Task-dependent modulation of functional connectivity between hand motor cortices and neuronal networks underlying language and music: a transcranial magnetic stimulation study in humans

Although language functions are, in general, attributed to the left hemisphere, it is still a matter of debate to what extent the cognitive functions underlying the processing of music are lateralized in the human brain. To investigate hemispheric specialization we evaluated the effect of different overt musical and linguistic tasks on the excitability of both left and right hand motor cortices using transcranial magnetic stimulation (TMS). Task-dependent changes of the size of the TMS-elicited motor evoked potentials were recorded in 12 right-handed, musically naive subjects during and after overt speech, singing and humming, i.e. the production of melody without word articulation. The articulation of meaningless syllables served as control condition. We found reciprocal lateralized effects of overt speech and musical tasks on motor cortex excitability. During overt speech, the corticospinal projection of the left (i.e. dominant) hemisphere to the right hand was facilitated. In contrast, excitability of the right motor cortex increased during both overt singing and humming, whereas no effect was observed on the left hemisphere. Although the traditional concept of hemispheric lateralization of music has been challenged by recent neuroimaging studies, our findings demonstrate that right-hemisphere preponderance of music is nevertheless present. We discuss our results in terms of the recent concepts on evolution of language and gesture, which hypothesize that cerebral networks mediating hand movement and those subserving language processing are functionally linked. TMS may constitute a useful tool to further investigate the relationship between cortical representations of motor functions, music and language using comparative approaches.     

Cortical activation studies in aphasia

Positron emission tomography and functional magnetic resonance imaging are the major techniques of functional brain imaging. Both techniques have been used successfully in studies of the speech-relevant cortex in normal individuals and in aphasic patients with brain lesions. The activation studies basically agree with the classic model of language organization in that the left inferior frontal and superior temporal cortex (Broca’s and Wernicke’s area, respectively) are the pivotal areas of speech processing. Activation studies additionally emphasize that the speech-relevant cortex is a rather widespread network. It also encompasses contributions from other left hemispheric regions and, to some degree, from the contralateral right hemisphere. The studies of aphasic patients point out that the functional preponderance of the left over the right cerebral hemisphere varies between individuals, and that language recovery after stroke depends on the restitution of the speech-relevant network in both brain hemispheres.     

The human cerebro-cerebellar system: its computing, cognitive, and language skills.

In this review of the human cerebro-cerebellar system, the focus is on the possible contributions of the cerebellum to cognitive and language functions. The role of the cerebellum in these human functions has tended to be obscured by the traditional preoccupation with the motor functions of the cerebellum, which have been widely observed in other vertebrates as well. In the human brain, some phylogenetically new parts evolved and enlarged in the cerebellum, concomitantly with the enlargement of association areas in the cerebral cortex. Anatomical evidence and behavioral evidence combine to suggest that this enlarged cerebellum contributes not only to motor function but also to some sensory, cognitive, linguistic, and emotional aspects of behavior. The anatomical evidence derives from the modularity of the cerebellum, whose cortical nerve cells are organized into longitudinal micro-modules, which are arrayed perpendicular to the cortical surface and parallel to each other. The number of these micro-modules increased when the cerebellum enlarged, which enlarged the computing capabilities of the network. (From principles underlying the processing of information, it is known that when modules with modest processing capabilities are assembled in large numbers in parallel, the resulting network can achieve remarkably powerful computing capabilities.) Such cerebellar computing capabilities can be utilized in the different areas of the cerebral cortex to which the cerebellum sends signals. The cerebellar output connections convey signals through the thalamus to the cerebral cortex in segregated channels of communication, which preserve the modularity of the cerebellum. Through these channels, modules in the lateral cerebellum can send signals to new cognitive and language areas of the cerebral cortex, such as Broca's area in the prefrontal cortex. The anatomy of the human cerebro-cerebellar system therefore suggests that the cerebellum can contribute to the learning not only of motor skills but also of some cognitive and language skills. Supporting this anatomical evidence is the mounting behavioral evidence, obtained both in normal brains and in clinical studies, which indicates that the lateral cerebellum is indeed involved in some cognitive and language functions.     

Crossed cerebro-cerebellar language dominance

In addition to its traditional role in motor control, the cerebellum has been implicated in various cognitive and linguistic functions. Lesion, anatomic, and functional imaging studies indicate a link between left frontal language regions and the right cerebellum. To probe the specificity of this circuit, we examined the association between language-related lateralized activation of the frontal cortex with lateralized activation of the cerebellum. Functional magnetic resonance imaging (fMRI) was carried out during letter-cued word generation in 14 healthy subjects: 7 subjects displayed typical left-hemisphere and 7 subjects displayed atypical right-hemisphere language dominance. We found activation of the cerebellar hemisphere contralateral to the language-dominant cerebral hemisphere in each subject. The cerebellar activation was confined to the lateral posterior cerebellar hemisphere (lobule VI, VII B, Cr I, Cr II). This study demonstrates that crossed cerebral and cerebellar language dominance is a typical characteristic of brain organization. The functional significance of the reported activations can now be tested in patients with lesions of the lateral posterior cerebellum.     

Word generation in bilinguals--fMRI study with implications for language and memory processes

For over a century the cerebral representation of language functions is a matter of debate. In Neuroscience language is regarded as one of the most lateralized cognitive functions. Thus, while the language which is acquired first in most cases is processed by the left hemisphere some studies in brain damaged but also experimental investigations propose a pivotal role of the right hemisphere in second language processing. By the advent of modern neuroimaging it is now possible to study language lateralization and bilinguality also in healthy subjects. We studied first and second language abilities in a group of bilingual, healthy individuals by means of functional magnetic resonance imaging (fMRI) with a word-fluency paradigm. While we found a predominantly left prefrontal activity during both first and also second language processing an additional right prefrontal activation was registered during the use of second language. Our findings are discussed on the basis of an interaction between language and memory processes.     

Localization of language function in the brain

Since the first report of an aphasic patient by Paul Broca, the localization of brain function has been disputed for 150 years. In lesion studies, double dissociation has been a key concept to show the localization of particular cognitive functions. The advancement of non-invasive brain imaging methods enables us to investigate the brain activities under well-controlled conditions, further promoting the studies on the localization of the cognitive functions, including language function. Brain imaging studies, together with subtraction and correlation analyses, have accumulated evidence that syntax, phonology, and sentence comprehension are separately processed by modules in different cortical regions. More specifically, it has been clarified that the module for syntax localizes in the left lateral premotor cortex and the opercular/triangular parts of the left inferior frontal gyrus. This modular structure further suggests that aphasia is interpreted as deficits in either syntactic or phonological processing. Therefore, the classical model of contrasting speech production and comprehension should be updated. According to theoretical linguistics, on the other hand, the recursive computation of syntactic structures is an essential feature of human language faculty. One direction of research would be to contrast human beings and animals for the abilities of processing symbolic sequences. Another direction is to clarify that the human brain is indeed specialized in language processing, which can be revealed by well-controlled language tasks and functional imaging techniques. Here we will review recent studies that demonstrate the existence of grammar center in the left frontal cortex. The future studies in the neuroscience of language will eventually elucidate the cortical localization of language function in a more precise way, i.e., what is really computed in the human brain.     

Neural correlates of formal thought disorder: An activation likelihood estimation meta‐analysis

Formal thought disorder (FTD) refers to a psychopathological dimension characterized by disorganized and incoherent speech. Whether symptoms of FTD arise from aberrant processing in language‐related regions or more general cognitive networks, however, remains debated. Here, we addressed this question by a quantitative meta‐analysis of published functional neuroimaging studies on FTD. The revised Activation Likelihood Estimation (ALE) algorithm was used to test for convergent aberrant activation changes in 18 studies (30 experiments) investigating FTD, of which 17 studies comprised schizophrenia patients and one study healthy subjects administered to S‐ketamine. Additionally, we analyzed task‐dependent and task‐independent (resting‐state) functional connectivity (FC) of brain regions showing convergence in activation changes. Subsequent functional characterization was performed for the initial clusters and the delineated connectivity networks by reference to the BrainMap database. Consistent activation changes were found in the left superior temporal gyrus (STG) and two regions within the left posterior middle temporal gyrus (p‐MTG), ventrally (vp‐MTG) and dorsally (dp‐MTG). Functional characterization revealed a prominent functional association of ensuing clusters from our ALE meta‐analysis with language and speech processing, as well as auditory perception in STG and with social cognition in dp‐MTG. FC analysis identified task‐dependent and task‐independent networks for all three seed regions, which were mainly related to language and speech processing, but showed additional involvement in higher order cognitive functions. Our findings suggest that FTD is mainly characterized by abnormal activation in brain regions of the left hemisphere that are associated with language and speech processing, but also extend to higher order cognitive functions. Hum Brain Mapp 38:4946–4965, 2017. © 2017 Wiley Periodicals, Inc.     

Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay

In humans, both language and fine motor skills are associated with left‐hemisphere specialization, whereas visuospatial skills are associated with right‐hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right‐handed adults with ASC and 69 age‐ and IQ‐matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel‐based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC. Hum Brain Mapp 37:230–253, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Mapping the functional neuroanatomy of the intact human brain with brain work imaging

The recent development of noninvasive methods for measuring local rates of energy metabolism or blood flow in the brain has made it possible to investigate functional neuroanatomy in healthy human subjects. The best of these methods, high resolution measurement of regional cerebral blood flow (rCBF) with positron emission tomography (PET), provides a precision of anatomical localization that far exceeds that attainable with human brain lesion studies. Moreover, the study of healthy subjects avoids possible confounding effects of brain lesions, such as compensatory reorganization of brain function. PET-rCBF studies have already identified several cortical areas involved in higher-order visual processing, indicating that functional neuroimaging may yield a map of human visual cortex analogous to maps that have been developed by vision research in nonhuman primates. PET-rCBF studies of imagery and language demonstrate the potential of functional neuroimaging to map regions of human cortex that perform functions that cannot be studied so easily in nonhuman primates or perform functions that humans do not share with other species.     

Structural connectivity of the human anterior temporal lobe: A diffusion magnetic resonance imaging study

The anterior temporal lobes (ATL) have been implicated in a range of cognitive functions including auditory and visual perception, language, semantic knowledge, and social‐emotional processing. However, the anatomical relationships between the ATLs and the broader cortical networks that subserve these functions have not been fully elucidated. Using diffusion tensor imaging (DTI) and probabilistic tractography, we tested the hypothesis that functional segregation of information in the ATLs is reflected by distinct patterns of structural connectivity to regions outside the ATLs. We performed a parcellation of the ATLs bilaterally based on the degree of connectivity of each voxel with eight ipsilateral target regions known to be involved in various cognitive networks. Six discrete segments within each ATL showed preferential connectivity to one of the ipsilateral target regions, via four major fiber tracts (uncinate, inferior longitudinal, middle longitudinal, and arcuate fasciculi). Two noteworthy interhemispheric differences were observed: connections between the ATL and orbito‐frontal areas were stronger in the right hemisphere, while the consistency of the connection between the ATL and the inferior frontal gyrus through the arcuate fasciculus was greater in the left hemisphere. Our findings support the hypothesis that distinct regions within the ATLs have anatomical connections to different cognitive networks. Hum Brain Mapp 37:2210–2222, 2016. © 2016 Wiley Periodicals, Inc.     

fMRI of syntactic processing in typically developing children: structural correlates in the inferior frontal gyrus

Development of syntactic processing was examined to evaluate maturational processes including left language lateralization functions and increased specialization of brain regions important for syntactic processing. We utilized multimodal methods, including indices of brain activity from fMRI during a syntactic processing task, cortical thickness measurements from structural MRI, and neuropsychological measures. To evaluate hypotheses about increasing lateralization and specialization with development, we examined relationships between cortical thickness and magnitude and spatial activation extent within the left inferior frontal gyrus (IFG) and its right hemisphere homologue. We predicted that increased activation in the left and decreased activation in the right IFG would be associated with increased syntactic proficiency. As predicted, a more mature pattern of increased thickness in the right pars triangularis was associated with decreased activation intensity and extent in the right IFG. These findings suggest a maturational shift towards decreased involvement of the right IFG for syntactic processing. Better syntactic skills were associated with increased activation in the left IFG independent from age, suggesting increased specialization of the left IFG with increased proficiency. Overall, our findings show relationships between structural and functional neurodevelopment that co-occur with improved syntactic processing in critical language regions of the IFG in typically developing children.     

Regionalized sensorimotor plasticity after hemispherectomy fMRI evaluation

This study demonstrates the transfer of both motor and sensory functions from one hemisphere to the other in children who had an entire cortical hemisphere surgically removed. The areas of the cortex responsible for these new functions in the remaining hemisphere are associative motor and sensory areas and do not include the typical primary motor and somatosensory regions, thus suggesting the regionalization of brain plasticity. This regionalization can be evaluated with functional magnetic resonance imaging, supporting this technique as an effective tool in the study of brain plasticity.     

Plasticity of the primate prefrontal cortex.

Cortical plasticity refers to flexible and long-lasting changes in neuronal circuitry and information processing, which is caused by learning and experience. Although cortical plasticity can be observed in every cortex of the brain, the plasticity of the prefrontal cortex (PFC) is particularly important because the PFC is involved in various cognitive functions, and its plasticity could lead to adaptive changes in the use of other brain regions. Cortical plasticity occurs at several levels, from functional molecules to the organization of large areas of the brain. Here, the authors focus mainly on the development and remodeling of the functional and structural organization of the primate PFC. They discuss how the columnar modules of the PFC develop in the immature brain, how these modules form a "cognitive field" that is responsible for a specific cognitive function, how the cognitive field could be reorganized by training in the mature brain, and how monoaminergic systems contribute to these various levels of plasticity. They suggest that monoaminergic systems, especially the dopaminergic system, are involved in various levels of cortical plasticity, such as behavioral learning and learning-dependent cortical remodeling, thereby contributing to the reorganization of the cognitive field in the primate PFC.     

What can atypical language hemispheric specialization tell us about cognitive functions?

Recent studies have made substantial progress in understanding the interactions between cognitive functions, from language to cognitive control, attention, and memory. However, dissociating these functions has been hampered by the close proximity of regions involved, as in the case in the prefrontal and parietal cortex. In this article, we review a series of studies that investigated the relationship between language and other cognitive functions in an alternative way –– by examining their functional(co-)lateralization. We argue that research on the hemispheric lateralization of language and its link with handedness can offer an appropriate startingpoint to shed light on the relationships between different functions. Besides functional interactions, anatomical asymmetries in non-human primates and those underlying language in humans can provide unique information about cortical organization. Finally, some open questions and criteria are raised for an ideal theoretical model of the cortex based on hemispheric specialization.     

Cholinergic innervation of the frontal cortex: differences among humans, chimpanzees, and macaque monkeys

Cholinergic innervation of the frontal cortex is important in higher cognitive functions and may have been altered in humans relative to other species to support human-specific intellectual capacities. To evaluate this hypothesis we conducted quantitative comparative analyses of choline acetyltransferase-immunoreactive axons in cortical areas 9, 32, and 4 among humans, chimpanzees, and macaque monkeys. Area 9 of the dorsolateral prefrontal cortex is involved in inductive reasoning and specific components of working memory processes, while area 32 of the medial prefrontal cortex has been implicated in theory of mind. Area 4 (primary motor cortex) was also evaluated because it is not directly associated with higher cognitive functions. The findings revealed no quantitative species differences in the three cortical areas examined, indicating that human cognitive specializations are not related to a quantitative increase in cortical cholinergic input. However, species-specific morphological specializations were observed. Clusters of cholinergic fibers that may be indicative of cortical plasticity events were present in chimpanzees and humans, but not in macaques. The other significant morphology noted was the common and distinctive oval or ovoid perisomatic staining in macaque cortices. This feature was also sporadically observed in chimpanzee cortex. Our findings suggest a potential alteration of cortical cholinergic afferents within the prefrontal cortex of humans and chimpanzees, to the exclusion of macaque monkeys.     

Functional connectivity between cortical hand motor and language areas during recovery from aphasia

Previous data indicate that in healthy subjects, there is a connectivity between cortical areas for hand movement and language on the left hemisphere. This link is possibly mediated by the so-called mirror neuron system. The present study investigated the functional relationship between linguistic and hand movement processing in patients who were recovering from post-stroke aphasia. The excitability of the right- and left-hand motor cortex during language production in patients who were recovering from post-stroke aphasia and age-matched controls was investigated. As control, phonation was investigated. Hand motor cortex excitability was assessed with Motor Evoked Potentials which were elicited by Transcranial Magnetic Stimulation (TMS). In patients, reading aloud enhanced the excitability of the right hemispheric hand motor cortex, whereas phonation had no effect on hand motor cortex excitability. In the control group, an increased excitability of the left hemispheric hand motor system was found during reading aloud in accordance with previous data. The present data suggest a functional connectivity between regions mediating hand movements and reading. This may indicate that the right hemisphere participates in language processing as far as involved in single word reading in patients recovering from aphasia. The coactivation between cerebral representations of hand movements and language may be used therapeutically for aphasia rehabilitation.     

Functional imaging of visual semantic processing in the human brain

Previous neuroimaging studies have identified a large network of cortical areas involved in semantic processing in the human brain, which includes left occipito-temporal and inferofrontal areas. Most studies, however, investigated exclusively the associative/functional semantic knowledge by using mainly words and/or language related tasks, and this factor may have contributed to the large left hemisphere superiority found in semantic processing and to the controversial involvement of left prefrontal structures. The present study investigates the neural basis of visual objects knowledge, accessed exclusively through pictorial information. Regional cerebral blood flow (rCBF) was assessed using positron emission tomography (PET) during 3 conditions in right-handed normal volunteers: resting with eyes closed, retrieval of semantic information related to visual properties of objects (real size), and visual categorization based on physical properties of the image. Confirming previous experiments and neuropsychological findings, most activations were found in left occipito-temporal areas during retrieval of visual semantic knowledge. The absence of any activation in the left prefrontal inferior cortex for visual semantic processing confirms recent observations which suggest that this region would not be involved in retrieval of visual semantic knowledge from living entities. Rather, such knowledge about visual properties of objects, situated closely to cortical regions mediating perception of the visual attributes, can be retrieved directly from these regions when visual images are used as entry level stimuli.     

Spared somatomotor and cognitive functions in a patient with a large porencephalic cyst revealed by fMRI

To date functional magnetic resonance imaging (fMRI) has not been extensively used in presurgical evaluation of patients with intractable epilepsy. Patient S.P. presented with left frontal originating seizures, secondary to a large porencephalic cyst that encompassed much of his occipital and temporal cortex and a substantial portion of ipsilateral parietal cortex. Nevertheless, S.P. did not demonstrate any gross impairments of praxis or speech. Scalp electroencephalogram (EEG) telemetry revealed reduced background activity in the left hemisphere, an absence of identifiable normal sleep states, and confirmed the left frontal origin of his seizures with a prolonged postictal state, suggesting that the remaining cortex in S.P.'s left hemisphere did not function normally despite his apparently normal appearance. Dichotic listening results also suggested that S.P. had an atypical language representation suggestive of either bilateral or right hemisphere speech representation. Surgical intervention to remove the remaining left hemisphere cortex was a serious consideration for treatment of S.P.'s seizures. We used fMRI to evaluate whether or not the remaining cortex in S.P.'s left hemisphere supported any cognitive or motor functions. Even though the volume of cerebral cortex was severely reduced and displaced in the left hemisphere, fMRI revealed significant activation in this remaining tissue in response to motor, somatosensory, and word generation tasks. In other words, we were able to demonstrate using fMRI that the remaining tissue in S.P.'s left hemisphere continued to support some motor and cognitive functions. The possible implications of these findings in terms of functional reorganisation are discussed briefly.     

Dynamics of event-related causality in brain electrical activity

A new method (Event-Related Causality, ERC) is proposed for the investigation of functional interactions between brain regions during cognitive processing. ERC estimates the direction, intensity, spectral content, and temporal course of brain activity propagation within a cortical network. ERC is based upon the short-time directed transfer function (SDTF), which is measured in short EEG epochs during multiple trials of a cognitive task, as well as the direct directed transfer function (dDTF), which distinguishes direct interactions between brain regions from indirect interactions via brain regions. ERC uses new statistical methods for comparing estimates of causal interactions during prestimulus "baseline" epochs and during poststimulus "activated" epochs in order to estimate event-related increases and decreases in the functional interactions between cortical network components during cognitive tasks. The utility of the ERC approach is demonstrated through its application to human electrocorticographic recordings (ECoG) of a simple language task. ERC analyses of these ECoG recordings reveal frequency-dependent interactions, particularly in high gamma (>60 Hz) frequencies, between brain regions known to participate in the recorded language task, and the temporal evolution of these interactions is consistent with the putative processing stages of this task. The method may be a useful tool for investigating the dynamics of causal interactions between various brain regions during cognitive task performance.     

Role of the inferior frontal cortex in coping with distracting emotions

The role of inferior frontal cortex in coping with emotional distracters presented concurrently with a working memory task was investigated using event-related functional magnetic resonance imaging. The study yielded two main findings: (i) processing of emotional distracters was associated with enhanced functional coupling between the amygdala and the inferior frontal cortex and (ii) the inferior frontal cortex showed a left-lateralized activation pattern discriminating successful from unsuccessful trials in the presence of emotional distraction. These findings provide evidence that coping with emotional distraction entails interactions between brain regions responsible for detection and inhibition of emotional distraction, and identified a hemispheric specialization in the inferior frontal cortex in controlling the impact of distracting emotions on cognitive performance (left hemisphere) vs. controlling the subjective feeling of being distracted (right hemisphere).