Subjective visual perception: from local processing to emergent phenomena of brain activity

The combination of electrophysiological recordings with ambiguous visual stimulation made possible the detection of neurons that represent the content of subjective visual perception and perceptual suppression in multiple cortical and subcortical brain regions. These neuronal populations, commonly referred to as the neural correlates of consciousness, are more likely to be found in the temporal and prefrontal cortices as well as the pulvinar, indicating that the content of perceptual awareness is represented with higher fidelity in higher-order association areas of the cortical and thalamic hierarchy, reflecting the outcome of competitive interactions between conflicting sensory information resolved in earlier stages. However, despite the significant insights into conscious perception gained through monitoring the activities of single neurons and small, local populations, the immense functional complexity of the brain arising from correlations in the activity of its constituent parts suggests that local, microscopic activity could only partially reveal the mechanisms involved in perceptual awareness. Rather, the dynamics of functional connectivity patterns on a mesoscopic and macroscopic level could be critical for conscious perception. Understanding these emergent spatio-temporal patterns could be informative not only for the stability of subjective perception but also for spontaneous perceptual transitions suggested to depend either on the dynamics of antagonistic ensembles or on global intrinsic activity fluctuations that may act upon explicit neural representations of sensory stimuli and induce perceptual reorganization. Here, we review the most recent results from local activity recordings and discuss the potential role of effective, correlated interactions during perceptual awareness.     

Experience-dependent emergence of a grouping bias

Humans share with non-human animals perceptual biases that might form the basis of complex cognitive abilities. One example comes from the principles described by the iambic–trochaic law (ITL). According to the ITL, sequences of sounds varying in duration are grouped as iambs, whereas sequences varying in intensity are grouped as trochees. These grouping biases have gained much attention because they might help pre-lexical infants bootstrap syntactic parameters (such as word order) in their language. Here, we explore how experience triggers the emergence of perceptual grouping biases in a non-human species. We familiarized rats with either long–short or short–long tone pairs. We then trained the animals to discriminate between sequences of alternating and randomly ordered tones. Results showed animals developed a grouping bias coherent with the exposure they had. Together with results observed in human adults and infants, these results suggest that experience modulates perceptual organizing principles that are present across species.     

Independent psychophysical measurement of experimental modulations in the somatotopy of cutaneous heat-pain stimuli

Distortions of the body image have been repeatedly reported for various clinical conditions, but direct experimental analyses of the perceptual changes involved are still scarce. In addition, most experimental studies rely on cerebral activation patterns to assess neuroplastic changes in central representation, although the relationship between cerebral topography and the topology of the perceptual space is not clear. This study examines whether the direct psychophysical mapping approach we introduced recently (Trojan et al., Brain Res 2006;1120:106–113) is capable of tracking perceptual distortions in the somatotopic representation of heat-pain stimuli. Eleven healthy participants indicated the perceived positions of CO₂ laser stimuli, repetitively presented to the dorsal forearm, with a 3D tracking system in two consecutive sessions, separated by the topical application of capsaicin cream. In line with earlier reports, we expected that the resulting individual perceptual maps (i.e., one-dimensional projections of the perceived positions onto the forearm surface) would be subject to modulation through the altered sensory input, to be measured in terms of altered topological parameters. We found that the topology and metrics of the somatotopic representation were well preserved in the second session, but that the perceptual map was compressed to a smaller range in 9 out of 11 participants. By providing dimensional measures of perceptual representations, perceptual maps constitute an independent, genuinely psychological complement to the topography of cortical activations measured with neuroimaging methods. In addition, we expect them to be useful in diagnosing pathological changes in body perception accompanying chronic pain and other disorders.     

Distortions of subjective time perception within and across senses

Background

The ability to estimate the passage of time is of fundamental importance for perceptual and cognitive processes. One experience of time is the perception of duration, which is not isomorphic to physical duration and can be distorted by a number of factors. Yet, the critical features generating these perceptual shifts in subjective duration are not understood.

Methodology/Findings

We used prospective duration judgments within and across sensory modalities to examine the effect of stimulus predictability and feature change on the perception of duration. First, we found robust distortions of perceived duration in auditory, visual and auditory-visual presentations despite the predictability of the feature changes in the stimuli. For example, a looming disc embedded in a series of steady discs led to time dilation, whereas a steady disc embedded in a series of looming discs led to time compression. Second, we addressed whether visual (auditory) inputs could alter the perception of duration of auditory (visual) inputs. When participants were presented with incongruent audio-visual stimuli, the perceived duration of auditory events could be shortened or lengthened by the presence of conflicting visual information; however, the perceived duration of visual events was seldom distorted by the presence of auditory information and was never perceived shorter than their actual durations.

Conclusions/Significance

These results support the existence of multisensory interactions in the perception of duration and, importantly, suggest that vision can modify auditory temporal perception in a pure timing task. Insofar as distortions in subjective duration can neither be accounted for by the unpredictability of an auditory, visual or auditory-visual event, we propose that it is the intrinsic features of the stimulus that critically affect subjective time distortions.     

Attentional Tuning Resets after Failures of Perceptual Awareness

Key to successfully negotiating our environment is our ability to adapt to current settings based on recent experiences and behaviour. Response conflict paradigms (e.g., the Stroop task) have provided evidence for increases in executive control after errors, leading to slowed responses that are more likely to be correct, and less susceptible to response congruency effects. Here we investigate whether failures of perceptual awareness, rather than failures at decisional or response stages of information processing, lead to similar adjustments in visual attention. We employed an attentional blink task in which subjects often fail to consciously register the second of two targets embedded in a rapid serial visual presentation stream of distractors, and examined how target errors influence performance on subsequent trials. Performance was inferior after Target 2 errors and these inter-trial effects were independent of the temporal lag between the targets and were not due to more global changes in attention across runs of trials. These results shed light on the nature of attentional calibration in response to failures of perceptual consciousness.     

Visual clutter causes high-magnitude errors

Perceptual decisions are often made in cluttered environments, where a target may be confounded with competing “distractor” stimuli. Although many studies and theoretical treatments have highlighted the effect of distractors on performance, it remains unclear how they affect thequality of perceptual decisions. Here we show that perceptual clutter leads not only to an increase in judgment errors, but also to an increase in perceived signal strength and decision confidence on erroneous trials. Observers reported simultaneously the direction and magnitude of the tilt of a target grating presented either alone, or together with vertical distractor stimuli. When presented in isolation, observers perceived isolated targets as only slightly tilted on error trials, and had little confidence in their decision. When the target was embedded in distractors, however, they perceived it to be strongly tilted on error trials, and had high confidence of their (erroneous) decisions. The results are well explained by assuming that the observers' internal representation of stimulus orientation arises from a nonlinear combination of the outputs of independent noise-perturbed front-end detectors. The implication that erroneous perceptual decisions in cluttered environments are made with high confidence has many potential practical consequences, and may be extendable to decision-making in general.     

Returning to basic principles to develop more effective treatments for central nervous system disorders

Development of new treatments for diseases of the central nervous system (CNS) is stalled. Of candidate drugs developed through costly preclinical research, 93% fail clinical trials. Hoped-for improvements in diagnosis or treatment from decades of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) imaging have yet to materialize. To understand what we are doing wrong, I begin with recognition that all aspects of life, including the brain and mind, are physical phenomena consistent with processes described by physicists. Two processes, emergence and entropy, are of particular relevance in complex arrangements of matter that constitute life in general and the brain in particular. The human brain functions through dynamically reconfiguring and hierarchically organized neural functional systems with emergent properties of cognition, emotion, and conscious experience. These systems are shaped and maintained by negentropic environmental input transformed by sensory receptors into neural signals that trigger epigenetic neuroplastic processes. CNS diseases produce clinical disorders by disrupting these systems. As researchers seek appropriate levels of system organization at which to characterize and treat illness, focus has been on medications that impact processes at lower levels or transcranial electric or magnetic stimulation that impact broad contiguous swaths of tissue. Neither align with the brain’s neurosystem organization and therefore lack specificity necessary to be effective and to limit side effects. Digital neurotherapies (DNTs), in contrast, align with neurosystem organization and achieve the needed specificity using the same input pathways and neuroplastic processes that created the neural systems organization to repair it. The omission of DNTs from major systems-based initiatives represents powerful residua of dualist thinking. Interventions based on perceptual and cognitive processes are not thought of as being as physical as drugs or electric or magnetic stimulation through the skull. In fact, they are examples of the most basic processes that create and support life itself.     

The complexity of targeting EGFR signalling in cancer: from expression to turnover

The epidermal growth factor receptor (ErbB1 or EGFR) has been found to be altered in a variety of human cancers. A number of agents targeting these receptors, including specific antibodies directed against the ligand-binding domain of the receptor and small molecules that inhibit kinase activity are either in clinical trials or are already approved for clinical treatment. However, identifying patients that are likely to respond to such treatments has been challenging. As a consequence, it still remains important to identify additional alterations of the tumor cell that contribute to the response to EGFR-targeted agents. While EGFR-mediated signalling pathways have been well established, there is still a rather limited understanding of how intracellular protein-protein interactions, ubiquitination, endocytosis and subsequent degradation of EGFR contribute to the determination of sensitivity to EGFR targeting agents and are emerging areas of investigation. This review primarily focuses on the basic signal transduction pathways mediated through activated membrane bound and/or endosomal EGFR and emphasizes the need to co-target additional proteins that function either upstream or downstream of EGFR to improve cancer therapy.     

Binaral Rivalry in the Presence of Visual Perceptual and Semantic Influences

When two different odorants are presented simultaneously to the two nostrils, we experience alternations in olfactory percepts, a phenomenon called binaral rivalry. Little is known about the nature of such alternations. Here we investigate this issue by subjecting unstable and stable olfactory percepts to the influences of visual perceptual or semantic cues as participants engage in simultaneous samplings of either two different odorants (binaral) or a single odorant and water (mononaral), one to each nostril. We show that alternations of olfactory percepts in the binaral setting persist in the presence of visual perceptual and semantic modulations. We also show that perceptual cues have a stronger effect than semantic cues in the binaral case, whereas their effects are comparable in the mononaral setting. Our findings provide evidence that an inherent, stimulus-driven process underlies binaral rivalry despite its general susceptibility to top-down influences.     

Processing laboratory considerations for multi-center cellular therapy clinical trials: a report from the Consortium for Pediatric Cellular Immunotherapy

``Cellular therapies first emerged as specialized therapies only available at a few “boutique” centers worldwide. To ensure broad access to these investigational therapies—regardless of geography, demographics and other factors—more and more academic clinical trials are becoming multi-center. Such trials are typically performed with a centralized manufacturing facility receiving the starting material and shipping the final product, either fresh or cryopreserved, to the patient's institution for infusion. As these academic multi-center trials increase in number, it is critical to have procedures and training programs in place to allow these sites that are remote from the production facility to successfully participate in these trials and satisfy regulatory compliance and patient safety best practices. Based on the collective experience of the Consortium for Pediatric Cellular Immunotherapy, the authors summarize the challenges encountered by institutions in shipping and receiving the starting material and final product as well as preparing the final product for infusion. The authors also discuss best practices implemented by each of the consortia institutions to overcome these challenges.     

Formal learning theory dissociates brain regions with different temporal integration

Learning can be characterized as the extraction of reliable predictions about stimulus occurrences from past experience. In two experiments, we investigated the interval of temporal integration of previous learning trials in different brain regions using implicit and explicit Pavlovian fear conditioning with a dynamically changing reinforcement regime in an experimental setting. With formal learning theory (the Rescorla-Wagner model), temporal integration is characterized by the learning rate. Using fMRI and this theoretical framework, we are able to distinguish between learning-related brain regions that show long temporal integration (e.g., amygdala) and higher perceptual regions that integrate only over a short period of time (e.g., fusiform face area, parahippocampal place area). This approach allows for the investigation of learning-related changes in brain activation, as it can dissociate brain areas that differ with respect to their integration of past learning experiences by either computing long-term outcome predictions or instantaneous reinforcement expectancies.     

Depth generalization from stereo to motion parallax in the owl

Although many sources of three-dimensional information have been isolated and demonstrated to contribute independently, to depth vision in animal studies, it is not clear whether these distinct cues are perceived to be perceptually equivalent. Such ability is observed in humans and would seem to be advantageous for animals as well in coping with the often co-varying (or ambiguous) information about the layout of physical space. We introduce the expression primary-depth-cue equivalence to refer to the ability to perceive mutually consistent information about differences in depth from either stereopsis or motion-parallax. We found that owls trained to detect relative depth as a perceptual category (objects versus holes) when specified by binocular disparity alone (stereopsis), immediately transferred this discrimination to novel stimuli where the equivalent depth categories were available only through differences in motion information produced by head movements (observer-produced motion-parallax). Motion-parallax discrimination did occur under monocular viewing conditions and reliable performance depended heavily on the amplitude of side-to-side head movements. The presence of primary-depth-cue equivalence in the visual system of the owl provides further conformation of the hypothesis that neural systems evolved to detect differences in either disparity or motion information are likely to share similar processing mechanisms.     

The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials

Objective To summarise comparisons of randomised clinical trials and non-randomised clinical trials, trials with adequately concealed random allocation versus inadequately concealed random allocation, and high quality trials versus low quality trials where the effect of randomisation could not be separated from the effects of other methodological manoeuvres.Design Systematic review.Selection criteria Cohorts or meta-analyses of clinical trials that included an empirical assessment of the relation between randomisation and estimates of effect.Data sources Cochrane Review Methodology Database, Medline, SciSearch, bibliographies, hand searching of journals, personal communication with methodologists, and the reference lists of relevant articles.Main outcome measures Relation between randomisation and estimates of effect.Results Eleven studies that compared randomised controlled trials with non-randomised controlled trials (eight for evaluations of the same intervention and three across different interventions), two studies that compared trials with adequately concealed random allocation and inadequately concealed random allocation, and five studies that assessed the relation between quality scores and estimates of treatment effects, were identified. Failure to use random allocation and concealment of allocation were associated with relative increases in estimates of effects of 150% or more, relative decreases of up to 90%, inversion of the estimated effect and, in some cases, no difference. On average, failure to use randomisation or adequate concealment of allocation resulted in larger estimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups.Conclusions Failure to use adequately concealed random allocation can distort the apparent effects of care in either direction, causing the effects to seem either larger or smaller than they really are. The size of these distortions can be as large as or larger than the size of the effects that are to be detected.

Key messages

• Empirical studies support using random allocation in clinical trials and ensuring that the allocation process is concealed—that is, that assignment is impervious to any influence by the people making the allocation
• The effect of not using concealed random allocation can be as large or larger than the effects of worthwhile interventions
• On average, failure to use concealed random allocation results in overestimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups, but it can result in underestimates of effect, reverse the direction of effect, mask an effect, or give similar estimates of effect
• The adequacy of allocation concealment may be a more sensitive measure of bias in clinical trials than scales used to assess the quality of clinical trials
• It is a paradox that the unpredictability of randomisation is the best protection against the unpredictability of the extent and direction of bias in clinical trials that are not properly randomised

     

Avoiding the pitfalls of sponsored multicentre research in general practice.

Research in general practice is becoming increasingly popular, and most general practitioners will sooner or later have to decide whether to become involved with clinical trials sponsored by drug companies. This paper outlines the advantages and disadvantages of multicentre research--based on experience of running a research group since the early 1980s--to enable doctors to reach the appropriate decision and to avoid involvement in trials which are either unethical or ineffective.     

Emerging trends in COVID-19 treatment: learning from inflammatory conditions associated with cellular therapies

Coronavirus disease 2019 (SARS-CoV2) is an active global health threat for which treatments are desperately being sought. Even though most people infected experience mild to moderate respiratory symptoms and recover with supportive care, certain vulnerable hosts develop severe clinical deterioration. While several drugs are currently being investigated in clinical trials, there are currently no approved treatments or vaccines for COVID-19 and hence there is an unmet need to explore additional therapeutic options. At least three inflammatory disorders or syndromes associated with immune dysfunction have been described in the context of cellular therapy. Specifically, Cytokine Release Syndrome (CRS), Immune Reconstitution Inflammatory Syndrome (IRIS), and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) all have clinical and laboratory characteristics in common with COVID19 and associated therapies that could be worth testing in the context of clinical trials. Here we discuss these diseases, their management, and potential applications of these treatment in the context of COVID-19. We also discuss current cellular therapies that are being evaluated for the treatment of COVID-19 and/or its associated symptoms.     

Improving the performance of the amblyopic visual system

Experience-dependent plasticity is closely linked with the development of sensory function; however, there is also growing evidence for plasticity in the adult visual system. This review re-examines the notion of a sensitive period for the treatment of amblyopia in the light of recent experimental and clinical evidence for neural plasticity. One recently proposed method for improving the effectiveness and efficiency of treatment that has received considerable attention is ‘perceptual learning’. Specifically, both children and adults with amblyopia can improve their perceptual performance through extensive practice on a challenging visual task. The results suggest that perceptual learning may be effective in improving a range of visual performance and, importantly, the improvements may transfer to visual acuity. Recent studies have sought to explore the limits and time course of perceptual learning as an adjunct to occlusion and to investigate the neural mechanisms underlying the visual improvement. These findings, along with the results of new clinical trials, suggest that it might be time to reconsider our notions about neural plasticity in amblyopia.     

Stimulus Familiarity Affects Perceptual Restoration in the European Starling (Sturnus vulgaris)

Background

Humans can easily restore a speech signal that is temporally masked by an interfering sound (e.g., a cough masking parts of a word in a conversation), and listeners have the illusion that the speech continues through the interfering sound. This perceptual restoration for human speech is affected by prior experience. Here we provide evidence for perceptual restoration in complex vocalizations of a songbird that are acquired by vocal learning in a similar way as humans learn their language.

Methodology/Principal Findings

European starlings were trained in a same/different paradigm to report salient differences between successive sounds. The birds'' response latency for discriminating between a stimulus pair is an indicator for the salience of the difference, and these latencies can be used to evaluate perceptual distances using multi-dimensional scaling. For familiar motifs the birds showed a large perceptual distance if discriminating between song motifs that were muted for brief time periods and complete motifs. If the muted periods were filled with noise, the perceptual distance was reduced. For unfamiliar motifs no such difference was observed.

Conclusions/Significance

The results suggest that starlings are able to perceptually restore partly masked sounds and, similarly to humans, rely on prior experience. They may be a suitable model to study the mechanism underlying experience-dependent perceptual restoration.     

Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy?

PURPOSE OF REVIEW: Subgroups with diabetes or with features of the metabolic syndrome have been increasingly highlighted in large clinical endpoint trials with lipid therapy. This review will focus on the results of trials with statins or fibrates and examine the strength of the evidence for major cardiovascular event reduction with each kind of therapy in these high-risk subgroups that typically have low-to-moderate levels of LDL cholesterol. RECENT FINDINGS: Of six statin trials in populations with moderately increased LDL cholesterol only one, the Heart Protection Study, has shown that statin therapy will significantly reduce the major coronary heart disease events of non-fatal myocardial infarction or coronary heart disease death in diabetes. None of these trials has shown that statins have a particular predilection for reducing cardiovascular events in individuals with higher levels of body weight or other features of the metabolic syndrome. There are far fewer trial data with fibrates than with statins. However, the Veterans Affairs High Density Lipoprotein Intervention Trial has shown that a fibrate can significantly reduce major cardiovascular events, most particularly coronary heart disease death, in those with diabetes as well as those without diabetes who have insulin resistance. Indeed, all fibrate trials show that this therapy appears to selectively benefit the individual with obesity and features of the metabolic syndrome. SUMMARY: Based principally on evidence from the Veterans Affairs High Density Lipoprotein Intervention Trial and the cumulative experience with statins, trial data would thus far suggest that the patient with a modest increase in LDL cholesterol who has diabetes or features of the metabolic syndrome might be likely to achieve more substantial cardiovascular benefit from fibrate than from statin therapy.     

Segregation of autosomes during spermatogenesis in the peach-potato aphid (Myzus persicae) (Sulzer) (Hemiptera: Aphididae)

Most aphids are cyclic parthenogens, so are ideal models in studies of the mechanisms and consequences of sex and recombination. However, owing to a shortage of physical and genetic markers, there have been few studies of the most fundamental genetic processes in these organisms. For example, it is not known whether autosomal segregation during male spermatogenesis is in Mendelian proportions: we address that question here. The aphid Myzus persicae has a typical karyotype of 2n = 12 in females (XX), while males are XO (2n = 11). During male meiosis, only the spermatocytes with an X chromosome are viable. We hypothesized that assortment of autosomes might be non-random because chromosomal imprinting leading to elimination of the paternal autosomes is seen in the closely related coccoids. In other aphid models, we have observed segregation distortions at single microsatellite loci (Wilson, 2000). Such distortions may have nothing to do with 'selfish' behaviour, but may be caused by mutation accumulation causing fitness differentials. Thus single-locus distortions might be predicted to be more likely to be detected via the male lines of clones that have lost the ability to reproduce sexually (male-producing obligate parthenogenesis (androcyclic)). Using microsatellites we show that genetic imprinting or selfish autosome behaviour does not occur in male M. persicae. Generally, loci segregated in Mendelian proportions in both sexes of cyclically parthenogenetic (holocyclic) clones. However, in androcyclic clones, segregation distortions consistently involved the same two autosomes. This is consistent with linkage of markers to deleterious mutations associated with a loss of sexual reproduction.