No abstract

This study investigated the processes reflected in the widely observed N400 and P600 event-related potential (ERP) effects and tested the hypothesis that the N400 and P600 effects are functionally linked in a tradeoff relationship, constrained in part by individual differences in cognitive ability. Sixty participants read sentences, and ERP effects of semantic anomaly, relative to plausible words, were calculated for each participant. Results suggested qualitatively different ERP patterns across participants: Some individuals generated N400-dominated effects, whereas others generated P600-dominated effects, for the same stimuli. To specify the sources of individual differences in brain responses, we also derived aggregate scores for verbal working memory (WM), nonverbal WM, and language experience/knowledge, based on 6 behavioral measures administered to each participant. Multiple regression analysis pitting these 3 constructs against each other showed that a larger verbal WM capacity was significantly associated with larger P600 and smaller N400 effect amplitudes across individuals, whereas the other constructs did not predict the ERP effects. The results suggest that N400 and P600 brain responses, which may be attributable to semantic integration difficulty and structural processing, respectively, vie for expression when comprehenders encounter semantically unexpected words and that which option wins out is constrained in part by each comprehender's verbal WM capacity. (PsycINFO Database Record

IMPORTANCE Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs.OBJECTIVE To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition.

Language comprehension involves not only constructing the literal meaning of a sentence but also going beyond the literal meaning to infer what was meant but not said. One widely-studied test case is scalar implicature: The inference that, e.g., Sally ate some of the cookies implies she did not eat all of them. Research is mixed on whether this is due to a rote, grammaticalized procedure or instead a complex, contextualized inference. We find that in sentences like If Sally ate some of the cookies, then the rest are on the counter, that the rest triggers a late, sustained positivity relative to Sally ate some of the cookies, and the rest are on the counter. This is consistent with behavioral results and linguistic theory suggesting that the former sentence does not trigger a scalar implicature. This motivates a view on which scalar implicature is contextualized but dependent on grammatical structure.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.

Background Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting‐state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. Methods We collected preoperative resting‐state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation‐induced (ON/OFF) 15O H2O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN‐seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. Results Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = −0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal‐subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. Discussion Preoperative pallidal‐subthalamic nucleus resting‐state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal‐subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system (CNS) progression is frequently an end-stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.