Digital Gait Measures Capture 1-Year Progression in Early-Stage Spinocerebellar Ataxia Type 2.

BACKGROUND: With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease. OBJECTIVE: Our aim is to unravel gait measures sensitive to longitudinal change in the-particularly trial-relevant-early stage of spinocerebellar ataxia type 2 (SCA2). METHODS: We performed a multicenter longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n = 23, including nine pre-ataxic expansion carriers; median, ATXN2 CAG repeat expansion 38 ± 2; median, Scale for the Assessment and Rating of Ataxia [SARA] score 4.8 ± 4.3). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focused on gait measures of spatio-temporal variability that have shown sensitivity to ataxia severity (eg, lateral step deviation). RESULTS: We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation P = 0.0001, effect size rprb = 0.78), whereas the SARA score showed no change (P = 0.67). Sample size estimation indicates a required cohort size of n = 43 to detect a 50% reduction in natural progression. Test-retest reliability and minimal detectable change analysis confirm the accuracy of detecting 50% of the identified 1-year change. CONCLUSIONS: Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just 1 year-in contrast to a clinical ataxia outcome. Lateral step deviation represents a promising outcome measure for upcoming multicenter interventional trials, particularly in the early stages of cerebellar ataxia. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adaptation aftereffects reveal representations for encoding of contingent social actions.

A hallmark of human social behavior is the effortless ability to relate one's own actions to that of the interaction partner, e.g., when stretching out one's arms to catch a tripping child. What are the behavioral properties of the neural substrates that support this indispensable human skill? Here we examined the processes underlying the ability to relate actions to each other, namely the recognition of spatiotemporal contingencies between actions (e.g., a "giving" that is followed by a "taking"). We used a behavioral adaptation paradigm to examine the response properties of perceptual mechanisms at a behavioral level. In contrast to the common view that action-sensitive units are primarily selective for one action (i.e., primary action, e.g., 'throwing"), we demonstrate that these processes also exhibit sensitivity to a matching contingent action (e.g., "catching"). Control experiments demonstrate that the sensitivity of action recognition processes to contingent actions cannot be explained by lower-level visual features or amodal semantic adaptation. Moreover, we show that action recognition processes are sensitive only to contingent actions, but not to noncontingent actions, demonstrating their selective sensitivity to contingent actions. Our findings show the selective coding mechanism for action contingencies by action-sensitive processes and demonstrate how the representations of individual actions in social interactions can be linked in a unified representation.

Representation of the observer's predicted outcome value in mirror and nonmirror neurons of macaque F5 ventral premotor cortex.

In the search for the function of mirror neurons, a previous study reported that F5 mirror neuron responses are modulated by the value that the observing monkey associates with the grasped object. Yet we do not know whether mirror neurons are modulated by the expected reward value for the observer or also by other variables, which are causally dependent on value (e.g., motivation, attention directed at the observed action, arousal). To clarify this, we trained two rhesus macaques to observe a grasping action on an object kept constant, followed by four fully predictable outcomes of different values (2 outcomes with positive and 2 with negative emotional valence). We found a consistent order in population activity of both mirror and nonmirror neurons that matches the order of the value of this predicted outcome but that does not match the order of the above-mentioned value-dependent variables. These variables were inferred from the probability not to abort a trial, saccade latency, modulation of eye position during action observation, heart rate, and pupil size. Moreover, we found subpopulations of neurons tuned to each of the four predicted outcome values. Multidimensional scaling revealed equal normalized distances of 0.25 between the two positive and between the two negative outcomes suggesting the representation of a relative value, scaled to the task setting. We conclude that F5 mirror neurons and nonmirror neurons represent the observer's predicted outcome value, which in the case of mirror neurons may be transferred to the observed object or action.NEW & NOTEWORTHY Both the populations of F5 mirror neurons and nonmirror neurons represent the predicted value of an outcome resulting from the observation of a grasping action. Value-dependent motivation, arousal, and attention directed at the observed action do not provide a better explanation for this representation. The population activity's metric suggests an optimal scaling of value representation to task setting.

Two Ways to Facial Expression Recognition? Motor and Visual Information Have Different Effects on Facial Expression Recognition.

Motor-based theories of facial expression recognition propose that the visual perception of facial expression is aided by sensorimotor processes that are also used for the production of the same expression. Accordingly, sensorimotor and visual processes should provide congruent emotional information about a facial expression. Here, we report evidence that challenges this view. Specifically, the repeated execution of facial expressions has the opposite effect on the recognition of a subsequent facial expression than the repeated viewing of facial expressions. Moreover, the findings of the motor condition, but not of the visual condition, were correlated with a nonsensory condition in which participants imagined an emotional situation. These results can be well accounted for by the idea that facial expression recognition is not always mediated by motor processes but can also be recognized on visual information alone.

The Default Mode Network Differentiates Biological From Non-Biological Motion.

The default mode network (DMN) has been implicated in an array of social-cognitive functions, including self-referential processing, theory of mind, and mentalizing. Yet, the properties of the external stimuli that elicit DMN activity in relation to these domains remain unknown. Previous studies suggested that motion kinematics is utilized by the brain for social-cognitive processing. Here, we used functional MRI to examine whether the DMN is sensitive to parametric manipulations of observed motion kinematics. Preferential responses within core DMN structures differentiating non-biological from biological kinematics were observed for the motion of a realistically looking, human-like avatar, but not for an abstract object devoid of human form. Differences in connectivity patterns during the observation of biological versus non-biological kinematics were additionally observed. Finally, the results additionally suggest that the DMN is coupled more strongly with key nodes in the action observation network, namely the STS and the SMA, when the observed motion depicts human rather than abstract form. These findings are the first to implicate the DMN in the perception of biological motion. They may reflect the type of information used by the DMN in social-cognitive processing.

Functional dissociation between anterior temporal lobe and inferior frontal gyrus in the processing of dynamic body expressions: Insights from behavioral variant frontotemporal dementia.

Several brain regions are involved in the processing of emotional stimuli, however, the contribution of specific regions to emotion perception is still under debate. To investigate this issue, we combined behavioral testing, structural and resting state imaging in patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and age matched controls, with task-based functional imaging in young, healthy volunteers. As expected, bvFTD patients were impaired in emotion detection as well as emotion categorization tasks, testing dynamic emotional body expressions as stimuli. Interestingly, their performance in the two tasks correlated with gray matter volume in two distinct brain regions, the left anterior temporal lobe for emotion detection and the left inferior frontal gyrus (IFG) for emotion categorization. Confirming this observation, multivoxel pattern analysis in healthy volunteers demonstrated that both ROIs contained information for emotion detection, but that emotion categorization was only possible from the pattern in the IFG. Furthermore, functional connectivity analysis showed reduced connectivity between the two regions in bvFTD patients. Our results illustrate that the mentalizing network and the action observation network perform distinct tasks during emotion processing. In bvFTD, communication between the networks is reduced, indicating one possible cause underlying the behavioral symptoms. Hum Brain Mapp 37:4472-4486, 2016. © 2016 Wiley Periodicals, Inc.

An intact action-perception coupling depends on the integrity of the cerebellum.

It is widely accepted that action and perception in humans functionally interact on multiple levels. Moreover, areas originally suggested to be predominantly motor-related, as the cerebellum, are also involved in action observation. However, as yet, few studies provided unequivocal evidence that the cerebellum is involved in the action perception coupling (APC), specifically in the integration of motor and multisensory information for perception. We addressed this question studying patients with focal cerebellar lesions in a virtual-reality paradigm measuring the effect of action execution on action perception presenting self-generated movements as point lights. We measured the visual sensitivity to the point light stimuli based on signal detection theory. Compared with healthy controls cerebellar patients showed no beneficial influence of action execution on perception indicating deficits in APC. Applying lesion symptom mapping, we identified distinct areas in the dentate nucleus and the lateral cerebellum of both hemispheres that are causally involved in APC. Lesions of the right ventral dentate, the ipsilateral motor representations (lobules V/VI), and most interestingly the contralateral posterior cerebellum (lobule VII) impede the benefits of motor execution on perception. We conclude that the cerebellum establishes time-dependent multisensory representations on different levels, relevant for motor control as well as supporting action perception. Ipsilateral cerebellar motor representations are thought to support the somatosensory state estimate of ongoing movements, whereas the ventral dentate and the contralateral posterior cerebellum likely support sensorimotor integration in the cerebellar-parietal loops. Both the correct somatosensory as well as the multisensory state representations are vital for an intact APC.

Brain activity correlates with emotional perception induced by dynamic avatars.

An accurate judgment of the emotional state of others is a prerequisite for successful social interaction and hence survival. Thus, it is not surprising that we are highly skilled at recognizing the emotions of others. Here we aimed to examine the neuronal correlates of emotion recognition from gait. To this end we created highly controlled dynamic body-movement stimuli based on real human motion-capture data (Roether et al., 2009). These animated avatars displayed gait in four emotional (happy, angry, fearful, and sad) and speed-matched neutral styles. For each emotional gait and its equivalent neutral gait, avatars were displayed at five morphing levels between the two. Subjects underwent fMRI scanning while classifying the emotions and the emotional intensity levels expressed by the avatars. Our results revealed robust brain selectivity to emotional compared to neutral gait stimuli in brain regions which are involved in emotion and biological motion processing, such as the extrastriate body area (EBA), fusiform body area (FBA), superior temporal sulcus (STS), and the amygdala (AMG). Brain activity in the amygdala reflected emotional awareness: for visually identical stimuli it showed amplified stronger response when the stimulus was perceived as emotional. Notably, in avatars gradually morphed along an emotional expression axis there was a parametric correlation between amygdala activity and emotional intensity. This study extends the mapping of emotional decoding in the human brain to the domain of highly controlled dynamic biological motion. Our results highlight an extensive level of brain processing of emotional information related to body language, which relies mostly on body kinematics.

Common neural correlates of emotion perception in humans.

Whether neuroimaging findings support discriminable neural correlates of emotion categories is a longstanding controversy. Two recent meta-analyses arrived at opposite conclusions, with one supporting (Vytal and Hamann []: J Cogn Neurosci 22:2864-2885) and the other opposing this proposition (Lindquist et al. []: Behav Brain Sci 35:121-143). To obtain direct evidence regarding this issue, we compared activations for four emotions within a single fMRI design. Angry, happy, fearful, sad and neutral stimuli were presented as dynamic body expressions. In addition, observers categorized motion morphs between neutral and emotional stimuli in a behavioral experiment to determine their relative sensitivities. Brain-behavior correlations revealed a large brain network that was identical for all four tested emotions. This network consisted predominantly of regions located within the default mode network and the salience network. Despite showing brain-behavior correlations for all emotions, muli-voxel pattern analyses indicated that several nodes of this emotion general network contained information capable of discriminating between individual emotions. However, significant discrimination was not limited to the emotional network, but was also observed in several regions within the action observation network. Taken together, our results favor the position that one common emotional brain network supports the visual processing and discrimination of emotional stimuli.

Mirror neurons encode the subjective value of an observed action.

Objects grasped by an agent have a value not only for the acting agent, but also for an individual observing the grasping act. The value that the observer attributes to the object that is grasped can be pivotal for selecting a possible behavioral response. Mirror neurons in area F5 of the monkey premotor cortex have been suggested to play a crucial role in the understanding of action goals. However, it has not been addressed if these neurons are also involved in representing the value of the grasped object. Here we report that observation-related neuronal responses of F5 mirror neurons are indeed modulated by the value that the monkey associates with the grasped object. These findings suggest that during action observation F5 mirror neurons have access to key information needed to shape the behavioral responses of the observer.

Physiologically inspired model for the visual recognition of transitive hand actions.

The visual recognition of actions is an important visual function that is critical for motor learning and social communication. Action-selective neurons have been found in different cortical regions, including the superior temporal sulcus, parietal and premotor cortex. Among those are mirror neurons, which link visual and motor representations of body movements. While numerous theoretical models for the mirror neuron system have been proposed, the computational basis of the visual processing of goal-directed actions remains largely unclear. While most existing models focus on the possible role of motor representations in action recognition, we propose a model showing that many critical properties of action-selective visual neurons can be accounted for by well-established visual mechanisms. Our model accomplishes the recognition of hand actions from real video stimuli, exploiting exclusively mechanisms that can be implemented in a biologically plausible way by cortical neurons. We show that the model provides a unifying quantitatively consistent account of a variety of electrophysiological results from action-selective visual neurons. In addition, it makes a number of predictions, some of which could be confirmed in recent electrophysiological experiments.

Show me how you walk and I tell you how you feel - a functional near-infrared spectroscopy study on emotion perception based on human gait.

The ability to recognize and adequately interpret emotional states in others plays a fundamental role in regulating social interaction. Body language presents an essential element of nonverbal communication which is often perceived prior to mimic expression. However, the neural networks that underlie the processing of emotionally expressive body movement and body posture are poorly understood. 33 healthy subjects have been investigated using the optically based imaging method functional near-infrared spectroscopy (fNIRS) during the performance of a newly developed emotion discrimination paradigm consisting of faceless avatars expressing fearful, angry, sad, happy or neutral gait patterns. Participants were instructed to judge (a) the presented emotional state (emotion task) and (b) the observed walking speed of the respective avatar (speed task). We measured increases in cortical oxygenated haemoglobin (O2HB) in response to visual stimulation during emotion discrimination. These O2HB concentration changes were enhanced for negative emotions in contrast to neutral gait sequences in right occipito-temporal and left temporal and temporo-parietal brain regions. Moreover, fearful and angry bodies elicited higher activation increases during the emotion task compared to the speed task. Haemodynamic responses were correlated with a number of behavioural measures, whereby a positive relationship between emotion regulation strategy preference and O2HB concentration increases after sad walks was mediated by the ability to accurately categorize sad walks. Our results support the idea of a distributed brain network involved in the recognition of bodily emotion expression that comprises visual association areas as well as body/movement perception specific cortical regions that are also sensitive to emotion. This network is activated less when the emotion is not intentionally processed (i.e. during the speed task). Furthermore, activity of this perceptive network is, mediated by the ability to correctly recognize emotions, indirectly connected to active emotion regulation processes. We conclude that a full understanding of emotion perception and its neural substrate requires the investigation of dynamic representations and means of expression other than the face.

Mirror representations innate versus determined by experience: a viewpoint from learning theory.

From the viewpoint of pattern recognition and computational learning, mirror neurons form an interesting multimodal representation that links action perception and planning. While it seems unlikely that all details of such representations are specified by the genetic code, robust learning of such complex representations likely requires an appropriate interplay between plasticity, generalization, and anatomical constraints of the underlying neural architecture.

Perceptual encoding of emotions in interactive bodily expressions.

For social species, e.g., primates, the perceptual analysis of social interactions is an essential skill for survival, emerging already early during development. While real-life emotional behavior includes predominantly interactions between conspecifics, research on the perception of emotional body expressions has primarily focused on perception of single individuals. While previous studies using point-light or video stimuli of interacting people suggest an influence of social context on the perception and neural encoding of interacting bodies, it remains entirely unknown how emotions of multiple interacting agents are perceptually integrated. We studied this question using computer animation by creating scenes with two interacting avatars whose emotional style was independently controlled. While participants had to report the emotional style of a single agent, we found a systematic influence of the emotion expressed by the other, which was consistent with the social interaction context. The emotional styles of interacting individuals are thus jointly encoded.

Effects of cerebellar lesions on working memory interacting with motor tasks of different complexities.

We examined the influence of focal cerebellar lesions on working memory (n-back task), gait, and the interaction between working memory and different gait tasks in a dual-task paradigm. The analysis included 17 young patients with chronic focal lesions after cerebellar tumor resection and 17 age-matched controls. Patients have shown mild to moderate ataxia. Lesion sites were examined on the basis of structural magnetic resonance imaging. N-back tasks were executed with different levels of difficulty (n = 1-4) during sitting (baseline), treadmill walking, and treadmill tandem walking (dual-task conditions). Patients exhibited decreased n-back performance particularly at difficult n-back levels and in dual-task conditions. Voxel-based lesion-symptom mapping revealed that decreased baseline n-back performance was associated with lesions of the posterolateral cerebellar hemisphere and the dentate nucleus. By contrast, decreased n-back performance in dual-task conditions was more associated with motor-related areas including dorsal portions of the dentate and the interposed nucleus, suggesting a prioritization of the motor task. During baseline walking, increased gait variability was associated with lesions in medial and intermediate regions, whereas for baseline tandem gait, lesions in the posterolateral hemispheres and the dentate nucleus became important. Posterolateral regions overlapped with regions related to baseline n-back performance. Consistently, we observed increased tandem gait variability with growing n-back difficulty in the dual-task condition. These findings suggest that dual-task effects in cerebellar patients are at least partially caused by a common involvement of posterolateral cerebellar regions in working memory and complex motor tasks.

Expression of emotion in the kinematics of locomotion.

Here, we examine how different emotions-happiness, fear, sadness and anger-affect the kinematics of locomotion. We focus on a compact representation of locomotion properties using the intersegmental law of coordination (Borghese et al. in J Physiol 494(3):863-879, 1996), which states that, during the gait cycle of human locomotion, the elevation angles of the thigh, shank and foot do not evolve independently of each other but form a planar pattern of co-variation. This phenomenon is highly robust and has been extensively studied. The orientation of the plane has been correlated with changes in the speed of locomotion and with reduction in energy expenditure as speed increases. An analytical model explaining the conditions underlying the emergence of this plane and predicting its orientation reveals that it suffices to examine the amplitudes of the elevation angles of the different segments along with the phase shifts between them (Barliya et al. in Exp Brain Res 193:371-385, 2009). We thus investigated the influence of different emotions on the parameters directly determining the orientation of the intersegmental plane and on the angular rotation profiles of the leg segments, examining both the effect of changes in walking speed and effects independent of speed. Subjects were professional actors and naïve subjects with no training in acting. As expected, emotions were found to strongly affect the kinematics of locomotion, particularly walking speed. The intersegmental coordination patterns revealed that emotional expression caused additional modifications to the locomotion patterns that could not be explained solely by a change in speed. For all emotions except sadness, the amplitude of thigh elevation angles changed from those in neutral locomotion. The intersegmental plane was also differently oriented, especially during anger. We suggest that, while speed is the dominant variable allowing discrimination between different emotional gaits, emotion can be reliably recognized in locomotion only when speed is considered together with these kinematic changes.

Spatiotemporal tuning of the facilitation of biological motion perception by concurrent motor execution.

The execution of motor behavior influences concurrent visual action observation and especially the perception of biological motion. The neural mechanisms underlying this interaction between perception and motor execution are not exactly known. In addition, the available experimental evidence is partially inconsistent because previous studies have reported facilitation as well as impairments of action perception by concurrent execution. Exploiting a novel virtual reality paradigm, we investigated the spatiotemporal tuning of the influence of motor execution on the perception of biological motion within a signal-detection task. Human observers were presented with point-light stimuli that were controlled by their own movements. Participants had to detect a point-light arm in a scrambled mask, either while executing waving movements or without concurrent motor execution (baseline). The temporal and spatial coherence between the observed and executed movements was parametrically varied. We found a systematic tuning of the facilitatory versus inhibitory influences of motor execution on biological motion detection with respect to the temporal and the spatial congruency between observed and executed movements. Specifically, we found a gradual transition between facilitatory and inhibitory interactions for decreasing temporal synchrony and spatial congruency. This result provides evidence for a spatiotemporally highly selective coupling between dynamic motor representations and neural structures involved in the visual processing of biological motion. In addition, our study offers a unifying explanation that reconciles contradicting results about modulatory effects of motor execution on biological motion perception in previous studies.

Norm-based face encoding by single neurons in the monkey inferotemporal cortex.

The rich and immediate perception of a familiar face, including its identity, expression and even intent, is one of the most impressive shared faculties of human and non-human primate brains. Many visually responsive neurons in the inferotemporal cortex of macaque monkeys respond selectively to faces, sometimes to only one or a few individuals, while showing little sensitivity to scale and other details of the retinal image. Here we show that face-responsive neurons in the macaque monkey anterior inferotemporal cortex are tuned to a fundamental dimension of face perception. Using a norm-based caricaturization framework previously developed for human psychophysics, we varied the identity information present in photo-realistic human faces, and found that neurons of the anterior inferotemporal cortex were most often tuned around the average, identity-ambiguous face. These observations are consistent with face-selective responses in this area being shaped by a figural comparison, reflecting structural differences between an incoming face and an internal reference or norm. As such, these findings link the tuning of neurons in the inferotemporal cortex to psychological models of face identity perception.

Neural theory for the perception of causal actions.

The efficient prediction of the behavior of others requires the recognition of their actions and an understanding of their action goals. In humans, this process is fast and extremely robust, as demonstrated by classical experiments showing that human observers reliably judge causal relationships and attribute interactive social behavior to strongly simplified stimuli consisting of simple moving geometrical shapes. While psychophysical experiments have identified critical visual features that determine the perception of causality and agency from such stimuli, the underlying detailed neural mechanisms remain largely unclear, and it is an open question why humans developed this advanced visual capability at all. We created pairs of naturalistic and abstract stimuli of hand actions that were exactly matched in terms of their motion parameters. We show that varying critical stimulus parameters for both stimulus types leads to very similar modulations of the perception of causality. However, the additional form information about the hand shape and its relationship with the object supports more fine-grained distinctions for the naturalistic stimuli. Moreover, we show that a physiologically plausible model for the recognition of goal-directed hand actions reproduces the observed dependencies of causality perception on critical stimulus parameters. These results support the hypothesis that selectivity for abstract action stimuli might emerge from the same neural mechanisms that underlie the visual processing of natural goal-directed action stimuli. Furthermore, the model proposes specific detailed neural circuits underlying this visual function, which can be evaluated in future experiments.

Toward a unifying framework for the modeling and identification of motor primitives.

A large body of evidence suggests that human and animal movements, despite their apparent complexity and flexibility, are remarkably structured. Quantitative analyses of various classes of motor behaviors consistently identify spatial and temporal features that are invariant across movements. Such invariant features have been observed at different levels of organization in the motor system, including the electromyographic, kinematic, and kinetic levels, and are thought to reflect fixed modules-named motor primitives-that the brain uses to simplify the construction of movement. However, motor primitives across space, time, and organization levels are often described with ad-hoc mathematical models that tend to be domain-specific. This, in turn, generates the need to use model-specific algorithms for the identification of both the motor primitives and additional model parameters. The lack of a comprehensive framework complicates the comparison and interpretation of the results obtained across different domains and studies. In this work, we take the first steps toward addressing these issues, by introducing a unifying framework for the modeling and identification of qualitatively different classes of motor primitives. Specifically, we show that a single model, the anechoic mixture model, subsumes many popular classes of motor primitive models. Moreover, we exploit the flexibility of the anechoic mixture model to develop a new class of identification algorithms based on the Fourier-based Anechoic Demixing Algorithm (FADA). We validate our framework by identifying eight qualitatively different classes of motor primitives from both simulated and experimental data. We show that, compared to established model-specific algorithms for the identification of motor primitives, our flexible framework reaches overall comparable and sometimes superior reconstruction performance. The identification framework is publicly released as a MATLAB toolbox (FADA-T, https://tinyurl.com/compsens) to facilitate the identification and comparison of different motor primitive models.