for the T allele (n = 23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts. Results: Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe. Conclusion: Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia.
doi:10.1002/brb3.203
PMCID: PMC3967537  PMID: 24683514
Anatomic connectivity; brain; DTI; gene; hippocampus; MRI; Neuregulin-1
25.  Functional MRI mapping of visual function and selective attention for performance assessment and presurgical planning using conjunctive visual search 
Brain and Behavior  2014;4(2):227-237.
Background
Accurate mapping of visual function and selective attention using fMRI is important in the study of human performance as well as in presurgical treatment planning of lesions in or near visual centers of the brain. Conjunctive visual search (CVS) is a useful tool for mapping visual function during fMRI because of its greater activation extent compared with high-capacity parallel search processes.
Aims
The purpose of this work was to develop and evaluate a CVS that was capable of generating consistent activation in the basic and higher level visual areas of the brain by using a high number of distractors as well as an optimized contrast condition.
Materials and methods
Images from 10 healthy volunteers were analyzed and brain regions of greatest activation and deactivation were determined using a nonbiased decomposition of the results at the hemisphere, lobe, and gyrus levels. The results were quantified in terms of activation and deactivation extent and mean z-statistic.
Results
The proposed CVS was found to generate robust activation of the occipital lobe, as well as regions in the middle frontal gyrus associated with coordinating eye movements and in regions of the insula associated with task-level control and focal attention. As expected, the task demonstrated deactivation patterns commonly implicated in the default-mode network. Further deactivation was noted in the posterior region of the cerebellum, most likely associated with the formation of optimal search strategy.
Conclusion
We believe the task will be useful in studies of visual and selective attention in the neuroscience community as well as in mapping visual function in clinical fMRI.
doi:10.1002/brb3.213
PMCID: PMC3967538  PMID: 24683515
fMRI; magnetic resonance imaging; neurosurgery; occipital lobe; visual function

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