AMYPAD Diagnostic and Patient Management Study: Rationale and design.

INTRODUCTION: Reimbursement of amyloid-positron emission tomography (PET) is lagging due to the lack of definitive evidence on its clinical utility and cost-effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease-Diagnostic and Patient Management Study (AMYPAD-DPMS) is designed to fill this gap. METHODS: AMYPAD-DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid-PET performed early in the diagnostic workup; ARM2, amyloid-PET performed after 8 months; and ARM3, amyloid-PET performed whenever the physician chooses to do so. ENDPOINTS: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very-high-confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient-related outcomes, and methods for image quantitation. EXPECTED IMPACTS: AMYPAD-DPMS will supply physicians and health care payers with real-world data to plan management decisions.

Upper limb cortical maps in amputees with targeted muscle and sensory reinnervation.

Neuroprosthetics research in amputee patients aims at developing new prostheses that move and feel like real limbs. Targeted muscle and sensory reinnervation (TMSR) is such an approach and consists of rerouting motor and sensory nerves from the residual limb towards intact muscles and skin regions. Movement of the myoelectric prosthesis is enabled via decoded electromyography activity from reinnervated muscles and touch sensation on the missing limb is enabled by stimulation of the reinnervated skin areas. Here we ask whether and how motor control and redirected somatosensory stimulation provided via TMSR affected the maps of the upper limb in primary motor (M1) and primary somatosensory (S1) cortex, as well as their functional connections. To this aim, we tested three TMSR patients and investigated the extent, strength, and topographical organization of the missing limb and several control body regions in M1 and S1 at ultra high-field (7 T) functional magnetic resonance imaging. Additionally, we analysed the functional connectivity between M1 and S1 and of both these regions with fronto-parietal regions, known to be important for multisensory upper limb processing. These data were compared with those of control amputee patients (n = 6) and healthy controls (n = 12). We found that M1 maps of the amputated limb in TMSR patients were similar in terms of extent, strength, and topography to healthy controls and different from non-TMSR patients. S1 maps of TMSR patients were also more similar to normal conditions in terms of topographical organization and extent, as compared to non-targeted muscle and sensory reinnervation patients, but weaker in activation strength compared to healthy controls. Functional connectivity in TMSR patients between upper limb maps in M1 and S1 was comparable with healthy controls, while being reduced in non-TMSR patients. However, connectivity was reduced between S1 and fronto-parietal regions, in both the TMSR and non-TMSR patients with respect to healthy controls. This was associated with the absence of a well-established multisensory effect (visual enhancement of touch) in TMSR patients. Collectively, these results show how M1 and S1 process signals related to movement and touch are enabled by targeted muscle and sensory reinnervation. Moreover, they suggest that TMSR may counteract maladaptive cortical plasticity typically found after limb loss, in M1, partially in S1, and in their mutual connectivity. The lack of multisensory interaction in the present data suggests that further engineering advances are necessary (e.g. the integration of somatosensory feedback into current prostheses) to enable prostheses that move and feel as real limbs.

Combining proprioception and touch to compute spatial information.

Localising a tactile stimulus in egocentric space involves integrating information from skin receptors with proprioceptive inputs about body posture. We investigated whether body posture automatically influences tactile spatial judgements, even when it is irrelevant to the task. In Experiment 1, participants received two successive tactile stimuli on the forearm and were asked to indicate whether the first or second touch of the pair was closer to an anatomical body landmark, either the wrist or the elbow. The task was administered in three experimental conditions involving different body postures: canonical body posture with extended forearm and hand pointing distally; a non-canonical body posture with forearm and hand pointing vertically up at 90° and a 'reversed' body posture with the elbow fully flexed at 180°, so that the hand pointed proximally. Thus, our task required localising touch on the skin and then relating skin locations to anatomical body landmarks. Critically, both functions are independent of the posture of the body in space. We nevertheless found reliable effects of body posture: judgement errors increased when the canonical forearm posture was rotated through 180°. These results were further confirmed in Experiment 2, in which stimuli were delivered to the finger. However, additionally reversing the canonical posture of the finger, as well as that of the forearm, so that the finger was restored to its canonical orientation in egocentric space, restored performance to normal levels. Our results confirm an automatic process of localising the body in external space underlying the process of tactile perception. This process appears to involve a combination of proprioceptive and tactile information.

Changes in cortical oscillations linked to multisensory modulation of nociception.

Pain can be modulated by several contextual factors. For example, simply viewing one's own body can reduce pain, suggesting that the visual context may influence the processing of nociceptive stimuli. We studied changes in electroencephalographic (EEG) oscillatory activity related to visual modulation of nociception, comparing cortical oscillations during innocuous or noxious contact heat, while participants viewed either their own hand or a neutral object at the same location. Viewing the body compared with viewing the object reduced the intensity ratings of noxious stimuli, but not of innocuous heat. Time-frequency analysis of EEG data revealed that noxious, as opposed to warm, stimulation was associated with reduced beta (15-25 Hz) power. Classically, such decreases in oscillatory power indicate increases in sensory cortical activation. These event-related oscillatory changes were moreover modulated by the visual context; viewing one's own body increased noxious stimulation-induced beta oscillatory activity bilaterally, relative to viewing a neutral object, possibly indicating inhibition of cortical nociceptive processing. These results demonstrate that visual-nociceptive interactions involve changes in sensorimotor EEG rhythms.

Tool-use reshapes the boundaries of body and peripersonal space representations.

Interaction with objects in the environment typically requires integrating information concerning the object location with the position and size of body parts. The former information is coded in a multisensory representation of the space around the body, a representation of peripersonal space (PPS), whereas the latter is enabled by an online, constantly updated, action-orientated multisensory representation of the body (BR). Using a tool to act upon relatively distant objects extends PPS representation. This effect has been interpreted as indicating that tools can be incorporated into BR. However, empirical data showing that tool-use simultaneously affects PPS representation and BR are lacking. To study this issue, we assessed the extent of PPS representation by means of an audio-tactile interaction task and BR by means of a tactile distance perception task and a body-landmarks localisation task, before and after using a 1-m-long tool to reach far objects. Tool-use extended the representation of PPS along the tool axis and concurrently shaped BR; after tool-use, subjects perceived their forearm narrower and longer compared to before tool-use, a shape more similar to the one of the tool. Tool-use was necessary to induce these effects, since a pointing task did not affect PPS and BR. These results show that a brief training with a tool induces plastic changes both to the perceived dimensions of the body part acting upon the tool and to the space around it, suggesting a strong overlap between peripersonal space and body representation.

Body and peripersonal space representations in chronic stroke patients with upper limb motor deficits.

The continuous stream of multisensory information between the brain and the body during body-environment interactions is crucial to maintain the updated representation of the perceived dimensions of body parts (metric body representation) and the space around the body (the peripersonal space). Such flow of multisensory signals is often limited by upper limb sensorimotor deficits after stroke. This would suggest the presence of systematic distortions of metric body representation and peripersonal space in chronic patients with persistent sensorimotor deficits. We assessed metric body representation and peripersonal space representation in 60 chronic stroke patients with unilateral upper limb motor deficits, in comparison with age-matched healthy controls. We also administered a questionnaire capturing explicit feelings towards the affected limb. These novel measures were analysed with respect to patients' clinical profiles and brain lesions to investigate the neural and functional origin of putative deficits. Stroke patients showed distortions in metric body representation of the affected limb, characterized by an underestimation of the arm length and an alteration of the arm global shape. A descriptive lesion analysis (subtraction analysis) suggests that these distortions may be more frequently associated with lesions involving the superior corona radiata and the superior frontal gyrus. Peripersonal space representation was also altered, with reduced multisensory facilitation for stimuli presented around the affected limb. These deficits were more common in patients reporting pain during motion. Explorative lesion analyses (subtraction analysis, disconnection maps) suggest that the peripersonal space distortions would be more frequently associated with lesions involving the parietal operculum and white matter frontoparietal connections. Moreover, patients reported altered feelings towards the affected limb, which were associated with right brain damage, proprioceptive deficits and a lower cognitive profile. These results reveal implicit and explicit distortions involving metric body representation, peripersonal space representation and the perception of the affected limb in chronic stroke patients. These findings might have important clinical implications for the longitudinal monitoring and the treatments of often-neglected deficits in body perception and representation.

Fronto-parietal areas necessary for a multisensory representation of peripersonal space in humans: an rTMS study.

A network of brain regions including the ventral premotor cortex (vPMc) and the posterior parietal cortex (PPc) is consistently recruited during processing of multisensory stimuli within peripersonal space (PPS). However, to date, information on the causal role of these fronto-parietal areas in multisensory PPS representation is lacking. Using low-frequency repetitive TMS (rTMS; 1 Hz), we induced transient virtual lesions to the left vPMc, PPc, and visual cortex (V1, control site) and tested whether rTMS affected audio-tactile interaction in the PPS around the hand. Subjects performed a timed response task to a tactile stimulus on their right (contralateral to rTMS) hand while concurrent task-irrelevant sounds were presented either close to the hand or 1 m far from the hand. When no rTMS was delivered, a sound close to the hand reduced RT-to-tactile targets as compared with when a far sound was presented. This space-dependent, auditory modulation of tactile perception was specific to a hand-centered reference frame. Such a specific form of multisensory interaction near the hand can be taken as a behavioral hallmark of PPS representation. Crucially, virtual lesions to vPMc and PPc, but not to V1, eliminated the speeding effect due to near sounds, showing a disruption of audio-tactile interactions around the hand. These findings indicate that multisensory interaction around the hand depends on the functions of vPMc and PPc, thus pointing to the necessity of this human fronto-parietal network in multisensory representation of PPS.

Mechanisms of the breathing contribution to bodily self-consciousness in healthy humans: Lessons from machine-assisted breathing?

Previous studies investigated bodily self-consciousness (BSC) by experimentally exposing subjects to multisensory conflicts (i.e., visuo-tactile, audio-tactile, visuo-cardiac) in virtual reality (VR) that involve the participant's torso in a paradigm known as the full-body illusion (FBI). Using a modified FBI paradigm, we found that synchrony of visuo-respiratory stimulation (i.e., a flashing outline surrounding an avatar in VR; the flash intensity depending on breathing), is also able to modulate BSC by increasing self-location and breathing agency toward the virtual body. Our aim was to investigate such visuo-respiratory effects and determine whether respiratory motor commands contributes to BSC, using non-invasive mechanical ventilation (i.e., machine-delivered breathing). Seventeen healthy participants took part in a visuo-respiratory FBI paradigm and performed the FBI during two breathing conditions: (a) "active breathing" (i.e., participants actively initiate machine-delivered breaths) and (b) "passive breathing" (i.e., breaths' timing was determined by the machine). Respiration rate, tidal volume, and their variability were recorded. In line with previous results, participants experienced subjective changes in self-location, breathing agency, and self-identification toward the avatar's body, when presented with synchronous visuo-respiratory stimulation. Moreover, drift in self-location was reduced and tidal volume variability were increased by asynchronous visuo-respiratory stimulations. Such effects were not modulated by breathing control manipulations. Our results extend previous FBI findings showing that visuo-respiratory stimulation affects BSC, independently from breathing motor command initiation. Also, variability of respiratory parameters was influenced by visuo-respiratory feedback and might reduce breathing discomfort. Further exploration of such findings might inform the development of respiratory therapeutic tools using VR in patients.

Interferences between breathing, experimental dyspnoea and bodily self-consciousness.

Dyspnoea, a subjective experience of breathing discomfort, is a most distressing symptom. It implicates complex cortical networks that partially overlap with those underlying bodily self-consciousness, the experience that the body is one's own within a given location (self-identification and self-location, respectively). Breathing as an interoceptive signal contributes to bodily self-consciousness: we predicted that inducing experimental dyspnoea would modify or disrupt this contribution. We also predicted that manipulating bodily self-consciousness with respiratory-visual stimulation would possibly attenuate dyspnoea. Twenty-five healthy volunteers were exposed to synchronous and asynchronous respiratory-visual illumination of an avatar during normal breathing and mechanically loaded breathing that elicited dyspnoea. During normal breathing, synchronous respiratory-visual stimulation induced illusory self-identification with the avatar and an illusory location of the subjects' breathing towards the avatar. This did not occur when respiratory-visual stimulation was performed during dyspnoea-inducing loaded breathing. In this condition, the affective impact of dyspnoea was attenuated by respiratory-visual stimulation, particularly when asynchronous. This study replicates and reinforces previous studies about the integration of interoceptive and exteroceptive signals in the construction of bodily self-consciousness. It confirms the existence of interferences between experimental dyspnoea and cognitive functions. It suggests that respiratory-visual stimulation should be tested as a non-pharmacological approach of dyspnoea treatment.

Conceptual processing is referenced to the experienced location of the self, not to the location of the physical body.

We tested whether an experimentally induced change in the experienced location of the self by means of the Full Body Illusion (FBI) would impact high-level cognitive processing. In an implicit association task, participants saw a landscape where words, conveying spatial ("Near", "Far") or social ("Us", "Them") semantic distance appeared either in a proximal or distal position. Words' "semantic" distance was congruent or incongruent to the words' spatial position. Participants were asked to classify words' spatial position. Implicit association judgements were intermingled with sessions of visuo-tactile stimulation, during which participants were touched on their back, while viewing an avatar in the distal position being touched either synchronously or asynchronously. In a control experiment, participants performed the same task while observing a neutral object being touched, as a control. When subjects self-identified with the avatar presented at the distal position, the facilitation effect of the words' spatial-semantic congruency disappeared. The congruency effect did not disappear in case of asynchronous stimulation as well as in the control experiment with the object, where no change in self-identification was observed. These results demonstrate that conceptual processing is not referenced to the location of the physical body, but to the experienced location of the self.

Dissociating effect of upper limb non-use and overuse on space and body representations.

Accurate and updated representations of the space where the body acts, i.e. the peripersonal space (PPS), and the location and dimension of body parts (body representation, BR) are essential to perform actions. Because both PPS and BR are involved in motor execution and display the same plastic proprieties after the use of a tool to reach far objects, it has been suggested that they overlap in a unique representation of the body in a space devoted to action. Here we determined whether manipulating actions in space, without modifying body metrics, i.e. through immobilization, induces a dissociation of the plastic properties of PPS and BR. In 39 healthy subjects we evaluated PPS and BR for the non-used right limb and the overused left limb before and after 10 h of right arm immobilization. We observed that non-use reduces PPS representation around the immobilized arm, without affecting the metric representation (i.e. perceived length) of that limb. In contrast, overuse modulates the metric representation of the free arm, leaving PPS unchanged around that limb. These results suggest that the plasticity in PPS and BR depends on different mechanisms; while PPS representation is shaped as a function of the dimension of the acting space, metric characteristics of BR are forged on a complex interplay between visual and sensorimotor information related to the body. This behavioral dissociation between PPS and BR defines a new scenario for the role of action in shaping space and body representations.

Moving sounds within the peripersonal space modulate the motor system.

Interactions between ourselves and the external world are mediated by a multisensory representation of the space surrounding the body, i.e. the peripersonal space (PPS). In particular, a special interplay is observed among tactile stimuli delivered on a body part, e.g. the hand, and visual or auditory external inputs presented close, but not far, from the same body part, e.g. within hand PPS. This coding of multisensory stimuli as a function of their distance from the hand has a role in upper limb actions. However, it remains unclear whether PPS representation affects the motor system only when stimuli occur specifically at the hand location or when they move within a continuous portion of space where the hand can potentially act. Here, in order to study these two alternatively hypotheses, we assessed the critical distance at which moving sounds have a direct effect on hand corticospinal excitability by using Transcranial Magnetic Stimulation (TMS). Specifically, TMS single pulses were delivered when a sound source was perceived at six different positions in space: from very close to subjects' hand (15 cm) to far away (90 cm). Moreover, sound direction was manipulated to test if stimuli approaching and receding from the hand might have the same relevance for the motor system. MEPs amplitude was enhanced when sounds were delivered within a limited distance from the hand (around 60 cm) as compared to when the sounds were beyond this space. This effect captures the spatial boundaries within which PPS representation modulates hand cortico-motor excitability. This spatially-dependent modulation of corticospinal activity was not further affected by the sound direction. Such findings support a strict link between the multisensory representation of the space around the body and the motor representation of potential approaching or defensive acts within that space.

The wheelchair as a full-body tool extending the peripersonal space.

Dedicated multisensory mechanisms in the brain represent peripersonal space (PPS), a limited portion of space immediately surrounding the body. Previous studies have illustrated the malleability of PPS representation through hand-object interaction, showing that tool use extends the limits of the hand-centered PPS. In the present study we investigated the effects of a special tool, the wheelchair, in extending the action possibilities of the whole body. We used a behavioral measure to quantify the extension of the PPS around the body before and after Active (Experiment 1) and Passive (Experiment 2) training with a wheelchair and when participants were blindfolded (Experiment 3). Results suggest that a wheelchair-mediated passive exploration of far space extended PPS representation. This effect was specifically related to the possibility of receiving information from the environment through vision, since no extension effect was found when participants were blindfolded. Surprisingly, the active motor training did not induce any modification in PPS representation, probably because the wheelchair maneuver was demanding for non-expert users and thus they may have prioritized processing of information from close to the wheelchair rather than at far spatial locations. Our results suggest that plasticity in PPS representation after tool use seems not to strictly depend on active use of the tool itself, but is triggered by simultaneous processing of information from the body and the space where the body acts in the environment, which is more extended in the case of wheelchair use. These results contribute to our understanding of the mechanisms underlying body-environment interaction for developing and improving applications of assistive technological devices in different clinical populations.

Extending peripersonal space representation without tool-use: evidence from a combined behavioral-computational approach.

Stimuli from different sensory modalities occurring on or close to the body are integrated in a multisensory representation of the space surrounding the body, i.e., peripersonal space (PPS). PPS dynamically modifies depending on experience, e.g., it extends after using a tool to reach far objects. However, the neural mechanism underlying PPS plasticity after tool use is largely unknown. Here we use a combined computational-behavioral approach to propose and test a possible mechanism accounting for PPS extension. We first present a neural network model simulating audio-tactile representation in the PPS around one hand. Simulation experiments showed that our model reproduced the main property of PPS neurons, i.e., selective multisensory response for stimuli occurring close to the hand. We used the neural network model to simulate the effects of a tool-use training. In terms of sensory inputs, tool use was conceptualized as a concurrent tactile stimulation from the hand, due to holding the tool, and an auditory stimulation from the far space, due to tool-mediated action. Results showed that after exposure to those inputs, PPS neurons responded also to multisensory stimuli far from the hand. The model thus suggests that synchronous pairing of tactile hand stimulation and auditory stimulation from the far space is sufficient to extend PPS, such as after tool-use. Such prediction was confirmed by a behavioral experiment, where we used an audio-tactile interaction paradigm to measure the boundaries of PPS representation. We found that PPS extended after synchronous tactile-hand stimulation and auditory-far stimulation in a group of healthy volunteers. Control experiments both in simulation and behavioral settings showed that the same amount of tactile and auditory inputs administered out of synchrony did not change PPS representation. We conclude by proposing a simple, biological-plausible model to explain plasticity in PPS representation after tool-use, which is supported by computational and behavioral data.

Body part-centered and full body-centered peripersonal space representations.

Dedicated neural systems represent the space surrounding the body, termed Peripersonal space (PPS), by integrating visual or auditory stimuli occurring near the body with somatosensory information. As a behavioral proxy to PPS, we measured participants' reaction time to tactile stimulation while task-irrelevant auditory or visual stimuli were presented at different distances from their body. In 7 experiments we delineated the critical distance at which auditory or visual stimuli boosted tactile processing on the hand, face, and trunk as a proxy of the PPS extension. Three main findings were obtained. First, the size of PPS varied according to the stimulated body part, being progressively bigger for the hand, then face, and largest for the trunk. Second, while approaching stimuli always modulated tactile processing in a space-dependent manner, receding stimuli did so only for the hand. Finally, the extension of PPS around the hand and the face varied according to their relative positioning and stimuli congruency, whereas the trunk PPS was constant. These results suggest that at least three body-part specific PPS representations exist, differing in extension and directional tuning. These distinct PPS representations, however, are not fully independent from each other, but referenced to the common reference frame of the trunk.

Social modulation of peripersonal space boundaries.

The space around the body, i.e., peripersonal space (PPS), is conceived as a multisensory-motor interface between body and environment. PPS is represented by frontoparietal neurons integrating tactile, visual, and auditory stimuli occurring near the body. PPS is plastic, because it extends by using a tool to reach far objects. Although interactions with others occur within PPS, little is known about how social environment modulates it. Here, we show that presence and interaction with others shape PPS representation. Participants performed a tactile detection task on their face while concurrent task-irrelevant sounds approached toward or receded from their face. Because a sound affects touch when occurring within PPS, we calculated the critical distance where sounds speeded up tactile reaction time as a proxy of PPS boundaries. Experiment 1 shows that PPS boundaries shrink when subjects face another individual, as compared to a mannequin, placed in far space. Experiment 2 and 3 show that, after playing an economic game with another person, PPS boundaries between self and other merge, but only if the other behaved cooperatively. These results reveal that PPS representation is sensitive to social modulation, showing a link between low-level sensorimotor processing and high-level social cognition.

Amputation and prosthesis implantation shape body and peripersonal space representations.

Little is known about whether and how multimodal representations of the body (BRs) and of the space around the body (Peripersonal Space, PPS) adapt to amputation and prosthesis implantation. In order to investigate this issue, we tested BR in a group of upper limb amputees by means of a tactile distance perception task and PPS by means of an audio-tactile interaction task. Subjects performed the tasks with stimulation either on the healthy limb or the stump of the amputated limb, while wearing or not wearing their prosthesis. When patients performed the tasks on the amputated limb, without the prosthesis, the perception of arm length shrank, with a concurrent shift of PPS boundaries towards the stump. Conversely, wearing the prosthesis increased the perceived length of the stump and extended the PPS boundaries so as to include the prosthetic hand, such that the prosthesis partially replaced the missing limb.

Dynamic sounds capture the boundaries of peripersonal space representation in humans.

BACKGROUND: We physically interact with external stimuli when they occur within a limited space immediately surrounding the body, i.e., Peripersonal Space (PPS). In the primate brain, specific fronto-parietal areas are responsible for the multisensory representation of PPS, by integrating tactile, visual and auditory information occurring on and near the body. Dynamic stimuli are particularly relevant for PPS representation, as they might refer to potential harms approaching the body. However, behavioural tasks for studying PPS representation with moving stimuli are lacking. Here we propose a new dynamic audio-tactile interaction task in order to assess the extension of PPS in a more functionally and ecologically valid condition. METHODOLOGY/PRINCIPAL FINDINGS: Participants vocally responded to a tactile stimulus administered at the hand at different delays from the onset of task-irrelevant dynamic sounds which gave the impression of a sound source either approaching or receding from the subject's hand. Results showed that a moving auditory stimulus speeded up the processing of a tactile stimulus at the hand as long as it was perceived at a limited distance from the hand, that is within the boundaries of PPS representation. The audio-tactile interaction effect was stronger when sounds were approaching compared to when sounds were receding. CONCLUSION/SIGNIFICANCE: This study provides a new method to dynamically assess pps representation: The function describing the relationship between tactile processing and the position of sounds in space can be used to estimate the location of PPS boundaries, along a spatial continuum between far and near space, in a valuable and ecologically significant way.