Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
Abstract Anhedonia is a hallmark symptom of major depressive disorder (MDD). Preliminary findings suggest that anhedonia is characterized by reduced reward anticipation and motivation of obtaining ...reward. However, relatively little is known about reward-based decision-making in depression. We tested the hypothesis that anhedonia in MDD may reflect specific impairments in motivation on reward-based decision-making and the deficits might be associated with depressive symptoms severity. In study 1, individuals with and without depressive symptoms performed the modified version of the Effort Expenditure for Rewards Task (EEfRT), a behavioral measure of cost/benefit decision-making. In study 2, MDD patients, remitted MDD patients and healthy controls were recruited for the same procedures. We found evidence for decreased willingness to make effort for rewards among individuals with subsyndromal depression; the effect was amplified in MDD patients, but dissipated in patients with remitted depression. We also found that reduced anticipatory and consummatory pleasure predicted decreased willingness to expend efforts to obtain rewards in MDD patients. For individuals with subsyndromal depression, the impairments were correlated with anticipatory anhedonia but not consummatory anhedonia. These data offer novel evidence that motivational deficits in MDD are correlated with depression severity and predicted by self-reported anhedonia.
•Multisensory temporal dysfunction represented by an extended temporal binding window is a common feature of ASD and SSD.•Unisensory temporal acuity is impaired in schizophrenia but may be spared in ...ASD.•Multisensory dysfunction is associated with incoherent perception and communicative deficit that characterize SSD and ASD.
Multisensory temporal integration could be compromised in both autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD) and may play an important role in perceptual and cognitive impairment in these two disorders. This review aimed to quantitatively compare the sensory temporal acuity between healthy controls and the two clinical groups (ASD and SSD). Impairment of sensory temporal integration was robust and comparable in both patients with SSD (Hedges’ g = 0.91, 95%CI0.62–1.19; Z = 6.21, p < .001) and ASD (Hedges’ g = 0.85, (95%CI0.54–1.15; Z = 5.39, p < .001). By further separating studies into unisensory and multisensory (bimodal: audiovisual) ones, subgroup analysis indicated heterogeneous and unstable effects for unisensory temporal binding in the ASD group, but a more consistent and severe impairment in multisensory temporal integration represented by an enlarged temporal binding window in both clinical groups. Such multisensory dysfunction is associated with symptoms like hallucinations and impaired social communications. Future studies focusing on improving multisensory temporal functions may have important implications for the amelioration of schizophrenia and autistic symptoms.
Machine learning has increasingly been applied to classification of schizophrenia in neuroimaging research. However, direct replication studies and studies seeking to investigate generalizability are ...scarce. To address these issues, we assessed within‐site and between‐site generalizability of a machine learning classification framework which achieved excellent performance in a previous study using two independent resting‐state functional magnetic resonance imaging data sets collected from different sites and scanners. We established within‐site generalizability of the classification framework in the main data set using cross‐validation. Then, we trained a model in the main data set and investigated between‐site generalization in the validated data set using external validation. Finally, recognizing the poor between‐site generalization performance, we updated the unsupervised algorithm to investigate if transfer learning using additional unlabeled data were able to improve between‐site classification performance. Cross‐validation showed that the published classification procedure achieved an accuracy of 0.73 using majority voting across all selected components. External validation found a classification accuracy of 0.55 (not significant) and 0.70 (significant) using the direct and transfer learning procedures, respectively. The failure of direct generalization from one site to another demonstrates the limitation of within‐site cross‐validation and points toward the need to incorporate efforts to facilitate application of machine learning across multiple data sets. The improvement in performance with transfer learning highlights the importance of taking into account the properties of data when constructing predictive models across samples and sites. Our findings suggest that machine learning classification result based on a single study should be interpreted cautiously.
Impairment in empathy has been demonstrated in patients with schizophrenia and individuals with psychosis proneness. In the present study, we examined the neural correlates underlying theory of mind ...(ToM) and empathy and the relationships between these two social cognitive abilities with schizotypy. Fifty-six first-year college students (31 males, 25 females) between 17 and 21 years of age (M = 19.3, SD = 0.9) from a medical university in China participated. All participants undertook a comic strips functional imaging task that specifically examined both empathy and ToM. In addition, they completed two self-report scales: the Chapman Psychosis Proneness scale and the Interpersonal Responsivity Index (IRI). Results showed that both empathy and ToM conditions of the task were associated with brain activity in the middle temporal gyrus, the temporo-parietal junction (TPJ), the precuneus and the posterior cingulate gyrus. In addition, we found positive correlations between negative schizotypy and brain activity in regions involved in social cognition, namely, the middle temporal gyrus, the TPJ, as well as the medial prefrontal gyrus. These findings highlight that different dimensions of schizotypy may show different associations with brain regions involved in social cognitive abilities. More importantly, the positive correlation between brain activity and anhedonia suggests the presence of compensatory mechanisms in high-risk populations.
Schizotypy refers to schizophrenia-like traits below the clinical threshold in the general population. The pathological development of schizophrenia has been postulated to evolve from the initial ...coexistence of 'brain disconnection' and 'brain connectivity compensation' to 'brain connectivity decompensation'.
In this study, we examined the brain connectivity changes associated with schizotypy by combining brain white matter structural connectivity, static and dynamic functional connectivity analysis of diffusion tensor imaging data and resting-state functional magnetic resonance imaging data. A total of 87 participants with a high level of schizotypal traits and 122 control participants completed the experiment. Group differences in whole-brain white matter structural connectivity probability, static mean functional connectivity strength, dynamic functional connectivity variability and stability among 264 brain sub-regions of interests were investigated.
We found that individuals with high schizotypy exhibited increased structural connectivity probability within the task control network and within the default mode network; increased variability and decreased stability of functional connectivity within the default mode network and between the auditory network and the subcortical network; and decreased static mean functional connectivity strength mainly associated with the sensorimotor network, the default mode network and the task control network.
These findings highlight the specific changes in brain connectivity associated with schizotypy and indicate that both decompensatory and compensatory changes in structural connectivity within the default mode network and the task control network in the context of whole-brain functional disconnection may be an important neurobiological correlate in individuals with high schizotypy.
Abstract
Background
Impairment in facial emotion perception is an important domain of social cognition deficits in schizophrenia. Although impaired facial emotion perception has been found in ...individuals with negative schizotypy (NS), little is known about the corresponding change in brain functional connectivity.
Methods
Sixty-four participants were classified into a high NS group (n = 34) and a low NS group (n = 30) based on their total scores on the Chapman scales for physical and social anhedonia. All participants undertook a facial emotion discrimination functional imaging task that consisted of four emotional valences (angry, fear, happy, and neutral). For univariate analysis, the signal change at the bilateral amygdala was compared for each emotional contrast using SPSS (P < .05). For the functional connectivity analysis, we calculated the beta-series functional connectivity of the bilateral amygdala with the medial prefrontal cortex (mPFC) and compared the group differences in SPM12 (P < .05, small volume family-wise error correction).
Results
No significant differences were found between the high and low NS groups in accuracy and reaction time in the facial emotion discrimination task. The high NS group showed reduced brain activations at the amygdala under fearful and neutral conditions. Reduced functional connectivity between the amygdala and the mPFC/dorsal anterior cingulate cortex under the happy and fearful conditions in the high NS group was also found.
Conclusions
Our findings suggest that the individuals with high NS showed altered brain activity and functional connectivity at the amygdala during facial emotion processing and provide new evidence for understanding social cognition deficits in at-risk individuals.
Abstract This study sought to determine the moderators in the treatment effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in schizophrenia. We performed a ...meta-analysis of prospective studies on the therapeutic application of rTMS in schizophrenia assessing the effects of both low-frequency and high-frequency rTMS on negative symptoms. Results indicate that rTMS is effective in alleviating negative symptoms in schizophrenia. The effect size was moderate (0.63 and 0.53, respectively). The effect size of rTMS on negative symptoms in sham-controlled trials was 0.80 as measured by the SANS and 0.41 as measured by the PANSS. A longer duration of illness was associated with poorer efficacy of rTMS on negative symptoms. A 10 Hz setting, at least 3 consecutive weeks of treatment, treatment site at the left dorsolateral prefrontal cortex (DLPFC) and a 110% motor threshold (MT) were found to be the best rTMS parameters for the treatment of negative symptoms. The results of our meta-analysis suggest that rTMS is an effective treatment option for negative symptoms in schizophrenia. The moderators of rTMS on negative symptoms included duration of illness, stimulus frequency, duration of illness, position and intensity of treatment as well as the type of outcome measures used.
PDF
