A new comparator account of auditory verbal hallucinations: how motor prediction can plausibly contribute to the sense of agency for inner speech

The comparator account holds that processes of motor prediction contribute to the sense of agency by attenuating incoming sensory information and that disruptions to this process contribute to misattributions of agency in schizophrenia. Over the last 25 years this simple and powerful model has gained widespread support not only as it relates to bodily actions but also as an account of misattributions of agency for inner speech, potentially explaining the etiology of auditory verbal hallucination (AVH). In this paper we provide a detailed analysis of the traditional comparator account for inner speech, pointing out serious problems with the specification of inner speech on which it is based and highlighting inconsistencies in the interpretation of the electrophysiological evidence commonly cited in its favor. In light of these analyses we propose a new comparator account of misattributed inner speech. The new account follows leading models of motor imagery in proposing that inner speech is not attenuated by motor prediction, but rather derived directly from it. We describe how failures of motor prediction would therefore directly affect the phenomenology of inner speech and trigger a mismatch in the comparison between motor prediction and motor intention, contributing to abnormal feelings of agency. We argue that the new account fits with the emerging phenomenological evidence that AVHs are both distinct from ordinary inner speech and heterogeneous. Finally, we explore the possibility that the new comparator account may extend to explain disruptions across a range of imagistic modalities, and outline avenues for future research.

HDAC Inhibition Overcomes Acute Resistance to MEK Inhibition in BRAF-Mutant Colorectal Cancer by Downregulation of c-FLIPL

Purpose: Activating mutations in the BRAF oncogene are found in 8% to 15% of colorectal cancer patients and have been associated with poor survival. In contrast with BRAF-mutant (MT) melanoma, inhibition of the MAPK pathway is ineffective in the majority of BRAFMT colorectal cancer patients. Therefore, identification of novel therapies for BRAFMT colorectal cancer is urgently needed.

Experimental Design: BRAFMT and wild-type (WT) colorectal cancer models were assessed in vitro and in vivo. Small-molecule inhibitors of MEK1/2, MET, and HDAC were used, overexpression and siRNA approaches were applied, and cell death was assessed by flow cytometry, Western blotting, cell viability, and caspase activity assays.

Results: Increased c-MET-STAT3 signaling was identified as a novel adaptive resistance mechanism to MEK inhibitors (MEKi) in BRAFMT colorectal cancer models in vitro and in vivo. Moreover, MEKi treatment resulted in acute increases in transcription of the endogenous caspase-8 inhibitor c-FLIPL in BRAFMT cells, but not in BRAFWT cells, and inhibition of STAT3 activity abrogated MEKi-induced c-FLIPL expression. In addition, treatment with c-FLIP–specific siRNA or HDAC inhibitors abrogated MEKi-induced upregulation of c-FLIPL expression and resulted in significant increases in MEKi-induced cell death in BRAFMT colorectal cancer cells. Notably, combined HDAC inhibitor/MEKi treatment resulted in dramatically attenuated tumor growth in BRAFMT xenografts.

Conclusions: Our findings indicate that c-MET/STAT3-dependent upregulation of c-FLIPL expression is an important escape mechanism following MEKi treatment in BRAFMT colorectal cancer. Thus, combinations of MEKi with inhibitors of c-MET or c-FLIP (e.g., HDAC inhibitors) could be potential novel treatment strategies for BRAFMT colorectal cancer.

Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition

We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome.

Sonification as Concurrent Augmented Feedback for Motor Skill Learning and the Importance of Mapping Design

In recent years, sonification of movement has emerged as a viable method for the provision of feedback in motor learning. Despite some experimental validation of its utility, controlled trials to test the usefulness of sonification in a motor learning context are still rare. As such, there are no accepted conventions for dealing with its implementation. This article addresses the question of how continuous movement information should be best presented as sound to be fed back to the learner. It is proposed that to establish effective approaches to using sonification in this context, consideration must be given to the processes that underlie motor learning, in particular the nature of the perceptual information available to the learner for performing the task at hand. Although sonification has much potential in movement performance enhancement, this potential is largely unrealised as of yet, in part due to the lack of a clear framework for sonification mapping: the relationship between movement and sound. By grounding mapping decisions in a firmer understanding of how perceptual information guides learning, and an embodied cognition stance in general, it is hoped that greater advances in use of sonification to enhance motor learning can be achieved.