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1.  Temporospatial identification of language‐related cortical function by a combination of transcranial magnetic stimulation and magnetoencephalography 
Brain and Behavior  2015;e00317.
Abstract
Introduction
Identification of language‐related cortical functions can be carried out noninvasively by transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), which allow for lesion‐based interrogation and global temporospatial investigation of cortices, respectively. Combining these two modalities can improve the accuracy of the identification, but the relationships between them remain unclear. We compared TMS and MEG responses during the same language task to elucidate their temporospatial relationships and used the results to develop a novel method to identify language‐related cortical functions.
Methods
Twelve healthy right‐handed volunteers performed a picture‐naming task during TMS and MEG. TMS was applied on the right or left inferior frontal gyrus (IFG) at five time points, and the reaction times (RTs) for naming the pictures were measured. The temporospatial oscillatory changes measured by MEG during the same task were then compared with the TMS results.
Results
Transcranial magnetic stimulation of the left IFG significantly lengthened RTs at 300 and 375 msec after picture presentation, whereas TMS of the right IFG did not change RTs significantly. Interestingly, the stimulus time point at which RTs increased significantly for each individual was correlated with when the low gamma event‐related desynchronizations (ERDs) peaked in the left IFG. Moreover, combining the results of TMS and MEG improved the detection rate for identifying the laterality of language function.
Conclusions
These results suggest that the low gamma ERDs measured by MEG strongly relate to the language function of picture naming in the left IFG. Finally, we propose a novel method to identify language‐related cortical functions by combining TMS and MEG.
doi:10.1002/brb3.317
PMCID: PMC4309891  PMID: 25642395
Event‐related desynchronizations; inferior frontal gyrus; language lateralization; language processing; low gamma; picture naming
2.  Characteristics of pain in amyotrophic lateral sclerosis 
Brain and Behavior  2015;e00296.
Abstract
Background
Pain is an often underestimated and neglected symptom in amyotrophic lateral sclerosis (ALS).
Methods
In a cross‐sectional survey, 46 patients with ALS, 46 age‐ and gender matched population‐based controls, and 23 diseased controls with myotonic dystrophy type 2 (DM2) were screened for occurrence, type, distribution, and treatment of pain and cramps. Data were collected with the use of the short form brief pain inventory (BPI).
Results
Pain was reported in 78% of ALS patients,79% of DM2 patients, and 54% of controls (P < 0.05). More ALS patients than controls reported moderate to severe pain (42% vs. 20%). Pain in ALS patients interfered significantly more with daily activities than in controls (median pain interference score: 3.0 vs. 1.2, P < 0.05), especially enjoyment of life (5.0 vs. 1.0) and mood (3.0 vs. 1.0). There was no correlation between the duration of the disease and the severity of pain. Movement‐induced cramps were reported in 63% of ALS patients, mostly in the distal extremities. There was no difference in the duration of ALS disease between patients reporting cramps and those who did not.
Discussion
Our study showed that pain was a relatively frequent symptom which had an important impact on the quality of life. Pain that requires treatment can occur at every stage of ALS.
doi:10.1002/brb3.296
PMCID: PMC4309879  PMID: 25642388
Amyotrophic lateral sclerosis; cramps; motor neuron disease; pain; spasticity
3.  Depression, anxiety disorders, and metabolic syndrome in a population at risk for type 2 diabetes mellitus 
Brain and Behavior  2015;e00306.
Abstract
Background
Depressive symptoms have been associated with type 2 diabetes mellitus (T2DM), but less is known about anxiety disorders that can be comorbid or exist without depression.
Methods
We evaluated the prevalence of psychiatric disorders in subjects consecutively examined at an outpatient clinic for diabetes prevention who were at‐risk for T2DM, defined by FINDRISK scores, and compared metabolic syndrome (MetS) frequencies between subjects with and without psychiatric morbidity, entering also relevant variables for MetS into multivariate analyses. All subjects underwent an oral glucose tolerance test (OGTT). Psychiatric diagnosis was confirmed using a Structured Clinical Interview for DSM‐IV.
Results
Of 260 consecutively screened subjects, 150 (56.9 ± 8.1 years old, males = 56.7%, BMI = 27.2 ± 4.1 kg/m2) were at‐risk for T2DM and were included. MetS, present in 27% of males and 25% of females, was significantly associated with having a current anxiety disorder (P < 0.001) and lifetime major depression (P < 0.001). In logistic regression analysis, MetS was significantly associated with lifetime major depression, presence of any anxiety disorder, body weight, and physical activity.
Conclusions
Our data in a high‐risk group for T2DM support the association between depressive disorders and MetS, pointing to a similar role of anxiety disorders. Screening for anxiety and depression is recommended in this group at risk for T2DM.
doi:10.1002/brb3.306
PMCID: PMC4309892  PMID: 25642391
Anxiety disorders; major depressive disorder; metabolic syndrome; mood disorders; type 2 diabetes mellitus
4.  Purkinje cell responses during visually and vestibularly driven smooth eye movements in mice 
Brain and Behavior  2015;e00310.
Abstract
Introduction
An essential complement to molecular‐genetic approaches for analyzing the function of the oculomotor circuitry in mice is an understanding of sensory and motor signal processing in the circuit. Although there has been extensive analysis of the signals carried by neurons in the oculomotor circuits of species, such as monkeys, rabbits and goldfish, relatively little in vivo physiology has been done in the oculomotor circuitry of mice. We analyzed the contribution of vestibular and nonvestibular signals to the responses of individual Purkinje cells in the cerebellar flocculus of mice.
Methods
We recorded Purkinje cells in the cerebellar flocculus of C57BL/6 mice during eye movement responses to vestibular and visual stimulation.
Results
As in other species, most individual Purkinje cells in mice carried both vestibular and nonvestibular signals, and the most common response across cells was an increase in firing in response to ipsiversive eye movement or ipsiversive head movement. When both the head and eyes were moving, the Purkinje cell responses were approximated as a linear summation of head and eye velocity inputs. Unlike other species, floccular Purkinje cells in mice were considerably more sensitive to eye velocity than head velocity.
Conclusions
The signal content of Purkinje cells in the cerebellar flocculus of mice was qualitatively similar to that in other species. However, the eye velocity sensitivity was higher than in other species, which may reflect a tuning to the smaller range of eye velocities in mice.
doi:10.1002/brb3.310
PMCID: PMC4309896  PMID: 25642393
Cerebellum; extracellular recording; oculomotor; optokinetic reflex; vestibulo‐ocular reflex
5.  Emotion recognition specialization and context‐dependent risk of anxiety and depression in adolescents 
Brain and Behavior  2015;e00299.
Abstract
Background
Some adolescents function poorly in apparently benign environments, while others thrive despite hassles and difficulties. The aim of this study was to examine if adolescents with specialized skills in the recognition of either positive or negative emotions have a context‐dependent risk of developing an anxiety or depressive disorder during adolescence, depending on exposure to positive or harsh parenting.
Methods
Data came from a large prospective Dutch population study (N = 1539). At age 11, perceived parental rejection and emotional warmth were measured by questionnaire, and emotion recognition skills by means of a reaction‐time task. Lifetime diagnoses of anxiety and depressive disorders were assessed at about age 19, using a standardized diagnostic interview.
Results
Adolescents who were specialized in the recognition of positive emotions had a relatively high probability to develop an anxiety disorder when exposed to parental rejection (Bspecialization*rejection = 0.23, P < 0.01) and a relatively low probability in response to parental emotional warmth (Bspecialization*warmth = −0.24, P = 0.01), while the opposite pattern was found for specialists in negative emotions. The effect of parental emotional warmth on depression onset was likewise modified by emotion recognition specialization (B = −0.13, P = 0.03), but the effect of parental rejection was not (B = 0.02, P = 0.72). In general, the relative advantage of specialists in negative emotions was restricted to fairly uncommon negative conditions.
Conclusions
Our results suggest that there is no unequivocal relation between parenting behaviors and the probability to develop an anxiety or depressive disorder in adolescence, and that emotion recognition specialization may be a promising way to distinguish between various types of context‐dependent reaction patterns.
doi:10.1002/brb3.299
PMCID: PMC4309882  PMID: 25642389
Anxiety/anxiety disorders; child/adolescent; depression; family/marital; stress
6.  Weekly multimodal MRI follow‐up of two multiple sclerosis active lesions presenting a transient decrease in ADC 
Brain and Behavior  2015;e00307.
Abstract
Background and purpose
Blood‐brain barrier disruption during the earliest phases of lesion formation in multiple sclerosis (MS) patients is commonly ascribed to perivenular inflammatory activity and is usually accompanied by increased diffusivity. Reduced diffusivity has also been shown in active lesions, albeit less frequently. This study aimed to characterize the development and natural history of contrast‐enhanced lesions by weekly following five relapsing remitting (RR) MS patients.
Materials and methods
Diffusion tensor imaging (DTI), perfusion imaging, FLAIR and contrast‐enhanced 3D T1‐weighted MR, were weekly performed on five untreated patients recently diagnosed with RR MS.
Results
All five patients showed significant increases of the apparent diffusion coefficient (ADC) in the lesions compared to the first time point. One of the five patients presented 98 active lesions on ADC maps among which 36 had a volume larger than 10 mm3. In two of these lesions, a 1 week transient decrease in ADC was detected at the time of the first gadolinium enhancement. Also, the perfusion analysis showed a concomitant increase in the relative cerebral blood volume.
Conclusions
The infrequency detection of such ADC decrease in a new lesion is probably due to its very short duration. This observation may be consistent with a hyper‐acute inflammatory stage concomitant with an increased reactional perfusion.
doi:10.1002/brb3.307
PMCID: PMC4309893  PMID: 25642392
Apparent diffusion coefficient; diffusion tensor imaging; lesions; multiple sclerosis; perfusion; relative cerebral blood volume
7.  The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington's disease: an exploratory study 
Brain and Behavior  2015;e00312.
Abstract
Background
There is a wealth of evidence detailing gray matter degeneration and loss of cognitive function over time in individuals with Huntington's disease (HD). Efforts to attenuate disease‐related brain and cognitive changes have been unsuccessful to date. Multidisciplinary rehabilitation, comprising motor and cognitive intervention, has been shown to positively impact on functional capacity, depression, quality of life and some aspects of cognition in individuals with HD. This exploratory study aimed to evaluate, for the first time, whether multidisciplinary rehabilitation can slow further deterioration of disease‐related brain changes and related cognitive deficits in individuals with manifest HD.
Methods
Fifteen participants who manifest HD undertook a multidisciplinary rehabilitation intervention spanning 9 months. The intervention consisted of once‐weekly supervised clinical exercise, thrice‐weekly self‐directed home based exercise and fortnightly occupational therapy. Participants were assessed using MR imaging and validated cognitive measures at baseline and after 9 months.
Results
Participants displayed significantly increased gray matter volume in the right caudate and bilaterally in the dorsolateral prefrontal cortex after 9 months of multidisciplinary rehabilitation. Volumetric increases in gray matter were accompanied by significant improvements in verbal learning and memory (Hopkins Verbal Learning‐Test). A significant association was found between gray matter volume increases in the dorsolateral prefrontal cortex and performance on verbal learning and memory.
Conclusions
This study provides preliminary evidence that multidisciplinary rehabilitation positively impacts on gray matter changes and cognitive functions relating to verbal learning and memory in individuals with manifest HD. Larger controlled trials are required to confirm these preliminary findings.
doi:10.1002/brb3.312
PMCID: PMC4309878  PMID: 25642394
Cognition; executive function; Huntington's disease; neuropathology; rehabilitation
8.  Dopamine D1 receptor blockade impairs alcohol seeking without reducing dorsal striatal activation to cues of alcohol availability 
Brain and Behavior  2015;e00305.
Abstract
Introduction
Alcohol‐associated cues activate both ventral and dorsal striatum in functional brain imaging studies of heavy drinkers. In rodents, alcohol‐associated cues induce changes in neuronal firing frequencies and increase dopamine release in ventral striatum, but the impact of alcohol‐associated cues on neuronal activity in dorsal striatum is unclear. We previously reported phasic changes in action potential frequency in the dorsomedial and dorsolateral striatum after cues that signaled alcohol availability, prompting approach behavior.
Methods
We investigated the hypothesis that dopamine transmission modulates these phasic firing changes. Rats were trained to self‐administer alcohol, and neuronal activity was monitored with extracellular electrophysiology during “anticipatory” cues that signaled the start of the operant session. Sessions were preceded by systemic administration of the D1‐type dopamine receptor antagonist SCH23390 (0, 10, and 20 μg/kg).
Results
SCH23390 significantly decreased firing rates during the 60 s prior to cue onset without reducing phasic excitations immediately following the cues. While neuronal activation to cues might be expected to initiate behavioral responses, in this study alcohol seeking was reduced despite the presence of dorsal striatal excitations to alcohol cues.
Conclusions
These data suggest that D1 receptor antagonism reduces basal firing rates in the dorsal striatum and modulates the ability of neuronal activation to “anticipatory” cues to initiate alcohol seeking in rats with an extensive history of alcohol self‐administration.
doi:10.1002/brb3.305
PMCID: PMC4309894  PMID: 25642390
dopamine D1 receptor antagonist SCH23390; dorsolateral striatum; dorsomedial striatum; extracellular electrophysiology; RRID:nif‐0000‐31484; RRID:nlx_153890; RRID:nlx_157643; RRID:nlx_158483; RRID:nlx_158484; RRID:nlx_158504
9.  Gestational ketogenic diet programs brain structure and susceptibility to depression & anxiety in the adult mouse offspring 
Brain and Behavior  2014;e00300.
Abstract
Introduction
The ketogenic diet (KD) has seen an increase in popularity for clinical and non‐clinical purposes, leading to rise in concern about the diet's impact on following generations. The KD is known to have a neurological effect, suggesting that exposure to it during prenatal brain development may alter neuro‐anatomy. Studies have also indicated that the KD has an anti‐depressant effect on the consumer. However, it is unclear whether any neuro‐anatomical and/or behavioral changes would occur in the offspring and persist into adulthood.
Methods
To fill this knowledge gap we assessed the brain morphology and behavior of 8‐week‐old young‐adult CD‐1 mice, who were exposed to the KD in utero, and were fed only a standard‐diet (SD) in postnatal life. Standardized neuro‐behavior tests included the Open‐Field, Forced‐Swim, and Exercise Wheel tests, and were followed by post‐mortem Magnetic Resonance Imaging (MRI) to assess brain anatomy.
Results
The adult KD offspring exhibit reduced susceptibility to anxiety and depression, and elevated physical activity level when compared with controls exposed to the SD both in utero and postnatally. Many neuro‐anatomical differences exist between the KD offspring and controls, including, for example, a cerebellar volumetric enlargement by 4.8%, a hypothalamic reduction by 1.39%, and a corpus callosum reduction by 4.77%, as computed relative to total brain volume.
Conclusions
These results suggest that prenatal exposure to the KD programs the offspring neuro‐anatomy and influences their behavior in adulthood.
doi:10.1002/brb3.300
PMCID: PMC4309881  PMID: 25642385
Behavior; development; ketogenic diet; magnetic resonance imaging; neuroimaging; prenatal programming
10.  Increased volume and impaired function: the role of the basal ganglia in writer's cramp 
Brain and Behavior  2014;e00301.
Abstract
Introduction
The pathophysiology of writer's cramp, a task‐specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writer's cramp patients.
Methods
We applied structural and functional imaging in 22 writer's cramp patients and 28 matched controls using 3T MRI. With the asymptomatic left hand all participants learned a complex, sequential, five‐element sequence‐tapping task as accurately and quickly as possible. Functional imaging was measured during a repeated (15 times), fixed block design with tapping (30 sec) and rest (30 sec). Additionally, gray matter volume of the basal ganglia was analyzed using voxel‐based morphometry (VBM).
Results
While behavior was comparable between groups, after small volume correction the anterior part of the right putamen and the left globus pallidus exhibited reduced blood oxygen level‐dependent (BOLD) activity in patients during the sequential finger‐tapping task. VBM analysis showed larger gray matter volume bilateral in the posterior part of the putamen and globus pallidus. There were no group differences in the cerebellum.
Conclusion
The results indicate an impairment of anterior basal ganglia loops involved in producing complex sequential movements of the unaffected hand. These findings are in line with previous reports of reduced neuronal activity in the globus pallidus internus. Higher gray matter volume of the putamen and globus pallidus may stem from elevated activity of the direct pathway, which could reflect a compensatory phenomenon or a primary predisposition, that is, endophenotypic trait.
doi:10.1002/brb3.301
PMCID: PMC4309880  PMID: 25642386
Focal hand dystonia; functional magnetic resonance imaging; motor learning; voxel‐based morphometry; writer's cramp
11.  Mean signal and response time influences on multivoxel signals of contextual retrieval in the medial temporal lobe 
Brain and Behavior  2014;e00302.
Abstract
Introduction
The medial temporal lobe supports integrating the “what,” “where,” and “when” of an experience into a unified memory. However, it remains unclear how representations of these contextual features are neurally encoded and distributed across medial temporal lobe subregions.
Methods
This study conducted functional magnetic resonance imaging of the medial temporal lobe, while participants retrieved pair, spatial, and temporal source memories. Multivoxel classifiers were trained to distinguish between retrieval conditions before and after correction for mean signal and response times, to more thoroughly characterize the multivoxel signal associated with memory context.
Results
Activity in perirhinal and parahippocampal cortex dissociated between memory for associated items and memory for their spatiotemporal context, and hippocampal activity was linked to memory for spatial context. However, perirhinal and hippocampal classifiers were, respectively, driven by effects of mean signal amplitude and task difficulty, whereas the parahippocampal classifier survived correction for these effects.
Conclusion
These findings demonstrate dissociable coding mechanisms for episodic memory context across the medial temporal lobe, and further highlight a critical distinction between multivoxel representations driven by spatially distributed activity patterns, and those driven by the regional signal.
doi:10.1002/brb3.302
PMCID: PMC4312925  PMID: 25646149
Episodic memory; fMRI; medial temporal lobe; multivoxel pattern analysis; retrieval
12.  Physiological reactivity to nonideographic virtual reality stimuli in veterans with and without PTSD 
Brain and Behavior  2014;e00304.
Abstract
Background
Post‐traumatic stress disorder (PTSD) currently is diagnosed via clinical interview in which subjective self reports of traumatic events and associated experiences are discussed with a mental health professional. The reliability and validity of diagnoses can be improved with the use of objective physiological measures.
Methods
In this study, physiological activity was recorded from 58 male veterans (PTSD Diagnosis n = 16; Trauma Exposed/No PTSD Diagnosis: n = 23; No Trauma/No PTSD Diagnosis: n = 19) with and without PTSD and combat trauma exposure in response to emotionally evocative non‐idiographic virtual reality stimuli.
Results
Statistically significant differences among the Control, Trauma, and PTSD groups were present during the viewing of two virtual reality videos. Skin conductance and interbeat interval features were extracted for each of ten video events (five events of increasing severity per video). These features were submitted to three stepwise discriminant function analyses to assess classification accuracy for Control versus Trauma, Control versus PTSD, and Trauma versus PTSD pairings of participant groups. Leave‐one‐out cross‐validation classification accuracy was between 71 and 94%.
Conclusions
These results are promising and suggest the utility of objective physiological measures in assisting with PTSD diagnosis.
doi:10.1002/brb3.304
PMCID: PMC4309895  PMID: 25642387
post‐traumatic stress disorder; diagnosis; skin conductance; interbeat interval; classification accuracy
13.  Intravoxel incoherent motion magnetic resonance imaging findings in the acute phase of MELAS: a case report 
Brain and Behavior  2014;4(6):798-800.
Objective
We report the clinical application of intravoxel incoherent motion (IVIM) magnetic resonance (MR) imaging to diagnose a case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in the acute phase.
Results
On IVIM MR Images of this patient, higher perfusion (f) and diffusion (D) values in the left occipital and temporal lobes were found compared to the contralateral areas.
Conclusion
These findings imply a breakdown of autoregulation with hyperperfusion and vasogenic edema during the acute phase of MELAS, as described in previous reports. IVIM imaging is a valuable, noninvasive tool that simultaneously quantifies perfusion and diffusion parameters.
doi:10.1002/brb3.282
PMCID: PMC4178247  PMID: 25365795
Diffusion MRI; IVIM; MELAS; perfusion MRI
14.  Impact of pregabalin treatment on synaptic plasticity and glial reactivity during the course of experimental autoimmune encephalomyelitis 
Brain and Behavior  2014;4(6):925-935.
Background
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin.
Aims
The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase.
Methods and results
The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment.
Conclusions
Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction.
doi:10.1002/brb3.276
PMCID: PMC4178248  PMID: 25365796
Experimental autoimmune encephalomyelitis; pregabalin; spinal motoneurons; synapse
15.  Reading acceleration training changes brain circuitry in children with reading difficulties 
Brain and Behavior  2014;4(6):886-902.
Introduction
Dyslexia is characterized by slow, inaccurate reading. Previous studies have shown that the Reading Acceleration Program (RAP) improves reading speed and accuracy in children and adults with dyslexia and in typical readers across different orthographies. However, the effect of the RAP on the neural circuitry of reading has not been established. In the current study, we examined the effect of the RAP training on regions of interest in the neural circuitry for reading using a lexical decision task during fMRI in children with reading difficulties and typical readers.
Methods
Children (8–12 years old) with reading difficulties and typical readers were studied before and after 4 weeks of training with the RAP in both groups.
Results
In addition to improvements in oral and silent contextual reading speed, training-related gains were associated with increased activation of the left hemisphere in both children with reading difficulties and typical readers. However, only children with reading difficulties showed improvements in reading comprehension, which were associated with significant increases in right frontal lobe activation.
Conclusions
Our results demonstrate differential effects of the RAP on neural circuits supporting reading in both children with reading difficulties and typical readers and suggest that the intervention may stimulate use of typical neural circuits for reading and engage compensatory pathways to support reading in the developing brain of children with reading difficulties.
doi:10.1002/brb3.281
PMCID: PMC4178249  PMID: 25365797
Children; dyslexia; fluency; imaging; reading
16.  Estimating intracranial volume using intracranial area in healthy children and those with childhood status epilepticus 
Brain and Behavior  2014;4(6):936-942.
Background
Correcting volumetric measurements of brain structures for intracranial volume (ICV) is important in comparing volumes across subjects with different ICV. The aim of this study was to investigate whether intracranial area (ICA) reliably predicts actual ICV in a healthy pediatric cohort and in children with convulsive status epilepticus (CSE).
Methods
T1-weighted volumetric MRI was performed on 20 healthy children (control group), 10 with CSE with structurally normal MRI (CSE/MR-), and 12 with CSE with structurally abnormal MRI (CSE/MR+). ICA, using a mid-sagittal slice, and the actual ICV were measured.
Results
A high Spearman correlation was found between the ICA and ICV measurements in the control (r = 0.96; P < 0.0001), CSE/MR− (r = 0.93; P = 0.0003), and CSE/MR+ (r = 0.94; P < 0.0001) groups. On comparison of predicted and actual ICV, there was no significant difference in the CSE/MR− group (P = 0.77). However, the comparison between predicted and actual ICV was significantly different in the CSE/MR+ (P = 0.001) group. Our Bland–Altman plot showed that the ICA method consistently overestimated ICV in children in the CSE/MR+ group, especially in those with small ICV or widespread structural abnormalities.
Conclusions
After further validation, ICA measurement may be a reliable alternative to measuring actual ICV when correcting volume measurements for ICV, even in children with localized MRI abnormalities. Caution should be applied when the method is used in children with small ICV and those with multilobar brain pathology.
doi:10.1002/brb3.271
PMCID: PMC4178250  PMID: 25365798
Epilepsy; intracranial area; intracranial volume; pediatric; volumetric
17.  Comparative efficacy of different acute reperfusion therapies for acute ischemic stroke: a comprehensive benefit–risk analysis of clinical trials 
Brain and Behavior  2014;4(6):789-797.
Background
Numerous acute reperfusion therapies (RPT) are currently investigated as potential new therapeutic targets in acute ischemic stroke (AIS). We conducted a comprehensive benefit–risk analysis of available clinical studies assessing different acute RPT, and investigated the utility of each intervention in comparison to standard intravenous thrombolysis (IVT) and in relation to the onset-to-treatment time (OTT).
Methods
A comprehensive literature search was conducted to identify all available published, peer-reviewed clinical studies that evaluated the efficacy of different RPT in AIS. Benefit-to-risk ratio (BRR), adjusted for baseline stroke severity, was estimated as the percentage of patients achieving favorable functional outcome (BRR1, mRS score: 0–1) or functional independence (BRR2, mRS score: 0–2) at 3 months divided by the percentage of patients who died during the same period.
Results
A total of 18 randomized (n = 13) and nonrandomized (n = 5) clinical studies fulfilled our inclusion criteria. IV therapy with tenecteplase (TNK) was found to have the highest BRRs (BRR1 = 5.76 and BRR2 = 6.82 for low-dose TNK; BRR1 = 5.80 and BRR2 = 6.87 for high-dose TNK), followed by sonothrombolysis (BRR1 = 2.75 and BRR2 = 3.38), while endovascular thrombectomy with MERCI retriever was found to have the lowest BRRs (BRR1 range, 0.31–0.65; BRR2 range, 0.52–1.18). A second degree negative polynomial correlation was detected between favorable functional outcome and OTT (R2 value: 0.6419; P < 0.00001) indicating the time dependency of clinical efficacy of all reperfusion therapies.
Conclusion
Intravenous thrombolysis (IVT) with TNK and sonothrombolysis have the higher BRR among investigational reperfusion therapies. The combination of sonothrombolysis with IV administration of TNK appears a potentially promising therapeutic option deserving further investigation.
doi:10.1002/brb3.279
PMCID: PMC4178251  PMID: 25365799
Acute stroke; analysis; benefit-to-risk ratio; reperfusion therapies
18.  Winning and losing: differences in reward and punishment sensitivity between smokers and nonsmokers 
Brain and Behavior  2014;4(6):915-924.
Background
Smokers show increased brain activation in reward processing regions in response to smoking-related cues, yet few studies have examined secondary rewards not associated with smoking (i.e., money). Inconsistencies exist in the studies that do examine secondary rewards with some studies showing increased brain activation in reward processing brain regions, while others show decreased activation or no difference in activation between smokers and nonsmokers.
Aims
The goal of the current study is to see if smokers process the evaluation and delivery of equally salient real world rewards similarly or differently than nonsmokers.
Methods
The current study employed functional magnetic resonance imaging (fMRI) to examine brain responses in smokers and nonsmokers during the evaluation and delivery of monetary gains and losses.
Results
In comparison to nonsmokers, smokers showed increased activation in the ventromedial prefrontal cortex to the evaluation of anticipated monetary losses and the brain response. Moreover, smokers compared to nonsmokers showed decreased activation in the inferior frontal gyrus to the delivery of expected monetary gains. Brain activations to both the evaluation of anticipated monetary losses and the delivery of expected monetary gains correlated with increased self-reported smoking craving to relieve negative withdrawal symptoms and craving related to positive aspects of smoking, respectively.
Discussion
Together these results indicate that smokers are hyperresponsive to the evaluation of anticipated punishment and hyporesponsive to the delivery of expected rewards. Although further research is needed, this hypersensitivity to punishments coupled with increased craving may negatively impact quit attempts as smokers anticipate the negative withdrawal symptoms associated with quitting.
doi:10.1002/brb3.285
PMCID: PMC4178298  PMID: 25365800
fMRI; punishment sensitivity; reward sensitivity; smoking
19.  Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study 
Brain and Behavior  2014;4(6):867-876.
Introduction
Childhood maltreatment, a well-known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.
Methods
We conducted a pilot study of the relationship between childhood maltreatment (evaluated with the Childhood Trauma Questionnaire; Bernstein and Fink 1998) and resting-state functional connectivity of the amygdala (bilateral region of interest) with functional magnetic resonance imaging in 15 abstinent, methamphetamine-dependent research participants. Within regions that showed connectivity with the amygdala as a function of maltreatment, we also evaluated whether amygdala connectivity was associated positively with negative affect and negatively with healthy emotional processing.
Results
The results indicated that childhood maltreatment was positively associated with resting-state connectivity between the amygdala and right hippocampus, right parahippocampal gyrus, right inferior temporal gyrus, right orbitofrontal cortex, cerebellum, and brainstem. Furthermore, connectivity between the amygdala and hippocampus was positively related to measures of depression, trait anxiety, and emotion dysregulation, and negatively related to self-compassion and dispositional mindfulness.
Conclusions
These findings suggest that childhood maltreatment may contribute to increased limbic connectivity and maladaptive emotional processing in methamphetamine-dependent adults, and that healthy emotion regulation strategies may serve as a therapeutic target to ameliorate the associated behavioral phenotype. Childhood maltreatment warrants further investigation as a potentially important etiological factor in the neurobiology and treatment of substance use disorders.
doi:10.1002/brb3.289
PMCID: PMC4178299  PMID: 25365801
Amygdala; brain imaging; childhood; connectivity; drug; fMRI; maltreatment; methamphetamine; substance abuse; trauma
20.  Task-dependent reorganization of functional connectivity networks during visual semantic decision making 
Brain and Behavior  2014;4(6):877-885.
Introduction
Functional MRI is widely used to study task-related changes in neuronal activity as well as resting-state functional connectivity. In this study, we explore task-related changes in functional connectivity networks using fMRI. Dynamic connectivity may represent a new measure of neural network robustness that would impact both clinical and research efforts. However, prior studies of task-related changes in functional connectivity have shown apparently conflicting results, leading to several competing hypotheses regarding the relationship between task-related and resting-state brain networks.
Methods
We used a graph theory-based network approach to compare functional connectivity in healthy subjects between the resting state and when performing a clinically used semantic decision task. We analyzed fMRI data from 21 healthy, right-handed subjects.
Results
While three nonoverlapping, highly intraconnected functional modules were observed in the resting state, an additional language-related module emerged during the semantic decision task. Both overall and within-module connectivity were greater in default mode network (DMN) and classical language areas during semantic decision making compared to rest, while between-module connectivity was diffusely greater at rest, revealing a more widely distributed pattern of functional connectivity at rest.
Conclusions
The results of this study suggest that there are differences in network topology between resting and task states. Specifically, semantic decision making is associated with a reduction in distributed connectivity through hub areas of the DMN as well as an increase in connectivity within both default and language networks.
doi:10.1002/brb3.286
PMCID: PMC4178300  PMID: 25365802
Connectomics; default mode network; functional magnetic resonance imaging; graph theory; language; memory; resting state
21.  Type 1 equilibrative nucleoside transporter regulates astrocyte-specific glial fibrillary acidic protein expression in the striatum 
Brain and Behavior  2014;4(6):903-914.
Background
Adenosine signaling has been implicated in several neurological and psychiatric disorders. Previously, we found that astrocytic excitatory amino acid transporter 2 (EAAT2) and aquaporin 4 (AQP4) are downregulated in the striatum of mice lacking type 1 equilibrative nucleoside transporter (ENT1).
Methods
To further investigate the gene expression profile in the striatum, we preformed Illumina Mouse Whole Genome BeadChip microarray analysis of the caudate–putamen (CPu) and nucleus accumbens (NAc) in ENT1 null mice. Gene expression was validated by RT-PCR, Western blot, and immunofluorescence. Using transgenic mice expressing enhanced green fluorescence protein (EGFP) under the control of the glial fibrillary acidic protein (GFAP) promoter, we examined EGFP expression in an ENT1 null background.
Results
Glial fibrillary acidic protein was identified as a top candidate gene that was reduced in ENT1 null mice compared to wild-type littermates. Furthermore, EGFP expression was significantly reduced in GFAP-EGFP transgenic mice in an ENT1 null background in both the CPu and NAc. Finally, pharmacological inhibition or siRNA knockdown of ENT1 in cultured astrocytes also reduced GFAP mRNA levels.
Conclusions
Overall, our findings demonstrate that ENT1 regulates GFAP expression and possibly astrocyte function.
doi:10.1002/brb3.283
PMCID: PMC4178301  PMID: 25365803
Adenosine transporter; astrocyte; ENT1; GFAP; microarray
22.  Correlations between brain structures and study time at home in healthy children: a longitudinal analysis 
Brain and Behavior  2014;4(6):801-811.
Introduction
Like sleeping and eating habits, the study habits adopted by children when they are at home are important contributors to lifestyle and they affect cognitive ability. It has recently been reported that sleeping and eating habits change the brain structure of children. However, no research on the effect of study habits at home on the brain structure of children has been conducted thus far. We investigated the effects of study habits at home on the brain structures of healthy children by examining correlations between study time at home and changes in brain structure over the course of 3 years.
Methods
We used the brain magnetic resonance images of 229 healthy children aged 5.6–18.4 years and computed the changes (time 2–time 1) in regional gray matter and white matter volume (rWMV) using voxel-based morphometry. Whole-brain multiple regression analysis revealed a significant positive correlation between study time at home and changes in rWMV in the right superior frontal gyrus (SFG). Behaviorally, we found a significant positive correlation between study time at home and change in the verbal comprehension index (VCI), one of the subscales of the Wechsler Intelligence Scale for Children–third edition (WISC–III).
Results and Conclusions
Given that the SFG is involved in memory control and that the VCI measures abilities related to vocabulary, our results indicate that greater SFG involvement in the memorization component of longer study times may result in greater increases in the number of axons and more axon branching and myelination, causing plastic changes in the neural network involved in memory processes.
doi:10.1002/brb3.278
PMCID: PMC4212108  PMID: 25365804
Children; study time at home; verbal; white matter volume
23.  Genetic variation in GABRA2 moderates peer influence on externalizing behavior in adolescents 
Brain and Behavior  2014;4(6):833-840.
Background
Genetic predisposition and environmental influences are both important factors in the development of problematic behavior leading to substance use in adolescence. Involvement with delinquent peers also strongly predicts adolescent externalizing behavior. Several lines of evidence support a role of GABRA2 on externalizing behavior related to disinhibition. However, whether this genetic association is influenced by the environment such as peer behavior remains unknown.
Methods
We examined the moderating role of GABRA2 genetic variation on the socialization model of delinquent peer affiliation (at ages 12–14 years) on externalizing behavior (at ages 15–17 years) in the Michigan Longitudinal Study (MLS) adolescent sample.
The sample consisted of 244 adolescents (75 females and 152 with at least one parent with a DSM-IV lifetime alcohol dependence/abuse diagnosis). Peer delinquent activity reported by the participant and teacher-reported adolescent externalizing behavior (Teacher Report Form (TRF) were assessed.
Results
No main effect of the GABRA2 SNP rs279826, which tags a large haplotype, on externalizing behavior was observed. However, there was a statistically reliable GABRA2 × peer delinquency interaction. The effect of peer delinquent involvement on externalizing scores and the rule breaking subscale is significantly stronger for those with the GG genotype compared to A-carriers, whereas there was no effect of genotype on externalizing in the absence of peer delinquent involvement. No interaction was observed for the aggression subscale.
Conclusion
Our results suggest that the genetic effect of GABRA2 on externalizing behavior, more specifically on rule breaking is, at least in part, due to its effect on susceptibility to environmental exposure (i.e., peer delinquency).
doi:10.1002/brb3.291
PMCID: PMC4212110  PMID: 25365806
Adolescence; externalizing; GABRA2; gene–environment interaction; peer delinquency
24.  Differentiation of primary central nervous system lymphoma from high-grade glioma and brain metastases using susceptibility-weighted imaging 
Brain and Behavior  2014;4(6):841-849.
Background and Purpose
Conventional MRI is often difficult to distinguish between primary central nervous system lymphomas (PCNSLs), high-grade gliomas and brain metastases due to the similarity of their appearance. The aim of this study was to investigate whether the susceptibility-weighted imaging (SWI) has higher sensitivity than conventional MRI in detecting hemorrhage between PCNSLs, high-grade gliomas and brain metastases, and can be used to differentiate the diagnosis between these tumors.
Methods
The number of lesions with hemorrhage was quantified by both the conventional MR imaging and SWI. The number of micro-hemorrhage and vessels within lesions were counted on SWI.
Results
The detection rate of hemorrhage on SWI was significantly higher than that on the conventional MR imaging. The intralesional hemorrhagic burden and the number of the vessels within lesions detected by SWI were significantly higher in high-grade gliomas and brain metastases than those in PCNSLs. There was no significant difference in these two parameters between high-grade gliomas and brain metastases. The best predictor to differentiate PCNSLs from high-grade gliomas and brain metastases was intralesional vessel number that yielded the best ROC characteristics and highest classification accuracy.
Conclusions
SWI is useful in differentiating of PCNSLs from high-grade gliomas and brain metastases.
doi:10.1002/brb3.288
PMCID: PMC4212111  PMID: 25365807
Brain metastases; differential diagnosis of intracranial malignancies; high-grade glioma; primary CNS lymphoma; susceptibility-weighted imaging
25.  Genetic basis of delay discounting in frequent gamblers: examination of a priori candidates and exploration of a panel of dopamine-related loci 
Brain and Behavior  2014;4(6):812-821.
Introduction
Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards. It has been consistently linked to pathological gambling and other forms of addictive behavior, and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders (i.e., an endophenotype). Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission. The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers.
Methods
Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva.
Results
In a priori tests, two loci previously associated with delayed reward discounting (rs1800497 and rs4680) were not replicated, however, the long form of DRD4 VNTR was significantly associated with lower discounting of delayed rewards. Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis, breakdown, reuptake, and receptor function (DRD3, SLC6A3, DDC, DBH, and SLC18A2). An aggregate genetic risk score from the nominally significant loci accounted for 17% of the variance in discounting. Mediational analyses largely supported the presence of indirect effects between the associated loci, delay discounting, and pathological gambling severity.
Conclusions
These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting.
doi:10.1002/brb3.284
PMCID: PMC4212112  PMID: 25365808
Delay discounting; dopamine; endophenotype; genetics; impulsivity; pathological gambling

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