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1.  Evidence of Conjoint Activation of the Anterior Insular and Cingulate Cortices during Effortful Tasks 
The ability to perform effortful tasks is a topic that has received considerable interest in the research of higher functions of the human brain. Neuroimaging studies show that the anterior insular and the anterior cingulate cortices are involved in a multitude of cognitive tasks that require mental effort. In this study, we investigated brain responses to effort using cognitive tasks with task-difficulty modulations and functional magnetic resonance imaging (fMRI). We hypothesized that effortful performance involves modulation of activation in the anterior insular and the anterior cingulate cortices, and that the modulation correlates with individual performance levels. Healthy participants performed tasks probing verbal working memory capacity using the reading span task, and visual perception speed using the inspection time task. In the fMRI analysis, we focused on identifying effort-related brain activation. The results showed that working memory and inspection time performances were directly related. The bilateral anterior insular and anterior cingulate cortices showed significantly increased activation during each task with common portions that were active across both tasks. We observed increased brain activation in the right anterior insula and the anterior cingulate cortex in participants with low working memory performance. In line with the reported results, we suggest that activation in the anterior insular and cingulate cortices is consistent with the neural efficiency hypothesis (Neubauer).
PMCID: PMC4306292
functional magnetic resonance imaging; working memory; visual perception; forebrain asymmetry
2.  Identification of BDNF Sensitive Electrophysiological Markers of Synaptic Activity and Their Structural Correlates in Healthy Subjects Using a Genetic Approach Utilizing the Functional BDNF Val66Met Polymorphism 
PLoS ONE  2014;9(4):e95558.
Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.
PMCID: PMC3997566  PMID: 24760076
3.  Decreased Brain Volume in Adults with Childhood Lead Exposure 
PLoS Medicine  2008;5(5):e112.
Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments.
Methods and Findings
Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation.
Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.
Using magnetic resonance imaging to assess brain volumes, Kim Cecil and colleagues find that inner-city children with higher blood lead levels showed regions of decreased gray matter as adults.
Editors' Summary
Lead is a highly toxic metal that is present throughout the environment because of various human activities. In particular, for many years, large amounts of lead were used in paint, in solder for water pipes, in gasoline, and in ceramic glazes. But, as the harmful health effects of lead have become clear, its use in these and other products has been gradually phased out. Breathing air, drinking water, or eating food that contains lead can damage almost every organ in the human body. The organ that is most sensitive to lead exposure is the brain, and children's brains are particularly vulnerable because they are still developing. Children who swallow large amounts of lead can develop widespread brain damage that causes convulsions and sometimes death. Children who are repeatedly exposed to low to moderate amounts of lead (e.g., through accidentally swallowing residues of old lead paint or contaminated soil) can develop learning or behavioral problems.
Why Was This Study Done?
Lead exposure has been linked with various types of brain damage. These include problems with thinking (cognition); difficulties with organizing actions, decisions, and behaviors (executive functions); abnormal social behavior (including aggression); and difficulties in coordinating fine movements, such as picking up small objects (fine motor control). However, we know little about how lead damages the brain in this way and little about which brain regions are affected by exposure to low to moderate levels of lead during childhood. In this study, the researchers wanted to test the possibility that childhood lead exposure might lead to shrinking (“volume loss”) parts of the brain, particularly the parts that are crucial to cognition and behavior. They therefore studied the relationship between childhood lead exposure and adult brain volume. They also explored whether there is a relationship between brain volume and measures of brain functioning, such as fine motor control, memory, and learning assessed during adolescence.
What Did the Researchers Do and Find?
Between 1979 and 1984, the researchers recruited babies born in poor areas of Cincinnati, where there were many old, lead-contaminated houses, into the Cincinnati Lead Study. They measured their blood lead levels regularly from birth until they were 78 months old and calculated each child's average blood lead level over this period. They then used brain scans (known as magnetic resonance imaging, or MRI) to measure the brain volumes of the participants when they were 19–24 years old. The researchers found that exposure to lead as a child was linked with brain volume loss in adulthood, particularly in men. There was a “dose-response” effect—in other words, the greatest brain volume loss was seen in participants with the greatest lead exposure in childhood. The brain volume loss was most noticeable in a part of the brain called the prefrontal cortex—especially a region called the “anterior cingulate cortex.” When they examined the relationship between brain volume and measures of brain functioning, they found a link between brain volume and fine motor control, but not with the other measures.
What Do These Findings Mean?
These findings indicate that childhood lead exposure is associated with brain volume loss in adults, in specific regions of the brain. These brain regions are responsible for executive functions, regulating behavior, and fine motor control. Lead exposure has a larger effect on brain volumes in men than in women, which might help to explain the higher incidence of antisocial behaviors among men than women. Overall, these findings may explain why children and adults who have a history of lead exposure have behavioral and other problems, and support ongoing efforts to reduce childhood lead exposure in the US and other countries.
Additional Information.
Please access these Web sites via the online version of this summary at
A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on child exposure to lead and criminal arrests in adulthood
Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish)
Medline Plus and the US National Library of Medicine Specialized Information Services provide lists of links to information on lead and human health (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program
The UK Health Protection Agency also provides information about lead and its health hazards
PMCID: PMC2689675  PMID: 18507499
4.  Resting State Functional Connectivity in Addiction: Lessons Learned and a Road Ahead 
NeuroImage  2012;62(4):2281-2295.
Despite intensive scientific investigation and public health imperatives, drug addiction treatment outcomes have not significantly improved in more than 50 years. Non-invasive brain imaging has, over the past several decades, contributed important new insights into the neuroplastic adaptations that result from chronic drug intake, but additional experimental approaches and neurobiological hypotheses are needed to better capture the totality of the motivational, affective, cognitive, genetic and pharmacological complexities of the disease. Recent advances in assessing network dynamics through resting-state functional connectivity (rsFC) may allow for such systems-level assessments. In this review, we first summarize the nascent addiction-related rsFC literature and suggest that in using this tool, circuit connectivity may inform specific neurobiological substrates underlying psychological dysfunctions associated with reward, affective and cognitive processing often observed in drug addicts. Using nicotine addiction as an exemplar, we subsequently provide a heuristic framework to guide future research by linking recent findings from intrinsic network connectivity studies with those interrogating nicotine’s neuropharmacological actions. Emerging evidence supports a critical role for the insula in nicotine addiction. Likewise, the anterior insula, potentially together with the anterior cingulate cortex, appears to pivotally influence the dynamics between large-scale brain networks subserving internal (default-mode network) and external (executive control network) information processing. We suggest that a better understanding of how the insula modulates the interaction between these networks is critical for elucidating both the cognitive impairments often associated with withdrawal and the performance-enhancing effects of nicotine administration. Such an understanding may be usefully applied in the design and development of novel smoking cessation treatments.
PMCID: PMC3401637  PMID: 22326834
fMRI; connectivity; drug abuse; nicotine; insula; default mode; attention
5.  Attentional effects of lesions to the anterior cingulate cortex: how prior reinforcement influences distractibility 
Behavioral neuroscience  2011;125(3):360-371.
Morphological changes in the anterior cingulate cortex are found in subjects with schizophrenia, attention deficit hyperactivity disorder, and obsessive compulsive disorder. These changes are hypothesized to underlie the impairments these individuals show on tasks that require cognitive control. The anterior cingulate cortex has previously been shown to be active in situations involving high conflict, presentation of salient, distracting stimuli, and error processing, i.e. situations that occur when a shift in attention or responding is required. However, there is some uncertainty as to what specific role the anterior cingulate cortex plays in these situations. The current study used converging evidence from two behavioral paradigms to determine the effects of excitotoxic lesions in the anterior cingulate cortex on executive control. The first assay tests reversal learning, attentional set formation and shifting. The second assesses sustained attention with and without distractors. Animals with anterior cingulate cortex lesions were impaired during reinforcement reversals, discriminations that required subjects to disregard previously relevant stimulus attributes and showed a more rapid decline in attentional ability than Sham-Lx subjects when maintaining sustained attention for extended periods of time. These results are consistent with the hypothesis that the anterior cingulate cortex is involved in attending to stimulus attributes that currently predict reinforcement in the presence of previously relevant, salient distractors and maintaining sustained attention over prolonged time on task.
PMCID: PMC3109123  PMID: 21480690
prefrontal cortex; cognitive control; executive function; selective attention; cingulated
6.  Assessing the Molecular Genetics of the Development of Executive Attention in Children: Focus on Genetic Pathways Related to the Anterior Cingulate Cortex and Dopamine 
Neuroscience  2009;164(1):241-246.
It is well-known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and fronto-striatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to-date that employs both adult and child-friendly versions of the Attention Network Task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention.
PMCID: PMC2792745  PMID: 19344637
7.  Toward A Physical Basis of Attention and Self Regulation1 
Physics of life reviews  2009;6(2):103-120.
The concept of self-regulation is central to the understanding of human development. Self-regulation allows effective socialization and predicts both psychological pathologies and levels of achievement in schools. What has been missing are neural mechanisms to provide understanding of the cellular and molecular basis for self-regulation. We show that self-regulation can be measured during childhood by parental reports and by self-reports of adolescents and adults. These reports are summarized by a higher order factor called effortful control, which reflects perceptions about the ability of a given person to regulate their behavior in accord with cultural norms. Throughout childhood effortful control is related to children’s performance in computerized conflict related tasks. Conflict tasks have been shown in neuroimaging studies to activate specific brain networks of executive attention. Several brain areas work together at rest and during cognitive tasks to regulate competing brain activity and thus control resulting behavior. The cellular structure of the anterior cingulate and insula contain cells, unique to humans and higher primates that provide strong links to remote brain areas. During conflict tasks, anterior cingulate activity is correlated with activity in remote sensory and emotional systems, depending upon the information selected for the task. During adolescence the structure and activity of the anterior cingulate has been found to be correlated with self-reports of effortful control.
Studies have provided a perspective on how genes and environment act to shape the executive attention network, providing a physical basis for self-regulation. The anterior cingulate is regulated by dopamine. Genes that influence dopamine levels in the CNS have been shown to influence the efficiency of self-regulation. For example, alleles of the COMT gene that influence the efficiency of dopamine transmission are related to the ability to resolve conflict. Humans with disorders involving deletion of this gene exhibit large deficits in self-regulation. Alleles of other genes influencing dopamine and serotonin transmission have also been found to influence ability to resolve conflict in cognitive tasks. However, as is the case for many genes, the effectiveness of COMT alleles in shaping self-regulation depends upon cultural influences such as parenting. Studies find that aspects of parenting quality and parent training can influence child behavior and the efficiency of self-regulation.
During development, the network that relates to self-regulation undergoes important changes in connectivity. Infants can use parts of the self-regulatory network to detect errors in sensory information, but the network does not yet have sufficient connectivity to organize brain activity in a coherent way. During middle childhood, along with increased projection cells involved in remote connections of dorsal anterior cingulate and prefrontal and parietal cortex, executive network connectivity increases and shifts from predominantly short to longer range connections. During this period specific exercises can influence network development and improve self-regulation. Understanding the physical basis of self-regulation has already cast light on individual differences in normal and pathological states and gives promise of allowing the design of methods to improve aspects of human development.
PMCID: PMC2748943  PMID: 20161073
Attention; genetic alleles; neural networks; self-regulation
8.  Heritability of working memory brain activation 
Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean age 23.6±1.8 S.D.) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at high magnetic field (4 Tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40 – 65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, pre- and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that non-genetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.
PMCID: PMC3163233  PMID: 21795540
twin study; heritability; genetic modeling; functional MRI; working memory; voxel-based analysis
9.  Provocation of obsessive–compulsive symptoms: a quantitative voxel-based meta-analysis of functional neuroimaging studies 
Recent functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies based on the symptom provocation paradigm have explored neural correlates of the cognitive and emotional processes associated with the emergence of obsessive–compulsive disorder (OCD) symptoms. Although most studies showed the involvement of cortico–subcortical loops originating in the orbitofrontal cortex and the anterior cingulate cortex, an increased activity within numerous other regions of the brain has inconsistently been reported across studies. To provide a quantitative estimation of the cerebral activation patterns related to the performance of the symptom provocation task by OCD patients, we conducted a voxel-based meta-analysis.
We searched the PubMed and MEDLINE databases for studies that used fMRI and PET and that were based on the symptom provocation paradigm. We entered data into a paradigm-driven activation likelihood estimation meta-analysis.
We found significant likelihoods of activation in cortical and subcortical regions of the orbitofrontal and anterior cingulate loops. The left dorsal frontoparietal network, including the dorsolateral prefrontal cortex and precuneus, and the left superior temporal gyrus also demonstrated significant likelihoods of activation.
Consistent results across functional neuroimaging studies suggest that the orbitofrontal and anterior cingulate cortices are involved in the mediation of obsessive–compulsive symptoms. Based on recent literature, we suggest that activations within the dorsal frontoparietal network might be related to patients' efforts to resist the obsessive processes induced by the provocation task. Further research should elucidate the specific neural correlates of the various cognitive and emotional functions altered in OCD.
PMCID: PMC2527721  PMID: 18787662
obsessive-compulsive disorder; magnetic resonance imaging; positron-emission tomography
10.  An Experiment of Nature: Brain Anatomy Parallels Cognition and Behavior in Williams Syndrome 
Williams syndrome (WS) is a neurogenetic–neurodevelopmental disorder characterized by a highly variable and enigmatic profile of cognitive and behavioral features. Relative to overall intellect, affected individuals demonstrate disproportionately severe visual-spatial deficits and enhanced emotionality and face processing. In this study, high-resolution magnetic resonance imaging data were collected from 43 individuals with WS and 40 age- and gender-matched healthy controls. Given the distinct cognitive-behavioral dissociations associated with this disorder, we hypothesized that neuroanatomical integrity in WS would be diminished most in regions comprising the visual-spatial system and most “preserved” or even augmented in regions involved in emotion and face processing. Both volumetric analysis and voxel-based morphometry were used to provide convergent approaches for detecting the hypothesized WS neuroanatomical profile. After adjusting for overall brain volume, participants with WS showed reduced thalamic and occipital lobe gray matter volumes and reduced gray matter density in subcortical and cortical regions comprising the human visual-spatial system compared with controls. The WS group also showed disproportionate increases in volume and gray matter density in several areas known to participate in emotion and face processing, including the amygdala, orbital and medial prefrontal cortices, anterior cingulate, insular cortex, and superior temporal gyrus. These findings point to specific neuroanatomical correlates for the unique topography of cognitive and behavioral features associated with this disorder.
PMCID: PMC3061615  PMID: 15163693
emotion; neuron; imaging; morphometry; visual; Williams syndrome; neuroanatomy
11.  Developmental Maturation of Dynamic Causal Control Signals in Higher-Order Cognition: A Neurocognitive Network Model 
PLoS Computational Biology  2012;8(2):e1002374.
Cognitive skills undergo protracted developmental changes resulting in proficiencies that are a hallmark of human cognition. One skill that develops over time is the ability to problem solve, which in turn relies on cognitive control and attention abilities. Here we use a novel multimodal neurocognitive network-based approach combining task-related fMRI, resting-state fMRI and diffusion tensor imaging (DTI) to investigate the maturation of control processes underlying problem solving skills in 7–9 year-old children. Our analysis focused on two key neurocognitive networks implicated in a wide range of cognitive tasks including control: the insula-cingulate salience network, anchored in anterior insula (AI), ventrolateral prefrontal cortex and anterior cingulate cortex, and the fronto-parietal central executive network, anchored in dorsolateral prefrontal cortex and posterior parietal cortex (PPC). We found that, by age 9, the AI node of the salience network is a major causal hub initiating control signals during problem solving. Critically, despite stronger AI activation, the strength of causal regulatory influences from AI to the PPC node of the central executive network was significantly weaker and contributed to lower levels of behavioral performance in children compared to adults. These results were validated using two different analytic methods for estimating causal interactions in fMRI data. In parallel, DTI-based tractography revealed weaker AI-PPC structural connectivity in children. Our findings point to a crucial role of AI connectivity, and its causal cross-network influences, in the maturation of dynamic top-down control signals underlying cognitive development. Overall, our study demonstrates how a unified neurocognitive network model when combined with multimodal imaging enhances our ability to generalize beyond individual task-activated foci and provides a common framework for elucidating key features of brain and cognitive development. The quantitative approach developed is likely to be useful in investigating neurodevelopmental disorders, in which control processes are impaired, such as autism and ADHD.
Author Summary
The human brain undergoes significant maturational changes between childhood and adulthood that are thought to enable increasingly sophisticated thoughts and behaviors. One of the skills that we develop over time is the ability to problem solve, which relies in turn on the ability to control our attention and successfully direct our cognitive efforts. Using a novel multi-pronged neuroimaging approach, we identify for the first time the dynamic brain systems underlying the maturation of problem solving abilities. We find that the anterior insula, part of a larger network of regions previously shown to be important for salience processing and generating influential control signals, shows weaker influences over other key brain regions important for task performance in children compared to adults. In addition, structural connections between the anterior insula and other key regions were found to be weaker in children compared to adults. Importantly, measures of causal influences between key regions could be used to predict individual differences in behavioral performance. Our study is the first to show that the anterior insula, by virtue of its dynamic influences on other key brain regions, shows developmental differences in both structural and functional connectivity, which may contribute to more mature cognitive abilities in adulthood compared to childhood.
PMCID: PMC3271018  PMID: 22319436
12.  A framework for interpreting functional networks in schizophrenia 
Some promising genetic correlates of schizophrenia have emerged in recent years but none explain more than a small fraction of cases. The challenge of our time is to characterize the neuronal networks underlying schizophrenia and other neuropsychiatric illnesses. Early models of schizophrenia have been limited by the ability to readily evaluate large-scale networks in living patients. With the development of resting state and advanced structural magnetic resonance imaging, it has become possible to do this. While we are at an early stage, a number of models of intrinsic brain networks have been developed to account for schizophrenia and other neuropsychiatric disorders. This paper reviews the recent voxel-based morphometry (VBM), diffusion tensor imaging (DTI), and resting functional magnetic resonance imaging literature in light of the proposed networks underlying these disorders. It is suggested that there is support for recently proposed models that suggest a pivotal role for the salience network. However, the interactions of this network with the default mode network and executive control networks are not sufficient to explain schizophrenic symptoms or distinguish them from other neuropsychiatric disorders. Alternatively, it is proposed that schizophrenia arises from a uniquely human brain network associated with directed effort including the dorsal anterior and posterior cingulate cortex (PCC), auditory cortex, and hippocampus while mood disorders arise from a different brain network associated with emotional encoding including the ventral anterior cingulate cortex (ACC), orbital frontal cortex, and amygdala. Both interact with the dorsolateral prefrontal cortex and a representation network including the frontal and temporal poles and the fronto-insular cortex, allowing the representation of the thoughts, feelings, and actions of self and others across time.
PMCID: PMC3380255  PMID: 22737116
schizophrenia; major depressive disorder; bipolar disorder; functional MRI; voxel-based morphometry; diffusion tensor imaging; default mode network; salience network
13.  Changes in grey matter development in autism spectrum disorder 
Brain Structure & Function  2012;218(4):929-942.
Results on grey matter (GM) structural alterations in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about age effects on brain-structure abnormalities in ASD beyond childhood. Here, we aimed to examine regional GM volumes in a large sample of children, adolescents, and adults with ASD. Magnetic resonance imaging scans were obtained in 47 male ASD subjects and 51 matched healthy controls aged 8–50 years. We used whole-brain voxel-based morphometry to first assess group differences in regional GM volume across age. Moreover, taking a cross-sectional approach, group differences in age effects on regional GM volume were investigated. Compared to controls, ASD subjects showed reduced GM volumes in the anterior cingulate cortex, posterior superior temporal sulcus, and middle temporal gyrus. Investigation of group differences in age effects on regional GM volume revealed complex, region-specific alterations in ASD. While GM volumes in the amygdala, temporoparietal junction, septal nucleus and middle cingulate cortex increased in a negative quadratic fashion in both groups, data indicated that GM volume curves in ASD subjects were shifted to the left along the age axis. Moreover, while GM volume in the right precentral gyrus decreased linearly with age in ASD individuals, GM volume development in controls followed a U-shaped pattern. Based on a large sample, our voxel-based morphometry results on group differences in regional GM volumes help to resolve inconclusive findings from previous studies in ASD. Results on age-related changes of regional GM volumes suggest that ASD is characterized by complex alterations in lifetime trajectories of several brain regions that underpin social-cognitive and motor functions.
Electronic supplementary material
The online version of this article (doi:10.1007/s00429-012-0439-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3695319  PMID: 22777602
Brain development; MRI; Voxel-based morphometry; Grey matter; Autism spectrum disorder
14.  Cerebral Blood Flow in Posterior Cortical Nodes of the Default Mode Network Decreases with Task Engagement but Remains Higher than in Most Brain Regions 
Cerebral Cortex (New York, NY)  2010;21(1):233-244.
Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic “default mode network” and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion.
PMCID: PMC3000573  PMID: 20484322
ASL; cerebral blood flow; cingulate; default mode network; precuneus
15.  Self-referential processing influences functional activation during cognitive control: an fMRI study 
Rostral anterior cingulate cortex (rACC) plays a central role in the pathophysiology of major depressive disorder (MDD). As we reported in our previous study (Wagner et al., 2006), patients with MDD were characterized by an inability to deactivate this region during cognitive processing leading to a compensatory prefrontal hyperactivation. This hyperactivation in rACC may be related to a deficient inhibitory control of negative self-referential processes, which in turn may interfere with cognitive control task execution and the underlying fronto-cingulate network activation. To test this assumption, a functional magnetic resonance imaging study was conducted in 34 healthy subjects. Univariate and functional connectivity analyses in statistical parametric mapping software 8 were used. Self-referential stimuli and the Stroop task were presented in an event-related design. As hypothesized, rACC was specifically engaged during negative self-referential processing (SRP) and was significantly related to the degree of depressive symptoms in participants. BOLD signal in rACC showed increased valence-dependent (negative vs neutral SRP) interaction with BOLD signal in prefrontal and dorsal anterior cingulate regions during Stroop task performance. This result provides strong support for the notion that enhanced rACC interacts with brain regions involved in cognitive control processes and substantiates our previous interpretation of increased rACC and prefrontal activation in patients during Stroop task.
PMCID: PMC3791071  PMID: 22798398
fMRI; rostral anterior cingulate; cognitive control; emotion; self-referential processing; functional connectivity; major depression
16.  The Effect of Neurogranin on Neural Correlates of Episodic Memory Encoding and Retrieval 
Schizophrenia Bulletin  2011;39(1):141-150.
Neurogranin (NRGN) is the main postsynaptic protein regulating the availability of calmodulin-Ca(2+) in neurons. NRGN is expressed exclusively in the brain, particularly in dendritic spines and has been implicated in spatial learning and hippocampal plasticity. Genetic variation in rs12807809 in the NRGN gene has recently been confirmed to be associated with schizophrenia in a meta-analysis of genome-wide association studies: the T-allele was found to be genome-wide significantly associated with schizophrenia. Cognitive tests and personality questionnaires were administered in a large sample of healthy subjects. Brain activation was measured with functional magnetic resonance imaging (fMRI) during an episodic memory encoding and retrieval task in a subsample. All subjects were genotyped for NRGN rs12807809. There was no effect of genotype on personality or cognitive measures in the large sample. Homozygote carriers of the T-allele showed better performance in the retrieval task during fMRI. After controlling for memory performance, differential brain activation was evident in the anterior cingulate cortex for the encoding and posterior cingulate regions during retrieval. We could demonstrate that rs12807809 of NRGN is associated with differential neural functioning in the anterior and posterior cingulate. These areas are involved in episodic memory processes and have been implicated in the pathophysiology of schizophrenia in structural and functional imaging as well as postmortem studies.
PMCID: PMC3523918  PMID: 21799211
NRGN; fMRI; memory; cingulate
17.  Functional Brain Correlates of Social and Non-Social Processes in Autism Spectrum Disorders: an ALE Meta-Analysis 
Biological psychiatry  2008;65(1):63-74.
Functional neuroimaging studies of autism spectrum disorders (ASD) have examined social and non-social paradigms, although rarely in the same study. Here, we provide an objective, unbiased survey of functional brain abnormalities in ASD, related to both social and non-social processing.
We conducted two separate voxel-wise activation likelihood estimation meta-analyses of 39 functional neuroimaging studies consisting of 24 studies examining social processes (e.g., theory of mind, face perception), and 15 studies examining non-social processes (e.g., attention control, working memory). Voxel-wise significance threshold was p< 0.05, corrected by false discovery rate.
Compared to neurotypical controls (NC), ASD showed greater likelihood of hypoactivation in two medial wall regions: perigenual anterior cingulate cortex (ACC) in social tasks only, and dorsal ACC in non-social studies. Further, right anterior insula, recently linked to social cognition, was more likely to be hypoactivated in ASD in the analyses of social studies. In non-social studies, group comparisons showed greater likelihood of activation for the ASD group in the rostral ACC region that is typically suppressed during attentionally demanding tasks.
Despite substantial heterogeneity of tasks, the rapidly increasing functional imaging literature showed ASD-related patterns of hypofunction and aberrant activation that depended on the specific cognitive domain, i.e., social and versus non-social. These results provide a basis for targeted extensions of these findings with younger subjects and a range of paradigms, including analyses of default mode network regulation in ASD.
PMCID: PMC2993772  PMID: 18996505
autism; pervasive developmental disorders (PDD); anterior cingulate cortex; insula; social cognition; cognitive control; meta-analysis; functional magnetic resonance imaging (fMRI); positron emission tomography (PET); default mode network
18.  Acute Aerobic Exercise Increases Cortical Activity during Working Memory: A Functional MRI Study in Female College Students 
PLoS ONE  2014;9(6):e99222.
There is increasing evidence that acute aerobic exercise is associated with improved cognitive function. However, neural correlates of its cognitive plasticity remain largely unknown. The present study examined the effect of a session of acute aerobic exercise on working memory task-evoked brain activity as well as task performance. A within-subjects design with a counterbalanced order was employed. Fifteen young female participants (M = 19.56, SD = 0.81) were scanned using functional magnetic resonance imaging while performing a working memory task, the N-back task, both following an acute exercise session with 20 minutes of moderate intensity and a control rest session. Although an acute session of exercise did not improve behavioral performance, we observed that it had a significant impact on brain activity during the 2-back condition of the N-back task. Specifically, acute exercise induced increased brain activation in the right middle prefrontal gyrus, the right lingual gyrus, and the left fusiform gyrus as well as deactivations in the anterior cingulate cortexes, the left inferior frontal gyrus, and the right paracentral lobule. Despite the lack of an effect on behavioral measures, significant changes after acute exercise with activation of the prefrontal and occipital cortexes and deactivation of the anterior cingulate cortexes and left frontal hemisphere reflect the improvement of executive control processes, indicating that acute exercise could benefit working memory at a macro-neural level. In addition to its effects on reversing recent obesity and disease trends, our results provide substantial evidence highlighting the importance of promoting physical activity across the lifespan to prevent or reverse cognitive and neural decline.
PMCID: PMC4050105  PMID: 24911975
19.  The therapeutic potential of the cerebellum in schizophrenia 
The cognitive role of the cerebellum is critically tied to its distributed connections throughout the brain. Accumulating evidence from anatomical, structural and functional imaging, and lesion studies advocate a cognitive network involving indirect connections between the cerebellum and non-motor areas in the prefrontal cortex. Cerebellar stimulation dynamically influences activity in several regions of the frontal cortex and effectively improves cognition in schizophrenia. In this manuscript, we summarize current literature on the cingulocerebellar circuit and we introduce a method to interrogate this circuit combining opotogenetics, neuropharmacology, and electrophysiology in awake-behaving animals while minimizing incidental stimulation of neighboring cerebellar nuclei. We propose the novel hypothesis that optogenetic cerebellar stimulation can restore aberrant frontal activity and rescue impaired cognition in schizophrenia. We focus on how a known cognitive region in the frontal cortex, the anterior cingulate, is influenced by the cerebellum. This circuit is of particular interest because it has been confirmed using tracing studies, neuroimaging reveals its role in cognitive tasks, it is conserved from rodents to humans, and diseases such as schizophrenia and autism appear in its aberrancy. Novel tract tracing results presented here provide support for how these two areas communicate. The primary pathway involves a disynaptic connection between the cerebellar dentate nuclei (DN) and the anterior cingulate cortex. Secondarily, the pathway from cerebellar fastigial nuclei (FN) to the ventral tegmental area, which supplies dopamine to the prefrontal cortex, may play a role as schizophrenia characteristically involves dopamine deficiencies. We hope that the hypothesis described here will inspire new therapeutic strategies targeting currently untreatable cognitive impairments in schizophrenia.
PMCID: PMC4163988  PMID: 25309350
schizophrenia; cerebellum; anterior cingulate; cognitive symptoms; optogenetic stimulation
20.  Dopamine Transporters in Striatum Correlate with Deactivation in the Default Mode Network during Visuospatial Attention 
PLoS ONE  2009;4(6):e6102.
Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task.
Methodology/Principal Findings
For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [11C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus.
These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.
PMCID: PMC2699543  PMID: 19564918
21.  Acute lesions that impair affective empathy 
Brain  2013;136(8):2539-2549.
Functional imaging studies of healthy participants and previous lesion studies have provided evidence that empathy involves dissociable cognitive functions that rely on at least partially distinct neural networks that can be individually impaired by brain damage. These studies converge in support of the proposal that affective empathy—making inferences about how another person feels—engages at least the following areas: prefrontal cortex, orbitofrontal gyrus, anterior insula, anterior cingulate cortex, temporal pole, amygdala and temporoparietal junction. We hypothesized that right-sided lesions to any one of these structures, except temporoparietal junction, would cause impaired affective empathy (whereas bilateral damage to temporoparietal junction would be required to disrupt empathy). We studied 27 patients with acute right hemisphere ischaemic stroke and 24 neurologically intact inpatients on a test of affective empathy. Acute impairment of affective empathy was associated with infarcts in the hypothesized network, particularly temporal pole and anterior insula. All patients with impaired affective empathy were also impaired in comprehension of affective prosody, but many patients with impairments in prosodic comprehension had spared affective empathy. Patients with impaired affective empathy were older, but showed no difference in performance on tests of hemispatial neglect, volume of infarct or sex distribution compared with patients with intact affective empathy.
PMCID: PMC3722353  PMID: 23824490
empathy; stroke; emotion perception; magnetic resonance imaging; prosody
22.  Toward literature-based feature selection for diagnostic classification: a meta-analysis of resting-state fMRI in depression 
Information derived from functional magnetic resonance imaging (fMRI) during wakeful rest has been introduced as a candidate diagnostic biomarker in unipolar major depressive disorder (MDD). Multiple reports of resting state fMRI in MDD describe group effects. Such prior knowledge can be adopted to pre-select potentially discriminating features for diagnostic classification models with the aim to improve diagnostic accuracy. Purpose of this analysis was to consolidate spatial information about alterations of spontaneous brain activity in MDD, primarily to serve as feature selection for multivariate pattern analysis techniques (MVPA). Thirty two studies were included in final analyses. Coordinates extracted from the original reports were assigned to two categories based on directionality of findings. Meta-analyses were calculated using the non-additive activation likelihood estimation approach with coordinates organized by subject group to account for non-independent samples. Converging evidence revealed a distributed pattern of brain regions with increased or decreased spontaneous activity in MDD. The most distinct finding was hyperactivity/hyperconnectivity presumably reflecting the interaction of cortical midline structures (posterior default mode network components including the precuneus and neighboring posterior cingulate cortices associated with self-referential processing and the subgenual anterior cingulate and neighboring medial frontal cortices) with lateral prefrontal areas related to externally-directed cognition. Other areas of hyperactivity/hyperconnectivity include the left lateral parietal cortex, right hippocampus and right cerebellum whereas hypoactivity/hypoconnectivity was observed mainly in the left temporal cortex, the insula, precuneus, superior frontal gyrus, lentiform nucleus and thalamus. Results are made available in two different data formats to be used as spatial hypotheses in future studies, particularly for diagnostic classification by MVPA.
PMCID: PMC4159995  PMID: 25309382
depression; depressive disorder; functional neuroimaging; magnetic resonance imaging; meta-analysis; feature selection
23.  Of Brain and Bone: The Unusual Case of Dr. A 
Neurocase  2009;15(3):190-205.
Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in social conduct and a focal pattern of frontal and temporal lobe damage. Its biological basis is still poorly understood but the focality of the brain degeneration provides a powerful model to study the cognitive and anatomical basis of social cognition. Here, we present Dr. A, a patient with a rare hereditary bone disease (hereditary multiple exostoses) and FTD (pathologically characterized as Pick’s disease), who presented with a profound behavioral disturbance characterized by acquired sociopathy. We conducted a detailed genetic, pathological, neuroimaging and cognitive study, including a battery of tests designed to investigate Dr. A’s abilities to understand emotional cues and to infer mental states and intentions to others (theory of mind). Dr. A’s genetic profile suggests the possibility that a mutation causing hereditary multiple exostoses, Ext2, may play a role in the pattern of neurodegeneration in frontotemporal dementia since knockout mice deficient in the Ext gene family member, Ext1, show severe CNS defects including loss of olfactory bulbs and abnormally small cerebral cortex. Dr. A showed significant impairment in emotion comprehension, second order theory of mind, attribution of intentions, and empathy despite preserved general cognitive abilities. Voxel-based morphometry on structural MRI images showed significant atrophy in the medial and right orbital frontal and anterior temporal regions with sparing of dorsolateral frontal cortex. This case demonstrates that social and emotional dysfunction in FTD can dissociate from preserved performance on classic executive functioning tasks. The specific pattern of anatomical damage shown by VBM emphasizes the importance of the network including the superior medial frontal gyrus as well as temporal polar areas, in regulation of social cognition and theory of mind. This case provides new evidence regarding the neural basis of social cognition and suggests a possible genetic link between bone disease and FTD.
PMCID: PMC2997763  PMID: 20183548
24.  Identification of atrophy of the subgenual anterior cingulate cortex, in particular the subcallosal area, as an effective auxiliary means of diagnosis for major depressive disorder 
Despite being a very common psychiatric disorder, physicians often have difficulty making a diagnosis of major depressive disorder (MDD) because, without established diagnostic criteria, they have to depend on interviews with patients and observation to assess psychiatric symptoms. However, previous researchers have reported that magnetic resonance imaging (MRI) scans identify morphological changes in the brains of patients with MDD, which inspired us to hypothesize that assessment of local changes in the brain using voxel-based morphometry would serve as an auxiliary diagnostic method for MDD. Therefore, we focused on the VSRAD® plus (voxel-based specific regional analysis system for Alzheimer’s disease), a diagnostic support system for use in early Alzheimer’s disease, which allowed us to identify regional atrophy in the brain easily based on images obtained from MRI scans.
The subjects were 75 patients with MDD, 15 with bipolar disorder, and 30 healthy subjects, aged 54–82 years. First, 1.5 T MRI equipment was used to scan three-dimensional T1-weighted images for the individual subjects, and the imaged data were analyzed by VSRAD advance (voxel-based morphometric software developed for diagnosis of early Alzheimer’s disease). The efficacy of the equipment for diagnosis of MDD was evaluated based on the distribution of atrophy in the subgenual anterior cingulate cortex (sACC) on the z-score map obtained.
No significant difference in atrophy was noted between the left and right sACCs. The VSRAD advance used in the present study was more effective than the VSRAD plus for diagnosis of MDD, with a sensitivity of 90.7%, specificity of 86.7%, accuracy of 89.5%, a positive predictive value of 94.4%, and a negative predictive value of 78.8%. In particular, atrophy was observed in the subcallosal area of the sACC.
The identification of atrophy in the sACC, in particular of the subcallosal area, with the use of updated voxel-based morphometric software proved to be effective as an auxiliary diagnostic method for MDD.
PMCID: PMC3422897  PMID: 22924012
major depressive disorder; magnetic resonance imaging; subgenual anterior cingulate cortex; voxel-based morphometry; VSRAD
25.  Cortical gray-matter thinning is associated with age-related improvements on executive function tasks 
Developmental cognitive neuroscience  2013;6:10.1016/j.dcn.2013.07.002.
Across development children show marked improvement in their executive functions (EFs), including the ability to hold information in working memory and to deploy cognitive control, allowing them to ignore prepotent responses in favor of newly learned behaviors. How does the brain support these age-related improvements? Age-related cortical gray-matter thinning, thought to result from selective pruning of inefficient synaptic connections and increases in myelination, may support age-related improvements in EFs. Here we used structural MRI to measure cortical thickness. We investigate the association between cortical thickness in three cortical regions of interest (ROIs), and age-related changes in cognitive control and working memory in 5–10 year old children. We found significant associations between reductions in cortical thickness and age-related improvements in performance on both working memory and cognitive control tasks. Moreover, we observed a dissociation between ROIs typically thought to underlie changes in cognitive control (right Inferior Frontal gyrus and Anterior Cingulate cortex) and age-related improvements in cognitive control, and ROIs for working memory (superior parietal cortex), and age-related changes in a working memory task. These data add to our growing understanding of how structural maturation of the brain supports vast behavioral changes in executive functions observed across childhood.
PMCID: PMC3876892  PMID: 23896579
Brain development; Executive functions; Cognitive control; Structural MRI

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