An Essential Role of the Intraparietal Sulcus in Response Inhibition Predicted by Parcellation-Based Network.

The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30-0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions.SIGNIFICANCE STATEMENT Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI ("parcellation-based network analysis"), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions.

Activation changes of the left inferior frontal gyrus for the factors of construction and scrambling in a sentence.

Our previous functional magnetic resonance imaging (fMRI) studies have indicated that the left dorsal inferior frontal gyrus (L. dF3op/F3t) and left lateral premotor cortex (L. LPMC) are crucial regions for syntactic processing among the syntax-related networks. In the present study, we further examined how activations in these regions were modified by the factors of construction and scrambling (object-initial type). Using various sentence types, we clarified three major points. First, we found that the main effects of construction and scrambling consistently activated the L. dF3op/F3t and L. LPMC. Secondly, the main effects of scrambling clearly localized activation in the L. dF3op/F3t and L. LPMC, indicating the more narrowed down processing of syntax. Thirdly, step-wise percent signal changes were observed in the L. dF3op/F3t, demonstrating synergistic effects of construction and scrambling. These results demonstrate the abstract and intensive nature of syntactic processing carried out by these regions, i.e., the grammar center.

Differential reorganization of three syntax-related networks induced by a left frontal glioma.

The opercular/triangular parts of the left inferior frontal gyrus and the left lateral premotor cortex are critical in syntactic processing. We have recently indicated that a glioma in one of these regions is sufficient to cause agrammatic comprehension. In the present study, we aimed to show how normally existing syntax-related networks are functionally reorganized by a lesion. Twenty-one patients with a left frontal glioma preoperatively performed a picture-sentence matching task, and underwent functional magnetic resonance imaging scans in an event-related design. We established two qualitatively different types of agrammatic comprehension, depending on glioma location. Patients with a glioma in the left lateral premotor cortex had a more profound deficit in the comprehension of scrambled sentences than that of active and passive sentences. In contrast, patients with a glioma in the opercular/triangular parts of the left inferior frontal gyrus had a more profound deficit in the comprehension of passive and scrambled sentences than that of active sentences. Moreover, we found dramatic changes in the activation patterns in these two patient groups, which accompanied abnormal overactivity and/or underactivity in the syntax-related regions. Furthermore, by examining functional connectivity in the normal brain, we identified three syntax-related networks among those regions, and anatomically visualized connections within individual networks by using diffusion tensor imaging. The first network consists of the opercular/triangular parts of the left inferior frontal gyrus, left intraparietal sulcus, right frontal regions, presupplementary motor area, and right temporal regions. These regions were overactivated in the patients with a glioma in the left lateral premotor cortex only for correct responses, indicating a cognitive change. The second network consists of the left lateral premotor cortex, left angular gyrus, lingual gyrus, and cerebellar nuclei. These regions were overactivated in the patients with a glioma in the opercular/triangular parts of the left inferior frontal gyrus for both correct and incorrect responses, indicating a neuronal change. The third network consists of the left ventral frontal and posterior temporal regions. These regions were underactivated in the patients with a glioma in the opercular/triangular parts of the left inferior frontal gyrus, indicating another neuronal change. These results demonstrate that agrammatic comprehension is associated with the global reorganization of functionally distinct networks, which indeed reflects a differential change in the relative contribution of these three networks to normal syntax-related functions.

Merge-Generability as the Key Concept of Human Language: Evidence From Neuroscience.

Ever since the inception of generative linguistics, various dependency patterns have been widely discussed in the literature, particularly as they pertain to the hierarchy based on "weak generation" - the so-called Chomsky Hierarchy. However, humans can make any possible dependency patterns by using artificial means on a sequence of symbols (e.g., computer programing). The differences between sentences in human language and general symbol sequences have been routinely observed, but the question as to why such differences exist has barely been raised. Here, we address this problem and propose a theoretical explanation in terms of a new concept of "Merge-generability," that is, whether the structural basis for a given dependency is provided by the fundamental operation Merge. In our functional magnetic resonance imaging (fMRI) study, we tested the judgments of noun phrase (NP)-predicate (Pred) pairings in sentences of Japanese, an SOV language that allows natural, unbounded nesting configurations. We further introduced two pseudo-adverbs, which artificially force dependencies that do not conform to structures generated by Merge, i.e., non-Merge-generable; these adverbs enable us to manipulate Merge-generability (Natural or Artificial). By employing this novel paradigm, we obtained the following results. Firstly, the behavioral data clearly showed that an NP-Pred matching task became more demanding under the Artificial conditions than under the Natural conditions, reflecting cognitive loads that could be covaried with the increased number of words. Secondly, localized activation in the left frontal cortex, as well as in the left middle temporal gyrus and angular gyrus, was observed for the [Natural - Artificial] contrast, indicating specialization of these left regions in syntactic processing. Any activation due to task difficulty was completely excluded from activations in these regions, because the Natural conditions were always easier than the Artificial ones. And finally, the [Artificial - Natural] contrast resulted in the dorsal portion of the left frontal cortex, together with wide-spread regions required for general cognitive demands. These results indicate that Merge-generable sentences are processed in these specific regions in contrast to non-Merge-generable sentences, demonstrating that Merge is indeed a fundamental operation, which comes into play especially under the Natural conditions.

Dissociating Effects of Scrambling and Topicalization within the Left Frontal and Temporal Language Areas: An fMRI Study in Kaqchikel Maya.

Some natural languages grammatically allow different types of changing word orders, such as object scrambling and topicalization. Scrambling and topicalization are more related to syntax and semantics/phonology, respectively. Here we hypothesized that scrambling should activate the left frontal regions, while topicalization would affect the bilateral temporal regions. To examine such distinct effects in our functional magnetic resonance imaging study, we targeted the Kaqchikel Maya language, a Mayan language spoken in Guatemala. In Kaqchikel, the syntactically canonical word order is verb-object-subject (VOS), but at least three non-canonical word orders (i.e., SVO, VSO, and OVS) are also grammatically allowed. We used a sentence-picture matching task, in which the participants listened to a short Kaqchikel sentence and judged whether a picture matched the meaning of the sentence. The advantage of applying this experimental paradigm to an understudied language such as Kaqchikel is that it will allow us to validate the universality of linguistic computation in the brain. We found that the conditions with scrambled sentences [+scrambling] elicited significant activation in the left inferior frontal gyrus and lateral premotor cortex, both of which have been proposed as grammar centers, indicating the effects of syntactic loads. In contrast, the conditions without topicalization [-topicalization] resulted in significant activation in bilateral Heschl's gyrus and superior temporal gyrus, demonstrating that the syntactic and phonological processes were clearly dissociated within the language areas. Moreover, the pre-supplementary motor area and left superior/middle temporal gyri were activated under relatively demanding conditions, suggesting their supportive roles in syntactic or semantic processing. To exclude any semantic/phonological effects of the object-subject word orders, we performed direct comparisons while making the factor of topicalization constant, and observed localized activations in the left inferior frontal gyrus and lateral premotor cortex. These results establish that the types of scrambling and topicalization have different impacts on the specified language areas. These findings further indicate that the functional roles of these left frontal and temporal regions involve linguistic aspects themselves, namely syntax versus semantics/phonology, rather than output/input aspects of speech processing.

Left frontal glioma induces functional connectivity changes in syntax-related networks.

BACKGROUND: A glioma leads to a global loss of functional connectivity among multiple regions. However, the relationships between performance/activation changes and functional connectivity remain unclear. Our previous studies (Brain 137:1193-1212; Brain Lang 110:71-80) have shown that a glioma in the left lateral premotor cortex or the opercular/triangular parts of the left inferior frontal gyrus causes agrammatic comprehension accompanied by abnormal activations in 14 syntax-related regions. We have also confirmed that a glioma in the other left frontal regions does not affect task performances and activation patterns. RESULTS: By a partial correlation method for the time-series functional magnetic resonance imaging data, we analyzed the functional connectivity in 21 patients with a left frontal glioma. We observed that almost all of the functional connectivity exhibited chaotic changes in the agrammatic patients. In contrast, some functional connectivity was preserved in an orderly manner in the patients who showed normal performances and activation patterns. More specifically, these latter patients showed normal connectivity between the left fronto-parietal regions, as well as normal connectivity between the left triangular and orbital parts of the left inferior frontal gyrus. CONCLUSIONS: Our results indicate that these pathways are most crucial among the syntax-related networks. Both data from the activation patterns and functional connectivity, which are different in temporal domains, should thus be combined to assess any behavioral deficits associated with brain abnormalities.

Identification and characterization of a multispecific monoclonal antibody G2 against chicken prion protein.

We previously generated a monoclonal antibody (mAb), G2, by immunizing mice with Residues 174-247 of the chicken prion protein (ChPrP(C) ). In this study, we found that G2 possessed an extremely unusual characteristic for a mAb; in particular, it could react with at least three proteins other than ChPrP(C) , the original antigenic protein. We immunoscreened a complementary DNA library from chicken brain DNA and found three proteins (SEPT3, ATP6V1C1, and C6H10orf76) that reacts with G2. There were no regions of amino acid sequence similarity between ChPrP(C) and SEPT3, ATP6V1C1, or C6H10orf76. We selected ATP6V1C1 as a representative of the three proteins and identified the epitope within ATP6V1C1 that reacts with G2. The amino acid sequence of the G2 epitope within ATP6V1C1 (Pep8) was not related to the G2 epitope within ChPrP(C) (Pep18mer). However, enzyme-linked immunosorbent assay, surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments indicated that these two peptides have similar binding affinity for G2. The apparent KD values of Pep18mer and Pep8 obtained from SPR experiments were 2.9 × 10(-8) and 1.6 × 10(-8) M, respectively. Antibody inhibition test using each peptide indicated that the binding sites of the two different peptides overlapped each other. We observed that these two peptides substantially differed in several binding characteristics. Based on the SPR experiments, the association and dissociation rate constants of Pep18mer were higher than those of Pep8. A clear difference was also observed in ITC experiments. These differences may be explained by G2 adopting different binding conformations and undergoing different binding pathways.

Syntactic computation in the human brain: the degree of merger as a key factor.

Our goal of this study is to characterize the functions of language areas in most precise terms. Previous neuroimaging studies have reported that more complex sentences elicit larger activations in the left inferior frontal gyrus (L. F3op/F3t), although the most critical factor still remains to be identified. We hypothesize that pseudowords with grammatical particles and morphosyntactic information alone impose a construction of syntactic structures, just like normal sentences, and that "the Degree of Merger" (DoM) in recursively merged sentences parametrically modulates neural activations. Using jabberwocky sentences with distinct constructions, we fitted various parametric models of syntactic, other linguistic, and nonlinguistic factors to activations measured with functional magnetic resonance imaging. We demonstrated that the models of DoM and "DoM+number of Search (searching syntactic features)" were the best to explain activations in the L. F3op/F3t and supramarginal gyrus (L. SMG), respectively. We further introduced letter strings, which had neither lexical associations nor grammatical particles, but retained both matching orders and symbol orders of sentences. By directly contrasting jabberwocky sentences with letter strings, localized activations in L. F3op/F3t and L. SMG were indeed independent of matching orders and symbol orders. Moreover, by using dynamic causal modeling, we found that the model with a inhibitory modulatory effect for the bottom-up connectivity from L. SMG to L. F3op/F3t was the best one. For this best model, the top-down connection from L. F3op/F3t to L. SMG was significantly positive. By using diffusion-tensor imaging, we confirmed that the left dorsal pathway of the superior longitudinal and arcuate fasciculi consistently connected these regions. Lastly, we established that nonlinguistic order-related and error-related factors significantly activated the right (R.) lateral premotor cortex and R. F3op/F3t, respectively. These results indicate that the identified network of L. F3op/F3t and L. SMG subserves the calculation of DoM in recursively merged sentences.

Computational principles of syntax in the regions specialized for language: integrating theoretical linguistics and functional neuroimaging.

The nature of computational principles of syntax remains to be elucidated. One promising approach to this problem would be to construct formal and abstract linguistic models that parametrically predict the activation modulations in the regions specialized for linguistic processes. In this article, we review recent advances in theoretical linguistics and functional neuroimaging in the following respects. First, we introduce the two fundamental linguistic operations: Merge (which combines two words or phrases to form a larger structure) and Search (which searches and establishes a syntactic relation of two words or phrases). We also illustrate certain universal properties of human language, and present hypotheses regarding how sentence structures are processed in the brain. Hypothesis I is that the Degree of Merger (DoM), i.e., the maximum depth of merged subtrees within a given domain, is a key computational concept to properly measure the complexity of tree structures. Hypothesis II is that the basic frame of the syntactic structure of a given linguistic expression is determined essentially by functional elements, which trigger Merge and Search. We then present our recent functional magnetic resonance imaging experiment, demonstrating that the DoM is indeed a key syntactic factor that accounts for syntax-selective activations in the left inferior frontal gyrus and supramarginal gyrus. Hypothesis III is that the DoM domain changes dynamically in accordance with iterative Merge applications, the Search distances, and/or task requirements. We confirm that the DoM accounts for activations in various sentence types. Hypothesis III successfully explains activation differences between object- and subject-relative clauses, as well as activations during explicit syntactic judgment tasks. A future research on the computational principles of syntax will further deepen our understanding of uniquely human mental faculties.