Pipes Output http://pipes.yahoo.com/pipes/pipe.info?_id=9b0454f0547e7cb2cc98919ca4118ed6 Thu, 01 Oct 2015 21:54:29 +0000 http://pipes.yahoo.com/pipes/ http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23002 This meta-analytic connectivity modeling (MACM) study explores the functional connectivity of the cerebellum with the cerebrum in social cognitive processes. In a recent meta-analysis, Van Overwalle, Baetens, Mariën, and Vandekerckhove () documented that the cerebellum is implicated in social processes of “body” reading (mirroring; e.g., understanding other persons' intentions from observing their movements) and “mind” reading (mentalizing, e.g., inferring other persons' beliefs, intentions or personality traits, reconstructing persons' past, future, or hypothetical events). In a recent functional connectivity study, Buckner et al. () offered a novel parcellation of cerebellar topography that substantially overlaps with the cerebellar meta-analytic findings of Van Overwalle et al. (). This overlap suggests that the involvement of the cerebellum in social reasoning depends on its functional connectivity with the cerebrum. To test this hypothesis, we explored the meta-analytic co-activations as indices of functional connectivity between the cerebellum and the cerebrum during social cognition. The MACM results confirm substantial and distinct connectivity with respect to the functions of (a) action understanding (“body” reading) and (b) mentalizing (“mind” reading). The consistent and strong connectivity findings of this analysis suggest that cerebellar activity during social judgments reflects distinct mirroring and mentalizing functionality, and that these cerebellar functions are connected with corresponding functional networks in the cerebrum. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 30 Sep 2015 03:09:26 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23003 The intrinsic relationship between the convoluted cortical folding and the underlying complex whiter matter fiber connections has received increasing attention in current neuroscience studies. Recently, the axonal pushing hypothesis of cortical folding has been proposed to explain the finding that the axonal fibers (derived from diffusion tensor images) connecting to gyri are significantly denser than those connecting to sulci in both adult human and non-human primate brains. However, it is still unclear about the spatiotemporal patterns of the fiber density on the cortical surface of the developing infant brains from birth to 2 years of age, which is the most dynamic phase of postnatal brain development. In this paper, for the first time, we systemically characterized the spatial distributions and longitudinal developmental trajectories of the cortical fiber density in the first 2 postnatal years, via joint analysis of longitudinal structural and diffusion tensor imaging from 33 healthy infants. We found that the cortical fiber density increases dramatically in the first year and then keeps relatively stable in the second year. Moreover, we revealed that the cortical fiber density on gyral regions was significantly higher at 0, 1, and 2 years of age than that on sulcal regions in the frontal, temporal, and parietal lobes. Meanwhile, the cortical fiber density was strongly positively correlated with cortical thickness at several three-hinge junction regions of gyri. These results significantly advanced our understanding of the intrinsic relationship between the cortical folding, cortical thickness and axonal wiring during early postnatal stages. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:57:49 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23004 Focusing attention on a target creates a center-surround inhibition such that distractors located close to the target do not capture attention. Recent research showed that a distractor can break through this surround inhibition when associated with reward. However, the brain basis for this reward-based attention is unclear. In this fMRI study, we presented a distractor associated with high or low reward at different distances from the target. Behaviorally the low-reward distractor did not capture attention and thus did not cause interference, whereas the high-reward distractor captured attention only when located near the target. Neural activity in extrastriate cortex mirrored the behavioral pattern. A comparison between the high-reward and the low-reward distractors presented near the target (i.e., reward-based attention) and a comparison between the high-reward distractors located near and far from the target (i.e., spatial attention) revealed a common frontoparietal network, including inferior frontal gyrus and inferior parietal sulcus as well as the visual cortex. Reward-based attention specifically activated the anterior insula (AI). Dynamic causal modelling showed that reward modulated the connectivity from AI to the frontoparietal network but not the connectivity from the frontoparietal network to the visual cortex. Across participants, the reward-based attentional effect could be predicted both by the activity in AI and by the changes of spontaneous functional connectivity between AI and ventral striatum before and after reward association. These results suggest that AI encodes reward-based salience and projects it to the stimulus-driven attentional network, which enables the reward-associated distractor to break through the surround inhibition in the visual cortex. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:57:21 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23006 Suppression of 5–25 Hz oscillations have been observed in MT+ during pursuit eye movements, suggesting oscillations that play a role in oculomotor control and/or the integration of extraretinal signals during pursuit. The amplitude of these rhythms appears to covary with head-centered eye position, but an alternative is that they depend on a velocity signal that lags the movement of the eyes. To investigate, we explored how alpha and beta amplitude changes related to ongoing eye movement depended on pursuit at different eccentricities. The results revealed largely identical patterns of modulation in the alpha and beta amplitude, irrespective of the eccentricity at which the pursuit eye movement was performed. The signals we measured therefore do not depend on head-centered position. A second experiment was designed to investigate whether the alpha and beta oscillations depended on the direction of pursuit, as opposed to just speed. We found no evidence that alpha or beta oscillations depended on direction, but there was a significant effect of eye speed on the magnitude of the beta suppression. This suggests distinct functional roles for alpha and beta suppression in pursuit behavior. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:56:57 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23005 In anorexia nervosa, problems with social relationships contribute to illness, and improvements in social support are associated with recovery. Using the multiround trust game and 3T MRI, we compare neural responses in a social relationship in three groups of women: women with anorexia nervosa, women in long-term weight recovery from anorexia nervosa, and healthy comparison women. Surrogate markers related to social signals in the game were computed each round to assess whether the relationship was improving (benevolence) or deteriorating (malevolence) for each subject. Compared with healthy women, neural responses to benevolence were diminished in the precuneus and right angular gyrus in both currently-ill and weight-recovered subjects with anorexia, but neural responses to malevolence differed in the left fusiform only in currently-ill subjects. Next, using a whole-brain regression, we identified an office assessment, the positive personalizing bias, that was inversely correlated with neural activity in the occipital lobe, the precuneus and posterior cingulate, the bilateral temporoparietal junctions, and dorsal anterior cingulate, during benevolence for all groups of subjects. The positive personalizing bias is a self-report measure that assesses the degree with which a person attributes positive experiences to other people. These data suggest that problems in perceiving kindness may be a consistent trait related to the development of anorexia nervosa, whereas recognizing malevolence may be related to recovery. Future work on social brain function, in both healthy and psychiatric populations, should consider positive personalizing biases as a possible marker of neural differences related to kindness perception. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:56:19 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23007 Group-level functional connectivity analyses often aim to detect the altered connectivity patterns between subgroups with different clinical or psychological experimental conditions, for example, comparing cases and healthy controls. We present a new statistical method to detect differentially expressed connectivity networks with significantly improved power and lower false-positive rates. The goal of our method was to capture most differentially expressed connections within networks of constrained numbers of brain regions (by the rule of parsimony). By virtue of parsimony, the false-positive individual connectivity edges within a network are effectively reduced, whereas the informative (differentially expressed) edges are allowed to borrow strength from each other to increase the overall power of the network. We develop a test statistic for each network in light of combinatorics graph theory, and provide p-values for the networks (in the weak sense) by using permutation test with multiple-testing adjustment. We validate and compare this new approach with existing methods, including false discovery rate and network-based statistic, via simulation studies and a resting-state functional magnetic resonance imaging case–control study. The results indicate that our method can identify differentially expressed connectivity networks, whereas existing methods are limited. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:55:55 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23008 Simultaneous collection of scalp EEG and fMRI has become an important tool for studying the hemodynamic changes associated with interictal epileptiform discharges (IEDs) in persons with epilepsy, and has become a standard presurgical assessment tool in some centres. We previously demonstrated that performing EEG-fMRI using intracranial electrodes (iEEG-fMRI) is of low risk to patients in our research centre, and offers unique insight into BOLD signal changes associated with IEDs recorded from very discrete sources. However, it is unknown whether the BOLD response corresponding to IEDs recorded by iEEG-fMRI follows the canonical hemodynamic response. We therefore scanned 11 presurgical epilepsy patients using iEEG-fMRI, and assessed the hemodynamic response associated with individual IEDs using two methods: assessment of BOLD signal changes associated with isolated IEDs at the location of the active intracranial electrode, and by estimating subject-specific impulse response functions to isolated IEDs. We found that the hemodynamic response associated with the intracranially recorded discharges varied by patient and by spike location. The observed shape and timing differences also deviated from the canonical hemodynamic response function traditionally used in many fMRI experiments. It is recommended that future iEEG-fMRI studies of IEDs use a flexible hemodynamic response model when performing parametric tests to accurately characterize these data. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:55:26 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23010 Worldwide racial prejudice is originated from in-group/out-group discrimination. This prejudice can bias face perception at the very beginning of social interaction. However, little is known about the neurocognitive mechanism underlying the influence of racial prejudice on facial emotion perception. Here, we examined the neural basis of disgust perception in racial prejudice using a passive viewing task and functional magnetic resonance imaging. We found that compared with the disgusted faces of in-groups, the disgusted faces of out-groups result in increased amygdala and insular engagement, positive coupling of the insula with amygdala-based emotional system, and negative coupling of the insula with anterior cingulate cortex (ACC)-based regulatory system. Furthermore, machine-learning algorithms revealed that the level of implicit racial prejudice could be predicted by functional couplings of the insula with both the amygdala and the ACC, which suggests that the insula is largely involved in racially biased disgust perception through two distinct neural circuits. In addition, individual difference in disgust sensitivity was found to be predictive of implicit racial prejudice. Taken together, our results suggest a crucial role of insula-centered circuits for disgust perception in racial prejudice. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:55:04 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23009 Individuals who are born blind due to dense bilateral cataracts and who later regain vision due to cataract surgery provide a unique model to evaluate the effect of early sensory experience in humans. In recent years, several studies have started to assess the functional consequences of early visual deprivation in these individuals, revealing a number of behavioral impairments in visual and multisensory functions. In contrast, the extent to which a transient period of congenital visual deprivation impacts brain structure has not yet been investigated. The present study investigated this by assessing cortical thickness of occipital areas in a group of six cataract-reversal individuals and a group of six age-matched normally sighted controls. This analysis revealed higher cortical thickness in cataract-reversal individuals in the left calcarine sulcus, in the superior occipital gyrus and in the transverse occipital sulcus bilaterally. In addition, occipital cortical thickness correlated negatively with behavioral performance in an audio–visual task for which visual input was critical, and positively with behavioral performance in auditory tasks. Together, these results underscore the critical role of early sensory experience in shaping brain structure and suggest that increased occipital cortical thickness, while potentially compensatory for auditory sensory processing, might be maladaptive for visual recovery in cases of sight restoration. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 06:54:42 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22997 Motor fMRI studies, comparing dominant (DH) and nondominant (NDH) hand activations have reported mixed findings, especially for the extent of ipsilateral (IL) activations and their relationship with task complexity. To date, no study has directly compared DH and NDH activations using an event-related visually guided dynamic power-grip paradigm with parametric (three) forces (GF) in healthy right-handed subjects. We implemented a hierarchical statistical approach aimed to: (i) identify the main effect networks engaged when using either hand; (ii) characterise DH/NDH responses at different GFs; (iii) assess contralateral (CL)/IL-specific and hemisphere-specific activations. Beyond confirming previously reported results, this study demonstrated that increasing GF has an effect on motor response that is contextualised also by the use of DH or NDH. Linear analysis revealed increased activations in sensorimotor areas, with additional increased recruitments of subcortical and cerebellar areas when using the NDH. When looking at CL/IL-specific activations, CL sensorimotor areas and IL cerebellum were activated with both hands. When performing the task with the NDH, several areas were also recruited including the CL cerebellum. Finally, there were hand-side-independent activations of nonmotor-specific areas in the right and left hemispheres, with the right hemisphere being involved more extensively in sensori-motor integration through associative areas while the left hemisphere showing greater activation at higher GF. This study shows that the functional networks subtending DH/NDH power-grip visuomotor functions are qualitatively and quantitatively distinct and this should be taken into consideration when performing fMRI studies, particularly when planning interventions in patients with specific impairments. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 00:56:59 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23001 To maintain steady motor output, distracting sensory stimuli need to be blocked. To study the effects of brief auditory and visual distractors on the human primary motor (M1) cortex, we monitored magnetoencephalographic (MEG) cortical rhythms, electromyogram (EMG) of finger flexors, and corticomuscular coherence (CMC) during right-hand pinch (force 5–7% of maximum) while 1-kHz tones and checkerboard patterns were presented for 100 ms once every 3.5–5 s. Twenty-one subjects (out of twenty-two) showed statistically significant ∼20-Hz CMC. Both distractors elicited a covert startle-like response evident in changes of force and EMG (∼50% of the background variation) but without any visible movement, followed by ∼1-s enhancement of CMC (auditory on average by 75%, P < 0.001; visual by 33%, P < 0.05) and rolandic ∼20-Hz rhythm (auditory by 14%, P < 0.05; visual by 11%, P < 0.01). Directional coupling of coherence from muscle to the M1 cortex (EMGMEG) increased for ∼0.5 s at the onset of the CMC enhancement, but only after auditory distractor (by 105%; P < 0.05), likely reflecting startle-related proprioceptive afference. The 20-Hz enhancements occurred in the left M1 cortex and were for the auditory stimuli preceded by an early suppression (by 7%, P < 0.05). Task-unrelated distractors modulated corticospinal coupling at ∼20 Hz. We propose that the distractors triggered covert startle-like responses, resulting in proprioceptive afference to the cortex, and that they also transiently disengaged the subject's attention from the fine-motor task. As a result, the corticospinal output was readjusted to keep the contraction force stable. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 29 Sep 2015 00:55:34 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22933 Regional specialization and functional integration are often viewed as two fundamental principles of human brain organization. They are closely intertwined because each functionally specialized brain region is probably characterized by a distinct set of long-range connections. This notion has prompted the quickly developing family of connectivity-based parcellation (CBP) methods in neuroimaging research. CBP assumes that there is a latent structure of parcels in a region of interest (ROI). First, connectivity strengths are computed to other parts of the brain for each voxel/vertex within the ROI. These features are then used to identify functionally distinct groups of ROI voxels/vertices. CBP enjoys increasing popularity for the in-vivo mapping of regional specialization in the human brain. Due to the requirements of different applications and datasets, CBP has diverged into a heterogeneous family of methods. This broad overview critically discusses the current state as well as the commonalities and idiosyncrasies of the main CBP methods. We target frequent concerns faced by novices and veterans to provide a reference for the investigation and review of CBP studies. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Sun, 27 Sep 2015 07:40:30 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.23000 Cortical oscillatory dynamics are known to be critical for human movement, although their functional significance remains unclear. In particular, there is a strong beta (15–30 Hz) desynchronization that begins before movement onset and continues during movement, before rebounding after movement termination. Several studies have connected this response to motor planning and/or movement selection operations, but to date such studies have examined only the early aspects of the response (i.e., before movement) and a limited number of parameters. In this study, we used magnetoencephalography (MEG) and a novel motor sequence paradigm to probe how motor plan complexity modulates peri-movement beta oscillations, and connectivity within activated circuits. We also examined the dynamics by imaging beta activity before and during movement execution and extracting virtual sensors from key regions. We found stronger beta desynchronization during complex relative to simple sequences in the right parietal and left dorsolateral prefrontal cortex (DLPFC) during movement execution. There was also an increase in functional connectivity between the left DLPFC and right parietal shortly after movement onset during complex but not simple sequences, which produced a significant conditional effect (i.e., complex > simple) that was not attributable to differences in response amplitude. This study is the first to demonstrate that complexity modulates the dynamics of the peri-movement beta ERD, which provides crucial new data on the functional role of this well-known oscillatory motor response. These data further suggest that execution of complex motor behavior may recruit key regions of the fronto-parietal network, in addition to traditional sensorimotor regions. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Fri, 25 Sep 2015 12:21:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22998 Gyrification brain abnormalities are considered a marker of early deviations from normal developmental trajectories and a putative predictor of poor outcome in psychiatric disorders. The aim of this study was to explore cortical folding morphology in patients with anorexia nervosa (AN). A MRI brain study was conducted on 38 patients with AN, 20 fully recovered patients, and 38 healthy women. Local gyrification was measured with procedures implemented in FreeSurfer. Vertex-wise comparisons were carried out to compare: (1) AN patients and healthy women; (2) patients with a full remission at a 3-year longitudinal follow-up assessment and patients who did not recover. AN patients exhibited significantly lower gyrification when compared with healthy controls. Patients with a poor 3-year outcome had significantly lower baseline gyrification when compared to both healthy women and patients with full recovery at follow-up, even after controlling for the effects of duration of illness and gray matter volume. No significant correlation has been found between gyrification, body mass index, amount of weight loss, onset age, and duration of illness. Brain gyrification significantly predicted outcome at follow-up even after controlling for the effects of duration of illness and other clinical prognostic factors. Although the role of starvation in determining our findings cannot be excluded, our study showed that brain gyrification might be a predictor of outcome in AN. Further studies are needed to understand if brain gyrification abnormalities are indices of early neurodevelopmental alterations, the consequence of starvation, or the interaction between both factors. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 16 Sep 2015 10:57:25 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22996 The existence of a behavioral advantage of bilinguals over monolinguals during executive tasks is controversial. A new approach to this issue is to investigate the effect of bilingualism on neural control when performing these tasks as a window to understand when behavioral differences are produced. Here, we tested if early bilinguals use more language-related networks than monolinguals while performing a go/no-go task that includes infrequent no-go and go trials. The RTs and accuracy in both groups did not differ. An independent component analyses (ICA) revealed, however, that bilinguals used the left fronto-parietal network and the salience network more than monolinguals while processing go infrequent cues and no-go cues, respectively. It was noteworthy that the modulation of these networks had opposite correlates with performance in bilinguals and monolinguals, which suggests that between-group differences were more qualitative than quantitative. Our results suggest that bilinguals may differently develop the involvement of the executive control networks that comprise the left inferior frontal gyrus during cognitive control tasks than monolinguals. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 16 Sep 2015 10:56:32 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22949 Autism spectrum disorder (ASD) is characterized by substantial social deficits. The notion that dysfunctions in neural circuits involved in sharing another's affect explain these deficits is appealing, but has received only modest experimental support. Here we evaluated a complex paradigm on the vicarious social pain of embarrassment to probe social deficits in ASD as to whether it is more potent than paradigms currently in use. To do so we acquired pupillometry and fMRI in young adults with ASD and matched healthy controls. During a simple vicarious physical pain task no differences emerged between groups in behavior, pupillometry, and neural activation of the anterior insula (AIC) and anterior cingulate cortex (ACC). In contrast, processing complex vicarious social pain yielded reduced responses in ASD on all physiological measures of sharing another's affect. The reduced activity within the AIC was thereby explained by the severity of autistic symptoms in the social and affective domain. Additionally, behavioral responses lacked correspondence with the anterior cingulate and anterior insula cortex activity found in controls. Instead, behavioral responses in ASD were associated with hippocampal activity. The observed dissociation echoes the clinical observations that deficits in ASD are most pronounced in complex social situations and simple tasks may not probe the dysfunctions in neural pathways involved in sharing affect. Our results are highly relevant because individuals with ASD may have preserved abilities to share another's physical pain but still have problems with the vicarious representation of more complex emotions that matter in life. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:53:19 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22953 Humans have the unique capacity to actively reflect on the thoughts, beliefs, and knowledge of others, but do we also track mental states spontaneously when observing other people? We asked this question by monitoring brain activity in belief-sensitive cortex using functional near-infrared spectroscopy (fNIRS) during free-viewing of social videos. More specifically, we identified a portion of the right temporal-parietal junction (rTPJ) selective for mental state processing using an established, explicit theory of mind task, and then analyzed the brain response in that region of interest (ROI) during free-viewing of video clips involving people producing goal-directed actions. We found a significant increase in oxygenated hemoglobin concentration in our rTPJ ROI during free-viewing for all of our test videos. Activity in this region was further modulated by the extent to which the knowledge state, or beliefs, of the protagonist regarding the location of an object contrasted with the reality of where the object was hidden. Open-ended questioning suggested our participants were not explicitly focusing on belief states of the characters during free-viewing. Further analyses ruled out lower-level details of the video clips or general attentional differences between conditions as likely explanations for the results. As such, these results call into question the traditional characterization of theory of mind as a resource intensive, deliberate process, and, instead, support an emerging view of theory of mind as a foundation for, rather than the pinnacle of, human social cognition. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:52:32 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22951 Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles. Hum Brain Mapp, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA Mon, 14 Sep 2015 07:52:02 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22988 The brain is a network and our intelligence depends in part on the efficiency of this network. The network of adolescents differs from that of adults suggesting developmental changes. However, whether the network changes over time at the individual level and, if so, how this relates to intelligence, is unresolved in adolescence. In addition, the influence of genetic factors in the developing network is not known. Therefore, in a longitudinal study of 162 healthy adolescent twins and their siblings (mean age at baseline 9.9 [range 9.0–15.0] years), we mapped local and global structural network efficiency of cerebral fiber pathways (weighted with mean FA and streamline count) and assessed intelligence over a three-year interval. We find that the efficiency of the brain's structural network is highly heritable (locally up to 74%). FA-based local and global efficiency increases during early adolescence. Streamline count based local efficiency both increases and decreases, and global efficiency reorganizes to a net decrease. Local FA-based efficiency was correlated to IQ. Moreover, increases in FA-based network efficiency (global and local) and decreases in streamline count based local efficiency are related to increases in intellectual functioning. Individual changes in intelligence and local FA-based efficiency appear to go hand in hand in frontal and temporal areas. More widespread local decreases in streamline count based efficiency (frontal cingulate and occipital) are correlated with increases in intelligence. We conclude that the teenage brain is a network in progress in which individual differences in maturation relate to level of intellectual functioning. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:51:10 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22957 Autism spectrum disorder (ASD) is a wide range of disabilities that cause life-long cognitive impairment and social, communication, and behavioral challenges. Early diagnosis and medical intervention are important for improving the life quality of autistic patients. However, in the current practice, diagnosis often has to be delayed until the behavioral symptoms become evident during childhood. In this study, we demonstrate the feasibility of using machine learning techniques for identifying high-risk ASD infants at as early as six months after birth. This is based on the observation that ASD-induced abnormalities in white matter (WM) tracts and whole-brain connectivity have already started to appear within 24 months after birth. In particular, we propose a novel multikernel support vector machine classification framework by using the connectivity features gathered from WM connectivity networks, which are generated via multiscale regions of interest (ROIs) and multiple diffusion statistics such as fractional anisotropy, mean diffusivity, and average fiber length. Our proposed framework achieves an accuracy of 76% and an area of 0.80 under the receiver operating characteristic curve (AUC), in comparison to the accuracy of 70% and the AUC of 70% provided by the best single-parameter single-scale network. The improvement in accuracy is mainly due to the complementary information provided by multiparameter multiscale networks. In addition, our framework also provides the potential imaging connectomic markers and an objective means for early ASD diagnosis. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:49:54 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22989 The presence of an anatomical connection between the orbitofrontal cortex and ventral striatum, forming a so-called reward network, is well established across species. This connection has important implications for reward processing and is relevant to a number of neuropsychiatric disorders. Moreover, white matter (WM) is known to continue to mature across adolescence and into early adulthood, and developmental change in the reward network is an important component of models of decision making and risk taking. Despite the importance of this connection, the underlying WM has only recently been characterized in humans histologically, and not yet in-vivo using brain imaging. Here, we implemented diffusion tensor imaging (DTI) in a large cross-sectional sample of 295 healthy individuals ages 8–68 to further characterize the WM of this connection and its development from childhood into adulthood. We demonstrate that the accumbofrontal tract, connecting the orbitofrontal cortex and nucleus accumbens, can be identified using standard DTI sequences. Using Poisson modeling, we show that the accumbofrontal tract undergoes significant change across the lifespan, with males showing a higher and earlier peak compared to females. Moreover, the change occurs in a pattern consistent with developmental models of decision-making. These findings support the hypothesis that developmental differences in WM integrity may be a contributing factor to the observed risk taking that occurs in adolescence. The accumbofrontal tract is not yet included in standard WM atlases, but may be important for inclusion in studies investigating fronto-striatal networks, as well as in investigations of substance abuse and decision making. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:49:23 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22992 The hippocampus is part of the default-mode network (DMN) and is functionally hit early in multiple sclerosis (MS). Hippocampal and DMN dysfunctions have been associated with depression, both in patients with MS and in major depressive disorders. We hypothesized that white matter lesions may contribute, through a disconnection mechanism, to hippocampal dysfunction. To test this, we assessed the relationship between hippocampal resting-state (RS) functional connectivity (FC) abnormalities with brain T2 lesion volumes and the presence and severity of depression. Structural and RS fMRI images were acquired from 69 patients with cognitively intact MS and 42 matched healthy controls (HC). Depression was quantified using the Montgomery–Asberg Depression Rating Scale. Seed-voxel hippocampal RS FC was assessed. SPM8 was used for between-group comparisons and correlation analysis between RS FC abnormalities with clinical and structural MRI variables. Compared to HC, patients with MS showed a significant atrophy of the whole brain and left hippocampus (P < 0.001), and a distributed pattern of decreased RS FC between the hippocampi and several cortical–subcortical regions, which were mostly located within the DMN. Reduced hippocampal RS FC with regions of the DMN was strongly correlated with higher T2 lesion volume, longer disease duration, and the severity of depression and disability. In patients with cognitively preserved MS, brain focal WM lesions are related to the functional integration of the hippocampus to other brain regions of the DMN, suggesting a disconnection syndrome. Such a disruption of hippocampal RS FC is likely to contribute to the occurrence of depression and to clinical disability. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:49:01 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22993 Temporal summation of second pain (TSSP) occurs when painful stimuli are presented repetitively (≥0.33 Hz) and results from a C-fibre evoked enhancement (or “wind-up”) of the dorsal horn neurons. Based on electrophysiological studies in intact animals, windup is considered a purely central phenomenon. With advancements in functional MRI (fMRI), we can now probe the central mechanisms of this pain response in humans. The aim of this study is to characterize the fMRI responses in the healthy human brainstem and spinal cord that correspond to TSSP. Functional MRI of healthy female adults (N = 15) was conducted while brief, repetitive heat pain stimuli were applied to the right thenar eminence (C6 dermatome), and TSSP (0.33 Hz) and control (0.17 Hz) heat pain paradigms were employed. The stimulus intensity was adjusted to each participant's heat pain sensitivity. Data were analyzed by means of a general linear model, and region-of-interest analyses. As predicted, participants demonstrated significant behavioural summation of pain in the TSSP condition. FMRI results identified enhanced activity in the spinal cord dorsal horn at C6 in response to the TSSP condition. Additionally, multiple areas of the brainstem (RVM and PAG) showed greater responses with the TSSP condition. These results suggest that, in humans, increased pain perception in the TSSP condition is reflected by greater responses in the dorsal horn and in regions known to play a role in the descending modulation of pain, which may modulate the spinal cord response. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 14 Sep 2015 07:47:35 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22994 Objective To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinson's disease and freezing of gait (PD-FoG). Methods T1-weighted, diffusion tensor (DT) MRI and RS functional MRI (fMRI) were obtained from 22 PD-FoG patients and 35 controls on a 3.0 T MR scanner. Patients underwent clinical, motor, and neuropsychological evaluations. Gray matter (GM) volumes and white matter (WM) damage were assessed using voxel based morphometry and tract-based spatial statistics, respectively. The pedunculopontine tract (PPT) was studied using tractography. RS fMRI data were analyzed using a model free approach investigating the main sensorimotor and cognitive brain networks. Multiple regression models were performed to assess the relationships between structural, functional, and clinical/cognitive variables. Analysis of GM and WM structural abnormalities was replicated in an independent sample including 28 PD-FoG patients, 25 PD patients without FoG, and 30 healthy controls who performed MRI scans on a 1.5 T scanner. Results Compared with controls, no GM atrophy was found in PD-FoG cases. PD-FoG patients showed WM damage of the PPT, corpus callosum, corticospinal tract, cingulum, superior longitudinal fasciculus, and WM underneath the primary motor, premotor, prefrontal, orbitofrontal, and inferior parietal cortices, bilaterally. In PD-FoG, right PTT damage was associated with a greater disease severity. Analysis on the independent PD sample showed similar findings in PD-FoG patients relative to controls as well as WM damage of the genu and body of the corpus callosum and right parietal WM in PD-FoG relative to PD no-FoG patients. RS fMRI analysis showed that PD-FoG is associated with a decreased functional connectivity of the primary motor cortex and supplementary motor area bilaterally in the sensorimotor network, frontoparietal regions in the default mode network, and occipital cortex in the visual associative network. Conclusions This study suggests that FoG in PD can be the result of a poor structural and functional integration between motor and extramotor (cognitive) neural systems. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Fri, 11 Sep 2015 08:47:05 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22907 The neural correlates of theory of mind (ToM) are typically studied using paradigms which require participants to draw explicit, task-related inferences (e.g., in the false belief task). In a natural setup, such as listening to stories, false belief mentalizing occurs incidentally as part of narrative processing. In our experiment, participants listened to auditorily presented stories with false belief passages (implicit false belief processing) and immediately after each story answered comprehension questions (explicit false belief processing), while neural responses were measured with functional magnetic resonance imaging (fMRI). All stories included (among other situations) one false belief condition and one closely matched control condition. For the implicit ToM processing, we modeled the hemodynamic response during the false belief passages in the story and compared it to the hemodynamic response during the closely matched control passages. For implicit mentalizing, we found activation in typical ToM processing regions, that is the angular gyrus (AG), superior medial frontal gyrus (SmFG), precuneus (PCUN), middle temporal gyrus (MTG) as well as in the inferior frontal gyrus (IFG) billaterally. For explicit ToM, we only found AG activation. The conjunction analysis highlighted the left AG and MTG as well as the bilateral IFG as overlapping ToM processing regions for both implicit and explicit modes. Implicit ToM processing during listening to false belief passages, recruits the left SmFG and billateral PCUN in addition to the “mentalizing network” known form explicit processing tasks. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 10 Sep 2015 10:18:27 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22950 Motor outcome is variable following neonatal arterial ischemic stroke (NAIS). We analyzed the relationship between lesion characteristics on brain MRI and motor function in children who had suffered from NAIS. Thirty eight full term born children with unilateral NAIS were investigated at the age of seven. 3D T1- and 3D FLAIR-weighted MR images were acquired on a 3T MRI scanner. Lesion characteristics were compared between patients with and without cerebral palsy (CP) using the following approaches: lesion localization either using a category-based analysis, lesion mapping as well as voxel-based lesion-symptom mapping (VLSM). Using diffusion-weighted imaging the microstructure of the cortico-spinal tract (CST) was related to the status of CP by measuring DTI parameters. Whereas children with lesions sparing the primary motor system did not develop CP, CP was always present when extensive lesions damaged at least two brain structures involving the motor system. The VLSM approach provided a statistical map that confirmed the cortical lesions in the primary motor system and revealed that CP was highly correlated with lesions in close proximity to the CST. In children with CP, diffusion parameters indicated microstructural changes in the CST at the level of internal capsule and the centrum semiovale. White matter damage of the CST in centrum semiovale was a highly reproducible marker of CP. This is the first description of the implication of this latter region in motor impairment after NAIS. In conclusion, CP in childhood was closely linked to the location of the infarct in the motor system. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 10 Sep 2015 05:43:38 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22920 Important issues for cognitive control are response selection processes, known to depend on fronto-striatal networks with recent evidence suggesting that striatal gamma-amino butyric acid (GABA) levels play an important role. Regional GABA concentrations have also been shown to modulate intrinsic connectivity, e.g. of the default mode network. However, the interrelation between striatal GABA levels, basal ganglia network (BGN) connectivity, and performance in cognitive control is elusive. In the current study, we measure striatal GABA levels using magnetic resonance spectroscopy (MRS) and resting state parameters using functional magnetic resonance imaging (fMRI). Resting state parameters include activity within the BGN, as determined by the low frequency power (LFP) within the network, and the functional connectivity between the BGN and somatomotor network (SMN). Specifically, we examine the interrelation between GABA, resting state parameters, and performance (i.e., accuracy) in conflict monitoring using a Simon task. Response control was affected by striatal GABA+ levels and activity within the BGN, especially when response selection was complicated by altered stimulus-response mappings. The data suggest that there are two mechanisms supporting response selection accuracy. One is related to resting state activity within the BGN and modulated by striatal GABA+ levels. The other is related to decreased cortico-striatal network connectivity, unrelated to the GABAergic system. The inclusion of all three factors (i.e., striatal GABA+ levels, activity within the BGN, and BGN-SMN network connectivity) explained a considerable amount of variance in task accuracy. Striatal neurobiochemical (GABA+) and parameters of the resting state BGN represent important modulators of response control. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 10 Sep 2015 05:43:07 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22986 Whether phonological deficits in developmental dyslexia are associated with impaired neural sampling of auditory information at either syllabic- or phonemic-rates is still under debate. In addition, whereas neuroanatomical alterations in auditory regions have been documented in dyslexic readers, whether and how these structural anomalies are linked to auditory sampling and reading deficits remains poorly understood. In this study, we measured auditory neural synchronization at different frequencies corresponding to relevant phonological spectral components of speech in children and adults with and without dyslexia, using magnetoencephalography. Furthermore, structural MRI was used to estimate cortical thickness of the auditory cortex of participants. Dyslexics showed atypical brain synchronization at both syllabic (slow) and phonemic (fast) rates. Interestingly, while a left hemispheric asymmetry in cortical thickness was functionally related to a stronger left hemispheric lateralization of neural synchronization to stimuli presented at the phonemic rate in skilled readers, the same anatomical index in dyslexics was related to a stronger right hemispheric dominance for neural synchronization to syllabic-rate auditory stimuli. These data suggest that the acoustic sampling deficit in development dyslexia might be linked to an atypical specialization of the auditory cortex to both low and high frequency amplitude modulations. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 10 Sep 2015 05:42:57 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22952 In this study we demonstrate that the pattern of an amygdala-centric network contributes to individual differences in trait anxiety. Individual differences in trait anxiety were predicted using maximum likelihood estimates of amygdala structural connectivity to multiple brain targets derived from diffusion-tensor imaging (DTI) and probabilistic tractography on 72 participants. The prediction was performed using a stratified sixfold cross validation procedure using a regularized least square regression model. The analysis revealed a reliable network of regions predicting individual differences in trait anxiety. Higher trait anxiety was associated with stronger connections between the amygdala and dorsal anterior cingulate cortex, an area implicated in the generation of emotional reactions, and inferior temporal gyrus and paracentral lobule, areas associated with perceptual and sensory processing. In contrast, higher trait anxiety was associated with weaker connections between amygdala and regions implicated in extinction learning such as medial orbitofrontal cortex, and memory encoding and environmental context recognition, including posterior cingulate cortex and parahippocampal gyrus. Thus, trait anxiety is not only associated with reduced amygdala connectivity with prefrontal areas associated with emotion modulation, but also enhanced connectivity with sensory areas. This work provides novel anatomical insight into potential mechanisms behind information processing biases observed in disorders of emotion. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 10 Sep 2015 05:40:54 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22991 Chinese processing has been suggested involving distinct brain areas from English. However, current functional localization studies on Chinese speech processing use mostly “indirect” techniques such as functional magnetic resonance imaging and electroencephalography, lacking direct evidence by means of electrocortical recording. In this study, awake craniotomies in 66 Chinese-speaking glioma patients provide a unique opportunity to directly map eloquent language areas. Intraoperative electrocortical stimulation was conducted and the positive sites for speech arrest, anomia, and alexia were identified separately. With help of stereotaxic neuronavigation system and computational modeling, all positive sites elicited by stimulation were integrated and a series of two- and three-dimension Chinese language probability maps were built. We performed statistical comparisons between the Chinese maps and previously derived English maps. While most Chinese speech arrest areas located at typical language production sites (i.e., 50% positive sites in ventral precentral gyrus, 28% in pars opercularis and pars triangularis), which also serve English production, an additional brain area, the left middle frontal gyrus (Brodmann's areas 6/9), was found to be unique in Chinese production (P < 0.05). Moreover, Chinese speakers’ inferior ventral precentral gyrus (Brodmann's area 6) was used more than that in English speakers. Our finding suggests that Chinese involves more perisylvian region (extending to left middle frontal gyrus) than English. This is the first time that direct evidence supports cross-cultural neurolinguistics differences in human beings. The Chinese language atlas will also helpful in brain surgery planning for Chinese-speakers. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 09 Sep 2015 01:34:57 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22987 Much of what was assumed about the functional topography of the hippocampus was derived from a single case study over half a century ago. Given advances in the imaging sciences, a new era of discovery is underway, with potential to transform the understanding of healthy processing as well as the ability to treat disorders. Coactivation-based parcellation, a meta-analytic approach, and ultra-high field, high-resolution functional and structural neuroimaging to characterize the neurofunctional topography of the hippocampus was employed. Data revealed strong support for an evolutionarily preserved topography along the long-axis. Specifically, the left hippocampus was segmented into three distinct clusters: an emotional processing cluster supported by structural and functional connectivity to the amygdala and parahippocampal gyrus, a cognitive operations cluster, with functional connectivity to the anterior cingulate and inferior frontal gyrus, and a posterior perceptual cluster with distinct structural connectivity patterns to the occipital lobe coupled with functional connectivity to the precuneus and angular gyrus. The right hippocampal segmentation was more ambiguous, with plausible 2- and 5-cluster solutions. Segmentations shared connectivity with brain regions known to support the correlated processes. This represented the first neurofunctional topographic model of the hippocampus using a robust, bias-free, multimodal approach. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 09 Sep 2015 01:34:24 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22846 It has been reported that mechanical vibrations of the magnetic resonance imaging scanner could produce spurious signal dropouts in diffusion-weighted images resulting in artifactual anisotropy in certain regions of the brain with red appearance in the Directionally Encoded Color maps. We performed a review of the frequency of this artifact across pediatric studies, noting differences by scanner manufacturer, acquisition protocol, as well as weight and position of the subject. We also evaluated the ability of automated and quantitative methods to detect this artifact. We found that the artifact may be present in over 50% of data in certain protocols and is not limited to one scanner manufacturer. While a specific scanner had the highest incidence, low body weight and positioning were also associated with appearance of the artifact for both scanner types evaluated, making children potentially more susceptible than adults. Visual inspection remains the best method for artifact identification. Software for automated detection showed very low sensitivity (10%). The artifact may present inconsistently in longitudinal studies. We discuss a published case report that has been widely cited and used as evidence to set policy about diagnostic criteria for determining vegetative state. That report attributed longitudinal changes in anisotropy to white matter plasticity without considering the possibility that the changes were caused by this artifact. Our study underscores the need to check for the presence of this artifact in clinical studies, analyzes circumstances for when it may be more likely to occur, and suggests simple strategies to identify and potentially avoid its effects. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 09 Sep 2015 01:33:49 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22921 Developmental adjustments in the balance of excitation and inhibition are thought to constrain the plasticity of sensory areas of the cortex. It is unknown however, how changes in excitatory or inhibitory neurochemical expression (glutamate, γ-aminobutyric acid (GABA)) contribute to skill acquisition during development. Here we used single-voxel proton magnetic resonance spectroscopy (1H-MRS) to reveal how differences in cortical glutamate vs. GABA ratios relate to face proficiency and working memory abilities in children and adults. We show that higher glutamate levels in the inferior frontal gyrus correlated positively with face processing proficiency in the children, but not the adults, an effect which was independent of age-dependent differences in underlying cortical gray matter. Moreover, we found that glutamate/GABA levels and gray matter volume are dissociated at the different maturational stages. These findings suggest that increased excitation during development is linked to neuroplasticity and the acquisition of new cognitive skills. They also offer a new, neurochemical approach to investigating the relationship between cognitive performance and brain development across the lifespan. Hum Brain Mapp, 2015. © 2015 The Authors. Human Brain Mapping Published byWiley Periodicals, Inc. Wed, 09 Sep 2015 01:33:22 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22985 Abnormal connectivity patterns have frequently been reported as involved in pathological mental states. However, most studies focus on “static,” stationary patterns of connectivity, which may miss crucial biological information. Recent methodological advances have allowed the investigation of dynamic functional connectivity patterns that describe non-stationary properties of brain networks. Here, we introduce a novel graphical measure of dynamic connectivity, called time-varying eigenvector centrality (tv-EVC). In a sample 655 children and adolescents (7–15 years old) from the Brazilian “High Risk Cohort Study for Psychiatric Disorders” who were imaged using resting-state fMRI, we used this measure to investigate age effects in the temporal in control and default-mode networks (CN/DMN). Using support vector regression, we propose a network maturation index based on the temporal stability of tv-EVC. Moreover, we investigated whether the network maturation is associated with the overall presence of behavioral and emotional problems with the Child Behavior Checklist. As hypothesized, we found that the tv-EVC at each node of CN/DMN become more stable with increasing age (P < 0.001 for all nodes). In addition, the maturity index for this particular network is indeed associated with general psychopathology in children assessed by the total score of Child Behavior Checklist (P = 0.027). Moreover, immaturity of the network was mainly correlated with externalizing behavior dimensions. Taken together, these results suggest that changes in functional network dynamics during neurodevelopment may provide unique insights regarding pathophysiology. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 09 Sep 2015 01:32:58 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22959 Later-life changes in brain tissue volumes—decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)—are strong candidates to explain some of the variation in ageing-related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow-age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow-up). We used latent variable modeling to extract error-free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r-values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life. Hum Brain Mapp, 2015. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc Mon, 07 Sep 2015 04:56:50 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22984 The Brief presentation of a complex scene entails that only a few objects can be selected, processed indepth, and stored in memory. Both low-level sensory salience and high-level context-related factors (e.g., the conceptual match/mismatch between objects and scene context) contribute to this selection process, but how the interplay between these factors affects memory encoding is largely unexplored. Here, during fMRI we presented participants with pictures of everyday scenes. After a short retention interval, participants judged the position of a target object extracted from the initial scene. The target object could be either congruent or incongruent with the context of the scene, and could be located in a region of the image with maximal or minimal salience. Behaviourally, we found a reduced impact of saliency on visuospatial working memory performance when the target was out-of-context. Encoding-related fMRI results showed that context–congruent targets activated dorsoparietal regions, while context–incongruent targets de-activated the ventroparietal cortex. Saliency modulated activity both in dorsal and ventral regions, with larger context-related effects for salient targets. These findings demonstrate the joint contribution of knowledge-based and saliency-driven attention for memory encoding, highlighting a dissociation between dorsal and ventral parietal regions. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 03 Sep 2015 01:36:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22943 Spatial leakage effects are particularly confounding for seed-based investigations of brain networks using source-level electroencephalography (EEG) or magnetoencephalography (MEG). Various methods designed to avoid this issue have been introduced but are limited to particular assumptions about its temporal characteristics. Here, we investigate the usefulness of a model-based geometric correction scheme (GCS) to suppress spatial leakage emanating from the seed location. We analyze its properties theoretically and then assess potential advantages and limitations with simulated and experimental MEG data (resting state and auditory-motor task). To do so, we apply Minimum Norm Estimation (MNE) for source reconstruction and use variation of error parameters, statistical gauging of spatial leakage correction and comparison with signal orthogonalization. Results show that the GCS has a local (i.e., near the seed) effect only, in line with the geometry of MNE spatial leakage, and is able to map spatially all types of brain interactions, including linear correlations eliminated after signal orthogonalization. Furthermore, it is robust against the introduction of forward model errors. On the other hand, the GCS can be affected by local overcorrection effects and seed mislocation. These issues arise with signal orthogonalization too, although significantly less extensively, so the two approaches complement each other. The GCS thus appears to be a valuable addition to the spatial leakage correction toolkits for seed-based FC analyses in source-projected MEG/EEG data. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 02 Sep 2015 04:22:12 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22914 This work examines the effect of midazolam-induced light sedation on intrinsic functional connectivity of human brain, using a randomized, double-blind, placebo-controlled, cross-over, within-subject design. Fourteen healthy young subjects were enrolled and midazolam (0.03 mg/kg of the participant's body mass, to a maximum of 2.5 mg) or saline were administrated with an interval of one week. Resting-state fMRI was conducted before and after administration for each subject. We focus on two types of networks: sensory related lower-level functional networks and higher-order functions related ones. Independent component analysis (ICA) was used to identify these resting-state functional networks. We hypothesize that the sensory (visual, auditory, and sensorimotor) related networks will be intact under midazolam-induced light sedation while the higher-order (default mode, executive control, salience networks, etc.) networks will be functionally disconnected. It was found that the functional integrity of the lower-level networks was maintained, while that of the higher-level networks was significantly disrupted by light sedation. The within-network connectivity of the two types of networks was differently affected in terms of direction and extent. These findings provide direct evidence that higher-order cognitive functions including memory, attention, executive function, and language were impaired prior to lower-level sensory responses during sedation. Our result also lends support to the information integration model of consciousness. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Fri, 28 Aug 2015 03:54:32 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22954 The polymorphism of the Apolipoprotein E (APOE) promoter rs405509 can regulate the transcriptional activity of the APOE gene and is related to Alzheimer's disease (AD). However, its effects on cognitive performance and the underlying brain mechanisms remain unknown. Here, we performed a battery of neuropsychological tests in a large sample (837 subjects) of nondemented elderly Chinese people, and explored the related brain mechanisms via the construction of diffusion MRI-based structural connectome and graph analysis from a subset (84 subjects) of the sample. Cognitively, the rs405509 risk allele (TT) carriers showed decreased attention and execution functions compared with noncarriers (GG/GT). Regarding the topological alterations of the brain connectome, the risk allele group exhibited reduced global and local efficiency of white matter structural networks, mainly in the left anterior and posterior cingulate cortices (PCC). Importantly, the efficiency of the left PCC is correlated with the impaired attention function and mediates the impacts of the rs405509 genotype on attention. These results demonstrated that the rs405509 polymorphism affects attention function in nondemented elderly people, possibly by modulating brain structural connectivity of the PCC. This polymorphism may help us to understand the neural mechanisms of cognitive aging and to serve as a potential marker assessing the risk of AD. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Fri, 28 Aug 2015 03:52:52 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22919 Information processing can be biased toward behaviorally relevant and salient stimuli by top-down (goal-directed) and bottom-up (stimulus-driven) attentional control processes respectively. However, the neural basis underlying the integration of these processes is not well understood. We employed functional magnetic resonance imaging (fMRI) and transcranial direct-current stimulation (tDCS) in humans to examine the brain mechanisms underlying the interaction between these two processes. We manipulated the cognitive load involved in top-down processing and stimulus surprise involved in bottom-up processing in a factorial design by combining a majority function task and an oddball paradigm. We found that high cognitive load and high surprise level were associated with prolonged reaction time compared to low cognitive load and low surprise level, with a synergistic interaction effect, which was accompanied by a greater deactivation of bilateral temporoparietal junction (TPJ). In addition, the TPJ displayed negative functional connectivity with right middle occipital gyrus, which is involved in bottom-up processing (modulated by the interaction effect), and the right frontal eye field (FEF), which is involved in top-down control. The enhanced negative functional connectivity between the TPJ and right FEF was accompanied by a larger behavioral interaction effect across subjects. Application of cathodal tDCS over the right TPJ eliminated the interaction effect. These results suggest that the TPJ plays a critical role in processing bottom-up information for top-down control of attention. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 26 Aug 2015 10:38:24 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22948 Sleep-induced changes in human brain connectivity/excitability and their physiologic basis remain unclear, especially in the frontal lobe. We investigated sleep-induced connectivity and excitability changes in 11 patients who underwent chronic implantation of subdural electrodes for epilepsy surgery. Single-pulse electrical stimuli were directly injected to a part of the cortices, and cortico-cortical evoked potentials (CCEPs) and CCEP-related high-gamma activities (HGA: 100–200 Hz) were recorded from adjacent and remote cortices as proxies of effective connectivity and induced neuronal activity, respectively. HGA power during the initial CCEP component (N1) correlated with the N1 size itself across all states investigated. The degree of cortical connectivity and excitability changed during sleep depending on sleep stage, approximately showing dichotomy of awake vs. non-rapid eye movement (REM) [NREM] sleep. On the other hand, REM sleep partly had properties of both awake and NREM sleep, placing itself in the intermediate state between them. Compared with the awake state, single-pulse stimulation especially during NREM sleep induced increased connectivity (N1 size) and neuronal excitability (HGA increase at N1), which was immediately followed by intense inhibition (HGA decrease). The HGA decrease was temporally followed by the N2 peak (the second CCEP component), and then by HGA re-increase during sleep across all lobes. This HGA rebound or re-increase of neuronal synchrony was largest in the frontal lobe compared with the other lobes. These properties of sleep-induced changes of the cortex may be related to unconsciousness during sleep and frequent nocturnal seizures in frontal lobe epilepsy. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 26 Aug 2015 10:34:49 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22923 Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks related to SLC6A4 promoter methylation (N = 74 healthy individuals). The amygdalae were defined as seed regions given that resting state functional connectivity in this brain area is under serotonergic control and relates to a broad range of psychiatric phenotypes. We further used bisulfite pyrosequencing to analyze quantitative methylation at 83 CpG sites within a promoter-associated CpG island of SLC6A4 from blood-derived DNA samples. The major finding of this study indicates a positive relation of SLC6A4 promoter methylation and amygdaloid resting state functional coupling with key nodes of the salience network (SN) including the anterior insulae and the dorsal anterior cingulate cortices. Increased intra-network connectivity in the SN is thought to facilitate the detection and subsequent processing of potentially negative stimuli and reflects a core feature of psychopathology. As such, epigenetic changes within the SLC6A4 gene predict connectivity patterns in clinically and behaviorally relevant brain networks which may in turn convey increased disease susceptibility. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 25 Aug 2015 00:12:12 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22937 Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene–brain–behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior–posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 25 Aug 2015 00:11:48 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22939 Certain kinds of stimuli can be processed on multiple levels. While the neural correlates of different levels of processing (LOPs) have been investigated to some extent, most of the studies involve skills and/or knowledge already present when performing the task. In this study we specifically sought to identify neural correlates of an evolving skill that allows the transition from perceptual to a lexico-semantic stimulus analysis. Eighteen participants were trained to decode 12 letters of Morse code that were presented acoustically inside and outside of the scanner environment. Morse code was presented in trains of three letters while brain activity was assessed with fMRI. Participants either attended to the stimulus length (perceptual analysis), or evaluated its meaning distinguishing words from nonwords (lexico-semantic analysis). Perceptual and lexico-semantic analyses shared a mutual network comprising the left premotor cortex, the supplementary motor area (SMA) and the inferior parietal lobule (IPL). Perceptual analysis was associated with a strong brain activation in the SMA and the superior temporal gyrus bilaterally (STG), which remained unaltered from pre and post training. In the lexico-semantic analysis post learning, study participants showed additional activation in the left inferior frontal cortex (IFC) and in the left occipitotemporal cortex (OTC), regions known to be critically involved in lexical processing. Our data provide evidence for cortical plasticity evolving with a learning process enabling the transition from perceptual to lexico-semantic stimulus analysis. Importantly, the activation pattern remains task-related LOP and is thus the result of a decision process as to which LOP to engage in. Hum Brain Mapp, 2015. © 2015 The Authors. Human Brain Mapping Published byWiley Periodicals, Inc. Tue, 25 Aug 2015 00:11:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22934 Lower parental education impairs cognitive abilities of their offspring such as general fluid intelligence dependent on the prefrontal cortex (PFC), but the independent contribution of mother's and father's education is unknown. We used an individual difference approach to test whether mother's and father's education independently affected general fluid intelligence in emerging adulthood at both the behavioral and neural level. Behaviorally, mother's but not father's education accounted for unique variance in general fluid intelligence in emerging adulthood (assessed by the Raven's advanced progressive matrices). Neurally, the whole-brain correlation analysis revealed that the regional gray matter volume (rGMV) in the medial PFC was related to both mother's education and general fluid intelligence but not father's education. Furthermore, after controlling for mother's education, the association between general fluid intelligence and the rGMV in medial PFC was no longer significant, indicating that mother's education plays an important role in influencing the structure of the medial PFC associated with general fluid intelligence. Taken together, our study provides the first behavioral and neural evidence that mother's education is a more important determinant of general cognitive ability in emerging adulthood than father's education. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 25 Aug 2015 00:10:26 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22942 Objective Chemotherapy (CT) is associated with adverse effects on cognition. Only few studies have investigated cognition in testicular cancer (TC) patients and studies on very late effects of CT on cognition are absent. Further, brain changes in relation to treatment have not been investigated in TC. The objective of the present study is to compare psychosocial functioning, cognitive performance and brain (micro)structure following surgery and CT for TC, against surgery (S)-only. Methods Twenty-eight CT (43.1 ± 7.5 y) and 23 S-only (48.2 ± 9.5y) TC survivors on average 14 yr post-treatment were examined using questionnaires, neurocognitive tests, and 3T-MRI [Diffusion Kurtosis Imaging (DKI), T1-weighted and Fluid Attenuated Inversion Recovery]. A multivariate cognitive performance score (Mahalanobis distance) was calculated to indicate the grade of cognitive performance. Kurtosis parameters, gray matter, and white matter (WM) volume were calculated from MRI data. Results Overall, the CT group showed lower cognitive performance (5.35 ± 1.7) compared with the S-only group (4.4 ± 0.9; P =0.03; d = 0.70). Further, TC patients reported more memory problems after CT. DKI revealed a significantly higher radial kurtosis after CT in several anterior and posterior brain areas (P < 0.05, corrected), but this was unrelated to cognitive performance. Conclusions This cross-sectional study suggests that men receiving CT for TC are at risk for long-term lower cognitive performance. Although CT affected WM microstructure, this was unrelated to cognitive performance. More extensive, preferably prospective studies are warranted to confirm these results and to provide more insight into the possible mechanisms behind the observed cognitive sequelae after treatment for TC. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 25 Aug 2015 00:09:29 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22945 Mapping brain connectivity based on neuroimaging data is a promising new tool for understanding brain structure and function. In this methods paper, we demonstrate that group independent component analysis (GICA) can be used to perform a dual parcellation of the brain based on its connectivity matrix (cmICA). This dual parcellation consists of a set of spatially independent source maps, and a corresponding set of paired dual maps that define the connectivity of each source map to the brain. These dual maps are called the connectivity profiles of the source maps. Traditional analysis of connectivity matrices has been used previously for brain parcellation, but the present method provides additional information on the connectivity of these segmented regions. In this paper, the whole brain structural connectivity matrices were calculated on a 5 mm3 voxel scale from diffusion imaging data based on the probabilistic tractography method. The effect of the choice of the number of components (30 and 100) and their stability were examined. This method generated a set of spatially independent components that are consistent with the canonical brain tracts provided by previous anatomic descriptions, with the high order model yielding finer segmentations. The corpus-callosum example shows how this method leads to a robust parcellation of a brain structure based on its connectivity properties. We applied cmICA to study structural connectivity differences between a group of schizophrenia subjects and healthy controls. The connectivity profiles at both model orders showed similar regions with reduced connectivity in schizophrenia patients. These regions included forceps major, right inferior fronto-occipital fasciculus, uncinate fasciculus, thalamic radiation, and corticospinal tract. This paper provides a novel unsupervised data-driven framework that summarizes the information in a large global connectivity matrix and tests for brain connectivity differences. It has the potential for capturing important brain changes related to disease in connectivity-based disorders. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 20 Aug 2015 09:47:24 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22947 Network properties can be estimated using functional connectivity MRI (fcMRI). However, regional variation of the fMRI signal causes systematic biases in network estimates including correlation attenuation in regions of low measurement reliability. Here we computed the spatial distribution of fcMRI reliability using longitudinal fcMRI datasets and demonstrated how pre-estimated reliability maps can correct for correlation attenuation. As a test case of reliability-based attenuation correction we estimated properties of the default network, where reliability was significantly lower than average in the medial temporal lobe and higher in the posterior medial cortex, heterogeneity that impacts estimation of the network. Accounting for this bias using attenuation correction revealed that the medial temporal lobe's contribution to the default network is typically underestimated. To render this approach useful to a greater number of datasets, we demonstrate that test-retest reliability maps derived from repeated runs within a single scanning session can be used as a surrogate for multi-session reliability mapping. Using data segments with different scan lengths between 1 and 30 min, we found that test-retest reliability of connectivity estimates increases with scan length while the spatial distribution of reliability is relatively stable even at short scan lengths. Finally, analyses of tertiary data revealed that reliability distribution is influenced by age, neuropsychiatric status and scanner type, suggesting that reliability correction may be especially important when studying between-group differences. Collectively, these results illustrate that reliability-based attenuation correction is an easily implemented strategy that mitigates certain features of fMRI signal nonuniformity. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Thu, 20 Aug 2015 09:43:50 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22936 Several neurobiological factors have been found to correlate with functional recovery after brain lesions. However, predicting the individual potential of recovery remains difficult. Here we used multivariate support vector machine (SVM) classification to explore the prognostic value of functional magnetic resonance imaging (fMRI) to predict individual motor outcome at 4–6 months post-stroke. To this end, 21 first-ever stroke patients with hand motor deficits participated in an fMRI hand motor task in the first few days post-stroke. Motor impairment was quantified assessing grip force and the Action Research Arm Test. Linear SVM classifiers were trained to predict good versus poor motor outcome of unseen new patients. We found that fMRI activity acquired in the first week post-stroke correctly predicted the outcome for 86% of all patients. In contrast, the concurrent assessment of motor function provided 76% accuracy with low sensitivity (<60%). Furthermore, the outcome of patients with initially moderate impairment and high outcome variability could not be predicted based on motor tests. In contrast, fMRI provided 87.5% prediction accuracy in these patients. Classifications were driven by activity in ipsilesional motor areas and contralesional cerebellum. The accuracy of subacute fMRI data (two weeks post-stroke), age, time post-stroke, lesion volume, and location were at 50%-chance-level. In conclusion, multivariate decoding of fMRI data with SVM early after stroke enables a robust prediction of motor recovery. The potential for recovery is influenced by the initial dysfunction of the active motor system, particularly in those patients whose outcome cannot be predicted by behavioral tests. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:40:19 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22930 Mild traumatic brain injury patients (mTBI) frequently report symptoms of increased distractability and sensory disturbances during mutisensory stimulation. These common post-concussive symptoms could putatively result from dysfunction within the cognitive control network (CCN; top-down) or from unisensory cortex (bottom-up) itself. Functional magnetic resonance imaging (fMRI) and high-resolution structural data were therefore prospectively collected during a multisensory (audio-visual) cognitive control task from 46 mTBI patients within 3 weeks of injury and 46 matched healthy controls (HC), with a subset of participants returning at 4 months. Multisensory stimuli were presented at two frequencies to manipulate cognitive and perceptual load. Patients self-reported more cognitive, emotional, somatic, vestibular and visual symptoms relative to HC, which improved, but did not entirely resolve, over the 4 month follow-up period. There were no group differences in behavior or functional activation during cognitive control (incongruent – congruent trials). In contrast, patients exhibited abnormal activation within different regions of visual cortex that depended on whether attention was focused on auditory or visual information streams. Patients also exhibited increased activation within bilateral inferior parietal lobules during higher cognitive/perceptual loads, suggesting a compensatory mechanism to achieve similar levels of behavioral performance. Functional abnormalities within the visual cortex and inferior parietal lobules were only partially resolved at 4 months post-injury, suggesting that neural abnormalities may take longer to resolve than behavioral measures used in most clinical settings. In summary, current results indicate that abnormalities within unisensory cortex (particularly visual areas) following mTBI, which likely contribute to deficits commonly reported during multisensory stimulation. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:38:34 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22938 Preliminary evidence suggests aberrant (mostly reduced) thalamocortical (TC) connectivity in autism spectrum disorder (ASD), but despite the crucial role of thalamus in sensorimotor functions and its extensive connectivity with cerebral cortex, relevant evidence remains limited. We performed a comprehensive investigation of region-specific TC connectivity in ASD. Resting-state functional MRI and diffusion tensor imaging (DTI) data were acquired for 60 children and adolescents with ASD (ages 7–17 years) and 45 age, sex, and IQ-matched typically developing (TD) participants. We examined intrinsic functional connectivity (iFC) and anatomical connectivity (probabilistic tractography) with thalamus, using 68 unilateral cerebral cortical regions of interest (ROIs). For frontal and parietal lobes, iFC was atypically reduced in the ASD group for supramodal association cortices, but was increased for cingulate gyri and motor cortex. Temporal iFC was characterized by overconnectivity for auditory cortices, but underconnectivity for amygdalae. Occipital iFC was broadly reduced in the ASD group. DTI indices (such as increased radial diffusion) for regions with group differences in iFC further indicated compromised anatomical connectivity, especially for frontal ROIs, in the ASD group. Our findings highlight the regional specificity of aberrant TC connectivity in ASD. Their overall pattern can be largely accounted for by functional overconnectivity with limbic and sensorimotor regions, but underconnectivity with supramodal association cortices. This could be related to comparatively early maturation of limbic and sensorimotor regions in the context of early overgrowth in ASD, at the expense of TC connectivity with later maturing cortical regions. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:37:05 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22935 Background Cognitive dysfunction is considered a core feature of schizophrenia, and impaired performances in episodic memory (EM) and executive function (EF) tasks are consistently reported in schizophrenia patients. Traditional fMRI and EEG studies have helped identifying brain areas, including the prefrontal cortex (PFC), involved in these tasks. However, it is unclear whether intrinsic defects in prefrontal function per se contribute to poor performance in schizophrenia, given the presence of confounds like reduced motivation and psychotic symptoms. TMS/hd-EEG measurements are obtained without cognitive effort, and can be calculated in any cortical area. Methods We performed TMS/hd-EEG recordings in parietal, motor, premotor, and PFC in healthy individuals (N = 20) and schizophrenia patients (N = 20). Source modeling of TMS-evoked responses was performed, and measures of cortical activity (significant current density, SCD) and connectivity (significant current scattering, SCS) were computed. Patients with schizophrenia also performed Penn Word memory delayed (CPWd) and Penn Conditional Exclusion Test (PCET). CPWd evaluates EM and involves primarily PFC, whereas PCET reflects EF and implicates PFC with other brain regions. Findings We found no difference in SCD and SCS after TMS of parietal/motor cortices, whereas those parameters were reduced in premotor/prefrontal areas in schizophrenia patients. In PFC, where these measures were most defective, SCD was negatively correlated with performance in CPWd whereas higher SCS values were associated with more errors in PCET. Conclusion These findings indicate that schizophrenia patients have intrinsic defects in both activity and connectivity of PFC, and that these defects are specifically associated with impairments in cognitive abilities. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:31:11 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22944 Symptoms of attention deficit hyperactivity disorder (ADHD) in children often persist into adulthood and can lead to severe antisocial behavior. However, to-date it remains unclear whether neuro-functional abnormalities cause ADHD, which in turn can then provide a marker of persistent ADHD. Using event-related functional magnetic resonance imaging (fMRI), we measured blood oxygenation level dependent (BOLD) signal changes in subjects during a reversal learning task in which choice of the correct stimulus led to a probabilistically determined ‘monetary’ reward or punishment. Participants were diagnosed with ADHD during their childhood (N = 32) and were paired with age, gender, and education matched healthy controls (N = 32). Reassessment of the ADHD group as adults resulted in a split between either persistent (persisters, N = 17) or remitted ADHDs (remitters, N = 15). All three groups showed significantly decreased activation in the medial prefrontal cortex (PFC) and the left striatum during punished correct responses, however only remitters and controls presented significant psycho-physiological interaction between these fronto-striatal reward and outcome valence networks. Comparing persisters to remitters and controls showed significantly inverted responses to punishment (P < 0.05, family-wise error corrected) in left PFC region. Interestingly, the decreased activation shown after punishment was located in different areas of the PFC for remitters compared with controls, suggesting that remitters might have learned compensation strategies to overcome their ADHD symptoms. Thus, fMRI helps understanding the neuro-functional basis of ADHD related behavior differences and differentiates between persistent and remittent ADHD. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:29:48 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22946 Using MR-based radial mapping, we assessed morphological alterations of the hippocampal dentate gyrus (DG) in patients with relapse-onset multiple sclerosis (MS). We analyzed different stages of the disease and the association of DG alterations with hippocampal-related cognitive functions. Using high-resolution morphological imaging, hippocampal radial mapping analysis was performed in 28 relapsing-remitting (RR), 34 secondary progressive, and 26 benign MS patients and 28 healthy controls (HC). Between-groups differences of DG radial distance (from surface points to the central core of the hippocampus) and correlations with clinical, neuropsychological, and radiological measures were evaluated using surface-based mesh modeling. Compared with HC, all MS clinical phenotypes revealed a larger radial distance of the DG, which was more marked on the left side. Radial distance enlargement was more pronounced in RRMS patients compared with the other disease clinical phenotypes and was inversely correlated to disease duration. Radial distance enlargement was correlated with higher T2 lesion volume and a better cognitive performance in RRMS and with a poor cognitive performance in secondary progressive and benign MS patients. Surface expansion of the DG might represent an inflammation-induced neurogenic (reactive) process of the subgranular zone of the hippocampus primarily aimed at rescuing the functional competence of hippocampal circuitry. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:29:22 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22940 Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to “entrainment” of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:28:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22941 Research in humans and animals has shown that negative childhood experiences (NCE) can have long-term effects on the structure and function of the brain. Alterations have been noted in grey and white matter, in the brain's resting state, on the glutamatergic system, and on neural and behavioural responses to aversive stimuli. These effects can be linked to psychiatric disorder such as depression and anxiety disorders that are influenced by excessive exposure to early life stressors. The aim of the current study was to investigate the effect of NCEs on these systems. Resting state functional MRI (rsfMRI), aversion task fMRI, glutamate magnetic resonance spectroscopy (MRS), and diffusion magnetic resonance imaging (dMRI) were combined with the Childhood Trauma Questionnaire (CTQ) in healthy subjects to examine the impact of NCEs on the brain. Low CTQ scores, a measure of NCEs, were related to higher resting state glutamate levels and higher resting state entropy in the medial prefrontal cortex (mPFC). CTQ scores, mPFC glutamate and entropy, correlated with neural BOLD responses to the anticipation of aversive stimuli in regions throughout the aversion-related network, with strong correlations between all measures in the motor cortex and left insula. Structural connectivity strength, measured using mean fractional anisotropy, between the mPFC and left insula correlated to aversion-related signal changes in the motor cortex. These findings highlight the impact of NCEs on multiple inter-related brain systems. In particular, they highlight the role of a prefrontal-insular-motor cortical network in the processing and responsivity to aversive stimuli and its potential adaptability by NCEs. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 19 Aug 2015 10:25:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22931 Volumetric assessments of the hippocampus and other brain structures during childhood provide useful indices of brain development and correlates of cognitive functioning in typically and atypically developing children. Automated methods such as FreeSurfer promise efficient and replicable segmentation, but may include errors which are avoided by trained manual tracers. A recently devised automated correction tool that uses a machine learning algorithm to remove systematic errors, the Automatic Segmentation Adapter Tool (ASAT), was capable of substantially improving the accuracy of FreeSurfer segmentations in an adult sample [Wang et al., 2011], but the utility of ASAT has not been examined in pediatric samples. In Study 1, the validity of FreeSurfer and ASAT corrected hippocampal segmentations were examined in 20 typically developing children and 20 children with autism spectrum disorder aged 2 and 3 years. We showed that while neither FreeSurfer nor ASAT accuracy differed by disorder or age, the accuracy of ASAT corrected segmentations were substantially better than FreeSurfer segmentations in every case, using as few as 10 training examples. In Study 2, we applied ASAT to 89 typically developing children aged 2 to 4 years to examine relations between hippocampal volume, age, sex, and expressive language. Girls had smaller hippocampi overall, and in left hippocampus this difference was larger in older than younger girls. Expressive language ability was greater in older children, and this difference was larger in those with larger hippocampi, bilaterally. Overall, this research shows that ASAT is highly reliable and useful to examinations relating behavior to hippocampal structure. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Mon, 17 Aug 2015 00:50:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22932 Spatial variation in connectivity is an integral aspect of the brain's architecture. In the absence of this variability, the brain may act as a single homogenous entity without regional specialization. In this study, we investigate the variability in functional links categorized on the basis of the presence of direct structural paths (primary) or indirect paths mediated by one (secondary) or more (tertiary) brain regions ascertained by diffusion tensor imaging. We quantified the variability in functional connectivity using an unbiased estimate of unpredictability (functional connectivity entropy) in a neuropsychiatric disorder where structure-function relationship is considered to be abnormal; 34 patients with schizophrenia and 32 healthy controls underwent DTI and resting state functional MRI scans. Less than one-third (27.4% in patients, 27.85% in controls) of functional links between brain regions were regarded as direct primary links on the basis of DTI tractography, while the rest were secondary or tertiary. The most significant changes in the distribution of functional connectivity in schizophrenia occur in indirect tertiary paths with no direct axonal linkage in both early (P = 0.0002, d = 1.46) and late (P = 1 × 10−17, d = 4.66) stages of schizophrenia, and are not altered by the severity of symptoms, suggesting that this is an invariant feature of this illness. Unlike those with early stage illness, patients with chronic illness show some additional reduction in the distribution of connectivity among functional links that have direct structural paths (P = 0.08, d = 0.44). Our findings address a critical gap in the literature linking structure and function in schizophrenia, and demonstrate for the first time that the abnormal state of functional connectivity preferentially affects structurally unconstrained links in schizophrenia. It also raises the question of a continuum of dysconnectivity ranging from less direct (structurally unconstrained) to more direct (structurally constrained) brain pathways underlying the progressive clinical staging and persistence of schizophrenia. Hum Brain Mapp, 2015. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc. Fri, 14 Aug 2015 09:42:23 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22925 Functional neuroimaging studies have revealed abnormal brain dynamics of male sexual arousal (SA) in psychogenic erectile dysfunction (pED). However, the neuroanatomical correlates of pED are still unclear. In this work, we obtained cortical thickness (CTh) measurements from structural magnetic resonance images of 40 pED patients and 39 healthy control subjects. Abnormalities in CTh related to pED were explored using a scale space search based brain morphometric analysis. Organizations of brain structural covariance networks were analyzed as well. Compared with healthy men, pED patients showed significantly decreased CTh in widespread cortical regions, most of which were previously reported to show abnormal dynamics of male SA in pED, such as the medial prefrontal, orbitofrontal, cingulate, inferotemporal, and insular cortices. CTh reductions in these areas were found to be significantly correlated with male sexual functioning degradation. Moreover, pED patients showed decreased interregional CTh correlations from the right lateral orbitofrontal cortex to the right supramarginal gyrus and the left angular cortex, implying disassociations between the cognitive, motivational, and inhibitory networks of male SA in pED. This work provides structural insights on the complex phenomenon of psychogenic sexual dysfunction in men, and suggests a specific vulnerability factor, possibly as an extra “organic” factor, that may play an important role in pED. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Wed, 12 Aug 2015 00:44:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22927 Alzheimer's disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel-based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, “visual variant,” n = 93), logopenic variant primary progressive aphasia (lvPPA, “language variant,” n = 74), and memory-predominant AD categorized as early age-of-onset (EOAD, <65 years, n = 114) and late age-of-onset (LOAD, >65 years, n = 114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n = 80). Even at the earliest clinical stage (CDR = 0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant-specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome-specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex-hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome-specific vulnerable networks at the earliest clinical stages of AD. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. Tue, 11 Aug 2015 05:27:37 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22835 Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e., prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATRs), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage. Hum Brain Mapp 36:3717–3732, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 07:40:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22874 Objectives To determine: (1) whether corpus callosum (CC) size and microstructure at 7 years of age or their change from infancy to 7 years differed between very preterm (VP) and full-term (FT) children; (2) perinatal predictors of CC size and microstructure at 7 years; and (3) associations between CC measures at 7 years or trajectories from infancy to 7 years and neurodevelopmental outcomes. Experimental design One hundred and thirty-six VP (gestational age [GA] <30 weeks and/or birth weight <1,250 g) and 33 FT children had usable magnetic resonance images at 7 years of age, and of these, 76 VP and 16 FT infants had usable data at term equivalent age. The CC was traced and divided into six sub-regions. Fractional anisotropy, mean, axial, radial diffusivity and volume were measured from tractography. Perinatal data were collected, and neurodevelopmental tests administered at 7 years' corrected age. Principal observations VP children had smaller posterior CC regions, higher diffusivity and lower fractional anisotropy compared with FT 7-year-olds. Reduction in diffusivity over time occurred faster in VP than FT children (P ≤ 0.002). Perinatal brain abnormality and earlier GA were associated with CC abnormalities. Microstructural abnormalities at 7 years or slower development of the CC were associated with motor dysfunction, poorer mathematics and visual perception. Conclusions This study is the first to demonstrate an accelerated trajectory of CC white matter diffusion following VP birth, associated with improved neurodevelopmental functioning. Findings suggest there is a window of opportunity for neurorestorative intervention to improve outcomes. Hum Brain Mapp 36:3733–3748, 2015. © 2015 Wiley Periodicals, Inc. Wed, 24 Jun 2015 07:24:13 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22875 A comprehensive analysis of the effect of lesion in-painting on the estimation of cortical thickness using magnetic resonance imaging was performed on a large cohort of 918 relapsing-remitting multiple sclerosis patients who participated in a phase III multicenter clinical trial. An automatic lesion in-painting algorithm was developed and implemented. Cortical thickness was measured using the FreeSurfer pipeline with and without in-painting. The effect of in-painting was evaluated using FreeSurfer's paired analysis pipeline. Multivariate regression analysis was also performed with field strength and lesion load as additional factors. Overall, the estimated cortical thickness was different with in-painting than without. The effect of in-painting was observed to be region dependent, more significant in the left hemisphere compared to the right, was more prominent at 1.5 T relative to 3 T, and was greater at higher lesion volumes. Our results show that even for data acquired at 1.5 T in patients with high lesion load, the mean cortical thickness difference with and without in-painting is ∼2%. Based on these results, it appears that in-painting has only a small effect on the estimated regional and global cortical thickness. Hum Brain Mapp 36:3749–3760, 2015. © 2015 Wiley Periodicals, Inc. Fri, 19 Jun 2015 07:24:54 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22876 Recent findings indicate that alterations of the amygdalar resting-state fMRI connectivity play an important role in the etiology of depression. While both depression and resting-state brain activity are shaped by genes and environment, the relative contribution of genetic and environmental factors mediating the relationship between amygdalar resting-state connectivity and depression remain largely unexplored. Likewise, novel neuroimaging research indicates that different mathematical representations of resting-state fMRI activity patterns are able to embed distinct information relevant to brain health and disease. The present study analyzed the influence of genes and environment on amygdalar resting-state fMRI connectivity, in relation to depression risk. High-resolution resting-state fMRI scans were analyzed to estimate functional connectivity patterns in a sample of 48 twins (24 monozygotic pairs) informative for depressive psychopathology (6 concordant, 8 discordant and 10 healthy control pairs). A graph-theoretical framework was employed to construct brain networks using two methods: (i) the conventional approach of filtered BOLD fMRI time-series and (ii) analytic components of this fMRI activity. Results using both methods indicate that depression risk is increased by environmental factors altering amygdalar connectivity. When analyzing the analytic components of the BOLD fMRI time-series, genetic factors altering the amygdala neural activity at rest show an important contribution to depression risk. Overall, these findings show that both genes and environment modify different patterns the amygdala resting-state connectivity to increase depression risk. The genetic relationship between amygdalar connectivity and depression may be better elicited by examining analytic components of the brain resting-state BOLD fMRI signals. Hum Brain Mapp 36:3761–3776, 2015. © 2015 Wiley Periodicals, Inc. Fri, 19 Jun 2015 09:04:34 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22877 Lifespan is a dynamic process with remarkable changes in brain structure and function. Previous neuroimaging studies have indicated age-related microstructural changes in specific white matter tracts during development and aging. However, the age-related alterations in the topological architecture of the white matter structural connectome across the human lifespan remain largely unknown. Here, a cohort of 113 healthy individuals (ages 9–85) with both diffusion and structural MRI acquisitions were examined. For each participant, the high-resolution white matter structural networks were constructed by deterministic fiber tractography among 1024 parcellation units and were quantified with graph theoretical analyses. The global network properties, including network strength, cost, topological efficiency, and robustness, followed an inverted U-shaped trajectory with a peak age around the third decade. The brain areas with the most significantly nonlinear changes were located in the prefrontal and temporal cortices. Different brain regions exhibited heterogeneous trajectories: the posterior cingulate and lateral temporal cortices displayed prolonged maturation/degeneration compared with the prefrontal cortices. Rich-club organization was evident across the lifespan, whereas hub integration decreased linearly with age, especially accompanied by the loss of frontal hubs and their connections. Additionally, age-related changes in structural connections were predominantly located within and between the prefrontal and temporal modules. Finally, based on the graph metrics of structural connectome, accurate predictions of individual age were obtained (r = 0.77). Together, the data indicated a dynamic topological organization of the brain structural connectome across human lifespan, which may provide possible structural substrates underlying functional and cognitive changes with age. Hum Brain Mapp 36:3777–3792, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 07:37:59 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22878 Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. Hum Brain Mapp 36:3793–3804, 2015. © 2015 Wiley Periodicals, Inc. Wed, 24 Jun 2015 07:23:44 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22879 Alexithymia, a major risk factor for a range of psychiatric and neurological disorders, has been recognized to comprise two dimensions, a cognitive dimension (difficulties identifying, analyzing, and verbalizing feelings) and an affective one (difficulties emotionalizing and fantasizing). Based on these dimensions, the existence of four distinct alexithymia subtypes has been proposed, but never empirically tested. In this study, 125 participants were assigned to four groups corresponding to the proposed alexithymia subtypes: Type I (impairment on both dimensions), Type II (impairment on the cognitive, but not the affective dimension), Type III (impairment on the affective, but not the cognitive dimension), and Lexithymics (no impairment on either dimension). By means of voxel-based morphometry, associations of the alexithymia dimensions and subtypes with gray and white matter volumes were analyzed. Type I and Type II alexithymia were characterized by gray matter volume reductions in the left amygdala and the thalamus. The cognitive dimension was further linked to volume reductions in the right amygdala, left posterior insula, precuneus, caudate, hippocampus, and parahippocampus. Type III alexithymia was marked by volume reduction in the MCC only, and the affective dimension was further characterized by larger sgACC volume. Moreover, individuals with the intermediate alexithymia Types II and III showed gray matter volume reductions in distinct regions, and had larger corpus callosum volumes compared to Lexithymics. These results substantiate the notion of a differential impact of the cognitive and affective alexithymia dimensions on brain morphology and provide evidence for separable neuroanatomical representations of the different alexithymia subtypes. Hum Brain Mapp 36:3805–3818, 2015. © 2015 Wiley Periodicals, Inc. Fri, 19 Jun 2015 07:24:31 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22880 Hippocampal atrophy in advanced healthy aging has frequently been reported. However, the vulnerability of different hippocampal subfields to age-related atrophy is still a source of debate. Moreover, the association of age with the microstructural integrity of subfields is largely unknown. In this study, we investigated the associations between age and volume as well as microstructural integrity of hippocampal subfields using a three-dimensional (3D) surface mapping approach. Forty-three healthy older adults spanning the age range from 60 to 85 years underwent T1-weighted and diffusion-tensor imaging. Analyses demonstrated an association of age with hippocampal volume predominantly in the most anterior part of the hippocampal head, mainly corresponding to the subiculum. In contrast, the association of age with hippocampal microstructural integrity was mainly confined to regions located in the hippocampal body and tail, corresponding to the subiculum and CA1. Results indicate that age-related volumetric and microstructural alterations within hippocampal subfields provide complementary information and reflect different age-related processes. Potential mechanisms underlying the differential associations of age with volume and microstructure of hippocampal subfields are discussed. Hum Brain Mapp 36:3819–3831, 2015. © 2015 Wiley Periodicals, Inc. Wed, 24 Jun 2015 07:24:35 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22881 How the human brain represents distinct motor features into a unique finalized action still remains undefined. Previous models proposed the distinct features of a motor act to be hierarchically organized in separated, but functionally interconnected, cortical areas. Here, we hypothesized that distinct patterns across a wide expanse of cortex may actually subserve a topographically organized coding of different categories of actions that represents, at a higher cognitive level and independently from the distinct motor features, the action and its final aim as a whole. Using functional magnetic resonance imaging and pattern classification approaches on the neural responses of 14 right-handed individuals passively watching short movies of hand-performed tool-mediated, transitive, and meaningful intransitive actions, we were able to discriminate with a high accuracy and characterize the category-specific response patterns. Actions are distinctively coded in distributed and overlapping neural responses within an action-selective network, comprising frontal, parietal, lateral occipital and ventrotemporal regions. This functional organization, that we named action topography, subserves a higher-level and more abstract representation of finalized actions and has the capacity to provide unique representations for multiple categories of actions. Hum Brain Mapp 36:3832–3844, 2015. © 2015 Wiley Periodicals, Inc. Thu, 02 Jul 2015 07:52:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22882 The present fMRI study examined whether upper-limb action classes differing in their motor goal are encoded by different PPC sectors. Action observation was used as a proxy for action execution. Subjects viewed actors performing object-related (e.g., grasping), skin-displacing (e.g., rubbing the skin), and interpersonal upper limb actions (e.g., pushing someone). Observation of the three action classes activated a three-level network including occipito-temporal, parietal, and premotor cortex. The parietal region common to observing all three action classes was located dorsally to the left intraparietal sulcus (DIPSM/DIPSA border). Regions specific for observing an action class were obtained by combining the interaction between observing action classes and stimulus types with exclusive masking for observing the other classes, while for regions considered preferentially active for a class the interaction was exclusively masked with the regions common to all observed actions. Left putative human anterior intraparietal was specific for observing manipulative actions, and left parietal operculum including putative human SII region, specific for observing skin-displacing actions. Control experiments demonstrated that this latter activation depended on seeing the skin being moved and not simply on seeing touch. Psychophysiological interactions showed that the two specific parietal regions had similar connectivities. Finally, observing interpersonal actions preferentially activated a dorsal sector of left DIPSA, possibly the homologue of ventral intraparietal coding the impingement of the target person's body into the peripersonal space of the actor. These results support the importance of segregation according to the action class as principle of posterior parietal cortex organization for action observation and by implication for action execution. Hum Brain Mapp 36:3845–3866, 2015. © 2015 Wiley Periodicals, Inc. Tue, 30 Jun 2015 23:55:56 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22883 Objectives Disorders of consciousness (DoC)—that is, unresponsive wakefulness syndrome/vegetative state and minimally conscious state—are debilitating conditions for which no reliable markers of consciousness recovery have yet been identified. Evidence points to the GABAergic system being altered in DoC, making it a potential target as such a marker. Experimental design In our preliminary study, we used [11C]Flumazenil positron emission tomography to establish global GABAA receptor binding potential values and the local-to-global (LTG) ratio of these for specific regions. These values were then compared between DoC patients and healthy controls. In addition, they were correlated with behavioral improvements for the patients between the time of scanning and 3 months later. Functional magnetic resonance imaging resting-state functional connectivity was also calculated and the same comparisons made. Principal observations lobal GABAA receptor binding was reduced in DoC, as was the LTG ratio in specifically the supragenual anterior cingulate. Both of these measures correlated with behavioral improvement after 3 months. In contrast to these measures of GABAA receptor binding, functional connectivity did not correlate with behavioral improvement. Conclusions Our preliminary findings point toward GABAA receptor binding being a marker of consciousness recovery in DoC. Hum Brain Mapp 36:3867–3877, 2015. © 2015 Wiley Periodicals, Inc. Fri, 03 Jul 2015 10:08:08 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22884 Benign epilepsy with centrotemporal spikes (BECTS) is often associated with neural circuit dysfunction, particularly during the transient active state characterized by interictal epileptiform discharges (IEDs). Little is known, however, about the functional neural circuit abnormalities in BECTS without IEDs, or if such abnormalities could be used to differentiate BECTS patients without IEDs from healthy controls (HCs) for early diagnosis. To this end, we conducted resting-state functional magnetic resonance imaging (RS-fMRI) and simultaneous Electroencephalogram (EEG) in children with BECTS (n = 43) and age-matched HC (n = 28). The simultaneous EEG recordings distinguished BECTS with IEDs (n = 20) from without IEDs (n = 23). Intrinsic brain activity was measured in all three groups using the amplitude of low frequency fluctuation at rest. Compared to HC, BECTS patients with IEDs exhibited an intrinsic activity abnormality in the thalamus, suggesting that thalamic dysfunction could contribute to IED emergence while patients without IEDs exhibited intrinsic activity abnormalities in middle frontal gyrus and superior parietal gyrus. Using multivariate pattern classification analysis, we were able to differentiate BECTS without IEDs from HCs with 88.23% accuracy. BECTS without epileptic transients can be distinguished from HC and BECTS with IEDs by unique regional abnormalities in resting brain activity. Both transient abnormalities as reflected by IEDs and chronic abnormalities as reflected by RS-fMRI may contribute to BECTS development and expression. Intrinsic brain activity and multivariate pattern classification techniques are promising tools to diagnose and differentiate BECTS syndromes. Hum Brain Mapp 36:3878–3889, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 07:37:54 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22885 Previous neuroimaging studies in adults have revealed that first and second languages (L1/L2) share similar neural substrates, and that proficiency is a major determinant of the neural organization of L2 in the lexical-semantic and syntactic domains. However, little is known about neural substrates of children in the phonological domain, or about sex differences. Here, we conducted a large-scale study (n = 484) of school-aged children using functional near-infrared spectroscopy and a word repetition task, which requires a great extent of phonological processing. We investigated cortical activation during word processing, emphasizing sex differences, to clarify similarities and differences between L1 and L2, and proficiency-related differences during early L2 learning. L1 and L2 shared similar neural substrates with decreased activation in L2 compared to L1 in the posterior superior/middle temporal and angular/supramarginal gyri for both sexes. Significant sex differences were found in cortical activation within language areas during high-frequency word but not during low-frequency word processing. During high-frequency word processing, widely distributed areas including the angular/supramarginal gyri were activated in boys, while more restricted areas, excluding the angular/supramarginal gyri were activated in girls. Significant sex differences were also found in L2 proficiency-related activation: activation significantly increased with proficiency in boys, whereas no proficiency-related differences were found in girls. Importantly, cortical sex differences emerged with proficiency. Based on previous research, the present results indicate that sex differences are acquired or enlarged during language development through different cognitive strategies between sexes, possibly reflecting their different memory functions. Hum Brain Mapp 36:3890–3911, 2015. © 2015 Wiley Periodicals, Inc. Fri, 03 Jul 2015 10:07:46 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22886 Homotopy reflects the intrinsic functional architecture of the brain through synchronized spontaneous activity between corresponding bilateral regions, measured as voxel mirrored homotopic connectivity (VMHC). Hypercapnia is known to have clear impact on brain hemodynamics through vasodilation, but have unclear effect on neuronal activity. This study investigates the effect of hypercapnia on brain homotopy, achieved by breathing 5% carbon dioxide (CO2) gas mixture. A total of 14 healthy volunteers completed three resting state functional MRI (RS-fMRI) scans, the first and third under normocapnia and the second under hypercapnia. VMHC measures were calculated as the correlation between the BOLD signal of each voxel and its counterpart in the opposite hemisphere. Group analysis was performed between the hypercapnic and normocapnic VMHC maps. VMHC showed a diffused decrease in response to hypercapnia. Significant regional decreases in VMHC were observed in all anatomical lobes, except for the occipital lobe, in the following functional hierarchical subdivisions: the primary sensory-motor, unimodal, heteromodal, paralimbic, as well as in the following functional networks: ventral attention, somatomotor, default frontoparietal, and dorsal attention. Our observation that brain homotopy in RS-fMRI is affected by arterial CO2 levels suggests that caution should be used when comparing RS-fMRI data between healthy controls and patients with pulmonary diseases and unusual respiratory patterns such as sleep apnea or chronic obstructive pulmonary disease. Hum Brain Mapp 36:3912–3921, 2015. © 2015 Wiley Periodicals, Inc. Thu, 02 Jul 2015 07:52:11 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22887 When visual patterns drifting in different directions and/or at different speeds are superimposed on the same plane, observers perceive transparent surfaces on planes of different depths. This phenomenon is known as transparent motion perception. In this study, cortical activities were measured using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) to reveal the cortical dynamics associated with determination of depth order during transparent motion perception. In addition, offline eye movement measurements were performed to determine the latencies of the start of both pursuit eye movements and depth attention that are important in determination of the depth order. MEG and fMRI data were analyzed by a normalized integrative fMRI–MEG method that enables reconstruction of time-varying dipole moments of activated regions from MEG signals. Statistical analysis of fMRI data was performed to identify activated regions. The activated regions were used as spatial constraints for the reconstruction using the integrative fMRI–MEG method. We focused on the period between latencies (216–405 ms) determined by eye movement experiment, which are related to determination of the depth order. The results of integrative analysis revealed that significant neural activities were observed in the visual association area, the human middle temporal area, the intraparietal sulcus, the lateral occipital cortex, and the anterior cingulate cortex between 216 and 405 ms. These results suggest that initial eye movement and accompanying cortical activations during focused duration play an important role in determining the depth order during transparent motion perception. Hum Brain Mapp 36:3922–3934, 2015. © 2015 Wiley Periodicals, Inc. Mon, 06 Jul 2015 00:07:44 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22888 Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a common childhood epilepsy associated with deficits in several neurocognitive domains. Neurophysiological studies in BECTS often focus on centro-temporal spikes, but these correlate poorly with morphology and cognitive impairments. To better understand the neural profile of BECTS, we studied background brain oscillations, thought to be integrally involved in neural network communication, in sensorimotor areas. We used independent component analysis of temporally correlated sources on magnetoencephalography recordings to assess sensorimotor resting-state network activity in BECTS patients and typically developing controls. We also investigated the variability of oscillatory characteristics within focal primary motor cortex (M1), localized with a separate finger abduction task. We hypothesized that background oscillations would differ between patients and controls in the sensorimotor network but not elsewhere, especially in the beta band (13–30 Hz) because of its role in network communication and motor processing. The results support our hypothesis: in the sensorimotor network, patients had a greater variability in oscillatory amplitude compared to controls, whereas there was no difference in the visual network. Network measures did not correlate with age. The coefficient of variation of resting M1 peak frequency correlated negatively with age in the beta band only, and was greater than average for a number of patients. Our results point toward a “disorganized” functional sensorimotor network in BECTS, supporting a neurodevelopmental delay in sensorimotor cortex. Our findings further suggest that investigating the variability of oscillatory peak frequency may be a useful tool to investigate deficits of disorganization in neurodevelopmental disorders. Hum Brain Mapp 36:3935–3949, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 07:40:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22889 Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)—the fear of bodily autonomic arousal—is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for ‘neural mediators’ of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex—a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder. Hum Brain Mapp 36:3950–3958, 2015. © 2015 Wiley Periodicals, Inc. Mon, 06 Jul 2015 00:07:20 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22890 Alterations in resting-state networks (RSNs) are often associated with psychiatric and neurologic disorders. Given this critical linkage, it has been hypothesized that RSNs can potentially be used as endophenotypes for brain diseases. To validate this notion, a critical step is to show that RSNs exhibit heritability. However, the investigation of the genetic basis of RSNs has only been attempted in the default-mode network at the region-of-interest level, while the genetic control on other RSNs has not been determined yet. Here, we examined the genetic and environmental influences on eight well-characterized RSNs using a twin design. Resting-state functional magnetic resonance imaging data in 56 pairs of twins were collected. The genetic and environmental effects on each RSN were estimated by fitting the functional connectivity covariance of each voxel in the RSN to the classic ACE twin model. The data showed that although environmental effects accounted for the majority of variance in wide-spread areas, there were specific brain sites that showed significant genetic control for individual RSNs. These results suggest that part of the human brain functional connectome is shaped by genomic constraints. Importantly, this information can be useful for bridging genetic analysis and network-level assessment of brain disorders. Hum Brain Mapp 36:3959–3972, 2015. © 2015 Wiley Periodicals, Inc. Mon, 06 Jul 2015 00:09:47 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22891 Introduction Blood oxygenation-level dependent (BOLD) magnetic resonance imaging signal changes in response to stimuli have been used to evaluate age-related changes in neuronal activity. Contradictory results from these types of experiments have been attributed to differences in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2). To clarify the effects of these physiological parameters, we investigated the effect of age on baseline CBF and CMRO2. Materials and Methods Twenty young (mean ± sd age, 28 ± 3 years), and 45 older subjects (66 ± 4 years) were investigated. A dual-echo pseudocontinuous arterial spin labeling (ASL) sequence was performed during normocapnic, hypercapnic, and hyperoxic breathing challenges. Whole brain and regional gray matter values of CBF, ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and CMRO2 were calculated. Results Whole brain CBF was 49 ± 14 and 40 ± 9 ml/100 g/min in young and older subjects respectively (P < 0.05). Age-related differences in CBF decreased to the point of nonsignificance (B=−4.1, SE=3.8) when EtCO2 was added as a confounder. BOLD CVR was lower in the whole brain, in the frontal, in the temporal, and in the occipital of the older subjects (P<0.05). Whole brain OEF was 43 ± 8% in the young and 39 ± 6% in the older subjects (P = 0.066). Whole brain CMRO2 was 181 ± 60 and 133 ± 43 µmol/100 g/min in young and older subjects, respectively (P<0.01). Discussion Age-related differences in CBF could potentially be explained by differences in EtCO2. Regional CMRO2 was lower in older subjects. BOLD studies should take this into account when investigating age-related changes in neuronal activity. Hum Brain Mapp 36:3973–3987, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 07:37:50 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22892 Despite an extensive body of work, it is still not clear how short term maintenance of information is implemented in the human brain. Most prior research has focused on “working memory”—typically involving the storage of a number of items, requiring the use of a phonological loop and focused attention during the delay period between encoding and retrieval. These studies largely support a model of enhanced activity in the delay interval as the central mechanism underlying working memory. However, multi-item working memory constitutes only a subset of storage phenomena that may occur during daily life. A common task in naturalistic situations is short term memory of a single item—for example, blindly reaching to a previously placed cup of coffee. Little is known about such single-item, effortless, storage in the human brain. Here, we examined the dynamics of brain responses during a single-item maintenance task, using intracranial recordings implanted for clinical purpose in patients (ECoG). Our results reveal that active electrodes were dominated by transient short latency visual and motor responses, reflected in broadband high frequency power increases in occipito-temporal, frontal, and parietal cortex. Only a very small set of electrodes showed activity during the early part of the delay period. Interestingly, no cortical site displayed a significant activation lasting to the response time. These results suggest that single item encoding is characterized by transient high frequency ECoG responses, while the maintenance of information during the delay period may be mediated by mechanisms necessitating only low-levels of neuronal activations. Hum Brain Mapp 36:3988–4003, 2015. © 2015 Wiley Periodicals, Inc. Fri, 03 Jul 2015 10:08:36 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22893 Previous research has demonstrated that brain stimulation can improve inhibitory control. However, the neural mechanisms underlying such artificially induced improvement remain unclear. In this study, by coupling anodal transcranial direct current stimulation (atDCS) with functional MRI, we found that atDCS over preSMA effectively improved stopping speed, which was associated with increased BOLD response in the preSMA and ventromedial prefrontal cortex (vmPFC). Furthermore, such atDCS-induced BOLD increase in vmPFC was positively correlated with participants’ improvement in stopping efficiency, and the functional connectivity between preSMA and vmPFC increased during successful stop. These results suggest that the rapid behavioral improvement from preSMA brain stimulation involves modulated medial-frontal activity and preSMA-vmPFC functional connectivity. Hum Brain Mapp 36:4004–4015, 2015. © 2015 Wiley Periodicals, Inc. Fri, 07 Aug 2015 02:22:41 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22894 Gestures represent an integral aspect of interpersonal communication, and they are closely linked with language and thought. Brain regions for language processing overlap with those for gesture processing. Two types of gesticulation, beat gestures and metaphoric gestures are particularly important for understanding the taxonomy of co-speech gestures. Here, we investigated gesture production during taped interviews with respect to regional brain volume. First, we were interested in whether beat gesture production is associated with similar regions as metaphoric gesture. Second, we investigated whether cortical regions associated with metaphoric gesture processing are linked to gesture production based on correlations with brain volumes. We found that beat gestures are uniquely related to regional volume in cerebellar regions previously implicated in discrete motor timing. We suggest that these gestures may be an artifact of the timing processes of the cerebellum that are important for the timing of vocalizations. Second, our findings indicate that brain volumes in regions of the left hemisphere previously implicated in metaphoric gesture processing are positively correlated with metaphoric gesture production. Together, this novel work extends our understanding of left hemisphere regions associated with gesture to indicate their importance in gesture production, and also suggests that beat gestures may be especially unique. This provides important insight into the taxonomy of co-speech gestures, and also further insight into the general role of the cerebellum in language. Hum Brain Mapp 36:4016–4030, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 11:04:40 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22895 Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine–glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition. Hum Brain Mapp 36:4031–4040, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 08:42:14 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22896 Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia. Hum Brain Mapp 36:4041–4052, 2015. © 2015 Wiley Periodicals, Inc. Wed, 15 Jul 2015 08:16:39 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22897 Functional connectivity analysis of brain networks has become an important tool for investigation of human brain function. Although functional connectivity computations are usually based on resting-state data, the application to task-specific fMRI has received growing attention. Three major methods for extraction of resting-state data from task-related signal have been proposed (1) usage of unmanipulated task data for functional connectivity; (2) regression against task effects, subsequently using the residuals; and (3) concatenation of baseline blocks located in-between task blocks. Despite widespread application in current research, consensus on which method best resembles resting-state seems to be missing. We, therefore, evaluated these techniques in a sample of 26 healthy controls measured at 7 Tesla. In addition to continuous resting-state, two different task paradigms were assessed (emotion discrimination and right finger-tapping) and five well-described networks were analyzed (default mode, thalamus, cuneus, sensorimotor, and auditory). Investigating the similarity to continuous resting-state (Dice, Intraclass correlation coefficient (ICC), R2) showed that regression against task effects yields functional connectivity networks most alike to resting-state. However, all methods exhibited significant differences when compared to continuous resting-state and similarity metrics were lower than test-retest of two resting-state scans. Omitting global signal regression did not change these findings. Visually, the networks are highly similar, but through further investigation marked differences can be found. Therefore, our data does not support referring to resting-state when extracting signals from task designs, although functional connectivity computed from task-specific data may indeed yield interesting information. Hum Brain Mapp 36:4053–4063, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. Wed, 15 Jul 2015 23:56:38 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22898 Background Recent studies have shown that response inhibition is impaired in patients with obsessive–compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive–compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive–compulsive disorder and their unaffected siblings. Methods Forty-one unmedicated patients with obsessive–compulsive disorder, 17 of their unaffected siblings and 37 healthy controls performed a stop signal task during functional magnetic resonance imaging. Psycho-physiological interaction analysis was used to examine functional connectivity between the following regions of interest: the bilateral inferior frontal gyri, presupplementary motor area, subthalamic nuclei, inferior parietal lobes, anterior cingulate cortex, and amygdala. We then used dynamic causal modeling to investigate the directionality of the networks involved. Results Patients, and to a lesser extent also their unaffected siblings, show altered connectivity between the inferior frontal gyrus and the amygdala during response inhibition. The follow-up dynamic causal modeling suggests a bottom-up influence of the amygdala on the inferior frontal gyrus in healthy controls, whereas processing occurs top-down in patients with obsessive–compulsive, and in both directions in siblings. Conclusions Our findings suggest that amygdala activation in obsessive–compulsive disorder interferes differently with the task-related recruitment of the inhibition network, underscoring the role of limbic disturbances in cognitive dysfunctions in obsessive–compulsive disorder. Hum Brain Mapp 36:4064–4075, 2015. © 2015 Wiley Periodicals, Inc. Wed, 15 Jul 2015 23:55:58 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22899 The bed nucleus of the stria terminalis (BNST), a portion of the “extended amygdala,” is implicated in the pathophysiology of anxiety and addiction disorders. Its small size and connection to other small regions prevents standard imaging techniques from easily capturing it and its connectivity with confidence. Seed-based resting state functional connectivity is an established method for mapping functional connections across the brain from a region of interest. We, therefore, mapped the BNST resting state network with high spatial resolution using 7 Tesla fMRI, demonstrating the in vivo reproduction of many human BNST connections previously described only in animal research. We identify strong BNST functional connectivity in amygdala, hippocampus and thalamic subregions, caudate, periaqueductal gray, hypothalamus, and cortical areas such as the medial PFC and precuneus. This work, which demonstrates the power of ultra-high field for mapping functional connections in the human, is an important step toward elucidating cortical and subcortical regions and subregions of the BNST network. Hum Brain Mapp 36:4076–4088, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 08:28:30 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22900 The application of global signal regression (GSR) to resting-state functional magnetic resonance imaging data and its usefulness is a widely discussed topic. In this article, we report an observation of segregated distribution of amygdala resting-state functional connectivity (rs-FC) within the fusiform gyrus (FFG) as an effect of GSR in a multi-center-sample of 276 healthy subjects. Specifically, we observed that amygdala rs-FC was distributed within the FFG as distinct anterior versus posterior clusters delineated by positive versus negative rs-FC polarity when GSR was performed. To characterize this effect in more detail, post hoc analyses revealed the following: first, direct overlays of task-functional magnetic resonance imaging derived face sensitive areas and clusters of positive versus negative amygdala rs-FC showed that the positive amygdala rs-FC cluster corresponded best with the fusiform face area, whereas the occipital face area corresponded to the negative amygdala rs-FC cluster. Second, as expected from a hierarchical face perception model, these amygdala rs-FC defined clusters showed differential rs-FC with other regions of the visual stream. Third, dynamic connectivity analyses revealed that these amygdala rs-FC defined clusters also differed in their rs-FC variance across time to the amygdala. Furthermore, subsample analyses of three independent research sites confirmed reliability of the effect of GSR, as revealed by similar patterns of distinct amygdala rs-FC polarity within the FFG. In this article, we discuss the potential of GSR to segregate face sensitive areas within the FFG and furthermore discuss how our results may relate to the functional organization of the face-perception circuit. Hum Brain Mapp 36:4089–4103, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 09:57:51 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22901 This functional magnetic resonance (fMRI) study was designed to investigate changes in functional patterns of brain activity during creative ideation as a result of a computerized, 3-week verbal creativity training. The training was composed of various verbal divergent thinking exercises requiring participants to train approximately 20 min per day. Fifty-three participants were tested three times (psychometric tests and fMRI assessment) with an intertest-interval of 4 weeks each. Participants were randomly assigned to two different training groups, which received the training time-delayed: The first training group was trained between the first and the second test, while the second group accomplished the training between the second and the third test session. At the behavioral level, only one training group showed improvements in different facets of verbal creativity right after the training. Yet, functional patterns of brain activity during creative ideation were strikingly similar across both training groups. Whole-brain voxel-wise analyses (along with supplementary region of interest analyses) revealed that the training was associated with activity changes in well-known creativity-related brain regions such as the left inferior parietal cortex and the left middle temporal gyrus, which have been shown as being particularly sensitive to the originality facet of creativity in previous research. Taken together, this study demonstrates that continuous engagement in a specific complex cognitive task like divergent thinking is associated with reliable changes of activity patterns in relevant brain areas, suggesting more effective search, retrieval, and integration from internal memory representations as a result of the training. Hum Brain Mapp 36:4104–4115, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 08:42:17 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22902 In this study, we used invasive tracing to evaluate white matter tractography methods based on ex vivo diffusion-weighted magnetic resonance imaging (dwMRI) data. A representative selection of tractography methods were compared to manganese tracing on a voxel-wise basis, and a more qualitative assessment examined whether, and to what extent, certain fiber tracts and gray matter targets were reached. While the voxel-wise agreement was very limited, qualitative assessment revealed that tractography is capable of finding the major fiber tracts, although there were some differences between the methods. However, false positive connections were very common and, in particular, we discovered that it is not possible to achieve high sensitivity (i.e., few false negatives) and high specificity (i.e., few false positives) at the same time. Closer inspection of the results led to the conclusion that these problems mainly originate from regions with complex fiber arrangements or high curvature and are not easily resolved by sophisticated local models alone. Instead, the crucial challenge in making tractography a truly useful and reliable tool in brain research and neurology lies in the acquisition of better data. In particular, the increase of spatial resolution, under preservation of the signal-to-noise-ratio, is key. Hum Brain Mapp 36:4116–4134, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 09:58:00 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22903 Individuals with Prader–Willi syndrome (PWS), a genetic disorder caused by mutations to the q11-13 region on chromosome 15, commonly show severe skin-picking behaviors that can cause open wounds and sores on the body. To our knowledge, however, no studies have examined the potential neural mechanisms underlying these behaviors. Seventeen individuals with PWS, aged 6–25 years, who showed severe skin-picking behaviors, were recruited and scanned on a 3T scanner. We used functional magnetic resonance imaging (fMRI) while episodes of skin picking were recorded on an MRI-safe video camera. Three participants displayed skin picking continuously throughout the scan, three participants did not display skin picking, and the data for one participant evidenced significant B0 inhomogeneity that could not be corrected. The data for the remaining 10 participants (six male, four female) who displayed a sufficient number of picking and nonpicking episodes were subjected to fMRI analysis. Results showed that regions involved in interoceptive, motor, attention, and somatosensory processing were activated during episodes of skin-picking behavior compared with nonpicking episodes. Scores obtained on the Self-Injury Trauma scale were significantly negatively correlated with mean activation within the right insula and left precentral gyrus. These data indicate that itch and pain processes appear to underlie skin-picking behaviors in PWS, suggesting that interoceptive disturbance may contribute to the severity and maintenance of abnormal skin-picking behaviors in PWS. Implications for treatments are discussed. Hum Brain Mapp 36:4135–4143, 2015. © 2015 Wiley Periodicals, Inc. Tue, 14 Jul 2015 08:37:54 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22904 The framework of assimilation and accommodation has been proposed to explain the brain mechanisms supporting second language reading acquisition (Perfetti et al. [2007]: Bilingual Lang Cogn 10:131). Assimilation refers to using the procedures of the native language network in the acquisition of a new writing system, whereas accommodation refers to using second language procedures for reading the newly acquired writing system. We investigated assimilation and accommodation patterns in the brains of bilingual individuals by recruiting a group of Chinese–English bilinguals and a group of English–Chinese bilinguals to perform lexical decision tasks in both English and Chinese. The key question was whether the assimilation/accommodation procedures supporting second language reading in the brains of Chinese–English and English–Chinese bilinguals were dynamic, i.e., modulated by proficiency in the second language and perceptual features of the second language's script. Perceptual features of the scripts were manipulated through orthographic degradation by inserting spaces between the radicals of a Chinese character or between the syllables of an English word. This manipulation disrupts the visual configuration of the orthography but does not change its more fundamental design principles. We found that for English–Chinese bilinguals, higher proficiency was associated with greater accommodation, suggesting that the accommodation procedure in a bilingual individual's brain is modulated by second language proficiency. Most interestingly, we found that the assimilation/accommodation effects vanished or diminished when orthographically degraded scripts were processed by both Chinese–English and English–Chinese bilinguals, suggesting that the assimilation/accommodation procedures in a bilingual individual's brain are modulated by perceptual features of orthography. This work therefore offers a new, dynamic perspective for our understanding of the assimilation/accommodation framework for second language acquisition. Hum Brain Mapp 36:4144–4157, 2015. © 2015 Wiley Periodicals, Inc. Mon, 20 Jul 2015 00:08:43 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22906 Individual differences in cognitive efficiency, particularly in relation to working memory (WM), have been associated both with personality dimensions that reflect enduring regularities in brain configuration, and with short-term neural plasticity, that reflects task-related changes in brain connectivity. To elucidate the relationship of these two divergent mechanisms, we tested the hypothesis that personality dimensions, which reflect enduring aspects of brain configuration, inform about the neurobiological framework within which short-term, task-related plasticity, as measured by effective connectivity, can be facilitated or constrained. As WM consistently engages the dorsolateral prefrontal (DLPFC), parietal (PAR), and anterior cingulate cortex (ACC), we specified a WM network model with bidirectional, ipsilateral, and contralateral connections between these regions from a functional magnetic resonance imaging dataset obtained from 40 healthy adults while performing the 3-back WM task. Task-related effective connectivity changes within this network were estimated using Dynamic Causal Modelling. Personality was evaluated along the major dimensions of Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. Only two dimensions were relevant to task-dependent effective connectivity. Neuroticism and Conscientiousness respectively constrained and facilitated neuroplastic responses within the WM network. These results suggest individual differences in cognitive efficiency arise from the interplay between enduring and short-term plasticity in brain configuration. Hum Brain Mapp 36:4158–4163, 2015. © 2015 Wiley Periodicals, Inc. Mon, 20 Jul 2015 00:08:16 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22909 Resonance with the inner states of another social actor is regarded as a hallmark of emotional closeness. Nevertheless, sensitivity to potential incongruities between one's own and an intimate partner's subjective experience is reportedly also important for close relationship quality. Here, we tested whether perceivers show greater neurobehavioral responsiveness to a spouse's positive (rather than negative) context-incongruent emotions, and whether this effect is influenced by the perceiver's satisfaction with the relationship. Thus, we used fMRI to scan older long-term married female perceivers while they judged either their spouse's or a stranger's affect, based on incongruent nonverbal and verbal cues. The verbal cues were selected to evoke strongly polarized affective responses. Higher perceiver marital satisfaction predicted greater neural processing of the spouse's (rather than the strangers) nonverbal cues. Nevertheless, across all perceivers, greater neural processing of a spouse's (rather than a stranger's) nonverbal behavior was reliably observed only when the behavior was positive and the context was negative. The spouse's positive (rather than negative) nonverbal behavior evoked greater activity in putative mirror neuron areas, such as the bilateral inferior parietal lobule (IPL). This effect was related to a stronger inhibitory influence of cognitive control areas on mirror system activity in response to a spouse's negative nonverbal cues, an effect that strengthened with increasing perceiver marital satisfaction. Our valence-asymmetric findings imply that neurobehavioral responsiveness to a close other's emotions may depend, at least partly, on cognitive control resources, which are used to support the perceiver's interpersonal goals (here, goals that are relevant to relationship stability). Hum Brain Mapp 36:4164–4183, 2015. © 2015 Wiley Periodicals, Inc. Tue, 28 Jul 2015 23:55:46 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22910 Whether neuroimaging findings support discriminable neural correlates of emotion categories is a longstanding controversy. Two recent meta-analyses arrived at opposite conclusions, with one supporting (Vytal and Hamann []: J Cogn Neurosci 22:2864–2885) and the other opposing this proposition (Lindquist et al. []: Behav Brain Sci 35:121–143). To obtain direct evidence regarding this issue, we compared activations for four emotions within a single fMRI design. Angry, happy, fearful, sad and neutral stimuli were presented as dynamic body expressions. In addition, observers categorized motion morphs between neutral and emotional stimuli in a behavioral experiment to determine their relative sensitivities. Brain–behavior correlations revealed a large brain network that was identical for all four tested emotions. This network consisted predominantly of regions located within the default mode network and the salience network. Despite showing brain–behavior correlations for all emotions, muli-voxel pattern analyses indicated that several nodes of this emotion general network contained information capable of discriminating between individual emotions. However, significant discrimination was not limited to the emotional network, but was also observed in several regions within the action observation network. Taken together, our results favor the position that one common emotional brain network supports the visual processing and discrimination of emotional stimuli. Hum Brain Mapp 36:4184–4201, 2015. © 2015 Wiley Periodicals, Inc. Tue, 28 Jul 2015 23:58:30 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22911 Psychopathy is a personality disorder characterized by callous lack of empathy, impulsive antisocial behavior, and criminal recidivism. Here, we performed the largest diffusion tensor imaging (DTI) study of incarcerated criminal offenders to date (N = 147) to determine whether psychopathy severity is linked to the microstructural integrity of major white matter tracts in the brain. Consistent with the results of previous studies in smaller samples, we found that psychopathy was associated with reduced fractional anisotropy in the right uncinate fasciculus (UF; the major white matter tract connecting ventral frontal and anterior temporal cortices). We found no such association in the left UF or in adjacent frontal or temporal white matter tracts. Moreover, the right UF finding was specifically related to the interpersonal features of psychopathy (glib superficial charm, grandiose sense of self-worth, pathological lying, manipulativeness), rather than the affective, antisocial, or lifestyle features. These results indicate a neural marker for this key dimension of psychopathic symptomatology. Hum Brain Mapp 36:4202–4209, 2015. © 2015 Wiley Periodicals, Inc. Tue, 28 Jul 2015 23:54:31 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22912 Imagining future events while performing an intertemporal choice task can attenuate the devaluation of future rewards. Here, we investigated whether this effect and its neural basis depend on the degree of personal prior experience associated with the simulated future scenarios. Functional magnetic resonance imaging was combined with a modified intertemporal choice task in which the delayed options were either purely monetary, or linked with a social event. Subject-specific events differed regarding familiarity, that is, meeting a close, familiar person or a celebrity in a café. In line with recent hypotheses on episodic construction, the simulation of future familiar and unfamiliar events equally attenuated delay discounting behavior in comparison with the control condition and both were imagined with similar richness. Imaging data, however, indicate that these results rely on differential neural activation patterns. The hippocampus was particularly involved in the simulation of unfamiliar future scenarios, probably reflecting enhanced construction processes when personal experience with similar past events is lacking. Consequently, functional coupling of the hippocampus with neural valuation signals in the anterior cingulate cortex predicted the subjective value only of rewards offered in the unfamiliar context. In contrast, valuation of rewards in a familiar context was predicted by activation in key nodes of emotional and autobiographical memory retrieval and dynamically modulated by frontal-striatal connectivity. The present data emphasize that the mechanisms underlying neural valuation of prospective rewards largely depend on the pre-experience with the context in which they are offered. Hum Brain Mapp 36:4210–4221, 2015. © 2015 Wiley Periodicals, Inc. Tue, 28 Jul 2015 23:55:21 +0000 http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fhbm.22913 Objectives Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT). Experimental design Amygdala activity and amygdala connectivity during the EFMT were assessed in 51 cocaine using males and 32 non-drug-using healthy males using functional magnetic resonance imaging (fMRI). Within the cocaine use group, we explored whether amygdala activation was associated with age of first use of cocaine and duration of cocaine use to distinguish between amygdala activation alterations as a cause or a consequence of cocaine use. Principal observations We observed hyperactivity of the amygdala, thalamus, and hippocampus and reduced amygdala connectivity with the anterior cingulate gyrus in response to angry and fearful facial expressions in current cocaine users compared to controls. Increased amygdala activation was independently associated with earlier age of first cocaine use and with longer exposure to cocaine. Conclusions Our findings suggest that amygdala hyperactivity to biologically salient stimuli may represent a risk factor for an early onset of cocaine use and that prolonged cocaine use may further sensitize amygdala activation. High amygdala activation to emotional face processing in current cocaine users may result from low prefrontal control of the amygdala response to such stimuli. Hum Brain Mapp 36:4222–4230, 2015. © 2015 Wiley Periodicals, Inc. Tue, 28 Jul 2015 23:54:55 +0000