The term person is used in multiple contexts (ethical, legal, philosophical, etc.) with varying definitions. This notion of person is critical when it comes to defining the status of the embryo that is said to be a potential person (Jouannet, Baertschi, and Guérin 2019). According to French law, the embryo becomes an individual when its cells lose their totipotentiality. In France, the National Consultative Committee on Ethics maintains that the child (the fetus) becomes a person at birth, but a philosopher like Kant believes that the child does not become a person until the age of 2-3 when he says "I". According to Kant, a person would thus be an individual endowed with reason. This definition probably needs to be adjusted when considering the person with a cognitive or mental disability. In addition, some associations and activists call for a legal status of "animal person" for domestic animals or a status of full person for great apes (chimpanzees, bonobos, gorillas and orangutans) (Cavalieri and Singer 1996). Some countries have even granted person status to non-living entities such as the Whanganui River in New Zealand or the Ganges and Yamuna rivers in India. A Maori adage relates: "I am the river and the river is me", suggesting an intimate relationship to the river as an alter ego. Finally, the status of the legal personality of robots and artificial intelligences was debated at the European Commission in 2018, a proposal that for some could eventually allow the recognition of a personality to these entities. Thus, the notion of person is at the center of important social issues. Our work on heterotopagnosia brings a social dimension to this notion of person in the field of neurology.
1.1. The discovery of heterotopagnosia
JD Degos and AC Bachoud-Lévi described in nine patients with a left parietal cerebral lesion who were unable to point at another person’s body parts. They called this new neuropsychological disorder heterotopagnosia (J. D. Degos and Bachoud-Levi 1998; J.-D. Degos et al. 1997). In typical cases, the patient with heterotopagnosia speaks and walks without showing any deficiency. Yet, when asked to show the examiner's nose for example, the patient becomes puzzled and worried, and then ends up showing his own nose (self-referencing behaviour). When he is told that he was wrong, he persists in his mistake and sometimes explains: "your nose is next to mine". However, when asked to show the examiner's glasses or any object on the examiner’s body, the patient succeeds easily. The patient can also show every object in his environment, as well as his own body parts. This disorder cannot be explained by another neuropsychological disorder, in particular a language or gesture disorder. Patients know how to attribute to its owner the part of the body designated by others and master the meaning of personal pronouns and possessive determiners.
1.2. Two core problems within heterotopagnosia syndrome
Only sixteen cases of heteropagnosia have been published to date, but the various authors do not agree on the interpretation of this disorder. For some, heteropagnosia is a disorder affecting a visuo-spatial representation of the human body (Felician et al. 2003), for others, heteropagnosia is the consequence of a difficulty in distinguishing between self and other combined to a disorder of the spatial coding of parts of the human body (Auclair et al. 2009). More recently, it has been suggested that this disorder results from an inability to integrate somatosensory information from the self with visual information from the body of others (Bassolino et al. 2019). However, these theories do not account for all the dimensions that make up the syndrome of heteropagnosia (Cleret de Langavant et al. 2009).
1.2.1. The human body of another person is a peculiar pointing target
Patients with heteropagnosia can point to their own body, but not that of others, whether the other person is the examiner (“point to my nose”) or a third party (“point to his/her nose”). Pointing performance improves when asked to point to body parts of a non-living human representation such as a doll, a photograph, or a drawing of a human body. Strikingly, patients with heteropagnosia better point at body parts of others when they are first asked to consider others as non-communicative and inanimate dolls, an object (Cleret de Langavant et al., 2009). Furthermore, we described the case of a woman with primary progressive logopenic aphasia who also showed heterotopagnosia. Unexpectedly, she better pointed at body parts of men than that of women (Cleret de Langavant et al. 2016). As a whole, pointing performance varies in patients with heterotopagnosia according to the proximity of the target to a person in the flesh: the closer the target is to an individual capable of communication, the more difficult it is to point at this person (Cleret de Langavant et al. 2012). We further interpreted the difficulty of designating women's bodies by their better abilities to communicate and show empathy compared to men. Because of their social skills, women may be seen as persons and not objects (Cleret de Langavant et al. 2016).
These results have been extended by the study of pointing kinematics (reaction time, speed and position) in healthy participants. In a first experiment, participants were asked to point at body parts or at objects located on themselves or on another person facing them. While pointing at one’s own body parts or objects on the body requires the same reaction time, there is a systematic delay for pointing at body parts of other persons compared to pointing at objects on others' body (Cleret de Langavant et al., 2012). In a second experiment, we replaced the person facing the tested participant by a non-communicating humanoid mannikin. Reaction times for pointing at the dummy's body or objects on the dummy were similar (Cleret de Langavant et al., 2012). In a third experiment, we asked healthy participants to alternately designate body parts on themselves or on a man or on a woman. Reaction times for pointing at another male body parts were shorter than for pointing to another female body parts, whatever the gender of the pointing participant. Thus, both men and women point more easily the body parts of men (Cleret de Langavant et al., 2016). In a final experiment, healthy participants pointed at the body parts of other persons or objects on other while lying in a PETscan (collaboration Prof Remy, CEA, SHFJ, Orsay). While participants pointed at another person’s body parts, we measured an increase of regional cerebral blood flow in a left parieto-occipital region, site of a lesion associated with heterotopagnosia (Cleret de Langavant, 2012).
As a whole, we have shown that pointing at the body of others and in particular that of women imposes an additional cognitive operation compared to pointing at objects and manikins, and that a left parieto-occipital region is the seat of this process. We hypothesize that this region makes it possible to see the body of others not as a person but as an object.
1.2.2. Heterotopagnosia is a trouble of non-verbal communication
The performance of patients with heterotopagnosia changes according to the used gesture. While the patient cannot point at other person’s body parts, he is able to name them, but also to touch and grasp them (Cleret de Langavant et al., 2009). Thus, heterotopagnosia cannot be explained by a visuospatial disorder (Felician et al. 2003), an incapacity to make the distinction between self and others (Auclair et al. 2009), or a deficit of somatosensory integration (Bassolino et al. 2019). Because the pointing gesture is by essence a means of non-verbal communication which cannot exist without an interlocutor to whom to address a message, we hypothesized that such communicative purpose of pointing related to the syndrome of heterotopagnosia.
In order to test the influence of the communication relationship during designation, we developed another experiment. The tested participant addressed pointing gestures either to the interlocutor on the left, to the interlocutor on the right, or to no one. The targets were objects located in front of the tested participant. The recording of the parameters of the pointing movement (left or right interlocutor or without communication) was carried out with a 3D camera. We showed that pointing without communication takes place in an egocentric frame of reference (refering to the position of the body schema of the tested participant). Conversely, the modifications of the spatial parameters of the pointing gesture suggest the use of a heterocentric frame of reference depending on the position of the interlocutor and his perspective while communicating with an interlocutor (Cleret de Langavant, 2011).
We replicated this experiment in H2O15 PETscan functional imaging (Coll. Prof Rémy, MIRCen). We compared declarative pointing (with communication relationship) and simple pointing (without communication relationship) with several target objects. The communication relationship during naming was associated with increased regional blood flow in the region of the right superior temporal sulcus, a region involved in sensing direction of averted gaze perception, visual and mental perspective taking, and representation of the mental states of others (Cleret de Langavant, 2011).
Altogether, this implies that declarative pointing is a communicative gesture that requires to model the interlocutor's perspective through a heterocentric reference frame using a right superior temporal sulcus area in the brain.
1.2.3. Description of typical heterotopagnosia
Heterotopagnosia is a complex neurological disorder which combines:
• An inability to point to other people's body parts
• A self-referencing behavior in case of pointing errors
• A spared ability to point at own's body parts
• A spared ability to point at objects even located on another person’s body
• A spared ability to grasp or touch the body parts of other persons
1.3. Can we understand heterotopagnosia?
1.3.1. What is known about pointing?
The pointing gesture is used for non-verbal communication. Thus, it always involves an interlocutor. Using this gesture, the subject who points indicates to his/her interlocutor the position of an object of interest to share an emotion or an information about it (declarative pointing) or to obtain this object from the interlocutor (imperative pointing). Pointing gestures are universal in the human species (Kita 2002). Pointing gestures have been observed in only few animal species (great apes, dolphins, canids) but probably lack a declarative communication intention in these species: they are not used for sharing emotions or information, but rather to obtain something from the interlocutor. A broad consensus of authors considers that declarative pointing is unique to mankind (Bullinger et al. 2011).
The pointing gesture is an important marker in the development of social skills in human children. The absence of the acquisition of such pointing gesture around the first year of age is often found in children with autistic spectrum disorders characterized by language and social skills impairments (Charman 2003).
The structure of any pointing gesture is similar to the triadic structure of verbal conversation: it involves three entities. The one who points is the first person “I”. The interlocutor is the second person “you”. Both the first and the second persons are truly persons, because they mutually grant each other the status of alter ego capable of communication. Conversely, the designated target, so-called the third person "him, her or it", is fundamentally an object, that is to say a non-person in this communication relationship. This point is critical and has long been recognized in linguistics: the third person represents the object is excluded from the communicative relationship between the persons “I” and “you”. According to Benveniste, the third person is the absentee (Benveniste 1966). According to Barthes, using the personal pronoun "he or she" when speaking of someone in his or her presence is like a "murder through language" (Barthes 1975) since by using it one deprives him of his status as a person. In brief, pointing and language set triadic communication relationships between two persons about an object.
This triadic structure explains the difficulty of pointing at the body of another person: it is a task that requires considering the body of a person (“you”) as an object (“him or her”). This structure of designation explains why pointing at another person’s body is impolite or even taboo in many cultures around the world: it is a kind of metaphysical insult depriving another human of his or her status of person (Cleret de Langavant et al. 2012; Tallis 2010).
Several cerebral representations of the human body have been described (Schwoebel, Coslett, and Buxbaum 2001; Sirigu et al. 1991). The body schema is an egocentric and dynamic representation of the subject's body, dependent on proprioceptive and visual afferences. The descriptive visuo-spatial representation of the human body describes the respective position of the parts of the human body without direct reference to the subject's own body.
We hypothesized that pointing at another person’s body requires to view this person as an object and thus to exclude this person from the communication relationship. This could explain why patients with heterotopagnosia are better pointing to non-living human representations such as photos or dolls. This also explains why patients' performance improves when they are asked to consider the human target as a doll, an object devoid of communication skills. Finally, the longer reaction time to point at another person’s body would reflect the cognitive cost imposed by the cognitive process necessary to view another human body, no longer as a person but as an object, thanks to a left parieto-occipital area (Cleret de Langavant et al. 2012).
Designation is essentially a gesture of communication that involves an interlocutor to whom the status of second person “you” is given and for which a heterocentric reference frame is created (Cleret de Langavant et al. 2011). To identify this interlocutor, a human body representation might be necessary, probably the visuo-spatial representation of the human body. Conversely, touch or grasping gestures are not necessarily used to communicate. They would not require the recognition of an interlocutor would not elicit the creation of a heterocentric reference frame. We hypothesize that patients with heterotopagnosia are able to point in general, can recognize their interlocutor via the visuo-spatial representation of the human body and retain the ability to generate a heterocentric reference frame for their interlocutor, but that cannot achieve the specific cognitive processing operation to view another person’s body as an object. In this failing process, when asked to point to body parts of others, patients point to the corresponding parts of their own body located in their egocentric body schema. When they are asked to grasp the parts of the body of others, they use the spared visuo-spatial representation of the human body.
1.4 Conclusion
From a neurological perspective, a person might a social construct because the person status is only attributed during a communicative relationship with an alter ego. This powerful process is largely given by the first person "I" who addresses a message to another individual. In that view, it explains why some humans attribute the status of a person to any kind of entity, including animals, robots, or geographical landscapes such as rivers. It could also explain why some humans can deprive other fellow humans from the status of person and consider them as objects leading them to racism acts or genocides for example.
In the neurological department of Henri Mondor Hospital, patients with Huntington's disease and Parkinson's disease are regularly followed-up. Some of these patients accept to participate in research programs to better understand and treat their disease.
1. Informed consent in innovative research trial in Huntington's disease
Huntington's disease is a rare and inherited disease affecting the brain in adults and causing cognitive, motor and psychiatric disorders leading to severe disability. Unfortunately, there is still no cure for such disease, but innovative research trials are regularly proposed to patients. Yet, in order to participate in a research trial, a patient should provide an informed consent. Given the cognitive and psychiatric disorders observed in Huntington's disease patients, the question of the obtention of valid informed consent is complex.
We analyzed the capacity for providing consent of Huntington's disease patients included in the MIG-HD trial which tested the potential therapeutic effect of grafting fetal neurons within the brain of patients (Bachoud-Lévi et al., 2021). At time of inclusion, comprehension of the research protocol and of free consent was evaluated using a questionnaire. The same questionnaire was proposed to the family caregiver. A year later, the same questionnaire was offered to them again, before their final consent and entry into the trial. We showed that patients with Huntington's disease understand the protocol as well as their family caregivers, although they were more likely to forget certain details after one year. It seemed that the patients benefited from the presence of their relative during the consent, probably because the latter were able to reformulate the information delivered by the research investigators. Patients and their relatives were also satisfied with the information given. Finally, the patients explained the participation in the clinical trial by altruistic reasons (to advance science and not exclusively for themselves). We have proposed recommendations (Cleret de Langavant et al. 2015) for patient consent in future innovative clinical research trials:
Patients' understanding of the protocol and their capacity to consent must be assessed by questionnaires involving feedback from the investigators.
If the patient is competent (sufficient cognitive abilities to understand and spared judgment), he must give his consent himself, not his relative. If the patient has limited ability to understand, if he does not have satisfactory competence to consent and if there is no treatment available, the relative can consent in the patient's place, with the patient's assent.
The identification of a person of trust is crucial for each patient participating in a research trial, because the patient could lose his ability to consent during the trial or after it has been carried out.
The participant's understanding of innovative research whose long-term impact is unknown should be reassessed without the participant being told before they receive the tested product, in order to verify the stability of their free choice to participate in the trial.
When providing information about innovative research such as gene therapy or cell therapy, the investigator must insist on the fact that unknown risks could arise during the trial, or after its end, and that it is not possible to eliminate the administered products.
2. Awareness of memory impairment in Huntington's disease
Patients with Huntington's disease have difficulty perceiving their own abnormal movements, even when others notice at first glance their frequent lurches when walking and the sudden movements imposed by their chorea (Snowden et al. 1998). It is often accepted that the decision-making abilities of people with Huntington's disease are impaired due to this anosognosia (unawareness for one's own deficit). We have shown that despite their lack of awareness about their motor disorders, patients with Huntington's disease are able to assess their memory disorders even better than their relatives (Cleret de Langavant et al. 2013). The autonomy of the person with a neurodegenerative disease is therefore complex and the skills of the person depend on the field of exploration. Just as the patient may be aware of some abilities and misunderstand others, it is possible that he remains competent to make decisions in some areas and not in others.
3. Illusions of presence in Parkinson's disease
In addition to the motor disorders caused by Parkinson's disease, the non-motor symptoms have a severe impact on the autonomy and quality of life of patients. Minor hallucinations such as illusions of presence, visual illusions and illusions of passage are frequent phenomena. They are now included in the spectrum of psychotic disorders associated with Parkinson's disease (Fénelon et al. 2010).
The illusions of presence, which correspond to the impression that someone is near the subject when no one is there, were until recently poorly defined. We analyzed the illusions of presence in 52 consecutive patients with Parkinson's disease without major cognitive impairment. We discovered that the illusions of presence are not sensory perceptions, but hallucinatory sensations projected into the patient's extra-personal space and often associated with other visual hallucinatory phenomena. This type of presence hallucination could correspond to the activation of a cerebral network specific to the recognition of a person independently of any external visual stimulus. We conclude from this work that hallucinations of presence could be a form of social hallucinations in Parkinson's disease (Fénelon et al. 2011). This type of hypothesis echoes our interpretation of the pointing disorders where the recognition of others as a second person “you” is an essential element in establishing a communication relationship (Cleret de Langavant et al. 2012). It is possible that the brain areas involved in the recognition of others as a person are spontaneously activated independently of any external stimulus in the presence hallucination in Parkinson's disease.
The aging of the world population will be accompanied by an increase in cases of dementia in the coming decades. The prevalence of dementia will triple between 2015 and 2050 to exceed 130 million cases worldwide (Prince 2015). In Europe, the aging of the population (+40% of people over 60 between 2015 and 2050) will be associated with a near doubling of cases of dementia (10 million in 2015, 19 million in 2050) (Prince 2015) and this despite a downward trend in the incidence of dementia in Europe and North America (Wolters et al. 2020). The care of a growing number of elderly people with cognitive impairment or dementia will have a major impact on the organization of our societies and their economies. The French population is worried about this prospect: one of the first fears concerning health in France is the risk of having Alzheimer's disease or dementia (Ipsos survey, 2017).
Despite this announced challenge, there are only a few therapies capable of influencing the progressive evolution of cognitive disorders and loss of autonomy in dementia (Livingston et al. 2017). The delisting of anticholinesterasic treatments since 2018 in France indicated in Alzheimer's disease limits access to the rare therapies available. Other therapies capable of acting directly on the molecular mechanisms of neurodegenerative diseases are still under development and sometimes controversial (case of anti-amyloid treatments). The care of people with dementia at home is essentially based on the collaboration of healthcare professionals (specialists in general medicine, neurology, geriatrics and/or psychiatry, speech therapists and/or physiotherapists, nurses, psychologists...) and especially family caregivers. This human cost is increasingly difficult to bear as the number of people with dementia increases.
The prevention of dementia by correcting modifiable risk factors of dementia represents a major hope (Barnes and Yaffe 2011; Norton et al. 2014; Livingston et al. 2017). In order to study dementia risk factors in different countries in order to compare their different impact, I used longitudinal studies of aging in the general population such as HRS survey (Health and Retirement Study) or SHARE survey (Survey of Health Aging and Retirement in Europe). Created by economists, sociologists and demographers to study the transition between the end of active life and the beginning of retirement, they capture all the social dimensions of an individual and contain the data necessary to discover the multiple dimensions of dementia. European SHARE and US HRS surveys collect information related to demography, health, cognition, psychiatric symptoms in representative samples of people over 50 years of age in each country concerned by the study. In the event of inability to respond by the respondent selected by demographic methods, relatives are authorized to complete the items that he/she cannot inform. Cognitive disorders are in particular assessed either by cognitive tests or by scales for relatives. Similarly, many items related to autonomy, motor skills and the social environment are available. These surveys are longitudinal and the participants are evaluated every two years with the same protocol. Finally, the same evaluation protocol exists not only for the USA and 27 European countries, but has also been applied to Mexico, Costa Rica, Brazil, the United Kingdom, Ireland, China, India, Japan, South Korea, South Africa which offers the possibility of making comparisons between different countries and continents.
Unsupervised machine-learning allowed me to exploit the massive data available in these studies of aging to identify people with probable dementia. Using hierarchical clustering on the first dimensions of the principal component analysis carried out on the HRS and SHARE databases, I identified three groups or clusters, very similar in European and US cohorts. A first cluster brought together young individuals, with spared cognitive performance, intact motor skills and perfect autonomy. A second cluster brought together older individuals, with slightly lower cognitive performance, moderate motor disorders affecting their mobility, but no loss of autonomy. Finally, the third cluster brought together the oldest participants, with declining cognitive, motor and functional performance as one would expect from people with dementia. I showed that the participants of the third cluster according to the unsupervised algorithm had a high probability of dementia (P > 0.95) when compared to a previously published algorithm (Cleret de Langavant, Bayen, and Yaffe 2018). I also examined the future of the individuals of the three clusters: I observed that the individuals of cluster 1 remained autonomous 4 years later, those of cluster 2 lost slightly in mobility, but it was especially the participants of cluster 3 who showed the steepest cognitive, motor and functional decline and the lowest survival (Cleret de Langavant et al., 2018). Altogether, this simple unsupervised algorithm uncovers a cluster of most likely demented participants in these aging cohorts. While the diagnosis of dementia (major neurocognitive disorder according to the DSM5 ('Diagnostic and Statistical Manual of Mental Disorders | DSM Library') is based on a few criteria largely influenced by the experience of the clinical expert who applies them, the unsupervised machine-learning algorithm discovers the state of dementia (major neurocognitive disorder) in an unbiased way.
By applying the same unsupervised algorithm to 10 general population aging cohorts modeled on HRS or SAGE (N = 146,749 individuals in total), we identified participants with probable dementia in 27 countries representing 64.5% of the world population over 50 and 68.3% of the population over 50 in low- and middle-income countries. We calculated for the different countries of these 10 cohorts the prevalence of dementia. The results of this study show that our estimates of the prevalence of dementia are close to those already estimated in developed countries such as the United States or Europe. On the other hand, our estimates are much higher than previous estimates in low- and middle-income countries. Our interpretation is that the prevalences of dementia have been underestimated in the low- and middle-income countries, due to the lack of good quality data (Nichols et al. 2019), the low efficiency of diagnostic criteria such as the DSM in these populations (Llibre Rodriguez et al. 2008), but also because of the underdiagnosis of dementia (these conditions are not diagnosed in more than 75% of cases) (Nakamura et al. 2015 ). We therefore estimate that in 2015 nearly 130 million people worldwide were living with dementia, compared to previous estimates of between 40 and 50 million (Nichols et al. 2019; Prince 2015). Knowing that cases of dementia are expected to triple by 2050 with a particularly strong increase in less developed countries, we further stress the global challenge that these conditions represent (Cleret de Langavant et al. 2020).