Abnormal connectivity and activation during audiovisual speech perception in schizophrenia.

The unconscious integration of vocal and facial cues during speech perception facilitates face-to-face communication. Recent studies have provided substantial behavioural evidence concerning impairments in audiovisual (AV) speech perception in schizophrenia. However, the specific neurophysiological mechanism underlying these deficits remains unknown. Here, we investigated activities and connectivities centered on the auditory cortex during AV speech perception in schizophrenia. Using magnetoencephalography, we recorded and analysed event-related fields in response to auditory (A: voice), visual (V: face) and AV (voice-face) stimuli in 23 schizophrenia patients (13 males) and 22 healthy controls (13 males). The functional connectivity associated with the subadditive response to AV stimulus (i.e., [AV] < [A] + [V]) was also compared between the two groups. Within the healthy control group, [AV] activity was smaller than the sum of [A] and [V] at latencies of approximately 100 ms in the posterior ramus of the lateral sulcus in only the left hemisphere, demonstrating a subadditive N1m effect. Conversely, the schizophrenia group did not show such a subadditive response. Furthermore, weaker functional connectivity from the posterior ramus of the lateral sulcus of the left hemisphere to the fusiform gyrus of the right hemisphere was observed in schizophrenia. Notably, this weakened connectivity was associated with the severity of negative symptoms. These results demonstrate abnormalities in connectivity between speech- and face-related cortical areas in schizophrenia. This aberrant subadditive response and connectivity deficits for integrating speech and facial information may be the neural basis of social communication dysfunctions in schizophrenia.

Aberrant thalamocortical connectivity and shifts between the resting state and task state in patients with schizophrenia.

Prominent pathological hypotheses for schizophrenia include auditory processing deficits and dysconnectivity within cerebral networks. However, most neuroimaging studies have focused on impairments in either resting-state or task-related functional connectivity in patients with schizophrenia. The aims of our study were to examine (1) blood oxygen level-dependent (BOLD) signals during auditory steady-state response (ASSR) tasks, (2) functional connectivity during the resting-state and ASSR tasks and (3) state shifts between the resting-state and ASSR tasks in patients with schizophrenia. To reduce the functional consequences of scanner noise, we employed resting-state and sparse sampling auditory fMRI paradigms in 25 schizophrenia patients and 25 healthy controls. Auditory stimuli were binaural click trains at frequencies of 20, 30, 40 and 80 Hz. Based on the detected ASSR-evoked BOLD signals, we examined the functional connectivity between the thalamus and bilateral auditory cortex during both the resting state and ASSR task state, as well as their alterations. The schizophrenia group exhibited significantly diminished BOLD signals in the bilateral auditory cortex and thalamus during the 80 Hz ASSR task (corrected p < 0.05). We observed a significant inverse relationship between the resting state and ASSR task state in altered functional connectivity within the thalamo-auditory network in schizophrenia patients. Specifically, our findings demonstrated stronger functional connectivity in the resting state (p < 0.004) and reduced functional connectivity during the ASSR task (p = 0.048), which was mediated by abnormal state shifts, within the schizophrenia group. These results highlight the presence of abnormal thalamocortical connectivity associated with deficits in the shift between resting and task states in patients with schizophrenia.

Scaffold-Hopped Compound Identification by Ligand-Based Approaches with a Prospective Affinity Test.

Scaffold-hopped (SH) compounds are bioactive compounds structurally different from known active compounds. Identifying SH compounds in the ligand-based approaches has been a central issue in medicinal chemistry, and various molecular representations of scaffold hopping have been proposed. However, appropriate representations for SH compound identification remain unclear. Herein, the ability of SH compound identification among several representations was fairly evaluated based on retrospective validation and prospective demonstration. In the retrospective validation, the combinations of two screening algorithms and four two- and three-dimensional molecular representations were compared using controlled data sets for the early identification of SH compounds. We found that the combination of the support vector machine and extended connectivity fingerprint with bond diameter 4 (SVM-ECFP4) and SVM and the rapid overlay of chemical structures (SVM-ROCS) showed a relatively high performance. The compounds that were highly ranked by SVM-ROCS did not share substructures with the active training compounds, while those ranked by SVM-ECFP4 were mostly recombinant. In the prospective demonstration, 93 SH compounds were prepared by screening the Namiki database using SVM-ROCS, targeting ABL1 inhibitors. The primary screening using surface plasmon resonance suggested five active compounds; however, in the competitive binding assays with adenosine triphosphate, no hits were found.

Cortical representation of speech temporal information through high gamma-band activity and its temporal modulation.

Numerous studies have investigated low-frequency (theta-band) and high-frequency (gamma-band) neural activities that are phase-locked to temporal structures, including the temporal envelope and fine structure (TFS) of speech signals. Nonetheless, the neural mechanisms underlying the interaction between envelope and TFS processing remain elusive. Here we examined high gamma-band activities and their low-frequency amplitude modulations while listening to monotone speech (MS) with a fundamental frequency (F0) of 80 Hz and non-speech sounds with similar temporal characteristics to MS, namely an amplitude-modulated click train (AMC). Additionally, we utilized noise-vocoded speech (NVS) to evaluate the impact of eliminating the TFS from MS on the high gamma-band activity. We observed discernible high gamma-band activity at the same frequency as F0 of MS and the train frequency of AMC (80 Hz). Furthermore, source localization analysis revealed that the high gamma-band activities exhibited left hemisphere dominance in both MS and AMC conditions. Finally, high gamma-band activities exhibited amplitude-modulation at the same rate as the stimulus envelope of MS and AMC (5 Hz), though such modulation was not observed in NVS. Our findings indicate that the high gamma-band activity in the left hemisphere is pivotal in the interaction of envelope and TFS information processing, regardless of the nature of the stimulus being speech or non-speech.

Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment-resistant and ultratreatment-resistant schizophrenia.

AIM: Validating the vulnerabilities and pathologies underlying treatment-resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS. METHODS: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first-line antipsychotics (FL-Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ-Resp) and 22 FL- and clozapine-resistant patients (patients with ultratreatment-resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis. RESULTS: Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [gH ] = 0.75; P = 0.013, gH  = 0.96) and FL-Resp (P = 0.007, gH  = 1.00; P = 0.002, gH  = 1.31) in the left medial parietal cortex (Lt-MPC). In addition, both CLZ-Resp and URS had lower SA in the Lt-MPC than FL-Resp (P < 0.001, gH  = 1.22; P < 0.001, gH  = 1.75). LGI and SA were positively correlated in non-TRS (FL-Resp) (ρ = 0.64, P = 0.008) and TRS (CLZ-Resp + URS) (ρ = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non-TRS versus TRS with LGI and SA in the Lt-MPC were 0.79 and 0.85, respectively. SA in the Lt-MPC was inversely correlated with negative symptoms (ρ = -0.40, P = 0.018) and clozapine plasma levels (ρ = -0.35, P = 0.042) in TRS. CONCLUSION: LGI and SA in the Lt-MPC, a functional hub in the default-mode network, were abnormally reduced in TRS compared with non-TRS. Thus, altered LGI and SA in the Lt-MPC might be structural features associated with genetic vulnerability to TRS.

Multi-modal imaging of the auditory-larynx motor network for voicing perception.

Voicing is one of the most important characteristics of phonetic speech sounds. Despite its importance, voicing perception mechanisms remain largely unknown. To explore auditory-motor networks associated with voicing perception, we firstly examined the brain regions that showed common activities for voicing production and perception using functional magnetic resonance imaging. Results indicated that the auditory and speech motor areas were activated with the operculum parietale 4 (OP4) during both voicing production and perception. Secondly, we used a magnetoencephalography and examined the dynamical functional connectivity of the auditory-motor networks during a perceptual categorization task of /da/-/ta/ continuum stimuli varying in voice onset time (VOT) from 0 to 40 ms in 10 ms steps. Significant functional connectivities from the auditory cortical regions to the larynx motor area via OP4 were observed only when perceiving the stimulus with VOT 30 ms. In addition, regional activity analysis showed that the neural representation of VOT in the auditory cortical regions was mostly correlated with categorical perception of voicing but did not reflect the perception of stimulus with VOT 30 ms. We suggest that the larynx motor area, which is considered to play a crucial role in voicing production, contributes to categorical perception of voicing by complementing the temporal processing in the auditory cortical regions.

The clinical benefits of performing staging laparoscopy for pancreatic cancer treatment.

BACKGROUND: The indications and benefits derived from staging laparoscopy (SL) for pancreatic cancer (PC) remain controversial. METHODS: This study involved PC patients in whom resection had been considered possible between 2009 and 2020. We classified the patients into before 2014 (training set) and 2014 and later (validation set) groups, as SL was introduced in 2014, in our institution. In the training set, the predictors of non-curative factors were investigated, and reproducibility was confirmed in the validation set. In addition, the outcomes were compared between the datasets. RESULTS: A total of 802 patients were classified into the training set (n = 241) and validation set (n = 561). In the training set, pancreatic body or tail tumors (odds ratio [OR]: 2.62: P = 0.039), CA19-9 > 88 U/ml (OR: 3.21: P = 0.018) and a tumor diameter >36 mm (OR: 6.07; P < 0.001) were independent predictors of non-curative factors. The increased rate of non-curative factors was confirmed as the number of predictors increased in the validation set. The curative resection (CR) rate was significantly higher in the validation set than in the training set (P = 0.035). Although there was no significant difference in the OS in the not-resected group (P = 0.895), the OS in the CR and non-CR group was significantly better in the validation set than in the training set (CR, P < 0.001; non-CR, P < 0.001). CONCLUSION: The findings suggest potential candidates for SL and revealed improved outcomes by the advent of treatment strategies including SL.

Ligand-based approaches to activity prediction for the early stage of structure-activity-relationship progression.

The retrospective evaluation of virtual screening approaches and activity prediction models are important for methodological development. However, for fair comparison, evaluation data sets must be carefully prepared. In this research, we compiled structure-activity-relationship matrix-based data sets for 15 biological targets along with many diverse inactive compounds, assuming the early stage of structure-activity-relationship progression. To use a large number of diverse inactive compounds and a limited number of active compounds, similarity profiles (SPs) are proposed as a set of molecular descriptors. Using these highly imbalanced data sets, we evaluated various approaches including SPs, under-sampling, support vector machine (SVM), and message passing neural networks. We found that for the under-sampling approaches, cluster-based sampling is better than random sampling. For virtual screening, SPs with inactive reference compounds and the under-sampling SVM also perform well. For classification, SPs with many inactive references performed as well as the under-sampling SVM trained on a balanced data set. Although the performance of SPs and the under-sampling SVM were comparable, SPs with many inactive references were preferable for selecting structurally distinct compounds from the active training compounds.

Interpretation of Ligand-Based Activity Cliff Prediction Models Using the Matched Molecular Pair Kernel.

Activity cliffs (ACs) are formed by two structurally similar compounds with a large difference in potency. Accurate AC prediction is expected to help researchers' decisions in the early stages of drug discovery. Previously, predictive models based on matched molecular pair (MMP) cliffs have been proposed. However, the proposed methods face a challenge of interpretability due to the black-box character of the predictive models. In this study, we developed interpretable MMP fingerprints and modified a model-specific interpretation approach for models based on a support vector machine (SVM) and MMP kernel. We compared important features highlighted by this SVM-based interpretation approach and the SHapley Additive exPlanations (SHAP) as a major model-independent approach. The model-specific approach could capture the difference between AC and non-AC, while SHAP assigned high weights to the features not present in the test instances. For specific MMPs, the feature weights mapped by the SVM-based interpretation method were in agreement with the previously confirmed binding knowledge from X-ray co-crystal structures, indicating that this method is able to interpret the AC prediction model in a chemically intuitive manner.

The evaluation of the 8th and 7th edition of the American joint committee on cancer tumor classification for distal cholangiocarcinoma: the proposal of a modified new tumor classification.

BACKGROUND: The 7th and 8th editions of the American Joint Committee on Cancer (AJCC) tumor (T) classification of distal cholangiocarcinoma (DCC), which are based on either layer or depth, may not accurately stratify patient survival. METHODS: A total of 121 patients who underwent resection for DCC between 2002 and 2016 were analyzed. The impact of the AJCC staging system on survival was examined and a new T classification was established based on independent prognostic factors. RESULTS: Regarding overall survival, the optimal depth of invasion (DOI) cut-off value (8 mm) was the only independent prognostic factor. Regarding the relapse-free survival (RFS), a DOI >8 mm, portal vein (PV) invasion, and duodenal or pancreatic invasion were independent prognostic factors. A new T classification was developed as follows: T1, no invasion of adjacent organs; T2, invasion of the duodenum or pancreas; T3, invasion >8 mm into the bile duct wall; and T4, invasion of the PV or arteries. There were no significant differences in RFS according to the 8th edition of the AJCC. However, significant differences were observed in the RFS between T1 and T2 and between T2 and T3. CONCLUSION: A new T classification based on the layer and depth may be more feasible.

A comparison of the outcomes between surgical resection and proton beam therapy for single primary hepatocellular carcinoma.

PURPOSE: There are many treatment choices for hepatocellular carcinoma (HCC), one of which is proton beam therapy (PBT). The purpose of this study was to compare surgical resection (SR) and PBT to clarify the prognostic factors for operable HCC based on a single institution's database. METHODS: Patients with single primary nodular HCC ≤ 100 mm without vessel invasion on pretreatment imaging were divided into the SR group and PBT group. In the PBT group, the patients with unresectable HCC due to their liver function and/or performance status were excluded. RESULTS: There were 314 and 31 patients who underwent SR and PBT, respectively. The median survival time in the SR group was significantly better than in the PBT group (104.1 vs. 64.6 months, p = 0.008). Regarding the relapse-free survival (RFS), there was no significant difference between the SR and PBT groups (33.8 vs. 14.0 months, p = 0.099). CONCLUSION: The RFS was comparable between the PBT and SR groups. However, the PBT group had a significantly worse overall survival than the SR group. SR may therefore be favorable as an initial treatment for HCC compared to PBT.

Development of R-Group Fingerprints Based on the Local Landscape from an Attachment Point of a Molecular Structure.

Molecular fingerprints are indispensable in medicinal chemistry for quantifying chemical structures. Fingerprints can be calculated for substructures with attachment points, which are positions where a substructure and a corresponding core structure connect. Because structures with attachment points can be crucial for understanding structure-activity relationships, fingerprints specialized for representing this structural feature are required. R-group fingerprints and R-group descriptors were proposed previously for this purpose; however, these molecular representations have limitations. Current R-group fingerprints do not emphasize information about attachment points, and R-group descriptors are too sensitive to changes in the topological path length from an attachment point. In the present work, we developed novel R-group fingerprints, termed R-path fingerprints, which contain substituent information from an attachment point without being sensitive to small differences in topological distances. The concept of the R-path fingerprints is to describe a chemical substructure from the viewpoint of an attachment point, to distinguish atomistic information around the attachment point and other parts of the substructure. This was achieved by considering all the paths on the shortest path between the attachment point and each atom in a substituent. Benchmark testing was conducted, including comparisons of similarity distributions and potency prediction for R-group substituents. The results showed that R-path fingerprints should be useful for classifying and comparing substructures with attachment points.

Precision of voicing perceptual identification is altered in association with voice-onset time production changes.

There is ample evidence that motor learning changes the function of perceptual systems. Previous studies examining the interactions between speech production and perception have shown that the discrimination of phonetic contrasts characterized by the difference in articulatory place features is altered following their production changes caused by the perturbation of auditory feedback. The present study focused on a voiced-voiceless contrast in stop consonants, which is characterized by a temporal articulatory parameter, voice-onset time (VOT). In the experiment, we manipulated the participants' motor functions concerning VOT using a cross-categorical auditory feedback (CAF) paradigm (Mitsuya et al. in J Acoust Soc Am 135:2986-2994, 2014), in which a pre-recorded syllable sound starting with a voiced stop consonant (/da/) was fed back simultaneously with the participant's utterance of a voiceless stop consonant (/ta/), and vice versa. The VOT difference between /da/ and /ta/ productions was increased by the CAF, which is consistent with the result of Mitsuya's study. In addition, we conducted perceptual identification tasks of /da/-/ta/ continuum stimuli varying in VOT before and after the CAF task, and found that the identification function became sharper after as compared to before the CAF task. A significant positive correlation between such production and perception changes was also found. On the basis of these results, we consider that the change in motor function concerning VOT affected voiced-voiceless perceptual processing. The present study is the first to show the involvement of the speech production system in the perception of phonetic contrasts characterized by articulatory temporal features.

Biochemical characterization of rhamnosyltransferase involved in biosynthesis of pectic rhamnogalacturonan I in plant cell wall.

The pectin in plant cell walls consists of three domains: homogalacturonan, rhamnogalacturonan (RG)-I, and RG-II. It is predicted that around 50 different glycosyltransferases are required for their biosynthesis. Among these, the activities of only a few glycosyltransferases have been detected because pectic oligosaccharides are not readily available for use as substrates. In this study, fluorogenic pyridylaminated RG-I-backbone oligosaccharides (PA-RGs) with 3-14 degrees of polymerization (DP) were prepared. Using these oligosaccharides, the activity of RG-I:rhamnosyltransferase (RRT), involved in the biosynthesis of the RG-I backbone diglycosyl repeating units (-4GalUAα1-2Rhaα1-), was detected from the microsomes of azuki bean epicotyls. RRT was found to prefer longer acceptor substrates, PA-RGs with a DP > 7, and it does not require any metal ions for its activity. RRT is located in the Golgi and endoplasmic reticulum. The activity of RRT coincided with epicotyl growth, suggesting that RG-I biosynthesis is involved in plant growth.

[A Case of Poorly Differentiated Adenocarcinoma of the Colon with Rapid Postoperative Progression Suggestive of Peritoneal Dissemination].

A 62-year-old man was admitted to our hospital because of pain in the right lower abdomen and was diagnosed with cecal cancer and an associated abscess. The patient subsequently underwent right hemicolectomy. Histopathological examination was positive for por1, se, bd3, ly3, v0, PM0, and DM0. He was discharged from the hospital 21 days postoperatively. He was hospitalized with bloating of the right lower abdomen and inflammation 31 days postoperatively. He was later diagnosed with recurrence of the initial abscess, but his symptoms did not improve, and he was considered to have peritoneal dissemination. His general condition deteriorated rapidly, and he died approximately 1.5 months postoperatively. Histopathological and anatomical examination later confirmed multiple organ failure with peritoneal dissemination. It is reported that prognosis of poorly differentiated adenocarcinoma is worse than that for well- or moderately differentiated adenocarcinoma. Poorly differentiated adenocarcinoma may recur immediately after curative surgery.

Large-scale prediction of activity cliffs using machine and deep learning methods of increasing complexity.

Activity cliffs (AC) are formed by pairs of structural analogues that are active against the same target but have a large difference in potency. While much of our knowledge about ACs has originated from the analysis and comparison of compounds and activity data, several studies have reported AC predictions over the past decade. Different from typical compound classification tasks, AC predictions must be carried out at the level of compound pairs representing ACs or nonACs. Most AC predictions reported so far have focused on individual methods or comparisons of two or three approaches and only investigated a few compound activity classes (from 2 to 10). Although promising prediction accuracy has been reported in most cases, different system set-ups, AC definitions, methods, and calculation conditions were used, precluding direct comparisons of these studies. Therefore, we have carried out a large-scale AC prediction campaign across 100 activity classes comparing machine learning methods of greatly varying complexity, ranging from pair-based nearest neighbor classifiers and decision tree or kernel methods to deep neural networks. The results of our systematic predictions revealed the level of accuracy that can be expected for AC predictions across many different compound classes. In addition, prediction accuracy did not scale with methodological complexity but was significantly influenced by memorization of compounds shared by different ACs or nonACs. In many instances, limited training data were sufficient for building accurate models using different methods and there was no detectable advantage of deep learning over simpler approaches for AC prediction. On a global scale, support vector machine models performed best, by only small margins compared to others including simple nearest neighbor classifiers.

Abnormal phase entrainment of low- and high-gamma-band auditory steady-state responses in schizophrenia.

Introduction: Gamma-band oscillatory deficits have attracted considerable attention as promising biomarkers of schizophrenia (SZ). Notably, a reduced auditory steady-state response (ASSR) in the low gamma band (40 Hz) is widely recognized as a robust finding among SZ patients. However, a comprehensive investigation into the potential utility of the high-gamma-band ASSR in detecting altered neural oscillations in SZ has not yet been conducted. Methods: The present study aimed to assess the ASSR using magnetoencephalography (MEG) data obtained during steady-state stimuli at frequencies of 20, 30, 40, and 80 Hz from 23 SZ patients and 21 healthy controls (HCs). To evaluate the ASSR, we examined the evoked power and phase-locking factor (PLF) in the time-frequency domain for both the primary and secondary auditory cortices. Furthermore, we calculated the phase-locking angle (PLA) to examine oscillatory phase lead or delay in SZ patients. Taking advantage of the high spatial resolution of MEG, we also focused on the hemispheric laterality of low- and high-gamma-band ASSR deficits in SZ. Results: We found abnormal phase delay in the 40 Hz ASSR within the bilateral auditory cortex of SZ patients. Regarding the 80 Hz ASSR, our investigation identified an aberrant phase lead in the left secondary auditory cortex in SZ, accompanied by reduced evoked power in both auditory cortices. Discussion: Given that abnormal phase lead on 80 Hz ASSR exhibited the highest discriminative power between HC and SZ, we propose that the examination of PLA in the 80 Hz ASSR holds significant promise as a robust candidate for identifying neurophysiological endophenotypes associated with SZ. Furthermore, the left-hemisphere phase lead observed in the deficits of 80 Hz PLA aligns with numerous prior studies, which have consistently proposed that SZ is characterized by left-lateralized brain dysfunctions.

Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia.

BACKGROUND: Thirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. METHOD: We compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. RESULTS: A total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. CONCLUSION: These results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

Late responses in the anterior insula reflect the cognitive component of pain: evidence of nonpain processing.

INTRODUCTION: Pain is a complex experience influenced by sensory and psychological factors. The insula is considered to be a core part of the pain network in the brain. Previous studies have suggested a relationship between the posterior insula (PI) and sensory processing, and between the anterior insula (AI) and cognitive-affective factors. OBJECTIVES: Our aim was to distinguish sensory and cognitive responses in pain-related insular activities. METHODS: We recorded spatiotemporal insular activation patterns of healthy participants (n = 20) during pain or tactile processing with painful or nonpainful movie stimuli, using a magnetoencephalography. We compared the peak latency between PI and AI activities in each stimulus condition, and between pain and tactile processing in each response. The peak latency and amplitude between different movies were then examined to explore the effects of cognitive influence. A visual analogue scale was used to assess subjective perception. RESULTS: The results revealed one clear PI activity and 2 AI activities (early and late) in insular responses induced by pain/tactile stimulation. The early response transmitted from the PI to AI was observed during sensory-associated brain activity, whereas the late AI response was observed during cognitive-associated activity. In addition, we found that painful movie stimuli had a significant influence on both late AI activity and subjective perception, caused by nonpainful actual stimulation. CONCLUSIONS: The current findings suggested that late AI activation reflects the processing of cognitive pain information, whereas the PI and early AI responses reflect sensory processing.