A fronto-insular-parietal network for the sense of body ownership.

Neuropsychological disturbances in the sense of limb ownership provide unique opportunities to study the neurocognitive basis of body ownership. Previous small sample studies that showed discrete cortical lesions cannot explain why multisensory, affective, and cognitive manipulations alter disownership symptoms. We tested the novel hypothesis that disturbances in the sense of limb ownership would be associated not only with discrete cortical lesions but also with disconnections of white-matter tracts supporting specific functional networks. We drew on an advanced lesion-analysis and Bayesian statistics approach in 49 right-hemisphere patients (23 with and 26 without limb disownership). Our results reveal that disturbances in the sense of ownership are associated with lesions in the supramarginal gyrus and disconnections of a fronto-insular-parietal network, involving the frontal-insular and frontal inferior longitudinal tracts, confirming previous disconnection hypotheses. Together with previous behavioral and neuroanatomical results, these findings lead us to propose that the sense of body ownership involves the convergence of bottom-up, multisensory integration, and top-down monitoring of sensory salience based on contextual demands.

Disturbed interoception in body dysmorphic disorder: A framework for future research.

Body dysmorphic disorder is a severe psychiatric condition characterised by a preoccupation with a perceived appearance flaw or flaws that are typically not observable to others. Although significant advances in understanding the disorder have been made in the past decade, current explanations focus on cognitive, behavioural and visual perceptual disturbances that contribute to the disorder. Such a focus does not consider how perception of the internal body or interoception may be involved, despite (1) clinical observations of disturbed perception of the body in body dysmorphic disorder and (2) disturbed interoception being increasingly recognised as a transdiagnostic factor underlying a wide range of psychopathologies. In this paper, we use an existing model of hierarchical brain function and neural (predictive) processing to propose that body dysmorphic disorder involves defective interoception, with perceived appearance flaws being the result of 'interoceptive prediction errors' that cause body parts to be experienced as 'not just right'. We aim to provide a framework for interoceptive research into body dysmorphic disorder, and outline areas for future research.

Strange face illusions: A systematic review and quality analysis.

BACKGROUND: Strange face illusions describe a range of visual apparitions that occur when an observer gazes at their image reflected in a mirror or at another person's face in a dimly lit room. The illusory effects range from mild alterations in colour, or contrast, to the perception of distorted facial features, or new strange faces.The current review critically evaluates studies investigating strange face illusions, their methodological quality, and existing interpretations. METHOD: Searches conducted using Scopus, PubMed, ScienceDirect and the grey literature until June 2022 identified 21 studies (N = 1,132; healthy participants n = 1,042; clinical participants n = 90) meeting the inclusion criteria (i.e., providing new empirical evidence relating to strange face illusions). The total sample had a mean age of 28.3 years (SD = 10.31) and two thirds (67 %) of participants tested to date are female. Results are reported using the Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) guidelines. The review was preregistered at the Open Science Framework (OSF: https://osf.io/ek48d). RESULTS: Pooling data across studies, illusory new strange faces are experienced by 58% (95%CI 48 to 68) of nonclinical participants. Study quality as assessed by the Appraisal Tool for Cross-Sectional Studies (AXIS) revealed that 3/21 (14.28%) studies were rated as high, 9/21 (42.86%) as moderate and 9/21 (42.86%) as low quality. Whilst the items relating specifically to reporting quality scored quite highly, those relating to study design and possible biases were lower and more variable. Overall, study quality accounted for 87% of the variance in reporting rates for strange faces, with higher quality being associated with lower illusion rates. The prevalence of illusions was also significantly greater in samples that were older, had higher proportions of female participants and for the interpersonal dyad (IGDT) compared to the mirror gaze paradigm (MGT). The moderating impact of study quality persisted in a multiple meta-regression involving participant age, paradigm type (IGDT vs MGT) and level of feature distortion. Our review point to the importance of reduced light levels, face stimuli and prolonged eye fixation for strange face illusions to emerge. CONCLUSION: Strange face illusions reliably occur in both mirror-gazing and interpersonal gazing dyad paradigms. Further research of higher quality is required to establish the prevalence and particularly, the mechanisms underpinning strange face illusions.

Psychological interventions for interoception in mental health disorders: A systematic review of randomized-controlled trials.

Disturbed interoception (i.e., the sensing, awareness, and regulation of internal body signals) has been found across several mental disorders, leading to the development of interoception-based interventions (IBIs). Searching PubMed and PsycINFO, we conducted the first systematic review of randomized-controlled trials (RCTs) investigating the efficacy of behavioral IBIs at improving interoception and target symptoms of mental disorders in comparison to a non-interoception-based control condition [CRD42021297993]. Thirty-one RCTs fulfilled inclusion criteria. Across all studies, a pattern emerged with 20 (64.5%) RCTs demonstrating IBIs to be more efficacious at improving interoception compared to control conditions. The most promising results were found for post-traumatic stress disorder, irritable bowel syndrome, fibromyalgia and substance use disorders. Regarding symptom improvement, the evidence was inconclusive. The IBIs were heterogenous in their approach to improving interoception. The quality of RCTs was moderate to good. In conclusion, IBIs are potentially efficacious at improving interoception for some mental disorders. In terms of symptom reduction, the evidence is less promising. Future research on the efficacy of IBIs is needed.

Embodied Precision: Intranasal Oxytocin Modulates Multisensory Integration.

Multisensory integration processes are fundamental to our sense of self as embodied beings. Bodily illusions, such as the rubber hand illusion (RHI) and the size-weight illusion (SWI), allow us to investigate how the brain resolves conflicting multisensory evidence during perceptual inference in relation to different facets of body representation. In the RHI, synchronous tactile stimulation of a participant's hidden hand and a visible rubber hand creates illusory body ownership; in the SWI, the perceived size of the body can modulate the estimated weight of external objects. According to Bayesian models, such illusions arise as an attempt to explain the causes of multisensory perception and may reflect the attenuation of somatosensory precision, which is required to resolve perceptual hypotheses about conflicting multisensory input. Recent hypotheses propose that the precision of sensorimotor representations is determined by modulators of synaptic gain, like dopamine, acetylcholine, and oxytocin. However, these neuromodulatory hypotheses have not been tested in the context of embodied multisensory integration. The present, double-blind, placebo-controlled, crossover study ( n = 41 healthy volunteers) aimed to investigate the effect of intranasal oxytocin (IN-OT) on multisensory integration processes, tested by means of the RHI and the SWI. Results showed that IN-OT enhanced the subjective feeling of ownership in the RHI, only when synchronous tactile stimulation was involved. Furthermore, IN-OT increased an embodied version of the SWI (quantified as estimation error during a weight estimation task). These findings suggest that oxytocin might modulate processes of visuotactile multisensory integration by increasing the precision of top-down signals against bottom-up sensory input.

Mentalizing the body: spatial and social cognition in anosognosia for hemiplegia.

Following right-hemisphere damage, a specific disorder of motor awareness can occur called anosognosia for hemiplegia, i.e. the denial of motor deficits contralateral to a brain lesion. The study of anosognosia can offer unique insights into the neurocognitive basis of awareness. Typically, however, awareness is assessed as a first person judgement and the ability of patients to think about their bodies in more 'objective' (third person) terms is not directly assessed. This may be important as right-hemisphere spatial abilities may underlie our ability to take third person perspectives. This possibility was assessed for the first time in the present study. We investigated third person perspective taking using both visuospatial and verbal tasks in right-hemisphere stroke patients with anosognosia (n = 15) and without anosognosia (n = 15), as well as neurologically healthy control subjects (n = 15). The anosognosic group performed worse than both control groups when having to perform the tasks from a third versus a first person perspective. Individual analysis further revealed a classical dissociation between most anosognosic patients and control subjects in mental (but not visuospatial) third person perspective taking abilities. Finally, the severity of unawareness in anosognosia patients was correlated to greater impairments in such third person, mental perspective taking abilities (but not visuospatial perspective taking). In voxel-based lesion mapping we also identified the lesion sites linked with such deficits, including some brain areas previously associated with inhibition, perspective taking and mentalizing, such as the inferior and middle frontal gyri, as well as the supramarginal and superior temporal gyri. These results suggest that neurocognitive deficits in mental perspective taking may contribute to anosognosia and provide novel insights regarding the relation between self-awareness and social cognition.

The 'not-so-strange' body in the mirror: A principal components analysis of direct and mirror self-observation.

In this study we adopted a psychometric approach to examine how the body is subjectively experienced in a mirror. One hundred and twenty-four healthy participants viewed their body for five minutes directly or via a mirror, and then completed a 20-item questionnaire designed to capture subjective experiences of the body. PCA revealed a two-component structure for both direct and mirror conditions, comprising body evaluations (and alienation) and unusual feelings and perceptions. The relationship between these components and pre-existing tendencies for appearance anxiety, body dysmorphic-type beliefs, dissociative symptomatology, self-objectification and delusion ideation further supported the similarity between direct and mirror conditions; however, the occurrence of strange experiences like those reported to occur during prolonged face viewing was not confirmed. These results suggest that, despite obvious differences in visual feedback, observing the body via a mirror (as an outside observer) is subjectively equivalent to observing the body directly (from our own viewpoint).

Anarchic hand with abnormal agency following right inferior parietal lobe damage: a case report.

Anarchic hand syndrome (AHS) is characterized by goal-directed movements performed without volitional control (agency). Different AHS subtypes have been identified; however, few studies have examined the posterior subtype. We report a case of AHS following right-hemisphere parietal damage, with left-sided somatosensory and proprioceptive impairment. Agency was examined for nonanarchic (volitional) movements performed using the anarchic hand. The patient experienced abnormal agency for movements whether motor intention and visual feedback were congruent or incongruent, but not when intention was absent (passive movement). Findings suggest a general disturbance of veridical motor awareness and agency in this case of parietal AHS.

New reflections on agency and body ownership: The moving rubber hand illusion in the mirror.

No previous study has simultaneously examined body ownership and agency in healthy subjects during mirror self-observation. We used a moving rubber hand illusion to examine how both body ownership and agency are affected by seeing (i) the body moving in a mirror, compared with (ii) directly viewing the moving hand, and (iii) seeing a visually identical hand rotated by 180°. We elicited ownership of the hand using direct visual feedback, finding this effect was further enhanced when looking at the hand in a mirror, whereas rotating the hand 180° abolished ownership. Agency was similarly elicited using direct visual feedback, and equally so in the mirror, but again reduced for the 180° hand. We conclude that the reflected body in a mirror is treated as 'special' in the mind, and distinct from other external objects. This enables bodies and actions viewed in a mirror to be directly related to the self.

Interoception in anxiety, depression, and psychosis: a review.

Research has examined the relationship between interoception and anxiety, depression, and psychosis; however, it is unclear which aspects of interoception have been systematically examined, what the combined findings are, and which areas require further research. To answer these questions, we systematically searched and narratively synthesised relevant reviews, meta-analyses, and theory papers (total n = 34). Existing systematic reviews and meta-analyses (anxiety n = 2; depression n = 2; psychosis n = 0), focus on cardiac interoceptive accuracy (heartbeat perception), and indicate that heartbeat perception is not systematically impaired in anxiety or depression. Heartbeat perception might be poorer in people with psychosis, but further evidence is needed. Other aspects of interoception, such as different body systems and processing levels, have been studied but not systematically reviewed. We highlight studies examining these alternative bodily domains and levels, review the efficacy of interoception-based psychological interventions, and make suggestions for future research. Funding: Wellcome Trust UK.

What I think she thinks about my paralysed body: Social inferences about disability-related content in anosognosia for hemiplegia.

The neuropsychological disorder of anosognosia for hemiplegia (AHP) can offer unique insights into the neurocognitive processes of body consciousness and representation. Previous studies have found associations between selective social cognition deficits and anosognosia. In this study, we examined how such social cognition deficits may directly interact with representations of one's body as disabled in AHP. We used a modified set of previously validated Theory of Mind (ToM) stories to create disability-related content that was related to post-stroke paralysis and to investigate differences between right hemisphere damage patients with (n = 19) and without (n = 19) AHP. We expected AHP patients to perform worse than controls when trying to infer paralysis-related mental states in the paralysis-related ToM stories and explored whether such differences depended on the inference patients were asked to perform (e.g. self or other referent perspective-taking). Using an advanced structural neuroimaging technique, we expected selective social cognitive deficits to be associated with posterior parietal cortex lesions and deficits in self-referent perspective-taking in paralysis-related mentalising to be associated with frontoparietal disconnections. Group- and individual-level results revealed that AHP patients performed worse than HP controls when trying to infer paralysis-related mental states. Exploratory lesion analysis results revealed some of the hypothesised lesions, but also unexpected white matter disconnections in the posterior body and splenium of the corpus collosum associated with a self-referent perspective-taking in paralysis-related ToM stories. The study has implications for the multi-layered nature of body awareness, including abstract, social perspectives and beliefs about the body.

Examining the role of self-reported somatosensory sensations in body (dis)ownership: A scoping review and empirical study of patients with a disturbed sense of limb ownership.

Patients with a disturbed sense of limb ownership (DSO) offer a unique window of insight into the multisensory processes contributing to the sense of body ownership. A limited amount of past research has examined the role of sensory deficits in DSO, and even less is known regarding the role of patient self-reported somatosensory sensations in the pathogenesis of DSO. To address this lack of knowledge we first conducted a systematic scoping review following PRISMA-SR guidelines, examining current research into somatosensory deficits and patient self-reported somatosensory sensations in patients with DSO. Eighty studies, including 277 DSO patients, were identified. The assessment of sensory deficits was generally limited in scope and quality, and deficits in tactile sensitivity and proprioception were most frequently found. The reporting of somatosensory sensations was even less frequent, with instances of paraesthesia (pins-and-needles), stiffness/rigidity, numbness and warmth, coldness and heaviness amongst the deficits recorded. In a second part of the study, we sought to directly address the lack of evidence concerning the impact of patient self-reported somatosensory sensations in DSO by measuring DSO and self-reported somatosensory sensations in a large (n = 121) sample of right-hemisphere stroke patients including N = 65 with DSO and N = 56 hemiplegic controls. Results show that feelings of coldness and stiffness modulate DSO symptoms. Sense of heaviness and numbness are more frequent in patients with DSO but do not have a clear impact on disownership symptomology. Although preliminary, these results suggest a role of subjective sensations about the felt body in the sense of limb ownership.

Tactile emoticons: Conveying social emotions and intentions with manual and robotic tactile feedback during social media communications.

Touch offers important non-verbal possibilities for socioaffective communication. Yet most digital communications lack capabilities regarding exchanging affective tactile messages (tactile emoticons). Additionally, previous studies on tactile emoticons have not capitalised on knowledge about the affective effects of certain mechanoreceptors in the human skin, e.g., the C-Tactile (CT) system. Here, we examined whether gentle manual stroking delivered in velocities known to optimally activate the CT system (defined as 'tactile emoticons'), during lab-simulated social media communications could convey increased feelings of social support and other prosocial intentions compared to (1) either stroking touch at CT sub-optimal velocities, or (2) standard visual emoticons. Participants (N = 36) felt more social intent with CT-optimal compared to sub-optimal velocities, or visual emoticons. In a second, preregistered study (N = 52), we investigated whether combining visual emoticons with tactile emoticons, this time delivered at CT-optimal velocities by a soft robotic device, could enhance the perception of prosocial intentions and affect participants' physiological measures (e.g., skin conductance rate) in comparison to visual emoticons alone. Visuotactile emoticons conveyed more social intent overall and in anxious participants affected physiological measures more than visual emoticons. The results suggest that emotional social media communications can be meaningfully enhanced by tactile emoticons.

Updating Prospective Self-Efficacy Beliefs About Cardiac Interoception in Anorexia Nervosa: An Experimental and Computational Study.

Patients with anorexia nervosa (AN) typically hold altered beliefs about their body that they struggle to update, including global, prospective beliefs about their ability to know and regulate their body and particularly their interoceptive states. While clinical questionnaire studies have provided ample evidence on the role of such beliefs in the onset, maintenance, and treatment of AN, psychophysical studies have typically focused on perceptual and 'local' beliefs. Across two experiments, we examined how women at the acute AN (N = 86) and post-acute AN state (N = 87), compared to matched healthy controls (N = 180) formed and updated their self-efficacy beliefs retrospectively (Experiment 1) and prospectively (Experiment 2) about their heartbeat counting abilities in an adapted heartbeat counting task. As preregistered, while AN patients did not differ from controls in interoceptive accuracy per se, they hold and maintain 'pessimistic' interoceptive, metacognitive self-efficacy beliefs after performance. Modelling using a simplified computational Bayesian learning framework showed that neither local evidence from performance, nor retrospective beliefs following that performance (that themselves were suboptimally updated) seem to be sufficient to counter and update pessimistic, self-efficacy beliefs in AN. AN patients showed lower learning rates than controls, revealing a tendency to base their posterior beliefs more on prior beliefs rather than prediction errors in both retrospective and prospective belief updating. Further explorations showed that while these differences in both explicit beliefs, and the latent mechanisms of belief updating, were not explained by general cognitive flexibility differences, they were explained by negative mood comorbidity, even after the acute stage of illness.

My social comfort zone: Attachment anxiety shapes peripersonal and interpersonal space.

Following positive social exchanges, the neural representation of interactive space around the body (peripersonal space; PPS) expands, whereas we also feel consciously more comfortable being closer to others (interpersonal distance; ID). However, it is unclear how relational traits, such as attachment styles, interact with the social malleability of our PPS and ID. A first, exploratory study (N=48) using a visuo-tactile, augmented reality task, found that PPS depended on the combined effects of social context and attachment anxiety. A follow-up preregistered study (N = 68), showed that those with high attachment anxiety demonstrated a sharper differentiation between peripersonal and extrapersonal space, even in a non-social context. A final, preregistered large-scale survey (N = 19,417) found that people scoring high in attachment anxiety prefer closer ID and differentiate their ID less based on feelings of social closeness. We conclude that attachment anxiety reduces the social malleability of both peripersonal and interpersonal space.

Awareness is in the eye of the observer: Preserved third-person awareness of deficit in anosognosia for hemiplegia.

In recent decades, the research traditions of (first-person) embodied cognition and of (third-person) social cognition have approached the study of self-awareness with relative independence. However, neurological disorders of self-awareness offer a unifying perspective to empirically investigate the contribution of embodiment and social cognition to self-awareness. This study focused on a neuropsychological disorder of bodily self-awareness following right-hemisphere damage, namely anosognosia for hemiplegia (AHP). A previous neuropsychological study has shown AHP patients, relative to neurological controls, to have a specific deficit in third-person perspective taking and allocentric stance (the other unrelated to the self) in higher order mentalizing tasks. However, no study has tested if verbal awareness of motor deficits is influenced by perspective-taking and centrism and identified the related anatomical correlates. Accordingly, two novel experiments were conducted with right-hemisphere stroke patients with (n = 17) and without AHP (n = 17) that targeted either their own (egocentric, experiment 1) or another stooge patients (allocentric, experiment 2) motor abilities from a first-or-third person perspective. In both experiments, neurological controls showed no significant difference in perspective-taking, suggesting that social cognition is not a necessary consequence of right-hemisphere damage. More specifically, experiment 1 found AHP patients more aware of their own motor paralysis (egocentric stance) when asked from a third compared to a first-person perspective, using both group level and individual level analysis. In experiment 2, AHP patients were less accurate than controls in making allocentric judgements about the stooge patient, but with only a trend towards significance and with no difference between perspectives. As predicted, deficits in egocentric and allocentric third-person perspective taking were associated with lesions in the middle frontal gyrus, superior temporal and supramarginal gyri, and white matter disconnections were more prominent with deficits in allocentricity. Behavioural and neuroimaging results demonstrate the intersecting relationship between bodily self-awareness and self-and-other-directed metacognition or mentalisation.

The Motor Unawareness Assessment (MUNA): A new tool for the assessment of Anosognosia for hemiplegia.

Introduction: Anosognosia for hemiplegia (AHP) is a condition in which patients with paralysis are unaware of their motor deficits. Research into AHP is important for improving its treatment and providing insight into the neurocognitive mechanism of motor awareness. Unfortunately, most studies use assessments with widely recognized limitations.The study aims at developing a psychometrically validated assessment of AHP.Method: We developed a 40-item Motor Unawareness Assessment (MUNA) and administered it to 131 right-hemisphere stroke patients. Principal Component Analysis (PCA) was used to identify the underlying factor structure. Receiver Operating Characteristics (ROC) analysis was used to determine diagnostic cutoffs, and Area Under the Curve (AUC) analysis used to assess these cutoffs. Relationships with demographic, clinical and neuropsychological variables were explored.Results: Five factors were identified: explicit motor awareness, implicit motor awareness, impaired sense of ownership, agency and illusory movement, and emotional reactions. Established cutoffs had excellent sensitivity and specificity. Clinical, neuropsychological and demographic variables did not predict overall MUNA score but were related to specific subcomponents.Conclusion: The MUNA can differentiate various facets of AHP and provides a detailed profile of (un)awareness. The MUNA can therefore provide robust assessment for research purposes and assist clinicians when developing targeted rehabilitation.

Damage to the right insula disrupts the perception of affective touch.

Specific, peripheral C-tactile afferents contribute to the perception of tactile pleasure, but the brain areas involved in their processing remain debated. We report the first human lesion study on the perception of C-tactile touch in right hemisphere stroke patients (N = 59), revealing that right posterior and anterior insula lesions reduce tactile, contralateral and ipsilateral pleasantness sensitivity, respectively. These findings corroborate previous imaging studies regarding the role of the posterior insula in the perception of affective touch. However, our findings about the crucial role of the anterior insula for ipsilateral affective touch perception open new avenues of enquiry regarding the cortical organization of this tactile system.

Welcoming back my arm: affective touch increases body ownership following right-hemisphere stroke.

Right-hemisphere stroke can impair the ability to recognize one's contralesional body parts as belonging to one's self. The study of this so-called 'disturbed sense of limb ownership' can provide unique insights into the neurocognitive mechanisms of body ownership. In this study, we address a hypothesis built upon experimental studies on body ownership in healthy volunteers. These studies have shown that affective (pleasant) touch, an interoceptive modality associated with unmyelinated, slow-conducting C-tactile afferents, has a unique role in the sense of body ownership. In this study, we systematically investigated whether affective touch stimulation could increase body ownership in patients with a disturbed sense of limb ownership following right-hemisphere stroke. An initial feasibility study in 16 adult patients with acute stroke enabled us to optimize and calibrate an affective touch protocol to be administered by the bedside. The main experiment, conducted with a different sample of 26 right hemisphere patients, assessed changes in limb ownership elicited following self- (patient) versus other- (experimenter) generated tactile stimulation, using a velocity known to optimally activate C-tactile fibres (i.e. 3 cm/s), and a second velocity that is suboptimal for C-tactile activation (i.e. 18 cm/s). We further examined the specificity and mechanism of observed changes in limb ownership in secondary analyses looking at (i) the influence of perceived intensity and pleasantness of touch, (ii) touch laterality and (iii) level of disturbed sense of limb ownership on ownership change and (iv) changes in unilateral neglect arising from touch. Findings indicated a significant increase in limb ownership following experimenter-administered, C-tactile-optimal touch. Voxel-based lesion-symptom mapping identified damage to the right insula and, more substantially, the right corpus callosum, associated with a failure to increase body ownership following experimenter-administered, affective touch. Our findings suggest that affective touch can increase the sense of body-part ownership following right-hemisphere stroke, potentially due to its unique role in the multisensory integration processes that underlie the sense of body ownership.

Imagining the impossible: motor representations in anosognosia for hemiplegia.

Anosognosia for hemiplegia (AHP) is characterised by poor insight or underestimation of hemiplegia after brain injury. Recent explanations of AHP have used an established 'forward model', which proposes that normal motor awareness involves comparing the predicted and actual sensory consequences of movements. These accounts propose that AHP patients may be able to form representations of their intended movements (i.e., motor representations), but fail to register discrepancy between intended and actual movements. A prediction arising from this proposal is that AHP patients are able to generate motor representations involving their hemiplegic limb(s). Our study provides the first direct examination of this prediction in patients with AHP. We used an existing 'grip selection task', which investigates motor representations by comparing how patients would grasp an object and how they actually grasp the same object. Eight right hemisphere stroke patients with AHP, 10 control patients (non-AHP), and 22 age-matched healthy volunteers (HVs) completed the task. Results showed that HVs outperformed both AHP and non-AHP patients in their motor representations for the hemiplegic limb; however, the performance of AHP and non-AHP patients did not differ significantly. Motor representations for the intact limb were lower than normal in AHP patients, whereas performance in non-AHP patients was midway between the AHP and HV groups. Findings suggested that the ability to form motor representations lie on a continuum, but that impaired motor representations for the paralysed limb cannot account for AHP. Distorted motor representations, in combination with other deficits, might contribute to the pathogenesis of AHP.