Feedforward and feedback pathways of nociceptive and tactile processing in human somatosensory system: A study of dynamic causal modeling of fMRI data.

Nociceptive and tactile information is processed in the somatosensory system via reciprocal (i.e., feedforward and feedback) projections between the thalamus, the primary (S1) and secondary (S2) somatosensory cortices. The exact hierarchy of nociceptive and tactile information processing within this 'thalamus-S1-S2' network and whether the processing hierarchy differs between the two somatosensory submodalities remains unclear. In particular, two questions related to the ascending and descending pathways have not been addressed. For the ascending pathways, whether tactile or nociceptive information is processed in parallel (i.e., 'thalamus-S1' and 'thalamus-S2') or in serial (i.e., 'thalamus-S1-S2') remains controversial. For the descending pathways, how corticothalamic feedback regulates nociceptive and tactile processing also remains elusive. Here, we aimed to investigate the hierarchical organization for the processing of nociceptive and tactile information in the 'thalamus-S1-S2' network using dynamic causal modeling (DCM) combined with high-temporal-resolution fMRI. We found that, for both nociceptive and tactile information processing, both S1 and S2 received inputs from thalamus, indicating a parallel structure of ascending pathways for nociceptive and tactile information processing. Furthermore, we observed distinct corticothalamic feedback regulations from S1 and S2, showing that S1 generally exerts inhibitory feedback regulation independent of external stimulation whereas S2 provides additional inhibition to the thalamic activity during nociceptive and tactile information processing in humans. These findings revealed that nociceptive and tactile information processing have similar hierarchical organization within the somatosensory system in the human brain.

Disrupted pathways from limbic areas to thalamus in schizophrenia highlighted by whole-brain resting-state effective connectivity analysis.

BACKGROUND: Numerous neuroimaging studies have revealed that schizophrenia was characterized by wide-spread dysconnection among brain regions during rest measured by functional connectivity (FC). In contrast with FC, effective connectivity (EC) provides information about directionality of brain connections and is thus valuable in mechanistic investigation of schizophrenic brain. However, a systematic characterization of whole-brain resting-state EC (rsEC) and how it captures different information compared with resting-state FC (rsFC) in schizophrenia are still lacking. AIMS: To systematically characterize the abnormalities of rsEC, compared with rsFC, in schizophrenia, and to test its discriminative power as a neuroimaging marker for schizophrenia diagnosis. METHOD: Whole-brain rsEC and rsFC networks were constructed using resting-state fMRI data and compared between 103 patients with schizophrenia and 110 healthy participants. Pattern classifications between patients and controls based on whole-brain rsEC and rsFC were further performed using multivariate pattern analysis. RESULTS: We identified 17 rsEC significantly disrupted (mostly decreased) in patients, among which all were associated with the thalamus and 15 were from limbic areas (including hippocampus, parahippocampus and cingulate cortex) to the thalamus. In contrast, abnormal rsFC were widely distributed in the whole brain. The classification accuracies for distinguishing patients and controls using whole-brain rsEC and rsFC patterns were 78.6% and 82.7%, respectively, and was further improved to 84.5% when combining rsEC and rsFC. CONCLUSIONS: Schizophrenia is featured by disrupted 'limbic areas-to-thalamus' rsEC, in contrast with diffusively altered rsFC. Moreover, both rsEC and rsFC contain valuable and complementary information which may be used as diagnostic markers for schizophrenia.

Polyphosphoester-Based Nanocarrier for Combined Radio-Photothermal Therapy of Breast Cancer.

Recently, clinical research on tumor therapy has gradually shifted from traditional monotherapy toward combination therapy as tumors are complex, diverse, and heterogeneous. Combination therapy may be essential for achieving the optimized treatment efficacy of tumors through distinct tumor-inhibiting mechanisms. At the same time, nanocarriers are emerging as an excellent strategy for delivering both drugs simultaneously. This work presents utilization of a polyphosphoester-based nanocarrier (NPIR/Cur) to achieve the codelivery of hydrophobic photothermal agent IR-780 and radiosensitizer curcumin (Cur). The IR-780 and curcumin coencapsulated NPIR/Cur exhibited adequate drug loading, a prolonged blood half-life, enhanced passive tumor homing, and improved curcumin bioavailability as well as combined therapeutic functions. Briefly, NPIR/Cur could not only achieve effective thermal ablation through the conversion of near-infrared light to heat, but also give rise to a significant boosted local radiation dose to trigger promoted radiation damages, thus resulting in enhanced tumor cell growth inhibition. In conclusion, the as-prepared NPIR/Cur manifested excellent performance in facilitating combined photothermal and radiation therapy, thus expanding the application range of PPE-based carriers in nanomedicine, and also prompting exploration of their potential for other effective combination therapies.

Altered Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity in Schizophrenia.

Background: Respective changes in resting-state cerebral blood flow (CBF) and functional connectivity in schizophrenia have been reported. However, their coupling alterations in schizophrenia remain largely unknown. Methods: 89 schizophrenia patients and 90 sex- and age-matched healthy controls underwent resting-state functional MRI to calculate functional connectivity strength (FCS) and arterial spin labeling imaging to compute CBF. The CBF-FCS coupling of the whole gray matter and the CBF/FCS ratio (the amount of blood supply per unit of connectivity strength) of each voxel were compared between the 2 groups. Results: Whole gray matter CBF-FCS coupling was decreased in schizophrenia patients relative to healthy controls. In schizophrenia patients, the decreased CBF/FCS ratio was predominantly located in cognitive- and emotional-related brain regions, including the dorsolateral prefrontal cortex, insula, hippocampus and thalamus, whereas an increased CBF/FCS ratio was mainly identified in the sensorimotor regions, including the putamen, and sensorimotor, mid-cingulate and visual cortices. Conclusion: These findings suggest that the neurovascular decoupling in the brain may be a possible neuropathological mechanism of schizophrenia.

Cerebral blood flow alterations specific to auditory verbal hallucinations in schizophrenia.

BackgroundAuditory verbal hallucinations (AVHs) have been associated with deficits in auditory and speech-related networks. However, the resting-state cerebral blood flow (CBF) alterations specific to AVHs in schizophrenia remain unknown.AimsTo explore AVH-related CBF alterations in individuals with schizophrenia.MethodIn total, 35 individuals with schizophrenia with AVHs, 41 individuals with schizophrenia without AVHs and 50 controls underwent arterial spin labelling magnetic resonance imaging. The CBF differences were voxel-wise compared across the three groups.ResultsWe found AVH-specific CBF increase in the right superior temporal gyrus and caudate, and AVH-specific CBF decrease in the bilateral occipital and left parietal cortices. We also observed consistent CBF changes in both schizophrenia subgroups (i.e. those with and without AVHs) including decreased CBF in the bilateral occipital regions, the left lateral prefrontal and insular cortices, and the right anterior cingulate cortex and increased CBF in the bilateral lateral temporal regions and putamen, the left middle cingulate cortex and the right thalamus.ConclusionsThe AVH-specific CBF increases in the auditory and striatal areas and CBF reductions in the visual and parietal areas suggest that there exists a CBF redistribution associated with AVHs.

Green and facile synthesis of a theranostic nanoprobe with intrinsic biosafety and targeting abilities.

Traditional targeting nanoprobes suffer from the risks of partial loss of targeting activity and nanoparticle aggregation induced by post-synthetic modifications, ambiguous toxicity, tedious synthesis procedures and environmentally hazardous processes. Herein, we report a green and facile strategy to fabricate transferrin-indocyanine green nanoparticles as a smart theranostic agent with intrinsic biosafety and active targeting abilities for near-infrared fluorescent imaging and photothermal therapy of tumors. Simple mixing of transferrin and indocyanine green enables their self-assembly in aqueous solution to form nanoparticles with excellent water solubility, colloidal stability, favorable biocompatibility and impressive active targeting theranostic effects in vitro and in vivo. The transferrin-indocyanine green nanoparticles show great potential in theranostic applications of tumors in clinical therapy.

Biomineralization of Versatile CuS/Gd2 O3 Hybrid Nanoparticles for MR Imaging and Antitumor Photothermal Chemotherapy.

The versatile application of nanoparticles in integrating imaging and therapy has aroused extensive research interest in precision medicine. Of the various nanoparticles that have been studied, CuS has shown great potential in the construction of multifunctional agents, owing to its excellent photothermal heating properties. Herein, we report a facile one-pot biomineralization approach for the preparation of versatile bovine-serum-albumin-conjugated CuS/Gd2 O3 hybrid nanoparticles (BSA-CuS/Gd2 O3 HNPs), which simultaneously possessed strong longitudinal relaxivity, an outstanding photothermal effect, high drug-loading capacity, and pH/temperature-responsive drug release. The versatile nanoparticles were used for magnetic resonance imaging (MRI) and antitumor photothermal chemotherapy, both in vitro and in vivo. In vivo MRI showed that the BSA-CuS/Gd2 O3 HNPs had a long circulation time and effective passive tumor-uptake ability. More importantly, combined in vitro and in vivo therapy demonstrated that drug-loaded BSA-CuS/Gd2 O3 HNPs offered outstanding synergistic therapeutic efficacy for tumor inhibition.

BSA-directed synthesis of CuS nanoparticles as a biocompatible photothermal agent for tumor ablation in vivo.

Photothermal therapy as a physical therapeutic approach has greatly attracted research interest due to its negligible systemic effects. Among the various photothermal agents, CuS nanoparticles have been widely used due to their easy preparation, low cost, high stability and strong absorption in the NIR region. However, the ambiguous biotoxicity of CuS nanoparticles limited their bio-application. So it is highly desirable to develop biocompatible CuS photothermal agents with the potential of clinical translation. Herein, we report a novel method to synthesize biocompatible CuS nanoparticles for photothermal therapy using bovine serum albumin (BSA) as a template via mimicking biomaterialization processes. Owing to the inherent biocompatibility of BSA, the toxicity assays in vitro and in vivo showed that BSA-CuS nanoparticles possessed good biocompatibility. In vitro and in vivo photothermal therapies were performed and good results were obtained. The bulk of the HeLa cells treated with BSA-CuS nanoparticles under laser irradiation (808 nm) were killed, and the tumor tissues of mice were also successfully eliminated without causing any obvious systemic damage. In summary, a novel strategy for the synthesis of CuS nanoparticles was developed using BSA as the template, and the excellent biocompatibility and efficient photothermal therapy effects of BSA-CuS nanoparticles show great potential as an ideal photothermal agent for cancer treatment.

Cross-modal activation of auditory regions during visuo-spatial working memory in early deafness.

Early deafness can reshape deprived auditory regions to enable the processing of signals from the remaining intact sensory modalities. Cross-modal activation has been observed in auditory regions during non-auditory tasks in early deaf subjects. In hearing subjects, visual working memory can evoke activation of the visual cortex, which further contributes to behavioural performance. In early deaf subjects, however, whether and how auditory regions participate in visual working memory remains unclear. We hypothesized that auditory regions may be involved in visual working memory processing and activation of auditory regions may contribute to the superior behavioural performance of early deaf subjects. In this study, 41 early deaf subjects (22 females and 19 males, age range: 20-26 years, age of onset of deafness < 2 years) and 40 age- and gender-matched hearing controls underwent functional magnetic resonance imaging during a visuo-spatial delayed recognition task that consisted of encoding, maintenance and recognition stages. The early deaf subjects exhibited faster reaction times on the spatial working memory task than did the hearing controls. Compared with hearing controls, deaf subjects exhibited increased activation in the superior temporal gyrus bilaterally during the recognition stage. This increased activation amplitude predicted faster and more accurate working memory performance in deaf subjects. Deaf subjects also had increased activation in the superior temporal gyrus bilaterally during the maintenance stage and in the right superior temporal gyrus during the encoding stage. These increased activation amplitude also predicted faster reaction times on the spatial working memory task in deaf subjects. These findings suggest that cross-modal plasticity occurs in auditory association areas in early deaf subjects. These areas are involved in visuo-spatial working memory. Furthermore, amplitudes of cross-modal activation during the maintenance stage were positively correlated with the age of onset of hearing aid use and were negatively correlated with the percentage of lifetime hearing aid use in deaf subjects. These findings suggest that earlier and longer hearing aid use may inhibit cross-modal reorganization in early deaf subjects. Granger causality analysis revealed that, compared to the hearing controls, the deaf subjects had an enhanced net causal flow from the frontal eye field to the superior temporal gyrus. These findings indicate that a top-down mechanism may better account for the cross-modal activation of auditory regions in early deaf subjects.See MacSweeney and Cardin (doi:10/1093/awv197) for a scientific commentary on this article.

DISC1 Ser704Cys impacts thalamic-prefrontal connectivity.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been thought as a putative susceptibility gene for various psychiatric disorders, and DISC1 Ser704Cys is associated with variations of brain morphology and function. Moreover, our recent diffusion magnetic resonance imaging (dMRI) study reported that DISC1 Ser704Cys was associated with information transfer efficiency in the brain anatomical network. However, the effects of the DISC1 gene on functional brain connectivity and networks, especially for thalamic-prefrontal circuit, which are disrupted in various psychiatric disorders, are largely unknown. Using a functional connectivity density (FCD) mapping method based on functional magnetic resonance imaging data in a large sample of healthy Han Chinese subjects, we first investigated the association between DISC1 Ser704Cys and short- and long-range FCD hubs. Compared with Ser homozygotes, Cys-allele individuals had increased long-range FCD hubs in the bilateral thalami. The functional and anatomical connectivity of the thalamus to the prefrontal cortex was further analyzed. Significantly increased thalamic-prefrontal functional connectivity and decreased thalamic-prefrontal anatomical connectivity were found in DISC1 Cys-allele carriers. Our findings provide consistent evidence that the DISC1 Ser704Cys polymorphism influences the thalamic-prefrontal circuits in humans and may provide new insights into the neural mechanisms that link DISC1 and the risk for psychiatric disorders.

Connectivity-based parcellation of the human temporal pole using diffusion tensor imaging.

The temporal pole (TP) is an association cortex capable of multisensory integration and participates in various high-order cognitive functions. However, an accepted parcellation of the human TP and its connectivity patterns have not yet been well established. Here, we sought to present a scheme for the parcellation of human TP based on anatomical connectivity and to reveal its subregional connectivity patterns. Three distinct subregions with characteristic fiber pathways were identified, including the dorsal (TAr), the medial (TGm), and lateral (TGl) subregions, which are located ventrally. According to the connectivity patterns, a dorsal/ventral sensory segregation of auditory and visual processing and the medial TGm involved in the olfactory processing were observed. Combined with the complementary resting-state functional connectivity analysis, the connections of the TGm with the orbitofrontal cortex and other emotion-related areas, the TGl connections with the MPFC and major default mode network regions, and the TAr connections with the perisylvian language areas were observed. To the best of our knowledge, the present study represents the first attempt to parcel the human TP based on its anatomical connectivity features, which may help to improve our understanding of its connectional anatomy and to extend the available knowledge in TP-related clinical research.

Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects.

The oxytocin receptor gene (OXTR) rs53576A has been associated with autism spectrum disorders (ASDs). A smaller hypothalamic volume has been reported in healthy male A-allele carriers than in male GG homozygotes and in patients with ASDs than in healthy controls. These findings prompt the hypothesis that male AA homozygotes may have weaker hypothalamic functional connectivity when compared to male G-allele carriers. We calculated local functional connectivity density (FCD) using a voxel-wise data-driven approach based on resting-state functional MRI data in 270 young healthy subjects. Both the main effect of genotype and the gender-by-genotype interaction were considered. Of the whole brain, only the local FCD of the hypothalamus exhibited the main effect of genotype. Post-hoc testing revealed significantly lower local FCD in male AA homozygotes compared to male G-allele carriers although there was only a trend of significance in the gender-by-genotype interaction. We further analyzed the resting-state functional connectivity (rsFC) of the hypothalamic region that demonstrating significant genotype differences in local FCD. We found a significant gender-by-genotype interaction in rsFC between the hypothalamic region and the left dorsolateral prefrontal cortex, but no significant main effect of genotype was found. Post-hoc testing revealed that this rsFC was significantly weaker in male AA homozygotes compared to male G-allele carriers. Our findings identify gender-dependent mechanisms of OXTR rs53576 gene variation impacting the functional connectivity of the hypothalamus in healthy individuals and suggest that these mechanisms are important for understanding ASDs.

Spontaneous activity associated with primary visual cortex: a resting-state FMRI study.

Brain functions during the resting state have attracted considerable attention in the past several years. However, little has been known about spontaneous activity in the sensory cortices in the task-free state. This study used functional magnetic resonance imaging (fMRI) to investigate the existence of spontaneous activity in the primary visual areas (PVA) of normal-sighted subjects and to explore the physiological implications of such activity. Our results revealed that we were able to detect spontaneous activity, which was nonrandom in that it was distinctly clustered both temporally and spatially in the PVA of each subject. In addition, the neural network associated with the PVA-related spontaneous activity included the visual association areas, the precuneus, the precentral/postcentral gyrus, the middle frontal gyrus, the fusiform gyrus, the inferior/middle temporal gyrus, and the parahippocampal gyrus. After considering the functions of these regions, we speculated that the PVA-related spontaneous activity may be associated with memory-related mental imagery and/or visual memory consolidation processes. These findings confirm the presence of spontaneous activity in the PVA and related brain areas. This confirmation supports the perspective that brain is a system intrinsically operating on its own, and sensory information interacts with rather than determines the operation of the system.