Magnetic two-dimensional nanocomposites for multimodal antitumor therapy: a recent review.

Magnetic two-dimensional nanocomposites (M2D NCs) that synergistically combine magnetic nanomedicine and 2D nanomaterials have emerged in multimodal antitumor therapy, attracting great interest in materials science and biomedical engineering. This review provides a summary of the recent advances of M2D NCs and their multimodal antitumor applications. We first introduce the design and fabrication of M2D NCs, followed by discussing new types of M2D NCs that have been recently reported. Then, a detailed analysis and discussions about the different types of M2D NCs are presented based on the structural categories of 2D NMs, including 2D graphene, transition metal dichalcogenides (TMDs), transition metal carbides/nitrides/carbonitrides (MXenes), black phosphorus (BP), layered double hydroxides (LDHs), metal organic frameworks (MOFs), covalent organic frameworks (COFs) and other 2D nanomaterials. In particular, we focus on the synthesis strategies, magnetic or optical responsive performance, and the versatile antitumor applications, which include magnetic hyperthermia therapy (MHT), photothermal therapy (PTT), photodynamic therapy (PDT), drug delivery, immunotherapy and multimodal imaging. We conclude the review by proposing future developments with an emphasis on the mass production and biodegradation mechanism of the M2D NCs. This work is expected to provide a comprehensive overview to researchers and engineers who are interested in such a research field and promote the clinical translation of M2D NCs in practical applications.

Hemispheric lateralization of language processing: insights from network-based symptom mapping and patient subgroups.

The hemispheric laterality of language processing has become a hot topic in modern neuroscience. Although most previous studies have reported left-lateralized language processing, other studies found it to be bilateral. A previous neurocomputational model has proposed a unified framework to explain that the above discrepancy might be from healthy and patient individuals. This model posits an initial symmetry but imbalanced capacity in language processing for healthy individuals, with this imbalance contributing to language recovery disparities following different hemispheric injuries. The present study investigated this model by analyzing the lateralization patterns of language subnetworks across multiple attributes with a group of 99 patients (compared to nonlanguage processing) and examining the lateralization patterns of language subnetworks in subgroups with damage to different hemispheres. Subnetworks were identified using a whole-brain network-based lesion-symptom mapping method, and the lateralization index was quantitatively measured. We found that all the subnetworks in language processing were left-lateralized, while subnetworks in nonlanguage processing had different lateralization patterns. Moreover, diverse hemisphere-injury subgroups exhibited distinct language recovery effects. These findings provide robust support for the proposed neurocomputational model of language processing.

Chirality-Dependent Tumor Phototherapy Using Amino Acid-Engineered Chiral Phosphorene.

Phosphorene, also known as black phosphorus nanosheet (BPNS), has been investigated as a nanoagent for tumor therapy. However, promoting its intracellular accumulation while preventing the cytoplasmic decomposition remains challenging. Herein, for the first time, we propose a chiral BPNS designed through surface engineering based on amino acids with high biocompatibility and an abundant source for application in chirality-dependent tumor phototherapy based on its intracellular metabolism. The advantage of using cysteine (Cys) over other amino acids was that its d, l, or dl-form could efficiently work as the chirality inducer to modify the BPNS through electrostatic interaction and prevent alterations in the intrinsic properties of the BPNS. In particular, d-Cys-BPNS displayed an approximately threefold cytotoxic effect on tumor cells compared with l-Cys-BPNS, demonstrating a chirality-dependent therapy behavior. d-Cys-BPNS not only promoted high intracellular content but also showed resistance to cytoplasmic decomposition. Cys-engineered BPNS also demonstrated chirality-dependent phototherapy effects on tumor-bearing mice, in proximity to the results in vitro. Chiral engineering is expected to open new avenues that could promote the use of BPNS in tumor phototherapy and boost chiral nanomedicine.

Temperature-Dependent CAT-Like RGD-BPNS@SMFN Nanoplatform for PTT-PDT Self-Synergetic Tumor Phototherapy.

Phototherapies such as photothermal therapy (PTT) and photodynamic therapy (PDT) are considered as alternatives for tumor remedies, because of their advantages of precise spatial orientation, minimally invasive, and nonradiative operation. However, most of phototherapeutic agents still suffer from low photothermal conversion efficacy and photodynamic performance, poor biocompatibility, and intratumor accumulation. Herein a biocompatible and target-deliverable PTT-PDT self-synergetic nanoplatform of RGD-BPNS@SMFN based on temperature-dependent catalase (CAT)-like behavior for tumor elimination is presented. The homogeneously dispersible nanoplatform is designed and fabricated through anchoring spherical manganese ferrite nanoparticles (SMFN) to black phosphorus nanosheets (BPNS), followed by arginine-glycine-aspartic acid (RGD) peptide modification. The nanoplatform exhibits excellent targeting ability and enhanced photonic response in comparison to plain BPNS and SMFN in vitro and in vivo. It is found that PTT and PDT have a self-synergetic behavior by means of the dual phototherapy mode interaction. The self-synergetic mechanism is mainly ascribed to PTT-promoted inherent CAT-like activity in the nanoplatform, which remodels the tumor hypoxia microenvironment and further ameliorates the PDT efficiency, providing promising high performance nanoplatform for synergetic dual mode phototherapy, enriching the design for the antitumor nanozyme.

Effect of the cPKCγ-Ng Signaling System on Rapid Eye Movement Sleep Deprivation-Induced Learning and Memory Impairment in Rats.

Objective: Rapid eye movement sleep deprivation (REM-SD) can cause a decline in learning and memory and lead to changes in behavior. Therefore, REM sleep plays a key role in processes that govern learning and memory. However, the mechanism underlying REM-SD-induced learning and memory impairment is unclear and the underlying molecular signaling still needs to be identified. In the present study, we investigated the role of the cPKCγ-Ng signaling pathway in REM-SD-induced learning and memory impairment. Method: Sixty male rats were divided into Control, REM-SD, REM-SD+cPKCγ activator PMA, REM-SD+cPKCγ inhibitor H-7, and sleep revival (SR) groups. The Morris water maze was used to assess spatial learning and memory. Western blot analysis was used to detect cPKCγ total protein expression and membrane translocation levels, and Ng total protein expression and phosphorylation levels. Results: The REM-SD group performed worse on the Morris water maze test than the control group. Western blot analysis showed that cPKCγ membrane translocation and Ng phosphorylation levels were significantly lower in the REM-SD group. SR following REM-SD restored learning and memory ability, cPKCγ transmembrane translocation, and Ng phosphorylation levels, but not to levels observed before REM-SD. PMA and H-7 significantly improved/disrupted task ability as well as cPKCγ transmembrane translocation and Ng phosphorylation levels in REM-SD rats. Conclusion: The REM-SD induced learning and memory impairment in rats and may be associated with the cPKCγ-Ng signaling pathway. Specifically, activation of the cPKCγ-Ng signaling pathway may protect against REM-SD.

White matter network of oral word reading identified by network-based lesion-symptom mapping.

Oral word reading is supported by a neural subnetwork that includes gray matter regions and white matter tracts connected by the regions. Traditional methods typically determine the reading-relevant focal gray matter regions or white matter tracts rather than the reading-relevant global subnetwork. The present study developed a network-based lesion-symptom mapping (NLSM) method to identify the reading-relevant global white matter subnetwork in 84 brain-damaged patients. The global subnetwork was selected among all possible subnetworks because its global efficiency exhibited the best explanatory power for patients' reading scores. This reading subnetwork was left lateralized and included 7 gray matter regions and 15 white matter tracts. Moreover, the reading subnetwork had additional explanatory power for the patients' reading performance after eliminating the effects of reading-related local regions and tracts. These findings refine the reading neuroanatomical architecture and indicate that the NLSM can be a better method for revealing behavior-specific subnetworks.

Effect of Anodic Transcranial Direct Current Stimulation Combined With Speech Language Therapy on Nonfluent Poststroke Aphasia.

OBJECTIVES: Transcranial direct current stimulation (tDCS) facilitates or inhibits spontaneous neuronal activity by low-intensity current. In this study, we evaluated the effects of tDCS and sham stimulation combined with speech language therapy (SLT) on nonfluent poststroke aphasia (PSA) patients. MATERIALS AND METHODS: Patients with PSA were randomly divided into the anode tDCS (A-tDCS) group (n = 8) and sham tDCS (S-tDCS) group (n = 10). The anodes and cathodes were fixed over left inferior gyrus frontalis (L-IFG) and the deltoid muscle of the right shoulder. A-tDCS consisted of 2 mA for 20 min, while S-tDCS current started at 2 mA but automatically decreased to 0 mA after 30 sec. Stimulation was concurrent with 30 min of SLT. Stimulation + SLT sessions occurred five times a week for four weeks. The Western Aphasia Battery (WAB) was given before treatment to obtain the baseline score and once more after all sessions were completed, and the Aphasia Quotient (AQ) was calculated. RESULTS: After tDCS treatment, the AQ mean(SD) in both groups was significantly higher than before treatment (p < 0.001) and the AQ of the A-tDCS group 72.99 (21.91) was significantly higher than that of the S-tDCS group 46.18 (19.29) (t = 2.760, p < 0.05). Upon further analysis of the WAB subscores, except for comprehension, all other items were significantly higher in the A-tDCS group than in the S-tDCS group (p < 0.05). CONCLUSION: Our results suggest that left inferior gyrus frontalis anodic transcranial direct current stimulation is an effective adjuvant to conventional speech language therapy for patients with nonfluent PSA.

Corrigendum: Effect of the cPKCγ-Ng Signaling System on Rapid Eye Movement Sleep Deprivation-Induced Learning and Memory Impairment in Rats.

[This corrects the article DOI: 10.3389/fpsyt.2021.763032.].

White matter networks dissociate semantic control from semantic knowledge representations: Evidence from voxel-based lesion-symptom mapping.

Although semantic system is composed of two distinctive processes (i.e., semantic knowledge and semantic control), it remains unknown in which way these two processes dissociate from each other. Investigating the white matter neuroanatomy underlying these processes helps improve understanding of this question. To address this issue, we recruited brain-damaged patients with semantic dementia (SD) and semantic aphasia (SA), who had selective predominant deficits in semantic knowledge and semantic control, respectively. We built regression models to identify the white matter network associated with the semantic performance of each patient group. Semantic knowledge deficits in the SD patients were associated with damage to the left medial temporal network, while semantic control deficits in the SA patients were associated with damage to the other two networks (left frontal-temporal/occipital and frontal-subcortical networks). The further voxel-based analysis revealed additional semantic-relevant white matter tracts. These findings specify different processing principles of the components in semantic system.

A prospective cohort study of MTHFR C677T gene polymorphism and its influence on the therapeutic effect of homocysteine in stroke patients with hyperhomocysteinemia.

BACKGROUND: Hyperhomocysteinemia (HHCY) is a risk factor for cardiovascular and cerebrovascular diseases. The C677T 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism increases homocysteine (HCY) levels. This study analyzed the relationship between C677T MTHFR polymorphism and the therapeutic effect of lowering HCY in stroke patients with HHCY. METHODS: Baseline data were collected from stroke patients with HHCY for this prospective cohort study. The C677T MTHFR genotype was detected by polymerase chain reaction-restriction fragment length polymorphism and the therapeutic effect to reduce HCY was compared. RESULTS: Of 200 stroke patients 162 (81.0%) completed follow-up and were evaluated. Most of them responded well to treatment (103 cases, 63.5%), but 59 (36.4%) patients were in the poor efficacy group. There was a significant difference in terms of age (P < 0.001), hypertension (P = 0.041), hyperuricemia (P = 0.042), HCY after treatment (P < 0.001), and MTHFR genotype (P < 0.001) between the poor efficacy and effective groups, with increased frequency of the TT genotype in the poor efficacy group. Logistic regression showed that the T allele was associated with poor efficacy (OR = 0.733, 95%CI: 0.693, 0.862, P < 0.001). In the codominant model the TT genotype was associated with poor outcome (OR = 0.862, 95%CI: 0.767, 0.970, P = 0.017) and this was also the case in the recessive model (OR = 0.585, 95%CI: 0.462, 0.741, P < 0.001) but there was no association between CT and TT in the dominant model. CONCLUSIONS: The T allele and TT genotype of the MTHFR C677T polymorphism was associated with poor HCY reduction treatment efficacy in stroke patients with HHCY. TRIAL REGISTRATION: The registration number of the clinical trial is ChiCTR1800020048. Registration date: December 12, 2018.

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology-Based Strategy.

BACKGROUND: Yisui Qinghuang powder (YSQHP) is an effective traditional Chinese medicinal formulation used for the treatment of myelodysplastic syndromes (MDS). However, its pharmacological mechanism of action is unclear. MATERIALS AND METHODS: In this study, the active compounds of YSQHP were screened using the traditional Chinese medicine systems pharmacology (TCMSP) and HerDing databases, and the putative target genes of YSQHP were predicted using the STITCH and DrugBank databases. Then, we further screened the correlative biotargets of YSQHP and MDS. Finally, the compound-target-disease (C-T-D) network was conducted using Cytoscape, while GO and KEGG analyses were conducted using R software. Furthermore, DDI-CPI, a web molecular docking analysis tool, was used to verify potential targets and pathways. Finally, binding site analysis was performed to identify core targets using MOE software. RESULTS: Our results identified 19 active compounds and 273 putative target genes of YSQHP. The findings of the C-T-D network revealed that Rb1, CASP3, BCL2, and MAPK3 showed the most number of interactions, whereas indirubin, tryptanthrin, G-Rg1, G-Rb1, and G-Rh2 showed the most number of potential targets. The GO analysis showed that 17 proteins were related with STPK activity, PUP ligase binding, and kinase regulator activity. The KEGG analysis showed that PI3K/AKT, apoptosis, and the p53 pathways were the main pathways involved. DDI-CPI identified the top 25 proteins related with PI3K/AKT, apoptosis, and the p53 pathways. CASP8, GSK3B, PRKCA, and VEGFR2 were identified as the correlative biotargets of DDI-CPI and PPI, and their binding sites were found to be indirubin, G-Rh2, and G-Rf. CONCLUSION: Taken together, our results revealed that YSQHP likely exerts its antitumor effects by binding to CASP8, GSK3B, PRKCA, and VEGFR2 and by regulating the apoptosis, p53, and PI3K/AKT pathways.

The left inferior longitudinal fasciculus supports orthographic processing: Evidence from a lesion-behavior mapping analysis.

Orthographic processing is a critical stage in visual word recognition. However, the white-matter pathways that support this processing are unclear, as prior findings might have been confounded by impure behavioral measures, potential structural reorganization of the brain, and limited sample sizes. To address this issue, we investigated the correlations between the integrity of 20 major tracts in the whole brain and the pure orthographic index across 67 patients with short-term brain damage. The integrity of the tracts was measured by the lesion volume percentage and the mean fractional anisotropy value. The orthographic index was calculated as the residual of the orthographic tasks after regressing out corresponding nonorthographic tasks and the orthographic factor from the principal component analysis (PCA) on the basis of four orthographic tasks. We found significant correlations associated with the left inferior longitudinal fasciculus (ILF), even after controlling for the influence of potential confounding variables. These observations strengthen evidence for the vital role of the left ILF in orthographic processing.

Application of functional near-infrared spectroscopy to explore the neural mechanism of transcranial direct current stimulation for post-stroke depression.

Objectives: We investigated the neural mechanism of transcranial direct current stimulation (tDCS) in the treatment of post-stroke depression (PSD) using functional near-infrared spectroscopy (fNIRS). Methods: Twenty-six patients with PSD were randomly divided into an experimental group receiving tDCS and a control group receiving sham stimulation. The anode and cathode were placed on the left and right dorsolateral prefrontal cortex (PFC). Patients underwent fNIRS before and after treatment, combined with an emotional face sex judgment task and a '1-back' working memory task to assess reaction times and relative concentration changes of oxyhemoglobin (Oxy-Hb) in the PFC. Results: Reaction times for faces showing positive emotions decreased after treatment in the experimental group (P < 0.05). For faces showing negative emotions, relative Oxy-Hb concentration changes in the PFC were higher after treatment (P < 0.05), but there was no significant difference between the experimental and the control group. Reaction times during the working memory task in the experimental group were shorter after treatment (P < 0.05), and there was a significant difference between the groups (P < 0.05). Relative Oxy-Hb concentration changes in the left PFC were significantly higher after treatment in the experimental group (P < 0.05), and concentration changes in the right PFC after treatment were significantly higher in the experimental than in the control group (P < 0.05). Discussion: tDCS may improve the processing of negative emotions and working memory in patients with PSD by enhancing aerobic metabolism in the PFC, thereby improving depressive symptoms.

Value of using the international classification of functioning, disability, and health for stroke rehabilitation assessment: A multicenter clinical study.

This study aimed to evaluate the efficiency of the International Classification of Functioning, Disability, and Health (ICF) in stroke rehabilitation assessment in China and to identify correlations between the ICF and several commonly used clinical assessment instruments for stroke.In total, 52 hospitals and 5 premier rehabilitation and neurology research centers participated in this cross-sectional multicenter clinical study. A total of 2822 stroke patients admitted to a neurology or rehabilitation department of a participating medical center between July 2012 and June 2014 were included. The ICF checklist contains 4 parts with 128 two-level items: body functions, body structures, activities and participation, and environmental factors. We analyzed the results of ICF assessments and determined whether correlations existed between the various items of the ICF and several commonly used clinical assessment instruments.In all but 3 instances, the scores for the ICF-b-body function, ICF-s-body structure-degree of impairment, ICF-s-body structure-impairment location, ICF-d-activity performance, ICF-d-ability performance, ICF-e-facilitator, and ICF-e-barrier correlated significantly (P < .05) with the scores for the commonly used clinical assessment instruments.The ICF checklist is a new rehabilitation assessment instrument that is compatible with commonly used clinical assessment scales for stroke and can be used in combination with these scales.

Motor imagery training induces changes in brain neural networks in stroke patients.

Motor imagery is the mental representation of an action without overt movement or muscle activation. However, the effects of motor imagery on stroke-induced hand dysfunction and brain neural networks are still unknown. We conducted a randomized controlled trial in the China Rehabilitation Research Center. Twenty stroke patients, including 13 males and 7 females, 32-51 years old, were recruited and randomly assigned to the traditional rehabilitation treatment group (PP group, n = 10) or the motor imagery training combined with traditional rehabilitation treatment group (MP group, n = 10). All patients received rehabilitation training once a day, 45 minutes per session, five times per week, for 4 consecutive weeks. In the MP group, motor imagery training was performed for 45 minutes after traditional rehabilitation training, daily. Action Research Arm Test and the Fugl-Meyer Assessment of the upper extremity were used to evaluate hand functions before and after treatment. Transcranial magnetic stimulation was used to analyze motor evoked potentials in the affected extremity. Diffusion tensor imaging was used to assess changes in brain neural networks. Compared with the PP group, the MP group showed better recovery of hand function, higher amplitude of the motor evoked potential in the abductor pollicis brevis, greater fractional anisotropy of the right dorsal pathway, and an increase in the fractional anisotropy of the bilateral dorsal pathway. Our findings indicate that 4 weeks of motor imagery training combined with traditional rehabilitation treatment improves hand function in stroke patients by enhancing the dorsal pathway. This trial has been registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-OCH-12002238).

Semantic representation in the white matter pathway.

Object conceptual processing has been localized to distributed cortical regions that represent specific attributes. A challenging question is how object semantic space is formed. We tested a novel framework of representing semantic space in the pattern of white matter (WM) connections by extending the representational similarity analysis (RSA) to structural lesion pattern and behavioral data in 80 brain-damaged patients. For each WM connection, a neural representational dissimilarity matrix (RDM) was computed by first building machine-learning models with the voxel-wise WM lesion patterns as features to predict naming performance of a particular item and then computing the correlation between the predicted naming score and the actual naming score of another item in the testing patients. This correlation was used to build the neural RDM based on the assumption that if the connection pattern contains certain aspects of information shared by the naming processes of these two items, models trained with one item should also predict naming accuracy of the other. Correlating the neural RDM with various cognitive RDMs revealed that neural patterns in several WM connections that connect left occipital/middle temporal regions and anterior temporal regions associated with the object semantic space. Such associations were not attributable to modality-specific attributes (shape, manipulation, color, and motion), to peripheral picture-naming processes (picture visual similarity, phonological similarity), to broad semantic categories, or to the properties of the cortical regions that they connected, which tended to represent multiple modality-specific attributes. That is, the semantic space could be represented through WM connection patterns across cortical regions representing modality-specific attributes.

Connectivity of the ventral visual cortex is necessary for object recognition in patients.

The functional profiles of regions in the ventral occipital-temporal cortex (VTC), a critical region for object visual recognition, are associated with the VTC connectivity patterns to nonvisual regions relevant to the corresponding object domain. However, whether and how whole-brain connections affect recognition behavior remains untested. We directly examined the necessity of VTC connectivity in object recognition behavior by testing 82 patients whose lesion spared relevant VTC regions but affected various white matter (WM) tracts and other regions. In these patients, we extracted the whole-brain anatomical connections of two VTC domain-selective (large manmade objects and animals) clusters with probabilistic tractography, and examined whether such connectivity pattern can predict recognition performance of the corresponding domains with support vector regression (SVR) analysis. We found that the whole-brain anatomical connectivity of large manmade object-specific cluster successfully predicted patients' large object recognition performance but not animal recognition or control tasks, even after we excluded connections with early visual regions. The contributing connections to large object recognition included tracts between VTC-large object cluster and distributed regions both within and beyond the visual cortex (e.g., putamen, superior, and middle temporal gyrus). These results provide causal evidence that the VTC whole-brain anatomical connectivity is necessary for at least certain domains of object recognition behavior.

Brain hubs in lesion models: Predicting functional network topology with lesion patterns in patients.

Various important topological properties of healthy brain connectome have recently been identified. However, the manner in which brain lesion changes the functional network topology is unknown. We examined how critical specific brain areas are in the maintenance of network topology using multivariate support vector regression analysis on brain structural and resting-state functional imaging data in 96 patients with brain damages. Patients' cortical lesion distribution patterns could significantly predict the functional network topology and a set of regions with significant weights in the prediction models were identified as "lesion hubs". Intriguingly, we found two different types of lesion hubs, whose lesions associated with changes of network topology towards relatively different directions, being either more integrated (global) or more segregated (local), and correspond to hubs identified in healthy functional network in complex manners. Our results pose further important questions about the potential dynamics of the functional brain network after brain damage.

Dissociable intrinsic functional networks support noun-object and verb-action processing.

The processing mechanism of verbs-actions and nouns-objects is a central topic of language research, with robust evidence for behavioral dissociation. The neural basis for these two major word and/or conceptual classes, however, remains controversial. Two experiments were conducted to study this question from the network perspective. Experiment 1 found that nodes of the same class, obtained through task-evoked brain imaging meta-analyses, were more strongly connected with each other than nodes of different classes during resting-state, forming segregated network modules. Experiment 2 examined the behavioral relevance of these intrinsic networks using data from 88 brain-damaged patients, finding that across patients the relative strength of functional connectivity of the two networks significantly correlated with the noun-object vs. verb-action relative behavioral performances. In summary, we found that verbs-actions and nouns-objects are supported by separable intrinsic functional networks and that the integrity of such networks accounts for the relative noun-object- and verb-action-selective deficits.

Structural connectivity subserving verbal fluency revealed by lesion-behavior mapping in stroke patients.

Tests of verbal fluency have been widely used to assess the cognitive functioning of persons, and are typically classified into two categories (semantic and phonological fluency). While widely-distributed divergent and convergent brain regions have been found to be involved in semantic and phonological fluency, the anatomical connectivity underlying the fluency is not well understood. The present study aims to construct a comprehensive white-matter network associated with semantic and phonological fluency by investigating the relationship between the integrity of 22 major tracts in the whole brain and semantic fluency (measured by 3 cues) and phonological fluency (measured by 2 cues) in a group of 51 stroke patients. We found five left-lateralized tracts including the anterior thalamic radiation (ATR), inferior fronto-occipital fasciculus (IFOF), uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and frontal aslant tract (FAT) were significantly correlated with the scores of both semantic and phonological fluencies. These effects persisted even when we ruled out the influence of potential confounding factors (e.g., total lesion volume). Moreover, the damage to the first three tracts caused additional impairments in the semantic compared to the phonological fluency. These findings reveal the white-matter neuroanatomical connectivity underlying semantic and phonological fluency, and deepen the understanding of the neural network of verbal fluency.