Figure-ground modulation in awake primate thalamus

[Abstract] Figure-ground discrimination refers to the perception of an object, the figure, against a nondescript background. Neural mechanisms of figure-ground detection have been associated with feedback interactions between higher centers and primary visual cortex and have been held to index the effect of global analysis on local feature encoding. Here, in recordings from visual thalamus of alert primates, we demonstrate a robust enhancement of neuronal firing when the figure, as opposed to the ground, component of a motion-defined figure-ground stimulus is located over the receptive field. In this paradigm, visual stimulation of the receptive field and its near environs is identical across both conditions, suggesting the response enhancement reflects higher integrative mechanisms. It thus appears that cortical activity generating the higher-order percept of the figure is simultaneously reentered into the lowest level that is anatomically possible (the thalamus), so that the signature of the evolving representation of the figure is imprinted on the input driving it in an iterative process.Biotechnology and Biological Sciences Research Council (United Kingdom); G022305/1Medical Research Council, (United Kingdom); G070153

A comparison of postcochlear implantation speech scores in an adult population

OBJECTIVES: The vast majority of cochlear implant recipients realize significant improvement in speech perception. However, there continue to be a small group that does not realize such a benefit. In an effort to identify possible predictors for this, we have compared pre- and postimplant audiologic data using Hearing In Noise Test (HINT), City University of New York (CUNY), or Central Institute for the Deaf (CID) scores for 445 consecutive English-speaking adult patients followed for a minimum of 1 year postimplantation in two distinct groups, poor versus excellent performers. STUDY DESIGN: Retrospective. METHODS: Poor performers were those who realized a worsening, no improvement, or an improvement of less than 10%. This group numbered 58 (13%). High performers consisted of a cadre of 194 (44%) patients who scored between 91 and 100% postimplantation. Demographic data relating to onset of deafness, education exposure, etiology, etc., were evaluated. RESULTS: Of the poor performers, 33 (57%) were pre-/perilingually deafened. Of these, 79% had not received any auditory/oral training in childhood. On the other hand, a total of 109 implant recipients were individuals who were pre-/perilingually deafened. Of these, 24 were in the excellent performer category. All were identified early and were recipients of a strong auditory/oral education. Of the high performers, 170 (88%) were deafened late. Other findings such as preoperative electronystagmography with caloric testing, hearing aid use, device type, and high-resolution computed tomography scan of the temporal bone will be discussed for both groups. CONCLUSIONS: A high preimplant speech score, auditory verbal therapy, and postlingual deafness statistically correlate with higher postimplant speech scores 1 year after cochlear implantation. Device type, caloric response and hearing aid use preimplantation, age at surgery, and sex do not statistically correlate with either poor or excellent speech discrimination scores postcochlear implantation

Differential feedback modulation of center and surround mechanisms in parvocellular cells in the visual thalamus

[Abstract] Many cells in both the central visual system and other sensory systems exhibit a center surround organization in their receptive field, where the response to a centrally placed stimulus is modified when a surrounding area is also stimulated. This can follow from laterally directed connections in the local circuit at the level of the cell in question but could also involve more complex interactions. In the lateral geniculate nucleus (LGN), the cells relaying the retinal input display a concentric, center surround organization that in part follows from the similar organization characterizing the retinal cells providing their input. However, local thalamic inhibitory interneurons also play a role, and as we examine here, feedback from the visual cortex too. Here, we show in the primate (macaque) that spatially organized cortical feedback provides a clear and differential influence serving to enhance both responses to stimulation within the center of the receptive field and the ability of the nonclassical surround mechanism to attenuate this. In short, both center and surround mechanisms are influenced by the feedback. This dynamically sharpens the spatial focus of the receptive field and introduces nonlinearities from the cortical mechanism into the LGN.Medical Research Council (United Kingdom); G070153

Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade

Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor κB (NF-κB), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)-mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations -somatic mutations, somatic copy number alterations, and structural variants-in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-κB signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies

Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion

Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry-sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus-positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV- cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines ("Aging"), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)-associated hypermutation. In particular, the mutational burden in EBV- cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases