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1.  The role of left and right hemispheres in the comprehension of idiomatic language: an electrical neuroimaging study 
BMC Neuroscience  2009;10:116.
Background
The specific role of the two cerebral hemispheres in processing idiomatic language is highly debated. While some studies show the involvement of the left inferior frontal gyrus (LIFG), other data support the crucial role of right-hemispheric regions, and particularly of the middle/superior temporal area. Time-course and neural bases of literal vs. idiomatic language processing were compared. Fifteen volunteers silently read 360 idiomatic and literal Italian sentences and decided whether they were semantically related or unrelated to a following target word, while their EEGs were recorded from 128 electrodes. Word length, abstractness and frequency of use, sentence comprehensibility, familiarity and cloze probability were matched across classes.
Results
Participants responded more quickly to literal than to idiomatic sentences, probably indicating a difference in task difficulty. Occipito/temporal N2 component had a greater amplitude in response to idioms between 250-300 ms. Related swLORETA source reconstruction revealed a difference in the activation of the left fusiform gyrus (FG, BA19) and medial frontal gyri for the contrast idiomatic-minus-literal. Centroparietal N400 was much larger to idiomatic than to literal phrases (360-550 ms). The intra-cortical generators of this effect included the left and right FG, the left cingulate gyrus, the right limbic area, the right MTG (BA21) and the left middle frontal gyrus (BA46). Finally, an anterior late positivity (600-800 ms) was larger to idiomatic than literal phrases. ERPs also showed a larger right centro-parietal N400 to associated than non-associated targets (not differing as a function of sentence type), and a greater right frontal P600 to idiomatic than literal associated targets.
Conclusion
The data indicate bilateral involvement of both hemispheres in idiom comprehension, including the right MTG after 350 ms and the right medial frontal gyrus in the time windows 270-300 and 500-780 ms. In addition, the activation of left and right limbic regions (400-450 ms) suggests that they have a role in the emotional connotation of colourful idiomatic language. The data support the view that there is direct access to the idiomatic meaning of figurative language, not dependent on the suppression of its literal meaning, for which the LIFG was previously thought to be responsible.
doi:10.1186/1471-2202-10-116
PMCID: PMC2749859  PMID: 19754932
2.  Effect of language task demands on the neural response during lexical access: a functional magnetic resonance imaging study 
Brain and Behavior  2013;3(4):402-416.
This study examined the effects of linguistic task demands on the neuroanatomical localization of the neural response related to automatic semantic processing of concrete German nouns combining the associative priming paradigm with functional magnetic resonance imaging (fMRI). To clarify the functional role of the inferior frontal gyrus (IFG) for semantic processing with respect to semantic decision making compared to semantic processing per se, we used a linguistic task that involved either a binary decision process (i.e., semantic categorization; Experiment 1) or not (i.e., silently thinking about a word's meaning; Experiment 2). We observed associative priming effects indicated as neural suppression in bilateral superior temporal gyri (STG), anterior cingulate cortex (ACC), occipito-temporal brain areas, and in medial frontal brain areas independently of the linguistic task. Inferior parietal brain areas were more active for silently thinking about a word's meaning compared to semantic categorization. A conjunction analysis of linguistic task revealed that both tasks activated the same left-lateralized occipito-temporo-frontal network including the IFG. Contrasting neural associative priming effects across linguistic task demands, we found a significant interaction in the right IFG. The present fMRI data give rise to the assumption that activation of the left inferior frontal gyrus (LIFG) in the semantic domain might be important for semantic processing in general and not only for semantic decision making. These findings contrast with a recent study regarding the role of the LIFG for binary decision making in the lexical domain (Wright et al. 2011).
doi:10.1002/brb3.133
PMCID: PMC3869681  PMID: 24381811
Associative priming; fMRI; mental lexicon; neural adaptation; semantic processing; suppression
3.  A coordinate-based ALE functional MRI meta-analysis of brain activation during verbal fluency tasks in healthy control subjects 
BMC Neuroscience  2014;15:19.
Background
The processing of verbal fluency tasks relies on the coordinated activity of a number of brain areas, particularly in the frontal and temporal lobes of the left hemisphere. Recent studies using functional magnetic resonance imaging (fMRI) to study the neural networks subserving verbal fluency functions have yielded divergent results especially with respect to a parcellation of the inferior frontal gyrus for phonemic and semantic verbal fluency. We conducted a coordinate-based activation likelihood estimation (ALE) meta-analysis on brain activation during the processing of phonemic and semantic verbal fluency tasks involving 28 individual studies with 490 healthy volunteers.
Results
For phonemic as well as for semantic verbal fluency, the most prominent clusters of brain activation were found in the left inferior/middle frontal gyrus (LIFG/MIFG) and the anterior cingulate gyrus. BA 44 was only involved in the processing of phonemic verbal fluency tasks, BA 45 and 47 in the processing of phonemic and semantic fluency tasks.
Conclusions
Our comparison of brain activation during the execution of either phonemic or semantic verbal fluency tasks revealed evidence for spatially different activation in BA 44, but not other regions of the LIFG/LMFG (BA 9, 45, 47) during phonemic and semantic verbal fluency processing.
doi:10.1186/1471-2202-15-19
PMCID: PMC3903437  PMID: 24456150
fMRI; Coordinate-based activation likelihood estimation (ALE); Meta-analysis; Verbal fluency; Healthy controls
4.  Cortical reorganization following anterior temporal lobectomy in patients with temporal lobe epilepsy 
Neurology  2009;73(7):518-525.
Background:
Functional MRI was used to study the impact of temporal lobe epilepsy (TLE) and anterior temporal lobectomy (ATL) on the cortical language network in patients with medically refractory TLE.
Methods:
Nineteen patients with medically refractory TLE and 11 healthy control subjects were enrolled in this study. Ten patients underwent left ATL (mean age 35.2 ± 3.8 years), and 9 underwent right ATL (mean age 35.9 ± 2.6 years). The subjects silently generated verbs in response to a series of visually presented nouns inside the scanner. Correlation analysis was performed between the subjects' performance on the clinical language tests and their neural response in the a priori cortical regions.
Results:
Preoperative data revealed that the patients with TLE showed increased neural activity in the right inferior frontal gyri (IFG) and middle frontal gyri (MFG). The right TLE patients demonstrated strong correlation between their language performance and the level of cortical activation within the typical language areas. However, such a correlation was absent in the left TLE patients. After the ATL surgery, the left TLE patients showed reduced activation in the left MFG and right IFG, whereas no difference was observed in the right TLE patients. In the right TLE patients, the correlation between language performance and neural response shifted from the typical language areas to the anterior cingulate cortex.
Conclusion:
This study demonstrates that the cortical language network is affected differently by the left and right temporal lobe epilepsy and is reorganized after anterior temporal lobectomy.
GLOSSARY
= anterior cingulate cortex;
= anterior temporal lobectomy;
= Boston Diagnostic Aphasia Examination;
= Boston Naming Test;
= blood oxygenation level–dependent;
= functional MRI;
= field of view;
= inferior frontal gyrus;
= London Health Sciences Centre;
= Language Quotient;
= middle frontal gyrus;
= Montreal Neurological Institute;
= region of interest;
= superior frontal gyrus;
= echo time;
= temporal lobe epilepsy;
= repetition time;
= Western Aphasia Battery.
doi:10.1212/WNL.0b013e3181b2a48e
PMCID: PMC2730795  PMID: 19687453
5.  Brain Activation for Language Dual-Tasking: Listening to Two People Speak at the Same Time and a Change in Network Timing 
Human brain mapping  2011;33(8):1868-1882.
The study used fMRI to investigate brain activation in participants who were able to listen to and successfully comprehend two people speaking at the same time (dual-tasking). The study identified brain mechanisms associated with high-level, concurrent dual-tasking, as compared to comprehending a single message. Results showed an increase in the functional connectivity among areas of the language network in the dual task. The increase in synchronization of brain activation for dual-tasking was brought about primarily by a change in the timing of left inferior frontal gyrus (LIFG) activation relative to posterior temporal activation, bringing the LIFG activation into closer correspondence with temporal activation. The results show that the change in LIFG timing was greater in participants with lower working memory capacity, and that recruitment of additional activation in the dual-task occurred only in the areas adjacent to the language network that was activated in the single task. The shift in LIFG activation may be a brain marker of how the brain adapts to high-level dual-tasking.
doi:10.1002/hbm.21327
PMCID: PMC3999975  PMID: 21618666
Multitasking; fMRI; Functional Connectivity; Language Comprehension
6.  Context-Dependent Interpretation Of Words: Evidence For Interactive Neural Processes 
NeuroImage  2007;35(3):1278-1286.
The meaning of a word usually depends on the context in which it occurs. This study investigated the neural mechanisms involved in computing word meanings that change as a function of syntactic context. Current semantic processing theories suggest that word meanings are retrieved from diverse cortical regions storing sensory-motor and other types of semantic information, and are further integrated with context in left inferior frontal gyrus (LIFG). Our fMRI data indicate that brain activity in an area sensitive to motion and action semantics – the posterior middle temporal gyrus (PMTG) – is modulated by a word's syntactic context. Ambiguous words such as bowl were presented in minimal disambiguating contexts indicating object (the bowl) or action (to bowl) meanings, and were compared to low-ambiguity controls. Ambiguous words elicited more activity than low-ambiguity controls in LIFG and various meaning-related areas such as PMTG. Critically, ambiguous words also elicited more activity in to-contexts than the-contexts in PMTG and LIFG, suggesting that contextual integration strengthened the action meaning in both areas. The pattern of results suggests that the activation of lexical information in PMTG was sensitive to contextual disambiguating information and that processing context-dependent meanings may involve interactions between frontal and posterior areas.
doi:10.1016/j.neuroimage.2007.01.015
PMCID: PMC2577612  PMID: 17321757
7.  Selecting Among Competing Alternatives: Selection and Retrieval in the Left Inferior Frontal Gyrus 
Cerebral cortex (New York, N.Y. : 1991)  2005;15(11):10.1093/cercor/bhi049.
It has been widely argued that the left inferior frontal gyrus (LIFG) is involved in the control of retrieval of information from long-term memory. Recent claims that the LIFG is involved in selecting among semantic alternatives have been challenged on the grounds that the manipulation of selection demands may have been confounded with controlled retrieval. The current study used an event-related functional magnetic resonance paradigm to re-examine the possibility that LIFG activation is involved in selection processes. In order to minimize potential confounding effects of controlled retrieval, we used an automatic retrieval task (picture naming) and held retrieval demands constant, while varying selection demands by way of competitor priming from earlier semantically related trials. We found significant activation in LIFG as a function of increased selection demands; activation centred on two peaks, one in anterior LIFG and a second more superior and posterior region. These data support the view that LIFG plays a role in selection among semantic information, even in the absence of controlled retrieval processes.
doi:10.1093/cercor/bhi049
PMCID: PMC3838943  PMID: 15728742
competition; LIFG; retrieval; selection; semantic
8.  Atypical Lexicosemantic Function of Extrastriate Cortex in Autism Spectrum Disorder: Evidence from Functional and Effective Connectivity 
NeuroImage  2012;62(3):10.1016/j.neuroimage.2012.06.008.
Previous studies have suggested atypically enhanced activity of visual cortex during language processing in autism spectrum disorder (ASD). However, it remains unclear whether visual cortical participation reflects isolated processing within posterior regions or functional cooperation with distal brain regions, such as left inferior frontal gyrus (LIFG). We addressed this question using functional connectivity MRI (fcMRI) and structural equation modeling in 14 adolescents and adults with ASD and 14 matched typically developing (TD) participants. Data were analyzed to isolate low-frequency intrinsic fluctuations, by regressing out effects of a semantic decision task. For a right extrastriate seed derived from the strongest cluster of atypical activation in the ASD group, widespread effects of increased connectivity in prefrontal and medial frontal lobes bilaterally were observed for the ASD group, compared to the TD group. A second analysis for a seed in LIFG, derived from pooled activation effects in both groups, also yielded widespread effects of overconnectivity in the ASD group, especially in temporal lobes. Structural equation modeling showed that whereas right extrastriate cortex did not impact function of language regions (left and right IFG, left middle temporal gyrus) in the TD model, it was an integral part of a language circuit in the ASD group. These results suggest that atypical extrastriate activation during language processing in ASD reflects integrative (not isolated) processing. Furthermore, our findings are inconsistent with previous reports of functional underconnectivity in ASD, probably related to removal of task effects required to isolate intrinsic low-frequency fluctuations.
doi:10.1016/j.neuroimage.2012.06.008
PMCID: PMC3857700  PMID: 22699044
Lexical; semantic; visual; functional connectivity; structural equation modeling; autism
9.  Resting-state connectivity deficits associated with impaired inhibitory control in non-treatment-seeking adolescents with psychotic symptoms 
Acta psychiatrica Scandinavica  2013;129(2):134-142.
Objective
Psychotic symptoms are common in the population and index risk for a range of severe psychopathological outcomes. We wished to investigate functional connectivity in a community sample of adolescents who reported psychotic symptoms (the extended psychosis phenotype).
Method
This study investigated intrinsic functional connectivity (iFC) during resting-state functional magnetic resonance imaging (fMRI; rs-fMRI). Following screening in schools, 11 non-treatment seeking, youth with psychotic symptoms (aged 11–13) and 14 community controls participated in the study. Seed regions of interest comprised brain regions previously shown to exhibit aberrant activation during inhibitory control in adolescents with psychotic symptoms.
Results
Relative to controls, adolescents with psychotic symptoms exhibited reduced iFC between regions supporting inhibitory control. Specifically, they showed weaker iFC between the right inferior frontal gyrus (IFG) and the cingulate, IFG and the striatum, anterior cingulate and claustrum, and precuneus and supramarginal gyrus. Conversely, the psychotic symptoms group exhibited stronger iFC between the superior frontal gyrus and claustrum and IFG and lingual gyrus.
Conclusion
The present findings are the first to reveal aberrant functional connectivity in resting-state networks in a community sample of adolescents with psychotic symptoms and suggest that disruption in integration between distributed neural networks (particularly between prefrontal, cingulate and striatal brain regions) may be a key neurobiological feature of the extended psychosis phenotype.
doi:10.1111/acps.12141
PMCID: PMC3787979  PMID: 23621452
psychosis; psychotic symptoms; functional magnetic resonance imaging; resting-state; intrinsic functional connectivity
10.  Independent Component Analysis of the Effect of L-dopa on fMRI of Language Processing 
PLoS ONE  2010;5(8):e11933.
L-dopa, which is a precursor for dopamine, acts to amplify strong signals, and dampen weak signals as suggested by previous studies. The effect of L-dopa has been demonstrated in language studies, suggesting restriction of the semantic network. In this study, we aimed to examine the effect of L-dopa on language processing with fMRI using Independent Component Analysis (ICA). Two types of language tasks (phonological and semantic categorization tasks) were tested under two drug conditions (placebo and L-dopa) in 16 healthy subjects. Probabilistic ICA (PICA), part of FSL, was implemented to generate Independent Components (IC) for each subject for the four conditions and the ICs were classified into task-relevant source groups by a correlation threshold criterion. Our key findings include: (i) The highly task-relevant brain regions including the Left Inferior Frontal Gyrus (LIFG), Left Fusiform Gyrus (LFUS), Left Parietal lobe (LPAR) and Superior Temporal Gyrus (STG) were activated with both L-dopa and placebo for both tasks, and (ii) as compared to placebo, L-dopa was associated with increased activity in posterior regions, including the superior temporal area (BA 22), and decreased activity in the thalamus (pulvinar) and inferior frontal gyrus (BA 11/47) for both tasks. These results raise the possibility that L-dopa may exert an indirect effect on posterior regions mediated by the thalamus (pulvinar).
doi:10.1371/journal.pone.0011933
PMCID: PMC2923146  PMID: 20808963
11.  Syntactic Computations in the Language Network: Characterizing Dynamic Network Properties Using Representational Similarity Analysis 
The core human capacity of syntactic analysis involves a left hemisphere network involving left inferior frontal gyrus (LIFG) and posterior middle temporal gyrus (LMTG) and the anatomical connections between them. Here we use magnetoencephalography (MEG) to determine the spatio-temporal properties of syntactic computations in this network. Listeners heard spoken sentences containing a local syntactic ambiguity (e.g., “… landing planes …”), at the offset of which they heard a disambiguating verb and decided whether it was an acceptable/unacceptable continuation of the sentence. We charted the time-course of processing and resolving syntactic ambiguity by measuring MEG responses from the onset of each word in the ambiguous phrase and the disambiguating word. We used representational similarity analysis (RSA) to characterize syntactic information represented in the LIFG and left posterior middle temporal gyrus (LpMTG) over time and to investigate their relationship to each other. Testing a variety of lexico-syntactic and ambiguity models against the MEG data, our results suggest early lexico-syntactic responses in the LpMTG and later effects of ambiguity in the LIFG, pointing to a clear differentiation in the functional roles of these two regions. Our results suggest the LpMTG represents and transmits lexical information to the LIFG, which responds to and resolves the ambiguity.
doi:10.3389/fpsyg.2013.00271
PMCID: PMC3656357  PMID: 23730293
syntax; sentence processing; syntactic ambiguity; language networks; magnetoencephalography; representational similarity analysis
12.  Executive Semantic Processing Is Underpinned by a Large-scale Neural Network: Revealing the Contribution of Left Prefrontal, Posterior Temporal, and Parietal Cortex to Controlled Retrieval and Selection Using TMS 
Journal of cognitive neuroscience  2011;24(1):133-147.
To understand the meanings of words and objects, we need to have knowledge about these items themselves plus executive mechanisms that compute and manipulate semantic information in a task-appropriate way. The neural basis for semantic control remains controversial. Neuroimaging studies have focused on the role of the left inferior frontal gyrus (LIFG), whereas neuropsychological research suggests that damage to a widely distributed network elicits impairments of semantic control. There is also debate about the relationship between semantic and executive control more widely. We used TMS in healthy human volunteers to create “virtual lesions” in structures typically damaged in patients with semantic control deficits: LIFG, left posterior middle temporal gyrus (pMTG), and intraparietal sulcus (IPS). The influence of TMS on tasks varying in semantic and nonsemantic control demands was examined for each region within this hypothesized network to gain insights into (i) their functional specialization (i.e., involvement in semantic representation, controlled retrieval, or selection) and (ii) their domain dependence (i.e., semantic or cognitive control). The results revealed that LIFG and pMTG jointly support both the controlled retrieval and selection of semantic knowledge. IPS specifically participates in semantic selection and responds to manipulations of nonsemantic control demands. These observations are consistent with a large-scale semantic control network, as predicted by lesion data, that draws on semantic-specific (LIFG and pMTG) and domain-independent executive components (IPS).
doi:10.1162/jocn_a_00123
PMCID: PMC3542522  PMID: 21861680
13.  A rostro-caudal gradient of structured sequence processing in the left inferior frontal gyrus 
In this paper, we present two novel perspectives on the function of the left inferior frontal gyrus (LIFG). First, a structured sequence processing perspective facilitates the search for functional segregation within the LIFG and provides a way to express common aspects across cognitive domains including language, music and action. Converging evidence from functional magnetic resonance imaging and transcranial magnetic stimulation studies suggests that the LIFG is engaged in sequential processing in artificial grammar learning, independently of particular stimulus features of the elements (whether letters, syllables or shapes are used to build up sequences). The LIFG has been repeatedly linked to processing of artificial grammars across all different grammars tested, whether they include non-adjacent dependencies or mere adjacent dependencies. Second, we apply the sequence processing perspective to understand how the functional segregation of semantics, syntax and phonology in the LIFG can be integrated in the general organization of the lateral prefrontal cortex (PFC). Recently, it was proposed that the functional organization of the lateral PFC follows a rostro-caudal gradient, such that more abstract processing in cognitive control is subserved by more rostral regions of the lateral PFC. We explore the literature from the viewpoint that functional segregation within the LIFG can be embedded in a general rostro-caudal abstraction gradient in the lateral PFC. If the lateral PFC follows a rostro-caudal abstraction gradient, then this predicts that the LIFG follows the same principles, but this prediction has not yet been tested or explored in the LIFG literature. Integration might provide further insights into the functional architecture of the LIFG and the lateral PFC.
doi:10.1098/rstb.2012.0009
PMCID: PMC3367683  PMID: 22688637
sequence processing; language; cognitive control; inferior frontal gyrus; lateral prefrontal cortex
14.  Semantic association investigated with fMRI and independent component analysis 
Epilepsy & behavior : E&B  2011;20(4):613-622.
Semantic association, an essential element of human language, enables discourse and inference. Neuroimaging studies have revealed localization and lateralization of semantic circuitry making substantial contributions to cognitive neuroscience. However, due to methodological limitations, these investigations have only identified individual functional components rather than capturing the behavior of the entire network. To overcome these limitations, we have implemented group independent component analysis (ICA) to investigate the cognitive modules used by healthy adults performing fMRI semantic decision task. When compared to the results of a standard GLM analysis, ICA detected several additional brain regions subserving semantic decision. Eight task-related group ICA maps were identified including left inferior frontal gyrus (BA44/45), middle posterior temporal gyrus (BA39/22), angular gyrus/inferior parietal lobule (BA39/40), posterior cingulate (BA30), bilateral lingual gyrus (BA18/23), inferior frontal gyrus (L>R, BA47), hippocampus with parahippocampal gyrus (L>R, BA35/36) and anterior cingulate (BA32/24). While most of the components were represented bilaterally, we found a single, highly left-lateralized component that included the inferior frontal gyrus and the medial and superior temporal gyri, the angular and supramarginal gyri and the inferior parietal cortex. The presence of these spatially independent ICA components implies functional connectivity and can be equated with their modularity. These results are analyzed and presented in the framework of a biologically plausible theoretical model in preparation for similar analyses in patients with right- or left-hemispheric epilepsies.
doi:10.1016/j.yebeh.2010.11.010
PMCID: PMC3078943  PMID: 21296027
Semantic decision; language; Independent component analysis (ICA); GLM; Functional magnetic resonance imaging; language network
15.  Functional Activation and Effective Connectivity Differences in Adolescent Marijuana Users Performing a Simulated Gambling Task 
Journal of Addiction  2015;2015:783106.
Background. Adolescent marijuana use is associated with structural and functional differences in forebrain regions while performing memory and attention tasks. In the present study, we investigated neural processing in adolescent marijuana users experiencing rewards and losses. Fourteen adolescents with frequent marijuana use (>5 uses per week) and 14 nonuser controls performed a computer task where they were required to guess the outcome of a simulated coin flip while undergoing magnetic resonance imaging. Results. Across all participants, “Wins” and “Losses” were associated with activations including cingulate, middle frontal, superior frontal, and inferior frontal gyri and declive activations. Relative to controls, users had greater activity in the middle and inferior frontal gyri, caudate, and claustrum during “Wins” and greater activity in the anterior and posterior cingulate, middle frontal gyrus, insula, claustrum, and declive during “Losses.” Effective connectivity analyses revealed similar overall network interactions among these regions for users and controls during both “Wins” and “Losses.” However, users and controls had significantly different causal interactions for 10 out of 28 individual paths during the “Losses” condition. Conclusions. Collectively, these results indicate adolescent marijuana users have enhanced neural responses to simulated monetary rewards and losses and relatively subtle differences in effective connectivity.
doi:10.1155/2015/783106
PMCID: PMC4321681
16.  Neural Aspects of Sentence Comprehension: Syntactic Complexity, Reversibility, and Reanalysis 
Cerebral Cortex (New York, NY)  2009;20(8):1853-1864.
Broca's area is preferentially activated by reversible sentences with complex syntax, but various linguistic factors may be responsible for this finding, including syntactic movement, working-memory demands, and post hoc reanalysis. To distinguish between these, we tested the interaction of syntactic complexity and semantic reversibility in a functional magnetic resonance imaging study of sentence–picture matching. During auditory comprehension, semantic reversibility induced selective activation throughout the left perisylvian language network. In contrast, syntactic complexity (object-embedded vs. subject-embedded relative clauses) within reversible sentences engaged only the left inferior frontal gyrus (LIFG) and left precentral gyrus. Within irreversible sentences, only the LIFG was sensitive to syntactic complexity, confirming a unique role for this region in syntactic processing. Nonetheless, larger effects of reversibility itself occurred in the same regions, suggesting that full syntactic parsing may be a nonautomatic process applied as needed. Complex reversible sentences also induced enhanced signals in LIFG and left precentral regions on subsequent picture selection, but with additional recruitment of the right hemisphere homolog area (right inferior frontal gyrus) as well, suggesting that post hoc reanalysis of sentence structure, compared with initial comprehension, engages an overlapping but larger network of brain regions. These dissociable effects may offer a basis for studying the reorganization of receptive language function after brain damage.
doi:10.1093/cercor/bhp249
PMCID: PMC2901020  PMID: 19920058
Broca's area; fMRI; language; semantic; syntax
17.  Alterations in functional connectivity for language in prematurely born adolescents 
Brain  2009;132(3):661-670.
Recent data suggest recovery of language systems but persistent structural abnormalities in the prematurely born. We tested the hypothesis that subjects who were born prematurely develop alternative networks for processing language. Subjects who were born prematurely (n = 22; 600–1250 g birth weight), without neonatal brain injury on neonatal cranial ultrasound, and 26 term control subjects were examined with a functional magnetic resonance imaging (fMRI) semantic association task, the Wechsler Intelligence Scale for Children-III (WISC-III) and the Clinical Evaluation of Language Fundamentals (CELF). In-magnet task accuracy and response times were calculated, and fMRI data were evaluated for the effect of group on blood oxygen level dependent (BOLD) activation, the correlation between task accuracy and activation and the functional connectivity between regions activating to task. Although there were differences in verbal IQ and CELF scores between the preterm (PT) and term control groups, there were no significant differences for either accuracy or response time for the in-magnet task. Both groups activated classic semantic processing areas including the left superior and middle temporal gyri and inferior frontal gyrus, and there was no significant difference in activation patterns between groups. Clear differences between the groups were observed in the correlation between task accuracy and activation to task at P < 0.01, corrected for multiple comparisons. Left inferior frontal gyrus correlated with accuracy only for term controls and left sensory motor areas correlated with accuracy only for PT subjects. Left middle temporal gyri correlated with task accuracy for both groups. Connectivity analyses at P < 0.001 revealed the importance of a circuit between left middle temporal gyri and inferior frontal gyrus for both groups. In addition, the PT subjects evidenced greater connectivity between traditional language areas and sensory motor areas but significantly fewer correlated areas within the frontal lobes when compared to term controls. We conclude that at 12 years of age, children born prematurely and children born at term had no difference in performance on a simple lexical semantic processing task and activated similar areas. Connectivity analyses, however, suggested that PT subjects rely upon different neural pathways for lexical semantic processing when compared to term controls. Plasticity in network connections may provide the substrate for improving language skills in the prematurely born.
doi:10.1093/brain/awn353
PMCID: PMC2664451  PMID: 19158105
connectivity; fMRI; volumetric; preterm; language
18.  Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms☆ 
NeuroImage : Clinical  2013;3:405-415.
Introduction
22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins.
Methods
High-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10–25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed.
Results
Relative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS.
Conclusion
Differential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.
Highlights
•22q11DS offers a valuable model for neurobiological mechanisms of psychosis.•First study of multiple structural MRI indices in 22q11DS.•Reduced surface area in multiple neuroanatomic regions in 22q11DS.•Increased cortical thickness in multiple frontal regions and insula in 22q11DS.•Orbitofrontal abnormalities associated with positive symptom severity in 22q11DS.
doi:10.1016/j.nicl.2013.09.013
PMCID: PMC3814944  PMID: 24273724
22q11DS, 22q11.2 deletion syndrome; CNV, copy number variation; CT, cortical thickness; SA, surface area; SIPS, Structured Interview for Prodromal Syndromes; MRI, magnetic resonance imaging; ANCOVA, analysis of covariance; Copy number variation; Structural magnetic resonance imaging; Psychosis; Schizophrenia; Velocardiofacial syndrome
19.  White matter microstructural differences linked to left perisylvian language network in children with dyslexia 
Studies of dyslexia using diffusion tensor imaging (DTI) have reported fractional anisotropy (FA) differences in left inferior frontal gyrus (LIFG) and left temporo-parietal white matter, suggesting that impaired reading is associated with atypical white matter microstructure in these regions. These anomalies might reflect abnormalities in the left perisylvian language network, long implicated in dyslexia. While DTI investigations frequently report analyses on multiple tensor-derived measures (e.g., FA, orientation, tractography), it is uncommon to integrate analyses to examine the relationships between atypical findings. For the present study, semi-automated techniques were applied to DTI data in an integrated fashion to examine white matter microstructure in 14 children with dyslexia and 17 typically developing readers (ages 7-16 years). Correlations of DTI metrics (FA and fiber orientation) to reading skill (accuracy and speed) and to probabilistic tractography maps of the left perisylvian language tracts were examined. Consistent with previous reports, our findings suggest FA decreases in dyslexia in LIFG and left temporo-parietal white matter. The LIFG FA finding overlaps an area showing differences in fiber orientation in an anterior left perisylvian language pathway. Additionally,a positive correlation of FA to reading speed was found in a posterior circuit previously associated with activation on functional imaging during reading tasks. Overall, integrating results from several complementary semi-automated analyses reveals evidence linking atypical white matter microstructure in dyslexia to atypical fiber orientation in circuits implicated in reading including the left perisylvian language network.
doi:10.1016/j.cortex.2009.07.008
PMCID: PMC2847658  PMID: 19682675
dyslexia; perisylvian language network; left inferior frontal gyrus; diffusion tensor imaging; fractional anisotropy
20.  Functional mapping of language networks in the normal brain using a word-association task 
Background:
Language functions are known to be affected in diverse neurological conditions, including ischemic stroke, traumatic brain injury, and brain tumors. Because language networks are extensive, interpretation of functional data depends on the task completed during evaluation.
Aim:
The aim was to map the hemodynamic consequences of word association using functional magnetic resonance imaging (fMRI) in normal human subjects.
Materials and Methods:
Ten healthy subjects underwent fMRI scanning with a postlexical access semantic association task vs lexical processing task. The fMRI protocol involved a T2*-weighted gradient-echo echo-planar imaging (GE-EPI) sequence (TR 4523 ms, TE 64 ms, flip angle 90°) with alternate baseline and activation blocks. A total of 78 scans were taken (interscan interval = 3 s) with a total imaging time of 587 s. Functional data were processed in Statistical Parametric Mapping software (SPM2) with 8-mm Gaussian kernel by convolving the blood oxygenation level-dependent (BOLD) signal with an hemodynamic response function estimated by general linear method to generate SPM{t} and SPM{F} maps.
Results:
Single subject analysis of the functional data (FWE-corrected, P≤0.001) revealed extensive activation in the frontal lobes, with overlaps among middle frontal gyrus (MFG), superior, and inferior frontal gyri. BOLD activity was also found in the medial frontal gyrus, middle occipital gyrus (MOG), anterior fusiform gyrus, superior and inferior parietal lobules, and to a smaller extent, the thalamus and right anterior cerebellum. Group analysis (FWE-corrected, P≤0.001) revealed neural recruitment of bilateral lingual gyri, left MFG, bilateral MOG, left superior occipital gyrus, left fusiform gyrus, bilateral thalami, and right cerebellar areas.
Conclusions:
Group data analysis revealed a cerebellar–occipital–fusiform–thalamic network centered around bilateral lingual gyri for word association, thereby indicating how these areas facilitate language comprehension by activating a semantic association network of words processed postlexical access. This finding is important when assessing the extent of cognitive damage and/or recovery and can be used for presurgical planning after optimization.
doi:10.4103/0971-3026.69352
PMCID: PMC2963756  PMID: 21042440
fMRI; language network; lingual gyrus; presurgical planning; word association
21.  Brain pathology in first-episode psychosis: Magnetization transfer imaging provides additional information to MRI measurements of volume loss 
Neuroimage  2010;49(1-24):185-192.
Background
Loss of brain volume in first-episode psychosis can be detected using conventional magnetic resonance imaging (MRI), but subtle changes – not leading to reduction in volume – that may contribute to clinical and cognitive abnormalities, may go undetected. Magnetization transfer imaging (MTI), a technique more sensitive to subtle neuropathological changes than conventional MRI, could yield important information on the extent and nature of structural abnormalities.
Methods
Forty-eight patients (33 males) from a population-based sample with first-episode psychosis (41 with schizophrenia and 7 with schizoaffective psychosis) and 47 healthy volunteers (27 males) were studied. Differences in magnetization transfer ratio (MTR) and white and grey matter volumes between groups were investigated.
Results
In patients, MTR was reduced in right entorhinal cortex, fusiform, dentate and superior frontal gyri and in left superior frontal and inferior/rostral cingulate gyri. Grey matter volume was reduced in right insula, frontal operculum and middle and superior temporal gyri and in left middle temporal gyrus. Grey matter volume increases were seen in patients in the superior frontal gyrus. White matter volume loss was found adjacent to grey matter loss. In patients MTR was lower in all areas of volumetric differences between groups suggesting that both changes may be related. Similar findings were observed when patients with schizoaffective psychosis were removed from the analysis. The correlations between clinical and MRI parameters did not survive correction for multiple comparisons.
Conclusions
MTI frontal and temporal abnormalities suggesting neuroaxonal and myelin changes were more extensive in our patients than those detected with conventional MRI. Our findings also suggest that there is regional variation in the severity of structural brain abnormalities.
doi:10.1016/j.neuroimage.2009.07.037
PMCID: PMC2806943  PMID: 19632338
22.  Disrupting the brain to validate hypotheses on the neurobiology of language 
Comprehension of words is an important part of the language faculty, involving the joint activity of frontal and temporo-parietal brain regions. Transcranial Magnetic Stimulation (TMS) enables the controlled perturbation of brain activity, and thus offers a unique tool to test specific predictions about the causal relationship between brain regions and language understanding. This potential has been exploited to better define the role of regions that are classically accepted as part of the language-semantic network. For instance, TMS has contributed to establish the semantic relevance of the left anterior temporal lobe, or to solve the ambiguity between the semantic vs. phonological function assigned to the left inferior frontal gyrus (LIFG). We consider, more closely, the results from studies where the same technique, similar paradigms (lexical-semantic tasks) and materials (words) have been used to assess the relevance of regions outside the classically-defined language-semantic network—i.e., precentral motor regions—for the semantic analysis of words. This research shows that different aspects of the left precentral gyrus (primary motor and premotor sites) are sensitive to the action-non action distinction of words' meanings. However, the behavioral changes due to TMS over these sites are incongruent with what is expected after perturbation of a task-relevant brain region. Thus, the relationship between motor activity and language-semantic behavior remains far from clear. A better understanding of this issue could be guaranteed by investigating functional interactions between motor sites and semantically-relevant regions.
doi:10.3389/fnhum.2013.00148
PMCID: PMC3633936  PMID: 23630480
neuromodulation; action understanding; neuroimaging; cognitive neuropsychology; language semantics
23.  Is inhibitory control a ‘no-go’ in adolescents with autism spectrum disorder? 
Molecular Autism  2014;5:6.
Background
Autism spectrum disorder (ASD) refers to a range of neurodevelopmental conditions characterized by social communication deficits, repetitive behaviours, and restrictive interests. Impaired inhibition has been suggested to exacerbate the core symptoms of ASD. This is particularly critical during adolescence when social skills are maturing to adult levels. Using magnetoencephalography (MEG), we identified the location and timing pattern of neural activity associated with inhibition in adolescents with autism, compared to typically developing adolescents.
Methods
The MEG data from 15 adolescents with ASD and 15 age-matched controls (13 to 17 years) were collected during a go/no-go task with inverse ratios of go/no-go trials in two conditions: an inhibition condition (1:2) and a baseline condition (2:1). No-go trials from the two conditions were analyzed using beamformer source localizations from 200 ms to 400 ms post-stimulus onset. Significant activations were determined using permutation testing.
Results
Adolescents with ASD recruited first the right middle frontal gyrus (200 to 250 ms) followed by the left postcentral gyrus (250 to 300 ms) and finally the left middle frontal and right medial frontal gyri (300 to 400 ms). Typically developing adolescents recruited first the left middle frontal gyrus (200 to 250 ms), followed by the left superior and inferior frontal gyri (250 to 300 ms), then the right middle temporal gyrus (300 to 350 ms), and finally the superior and precentral gyri and right inferior lobule (300 to 400 ms).
Conclusions
Adolescents with ASD showed recruitment limited largely to the frontal cortex unlike typically developing adolescents who recruited parietal and temporal regions as well. These findings support the presence of an atypical, restricted inhibitory network in adolescents with ASD compared to controls.
doi:10.1186/2040-2392-5-6
PMCID: PMC3939401  PMID: 24485230
Autism spectrum disorder; Adolescence; Brain imaging; Inhibition
24.  Neural Network Development in Late Adolescents during Observation of Risk-Taking Action 
PLoS ONE  2012;7(6):e39527.
Emotional maturity and social awareness are important for adolescents, particularly college students beginning to face the challenges and risks of the adult world. However, there has been relatively little research into personality maturation and psychological development during late adolescence and the neural changes underlying this development. We investigated the correlation between psychological properties (neuroticism, extraversion, anxiety, and depression) and age among late adolescents (n = 25, from 18 years and 1 month to 22 years and 8 months). The results revealed that late adolescents became less neurotic, less anxious, less depressive and more extraverted as they aged. Participants then observed video clips depicting hand movements with and without a risk of harm (risk-taking or safe actions) during functional magnetic resonance imaging (fMRI). The results revealed that risk-taking actions elicited significantly stronger activation in the bilateral inferior parietal lobule, temporal visual regions (superior/middle temporal areas), and parieto-occipital visual areas (cuneus, middle occipital gyri, precuneus). We found positive correlations of age and extraversion with neural activation in the insula, middle temporal gyrus, lingual gyrus, and precuneus. We also found a negative correlation of age and anxiety with activation in the angular gyrus, precentral gyrus, and red nucleus/substantia nigra. Moreover, we found that insula activation mediated the relationship between age and extraversion. Overall, our results indicate that late adolescents become less anxious and more extraverted with age, a process involving functional neural changes in brain networks related to social cognition and emotional processing. The possible neural mechanisms of psychological and social maturation during late adolescence are discussed.
doi:10.1371/journal.pone.0039527
PMCID: PMC3387168  PMID: 22768085
25.  Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease 
Brain  2012;135(4):1165-1179.
Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.
doi:10.1093/brain/aws024
PMCID: PMC3326253  PMID: 22505631
emotion; Huntington's disease; neurodegenerative disorders; cognitive impairment; functional MRI

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