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1.  Repetition of letter strings leads to activation of and connectivity with word-related regions 
Neuroimage  2011;59(3):2839-2849.
Individuals learn to read by gradually recognizing repeated letter combinations. However, it is unclear how or when neural mechanisms associated with repetition of basic stimuli (i.e., strings of letters) shift to involvement of higher-order language networks. The present study investigated this question by repeatedly presenting unfamiliar letter strings in a one-back matching task during an hour-long period. Activation patterns indicated that only brain areas associated with visual processing were activated during the early period, but additional regions that are usually associated with semantic and phonological processing in inferior frontal gyrus were recruited after stimuli became more familiar. Changes in activation were also observed in bilateral superior temporal cortex, also suggestive of a shift toward a more language-based processing strategy. Connectivity analyses reveal two distinct networks that correspond to phonological and visual processing, which may reflect the indirect and direct routes of reading. The phonological route maintained a similar degree of connectivity throughout the experiment, whereas visual areas increased connectivity with language areas as stimuli became more familiar, suggesting early recruitment of the direct route. This study provides insight about plasticity of the brain as individuals become familiar with unfamiliar combinations of letters (i.e., words in a new language, new acronyms) and has implications for engaging these linguistic networks during development of language remediation therapies.
doi:10.1016/j.neuroimage.2011.09.047
PMCID: PMC3254793  PMID: 21982931
letter strings; fMRI; connectivity; reading; learning; plasticity
2.  The Temporal Dynamics of Implicit Processing of Non-Letter, Letter, and Word-Forms in the Human Visual Cortex 
The decoding of visually presented line segments into letters, and letters into words, is critical to fluent reading abilities. Here we investigate the temporal dynamics of visual orthographic processes, focusing specifically on right hemisphere contributions and interactions between the hemispheres involved in the implicit processing of visually presented words, consonants, false fonts, and symbolic strings. High-density EEG was recorded while participants detected infrequent, simple, perceptual targets (dot strings) embedded amongst a of character strings. Beginning at 130 ms, orthographic and non-orthographic stimuli were distinguished by a sequence of ERP effects over occipital recording sites. These early latency occipital effects were dominated by enhanced right-sided negative-polarity activation for non-orthographic stimuli that peaked at around 180 ms. This right-sided effect was followed by bilateral positive occipital activity for false-fonts, but not symbol strings. Moreover the size of components of this later positive occipital wave was inversely correlated with the right-sided ROcc180 wave, suggesting that subjects who had larger early right-sided activation for non-orthographic stimuli had less need for more extended bilateral (e.g., interhemispheric) processing of those stimuli shortly later. Additional early (130–150 ms) negative-polarity activity over left occipital cortex and longer-latency centrally distributed responses (>300 ms) were present, likely reflecting implicit activation of the previously reported ‘visual-word-form’ area and N400-related responses, respectively. Collectively, these results provide a close look at some relatively unexplored portions of the temporal flow of information processing in the brain related to the implicit processing of potentially linguistic information and provide valuable information about the interactions between hemispheres supporting visual orthographic processing.
doi:10.3389/neuro.09.056.2009
PMCID: PMC2796900  PMID: 20046826
word reading; ERPs; visual cortex; visual orthography
3.  A comparison of brain activity evoked by single content and function words: An fMRI investigation of implicit word processing 
Brain research  2009;1282:38-49.
Content and function words have different roles in language and differ greatly in their semantic content. Although previous research has suggested that these different roles may be mediated by different neural substrates, the neuroimaging literature on this topic is particularly scant. Moreover, fMRI studies that have investigated differences between content and function words have utilized tasks that focus the subjects’ attention on the differences between these word types. It is possible, then, that task-related differences in attention, working memory, and decision-making contribute to the differential patterns of activation observed. Here, subjects were engaged in a continuous working memory cover task while single, task-irrelevant content and function words were infrequently and irregularly presented. Nonword letter strings were displayed in black font at a fast rate (2/sec). Subjects were required to either remember or retrieve occasional nonwords that were presented in colored fonts. Incidental and irrelevant to the memory task, content and function words were interspersed among nonwords at intervals of 12 to 15 sec. Both word types strongly activated temporal-parietal cortex, middle and anterior temporal cortex, inferior frontal gyrus, parahippocampal gyrus, and orbital frontal cortex. Activations were more extensive in the left hemisphere. Content words elicited greater activation than function words in middle and anterior temporal cortex, a sub-region of orbital frontal cortex, and the parahippocampal region. Words also evoked extensive deactivation, most notably in brain regions previously associated with working memory and attention.
doi:10.1016/j.brainres.2009.05.043
PMCID: PMC2755079  PMID: 19465009
fMRI; language; semantic processing; content and function words
4.  An fMRI study of semantic processing in men with schizophrenia 
NeuroImage  2003;20(4):1923-1933.
As a means toward understanding the neural bases of schizophrenic thought disturbance, we examined brain activation patterns in response to semantically and superficially encoded words in patients with schizophrenia. Nine male schizophrenic and 9 male control subjects were tested in a visual levels of processing (LOP) task first outside the magnet and then during the fMRI scanning procedures (using a different set of words). During the experiments visual words were presented under two conditions. Under the deep, semantic encoding condition, subjects made semantic judgments as to whether the words were abstract or concrete. Under the shallow, nonsemantic encoding condition, subjects made perceptual judgments of the font size (uppercase/lowercase) of the presented words. After performance of the behavioral task, a recognition test was used to assess the depth of processing effect, defined as better performance for semantically encoded words than for perceptually encoded words. For the scanned version only, the words for both conditions were repeated in order to assess repetition-priming effects. Reaction times were assessed in both testing scenarios. Both groups showed the expected depth of processing effect for recognition, and control subjects showed the expected increased activation of the left inferior prefrontal cortex (LIPC) under semantic encoding relative to perceptual encoding conditions as well as repetition priming for semantic conditions only. In contrast, schizophrenics showed similar patterns of fMRI activation regardless of condition. Most striking in relation to controls, patients showed decreased LIFC activation concurrent with increased left superior temporal gyrus activation for semantic encoding versus shallow encoding. Furthermore, schizophrenia subjects did not show the repetition priming effect, either behaviorally or as a decrease in LIPC activity. In patients with schizophrenia, LIFC underactivation and left superior temporal gyrus overactivation for semantically encoded words may reflect a disease-related disruption of a distributed frontal temporal network that is engaged in the representation and processing of meaning of words, text, and discourse and which may underlie schizophrenic thought disturbance.
PMCID: PMC2806220  PMID: 14683698
5.  Failure of language lateralization in schizophrenia patients: an ERP study on early linguistic components 
Objective
In line with Crow's hypothesis, altered hemispheric lateralization of language would cause the main symptoms of schizophrenia. The present experiment aimed to demonstrate the loss of the hemispheric specialization for linguistic processing in schizophrenia patients at the level of early automatic evoked potentials (N150).
Methods
A sample of 10 outpatients with schizophrenia treated with low levels of neuroleptics and 10 matched healthy control subjects were administered 3 linguistic tasks based on stimulus pair comparisons (phonological, semantic and word–picture matching tasks). Laterality scores of early evoked potentials were analyzed during 2 time windows corresponding to the N150- and N400-like components.
Results
The patients failed to develop the typical left hemispheric N150 component evoked by the first word (S1), which was consistently achieved by the healthy control group in posterior sites (p < 0.01). The effect was specific and stable for linguistic stimuli. As well, for the N150 elicited by the target stimulus (S2), the patients exhibited a lack of linguistic lateralization. In the control task (word–picture matching task), in which S2 was a picture, the 2 groups revealed very similar bilateral recognition potentials.
Conclusion
The results point to a failure of language lateralization in patients with schizophrenia, a deficit involving those linguistic networks automatically activated in the earliest phase of word recognition (N150). Consistent with the current view of schizophrenia, this finding may be related to lack of integration among specific processes and reduced interconnection of underlying linguistic networks.
PMCID: PMC2441888  PMID: 18592042
schizophrenia; language; hemispheric asymmetry; evoked potentials; recognition potential; N150
6.  Delta EEG Band as a Marker of Left Hypofrontality for Language in Schizophrenia Patients 
Schizophrenia Bulletin  2009;37(4):757-767.
Frontal hypoactivation has consistently been demonstrated in schizophrenia patients. We hypothesized that this well-known deficit is asymmetrical, ie, centered over left frontal locations and, in-line with Crow's theory, associated with both loss of linguistic asymmetry and correlated with positive symptoms. Electroencephalography delta band was used as a quantitative index of cortical inhibition in 17 paranoid schizophrenia patients with prevailing positive symptoms and 17 matched control subjects. Delta amplitude was measured by 38 electrodes, while participants performed 3 linguistic tasks, visuoperceptual, rhyming, and semantic judgment. Compared with control subjects, patients did not show overall delta band differences, revealing no detrimental effects of pharmacological treatment. In healthy participants, analysis of 4 quadrants/regions of interest revealed higher delta amplitude in right vs left anterior sites, indicating significant left anterior disinhibition during linguistic processing. Instead, patients showed bilateral delta band distribution and, compared with control subjects, significant greater delta amplitude (ie, brain inhibition) in linguistic left anterior centers. Patients’ left hypofrontality was functionally related to their lack of hemispheric specialization for language and was positively correlated with higher levels of delusions (P1) and conceptual disorganization (P2) Positive and Negative Syndrome Scale subscales. Results suggest, in schizophrenia patients, a functional deficit of Broca's area, a region playing a fundamental hierarchical role between and within hemispheres by integrating many basic processes in linguistic and conceptual organization. The significant correlation between lack of anterior asymmetry and increased positive symptoms is in-line with Crow's hypothesis postulating the etiological role of disrupted linguistic frontal asymmetry on the onset of the key symptoms of schizophrenia.
doi:10.1093/schbul/sbp145
PMCID: PMC3122275  PMID: 19933713
EEG rhythm; psychosis; delusions; lateralization; electroencephalography
7.  Dysfunctional visual word form processing in progressive alexia 
Brain  2013;136(4):1260-1273.
Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the ‘visual word form area’. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy.
doi:10.1093/brain/awt034
PMCID: PMC3613714  PMID: 23471694
progressive alexia; letter-by-letter reading; posterior cortical atrophy; logopenic primary progressive aphasia; visual word form system
8.  Dissociating object familiarity from linguistic properties in mirror word reading 
Background
It is known that the orthographic properties of linguistic stimuli are processed within the left occipitotemporal cortex at about 150–200 ms. We recorded event-related potentials (ERPs) to words in standard or mirror orientation to investigate the role of visual word form in reading. Word inversion was performed to determine whether rotated words lose their linguistic properties.
Methods
About 1300 Italian words and legal pseudo-words were presented to 18 right-handed Italian students engaged in a letter detection task. EEG was recorded from 128 scalp sites.
Results
ERPs showed an early effect of word orientation at ~150 ms, with larger N1 amplitudes to rotated than to standard words. Low-resolution brain electromagnetic tomography (LORETA) revealed an increase in N1 to rotated words primarily in the right occipital lobe (BA 18), which may indicate an effect of stimulus familiarity. N1 was greater to target than to non-target letters at left lateral occipital sites, thus reflecting the first stage of orthographic processing. LORETA revealed a strong focus of activation for this effect in the left fusiform gyrus (BA 37), which is consistent with the so-called visual word form area (VWFA). Standard words (compared to pseudowords) elicited an enhancement of left occipito/temporal negativity at about 250–350 ms, followed by a larger anterior P3, a reduced frontal N400 and a huge late positivity. Lexical effects for rotated strings were delayed by about 100 ms at occipito/temporal sites, and were totally absent at later processing stages. This suggests the presence of implicit reading processes, which were pre-attentive and of perceptual nature for mirror strings.
Conclusion
The contrast between inverted and standard words did not lead to the identification of a purely linguistic brain region. This finding suggests some caveats in the interpretation of the inversion effect in subtractive paradigms.
doi:10.1186/1744-9081-3-43
PMCID: PMC1995209  PMID: 17708767
9.  Activation of the Left Inferior Frontal Gyrus in the First 200 ms of Reading: Evidence from Magnetoencephalography (MEG) 
PLoS ONE  2009;4(4):e5359.
Background
It is well established that the left inferior frontal gyrus plays a key role in the cerebral cortical network that supports reading and visual word recognition. Less clear is when in time this contribution begins. We used magnetoencephalography (MEG), which has both good spatial and excellent temporal resolution, to address this question.
Methodology/Principal Findings
MEG data were recorded during a passive viewing paradigm, chosen to emphasize the stimulus-driven component of the cortical response, in which right-handed participants were presented words, consonant strings, and unfamiliar faces to central vision. Time-frequency analyses showed a left-lateralized inferior frontal gyrus (pars opercularis) response to words between 100–250 ms in the beta frequency band that was significantly stronger than the response to consonant strings or faces. The left inferior frontal gyrus response to words peaked at ∼130 ms. This response was significantly later in time than the left middle occipital gyrus, which peaked at ∼115 ms, but not significantly different from the peak response in the left mid fusiform gyrus, which peaked at ∼140 ms, at a location coincident with the fMRI–defined visual word form area (VWFA). Significant responses were also detected to words in other parts of the reading network, including the anterior middle temporal gyrus, the left posterior middle temporal gyrus, the angular and supramarginal gyri, and the left superior temporal gyrus.
Conclusions/Significance
These findings suggest very early interactions between the vision and language domains during visual word recognition, with speech motor areas being activated at the same time as the orthographic word-form is being resolved within the fusiform gyrus. This challenges the conventional view of a temporally serial processing sequence for visual word recognition in which letter forms are initially decoded, interact with their phonological and semantic representations, and only then gain access to a speech code.
doi:10.1371/journal.pone.0005359
PMCID: PMC2671164  PMID: 19396362
10.  Schizophrenia as Failure of Left Hemispheric Dominance for the Phonological Component of Language 
PLoS ONE  2009;4(2):e4507.
Background
T. J. Crow suggested that the genetic variance associated with the evolution in Homo sapiens of hemispheric dominance for language carries with it the hazard of the symptoms of schizophrenia. Individuals lacking the typical left hemisphere advantage for language, in particular for phonological components, would be at increased risk of the typical symptoms such as auditory hallucinations and delusions.
Methodology/Principal Findings
Twelve schizophrenic patients treated with low levels of neuroleptics and twelve matched healthy controls participated in an event-related potential experiment. Subjects matched word-pairs in three tasks: rhyming/phonological, semantic judgment and word recognition. Slow evoked potentials were recorded from 26 scalp electrodes, and a laterality index was computed for anterior and posterior regions during the inter stimulus interval. During phonological processing individuals with schizophrenia failed to achieve the left hemispheric dominance consistently observed in healthy controls. The effect involved anterior (fronto-temporal) brain regions and was specific for the Phonological task; group differences were small or absent when subjects processed the same stimulus material in a Semantic task or during Word Recognition, i.e. during tasks that typically activate more widespread areas in both hemispheres.
Conclusions/Significance
We show for the first time how the deficit of lateralization in the schizophrenic brain is specific for the phonological component of language. This loss of hemispheric dominance would explain typical symptoms, e.g. when an individual's own thoughts are perceived as an external intruding voice. The change can be interpreted as a consequence of “hemispheric indecision”, a failure to segregate phonological engrams in one hemisphere.
doi:10.1371/journal.pone.0004507
PMCID: PMC2637431  PMID: 19223971
11.  A Comparison of Five FMRI Protocols for Mapping Speech Comprehension Systems 
Epilepsia  2008;49(12):1980-1997.
Aims
Many fMRI protocols for localizing speech comprehension have been described, but there has been little quantitative comparison of these methods. We compared five such protocols in terms of areas activated, extent of activation, and lateralization.
Methods
FMRI BOLD signals were measured in 26 healthy adults during passive listening and active tasks using words and tones. Contrasts were designed to identify speech perception and semantic processing systems. Activation extent and lateralization were quantified by counting activated voxels in each hemisphere for each participant.
Results
Passive listening to words produced bilateral superior temporal activation. After controlling for pre-linguistic auditory processing, only a small area in the left superior temporal sulcus responded selectively to speech. Active tasks engaged an extensive, bilateral attention and executive processing network. Optimal results (consistent activation and strongly lateralized pattern) were obtained by contrasting an active semantic decision task with a tone decision task. There was striking similarity between the network of brain regions activated by the semantic task and the network of brain regions that showed task-induced deactivation, suggesting that semantic processing occurs during the resting state.
Conclusions
FMRI protocols for mapping speech comprehension systems differ dramatically in pattern, extent, and lateralization of activation. Brain regions involved in semantic processing were identified only when an active, non-linguistic task was used as a baseline, supporting the notion that semantic processing occurs whenever attentional resources are not controlled. Identification of these lexical-semantic regions is particularly important for predicting language outcome in patients undergoing temporal lobe surgery.
doi:10.1111/j.1528-1167.2008.01683.x
PMCID: PMC2645716  PMID: 18513352
language; fMRI; speech; comprehension; semantics; temporal lobe
12.  Sound to Language: Different Cortical Processing for First and Second Languages in Elementary School Children as Revealed by a Large-Scale Study Using fNIRS 
Cerebral Cortex (New York, NY)  2011;21(10):2374-2393.
A large-scale study of 484 elementary school children (6–10 years) performing word repetition tasks in their native language (L1-Japanese) and a second language (L2-English) was conducted using functional near-infrared spectroscopy. Three factors presumably associated with cortical activation, language (L1/L2), word frequency (high/low), and hemisphere (left/right), were investigated. L1 words elicited significantly greater brain activation than L2 words, regardless of semantic knowledge, particularly in the superior/middle temporal and inferior parietal regions (angular/supramarginal gyri). The greater L1-elicited activation in these regions suggests that they are phonological loci, reflecting processes tuned to the phonology of the native language, while phonologically unfamiliar L2 words were processed like nonword auditory stimuli. The activation was bilateral in the auditory and superior/middle temporal regions. Hemispheric asymmetry was observed in the inferior frontal region (right dominant), and in the inferior parietal region with interactions: low-frequency words elicited more right-hemispheric activation (particularly in the supramarginal gyrus), while high-frequency words elicited more left-hemispheric activation (particularly in the angular gyrus). The present results reveal the strong involvement of a bilateral language network in children’s brains depending more on right-hemispheric processing while acquiring unfamiliar/low-frequency words. A right-to-left shift in laterality should occur in the inferior parietal region, as lexical knowledge increases irrespective of language.
doi:10.1093/cercor/bhr023
PMCID: PMC3169662  PMID: 21350046
foreign language; functional near-infrared spectroscopy (fNIRS); learning; native language; phonology
13.  fMRI Study of Language Activation in Schizophrenia, Schizoaffective Disorder and in Individuals Genetically at High Risk 
Schizophrenia research  2007;96(1-3):14-24.
Background:
Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals.
Method:
A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning.
Results:
Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group.
Conclusions:
This study reinforces previous language related imaging studies in high-risk subjects and patients with schizophrenia suggesting that reduced functional lateralization in language related frontal cortex may be a vulnerability marker for schizophrenia. Future studies will determine whether it is predictive of who develops illness.
doi:10.1016/j.schres.2007.07.013
PMCID: PMC2212592  PMID: 17719745
fMRI; schizophrenia; High risk, genetic; Language lateralization; ROI based study
14.  Time course of semantic processes during sentence comprehension: an fMRI study 
NeuroImage  2007;36(3):924-932.
The ability to create new meanings from combinations of words is one important function of the language system. We investigated the neural correlates of combinatorial semantic processing using fMRI. During scanning, participants performed a rating task on auditory word or pseudoword strings that differed in the presence of combinatorial and word-level semantic information. Stimuli included normal sentences comprised of thematically related words that could be readily combined to produce a more complex meaning, semantically incongruent sentences in which content words were randomly replaced with other content words, pseudoword sentences, and versions of these three sentence types in which syntactic structure was removed by randomly re-ordering the words. Several regions showed greater BOLD signal for stimuli with words than for those with pseudowords, including the left angular gyrus, left superior temporal sulcus, and left inferior frontal gyrus, suggesting that these areas are involved in semantic access at the single word level. In the angular and inferior frontal gyri these differences emerged early in the course of the hemodynamic response. An effect of combinatorial semantic structure was observed in the left angular gyrus and left lateral temporal lobe, which showed greater activation for normal compared to semantically incongruent sentences. These effects appeared later in the time course of the hemodynamic response, beginning after the entire stimulus had been presented. The data indicate a complex spatiotemporal pattern of activity associated with computation of word and sentence-level semantic information, and suggest a particular role for the left angular gyrus in processing overall sentence meaning.
doi:10.1016/j.neuroimage.2007.03.059
PMCID: PMC1941617  PMID: 17500009
15.  Neural dynamics of inflectional and derivational processing in spoken word comprehension: laterality and automaticity 
Rapid and automatic processing of grammatical complexity is argued to take place during speech comprehension, engaging a left-lateralized fronto-temporal language network. Here we address how neural activity in these regions is modulated by the grammatical properties of spoken words. We used combined magneto- and electroencephalography to delineate the spatiotemporal patterns of activity that support the recognition of morphologically complex words in English with inflectional (-s) and derivational (-er) affixes (e.g., bakes, baker). The mismatch negativity, an index of linguistic memory traces elicited in a passive listening paradigm, was used to examine the neural dynamics elicited by morphologically complex words. Results revealed an initial peak 130–180 ms after the deviation point with a major source in left superior temporal cortex. The localization of this early activation showed a sensitivity to two grammatical properties of the stimuli: (1) the presence of morphological complexity, with affixed words showing increased left-laterality compared to non-affixed words; and (2) the grammatical category, with affixed verbs showing greater left-lateralization in inferior frontal gyrus compared to affixed nouns (bakes vs. beaks). This automatic brain response was additionally sensitive to semantic coherence (the meaning of the stem vs. the meaning of the whole form) in left middle temporal cortex. These results demonstrate that the spatiotemporal pattern of neural activity in spoken word processing is modulated by the presence of morphological structure, predominantly engaging the left-hemisphere’s fronto-temporal language network, and does not require focused attention on the linguistic input.
doi:10.3389/fnhum.2013.00759
PMCID: PMC3831605  PMID: 24302902
morphology; MEG; EEG; inflection; derivation; language comprehension; attention
16.  The cortical microstructural basis of lateralized cognition: a review 
The presence of asymmetry in the human cerebral hemispheres is detectable at both the macroscopic and microscopic scales. The horizontal expansion of cortical surface during development (within individual brains), and across evolutionary time (between species), is largely due to the proliferation and spacing of the microscopic vertical columns of cells that form the cortex. In the asymmetric planum temporale (PT), minicolumn width asymmetry is associated with surface area asymmetry. Although the human minicolumn asymmetry is not large, it is estimated to account for a surface area asymmetry of approximately 9% of the region’s size. Critically, this asymmetry of minicolumns is absent in the equivalent areas of the brains of other apes. The left-hemisphere dominance for processing speech is thought to depend, partly, on a bias for higher resolution processing across widely spaced minicolumns with less overlapping dendritic fields, whereas dense minicolumn spacing in the right hemisphere is associated with more overlapping, lower resolution, holistic processing. This concept refines the simple notion that a larger brain area is associated with dominance for a function and offers an alternative explanation associated with “processing type.” This account is mechanistic in the sense that it offers a mechanism whereby asymmetrical components of structure are related to specific functional biases yielding testable predictions, rather than the generalization that “bigger is better” for any given function. Face processing provides a test case – it is the opposite of language, being dominant in the right hemisphere. Consistent with the bias for holistic, configural processing of faces, the minicolumns in the right-hemisphere fusiform gyrus are thinner than in the left hemisphere, which is associated with featural processing. Again, this asymmetry is not found in chimpanzees. The difference between hemispheres may also be seen in terms of processing speed, facilitated by asymmetric myelination of white matter tracts (Anderson et al., 1999 found that axons of the left posterior superior temporal lobe were more thickly myelinated). By cross-referencing the differences between the active fields of the two hemispheres, via tracts such as the corpus callosum, the relationship of local features to global features may be encoded. The emergent hierarchy of features within features is a recursive structure that may functionally contribute to generativity – the ability to perceive and express layers of structure and their relations to each other. The inference is that recursive generativity, an essential component of language, reflects an interaction between processing biases that may be traceable in the microstructure of the cerebral cortex. Minicolumn organization in the PT and the prefrontal cortex has been found to correlate with cognitive scores in humans. Altered minicolumn organization is also observed in neuropsychiatric disorders including autism and schizophrenia. Indeed, altered interhemispheric connections correlated with minicolumn asymmetry in schizophrenia may relate to language-processing anomalies that occur in the disorder. Schizophrenia is associated with over-interpretation of word meaning at the semantic level and over-interpretation of relevance at the level of pragmatic competence, whereas autism is associated with overly literal interpretation of word meaning and under-interpretation of social relevance at the pragmatic level. Both appear to emerge from a disruption of the ability to interpret layers of meaning and their relations to each other. This may be a consequence of disequilibrium in the processing of local and global features related to disorganization of minicolumnar units of processing.
doi:10.3389/fpsyg.2014.00820
PMCID: PMC4115615  PMID: 25126082
minicolumn; cytoarchitecture; lateralization; asymmetry; face-processing; language; schizophrenia; autism
17.  Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia 
Summary
Background
Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca’s area for chronic aphasia treatment.
Material/Methods
We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca’s area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca’s.
Results
6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS.
Conclusions
FMRI-guided, excitatory rTMS applied to the affected Broca’s area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.
PMCID: PMC3057942  PMID: 21358599
aphasia; language; fMRI; rTMS; rehabilitation; stroke
18.  Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia 
Summary
Background
Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca’s area for chronic aphasia treatment.
Material/Methods
We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca’s area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca’s.
Results
6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS.
Conclusions
FMRI-guided, excitatory rTMS applied to the affected Broca’s area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.
doi:10.12659/MSM.881446
PMCID: PMC3057942  PMID: 21358599
aphasia; language; fMRI; rTMS; rehabilitation; stroke
19.  Functional Reorganization Associated with Semantic Language Processing in Temporal Lobe Epilepsy Patients after Anterior Temporal Lobectomy : A Longitudinal Functional Magnetic Resonance Image Study 
Objective
The focus of this study is brain plasticity associated with semantic aspects of language function in patients with medial temporal lobe epilepsy (mTLE).
Methods
Using longitudinal functional magnetic resonance imaging (fMRI), patterns of brain activation were observed in twelve left and seven right unilateral mTLE patients during a word-generation task relative to a pseudo-word reading task before and after anterior temporal section surgery.
Results
No differences were observed in precentral activations in patients relative to normal controls (n = 12), and surgery did not alter the phonological-associated activations. The two mTLE patient groups showed left inferior prefrontal activations associated with semantic processing (word-generation > pseudo-word reading), as did control subjects. The amount of semantic-associated activation in the left inferior prefrontal region was negatively correlated with epilepsy duration in both patient groups. Following temporal resection, semantic-specific activations in inferior prefrontal region became more bilateral in left mTLE patients, but more left-lateralized in right mTLE patients. The longer the duration of epilepsy in the patients, the larger the increase in the left inferior prefrontal semantic-associated activation after surgery in both patient groups. Semantic activation of the intact hippocampus, which had been negatively correlated with seizure frequency, normalized after the epileptic side was removed.
Conclusion
These results indicate alternation of semantic language network related to recruitment of left inferior prefrontal cortex and functional recovery of the hippocampus contralateral to the epileptogenic side, suggesting an intra- and inter-hemispheric reorganization following surgery.
doi:10.3340/jkns.2010.47.1.17
PMCID: PMC2817510  PMID: 20157373
fMRI; Language; Epilepsy; Brain plasticity; Hippocampus
20.  Isn’t it ironic? Neural Correlates of Irony Comprehension in Schizophrenia 
PLoS ONE  2013;8(9):e74224.
Ironic remarks are frequent in everyday language and represent an important form of social cognition. Increasing evidence indicates a deficit in comprehension in schizophrenia. Several models for defective comprehension have been proposed, including possible roles of the medial prefrontal lobe, default mode network, inferior frontal gyri, mirror neurons, right cerebral hemisphere and a possible mediating role of schizotypal personality traits. We investigated the neural correlates of irony comprehension in schizophrenia by using event-related functional magnetic resonance imaging (fMRI). In a prosody-free reading paradigm, 15 female patients with schizophrenia and 15 healthy female controls silently read ironic and literal text vignettes during fMRI. Each text vignette ended in either an ironic (n = 22) or literal (n = 22) statement. Ironic and literal text vignettes were matched for word frequency, length, grammatical complexity, and syntax. After fMRI, the subjects performed an off-line test to detect error rate. In this test, the subjects indicated by button press whether the target sentence has ironic, literal, or meaningless content. Schizotypal personality traits were assessed using the German version of the schizotypal personality questionnaire (SPQ). Patients with schizophrenia made significantly more errors than did the controls (correct answers, 85.3% vs. 96.3%) on a behavioural level. Patients showed attenuated blood oxygen level-dependent (BOLD) response during irony comprehension mainly in right hemisphere temporal regions (ironic>literal contrast) and in posterior medial prefrontal and left anterior insula regions (for ironic>visual baseline, but not for literal>visual baseline). In patients with schizophrenia, the parahippocampal gyrus showed increased activation. Across all subjects, BOLD response in the medial prefrontal area was negatively correlated with the SPQ score. These results highlight the role of the posterior medial prefrontal and right temporal regions in defective irony comprehension in schizophrenia and the mediating role of schizotypal personality traits.
doi:10.1371/journal.pone.0074224
PMCID: PMC3769349  PMID: 24040207
21.  Differentiating Hemispheric Contributions to Syntax and Semantics in Patients with Left-Hemisphere Lesions 
Understanding the relationship between brain and cognition critically depends on data from brain-damaged patients since these provide major constraints on identifying the essential components of brain–behavior systems. Here we relate structural and functional fMRI data with behavioral data in 21 human patients with chronic left hemisphere (LH) lesions and a range of language impairments to investigate the controversial issue of the role of the hemispheres in different language functions. We address this issue within a dual neurocognitive model of spoken language comprehension in which core linguistic functions, e.g., syntax, depend critically upon an intact left frontotemporal system, whereas more general communicative abilities, e.g., semantics, are supported by a bilateral frontotemporal system and may recover from LH damage through normal or enhanced activity in the intact right hemisphere. The fMRI study used a word-monitoring task that differentiated syntactic and semantic aspects of sentence comprehension. We distinguished overlapping interactions between structure, neural activity, and performance using joint independent components analysis, identifying two structural–functional networks, each with a distinct relationship with performance. Syntactic performance correlated with tissue integrity and activity in a left frontotemporal network. Semantic performance correlated with activity in right superior/middle temporal gyri regardless of tissue integrity. Right temporal activity did not differ between patients and controls, suggesting that the semantic network is degenerately organized, with regions in both hemispheres able to perform similar computations. Our findings support the dual neurocognitive model of spoken language comprehension and emphasize the importance of linguistic specificity in investigations of language recovery in patients.
doi:10.1523/JNEUROSCI.0485-12.2012
PMCID: PMC3575031  PMID: 22699896
22.  Mechanisms of recovery from aphasia: evidence from positron emission tomography studies 
OBJECTIVES—Language functions comprise a distributed neural system, largely lateralised to the left cerebral hemisphere. Late recovery from aphasia after a focal lesion, other than by behavioural strategies, has been attributed to one of two changes at a systems level: a laterality shift, with mirror region cortex in the contralateral cortex assuming the function(s) of the damaged region; or a partial lesion effect, with recovery of perilesional tissue to support impaired language functions. Functional neuroimaging with PET allows direct observations of brain functions at systems level. This study used PET to compare regional brain activations in response to a word retrieval task in normal subjects and in aphasic patients who had shown at least some recovery and were able to attempt the task. Emphasis has been placed on single subject analysis of the results as there is no reason to assume that the mechanisms of recovery are necessarily uniform among aphasic patients.
METHODS—Six right handed aphasic patients, each with a left cerebral hemispheric lesion (five strokes and one glioma), were studied. Criteria for inclusion were symptomatic or formal test evidence of at least some recovery and an ability to attempt word retrieval in response to heard word cues. Each patient underwent 12 PET scans using oxygen-15 labelled water (H215O) as tracer to index regional cerebral blood flow (rCBF). The task, repeated six times, required the patient to think of verbs appropriate to different lists of heard noun cues. The six scans obtained during word retrieval were contrasted with six made while the subject was "at rest". The patients' individual results were compared with those of nine right handed normal volunteers undergoing the same activation study. The data were analysed using statistical parametric mapping (SPM96, Wellcome Department of Cognitive Neurology, London, UK).
RESULTS—Perception of the noun cues would be expected to result in bilateral dorsolateral temporal cortical activations, but as the rate of presentation was only four per minute the auditory perceptual activations were not evident in all people. Anterior cingulate, medial premotor (supplementary speech area) and dorsolateral frontal activations were evident in all normal subjects and patients. There were limited right dorsolateral frontal activations in three of the six patients, but a similar pattern was also found in four of the nine normal subjects. In the left inferolateral temporal cortex, activation was found for the normal subjects and five of the six patients, including two of the three subjects with lesions involving the left temporal lobe. The only patient who showed subthreshold activation in the left inferolateral temporal activation had a very high error rate when performing the verb retrieval task.
CONCLUSIONS—The normal subjects showed a left lateralised inferolateral temporal activation, reflecting retrieval of words appropriate in meaning to the cue from the semantic system. Lateralisation of frontal activations to the left was only relative, with right prefrontal involvement in half of the normal subjects. Frontal activations are associated with parallel psychological processes involved in word retrieval, including task initiation, short term (working) memory for the cue and responses, and prearticulatory processes (even though no overt articulation was required). There was little evidence of a laterality shift of word retrieval functions to the right temporal lobe after a left hemispheric lesion. In particular, left inferolateral temporal activation was seen in all patients except one, and he proved to be very inefficient at the task. The results provide indirect evidence that even limited salvage of peri-infarct tissue with acute stroke treatments will have an important impact on the rehabilitation of cognitive functions.


PMCID: PMC1736204  PMID: 10071093
23.  The role of the precuneus in metaphor comprehension: evidence from an fMRI study in people with schizophrenia and healthy participants 
Comprehension of conventional and novel metaphors involves traditional language-related cortical regions as well as non-language related regions. While semantic processing is crucial for understanding metaphors, it is not sufficient. Recently the precuneus has been identified as a region that mediates complex and highly integrated tasks, including retrieval of episodic memory and mental imagery. Although the understanding of non-literal language is relatively easy for healthy individuals, people with schizophrenia exhibit deficits in this domain. The present study aims to examine whether people with schizophrenia differentially recruit the precuneus, extending to the superior parietal (SP) cortex (SPL), to support their deficit in metaphor comprehension. We also examine interregional associations between the precuneus/SPL and language-related brain regions. Twelve people with schizophrenia and twelve healthy controls were scanned while silently reading literal word pairs, conventional metaphors, and novel metaphors. People with schizophrenia showed reduced comprehension of both conventional and novel metaphors. Analysis of functional connectivity found that the correlations between activation in the left precuneus/SPL and activation in the left posterior superior temporal sulcus (PSTS) were significant for both literal word pairs and novel metaphors, and significant correlations were found between activation in the right precuneus/SPL and activation in the right PSTS for the three types of semantic relations. These results were found in the schizophrenia group alone. Furthermore, relative to controls, people with schizophrenia demonstrated increased activation in the right precuneus/SPL. Our results may suggest that individuals with schizophrenia use mental imagery to support comprehension of both literal and metaphoric language. In particular, our findings indicate over-integration of language and non-language brain regions during more effortful processes of novel metaphor comprehension.
doi:10.3389/fnhum.2014.00818
PMCID: PMC4199320  PMID: 25360101
schizophrenia; novel metaphors; precuneus; language; fMRI
24.  Explaining left lateralization for words in the ventral occipito-temporal cortex 
Summary
Reading is a uniquely human task and therefore any sign that neuronal activation is specific to reading has been of considerable interest. One intriguing observation is that ventral occipito-temporal (vOT) activation is more strongly left lateralized for written words than other visual stimuli. This has contributed to claims that left vOT plays a special role in reading. Here, we investigated whether left lateralized vOT responses for words were the consequence of visual feature processing, visual word form selectivity or higher level language processing. Using fMRI in 82 skilled readers, our paradigm compared activation and lateralization for words and non-linguistic stimuli during different tasks. We found that increased left lateralization for words relative to pictures was the consequence of reduced activation in right vOT rather than increased activation in left vOT. We also found that the determinants of lateralization varied with the subregion of vOT tested. In posterior vOT, lateralization depended on the spatial frequency of the visual inputs. In anterior vOT, lateralization depended on the semantic demands of the task. In middle vOT, lateralization depended on a combination of visual expertise in the right hemisphere and semantics in the left hemisphere. These results have implications for interpreting left lateralized vOT activation during reading. Specifically, left lateralized activation in vOT does not necessarily indicate an increase in left vOT processing but is instead a consequence of decreased right vOT function. Moreover, the determinants of lateralization include both visual and semantic factors depending on the subregion tested.
doi:10.1523/JNEUROSCI.2238-11.2011
PMCID: PMC3232449  PMID: 21994390
functional MRI; language; laterality; words and objects; fusiform gyrus
25.  Patterns of longitudinal brain atrophy in the logopenic variant of primary progressive aphasia 
Brain and Language  2013;127(2):121-126.
Highlights
► Patterns of cell loss in lvPPA remain asymmetrical over time. ► More anterior left hemisphere areas become involved over time. ► Right hemisphere regions become affected that mirror early left hemisphere change. ► Left hemisphere atrophy rates are greater than right hemisphere. ► Over time patients with lvPPA develop single word level processing deficits.
The logopenic variant of primary progressive aphasia (PPA) is characterised by impaired sentence repetition and word retrieval difficulties. Post mortem studies, amyloid imaging and CSF tau/Aβ measurements suggest Alzheimer’s disease (AD) pathology as the underlying cause. Relatively little is known about patterns of progression in patients with the logopenic variant of PPA. 21 patients (3 with post mortem confirmation of AD and 5 with positive amyloid PIB-PET scans) were studied with longitudinal T1-weighted MR imaging (mean interscan interval 1.2 years) using volumetric analysis and voxel-based morphometry (VBM). Baseline imaging showed asymmetrical (left greater than right) involvement of the posterior superior temporal and inferior parietal lobes as well as posterior cingulate and medial temporal lobes. The whole brain rate of volume loss was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%/year) than right hemisphere (1.6%/year). Longitudinal VBM analysis showed increasing involvement of other areas in the left hemisphere (temporal, parietal, frontal and caudate) and atrophy of areas in the right hemisphere that had been involved earlier in the disease in the left hemisphere, particularly posterior cingulate/precuneus. With disease progression there was worsening of anomia, sentence repetition and sentence comprehension but consistent with the spread of imaging changes also deficits in single word comprehension, single word repetition and verbal memory. This study shows that the logopenic variant of PPA remains an asymmetrical disease, with spread through the left hemisphere language network but also involvement to a lesser degree of regions in the right hemisphere that mirror the earlier left hemisphere changes.
doi:10.1016/j.bandl.2012.12.008
PMCID: PMC3880853  PMID: 23395096
Primary progressive aphasia; Logopenic aphasia

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