Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematic in vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking. Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layers in vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI data (qT1, QSM), functional localizers of body parts (upper limb, lower limb, face) and layer modelling to systematically describe pathology in the primary motor cortex (M1), in 12 living ALS patients with reference to 12 matched controls. Longitudinal sampling was performed for a subset of patients. We calculated multimodal pathology maps for each layer (superficial layer, layer 5a, layer 5b, layer 6) of M1 to identify hot spots of demyelination, iron and calcium accumulation in different cortical fields. We show preserved mean cortical thickness and layer architecture of M1, despite significantly increased iron in layer 6 and significantly increased calcium in layer 5a and superficial layer, in patients compared to controls. The behaviourally first-affected cortical field shows significantly increased iron in L6 compared to other fields, while calcium accumulation is atopographic and significantly increased in the low myelin borders between cortical fields compared to the fields themselves. A subset of patients with longitudinal data shows that the low myelin borders are particularly disrupted and that calcium hot spots, but to a lesser extent iron hot spots, precede demyelination. Finally, we highlight that a very slow progressing patient (Patient P4) shows a distinct pathology profile compared to the other patients. Our data show that layer-specific markers of in vivo pathology can be identified in ALS patients with a single 7 T MRI measurement after first diagnosis, and that such data provide critical insights into the individual disease state. Our data highlight the non-topographic architecture of ALS disease spread and the role of calcium, rather than iron accumulation, in predicting future demyelination. We also highlight a potentially important role of low myelin borders, that are known to connect to multiple areas within the M1 architecture, in disease spread. Finally, the distinct pathology profile of a very-slow progressing patient (Patient P4) highlights a distinction between disease duration and progression. Our findings demonstrate the importance of in vivo histology imaging for the diagnosis and prognosis of neurodegenerative diseases such as ALS.

The 3D Structural Architecture of the Human Hand Area Is Nontopographic.

The functional topography of the human primary somatosensory cortex hand area is a widely studied model system to understand sensory organization and plasticity. It is so far unclear whether the underlying 3D structural architecture also shows a topographic organization. We used 7 Tesla (7T) magnetic resonance imaging (MRI) data to quantify layer-specific myelin, iron, and mineralization in relation to population receptive field maps of individual finger representations in Brodman area 3b (BA 3b) of human S1 in female and male younger adults. This 3D description allowed us to identify a characteristic profile of layer-specific myelin and iron deposition in the BA 3b hand area, but revealed an absence of structural differences, an absence of low-myelin borders, and high similarity of 3D microstructure profiles between individual fingers. However, structural differences and borders were detected between the hand and face areas. We conclude that the 3D structural architecture of the human hand area is nontopographic, unlike in some monkey species, which suggests a high degree of flexibility for functional finger organization and a new perspective on human topographic plasticity.SIGNIFICANCE STATEMENT Using ultra-high-field MRI, we provide the first comprehensive in vivo description of the 3D structural architecture of the human BA 3b hand area in relation to functional population receptive field maps. High similarity of precise finger-specific 3D profiles, together with an absence of structural differences and an absence of low-myelin borders between individual fingers, reveals the 3D structural architecture of the human hand area to be nontopographic. This suggests reduced structural limitations to cortical plasticity and reorganization and allows for shared representational features across fingers.

Reduced dimension stimulus decoding and column-based modeling reveal architectural differences of primary somatosensory finger maps between younger and older adults.

The primary somatosensory cortex (SI) contains fine-grained tactile representations of the body, arranged in an orderly fashion. The use of ultra-high resolution fMRI data to detect group differences, for example between younger and older adults' SI maps, is challenging, because group alignment often does not preserve the high spatial detail of the data. Here, we use robust-shared response modeling (rSRM) that allows group analyses by mapping individual stimulus-driven responses to a lower dimensional shared feature space, to detect age-related differences in tactile representations between younger and older adults using 7T-fMRI data. Using this method, we show that finger representations are more precise in Brodmann-Area (BA) 3b and BA1 compared to BA2 and motor areas, and that this hierarchical processing is preserved across age groups. By combining rSRM with column-based decoding (C-SRM), we further show that the number of columns that optimally describes finger maps in SI is higher in younger compared to older adults in BA1, indicating a greater columnar size in older adults' SI. Taken together, we conclude that rSRM is suitable for finding fine-grained group differences in ultra-high resolution fMRI data, and we provide first evidence that the columnar architecture in SI changes with increasing age.

Cross-dimensional interference between time and distance during spatial navigation is mediated by speed representations in intraparietal sulcus and area hMT.

When navigating a straight path, perceived travel time and perceived traveled distance are linked via movement speed. Behavioral studies have revealed systematic interferences between the perception of travel time and distance, but the role of neuronal representations of movement speed for these effects has not been addressed to date. Using a combined fMRI-behavioral paradigm, we investigate the neuronal representations that underlie cross-dimensional interferences between travel time and traveled distance. Participants underwent fMRI while experiencing visual forward movements for either a short or a long duration, and covering either a short or a long distance. At the behavioral level, we found bi-directional interference effects between time and distance perception, which was correlated with greater representational similarity in speed-sensitive brain regions. The strength of the distance-on-time effect scaled with representational similarity in the left human middle temporal complex (hMT+), and the strength of the time-on-distance effect scaled with representational similarity in the right intraparietal sulcus (IPS). In accordance with the idea that the interference is mediated by the perception of speed, distance-on-time and time-on-distance effects were of opposing directions. Increases in traveled distance led to increases in perceived travel time, while increases in travel time led to decreases in perceived traveled distance. Together, these findings support the view that cross-dimensional interference effects between travel time and traveled distance are mediated by neuronal representations of movement speed.

Autosuggestion: a cognitive process that empowers your brain?

Autosuggestion is a cognitive process that is believed to enable control over one's own cognitive and physiological states. Despite its potential importance for basic science and clinical applications, such as in rehabilitation, stress reduction, or pain therapy, the neurocognitive mechanisms and psychological concepts that underlie autosuggestion are poorly defined. Here, by reviewing empirical data on autosuggestion and related phenomena such as mental imagery, mental simulation, and suggestion, we offer a neurocognitive concept of autosuggestion. We argue that autosuggestion is characterized by three major factors: reinstantiation, reiteration, and volitional, active control over one's own physiological states. We also propose that autosuggestion might involve the 'overwriting' of existing predictions or brain states that expect the most common (but not desired) outcome. We discuss potential experimental paradigms that could be used to study autosuggestion in the future, and discuss the strengths and weaknesses of current evidence. This review provides a first overview on how to define, experimentally induce, and study autosuggestion, which may facilitate its use in basic science and clinical practice.

Discriminating Free Hand Movements Using Support Vector Machine and Recurrent Neural Network Algorithms.

Decoding natural hand movements is of interest for human-computer interaction and may constitute a helpful tool in the diagnosis of motor diseases and rehabilitation monitoring. However, the accurate measurement of complex hand movements and the decoding of dynamic movement data remains challenging. Here, we introduce two algorithms, one based on support vector machine (SVM) classification combined with dynamic time warping, and the other based on a long short-term memory (LSTM) neural network, which were designed to discriminate small differences in defined sequences of hand movements. We recorded hand movement data from 17 younger and 17 older adults using an exoskeletal data glove while they were performing six different movement tasks. Accuracy rates in decoding the different movement types were similarly high for SVM and LSTM in across-subject classification, but, for within-subject classification, SVM outperformed LSTM. The SVM-based approach, therefore, appears particularly promising for the development of movement decoding tools, in particular if the goal is to generalize across age groups, for example for detecting specific motor disorders or tracking their progress over time.

Encoding schemes in somatosensation: From micro- to meta-topography.

Encoding schemes are systematic large-scale arrangements that convert incoming sensory information into a format required for further information processing. The increased spatial resolution of brain images obtained with ultra-high field magnetic resonance imaging at 7 T (7T-MRI) and above increases the granularity and precision of processing units that mediate the link between neuronal encoding and functional readouts. Here, these new developments are reviewed with a focus on human tactile encoding schemes derived from small-scale processing units (in the order of 0.5-5 mm) that are relevant for theoretical and practical concepts of somatosensory encoding and cortical plasticity. Precisely, we review recent approaches to characterize meso-scale maps, layer units, and cortical fields in the sensorimotor cortex of the living human brain and discuss their impact on theories of perception, motor control, topographic encoding, and cortical plasticity. Finally, we discuss concepts on the integration of small-scale processing units into functional networks that span multiple topographic maps and multiple cortical areas. Novel research areas are highlighted that may help to bridge the gap between cortical microstructure and meta-topographic models on brain anatomy and function.

Visually-Driven Maps in Area 3b.

Sensory perception relies on the precise neuronal encoding of modality-specific environmental features in primary sensory cortices. Some studies have reported the penetration of signals from other modalities even into early sensory areas. So far, no comprehensive account of maps induced by "foreign sources" exists. We addressed this question using surface-based topographic mapping techniques applied to ultra-high resolution fMRI neuroimaging data, measured in female participants. We show that fine-grained finger maps in human primary somatosensory cortex, area 3b, are somatotopically activated not only during tactile mechanical stimulation, but also when viewing the same fingers being touched. Visually-induced maps were weak in amplitude, but overlapped with the stronger tactile maps tangential to the cortical sheet when finger touches were observed in both first- and third-person perspectives. However, visually-induced maps did not overlap tactile maps when the observed fingers were only approached by an object but not actually touched. Our data provide evidence that "foreign source maps" in early sensory cortices are present in the healthy human brain, that their arrangement is precise, and that their induction is feature-selective. The computations required to generate such specific responses suggest that counterflow (feedback) processing may be much more spatially specific than has been often assumed.SIGNIFICANCE STATEMENT Using ultra-high field fMRI, we provide empirical evidence that viewing touches activates topographically aligned single finger maps in human primary somatosensory cortical area 3b. This shows that "foreign source maps" in early sensory cortices are topographic, precise, and feature-selective in healthy human participants with intact sensory pathways.

Social targets improve body-based and environment-based strategies during spatial navigation.

Encoding the position of another person in space is vital for everyday life. Nevertheless, little is known about the specific navigational strategies associated with encoding the position of another person in the wider spatial environment. We asked two groups of participants to learn the location of a target (person or object) during active navigation, while optic flow information, a landmark, or both optic flow information and a landmark were available in a virtual environment. Whereas optic flow information is used for body-based encoding, such as the simulation of motor movements, landmarks are used to form an abstract, disembodied representation of the environment. During testing, we passively moved participants through virtual space, and compared their abilities to correctly decide whether the non-visible target was before or behind them. Using psychometric functions and the Bayes Theorem, we show that both groups assigned similar weights to body-based and environment-based cues in the condition, where both cue types were available. However, the group who was provided with a person as target showed generally reduced position errors compared to the group who was provided with an object as target. We replicated this effect in a second study with novel participants. This indicates a social advantage in spatial encoding, with facilitated processing of both body-based and environment-based cues during spatial navigation when the position of a person is encoded. This may underlie our critical ability to make accurate distance judgments during social interactions, for example, during fight or flight responses.

Body Topography Parcellates Human Sensory and Motor Cortex.

The cytoarchitectonic map as proposed by Brodmann currently dominates models of human sensorimotor cortical structure, function, and plasticity. According to this model, primary motor cortex, area 4, and primary somatosensory cortex, area 3b, are homogenous areas, with the major division lying between the two. Accumulating empirical and theoretical evidence, however, has begun to question the validity of the Brodmann map for various cortical areas. Here, we combined in vivo cortical myelin mapping with functional connectivity analyses and topographic mapping techniques to reassess the validity of the Brodmann map in human primary sensorimotor cortex. We provide empirical evidence that area 4 and area 3b are not homogenous, but are subdivided into distinct cortical fields, each representing a major body part (the hand and the face). Myelin reductions at the hand-face borders are cortical layer-specific, and coincide with intrinsic functional connectivity borders as defined using large-scale resting state analyses. Our data extend the Brodmann model in human sensorimotor cortex and suggest that body parts are an important organizing principle, similar to the distinction between sensory and motor processing.

How Visual Body Perception Influences Somatosensory Plasticity.

The study of somatosensory plasticity offers unique insights into the neuronal mechanisms that underlie human adaptive and maladaptive plasticity. So far, little attention has been paid on the specific influence of visual body perception on somatosensory plasticity and learning in humans. Here, we review evidence on how visual body perception induces changes in the functional architecture of the somatosensory system and discuss the specific influence the social environment has on tactile plasticity and learning. We focus on studies that have been published in the areas of human cognitive and clinical neuroscience and refer to animal studies when appropriate. We discuss the therapeutic potential of socially mediated modulations of somatosensory plasticity and introduce specific paradigms to induce plastic changes under controlled conditions. This review offers a contribution to understanding the complex interactions between social perception and somatosensory learning by focusing on a novel research field: socially mediated sensory plasticity.

On the bimanual integration of proprioceptive information.

Proprioception can be defined as the sense for body movement and position. While most sensory information can be successfully integrated across hemispheres, little is known about the bilateral integration of proprioceptive information. In two behavioural experiments, we investigated whether estimates of the position of one hand are influenced by simultaneous proprioceptive information from the other hand. We further investigated whether such putative bimanual proprioceptive integration would differ between expert dancers and non-dancer controls. Either one hand or both hands were passively moved to novel positions, and participants indicated the perceived location of the index finger tip of the designated target hand, by orienting a visible laser beam mounted on a cap. Synchronized bimanual movements compared to unimanual movements significantly improved proprioceptive position sense. In particular, we found a bias reduction to perceive the target hand's index finger tip as shifted away from the midline in the bimanual condition, compared to the unimanual condition. Expert dancers, in contrast, did not show this change in proprioceptive position sense after bimanual movements. We suggest that bimanual movements may improve proprioception due to interhemispheric integration in controls, but not in expert dancers.

How the inner repetition of a desired perception changes actual tactile perception.

Autosuggestion is a cognitive process where the inner repetition of a thought actively influences one's own perceptual state. In spite of its potential benefits for medical interventions, this technique has gained little scientific attention so far. Here, we took advantage of the known link between intensity and frequency perception in touch ('Békésy effect'). In three separate experiments, participants were asked to modulate the perceived intensity of vibrotactile stimuli at the fingertip through the inner reiteration of the thought that this perception feels very strong (Experiment 1, n = 19) or very weak (Experiments 2, n = 38, and 3, n = 20), while they were asked to report the perceived frequency. We show that the task to change the perceived intensity of a tactile stimulus via the inner reiteration of a thought modulates tactile frequency perception. This constitutes the first experimental demonstration that an experimental design that triggers autosuggestion alters participants' tactile perception using a response orthogonal to the suggested variable. We discuss whether this cognitive process could be used to influence the perception of pain in a clinical context.

Tactile memory impairments in younger and older adults.

Human tactile memory allows us to remember and retrieve the multitude of somatosensory experiences we undergo in everyday life. An unsolved question is how tactile memory mechanisms change with increasing age. We here use the ability to remember fine-grained tactile patterns passively presented to the fingertip to investigate age-related changes in tactile memory performance. In experiment 1, we varied the degree of similarity between one learned and several new tactile patterns to test on age-related changes in the "uniqueness" of a stored tactile memory trace. In experiment 2, we varied the degree of stimulus completeness of both known and new tactile patterns to test on age-related changes in the weighting between known and novel tactile information. Results reveal that older adults show only weak impairments in both precision and bias of tactile memories, however, they show specific deficits in reaching peak performance > 85% in both experiments. In addition, both younger and older adults show a pattern completion bias for touch, indicating a higher weighting of known compared to new information. These results allow us to develop new models on how younger and older adults store and recall tactile experiences of the past, and how this influences their everyday behavior.

Age-related differences in finger interdependence during complex hand movements.

The well-known decrease in finger dexterity during healthy aging leads to a significant reduction in quality of life. Still, the exact patterns of altered finger kinematics of older adults in daily life are fairly unexplored. Finger interdependence is the unintentional comovement of fingers that are not intended to move, and it is known to vary across the lifespan. Nevertheless, the magnitude and direction of age-related differences in finger interdependence are ambiguous across studies and tasks and have not been explored in the context of daily life finger movements. We investigated five different free and daily-life-inspired finger movements of the right, dominant hand as well as a sequential finger tapping task of the thumb against the other fingers, in 17 younger (22-37 yr) and 17 older (62-80 yr) adults using an exoskeleton data glove for data recording. Using inferential statistics, we found that the unintentional comovement of fingers generally decreases with age in all performed daily-life-inspired movements. Finger tapping, however, showed a trend towards higher finger interdependence for older compared with younger adults. Using machine learning, we predicted the age group of a person from finger interdependence features of single movement trials significantly better than chance level for the daily-life-inspired movements, but not for finger tapping. Taken together, we show that for specific tasks, decreased finger interdependence (i.e., less comovement) could potentially act as a marker of human aging that specifically characterizes older adults' complex finger movements in daily life.NEW & NOTEWORTHY Kinematic finger movement data were analyzed with regard to age-related differences. Extensive analyses of complex and daily-life-inspired movements reveal that the direction of age effects is not uniform but task-dependent: Although older adults generally show more finger interdependence than younger adults in a simple finger tapping task, this effect is reversed for daily-life-inspired movement tasks. For these tasks, finger interdependence indices offer potential new markers to predict the age group of an individual using machine learning approaches.

Judging roughness by sight--a 7-Tesla fMRI study on responsivity of the primary somatosensory cortex during observed touch of self and others.

Observing another person being touched activates our own somatosensory system. Whether the primary somatosensory cortex (S1) is also activated during the observation of passive touch, and which subregions of S1 are responsible for self- and other-related observed touch is currently unclear. In our study, we first aimed to clarify whether observing passive touch without any action component can robustly increase activity in S1. Secondly, we investigated whether S1 activity only increases when touch of others is observed, or also when touch of one's own body is observed. We were particularly interested in which subregions of S1 are responsible for either process. We used functional magnetic resonance imaging at 7 Tesla to measure S1 activity changes when participants observed videos of their own or another's hand in either egocentric or allocentric perspective being touched by different pieces of sandpaper. Participants were required to judge the roughness of the different sandpaper surfaces. Our results clearly show that S1 activity does increase in response to observing passive touch, and that activity changes are localized in posterior but not in anterior parts of S1. Importantly, activity increases in S1 were particularly related to observing another person being touched. Self-related observed touch, in contrast, caused no significant activity changes within S1. We therefore assume that posterior but not anterior S1 is part of a system for sharing tactile experiences with others.

Layer-specific vulnerability is a mechanism of topographic map aging.

Topographic maps form a critical feature of cortical organization, yet are poorly described with respect to their microstructure in the living aging brain. We acquired quantitative structural and functional 7T-MRI data from younger and older adults to characterize layer-wise topographic maps of the primary motor cortex (M1). Using parcellation-inspired techniques, we show that quantitative T1 and Quantitative Susceptibility Maps values of the hand, face, and foot areas differ significantly, revealing microstructurally distinct cortical fields in M1. We show that these fields are distinct in older adults and that myelin borders between them do not degenerate. We further show that the output layer 5 of M1 shows a particular vulnerability to age-related increased iron, while layer 5 and the superficial layer show increased diamagnetic substance, likely reflecting calcifications. Taken together, we provide a novel 3D model of M1 microstructure, where body parts form distinct structural units, but layers show specific vulnerability toward increased iron and calcium in older adults. Our findings have implications for understanding sensorimotor organization and aging, in addition to topographic disease spread.

Clinical Manifestations of Body Memories: The Impact of Past Bodily Experiences on Mental Health.

Bodily experiences such as the feeling of touch, pain or inner signals of the body are deeply emotional and activate brain networks that mediate their perception and higher-order processing. While the ad hoc perception of bodily signals and their influence on behavior is empirically well studied, there is a knowledge gap on how we store and retrieve bodily experiences that we perceived in the past, and how this influences our everyday life. Here, we explore the hypothesis that negative body memories, that is, negative bodily experiences of the past that are stored in memory and influence behavior, contribute to the development of somatic manifestations of mental health problems including somatic symptoms, traumatic re-experiences or dissociative symptoms. By combining knowledge from the areas of cognitive neuroscience and clinical neuroscience with insights from psychotherapy, we identify Clinical Body Memory (CBM) mechanisms that specify how mental health problems could be driven by corporeal experiences stored in memory. The major argument is that the investigation of the neuronal mechanisms that underlie the storage and retrieval of body memories provides us with empirical access to reduce the negative impact of body memories on mental health.

An Automated Tongue Tracker for Quantifying Bulbar Function in ALS.

Introduction: Bulbar symptoms, including difficulty swallowing and speaking, are common in amyotrophic lateral sclerosis (ALS) and other neurological disorders, such as stroke. The presence of bulbar symptoms provides important information regarding clinical outcomes, such as survival time after diagnosis. Nevertheless, there are currently no easily accessible, quantitative methods to measure bulbar function in patients. Methods: We developed an open-source tool called Tongue Tracker (TT) to quantify bulbar function by training a neural network to track kinematic tongue features of short video clips of lateral tongue movements. We tested 16 healthy controls and ten patients with ALS, of whom two patients were clinically diagnosed with bulbar-onset type and eight patients were clinically diagnosed with limb-onset type. Of the limb-onset patients, five patients also showed symptoms of bulbar impairment. Results: We validated TT by comparing the results with manual delineation of tongue movements in the clips. We demonstrate an early-stage bulbar-onset patient who showed fewer and slower tongue sweeps compared to healthy controls and limb-onset patients and we show that five bulbar-impaired limb-onset patients have a different tongue kinematic profile compared to healthy controls. Discussion: TT may serve to detect quantitative markers of bulbar dysfunction in ALS and other motor disorders, such as stroke, by identifying signatures of spasticity or muscle weakness that affects tongue movement speed and/or tongue movement topography.