In February this year, a few members of our lab attended the 2023 International Congress for Human Genetics in Cape Town. My supervisor and I presented some of our recent work at the daily poster sessions (if you are interested, you can find our poster here). I discussed some of this work in my previous blog post, which described how understanding autistic experiences from the inside can play a crucial role in improving relationships, mental well-being and quality of life for autistic individuals and their families. At the genomics conference, I also spoke more about how valuable this approach could be from a molecular perspective.
This proved to be an interesting experience. In the midst of top geneticists and statisticians presenting complex bioinformatic modelling, I felt that I may have bemused some of the conference delegates with the psychosocial aspects of our model. This made me realize that it might be useful to discuss how our conceptual framework could lead to tangible molecular discoveries. And to do that, perhaps I would need more space than one A3 poster board.
This is what today's blog post aims to do - to illustrate why a more interdisciplinary framework for molecular autism research could help us to understand physiological mechanisms that directly impact psychological health and quality of life. In particular, I am interested in integrating psychology, sociology, neurology and biochemistry to try and understand the relationship between social camouflaging, autistic burnout and psychopathology.
Social camouflaging, autistic burnout & allostatic load
Social camouflaging and autistic burnout are two concepts that have emerged from autistic individuals' own descriptions of their internal experiences. While both of these ideas have long been used in autistic communities to convey shared experiences, it is only recently that researchers have begun to formally define, characterize, or quantify these constructs in an academic context. This task is no small feat - given the heterogeneity of the autism spectrum (and of human experience) it is impossible for any individual to accurately capture the personal experiences of an entire group. Current conceptualizations are no doubt limited by the fact that they largely represent individuals with more capacity for written or verbal communication. And they still need to be validated in a clinical context.
This is not to say that these constructs are without value - almost all previous understandings of autism were based solely on the external observations of non-autistic observers, with no attempt to incorporate the internal lived experiences of autistic individuals. As research keeps emerging, it is clear that social camouflaging and autistic burnout both significantly contribute to the increased rates of psychopathology and suicidality in autism. So it is critical for us to better understand these phenomena if we aim to work towards improving quality of life.
What I hope to highlight here, is how difficult it might seem to try and incorporate such new, subjectively defined, and immeasurable concepts into a field as complex and data-oriented as molecular biology. In fact, I think this would be entirely impossible for a molecular scientist to do in isolation. But..... what if there were fundamental similarities between these new ideas and another psychological construct that has already been well-defined and integrated into a molecular context?
This is where we can look to the field of research on Early Life Stress (ELS). ELS was first explored by sociologists and psychologists who noticed a link between traumatic experiences in early childhood and poor health outcomes later in life. ELS is currently defined as any condition that objectively threatens the well-being of a child or undermines their sense of safety or stability. This could include emotional or physical abuse, neglect, physical illness, parental loss, or socio-economic factors like poverty and discrimination.
Research has subsequently validated a significant association between ELS and mood disorders, anxiety, suicidality, neurodegeneration, diabetes, auto-immune conditions and cardiovascular disease. We now know that stress during sensitive periods of post-natal development alters neurophysiology, neurochemistry, and neuroimmune regulation, leading to psychological and behavioural changes in adulthood. More recently, researchers have discovered that stress exposure during adolescence, which is another vulnerable developmental period, has similar detrimental consequences.
The relationship between Early Life Stress and psychopathology (Gee et al, 2022). The cumulative toll of ELS is determined by interactions between social context (the type of stress each person is exposed to), underlying physiology (each individual's unique genetic code), their different stress responses (at the psychological and physiological level), and the presence or absence of protective factors.
Importantly, ELS researchers have divided different types of stress into three different categories: "good" stress leads to adaptation, "tolerable" stress leads to resilience and "toxic" stress leads to pathology or disease. The difference between these types of stressors is not actually the type of stressful event that is experienced. Rather, these categories of stress refer to different physiological stress responses and their effects on the body. And what distinguishes harmful or toxic forms of stress is “a lack of internal resources or external support systems".
So, how is all this relevant to autism? Firstly, people with autism are statistically more likely to experience traditional forms of ELS during childhood - such as discrimination, bullying, social isolation and interpersonal abuse. But it is also important to remember that situations that may be tolerable for neurotypical children actually induce toxic stress responses in autistic children due to their distinct neurophysiological differences. Exposure to every-day sensory stimuli is painful, uncontrollable, and personally threatening. Autistic children have described their day-to-day environment at school as “physically assaultive”, “uncertain" and "exhausting". Personal accounts from autistic adolescents and adults describe social camouflaging as "exceeding what nature has given" while autistic burnout is explained as “having all of your internal resources exhausted beyond measure". At every life-stage, autistic individuals are consistently pushed beyond their capacity just to achieve a degree of social participation. And even further resources are expended to achieve social acceptance. Together, these experiences resonate closely with the definition for toxic stress.
The conceptual overlap between ELS, Social Camouflaging and Autistic Burnout.
In fact, it turns out that current models for early life stress, social camouflaging and autistic burnout converge on a fundamental overlap: a mismatch between internal coping resources and external stressors. Importantly, this type of toxic stress is a model that is already widely studied in molecular neuroscience. When you don't have the capacity to withstand or adapt to stress, your physiology takes the toll in the form of something called allostatic load. Allostatic load means a dysregulation of crucial endocrine, metabolic and immune systems that usually help your body to maintain homeostasis - or a healthy state of equilibrium. What is so valuable about the model for allostasis is that it gives us a way to quantify the cumulative impact of biological, psychological and social factors that lead to pathology.
Against this backdrop, perhaps we can view social camouflaging and autistic burnout through a new lens. Maybe social camouflaging acts as a unique form of toxic stress that increases allostatic load in autism. Autistic burnout, on the other hand, might be a distinct pathological state that results from allostatic overload, leading to neurological and psychological dysregulation that manifests as psychopathology. The question that remains is, if we consider autistic burnout through the lens of allostatic load, could this help us to understand it on a mechanistic level?
Of mice and men... and mitochondria
As I mentioned before, the model for early life stress is well studied by neuroscientists. We have an increasing database of correlations between ELS and different molecular biomarkers, and researchers have gone on to validate many of these biomarkers in mechanistic studies. Mostly, this has involved creating and studying generations of psychologically traumatized rodents (though I won't go into detail for the sake of my fellow animal-oriented souls). We have found that many established models for ELS lead to signs of depression, anxiety and PTSD, as well as behavioural, motor and cognitive changes in adult mice. And these changes seem to be driven by neuroendocrine-immune signaling and mitochondrial metabolism.
The main player in stress signaling is something called the HPA axis, which is responsible for releasing cortisol to induce stress-responsive signaling. For a long time, researchers have known that the HPA axis seems to influence neuroimmune responses, and neuroinflammation is one of the well-validated biomarkers associated with ELS. More recently, we have discovered an intriguing relationship between HPA, immune and mitochondrial state.
A group of researchers led by Martin Picard at Columbia University have been exploring the role of mitochondria in chronic stress, and they have defined something called mitochondrial allostatic load (MAL). MAL refers to changes in mitochondrial shape, behaviour and function that play a central role in pathological stress responses. It turns out that mitochondria are not only important regulators of the neuroimmune system, but are also tightly coupled to HPA axis activation. And, research over the past decade shows that mitochondria play a key role in the development of depression and suicidality in the wake of ELS. This has informed a new field of research called mitochondrial psychobiology, looking at how mitochondria can be targeted to predict or mitigate the long-term consequences of chronic stress.
This field is fascinating in it's own right, but my interest was particularly sparked because of the autism literature I had been studying during my postgrad. In 2021, I was in the second year of my MSc and I was starting to get a sense of just how varied and complex the molecular landscape of autism was. So, I gathered about 20 studies and meta-analyses of molecular data from autism cohorts and I analyzed them to try and find shared biological pathways.
Biological pathways implicated across 19 molecular autism studies (Mahony and O'Ryan, 2021).
What came out as the top three pathways were those involved in 1) mitochondrial metabolism; 2) neuroimmune signaling and 3) neurodevelopment. Noticing the overlap with the mechanisms involved in the stress response, I looked further into the link between mitochondrial and stress signaling in autism. In fact, there is a growing body of data showing that autism is often associated with molecular markers for mitochondrial, neuroimmune, and HPA axis dysregulation. Again, I will spare you the waterfall of molecular details, but this is actually quite interesting: what if people with autism have an underlying molecular susceptibility to stress as well as increased exposure to toxic forms? Could this help us to understand why the rates of psychopathology and suicidality are so high in autism?
This is the crux of our biopsychosocial model for autistic burnout, which highlights some new avenues for molecular autism research. Perhaps we could investigate a molecular vulnerability in autism that contributes to the high rates of psychopathology. Or, we could try to develop diagnostic tools to differentiate autistic burnout from clinical depression. Maybe we could explore how social camouflaging leads to autistic burnout on a physiological level. Or we could work towards therapies to reduce the cumulative toll of chronic stress that leads to a host of negative clinical outcomes in autism.
It is important to emphasize that this is just a hypothesis - it's not like other types of scientific papers that are already backed up by data. But no piece of this model is necessarily new. Different people in different fields have been working to validate separate aspects of this framework for the last decade - and we are just starting to put them all together. As a biochemistry research student, I spend most of my time fighting with invisible molecules in a tube – so I am all too aware of how much work it will take to validate this hypothesis. Still, it is exciting to zoom out a little bit and see how all of these disparate fields are starting to connect in a way that could one day help us to understand how and why autistic burnout happens. And, even while we work towards molecular validation, this framework could still have some useful take-aways for many of us involved in autism research.
For molecular researchers like me, this discussion shows us that integrating lived experiences into our work is not just good participatory research practice - but actually holds real potential to provide new insights into the molecular etiology of autism. Specifically, this model gives us a new angle to tackle understudied mechanisms that directly impact the health and quality of life in autism. For autistic individuals, I hope this model helps to explain the fatigue and incapacitation you may experience – and that is not because you are broken, misbehaving, lazy or oversensitive. What you are experiencing is physiologically underpinned, it is not your fault, and it has probably happened because you have always had to work so hard to exceed your own capacity for the sake of other people.
For family members, this framework might help us to be more aware of the chronic, and often unrecognized, forms of stress that are imposed on autistic children as they grow up. I hope it helps you to understand autistic burnout as more than psychological exhaustion – but rather systemic physiological dysregulation that can have profound, long-lasting consequences if it is misunderstood or overlooked. And for clinicians, teachers and employers - much of this literature highlights the importance of earlier diagnosis, improved access to accommodations, and decreased stigmatization of autistic traits in mitigating psychopathology. When autistic traits become more apparent or disruptive as a consequence of burnout, it is so important to remember that these traits themselves should not be punished or labelled the problem. The problem is the underlying burnout that reflects the immense physiological cost of trying to survive in the world.
As we have become more informed about the physiological basis of many other neuropsychiatric conditions, society at large has become (somewhat) more inclusive when it comes to accommodating these invisible disabilities in schools and workplaces. Better understanding autistic burnout and it's physiological manifestations could play an important role in making the world more inclusive and more accessible to people with different neurotypes. I hope that one day, this research will translate into prevention and intervention strategies that are able to protect autistic individuals from so much physiological and psychological distress. In the meantime, more interdisciplinary frameworks help us to build bridges across the double empathy problem from both sides - to perhaps minimize the harm that is done in the first place.
