Microgravity and Cosmic Radiations During Space Exploration as a Window Into Neurodegeneration on Earth. Giulia Sprugnoli, Yvonne D. Cagle, Emiliano Santarnecchi. JAMA Neurol. November 25, 2019. doi:https://doi.org/10.1001/jamaneurol.2019.4003
Astronauts involved in long-duration spaceflight missions are exposed to specific risk factors known to induce profound changes of brain structure and function whose potential long-lasting effects are still under investigation.1 These changes range from sleep alterations, modifications of brain morphometry, vision impairment, mood shifts, and loss of appetite as well as cognitive deficits, including decrements in attention and executive functions.2 Among the substantial list of stressors, the effects of microgravity and galactic cosmic radiations constitute the most relevant ones and are at the core of current and future NASA efforts to identify effective countermeasures. Interestingly, while reduced gravity force seems responsible for cephalad fluid shift that potentially affects protein clearance mechanisms, cosmic radiations seem to promote the accumulation of amyloid-β in mouse models, induce neuroinflammation, and further alter hippocampal-related cognition.2 Considering available evidence, a pattern of spaceflight-induced accelerated brain aging seems to emerge in addition to established aging-like effects on cardiovascular and musculoskeletal systems (ie, carotid intima-media thickness increments, inflammatory response, bone loss, muscle atrophy, and DNA telomere modifications, as documented in the recent 1-year long NASA Twin Study1). While this raises important issues about astronauts’ health, it can also constitute a window into the neurophysiopathology of neurodegenerative processes in humans, which could potentially benefit life on Earth.
The Effect of Microgravity
Microgravity determines a conspicuous fluid shift from the lower to upper body (approximately 2 L, mostly on the venous compartment) because of the loss of hydrostatic gradient pressure, normally attracting fluid toward lower limbs.3 On the other hand, the effect of slightly elevated levels of carbon dioxide in the International Space Station is currently under investigation regarding the theoretical potential for arteriolar vasodilatation induction, similarly to what is typically observed after acute high-level carbon dioxide exposure on Earth.3 The loss of hydrostatic gradient seems to cause an imbalance of intracranial pressure (ICP) diurnal variation, now considered the most likely mechanism behind spaceflight-associated neuro-ocular syndrome (SANS3). In particular, nonpathological partial elevation in ICP during long-term missions (comparable with the nocturnal increase of ICP on Earth) could be transmitted to the subarachnoid space enveloping the optic nerve, consequently causing a pattern characterized by, for example, optic disc edema, hyperopic shifts, globe flattening, cotton-wool spots, and choroidal folds that is experienced by 40% of astronauts after long-term spaceflight.1 Data collected in the recently released NASA Twins study support this pathophysiological model, showing distension and increased pressure in the internal jugular veins as well as SANS signs,1 even though many potential additional factors should be considered, such as the role of reduced central venous pressure.3
Interestingly, venous congestion could also impair cerebrospinal fluid (CSF) outflow, which under normal conditions drains into the dural sinuses via the arachnoid granulations. If the CSF outflow is altered, it is reasonable to postulate that protein clearance might be negatively affected, leading to an accumulation of waste products in the brain, such as amyloid-β and tau protein.4 Moreover, the modification of brain structures experienced after a long-term space mission could also compress venous as well as lymphatic vessels responsible for CSF drainage. In this regard, Roberts and colleagues5 have showed how the subarachnoid space at the vertex of the head and in posterior brain regions is reduced in healthy nonastronaut participants undergoing a spaceflight analog-based experiment (ie, head-down tilt), a phenomenon also partially observed in astronauts after long-duration missions. Such “brain shift” could reduce CSF drainage at the level of arachnoid granulation (ie, vertex) into the meningeal lymphatic vessels. This also aligns with a proposed theory stating that the alteration of the CSF circulatory system may represent a potential substrate of Alzheimer disease (AD) and normal-pressure hydrocephalus (NPH) depending on the prevalent impaired mechanism being CSF production or reabsorption, respectively.4 Accordingly, the coexistence of AD and NPH has been repeatedly demonstrated, suggesting an association between the 2 disorders, even though the evidence is still limited. Interestingly, brain morphology alterations reported in astronauts closely resemble those of NPH (eg, ventriculomegaly, a narrowing of the vertex sulci, and a dilatation of the Sylvian fissures); however, they lack the classic clinical presentation (eg, gait apraxia and urinary incontinence). As recently suggested by Roberts and Petersen,6 hydrocephalus associated with long-term spaceflight (HALS) is likely to represent a peculiar syndrome caused by microgravity in which brain maladaptive mechanisms are to some extent similar to those observed on Earth. Presumably there is no single agent factor responsible for HALS, but rather a multifactorial pathogenesis with structural and functional changes leading up to a synergistic effect. Investigating HALS and SANS syndromes can help elucidate the complex association between exposure to space-related stressors, CSF dynamics, fluid shift, AD, and NPH, with possible insights for space exploration and clinical research on neurodegeneration.
Role of Cosmic Radiation
Within the same framework, cosmic radiation might also play a substantial role. Mice studies involving exposition to space-equivalent radiation (56Fe) doses demonstrate an increase of amyloid-β and fibrillary proteins that is paralleled by impaired cognition and behavior.2 Interestingly, the brain regions most sensitive to cosmic radiation in mice studies are the (1) hippocampus (associated with impairments in episodic and short-term memory as well as recognition and spatial learning) and (2) the prefrontal cortex, which is associated with the alteration of executive functions.2 Microscopically, these regions exhibit immature spine and a reduction of dendritic complexity/density, which are positively associated with the grade of memory impairments and persist for up to 1 year after irradiation. These cellular modifications are similar to those presented by neurodegenerative diseases within the dementia spectrum, with epigenetic studies showing how modifying DNA methylation status can lead to the impairment of memory and learning. Evidence of DNA methylations was also reported in the aforementioned Nasa Twin study1; however, its association with cognitive deficits has not been tested yet. Moreover, alterations of sleep patterns and sleep quality, typically experienced by astronauts during long-duration missions, can increase the accumulation of waste proteins in the brain, considering that perivascular and nonperivascular protein clearance is prominent during sleep. Additionally, anxiety and depression symptoms have been found in irradiated rodents along with a cognitive flexibility deficit, closely resembling symptoms reported by astronauts during sustained exposure to isolated confined environments. However, microgravity seems to indirectly affect the hippocampus as well, inducing oxidative stress mediated by glucocorticoid receptors and decreasing the quantity of β-synuclein responsible for the prevention of α-synuclein aggregation (increased in microgravity studies2). Importantly, although microgravity and cosmic radiation are discussed separately in this article, their association with brain physiology is likely due to a complex synergistic effect. For instance, microgravity-induced fluid shift could affect the dynamics of CSF production (eg, at the level of the choroid plexus) as well as reabsorption (eg, from arachnoid granulations), therefore affecting protein clearance in the context of an already increased level of circulating proteins in the parenchyma due to exposure to cosmic radiations. This, as well as many other potential interactions, should be mapped and addressed as part of a comprehensive multidisciplinary model including neuroimaging, electrophysiology, biological, and clinical data.
Conclusions
All this evidence suggests the opportunity to investigate brain adaptation to long-term spaceflight as a model of aging, possibly informing novel diagnostic markers and countermeasures with relevance for space exploration and patients on Earth. At the same time, recent pathophysiological models of AD and other dementias could be leveraged to adapt countermeasures currently being tested in patients. For instance, gamma aminobutyric acid—ergic dysfunction and inhibitory interneurons’ pathology are getting attention as a core element of Alzheimer pathophysiology, leading to cascade effects, including the deficit of high-frequency brain oscillatory activity, altered brain plasticity and excitation/inhibition balance, the accumulation of amyloid-β/tau proteins, and cognitive deficits. Novel noninvasive promising therapies are currently under investigation (eg, multisensory and transcranial electrical stimulation7) and could constitute a countermeasure to “accelerated aging” during spaceflight as well as on return to Earth.
As scientists and astronauts navigating the field of space-related aging research, we recognize the need for increasing integration between NASA efforts and academic research. Dedicated conferences and other opportunities for a guided exchange of knowledge could be promoted across federal and academic institutions (eg, the National Institute on Aging), possibly leading to access to facilities for high-complexity experiments (eg, irradiation chambers), novel analogs to mimic the association of microgravity with fluid shift and ICP in-vivo, and an overall simplification of data-sharing procedures. A synergistic effort between clinicians, scientists, and aerospace institutions is needed to ensure this unique opportunity for advancing science and benefitting patients and astronauts will not be missed.
References, etc., at the DOI above.
The
central thrust of the current research was to (1) establish if sex
differences existing in jealousy manifestation upon the discovery of
infidelity-revealing social media (Snapchat) messages are reflective of
those found in the offline world and (2) to explore the extent to which
feelings of jealousy elicited by imagined infidelity discovered whilst
snooping on a partner’s Snapchat account differ depending on the
identity of the third party. Broad support for the evolutionary
psychological perspective was found as women reported more jealousy to
emotional than sexual infidelity and higher emotional jealousy overall
in comparison to males, whereas males reported higher jealousy to sexual
as opposed to emotional partner infidelity. No differences were
recorded however between men and women with regard to jealousy elicited
by sexual infidelity. The identity of the ‘other-person’ was also shown
to have a considerable bearing on reported jealousy and, once again,
intriguing sex differences were evident. Women experienced significantly
higher jealousy when the same-sex rival was a sibling than when the
rival was either a best friend or a stranger. Conversely, men reported
significantly lower imagined infidelity-elicited jealousy directed
towards their own brother than imagined infidelity-elicited jealousy
occurring between their partner and a same-sex stranger.
Firstly,
the current study augments a growing body of research showing modest
yet consistent sex differences in jealousy manifestation resulting from
the discovery of infidelity online with women showing more pronounced
emotional jealousy than sexual jealousy, and men more pronounced sexual
jealousy than emotional jealousy (Dunn and Billett 2018; Dunn and McLean 2015; Groothof et al. 2009; Guadagno and Sagarin 2010; Hudson et al. 2015; Muise et al. 2014). These findings are supportive of sex differences consistently reported in offline jealousy-evoking scenarios (Archer 1996; Cann et al. 2001; Cramer et al. 2001; Fernandez et al. 2007; Harris 2002; Harris and Christenfeld 1996; Pietrzak et al. 2002; Schützwohl 2005; Schützwohl and Koch 2004).
The findings also challenge the criticism that sex differences in
jealousy are only evident using a forced-choice paradigm. Just as in the
case of Bendixen et al. (2015),
sex differences in the current study were found using continuous
measures. In utilising Snapchat, this study has revealed that sex
differences in jealousy manifestation in response to partner infidelity
discovery are not restricted to text messages (Dunn and McLean 2015) or Facebook (Dunn and Billett 2018).
One hypothesis, however, ‘males will be significantly more jealous over
the sexual messages than females’, was not supported. A plausible
explanation for this is that society may have become more sexualised
over recent years (Gill 2012) and females have become more promiscuously inclined (Thornhill and Gangestad 2008) and more likely to engage in infidelity (Brand et al. 2007).
Possibly, the enhanced opportunity to engage in online infidelity has
resulted in both sexes becoming extra-vigilant of sexual betrayal. In a
similar vein, Klettke et al. (2014)
published a systematic literature review revealing no differences in
the prevalence of sexting behaviour between men and women.
One
unexpected finding relates to the fact that women were shown to be more
jealous by the thought of infidelity occurring between their partner
and their sister than between their partner and both their best friend
or with a stranger. Biegler and Kennair (2016)
found that when asked to list the relevance of traits either for their
own or their sisters’ idealised long-term partner even though they
agreed on the majority of traits, differences were reported.
Participants emphasised the importance of genetic fitness for their own
idealised partners compared to what they thought would be good for their
sister’s idealised partner, e.g. that their sister’s potential partners
would prioritise extended family members. Consequently, there would be
more direct rivalry between sisters for access to the best genetic mates
during ovulation and these evolved mechanisms of heightened jealousy
have filtered down to the modern technological world. In summary, the
current study found that female relatives appear to possess more actual
and genetic conflict than male relatives (Biegler and Kennair 2016) with sisters perhaps being more emotionally invested in each other than brothers (Fletcher et al. 2013).
One
finding of particular prominence and significance in the current study
is the fact that men were more tolerant of the distressing thought of
infidelity revealed by a Snapchat message between their partner and
their own brother than they were between their partner and a same-sex
stranger. This is in direct contradiction of previous research findings
showing that when invited to imagine partners having cheated,
participants evidenced significantly higher distress when the partner
infidelity was with a relative compared to a non-relative (Fisher et al.
2009). Kostic and Yadon (2014)
have argued that such higher distress may be explained by the fact that
this is related to greater feelings of closeness with genetically
related relatives. The current study differed in one prominent way from
these earlier studies in that the jealousy-evoking scenarios were
contextualised within a social media platform. The mitigation of
jealousy by genetic relatedness in this case could be explained once
again by adopting an evolutionary interpretation. Evolutionary
psychology, like all scientific movements is guided by and owes enormous
gratitude to the formulation and inception of key seminal theories.
Hamilton’s (1964a, b)
inclusive fitness theory is one such theory. Not only did the theory
solve the seemingly imponderable mystery of the existence of altruism in
nature, it also allowed researchers to construct and test intricate
hypotheses relating to a range of social behaviours. One key postulate
is that individuals should show greater selfish restraint, and behave
altruistically, when interacting with closer genetic relatives including
those who are not directly related, e.g. sibling’s offspring (Hamilton 1964a, b).
In support of the theory, countless studies have shown that in a social
context as genetic relatedness diminishes so does the degree of
altruism directed from the donor to the recipient (Essock-Vitale and
McGuire 1985; Burnstein et al. 1994; Korchmaros and Kenny 2008) with genetic relatedness being a strong predictor of subjective closeness (Stewart-Williams 2008).
Apparent concerns for inclusive fitness costs pertaining to infidelity
have been shown in a study where participants, regardless of their own
sex, expressed most distress by a brother’s partner’s sexual infidelity
and a sister’s partner’s emotional infidelity (Michalski et al. 2007).
In summary, the current study illustrates that Hamilton’s inclusive
fitness theory is still relevant today in the technological era of
‘Snapchat’ at least with regard to explaining male jealousy attenuation
to partner/sibling infidelity. After all, extra-pair copulation between a
man’s partner and a brother may still result nevertheless in
genetically related offspring enhancing that man’s inclusive fitness.
Before
concluding, it is worthwhile pointing out potential weaknesses in the
methodology of the study. Since the incorporation of scenario methods
into research pertaining to infidelity and jealousy, and in an attempt
to address challenges to the evolutionary position presented by authors
such as DeSteno and Salovey (1996),
researchers have repeatedly attempted to present sexual and emotional
infidelity scenarios as being mutually exclusive (Buss et al. 1999).
When constructing infidelity-revealing messages in a social media
context, it is difficult for example to create an emotional infidelity
scenario without at least hinting at the potential for future sexual
liaison and vice versa. In addition to emphasising message ‘ecological
validity’, future studies need to further disambiguate the two by for
example making it clear that sexual infidelity is restricted to sexual
cheating alone without any emotional involvement. For example, current
research in our laboratory uses wording contained within a message such
as ‘we both know our affair will only ever be sexual’ or ‘no-strings
attached’ sexual fun.
In conclusion and in
support of previous findings, it is argued that manifestly different
jealousy inclinations in both sexes evolved as they were advantageous
during the time of our EEA to help solve adaptive problems
differentially pertinent to each sex (Geher and Miller 2012; Hart 2010).
Moreover, the current study has provided evidence that sex differences
in jealousy extend farther than purely inclinations towards jealousy
type; there may also be sex differences in the extent to which
third-party identity evokes jealousy. Miscellaneous adaptations
pertaining to jealousy appear impervious to change in the current
technological age. With a current pandemic in social media–mediated,
jealousy-elicited infidelity, research utilising fictitious,
jealousy-evoking scenarios may help shed light on, and hopefully
mitigate, societal and personal problems associated with this
phenomenon.