Neurite orientation and dispersion density imaging (NODDI) detects cortical and corticospinal tract degeneration in ALS.

BACKGROUND: Corticospinal tract (CST) degeneration and cortical atrophy are consistent features of amyotrophic lateral sclerosis (ALS). We hypothesised that neurite orientation dispersion and density imaging (NODDI), a multicompartment model of diffusion MRI, would reveal microstructural changes associated with ALS within the CST and precentral gyrus (PCG) 'in vivo'. METHODS: 23 participants with sporadic ALS and 23 healthy controls underwent diffusion MRI. Neurite density index (NDI), orientation dispersion index (ODI) and free water fraction (isotropic compartment (ISO)) were derived. Whole brain voxel-wise analysis was performed to assess for group differences. Standard diffusion tensor imaging (DTI) parameters were computed for comparison. Subgroup analysis was performed to investigate for NODDI parameter differences relating to bulbar involvement. Correlation of NODDI parameters with clinical variables were also explored. The results were accepted as significant where p<0.05 after family-wise error correction at the cluster level, clusters formed with p<0.001. RESULTS: In the ALS group NDI was reduced in the extensive regions of the CST, the corpus callosum and the right PCG. ODI was reduced in the right anterior internal capsule and the right PCG. Significant differences in NDI were detected between subgroups stratified according to the presence or absence of bulbar involvement. ODI and ISO correlated with disease duration. CONCLUSIONS: NODDI demonstrates that axonal loss within the CST is a core feature of degeneration in ALS. This is the main factor contributing to the altered diffusivity profile detected using DTI. NODDI also identified dendritic alterations within the PCG, suggesting microstructural cortical dendritic changes occur together with CST axonal damage.

Visual Perceptual Echo Reflects Learning of Regularities in Rapid Luminance Sequences.

A novel neural signature of active visual processing has recently been described in the form of the "perceptual echo", in which the cross-correlation between a sequence of randomly fluctuating luminance values and occipital electrophysiological signals exhibits a long-lasting periodic (∼100 ms cycle) reverberation of the input stimulus (VanRullen and Macdonald, 2012). As yet, however, the mechanisms underlying the perceptual echo and its function remain unknown. Reasoning that natural visual signals often contain temporally predictable, though nonperiodic features, we hypothesized that the perceptual echo may reflect a periodic process associated with regularity learning. To test this hypothesis, we presented subjects with successive repetitions of a rapid nonperiodic luminance sequence, and examined the effects on the perceptual echo, finding that echo amplitude linearly increased with the number of presentations of a given luminance sequence. These data suggest that the perceptual echo reflects a neural signature of regularity learning.Furthermore, when a set of repeated sequences was followed by a sequence with inverted luminance polarities, the echo amplitude decreased to the same level evoked by a novel stimulus sequence. Crucially, when the original stimulus sequence was re-presented, the echo amplitude returned to a level consistent with the number of presentations of this sequence, indicating that the visual system retained sequence-specific information, for many seconds, even in the presence of intervening visual input. Altogether, our results reveal a previously undiscovered regularity learning mechanism within the human visual system, reflected by the perceptual echo.SIGNIFICANCE STATEMENT How the brain encodes and learns fast-changing but nonperiodic visual input remains unknown, even though such visual input characterizes natural scenes. We investigated whether the phenomenon of "perceptual echo" might index such learning. The perceptual echo is a long-lasting reverberation between a rapidly changing visual input and evoked neural activity, apparent in cross-correlations between occipital EEG and stimulus sequences, peaking in the alpha (∼10 Hz) range. We indeed found that perceptual echo is enhanced by repeatedly presenting the same visual sequence, indicating that the human visual system can rapidly and automatically learn regularities embedded within fast-changing dynamic sequences. These results point to a previously undiscovered regularity learning mechanism, operating at a rate defined by the alpha frequency.

Response to Ruby et al: On a 'failed' attempt to manipulate conscious perception with transcranial magnetic stimulation to prefrontal cortex.

Does disruption of prefrontal cortical activity using transcranial magnetic stimulation (TMS) impair visual metacognition? An initial study supporting this idea (Rounis, Maniscalco, Rothwell, Passingham, & Lau, 2010) motivated an attempted replication and extension (Bor, Schwartzman, Barrett, & Seth, 2017). Bor et al. failed to replicate the initial study, concluding that there was not good evidence that TMS to dorsolateral prefrontal cortex impairs visual metacognition. This failed replication has recently been critiqued by some of the authors of the initial study (Ruby, Maniscalco, & Peters, 2018). Here we argue that these criticisms are misplaced. In our response, we encounter some more general issues concerning good practice in replication of cognitive neuroscience studies, and in setting criteria for excluding data when employing statistical analyses like signal detection theory. We look forward to further studies investigating the role of prefrontal cortex in metacognition, with increasingly refined methodologies, motivated by the discussions in this series of papers.

Modelling phenomenological differences in aetiologically distinct visual hallucinations using deep neural networks.

Visual hallucinations (VHs) are perceptions of objects or events in the absence of the sensory stimulation that would normally support such perceptions. Although all VHs share this core characteristic, there are substantial phenomenological differences between VHs that have different aetiologies, such as those arising from Neurodegenerative conditions, visual loss, or psychedelic compounds. Here, we examine the potential mechanistic basis of these differences by leveraging recent advances in visualising the learned representations of a coupled classifier and generative deep neural network-an approach we call 'computational (neuro)phenomenology'. Examining three aetiologically distinct populations in which VHs occur-Neurodegenerative conditions (Parkinson's Disease and Lewy Body Dementia), visual loss (Charles Bonnet Syndrome, CBS), and psychedelics-we identified three dimensions relevant to distinguishing these classes of VHs: realism (veridicality), dependence on sensory input (spontaneity), and complexity. By selectively tuning the parameters of the visualisation algorithm to reflect influence along each of these phenomenological dimensions we were able to generate 'synthetic VHs' that were characteristic of the VHs experienced by each aetiology. We verified the validity of this approach experimentally in two studies that examined the phenomenology of VHs in Neurodegenerative and CBS patients, and in people with recent psychedelic experience. These studies confirmed the existence of phenomenological differences across these three dimensions between groups, and crucially, found that the appropriate synthetic VHs were rated as being representative of each group's hallucinatory phenomenology. Together, our findings highlight the phenomenological diversity of VHs associated with distinct causal factors and demonstrate how a neural network model of visual phenomenology can successfully capture the distinctive visual characteristics of hallucinatory experience.

Using Extended Reality to Study the Experience of Presence.

Extended reality (XR), encompassing various forms of virtual reality (VR) and augmented reality (AR), has become a powerful experimental tool in consciousness research due to its capability to create holistic and immersive experiences of oneself and surrounding environments through simulation. One hallmark of a successful XR experience is when it elicits a strong sense of presence, which can be thought of as a subjective sense of reality of the self and the world. Although XR research has shed light on many factors that may influence presence (or its absence) in XR environments, there remains much to be discovered about the detailed and diverse phenomenology of presence, and the neurocognitive mechanisms that underlie it. In this chapter, we analyse the concept of presence and relate it to the way in which humans may generate and maintain a stable sense of reality during both natural perception and virtual experiences. We start by reviewing the concept of presence as developed in XR research, covering both factors that may influence presence and potential ways of measuring presence. We then discuss the phenomenological characteristics of presence in human consciousness, drawing on clinical examples where presence is disturbed. Next, we describe two experiments using XR that investigated the effects of sensorimotor contingency and affordances on a specific form of presence related to the sense of objects as really existing in the world, referred to as 'objecthood'. We then go beyond perceptual presence to discuss the concept of 'conviction about reality', which corresponds to people's beliefs about the reality status of their perceptual experiences. We finish by exploring how the novel XR method of 'Substitutional Reality' can allow experimental investigation of these topics, opening new experimental directions for studying presence beyond the 'as-if' experience of fully simulated environments.

Sensorimotor contingency modulates breakthrough of virtual 3D objects during a breaking continuous flash suppression paradigm.

To investigate how embodied sensorimotor interactions shape subjective visual experience, we developed a novel combination of Virtual Reality (VR) and Augmented Reality (AR) within an adapted breaking continuous flash suppression (bCFS) paradigm. In a first experiment, participants manipulated novel virtual 3D objects, viewed through a head-mounted display, using three interlocking cogs. This setup allowed us to manipulate the sensorimotor contingencies governing interactions with virtual objects, while characterising the effects on subjective visual experience by measuring breakthrough times from bCFS. We contrasted the effects of the congruency (veridical versus reversed sensorimotor coupling) and contingency (live versus replayed interactions) using a motion discrimination task. The results showed that the contingency but not congruency of sensorimotor coupling affected breakthrough times, with live interactions displaying faster breakthrough times. In a second experiment, we investigated how the contingency of sensorimotor interactions affected object category discrimination within a more naturalistic setting, using a motion tracker that allowed object interactions with increased degrees of freedom. We again found that breakthrough times were faster for live compared to replayed interactions (contingency effect). Together, these data demonstrate that bCFS breakthrough times for unfamiliar 3D virtual objects are modulated by the contingency of the dynamic causal coupling between actions and their visual consequences, in line with theories of perception that emphasise the influence of sensorimotor contingencies on visual experience. The combination of VR/AR and motion tracking technologies with bCFS provides a novel methodology extending the use of binocular suppression paradigms into more dynamic and realistic sensorimotor environments.

Neurophenomenology of induced and natural synaesthesia.

People with synaesthesia have additional perceptual experiences, which are automatically and consistently triggered by specific inducing stimuli. Synaesthesia therefore offers a unique window into the neurocognitive mechanisms underlying conscious perception. A long-standing question in synaesthesia research is whether it is possible to artificially induce non-synaesthetic individuals to have synaesthesia-like experiences. Although synaesthesia is widely considered a congenital condition, increasing evidence points to the potential of a variety of approaches to induce synaesthesia-like experiences, even in adulthood. Here, we summarize a range of methods for artificially inducing synaesthesia-like experiences, comparing the resulting experiences to the key hallmarks of natural synaesthesia which include consistency, automaticity and a lack of 'perceptual presence'. We conclude that a number of aspects of synaesthesia can be artificially induced in non-synaesthetes. These data suggest the involvement of developmental and/or learning components in the acquisition of synaesthesia, and they extend previous reports of perceptual plasticity leading to dramatic changes in perceptual phenomenology in adults. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.

Coordinated neural, behavioral, and phenomenological changes in perceptual plasticity through overtraining of synesthetic associations.

Synesthesia is associated with additional perceptual experiences, which are automatically and consistently triggered by specific inducing stimuli. Synesthesia is also accompanied by more general sensory and cortical changes, including enhanced modality-specific cortical excitability. Extensive cognitive training has been shown to generate synesthesia-like phenomenology but whether these experiences are accompanied by neurophysiological changes characteristic of synesthesia remains unknown. Addressing this question provides a unique opportunity to elucidate the neural basis of perceptual plasticity relevant to conscious experiences. Here we investigate whether extensive training of letter-color associations leads not only to synesthetic experiences, but also to changes in cortical excitability. We confirm that overtraining synesthetic associations results in synesthetic phenomenology. Stroop tasks further reveal synesthesia-like performance following training. Electroencephalography and transcranial magnetic stimulation show, respectively, enhanced visual evoked potentials (in response to untrained patterns) and lower phosphene thresholds, demonstrating specific cortical changes. An active (using letter-symbol training) and a passive control confirmed these results were due to letter-color training and not simply to repeated testing. Summarizing, we demonstrate specific cortical changes, following training-induced acquisition of synesthetic phenomenology that are characteristic of genuine synesthesia. Collectively, our data reveal dramatic plasticity in human visual perception, expressed through a coordinated set of behavioral, neurophysiological, and phenomenological changes.

Theta-burst transcranial magnetic stimulation to the prefrontal or parietal cortex does not impair metacognitive visual awareness.

Neuroimaging studies commonly associate dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex with conscious perception. However, such studies only investigate correlation, rather than causation. In addition, many studies conflate objective performance with subjective awareness. In an influential recent paper, Rounis and colleagues addressed these issues by showing that continuous theta burst transcranial magnetic stimulation (cTBS) applied to the DLPFC impaired metacognitive (subjective) awareness for a perceptual task, while objective performance was kept constant. We attempted to replicate this finding, with minor modifications, including an active cTBS control site. Using a between-subjects design for both DLPFC and posterior parietal cortices, we found no evidence of a cTBS-induced metacognitive impairment. In a second experiment, we devised a highly rigorous within-subjects cTBS design for DLPFC, but again failed to find any evidence of metacognitive impairment. One crucial difference between our results and the Rounis study is our strict exclusion of data deemed unsuitable for a signal detection theory analysis. Indeed, when we included this unstable data, a significant, though invalid, metacognitive impairment was found. These results cast doubt on previous findings relating metacognitive awareness to DLPFC, and inform the current debate concerning whether or not prefrontal regions are preferentially implicated in conscious perception.

A Deep-Dream Virtual Reality Platform for Studying Altered Perceptual Phenomenology.

Altered states of consciousness, such as psychotic or pharmacologically-induced hallucinations, provide a unique opportunity to examine the mechanisms underlying conscious perception. However, the phenomenological properties of these states are difficult to isolate experimentally from other, more general physiological and cognitive effects of psychoactive substances or psychopathological conditions. Thus, simulating phenomenological aspects of altered states in the absence of these other more general effects provides an important experimental tool for consciousness science and psychiatry. Here we describe such a tool, which we call the Hallucination Machine. It comprises a novel combination of two powerful technologies: deep convolutional neural networks (DCNNs) and panoramic videos of natural scenes, viewed immersively through a head-mounted display (panoramic VR). By doing this, we are able to simulate visual hallucinatory experiences in a biologically plausible and ecologically valid way. Two experiments illustrate potential applications of the Hallucination Machine. First, we show that the system induces visual phenomenology qualitatively similar to classical psychedelics. In a second experiment, we find that simulated hallucinations do not evoke the temporal distortion commonly associated with altered states. Overall, the Hallucination Machine offers a valuable new technique for simulating altered phenomenology without directly altering the underlying neurophysiology.

Adults can be trained to acquire synesthetic experiences.

Synesthesia is a condition where presentation of one perceptual class consistently evokes additional experiences in different perceptual categories. Synesthesia is widely considered a congenital condition, although an alternative view is that it is underpinned by repeated exposure to combined perceptual features at key developmental stages. Here we explore the potential for repeated associative learning to shape and engender synesthetic experiences. Non-synesthetic adult participants engaged in an extensive training regime that involved adaptive memory and reading tasks, designed to reinforce 13 specific letter-color associations. Following training, subjects exhibited a range of standard behavioral and physiological markers for grapheme-color synesthesia; crucially, most also described perceiving color experiences for achromatic letters, inside and outside the lab, where such experiences are usually considered the hallmark of genuine synesthetes. Collectively our results are consistent with developmental accounts of synesthesia and illuminate a previously unsuspected potential for new learning to shape perceptual experience, even in adulthood.

In the blink of an eye: the contribution of microsaccadic activity to the induced γ band response.

In 2008 an article by Yuval-Greenberg and colleagues initiated a lively debate within the field of induced gamma band research. Their article suggested that scalp-recorded induced gamma band responses (iGBRs) to visual stimuli could be obscured by minute movements of extraocular muscles, called microsaccades, which are associated with the saccadic spike potentials (SPs). Yuval-Greenberg et al. (2008) proposed that the temporal and spectral characteristics of SPs could mask and have been previously mistaken for cortical induced gamma band activity. This review summarises the main findings of the report by Yuval-Greenberg et al. (2008) and the research that has emerged since its publication. Microsaccades and the associated SP waveforms are described in detail and their contribution to the iGBR discussed. Different lines of argument are considered that suggest that the scalp-recorded iGBR exists separate from ocular contributions. The article then considers techniques that are widely used to remove electroencephalogram (EEG) artefacts and their potential adaptation for the removal of SPs. The review closes by pointing to future directions that researchers may explore in order to disentangle neural iGBRs and artefactual, SP-related iGBRs, and to several routes which researchers may consider in order to increase the informative value of their scalp-recorded iGBR data. We conclude that further investigation and testing is necessary to develop signal processing tools that successfully identify and correct SPs in EEG data without distorting the neural iGBR.