Submitted by Julia McCabe
April 12, 2022
Evaluating the evidence on the effects of mindfulness-based stress reduction (MBSR) on biological stress markers
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by aberrant asociality, communication skills and repetitive behaviours that affect the quality of one's life. The aetiology of ASD is still not fully known (Santos-Terra et al., 2021) and while its prevalence has increased significantly since the 1990s (Chen et al., 2018), so too has the urgency for research in diagnosing, treating and possibly preventing the disorder. The following examines the nexus of ASD with animal-based research and the shared genetic and environmental hypotheses underlying this disorder. While animals have been critical to the pathophysiology of ASD, the heterogeneous nature of ASD warrants deeper inquiry as each animal has their caveats. The following may help clarify the utility of animals in context to the contemporaneous research in gene-related pathophysiology, from polygenic, to the monogenic models presented here: Methyl-CpG binding protein 2 (MECEP2), contactin associated protein 2 (CNTAP2) and SH3 and multiple ankyrin repeat domains protein 3 (SHANK3). As well as environmental factors, like in-utero exposure to valproic acid (VPA). Most notably, the use of Mus musculus (common mice), Danio rerio (zebrafish), marmosets and Macaca fascicularis (monkeys) and Rattus norwegicus (Wister rats) are example species that have provided invaluable momentum with room for critical analysis.
Mouse models have been widely used in genetic-based studies of ASD, given the availability of transgenic, knockin, and knockout mice used to mutate specific genes like CNTNAP2 and SHANK3 (Otazu et al., 2021). When the encoding for both proteins is hindered in a developing fetus, dysfunctional symptoms occur, and mice exhibit typical signs of autism, like repetitive movements and an increase in spontaneous seizures (Otazu et al., 2021). Mice also behold human-like characteristics like mating, playing, and establishing territory when considering ASD social deficits, and their short gestation allows.
for time-efficient investigations, as demonstrated by Otazu et al. (2021). In their study, Nissl-stained sections of the cerebellar vermis and neocortex isolated precise brain areas relevant to ASD and mutations of CNTNAP2 and SHANK3 in transgenic mice were used. However, the measurement of social and motor behavioural phenotypes in a rodent-gene model of autism, like repetitive/asocial behaviour, do not necessarily hold face validity. The cerebellar and neocortical malformations found by Otazu et al. (2021) supports previous genotype models and histological findings, but the social behaviour aspect is assumed, as they noted in their conclusion. This study is an example of how the heterogeneity of the disorder can allow for a greater occurrence of subjectivity and open-ended conclusions in research, and in this case, with mice (Otazu et al., 2021).
Prenatal exposure to valproic acid (VPA) commonly found in migraine, bipolar and anti-seizure medications have also been strongly correlated to ASD causality and tested vigorously in-utero using animal models in neurotoxicology, teratology and autism. Zebrafish are egg-born in water, and their larval are translucent, making their behaviour and biology easily observable as embryonic development occurs outside of the mother's body. The administering of VPA to zebrafish is also preferential because water allows for instant immersion of the compounds (Chen et al., 2018). Zebrafish are also commonly used for ASD research because of their socializing, mating, and behavioural phenotypes that are notably homologous to humans and human genes (Chen et al., 2018). In the Chen et al. (2018) study, larval social behaviour was refined to single-fish behaviour using custom-made equipment to assess their movements. Ethical issues limit research from doing the same to human embryos. However, the stages of embryonic development in zebrafish differ from human fetal development, particularly during neurulation (Chen et al., 2018), posing potential limitations in results. Where other vertebrates and humans develop a neural tube, a "secondary neurulation" occurs with zebrafish. (Chen et al., 2018).
Liu et al. (2018) also used zebrafish with the mutation of SHANK3, a scaffolding protein involved in postsynaptic density, excitation, and strong gene candidate for autism. Humans and zebrafish notably share SHANK3 duplication, that is, shank3a and shank3b in zebrafish are 59% and 68% homologous to human SHANK3, and they share almost 100% identity in amino acids blocks within this genome duplication (Liu et al., 2018). Mutating these similar gene lines allowed the researchers to record an entire assay. Shank3b deficiency was found to correlate with phenotypes like delayed behaviours observed in the tails of the fish, as well as brain size and movements - repetitive figure "8’s." However, even monogenic studies like this cannot assume all results as being ASD-related. When one gene has more than one phenotypic effect, pleiotropism also posits the risk in assuming that repetitive figure “8's", for example, is only an ASD-like effect being observed (Liu et al., 2018).
Sanagi et al. (2019) also examined VPA maternal exposure and subsequent disruption of microglia in-utero using transgenic monkeys over an entire lifespan. Evidence has shown that children with ASD have altered microglia morphology, and the specific microglia markers Iba-1 and P2RY12 in VPA-exposed marmosets showed the same (Sanagi et al., 2019). Microglia processes were thinner and separated by what was labelled as Iba-1 positive structures (Sanagi et al., 2019). Cai et al. (2020) also used transgenic monkeys to detect markers of ASD in the pre-frontal cortex but with a three-fold approach: gene mutation (MECEP2), behaviour analysis, and the use of EEG and fMRI results for cross-species neural mapping between transgenic monkeys and autistic human brains. Eighteen genes were found to be downregulated in the monkeys with MECEP2, a causative gene associated with brain and mood abnormalities common in autism (Cai et al., 2020). Their findings positively overlapped; that is, ASD-like patterns of hypo and hyperconnectivity between monkeys and humans mirrored one another. Non-human primates also present striking similarities with humans, particularly the reliance on the visual system for socialization, cueing and appropriate ways to respond to others. Zebrafish respond with tail movements; rodents use smell, but monkeys use their eyes like humans. However, studies using non-human primates in this context can take substantially longer. For example, separation anxiety is an ASD trait where visual feedback would be an essential factor, and it took an entire year to measure after familiar peer monkeys were housed in the same room then isolated from one another. The mercurial nature and complexity of measuring human traits, like the visual-behavioural factor, still poses a challenge using non-human primates considering upbringing, past traumas, and comorbidities unique to humans. In addition, using monkeys with technologies like fMRI and EEG devices can be tenuous. The monkeys in the Cai et al. (2020) study required light anesthesia and restraint, which may have been distressing, impacting the measurements. Noise contamination, for example, was an issue with the EEG experiments (Cai et al., 2020). The authors noted in their conclusion that the impact was not significant; however, the plausibility of missed results, given the unpredictable behaviours of animals, is noteworthy.
Resveratrol (RSV) is a neuroprotective molecule posited to protect against in utero exposure to VPA (Santos-Terrea et al., 2021). RSV prevented long-term damage of VPA exposure in rats, including the impact on neuronal populations within the dentate gyrus in a study conducted by Santos-Terrea et al. (2021). The brains of rats have been long-standing models in science because they are typically larger (in comparison to mice) for observational purposes and have similar anatomy to the human brain, especially for methods like immunofluorescence staining, as seen in this study. The CA1, CA2, CA3 and DG, are critical regions where RSV has been shown to salvage the deleterious effects of exposure, particularly somatostatin-positive interneurons (Santos-Terra et al., 2021). Increased excitability and disruption of electrophysiological homeostasis in the hippocampus is linked to ASD (Santos-Terra et al., 2021). However, RSV is a relatively new finding, and is still a hypothesis, and the effects of RSV in the CA1 human brain beyond this animal model is debatable.
The complexity of ASD causality, from genetics to environmental, and the use of animal models, whether in vivo or in utero, commands researchers to do the opposite of the disorder's heterogeneity: to be homogenous in their approach. There are hundreds of hypotheses and factors as to why autism may occur, and each of them requires steadfast measurements. The invaluable use, particularly of transgenic animal models in response to ASD prevalence, is evident. However, as Cai et al. (2020) demonstrated whether zebrafish, rodents or monkeys are used to identify neurotoxicity or from the hundreds of gene candidates, a multi-fold approach seems to be the most prudent. Using animals alongside human data and multiple assays (histological, behavioural, fMRI, EEGs) may provide some of the best validity. Furthermore, there are disadvantages in animal models that cannot be changed or reproduced as the nuances of human emotion and behaviours cannot be replicated nor confined to animal research only. Cross-species comparisons from humans to animals, from neural circuitry to gene deletions, would encourage high fidelity for future studies in autism.
References
Cai, D. C., Wang, Z., Bo, T., Yan, S., Liu, Y., Liu, Z., ... & Wang, Z. (2020). MECP2 duplication causes aberrant GABA pathways, circuits, and behaviors in transgenic monkeys: neural mappings to patients with autism. Journal of Neuroscience, 40(19), 3799-3814.
Chen, J., Lei, L., Tian, L., Hou, F., Roper, C., Ge, X., ... & Huang, C. (2018). Developmental and behavioural alterations in zebrafish embryonically exposed to valproic acid (VPA): An aquatic model for autism. Neurotoxicology and teratology, 66, 8-16.
Liu, C. X., Li, C. Y., Hu, C. C., Wang, Y., Lin, J., Jiang, Y. H., ... & Xu, X. (2018). CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviours. Molecular autism, 9(1), 1-13.
Otazu, G. H., Li, Y., Lodato, Z., Elnasher, A., Keever, K. M., Li, Y., & Ramos, R. L. (2021). Neurodevelopmental malformations of the cerebellum and neocortex in the Shank3 and Cntnap2 mouse models of autism. Neuroscience Letters, 136257.
Sanagi, T., Sasaki, T., Nakagaki, K., Minamimoto, T., Kohsaka, S., & Ichinohe, N. (2019). Segmented iba1-positive processes of microglia in autism model marmosets. Frontiers in cellular neuroscience, 13, 344.
Santos-Terra, J., Deckmann, I., Schwingel, G. B., Paz, A. V. C., Gama, C. S., Bambini-Junior, V., ... & Gottfried, C. (2021). Resveratrol prevents long-term structural hippocampal alterations and modulates interneuron organization in an animal model of ASD. Brain research, 1768, 147593.
Mouse models have been widely used in genetic-based studies of ASD, given the availability of transgenic, knockin, and knockout mice used to mutate specific genes like CNTNAP2 and SHANK3 (Otazu et al., 2021). When the encoding for both proteins is hindered in a developing fetus, dysfunctional symptoms occur, and mice exhibit typical signs of autism, like repetitive movements and an increase in spontaneous seizures (Otazu et al., 2021). Mice also behold human-like characteristics like mating, playing, and establishing territory when considering ASD social deficits, and their short gestation allows.
for time-efficient investigations, as demonstrated by Otazu et al. (2021). In their study, Nissl-stained sections of the cerebellar vermis and neocortex isolated precise brain areas relevant to ASD and mutations of CNTNAP2 and SHANK3 in transgenic mice were used. However, the measurement of social and motor behavioural phenotypes in a rodent-gene model of autism, like repetitive/asocial behaviour, do not necessarily hold face validity. The cerebellar and neocortical malformations found by Otazu et al. (2021) supports previous genotype models and histological findings, but the social behaviour aspect is assumed, as they noted in their conclusion. This study is an example of how the heterogeneity of the disorder can allow for a greater occurrence of subjectivity and open-ended conclusions in research, and in this case, with mice (Otazu et al., 2021).
Prenatal exposure to valproic acid (VPA) commonly found in migraine, bipolar and anti-seizure medications have also been strongly correlated to ASD causality and tested vigorously in-utero using animal models in neurotoxicology, teratology and autism. Zebrafish are egg-born in water, and their larval are translucent, making their behaviour and biology easily observable as embryonic development occurs outside of the mother's body. The administering of VPA to zebrafish is also preferential because water allows for instant immersion of the compounds (Chen et al., 2018). Zebrafish are also commonly used for ASD research because of their socializing, mating, and behavioural phenotypes that are notably homologous to humans and human genes (Chen et al., 2018). In the Chen et al. (2018) study, larval social behaviour was refined to single-fish behaviour using custom-made equipment to assess their movements. Ethical issues limit research from doing the same to human embryos. However, the stages of embryonic development in zebrafish differ from human fetal development, particularly during neurulation (Chen et al., 2018), posing potential limitations in results. Where other vertebrates and humans develop a neural tube, a "secondary neurulation" occurs with zebrafish. (Chen et al., 2018).
Liu et al. (2018) also used zebrafish with the mutation of SHANK3, a scaffolding protein involved in postsynaptic density, excitation, and strong gene candidate for autism. Humans and zebrafish notably share SHANK3 duplication, that is, shank3a and shank3b in zebrafish are 59% and 68% homologous to human SHANK3, and they share almost 100% identity in amino acids blocks within this genome duplication (Liu et al., 2018). Mutating these similar gene lines allowed the researchers to record an entire assay. Shank3b deficiency was found to correlate with phenotypes like delayed behaviours observed in the tails of the fish, as well as brain size and movements - repetitive figure "8’s." However, even monogenic studies like this cannot assume all results as being ASD-related. When one gene has more than one phenotypic effect, pleiotropism also posits the risk in assuming that repetitive figure “8's", for example, is only an ASD-like effect being observed (Liu et al., 2018).
Sanagi et al. (2019) also examined VPA maternal exposure and subsequent disruption of microglia in-utero using transgenic monkeys over an entire lifespan. Evidence has shown that children with ASD have altered microglia morphology, and the specific microglia markers Iba-1 and P2RY12 in VPA-exposed marmosets showed the same (Sanagi et al., 2019). Microglia processes were thinner and separated by what was labelled as Iba-1 positive structures (Sanagi et al., 2019). Cai et al. (2020) also used transgenic monkeys to detect markers of ASD in the pre-frontal cortex but with a three-fold approach: gene mutation (MECEP2), behaviour analysis, and the use of EEG and fMRI results for cross-species neural mapping between transgenic monkeys and autistic human brains. Eighteen genes were found to be downregulated in the monkeys with MECEP2, a causative gene associated with brain and mood abnormalities common in autism (Cai et al., 2020). Their findings positively overlapped; that is, ASD-like patterns of hypo and hyperconnectivity between monkeys and humans mirrored one another. Non-human primates also present striking similarities with humans, particularly the reliance on the visual system for socialization, cueing and appropriate ways to respond to others. Zebrafish respond with tail movements; rodents use smell, but monkeys use their eyes like humans. However, studies using non-human primates in this context can take substantially longer. For example, separation anxiety is an ASD trait where visual feedback would be an essential factor, and it took an entire year to measure after familiar peer monkeys were housed in the same room then isolated from one another. The mercurial nature and complexity of measuring human traits, like the visual-behavioural factor, still poses a challenge using non-human primates considering upbringing, past traumas, and comorbidities unique to humans. In addition, using monkeys with technologies like fMRI and EEG devices can be tenuous. The monkeys in the Cai et al. (2020) study required light anesthesia and restraint, which may have been distressing, impacting the measurements. Noise contamination, for example, was an issue with the EEG experiments (Cai et al., 2020). The authors noted in their conclusion that the impact was not significant; however, the plausibility of missed results, given the unpredictable behaviours of animals, is noteworthy.
Resveratrol (RSV) is a neuroprotective molecule posited to protect against in utero exposure to VPA (Santos-Terrea et al., 2021). RSV prevented long-term damage of VPA exposure in rats, including the impact on neuronal populations within the dentate gyrus in a study conducted by Santos-Terrea et al. (2021). The brains of rats have been long-standing models in science because they are typically larger (in comparison to mice) for observational purposes and have similar anatomy to the human brain, especially for methods like immunofluorescence staining, as seen in this study. The CA1, CA2, CA3 and DG, are critical regions where RSV has been shown to salvage the deleterious effects of exposure, particularly somatostatin-positive interneurons (Santos-Terra et al., 2021). Increased excitability and disruption of electrophysiological homeostasis in the hippocampus is linked to ASD (Santos-Terra et al., 2021). However, RSV is a relatively new finding, and is still a hypothesis, and the effects of RSV in the CA1 human brain beyond this animal model is debatable.
The complexity of ASD causality, from genetics to environmental, and the use of animal models, whether in vivo or in utero, commands researchers to do the opposite of the disorder's heterogeneity: to be homogenous in their approach. There are hundreds of hypotheses and factors as to why autism may occur, and each of them requires steadfast measurements. The invaluable use, particularly of transgenic animal models in response to ASD prevalence, is evident. However, as Cai et al. (2020) demonstrated whether zebrafish, rodents or monkeys are used to identify neurotoxicity or from the hundreds of gene candidates, a multi-fold approach seems to be the most prudent. Using animals alongside human data and multiple assays (histological, behavioural, fMRI, EEGs) may provide some of the best validity. Furthermore, there are disadvantages in animal models that cannot be changed or reproduced as the nuances of human emotion and behaviours cannot be replicated nor confined to animal research only. Cross-species comparisons from humans to animals, from neural circuitry to gene deletions, would encourage high fidelity for future studies in autism.
References
Cai, D. C., Wang, Z., Bo, T., Yan, S., Liu, Y., Liu, Z., ... & Wang, Z. (2020). MECP2 duplication causes aberrant GABA pathways, circuits, and behaviors in transgenic monkeys: neural mappings to patients with autism. Journal of Neuroscience, 40(19), 3799-3814.
Chen, J., Lei, L., Tian, L., Hou, F., Roper, C., Ge, X., ... & Huang, C. (2018). Developmental and behavioural alterations in zebrafish embryonically exposed to valproic acid (VPA): An aquatic model for autism. Neurotoxicology and teratology, 66, 8-16.
Liu, C. X., Li, C. Y., Hu, C. C., Wang, Y., Lin, J., Jiang, Y. H., ... & Xu, X. (2018). CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviours. Molecular autism, 9(1), 1-13.
Otazu, G. H., Li, Y., Lodato, Z., Elnasher, A., Keever, K. M., Li, Y., & Ramos, R. L. (2021). Neurodevelopmental malformations of the cerebellum and neocortex in the Shank3 and Cntnap2 mouse models of autism. Neuroscience Letters, 136257.
Sanagi, T., Sasaki, T., Nakagaki, K., Minamimoto, T., Kohsaka, S., & Ichinohe, N. (2019). Segmented iba1-positive processes of microglia in autism model marmosets. Frontiers in cellular neuroscience, 13, 344.
Santos-Terra, J., Deckmann, I., Schwingel, G. B., Paz, A. V. C., Gama, C. S., Bambini-Junior, V., ... & Gottfried, C. (2021). Resveratrol prevents long-term structural hippocampal alterations and modulates interneuron organization in an animal model of ASD. Brain research, 1768, 147593.
Submitted by Julia McCabe
Oct 10, 2021
The Advantages and Limitations of Animal Models and Autism Spectrum Disorder
The last decade of research in neuroscience and the pathophysiology of Major Depressive Disorder (MDD) has witnessed a significant shift from placing neurons as primary to the central nervous system (CNS) function toward a model inclusive of astrocytes as being equally supportive. Regions of the brain associated with depression, specifically the hippocampal region and anterior cingulate cortex (ACC), may reflect this well-established role of astrogliopathology. The following examines why this relatively fragile homeostasis between astrocytes and neurons and specific markers of disruption to astrocytic expression are significant for understanding the potential onset of MDD. The aetiology of depression becomes multifold through this astrocyte-centric lens: why intracellular/extracellular calcium ions (CA2+) between astrocytes and neuronal activity are integral to overall CNS health, as well as glial-fibrillary acid protein (GFAP) as a notable marker for studying activated astrocytes under stress, the role of calcium-binding protein B (S100B) to astrocytic pathology, and fibrous astrocytic morphology in the white matter of the ACC. The highlighted research also provides valuable insight into preventive measures of depression, which inversely presents evidence as to why MDD may manifest in the first place.
The symbiotic exchange between neurons and astrocytes is key to understanding the aetiology of MDD and the significance of astrocytes. Depression, therefore, may be connected to the disruption of CA2+ signaling in astrocytes' intracellular and extracellular spaces (Aguado, Espinosa-Parrilla, Carmona, & Soriano, 2002). Astrocytes demonstrate spontaneous Ca2+ oscillations, and mood may subsequently be altered if synaptic propagation is hindered within the hippocampus and other regions of the brain associated with emotion and cognition (Aguado et al., 2002). Neuroscience has demarcated these as calcium waves (Torres-Platas, Hercher, Davoli, Maussion, Labonté, Turecki, & Mechawar, 2011). Once glutamate is released, there is an increase in excitatory and inhibitory post-synaptic activity in neurons, and the excitatory response of neurons also results in astrocytic activity (Aguado et al., (2002). In the Aguado et al. (2002) study of calcium transients in astrocytes in situ, mood regions of the brain exhibited astrocyte-to-astrocyte CA2+ recruitment and
notably distant projections in and around the brain's hippocampal region. Eighty per cent of spontaneously active astrocytes exhibited this feature. An implication of this study is that it focuses on calcium's role in astrocytic function due to brain lesions in the hippocampal region, not depression. However, it is still helpful as it provides critical information about how the hippocampus is affected when damaged and the disruption of synaptic plasticity and propagation.
Regulation of GFAP in the hippocampal dentate gyrus is also of interest to the onset of MDD because of its astrocyte-specificity trait and notable upregulation during CNS injury and chronic stress (Aguado et al., 2002). In the Eldomiaty, Makarenko, Hassan, Almasry, Petrov, & Elnaggar study (2020), GFAP levels were significantly decreased in the hippocampal area in an experiment that subjected rats to five weeks of chronic stress in a forced-swimming experiment inducing depression. Three groups were compared in a longitudinal study: a control group (fed, no forced-swimming nor voluntary exercise), a depressive group (fed, forced-swimming), and a depressive-exercise group (fed, forced swimming, and voluntary use of a running wheel). Interestingly, decreased levels of GFAP in the depressive group were quite specific to astrocytes with no observable changes to neuronal effects. (Eldomiaty et al., 2020). The decrease also suggests that under repeated stress, this mechanism eventually becomes defective.
The study also measured all types of glia: oligodendrocytes, microglia, and astrocytes. When measuring the quantity of each cell type, there were no notable changes to any of the glia. However, after immunohistochemical treatment that measured all processes and morphology of the various cell bodies, a significant difference was found only in astrocytes of the depressive group versus the others. The star-like bushy features characteristic of astrocytes were weakened and erratic in the depressive samples compared to the controls and depressive-exercise group. One drawback to this study is that although astrocytes express GFAP, not all astrocytes express it (Eldomiaty et al., 2020). Nonetheless, it is indicative of how continuous exposure to stress may lead to MDD.
Eldomiaty, M.A. et al. (2020) also posited the benefits of exercise and that the same effects could be helpful for human subjects. Exercise was beneficial even to the animals being subjected to continuous stress and while in a depressive state. After five weeks, data revealed that astrocyte morphology was far more robust in the depressive-exercise group and found an overall improvement in all glial measures. It is also an insightful observation that when rats were forced to swim, depression occurred, and when given the freedom to choose exercise (running wheel), depression was alleviated. Exercising from one's own volition is notable to the results, revealing why it may be challenging to measure the nuances of emotion and mood in neuroscience.
Machado-Santos, Alves, Araújo, Correia, Patrício, Mateus-Pinheiro, & Pinto (2019) reported the significance of S100B, a calcium-binding peptide, to astrocyte cell density and expression within the hippocampus and dentate gyrus, supporting a similar hypothesis to MDD. Continuous exposure to stress in an animal model was measured, reflecting how the human CNS might respond. For six weeks, stress was induced longitudinally, measuring the expression of genes, cell density, and morphology. Mice were subjected to unpredictable chronic mild stress. Intentional methods like tilting cages and deprivation of food were tracked. After one exposure, there were no notable changes in the astrocytic density or quantity in any of the animals. However, after a second exposure to stress, there was an increase of S100B (Machado-Santos et al.,2019). S100B, a parameter of glial activation, indicates disorders of the CNS and neuroinflammation in glia, specifically an increase in cytokines correlated to the onset of depression (Machado-Santos et al., 2019).
The increase of S100B, like GFAP, may also signal damage to the blood-brain barrier in the CNS and is a calcium signalling protein. As discussed, calcium acts as a crucial partner in binding potentially weaker calcium signals and increasing them. Machado et al. (2019) cited a 200-400-fold increase of S100B due to recurrent stress, or astrogliosis, wherein neuroprotection ends up harming
the nervous system. Preventing stress is possibly synonymous with preventing an unnecessary increase of S100B. It is also noteworthy that the conditions of S100B and GFAP were reversed in this
study with the intervention of anti-depressants (Machado-Santos et al., 2019). The authors also highlighted their study as the first to link the hippocampus with the observation of increased S100B due to unpredictable chronic mild stress.
In addition to these two markers, changes in dendritic morphology, specifically fibrous astrocytes in the anterior cingulate cortex (ACC), may also affect other brain regions associated with depression (Torres-Platas, Hercher, Davoli, Maussion, Labonté, Turecki, & Mechawar, 2011). The hypertrophic morphology of fibrous astrocytes in this study (unique to white matter) was twice as present in the ACC of ten depressed suicides post-mortem versus controlled post-mortem subjects (Torres-Platas et al., 2011). The findings suggest a link of depression to neuroinflammation and disruption of intracellular calcium waves. Factors like prior pharmaceutical/recreational drugs and possibly alcohol usage on the cortex cannot precisely be measured or assumed of either group; however, the white matter samples of hyper-intensities in the depressed suicide completers strongly suggests a correlation to MDD. Furthermore, the cell bodies of the depressed suicides were more prominent, and the dendritic spines showed two-fold the number of nodes and branching than controlled subjects, suggesting inflammation and interference of cortical white matter (Torres-Plata et al.,2011). Their results were backed up by a Sholl analysis revealing similar outcomes for each parameter, suggesting that fibrous astrocytes in white matter can be remodelled due to long-term depressive symptoms compared to the protoplasmic astrocytes (grey matter) that did not change in either the controlled or suicide completers and in all tests (Torres-Platas et al.,2011). They posit that if the ACC white matter is altered, so too would the other regions of the brain associated with mood.
Without astroglia homeostasis, all studies reveal the onset or presence of depression. The longitudinal data of induced stress in animal models and post-mortem suicide completers and the findings: CA2+ disturbance, astrocyte markers GFAP and S100B in the hippocampal region,
and disproportioned ACC fibrous astrocytes, align with recorded behaviours or outcomes characteristic of MDD. The results of all studies reveal a common knowledge: that repeated
stress over time increases the likelihood of depression. Exercise is also examined as a valuable tool for the prevention of astroglia degradation and S100B cell hyperactivity (Eldomiaty, M.A. et al., 2020); however, exercise alone is inconclusive as the mechanisms and efficacy vary in individuals. The animal models in all studies also present many disadvantages in attempting to measure mood disorders in humans. The delicate balance of each marker presented also requires further examination as longitudinal, and post-mortem studies are often tedious, time-consuming, and allow for assumptions rather than evidence. The consistent findings, however, of astrocytic dysfunction synonymous with the onset of depression are indisputable.
References
Aguado, F., Espinosa-Parrilla, J. F., Carmona, M. A., & Soriano, E. (2002). Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ. Journal of Neuroscience, 22(21), 9430-9444.
Eldomiaty, M. A., Makarenko, O., Hassan, Z. A., Almasry, S. M., Petrov, P., & Elnaggar, A. M. (2020). Contribution of glia cells specifically astrocytes in the pathology of depression: immunohistochemical study in different brain areas. Folia morphologica, 79(3), 419-428.
Machado-Santos, A. R., Alves, N. D., Araújo, B., Correia, J. S., Patrício, P., Mateus-Pinheiro, A., ... & Pinto, L. (2019). Astrocytic plasticity at the dorsal dentate gyrus on an animal model of recurrent depression. Neuroscience.
Torres-Platas, S. G., Hercher, C., Davoli, M. A., Maussion, G., Labonté, B., Turecki, G., & Mechawar, N. (2011). Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology, 36(13), 2650-2658.
The last decade of research in neuroscience and the pathophysiology of Major Depressive Disorder (MDD) has witnessed a significant shift from placing neurons as primary to the central nervous system (CNS) function toward a model inclusive of astrocytes as being equally supportive. Regions of the brain associated with depression, specifically the hippocampal region and anterior cingulate cortex (ACC), may reflect this well-established role of astrogliopathology. The following examines why this relatively fragile homeostasis between astrocytes and neurons and specific markers of disruption to astrocytic expression are significant for understanding the potential onset of MDD. The aetiology of depression becomes multifold through this astrocyte-centric lens: why intracellular/extracellular calcium ions (CA2+) between astrocytes and neuronal activity are integral to overall CNS health, as well as glial-fibrillary acid protein (GFAP) as a notable marker for studying activated astrocytes under stress, the role of calcium-binding protein B (S100B) to astrocytic pathology, and fibrous astrocytic morphology in the white matter of the ACC. The highlighted research also provides valuable insight into preventive measures of depression, which inversely presents evidence as to why MDD may manifest in the first place.
The symbiotic exchange between neurons and astrocytes is key to understanding the aetiology of MDD and the significance of astrocytes. Depression, therefore, may be connected to the disruption of CA2+ signaling in astrocytes' intracellular and extracellular spaces (Aguado, Espinosa-Parrilla, Carmona, & Soriano, 2002). Astrocytes demonstrate spontaneous Ca2+ oscillations, and mood may subsequently be altered if synaptic propagation is hindered within the hippocampus and other regions of the brain associated with emotion and cognition (Aguado et al., 2002). Neuroscience has demarcated these as calcium waves (Torres-Platas, Hercher, Davoli, Maussion, Labonté, Turecki, & Mechawar, 2011). Once glutamate is released, there is an increase in excitatory and inhibitory post-synaptic activity in neurons, and the excitatory response of neurons also results in astrocytic activity (Aguado et al., (2002). In the Aguado et al. (2002) study of calcium transients in astrocytes in situ, mood regions of the brain exhibited astrocyte-to-astrocyte CA2+ recruitment and
notably distant projections in and around the brain's hippocampal region. Eighty per cent of spontaneously active astrocytes exhibited this feature. An implication of this study is that it focuses on calcium's role in astrocytic function due to brain lesions in the hippocampal region, not depression. However, it is still helpful as it provides critical information about how the hippocampus is affected when damaged and the disruption of synaptic plasticity and propagation.
Regulation of GFAP in the hippocampal dentate gyrus is also of interest to the onset of MDD because of its astrocyte-specificity trait and notable upregulation during CNS injury and chronic stress (Aguado et al., 2002). In the Eldomiaty, Makarenko, Hassan, Almasry, Petrov, & Elnaggar study (2020), GFAP levels were significantly decreased in the hippocampal area in an experiment that subjected rats to five weeks of chronic stress in a forced-swimming experiment inducing depression. Three groups were compared in a longitudinal study: a control group (fed, no forced-swimming nor voluntary exercise), a depressive group (fed, forced-swimming), and a depressive-exercise group (fed, forced swimming, and voluntary use of a running wheel). Interestingly, decreased levels of GFAP in the depressive group were quite specific to astrocytes with no observable changes to neuronal effects. (Eldomiaty et al., 2020). The decrease also suggests that under repeated stress, this mechanism eventually becomes defective.
The study also measured all types of glia: oligodendrocytes, microglia, and astrocytes. When measuring the quantity of each cell type, there were no notable changes to any of the glia. However, after immunohistochemical treatment that measured all processes and morphology of the various cell bodies, a significant difference was found only in astrocytes of the depressive group versus the others. The star-like bushy features characteristic of astrocytes were weakened and erratic in the depressive samples compared to the controls and depressive-exercise group. One drawback to this study is that although astrocytes express GFAP, not all astrocytes express it (Eldomiaty et al., 2020). Nonetheless, it is indicative of how continuous exposure to stress may lead to MDD.
Eldomiaty, M.A. et al. (2020) also posited the benefits of exercise and that the same effects could be helpful for human subjects. Exercise was beneficial even to the animals being subjected to continuous stress and while in a depressive state. After five weeks, data revealed that astrocyte morphology was far more robust in the depressive-exercise group and found an overall improvement in all glial measures. It is also an insightful observation that when rats were forced to swim, depression occurred, and when given the freedom to choose exercise (running wheel), depression was alleviated. Exercising from one's own volition is notable to the results, revealing why it may be challenging to measure the nuances of emotion and mood in neuroscience.
Machado-Santos, Alves, Araújo, Correia, Patrício, Mateus-Pinheiro, & Pinto (2019) reported the significance of S100B, a calcium-binding peptide, to astrocyte cell density and expression within the hippocampus and dentate gyrus, supporting a similar hypothesis to MDD. Continuous exposure to stress in an animal model was measured, reflecting how the human CNS might respond. For six weeks, stress was induced longitudinally, measuring the expression of genes, cell density, and morphology. Mice were subjected to unpredictable chronic mild stress. Intentional methods like tilting cages and deprivation of food were tracked. After one exposure, there were no notable changes in the astrocytic density or quantity in any of the animals. However, after a second exposure to stress, there was an increase of S100B (Machado-Santos et al.,2019). S100B, a parameter of glial activation, indicates disorders of the CNS and neuroinflammation in glia, specifically an increase in cytokines correlated to the onset of depression (Machado-Santos et al., 2019).
The increase of S100B, like GFAP, may also signal damage to the blood-brain barrier in the CNS and is a calcium signalling protein. As discussed, calcium acts as a crucial partner in binding potentially weaker calcium signals and increasing them. Machado et al. (2019) cited a 200-400-fold increase of S100B due to recurrent stress, or astrogliosis, wherein neuroprotection ends up harming
the nervous system. Preventing stress is possibly synonymous with preventing an unnecessary increase of S100B. It is also noteworthy that the conditions of S100B and GFAP were reversed in this
study with the intervention of anti-depressants (Machado-Santos et al., 2019). The authors also highlighted their study as the first to link the hippocampus with the observation of increased S100B due to unpredictable chronic mild stress.
In addition to these two markers, changes in dendritic morphology, specifically fibrous astrocytes in the anterior cingulate cortex (ACC), may also affect other brain regions associated with depression (Torres-Platas, Hercher, Davoli, Maussion, Labonté, Turecki, & Mechawar, 2011). The hypertrophic morphology of fibrous astrocytes in this study (unique to white matter) was twice as present in the ACC of ten depressed suicides post-mortem versus controlled post-mortem subjects (Torres-Platas et al., 2011). The findings suggest a link of depression to neuroinflammation and disruption of intracellular calcium waves. Factors like prior pharmaceutical/recreational drugs and possibly alcohol usage on the cortex cannot precisely be measured or assumed of either group; however, the white matter samples of hyper-intensities in the depressed suicide completers strongly suggests a correlation to MDD. Furthermore, the cell bodies of the depressed suicides were more prominent, and the dendritic spines showed two-fold the number of nodes and branching than controlled subjects, suggesting inflammation and interference of cortical white matter (Torres-Plata et al.,2011). Their results were backed up by a Sholl analysis revealing similar outcomes for each parameter, suggesting that fibrous astrocytes in white matter can be remodelled due to long-term depressive symptoms compared to the protoplasmic astrocytes (grey matter) that did not change in either the controlled or suicide completers and in all tests (Torres-Platas et al.,2011). They posit that if the ACC white matter is altered, so too would the other regions of the brain associated with mood.
Without astroglia homeostasis, all studies reveal the onset or presence of depression. The longitudinal data of induced stress in animal models and post-mortem suicide completers and the findings: CA2+ disturbance, astrocyte markers GFAP and S100B in the hippocampal region,
and disproportioned ACC fibrous astrocytes, align with recorded behaviours or outcomes characteristic of MDD. The results of all studies reveal a common knowledge: that repeated
stress over time increases the likelihood of depression. Exercise is also examined as a valuable tool for the prevention of astroglia degradation and S100B cell hyperactivity (Eldomiaty, M.A. et al., 2020); however, exercise alone is inconclusive as the mechanisms and efficacy vary in individuals. The animal models in all studies also present many disadvantages in attempting to measure mood disorders in humans. The delicate balance of each marker presented also requires further examination as longitudinal, and post-mortem studies are often tedious, time-consuming, and allow for assumptions rather than evidence. The consistent findings, however, of astrocytic dysfunction synonymous with the onset of depression are indisputable.
References
Aguado, F., Espinosa-Parrilla, J. F., Carmona, M. A., & Soriano, E. (2002). Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ. Journal of Neuroscience, 22(21), 9430-9444.
Eldomiaty, M. A., Makarenko, O., Hassan, Z. A., Almasry, S. M., Petrov, P., & Elnaggar, A. M. (2020). Contribution of glia cells specifically astrocytes in the pathology of depression: immunohistochemical study in different brain areas. Folia morphologica, 79(3), 419-428.
Machado-Santos, A. R., Alves, N. D., Araújo, B., Correia, J. S., Patrício, P., Mateus-Pinheiro, A., ... & Pinto, L. (2019). Astrocytic plasticity at the dorsal dentate gyrus on an animal model of recurrent depression. Neuroscience.
Torres-Platas, S. G., Hercher, C., Davoli, M. A., Maussion, G., Labonté, B., Turecki, G., & Mechawar, N. (2011). Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology, 36(13), 2650-2658.
The symbiotic exchange between neurons and astrocytes is key to understanding the aetiology of MDD and the significance of astrocytes. Depression, therefore, may be connected to the disruption of CA2+ signaling in astrocytes' intracellular and extracellular spaces (Aguado, Espinosa-Parrilla, Carmona, & Soriano, 2002). Astrocytes demonstrate spontaneous Ca2+ oscillations, and mood may subsequently be altered if synaptic propagation is hindered within the hippocampus and other regions of the brain associated with emotion and cognition (Aguado et al., 2002). Neuroscience has demarcated these as calcium waves (Torres-Platas, Hercher, Davoli, Maussion, Labonté, Turecki, & Mechawar, 2011). Once glutamate is released, there is an increase in excitatory and inhibitory post-synaptic activity in neurons, and the excitatory response of neurons also results in astrocytic activity (Aguado et al., (2002). In the Aguado et al. (2002) study of calcium transients in astrocytes in situ, mood regions of the brain exhibited astrocyte-to-astrocyte CA2+ recruitment and
notably distant projections in and around the brain's hippocampal region. Eighty per cent of spontaneously active astrocytes exhibited this feature. An implication of this study is that it focuses on calcium's role in astrocytic function due to brain lesions in the hippocampal region, not depression. However, it is still helpful as it provides critical information about how the hippocampus is affected when damaged and the disruption of synaptic plasticity and propagation.
Regulation of GFAP in the hippocampal dentate gyrus is also of interest to the onset of MDD because of its astrocyte-specificity trait and notable upregulation during CNS injury and chronic stress (Aguado et al., 2002). In the Eldomiaty, Makarenko, Hassan, Almasry, Petrov, & Elnaggar study (2020), GFAP levels were significantly decreased in the hippocampal area in an experiment that subjected rats to five weeks of chronic stress in a forced-swimming experiment inducing depression. Three groups were compared in a longitudinal study: a control group (fed, no forced-swimming nor voluntary exercise), a depressive group (fed, forced-swimming), and a depressive-exercise group (fed, forced swimming, and voluntary use of a running wheel). Interestingly, decreased levels of GFAP in the depressive group were quite specific to astrocytes with no observable changes to neuronal effects. (Eldomiaty et al., 2020). The decrease also suggests that under repeated stress, this mechanism eventually becomes defective.
The study also measured all types of glia: oligodendrocytes, microglia, and astrocytes. When measuring the quantity of each cell type, there were no notable changes to any of the glia. However, after immunohistochemical treatment that measured all processes and morphology of the various cell bodies, a significant difference was found only in astrocytes of the depressive group versus the others. The star-like bushy features characteristic of astrocytes were weakened and erratic in the depressive samples compared to the controls and depressive-exercise group. One drawback to this study is that although astrocytes express GFAP, not all astrocytes express it (Eldomiaty et al., 2020). Nonetheless, it is indicative of how continuous exposure to stress may lead to MDD.
Eldomiaty, M.A. et al. (2020) also posited the benefits of exercise and that the same effects could be helpful for human subjects. Exercise was beneficial even to the animals being subjected to continuous stress and while in a depressive state. After five weeks, data revealed that astrocyte morphology was far more robust in the depressive-exercise group and found an overall improvement in all glial measures. It is also an insightful observation that when rats were forced to swim, depression occurred, and when given the freedom to choose exercise (running wheel), depression was alleviated. Exercising from one's own volition is notable to the results, revealing why it may be challenging to measure the nuances of emotion and mood in neuroscience.
Machado-Santos, Alves, Araújo, Correia, Patrício, Mateus-Pinheiro, & Pinto (2019) reported the significance of S100B, a calcium-binding peptide, to astrocyte cell density and expression within the hippocampus and dentate gyrus, supporting a similar hypothesis to MDD. Continuous exposure to stress in an animal model was measured, reflecting how the human CNS might respond. For six weeks, stress was induced longitudinally, measuring the expression of genes, cell density, and morphology. Mice were subjected to unpredictable chronic mild stress. Intentional methods like tilting cages and deprivation of food were tracked. After one exposure, there were no notable changes in the astrocytic density or quantity in any of the animals. However, after a second exposure to stress, there was an increase of S100B (Machado-Santos et al.,2019). S100B, a parameter of glial activation, indicates disorders of the CNS and neuroinflammation in glia, specifically an increase in cytokines correlated to the onset of depression (Machado-Santos et al., 2019).
The increase of S100B, like GFAP, may also signal damage to the blood-brain barrier in the CNS and is a calcium signalling protein. As discussed, calcium acts as a crucial partner in binding potentially weaker calcium signals and increasing them. Machado et al. (2019) cited a 200-400-fold increase of S100B due to recurrent stress, or astrogliosis, wherein neuroprotection ends up harming
the nervous system. Preventing stress is possibly synonymous with preventing an unnecessary increase of S100B. It is also noteworthy that the conditions of S100B and GFAP were reversed in this
study with the intervention of anti-depressants (Machado-Santos et al., 2019). The authors also highlighted their study as the first to link the hippocampus with the observation of increased S100B due to unpredictable chronic mild stress.
In addition to these two markers, changes in dendritic morphology, specifically fibrous astrocytes in the anterior cingulate cortex (ACC), may also affect other brain regions associated with depression (Torres-Platas, Hercher, Davoli, Maussion, Labonté, Turecki, & Mechawar, 2011). The hypertrophic morphology of fibrous astrocytes in this study (unique to white matter) was twice as present in the ACC of ten depressed suicides post-mortem versus controlled post-mortem subjects (Torres-Platas et al., 2011). The findings suggest a link of depression to neuroinflammation and disruption of intracellular calcium waves. Factors like prior pharmaceutical/recreational drugs and possibly alcohol usage on the cortex cannot precisely be measured or assumed of either group; however, the white matter samples of hyper-intensities in the depressed suicide completers strongly suggests a correlation to MDD. Furthermore, the cell bodies of the depressed suicides were more prominent, and the dendritic spines showed two-fold the number of nodes and branching than controlled subjects, suggesting inflammation and interference of cortical white matter (Torres-Plata et al.,2011). Their results were backed up by a Sholl analysis revealing similar outcomes for each parameter, suggesting that fibrous astrocytes in white matter can be remodelled due to long-term depressive symptoms compared to the protoplasmic astrocytes (grey matter) that did not change in either the controlled or suicide completers and in all tests (Torres-Platas et al.,2011). They posit that if the ACC white matter is altered, so too would the other regions of the brain associated with mood.
Without astroglia homeostasis, all studies reveal the onset or presence of depression. The longitudinal data of induced stress in animal models and post-mortem suicide completers and the findings: CA2+ disturbance, astrocyte markers GFAP and S100B in the hippocampal region,
and disproportioned ACC fibrous astrocytes, align with recorded behaviours or outcomes characteristic of MDD. The results of all studies reveal a common knowledge: that repeated
stress over time increases the likelihood of depression. Exercise is also examined as a valuable tool for the prevention of astroglia degradation and S100B cell hyperactivity (Eldomiaty, M.A. et al., 2020); however, exercise alone is inconclusive as the mechanisms and efficacy vary in individuals. The animal models in all studies also present many disadvantages in attempting to measure mood disorders in humans. The delicate balance of each marker presented also requires further examination as longitudinal, and post-mortem studies are often tedious, time-consuming, and allow for assumptions rather than evidence. The consistent findings, however, of astrocytic dysfunction synonymous with the onset of depression are indisputable.
References
Aguado, F., Espinosa-Parrilla, J. F., Carmona, M. A., & Soriano, E. (2002). Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ. Journal of Neuroscience, 22(21), 9430-9444.
Eldomiaty, M. A., Makarenko, O., Hassan, Z. A., Almasry, S. M., Petrov, P., & Elnaggar, A. M. (2020). Contribution of glia cells specifically astrocytes in the pathology of depression: immunohistochemical study in different brain areas. Folia morphologica, 79(3), 419-428.
Machado-Santos, A. R., Alves, N. D., Araújo, B., Correia, J. S., Patrício, P., Mateus-Pinheiro, A., ... & Pinto, L. (2019). Astrocytic plasticity at the dorsal dentate gyrus on an animal model of recurrent depression. Neuroscience.
Torres-Platas, S. G., Hercher, C., Davoli, M. A., Maussion, G., Labonté, B., Turecki, G., & Mechawar, N. (2011). Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology, 36(13), 2650-2658.
Major Depressive Disorder (MDD) has become a global mental health crisis, with an estimated 264 million individuals (Maupomé et al., 2021) experiencing its immobilizing effects characterized by hopelessness, anhedonia, and increased risk of suicide. It is projected to be the number one disease burden of first world countries by 2030, with two-thirds of sufferers never experiencing complete remission from symptoms (Li et al., 2018). In the 1960s, a burgeoning wave of research in the psychopathology of depression was pioneered by American psychiatrist Aaron T. Beck whose model of depression and Cognitive Behavioural Therapy (CBT) inspired empirically founded principles for psychiatric treatment. Prior to this, the psychopathology of depression was defined mainly by psychoanalytic theory, or Freudian analysis, deeming depression to be a product of inverted hostility with an emphasis on the unconscious and childhood experiences (Beck, 1961). Beck's findings invalidated Freudian theory. When working with subjects to measure hostility, the depressed patients showed less hostility than non-depressives, and notable improvements after a reappraisal of their negative internal bias were brought forth (Beck & Ward, 1961). Beck's three-part model of depression describes (1) dysfunctional attitudes, (2) negative schemas and (3) the cognitive triad, that is, a negative view of the self, world, and the future. Negative automatic thoughts and the symptoms of MDD then manifest. His model has continued to be a comprehensive psychotherapeutic guide both supported and challenged with empirical rigour and evidence. The saliency of CBT is due to its many revisions and psychometric tools juxtaposed to contemporaneous research, including the Dysfunctional Attitude Scale (DAS), Beck Depression Inventory (BDI-I and BDI-I), Cognitive Triad Inventory (CTI), and inclusion of neurobiological and genetic correlates to the aetiology of MDD.
Dysfunctional attitudes are considered the first and most distal in Beck's construct of depression, also known as a causal mediation model (Joiner et al.,1999) and the most proximal being the symptoms of automatic negative thoughts and the onset of depression (Pössel & Black, 2014). Beck posited that dysfunctional attitudes are typically rigid and self-loathing in nature ("Nobody loves me"), increasing the diathesis (vulnerability) for MDD onset and as a diathesis-stress model (Pössel & Black, 2014). The BDI-I, BD-II and DAS are psychometric tests for evaluating MDD severity and clinical observations of attitudes like pessimism and sense of failure. The BDI was created in 1961 and revised in 1978, and 1996 - signalling it flexibility (Beck et al., 1987) and the DAS created by Beck and Weissman in 1978 (Beck et al., 1987) also reflects this. Years after its inception, the wording of the DAS was deemed inappropriate for children and Abela and D'Allesandro created a children's version, the CDAS (Abela & D'Alessandro 2002). In 2003, Abela and Sullivan tested diathesis-stress with adolescents. Contrary to Beck's hypothesis, dysfunctional attitudes increased MDD vulnerability for adolescents with high self-esteem and social supports, not those with low self-esteem and social supports (Abela & Sullivan, 2003). Depression was not necessarily observed; however, the vulnerability aspect was significant. In 1999, Joiner et al. tested Beck's causal mediation and diathesis-stress components with 119 high school students preceding and following midterm exams, completing the DAS and BDI-II. Those who scored high in dysfunctional attitudes and received a poor grade showed the highest increase of depression; the others, regardless of their grade, scored low for MDD (Joiner et al., 1999). Notably, the authors stated their work as one of the first to support Beck's diathesis-stress component (Joiner et al., 1999).
In 2021, a thorough meta-analysis of the BDI's efficacy found that both versions, BDI and BDI-II, had high internal consistency (Eser et al., 2021) using a meta-analytical tool, the Reliability Generalization (RG), comparing university students and psychiatric outpatients for depression (Eser et al., 2021). And in addition to evolving CBT for adolescents and children, the cultural translation of the model has also been tested. In 2020, a unique study measured the validity of the DAS after being translated into Urdu and a sample of 641 college students (Siddique & Hanif, 2021). The results were steadfast in supporting Beck's theories; however, students were tested from only two cities and in highly educated sectors (Siddique & Hanif, 2021). CBT and its accessibility for populations with limited resources to mental health care is illuminated here.
The next more proximal component to MDD in accordance with CBT is the depressogenic schema, designated from Beck's observations in his early years spent observing psychiatric patients. Patients with dysfunctional attitudes reported automatic negative thoughts embedded in their cognitive structure, and when triggered, produced a maladaptive schema and an increased vulnerability to MDD onset (Clark & Beck, 2010). The depressogenic schema exacerbates the attentional bias of an individual; and as Beck theorized, those biased perceptions can be latent or activated by a life event (Evans et al., 2005). He also stated that schemas would be challenging to measure in self-questionnaires for MDD vulnerability because of this latency (Evans et al., 2005). However, Evans and colleagues tested this, intentionally selecting 8540 non-depressed expectant mothers using the Edinburgh Post-Natal Depression Scale (EPDS) and a negative self-schema score. At thirty-two weeks, 790 women were reported depressed, and 736 of them scored the highest tertile for negative schema (Evans et al., 2005). However, the authors reflected that the questionnaires were designed to measure personality, not cognitions (Evans et al., 2005). The Theory of Modes was introduced to address CBT’s limitations for clinical interventions and shortcomings of schematic processing (Evans et al., 2005). That depression may be a schematic blend of Axis I and Axis II disorders (i.e., anxiety, panic disorders) with symptoms of depression (Frances-Raniere et al., 2006). As well, the construct of a negative schema later included the influence of mildly stressful events, adapting the "kindling" effect (Kendler et al., 2000), recognizing that severe life events (i.e., death of a loved one) are not the only precipitators for depression. That is, a continuation of depressive episodes related to psychosocial pressure over shorter periods, even mild in nature, can also trigger depression (Kendler et al., 2000).
The most proximal construct to the onset of MDD, the cognitive triad, interconnects negative views of the world, self, and future ideations (Pössel et al., 2020). The Cognitive Triad Inventory (CTI) was created in 1986 by Beckham et al. as a self-report instrument for depression. An empirical study of CTI's factorial validity led by Anderson and Skidmore (1995) supported the efficacy of the triad in therapy. However, the negatively phrased "self" items lacked robustness in their findings (Anderson & Skidmore, 1995). The authors pointed out that from the triad, the negative-self items are the most imperative corelates to MDD onset, with the suggestion that the phrasing of "negative" and "positive" be considered for revision (Anderson et al., 1995).
By the early 2000s, CBT and Beck's model became multidimensional, uniting clinical, cognitive, and neural mechanisms. Goldapple et al. (2004) tested CBT principles using neuroimaging to study genetic risk and depression. In depressive subjects, they found that bottom-up processing (sensory information to the brain) and negative schemas were overactivated, and top-down processing (cognition driven perception) were inhibited (Goldapple et al., 2004). After undergoing CBT, the depressed subjects showed an increase in hippocampal and orbital frontal activity (Goldapple et al., 2004) due to the encouragement of top-down processing and significant mood improvement (Goldapple et al., 2004). In 2009, the integration of CBT and a genetic risk factor, 5-HTTLPR, a genotype associated with cognitive processing in children, was published by Gibb et al. Mothers and children completed the BDI-II, the children were measured for attentional biases (happy, sad, angry faces) and DNA swabs were obtained. Assessment of attentional biases found that preference for sad faces was higher for children with the 5-HTTLPR genotype and associated with greater amygdala reactivity (Gibb et al., 2009). This evidence suggests the plausibility of nervous system dysregulation, as regulated babies tend to prefer happy faces (Gibb et al.,2009). Top-down processing and Beck's event congruency theory (a personality style) (Gibb et al., 2009) were present plausibly due to genetic inheritance, increasing their probability for depression.
Beck's CBT and model of depression has helped distinguish a standard for researchers in the fields of psychotherapy and psychopathology to follow. CBT continues to address not only depression but its confluence with other mood disorders and their aetiologies. The tools created, such as the DAS, BDI and CTI, were unique in that they courageously helped shift the lexicon of depression during an era when mental health issues were still considered taboo. The current model and CBT still, however, requires further investigation. Despite its empirical robustness and shifts with modernity, depression's aetiology remains insidiously complex and multidimensional in its pathology. The aforementioned findings of Abela and Sullivan (2003), for example, highlights the risk that all hypotheses of depression and mood disorders carry: they are inherently non-linear and complex. Future research and testing need to distinguish nuances like Abela and Sullivan’s (2003) findings of vulnerability to MDD versus the actual onset of depression. The current global mental health crisis and the gravitas of depression’s prevalence also commands that CBT and its nexus with other schools of thought address inclusivity and accessibility of treatments to underprivileged populations. The success of CBT and its future iterations depends upon this.
References
Abela, J. R., & D'Alessandro, D. U. (2002). Beck's cognitive theory of depression: A test of the diathesis‐stress and causal mediation components. British Journal of Clinical Psychology, 41(2), 111-128.
Abela, J. R., & Sullivan, C. (2003). A test of Beck's cognitive diathesis-stress theory of depression in early adolescents. The Journal of Early Adolescence, 23(4), 384-404.
Anderson, K. W., & Skidmore, J. R. (1995). Empirical analysis of factors in depressive cognition: The Cognitive Triad Inventory. Journal of clinical psychology, 51(5), 603-609.
Beck, A. T. (1961). A systematic investigation of depression. Comprehensive psychiatry, 2(3), 163-170.
Beck, A. T., Brown, G., Steer, R. A., Eidelson, J. I. & Riskind, J. H. (1987). Differentiating Anxiety and Depression. Journal of Abnormal Psychology, 96 (3), 179-183.
Clark, D. A., & Beck, A. T. (2010). Cognitive theory and therapy of anxiety and depression: Convergence with neurobiological findings. Trends in cognitive sciences, 14(9), 418-424.
Evans, J., Heron, J., Lewis, G., Araya, R., & Wolke, D. (2005). Negative self-schemas and the onset of depression in women: longitudinal study. The British Journal of Psychiatry, 186(4), 302-307.
Francis‐Raniere, E. L., Alloy, L. B., & Abramson, L. Y. (2006). Depressive personality styles and bipolar spectrum
Gibb, B. E., Benas, J. S., Grassia, M., & McGeary, J. (2009). Children's attentional biases and 5-HTTLPR genotype: Potential mechanisms linking mother and child depression. Journal of Clinical Child & Adolescent Psychology, 38(3), 415-426.
Goldapple, K., Segal, Z., Garson, C., Lau, M., Bieling, P., Kennedy, S., & Mayberg, H. (2004). Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behaviour therapy. Archives of general psychiatry, 61(1), 34-41.
Joiner, T. E., Metalsky, G. I., Lew, A., & Klocek, J. (1999). Testing the causal mediation component of Beck's theory of depression: Evidence for specific mediation. Cognitive therapy and research, 23(4), 401-412.
Kendler, K. S., Thornton, L. M., & Gardner, C. O. (2000). Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. American Journal of Psychiatry, 157(8), 1243-1251.
Li, J. M., Zhang, Y., Su, W. J., Liu, L. L., Gong, H., Peng, W., & Jiang, C. L. (2018). Cognitive behavioral therapy for treatment-resistant depression: A systematic review and meta-analysis. Psychiatry research, 268, 243-250.
Maupomé, D., Armstrong, M. D., Rancourt, F., & Meurs, M. J. (2021). Leveraging Textual Similarity to Predict Beck Depression Inventory Answers. In Proceedings of the Canadian Conference on Artificial Intelligence.
Pössel, P., & Black, S. W. (2014). Testing three different sequential mediational interpretations of Beck's cognitive model of the development of depression. Journal of clinical psychology, 70(1), 72-94.
Siddique, M. P., & Hanif, R. (2021) Measurement of Vulnerability Markers for Depression: A Study on Translation, and Validation of DAS-A. JIIMC 2021 Vol. 16, No.1
Dysfunctional attitudes are considered the first and most distal in Beck's construct of depression, also known as a causal mediation model (Joiner et al.,1999) and the most proximal being the symptoms of automatic negative thoughts and the onset of depression (Pössel & Black, 2014). Beck posited that dysfunctional attitudes are typically rigid and self-loathing in nature ("Nobody loves me"), increasing the diathesis (vulnerability) for MDD onset and as a diathesis-stress model (Pössel & Black, 2014). The BDI-I, BD-II and DAS are psychometric tests for evaluating MDD severity and clinical observations of attitudes like pessimism and sense of failure. The BDI was created in 1961 and revised in 1978, and 1996 - signalling it flexibility (Beck et al., 1987) and the DAS created by Beck and Weissman in 1978 (Beck et al., 1987) also reflects this. Years after its inception, the wording of the DAS was deemed inappropriate for children and Abela and D'Allesandro created a children's version, the CDAS (Abela & D'Alessandro 2002). In 2003, Abela and Sullivan tested diathesis-stress with adolescents. Contrary to Beck's hypothesis, dysfunctional attitudes increased MDD vulnerability for adolescents with high self-esteem and social supports, not those with low self-esteem and social supports (Abela & Sullivan, 2003). Depression was not necessarily observed; however, the vulnerability aspect was significant. In 1999, Joiner et al. tested Beck's causal mediation and diathesis-stress components with 119 high school students preceding and following midterm exams, completing the DAS and BDI-II. Those who scored high in dysfunctional attitudes and received a poor grade showed the highest increase of depression; the others, regardless of their grade, scored low for MDD (Joiner et al., 1999). Notably, the authors stated their work as one of the first to support Beck's diathesis-stress component (Joiner et al., 1999).
In 2021, a thorough meta-analysis of the BDI's efficacy found that both versions, BDI and BDI-II, had high internal consistency (Eser et al., 2021) using a meta-analytical tool, the Reliability Generalization (RG), comparing university students and psychiatric outpatients for depression (Eser et al., 2021). And in addition to evolving CBT for adolescents and children, the cultural translation of the model has also been tested. In 2020, a unique study measured the validity of the DAS after being translated into Urdu and a sample of 641 college students (Siddique & Hanif, 2021). The results were steadfast in supporting Beck's theories; however, students were tested from only two cities and in highly educated sectors (Siddique & Hanif, 2021). CBT and its accessibility for populations with limited resources to mental health care is illuminated here.
The next more proximal component to MDD in accordance with CBT is the depressogenic schema, designated from Beck's observations in his early years spent observing psychiatric patients. Patients with dysfunctional attitudes reported automatic negative thoughts embedded in their cognitive structure, and when triggered, produced a maladaptive schema and an increased vulnerability to MDD onset (Clark & Beck, 2010). The depressogenic schema exacerbates the attentional bias of an individual; and as Beck theorized, those biased perceptions can be latent or activated by a life event (Evans et al., 2005). He also stated that schemas would be challenging to measure in self-questionnaires for MDD vulnerability because of this latency (Evans et al., 2005). However, Evans and colleagues tested this, intentionally selecting 8540 non-depressed expectant mothers using the Edinburgh Post-Natal Depression Scale (EPDS) and a negative self-schema score. At thirty-two weeks, 790 women were reported depressed, and 736 of them scored the highest tertile for negative schema (Evans et al., 2005). However, the authors reflected that the questionnaires were designed to measure personality, not cognitions (Evans et al., 2005). The Theory of Modes was introduced to address CBT’s limitations for clinical interventions and shortcomings of schematic processing (Evans et al., 2005). That depression may be a schematic blend of Axis I and Axis II disorders (i.e., anxiety, panic disorders) with symptoms of depression (Frances-Raniere et al., 2006). As well, the construct of a negative schema later included the influence of mildly stressful events, adapting the "kindling" effect (Kendler et al., 2000), recognizing that severe life events (i.e., death of a loved one) are not the only precipitators for depression. That is, a continuation of depressive episodes related to psychosocial pressure over shorter periods, even mild in nature, can also trigger depression (Kendler et al., 2000).
The most proximal construct to the onset of MDD, the cognitive triad, interconnects negative views of the world, self, and future ideations (Pössel et al., 2020). The Cognitive Triad Inventory (CTI) was created in 1986 by Beckham et al. as a self-report instrument for depression. An empirical study of CTI's factorial validity led by Anderson and Skidmore (1995) supported the efficacy of the triad in therapy. However, the negatively phrased "self" items lacked robustness in their findings (Anderson & Skidmore, 1995). The authors pointed out that from the triad, the negative-self items are the most imperative corelates to MDD onset, with the suggestion that the phrasing of "negative" and "positive" be considered for revision (Anderson et al., 1995).
By the early 2000s, CBT and Beck's model became multidimensional, uniting clinical, cognitive, and neural mechanisms. Goldapple et al. (2004) tested CBT principles using neuroimaging to study genetic risk and depression. In depressive subjects, they found that bottom-up processing (sensory information to the brain) and negative schemas were overactivated, and top-down processing (cognition driven perception) were inhibited (Goldapple et al., 2004). After undergoing CBT, the depressed subjects showed an increase in hippocampal and orbital frontal activity (Goldapple et al., 2004) due to the encouragement of top-down processing and significant mood improvement (Goldapple et al., 2004). In 2009, the integration of CBT and a genetic risk factor, 5-HTTLPR, a genotype associated with cognitive processing in children, was published by Gibb et al. Mothers and children completed the BDI-II, the children were measured for attentional biases (happy, sad, angry faces) and DNA swabs were obtained. Assessment of attentional biases found that preference for sad faces was higher for children with the 5-HTTLPR genotype and associated with greater amygdala reactivity (Gibb et al., 2009). This evidence suggests the plausibility of nervous system dysregulation, as regulated babies tend to prefer happy faces (Gibb et al.,2009). Top-down processing and Beck's event congruency theory (a personality style) (Gibb et al., 2009) were present plausibly due to genetic inheritance, increasing their probability for depression.
Beck's CBT and model of depression has helped distinguish a standard for researchers in the fields of psychotherapy and psychopathology to follow. CBT continues to address not only depression but its confluence with other mood disorders and their aetiologies. The tools created, such as the DAS, BDI and CTI, were unique in that they courageously helped shift the lexicon of depression during an era when mental health issues were still considered taboo. The current model and CBT still, however, requires further investigation. Despite its empirical robustness and shifts with modernity, depression's aetiology remains insidiously complex and multidimensional in its pathology. The aforementioned findings of Abela and Sullivan (2003), for example, highlights the risk that all hypotheses of depression and mood disorders carry: they are inherently non-linear and complex. Future research and testing need to distinguish nuances like Abela and Sullivan’s (2003) findings of vulnerability to MDD versus the actual onset of depression. The current global mental health crisis and the gravitas of depression’s prevalence also commands that CBT and its nexus with other schools of thought address inclusivity and accessibility of treatments to underprivileged populations. The success of CBT and its future iterations depends upon this.
References
Abela, J. R., & D'Alessandro, D. U. (2002). Beck's cognitive theory of depression: A test of the diathesis‐stress and causal mediation components. British Journal of Clinical Psychology, 41(2), 111-128.
Abela, J. R., & Sullivan, C. (2003). A test of Beck's cognitive diathesis-stress theory of depression in early adolescents. The Journal of Early Adolescence, 23(4), 384-404.
Anderson, K. W., & Skidmore, J. R. (1995). Empirical analysis of factors in depressive cognition: The Cognitive Triad Inventory. Journal of clinical psychology, 51(5), 603-609.
Beck, A. T. (1961). A systematic investigation of depression. Comprehensive psychiatry, 2(3), 163-170.
Beck, A. T., Brown, G., Steer, R. A., Eidelson, J. I. & Riskind, J. H. (1987). Differentiating Anxiety and Depression. Journal of Abnormal Psychology, 96 (3), 179-183.
Clark, D. A., & Beck, A. T. (2010). Cognitive theory and therapy of anxiety and depression: Convergence with neurobiological findings. Trends in cognitive sciences, 14(9), 418-424.
Evans, J., Heron, J., Lewis, G., Araya, R., & Wolke, D. (2005). Negative self-schemas and the onset of depression in women: longitudinal study. The British Journal of Psychiatry, 186(4), 302-307.
Francis‐Raniere, E. L., Alloy, L. B., & Abramson, L. Y. (2006). Depressive personality styles and bipolar spectrum
Gibb, B. E., Benas, J. S., Grassia, M., & McGeary, J. (2009). Children's attentional biases and 5-HTTLPR genotype: Potential mechanisms linking mother and child depression. Journal of Clinical Child & Adolescent Psychology, 38(3), 415-426.
Goldapple, K., Segal, Z., Garson, C., Lau, M., Bieling, P., Kennedy, S., & Mayberg, H. (2004). Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behaviour therapy. Archives of general psychiatry, 61(1), 34-41.
Joiner, T. E., Metalsky, G. I., Lew, A., & Klocek, J. (1999). Testing the causal mediation component of Beck's theory of depression: Evidence for specific mediation. Cognitive therapy and research, 23(4), 401-412.
Kendler, K. S., Thornton, L. M., & Gardner, C. O. (2000). Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. American Journal of Psychiatry, 157(8), 1243-1251.
Li, J. M., Zhang, Y., Su, W. J., Liu, L. L., Gong, H., Peng, W., & Jiang, C. L. (2018). Cognitive behavioral therapy for treatment-resistant depression: A systematic review and meta-analysis. Psychiatry research, 268, 243-250.
Maupomé, D., Armstrong, M. D., Rancourt, F., & Meurs, M. J. (2021). Leveraging Textual Similarity to Predict Beck Depression Inventory Answers. In Proceedings of the Canadian Conference on Artificial Intelligence.
Pössel, P., & Black, S. W. (2014). Testing three different sequential mediational interpretations of Beck's cognitive model of the development of depression. Journal of clinical psychology, 70(1), 72-94.
Siddique, M. P., & Hanif, R. (2021) Measurement of Vulnerability Markers for Depression: A Study on Translation, and Validation of DAS-A. JIIMC 2021 Vol. 16, No.1
The Evidence of Astrocytes in Depression &
Disrupted Astrocytic Networks in Depressed Behaviour
Disrupted Astrocytic Networks in Depressed Behaviour
Beck’s Cognitive Behavioural Therapy and Evolution as a Model for Depression
Quality of Life (QoL) is a widely defined concept that extends beyond the lexicon of psychometrics and psychiatric epidemiology as it tacitly acknowledges the idea of “a life well-lived.” Holistic variables like belongingness, purpose, and self-efficacy have become increasingly critical to mental health sectors in the wake of the 1960’s deinstitutionalization of asylums to the modern-day inclusion of service user input for individuals with mental health challenges. However, despite the many attempts to refine its definition, including the World Health Organization (WHO) stating QoL as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” it has remained inherently flawed as it lacks a gold standard definition (World Health Organization, 1998). In addition, the Short-Form Six Dimensions (SF-36) and its iterations (SF-6D, SF-12) and the European Quality of Life Five Dimensions (EQ-5D) have been widely used instruments in determining QoL and criticized as generic and short-sighted. The following examines QoL based on the assumption that all mental health care domains unanimously agree on QoL as a critical outcome for all treatments and interventions and that the impacts of the SF-36, EQ-5D and the policymakers utilizing them has necessitated a path forward for future research beyond economic calculations (Holloway and Carson, 2002). Examples include how the SF-36 and EQ-5D have failed in cases of severe mental illness (SMI) like schizophrenia, personality disorders, psychosis, and bipolar disorder, as well as the QoL of caregivers and the global destigmatization of all SMI.
To help refine the ubiquitous nature of QoL, Holloway and Carson identified six models: objective indicators, needs satisfaction, subjective wellbeing, capabilities, psychological health, and health-related quality of life (HRQoL) (Connell et al. 2012). Of these, the HRQoL, as defined by the Centre for Disease Control and Prevention, helped diminish some ambiguity. Quality-adjusted life year or QALY is a measurement that combines health years with HRQoL and has been used by policymakers like the National Institute for Health Care and Excellence (NICE) to assess interventions and costs for major surgeries like a coronary bypass, not necessarily the heterogeneous symptoms of severe mental illness (Saarni et al., 2010). In contrast, the DALY or disability-adjusted life year was designed to assess the global burden of disease and developed by WHO (World Health Organization, 1998). The SF-36 and EQ-5D are the most globally used instruments for determining QALYs and DALYs, often in place of diagnostic categories and clinical intervention (Brazier et al., 2014). In a 2010 investigation of the EQ-5D, 8028 individuals diagnosed with bipolar, schizophrenia and psychosis showed minimal decreases in HRQoL results (Saarni et al., 2010). The researchers then supplemented the study with the BDI, or Beck’s Depression Inventory and the results more accurately reflected the impact of severe depression due to their condition (Saarni et al., 2010). Connell and colleagues in 2013 interviewed nineteen men and women with SMI, and when asked what would improve their HRQoL, depression was reported as the worst symptom, more so than intrusive voices and hallucinations (Connell et al., 2013). They reported inclusivity as the variable, highlighting the importance of destigmatization research.
The Grand Challenges in Global Mental Health initiative, a symposium of numerous multi-disciplinaries in mental health, broached the need for a life-course approach for HRQoL and destigmatization (Collins et al., 2013). Recommendations included pre-natal intervention for mothers with depression in lower-income situations who are prone to increased risk for in-utero disturbances and their child’s risk for developing a SMI (Collins et al., 2013) and early adulthood mental resilience school programs that are service-user informed. The teaching of coping strategies and mental health tools from a young age was strongly suggested in the symposium considering there are no cures for many disorders, and most SMI’s manifest by adolescence (Collins et al., 2013).
The implications of self-reported HRQoL metrics are also problematic in cases of SMI, that is if participants are responding during a time when their condition has stabilized (Saarni et al., 2010). Positive subjective wellbeing for an individual with schizophrenia, for example, might be self-reported when the reality of their quality of life may be bleak (Saarni et al., 2010). However, this poses an ethical dilemma when measuring HRQoL and the ongoing tension between objective and subjective data. The content validity of HRQoL, in this case, could be considered by some researchers as inaccurate and that the temporary lack of symptoms of a disorder is affecting results versus the subjective wellbeing of an individual who reports they feel good, regardless of what “good” is from a researcher’s perspective.
In 2012, Connell and colleagues synthesized semi-structured interviews also addressing this issue, including individuals with a broad range of mental health disorders, asking them directly how their condition had affected their QoL and what it meant to them. Of the themes identified: wellbeing and ill-being, control, autonomy, choice, self-perception, belonging, activity, hope and hopelessness - belonging was the most critical variable identified (Connell et al., 2012). The gravitas of belongingness was considered the missing link in research between ill-being and wellbeing (Connell et al., 2012). The EQ-5D starkly misses this within its five dimensions focusing on mobility, self-care, usual activities, pain and discomfort, and depression and anxiety.
In addition to the implications of HRQoL metrics, mental health issues amongst caregivers have also been overlooked and under-supported. In a 1999 study profiling 1594 caregivers of veterans, the researchers suggested that the items on the SF-36 subscales also be aggregated into a Mental Component Scale (MCS) and a Physical Component Scale (PCS) for clinicians and future research (Hughes et al., 1999). The inclusion of burden scores caused a 22% increase when explained on the MCS compared to the increase of 4% found with the PCS, providing insight into the likelihood of caregiving and depression and stress more than physical health scores (Hughes et al., 1999). In addition, caregivers of those with SMI’s experience stigma, social isolation and have lower HRQoL ten times more than those caring for someone with somatic diseases like diabetes or stroke, and also scored high on the criteria for depression (Hayes et al., 2014).
However, some research also supports the utility of EQ-5D and SF-36 and their value in HRQoL studies. Between 2003-2006, 1708 patients admitted with personality disorders responded to the questionnaires and were compared with patients who suffered severe illnesses like diabetes and cancer. In both cases, the necessity for financial reimbursement and support was evident. The authors found the use of EQ-5D favourably revealed a substantial burden of disease for those with personality disorders and encouraged its use for future researchers seeking tools for funding applications (Soeteman et al., 2008). The EQ-5D index of patients with personality disorders was comparable to those with lung cancer and Parkinson’s (Soeteman et al., 2008).
One could also posit that SF-36 and EQ-5D have played a part in the global destigmatizing of mental illness, particularly depression and anxiety. The Global Burden of Disease (GBD), regarded as one of the most comprehensive tools for calculating mortality and morbidity rates, also provides a global perspective on the prevalence and harm of mental health issues, including major depressive disorder and anxiety disorders (GBD 2019 Mental Disorders Collaborators, 2022). Although it could be criticized as too large-scale for determining the needs of an individual’s QoL, one could argue the GBD as integral for helping to destigmatize the gravitas of what have become common mental health issues, particularly depression and anxiety, simply by publishing the staggering statistics since 1990. The GBD utilized the DALY or disability-adjusted life-years (DALYs) to measure across cultures, and of the 204 countries studied, mental disorders increased from 80.8 million to 125.3 million global DALYs between 1990 and 2019 and depression and anxiety accounted for 37.3% of global DALYs of all mental health disorders (GBD 2019 Mental Disorders Collaborators, 2022). A significant finding was that the years lived with disabilities (YLDs) revealed those with a mental health burden had some of the highest, with 125·3 million YLDs due to mental disorders (GBD 2019 Mental Disorders Collaborators, 2022).
The generic metrics of HRQoL have clearly failed to reflect the complex and heterogenous dimensions of severe mental health disorders. The way forward will be dependent upon the nexus of service user involvement, financial and emotional support programs for caregivers, and a continuous multidisciplinary approach to measuring HRQoL beyond the economic calculations of the SF-36 and EQ-5D. Belongingness, for example, is a measurable variable for all disciplines in psychiatry and mental health policy to consider, from ill-being toward wellbeing. Further funding and work in the destigmatization of severe mental illnesses are relevant for lessening the global burden as much as cure-driven disease models. The estimated cost of mental health is projected to rise to six trillion by 2030 (The Lancet Global Health, 2020), and the statistics have yet to reflect the impact of the COVID-19 pandemic on depression, anxiety, and severe mental illnesses. As discussed in the Great Challenges’ data, even a little progress from life-approach research and intervention would lead to a beneficial global increase in HRQoL (Collin et al., 2013).
References:
Brazier, Connell, J., Papaioannou, D., Mukuria, C., Mulhern, B., Peasgood, T., Jones, M. L., Paisley, S., O’Cathain, A., Barkham, M., Knapp, M., Byford, S., Gilbody, S., & Parry, G. (2014). A systematic review, psychometric analysis, and qualitative assessment of generic preference-based measures of health in mental health populations and the estimation of mapping functions from widely used specific measures. Health Technology Assessment (Winchester, England), 18(34), vii–viii.
Collins, P. Y., Insel, T. R., Chockalingam, A., Daar, A., & Maddox, Y. T. (2013). Grand challenges in global mental health: integration in research, policy, and practice. PLoS medicine, 10(4), e1001434.
Connell, J., O'Cathain, A., & Brazier, J. (2014). Measuring quality of life in mental health: are we asking the right questions? Social science & medicine, 120, 12-20.
Connell, J., Brazier, J., O’Cathain, A., Lloyd-Jones, M., & Paisley, S. (2012). Quality of life of people with mental health problems: a synthesis of qualitative research. Health and quality of life outcomes, 10(1), 1-16.
GBD 2019 Mental Disorders Collaborators. (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry.
Hayes, L., Hawthorne, G., Farhall, J., O’Hanlon, B., & Harvey, C. (2015). Quality of life and social isolation among caregivers of adults with schizophrenia: policy and outcomes. Community mental health journal, 51(5), 591-597.
Health, T. L. G. (2020). Mental health matters. The Lancet. Global Health, 8(11), e1352.
Hughes, S. L., Giobbie-Hurder, A., Weaver, F. M., Kubal, J. D., & Henderson, W. (1999). Relationship between caregiver burden and health-related quality of life. The Gerontologist, 39(5), 534-545.
Holloway, F., & Carson, J. (2002). Quality of life in severe mental illness. International Review of Psychiatry, 14(3), 175-184.
Saarni, S. I., Viertiö, S., Perälä, J., Koskinen, S., Lönnqvist, J., & Suvisaari, J. (2010). Quality of life of people with schizophrenia, bipolar disorder, and other psychotic disorders. The British Journal of Psychiatry, 197(5), 386-394.
Soeteman, D. I., Verheul, R., & Busschbach, J. J. (2008). The burden of disease in personality disorders: diagnosis-specific quality of life. Journal of personality disorders, 22(3), 259-268.
World Health Organization. (1998). Programme on mental health: WHOQOL user manual (No. WHO/HIS/HSI Rev. 2012.03). World Health Organization.
Quality of Life: Its Application and Value in Understanding Mental Health Burdens
Submitted by Julia McCabe
Dec 4, 2021
Submitted by Julia McCabe
Aug 9, 2021
The aetiology of aggressive behaviour and its subsequent societal impact has challenged research in psychology since the 1960s. Aggression in empirical research has struggled to agree on one definition, and a bifurcated "nature versus nurture" debate has resulted in an arduous disentanglement of data. Aggression's evolutionary role in survival, mating, and social order of homo sapiens to present-day iterations of domestic abuse and violence, illuminates a spectrum from normal to pathological (Waltes et al., 2016). Moreover, dysregulated acts of intentional harm (physical or emotional) are indicated in many neuropsychiatric disorders (Anholt & MacKay, 2012). Phenotypic aggregates include conduct disorder, antisocial behaviour, and oppositional defiant disorder (Anholt & MacKay, 2012). Earlier models beginning with Bandura's Bobo Doll study, Social Learning Theory and later the General Aggression Model (GAM), set an arguably moralistic and myopic tone with the assumption of aggression as a learned behaviour (Ferguson, 2016). However, contemporaneous data, including neurobiological and genetic mechanisms, estimates that aggressive behaviour heritability is around 50% (Odintsova et al., 2019). The complex interplay between genes, neural correlates, and the environment has necessitated the emergence of modern coalesced models (Siegel & Victoroff, 2009).
Social Learning Theory posits that aggression is due to observational learning and direct experience during early childhood (Bandura et al., 1961). The assumption that a child cannot distinguish between reality and fiction nor exercise discernment, thus prone to being more aggressive, is confounded in earlier work. It has been well established in cognitive development that children between three and five can follow instructions and discern what is real from fiction (Ferguson & Dyck, 2012). Tedeschi and Quigley, in their "Big Four" study, measured the construct validity of four laboratory paradigms commonly used in studying aggression. The Bobo study was concluded as an example of imitation, children following instructions, not a potentiation of pathological or playground aggression (Tedeschi & Quigley, 1996). They observed that although kicking and punching had been sustained months after the experiment, the factor of intentional harm was null. Another early 1976 study found implications within Bandura’s hypothesis: the variables of perception and manipulated action of the model adults. Sixty university students participated in a Bobo replication as naïve observers of children. They were asked to label whether a child was considered more or less aggressive. The adult models were instructed to use destructive or constructive behaviours and actions. The results showed that the more aggressively the adult model performed (kicking, punching etc.), the naïve observers would rate the child as less aggressive, and the less aggressive the adult model, the observers would rate the child as more aggressive (Joseph et al., 1977).
GAM, an extension of collaborative work following Bandura's theory, united several aggression theories into one framework (i.e., social learning, script theory, cognitive neo-association theory) and examined maladaptive behaviour during childhood as influenced by knowledge structures (beliefs, attitudes, and behavioural scripts) (Allen et al., 2018). From simple to complex social situations, "inputs" influence a child's arousal from people or situations that increase or decrease aggression (Allen et al., 2018). However, the arousal GAM assumes is primarily cognitive, as aggressive scripts and schemas fail to consider the arousal responses of the autonomic nervous system (Ferguson & Dyck, 2012). The social behaviour network (Newman, 1999) is an example hypothesis that identifies six nodes in the brain specific to the modulation of social behaviour. It demarcates the potentiation of reactive aggression as neural excitation of the amygdala, signalling glutamatergic neurons in the medial hypothalamus and periaqueductal gray (Carré et al., 2011).
GAM also has a history of basing its findings on unreliable effect sizes and statistical tools, and despite being considered antiquated by some, it is still utilised in research for measuring media-related violence (video games/animation) and aggression in children (Ferguson, 2016). Ferguson illuminates the common occurrence of errors in effect sizes and data, wherein effect size estimate-options confuse researchers. What is also known as null-hypothesis significance testing has been considered inappropriate for judging validity (Ferguson & Dyck, 2012). In a 2012 study of media-related aggressive behaviour, researchers were asked to avoid using smaller sample sizes and instructed that 230+ sizes were standard for reliability. However, research with large samples often exacerbates results, while smaller samples can also offer accurate evidence – in this case, determining "aggressive thoughts" as an outcome of children viewing video games (Ferguson & Dyck, 2012).
There are also inconsistencies in neurobiological data between what has been defined as reactive (impulsivity) and proactive (pre-meditated) aggression – wherein the variances demonstrate different heritability (Ghodsian et al., 1987). The aminergic system has been identified as critical to reactive and proactive aggression, and low serotonergic activity (5-HT) is inversely indicated to increased aggression (Waltes et al., 2016). In contrast, the endocrine system correlates solely to reactive aggression and high levels of impulsivity (Waltes et al., 2016). Serotonergic expression and its relationships with aggression also depend on genes and co-morbidities—specifically, tryptophan or the TPH1 and TPH2 genes from which serotonin is also synthesised (Waltes et al., 2016). For example, gene TPH1 has also been documented in male patients with Alzheimer's and increased aggressive behaviour (Waltes et al., 2016). Associations with the TPH2 gene and enhanced aggressive behaviour have also been found; however, research also emphasises the mechanisms by which the brain anabolises TPH2 versus TPH1 (Waltes et al., 2016). Pending on a person’s biological sex, results can be inconclusive. For example, in studies using female knock-out mice, TPH1 showed impaired brain development (Waltes et al., 2016). With TPH2 and the haplotype associated with impeded serotonin levels and increased aggression, tagging used by experimenters has been noted to vary, increasing the likelihood of inconclusive data (Waltes et al., 2016). However, robust animal model research has also challenged the serotonin deficit hypothesis. For example, wild rats whose forebrains were injected with 5-HT(1A/B) showed increased and decreased aggressive traits (De Boer & Koolhaas, 2005). In vivo testing of fish and rats has also revealed enhanced aggressive behaviour by increasing 5-HT dorsal raphe neurons, encouraging excess arousal and motor output (De Boer & Koolhaas, 2005).
Heritability estimates also vary due to research methods, including age and gender (Waltes et al., 2016). Waltes and colleagues conducted a meta-analysis of twin and adoption studies published before 2007. They used PubMed and keywords (i.e., "aggression", "neuroendocrine", "epigenetics", and more) and aggression-related scales (i.e., Brown–Goodwin Lifetime History of Aggression, Aggressive Behaviour Scale and more). The results reflected high variability. For example, before 2007, 65% heritability of aggressive behaviour was found. However, proactive aggression estimated slightly higher heritability (32–48%) than reactive aggression (20–43%), and other genetic findings reflected 85% heritability for proactive aggression and 48% for reactive (Waltes et al., 2016). There is also the implication of the "equal environments assumption" in twin studies that assume identical and fraternal twins choose similar environments because of the genes they share (i.e., friends and social interests) but disregard the possibility that regardless of the type of twins, this may be characteristic of sibling behaviour. Sharing common interests does not necessarily mean an increased likelihood of shared psychological traits, including psychopathologies like aggression and severe iterations (Porsch et al., 2016).
Research measurements are also biased by the age, position (teacher/parent) and gender of the rater. For example, an environmental-genetic twin study using the Mothers' Observations Checklist (MOCL) and Child Behaviour Checklist Aggressive (CBCL-A) subscales resulted in a variance of 94% heritability estimate; however, the ratings and data were based on the mother's observations which are inevitably biased (DiLalla, 2002) (Porsch et al., 2016). Moreover, different intensities of aggression were measured. For example, the MOCL measures milder aggression, whereas the CBCL-A measures extreme aggression (Porsch et al., 2016). The influences of age and sex in this data also found that heritability for aggression (for both biological sexes) between three and seven years was around 60%. However, between ten and twelve, heritability was 67% for boys and 50-55% for girls, while shared environmental factors were more critical for the boys at 29% (Porsch et al., 2016).
Updated gene-environment research also supports what was once overlooked in prior research, including in psychology: trauma and how patterns of aggression arise due to early life adversity. For example, unresolved trauma is associated with higher DNA methylation levels impacting serotonergic modulation and aggression onset (Klengel et al., 2013). Methylation occurs when immune cell function and brain areas associated with stress and coping are compromised. In a 2013 comprehensive review, it was found that males with chronic physical aggression also had elevated levels of pro-inflammatory cytokines and compromised monoaminergic systems (Klengel et al., 2013). Specifically, the FKBP5 gene is related to this compromised effect of the stress hormone system. The men had experienced childhood maternal deprivation, abuse, PTSD, and low socioeconomic status (Klengel et al., 2013). However, the FKBP5 is one gene of many hypothesised in aggression research. Controlling data for trauma-related research poses a challenge considering the ubiquitous experiences that shape a child's environment and the potentiation of adult-onset aggression, gene expression and potential co-morbidities (Waltes et al., 2016).
The behavioural outcomes of aggression on a pathological and societal level reveal a complicated interplay between biological, environmental, and genetic influences. It is also important to note the limitation of definitions referenced here; proactive vs reactive aggression represents two of many. The earlier social learning models and GAM has helped illuminate the importance of avoiding future myopic models. For example, if genes account for up to 50% of why an individual may be aggressive, theoretically, 50% of the causality remains to be explored (Odintsova et al., 2019). The environment is as essential to consider as the incoming epigenetic updates. The imminent future of artificial intelligence and its utility for siphoning environmental, genetic, and biological information will be instrumental and revolutionary for breakthroughs in this field.
References
Allen, J. J., Anderson, C. A., & Bushman, B. J. (2018). The general aggression models. Current opinion in psychology, 19, 75-80.
Anholt, R. R., & Mackay, T. F. (2012). Genetics of aggression. Annual review of genetics, 46, 145-164.
Bandura, A., Ross, D., & Ross, S. A. (1961). Transmission of aggression through imitation of aggressive models. The Journal of Abnormal and Social Psychology, 63(3), 575.
Carré, J. M., McCormick, C. M., & Hariri, A. R. (2011). The social neuroendocrinology of human aggression. Psychoneuroendocrinology, 36(7), 935-944.
De Boer, S. F., & Koolhaas, J. M. (2005). 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis. European journal of pharmacology, 526(1-3), 125-139.
DiLalla, L. F. (2002). Behaviour genetics of aggression in children: Review and future directions. Developmental Review, 22(4), 593-622.
Ferguson, C. J. (2016). An effect size primer: a guide for clinicians and researchers.
Ferguson, C. J., & Dyck, D. (2012). Paradigm change in aggression research: The time has come to retire the General Aggression Model. Aggression and violent behaviour, 17(3), 220-228.
Joseph, J. M., Kane, T. R., Nacci, P. L., & Tedeschi, J. T. (1977). Perceived aggression: A re-evaluation of the Bandura modeling paradigm. The Journal of Social Psychology, 103(2), 277-289.
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., ... & Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature neuroscience, 16(1), 33-41.
Newman, S. W. (1999). The medial extended amygdala in male reproductive behavior a node in the mammalian social behaviour network. Annals of the New York Academy of Sciences, 877(1), 242-257.
Odintsova, V. V., Roetman, P. J., Ip, H. F., Pool, R., Van der Laan, C. M., Tona, K. D., ... & Boomsma, D. I. (2019). Genomics of human aggression: current state of genome-wide studies and an automated systematic review tool. Psychiatric genetics, 29(5), 170-190.
Porsch, R. M., Middeldorp, C. M., Cherny, S. S., Krapohl, E., Van Beijsterveldt, C. E., Loukola, A., ... & Bartels, M. (2016). Longitudinal heritability of childhood aggression. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 171(5), 697-707.
Siegel, A., & Victoroff, J. (2009). Understanding human aggression: New insights from neuroscience. International Journal of Law and Psychiatry, 32(4), 209-215.
Tedeschi, J. T., & Quigley, B. M. (1996). Limitations of laboratory paradigms for studying aggression. Aggression and Violent Behavior, 1(2), 163-177.
Waltes, R., Chiocchetti, A. G., & Freitag, C. M. (2016). The neurobiological basis of human aggression: a review on genetic and epigenetic mechanisms. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 171(5), 650-675.
What can neuroscience contribute to our understanding of why conspiracy theories emerge and how they can be prevented or challenged?
From political to personal, a conspiracy theory (CT) has the gravitas of implicating communication and relational well-being on an individual and global level. The contemporary zeitgeist surrounding conspiracy aetiology has inspired both psychological debate and research within neuroscience. Belief in a conspiracy may temporarily salve an individual's anxiety in the face of crisis but with a psychosocial cost, increasing the likelihood of anxiety, paranoia, and social stress (Hattersley et al., 2021). Orosz and colleagues (2016) investigated three strategies for reducing conspiracy theories using rationality, empathy, and ridicule with subjects. Although ridicule and rationality trumped empathy in their efforts to reduce conspiratorial misinformation, the following will solely utilise the measure of rationality in the form of empirical data. That is, how conspiracy beliefs may be encoded on a neural level with the nexus of the somatic marker hypothesis (SMH), default mode network (DMN) and their relevant neurobiological substrates. This will include the dorsal medial prefrontal cortex (DMPFC), ventral medial prefrontal cortex (VMPFC), dorsal lateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), amygdala, insula, and parietal lobes.
The somatic marker hypothesis suggests that belief in conspiracies may be due to the autonomic stress response and neural substrates involved in bodily emotions and decision-making (Dunn et al., 2006). Connections have been identified between the amygdala's activation to threat, the VMPFC (primary induction), and the "as-if" loop in potentiating the learning of a conspiracy (Apperly et al., 2004; Bechara & Damasio, 2005). The "as if it is already happening" loop (i.e., "The government is out to get us.”) may predict the biological signalling of feelings and emotional regulators implicating decision-making (Dunn et al., 2006). The somatic response of viscera and musculoskeletal structures induces biomarkers like the increased heart rate characteristic of anxiety underlying a conspiracy (i.e., the COVID crisis and vaccine conspiracies). This may trigger faster decision-making and impaired discernment (Apperly et al., 2004). When the VMPFC is lesioned, emotional salience and reality monitoring functions are disrupted, illuminating how bottom-up inputs influence this region's highly plastic environment, positing why belief bias may overrun discernment (Harris et al., 2008; Hattersley et al., 2022; Rollwage et al., 2020). Hattersley and colleagues also observed confabulatory behaviour and the tendency to "jump to conclusions" in individuals with traits synonymous with the implausible nature of some conspiracies (Hattersley et al., 2022).
Hattersley and colleagues examined this trait of over-generalisation of beliefs in response to implausible conspiracies by placing subjects' responses on a belief-choice continuum based on the "overfitting" hypothesis. For example, "the earth is flat" (less plausible) versus confounding information on the opposite, such as photos of the earth from space (more plausible). Although the latter has been proven true, immediate sensory/physical environment cues from the body were observed in those most prone to believing implausible CTs. They were found to be less reflective and exhibited a maladaptive belief response. Other examples included "climate hoax" (less plausible) to "climate cover-up by big companies" (more plausible). Belief in three other implausible versus plausible categories was most evident in those who scored highest in a jumping-to-conclusions task and reasoning biases. In addition, the amygdala and the anterior insula have also been found to co-activate when a strong belief, despite subjective plausibility, is intentionally challenged (Kaplan et al., 2016). The anterior insula has been found to receive interoceptive projections regarding the affective perception of threat (Kaplan et al., 2016). This suggests that the faster somatic loop may support a sense of false agency under the influence of a conspiracy and may override the reasoning functions of the VMPFC (Dunn et al., 2006).
Memory consolidation during a CT also involves the VMPFC, where a belief may be indirectly strengthened/weakened when the brain seeks meaning and forms theories in memory regions (Duch, 2021; Race et al., 2023). From a neurobiological perspective, learning is energy-consuming (Duch, 2021). A conspiracy may elicit a stress response of increased norepinephrine, acetylcholine, dopamine, and serotonin, facilitating the increased neuroplasticity observed during rapid learning (Duch, 2021). After learning, usually due to the urgent nature of a conspiracy, the brain requires rest, and a rapid neuroplasticity decrease occurs. (Duch, 2021). In the case of a CT, this may also illuminate how increased learning inversely decreases mental flexibility, regardless of confounding information (Duch, 2021; Harris et al., 2009). The original findings of the somatic marker hypothesis utilised the Iowa Gambling Task, which measured skin conductance and the body-state feedback loop (Damasio, 1996). Indirect connections between the amygdala and VMPFC were revealed in further research, wherein body-states could also be induced intra-cerebrally, via memory, not just from the body alone (Bechara & Damasio, 2005).
An additional bias in relation to the SMH is regarding one's agency or the "illusion of control" (Xue et al., 2016). Xue and colleagues utilised a card-guessing decision test and fMRI with healthy individuals in the context of two states: manipulated uncertainty (when the computer guessed the answers) versus the individual and their perceived agency over one's decisions. The fMRI revealed that the right insula was activated when subjects were perceiving/experiencing agency. In addition, faster autonomic arousal conditions and interoceptive reward seeking were also activated, increasing the likelihood of error in judgement as illuminated in the hypothesis (Xue et al., 2016).
Conspiracy may also be understood in the context of the default mode network hypothesis implicated when an individual defends and thinks about strong beliefs (Kaplan et al., 2016). Kaplan and colleagues (2016) found that in forty subjects, the activation of the DMPFC and inhibition of the orbitofrontal cortex were observed when presented with counterevidence against their political beliefs. The processing of conflicting evidence also correlated with increased amygdala and dorsal insula activity (Bechara & Damasio, 2005; Kaplan et al., 2016). Although political and conspiratorial beliefs may differ, the protective neural mechanisms of holding to one's beliefs do not. When presented with alternative arguments, the DMN was found to assist in the disengagement from external reality and increased inward focus involving the posterior and anterior midline structures and the lateral inferior parietal lobes (Kaplan et al., 2016). Synonymous with the interoceptive nature of the somatic marker hypothesis, the insular cortex was also involved in the perception of threat, connection to inward monitoring and correlated activation of the amygdala's autonomic fear response (Kaplan et al., 2016).
Moreover, in the same study, the activation of the OFC and the DLPFC was involved in cognitive flexibility and the reversal learning that may be required in dismantling a conspiracy when presented with counterevidence (Kaplan et al., 2016). When OFC and DLPFC activation is dysregulated, the authors also noted that neuropsychological disorders such as obsessive-compulsive disorder and addiction could also be found (Kaplan et al., 2016). In contrast, the DMPFC is activated in the downplaying or resistance of learning new information and cognitive reappraisal, which may explain the internal reasoning processes within the schema of CT believers (Kaplan et al., 2016).
Research in the neural basis of persuasion and the brain's value system is also informative data when considering the DMN and an individual's susceptibility to persuasion. The inherent values marked as “self-relevance” and “social relevance” are outcomes defined in neural coupling and determinants of "successful communication" but can also inversely trigger a stress response between "communicators and receivers" in conflict (Falk & Scholz, 2018; Kaplan et al., 2016). The VMPFC is consistently implicated in studies of persuasive messaging and is a necessary predictor for behaviours relevant to conspiratorial belief (Falk & Scholz, 2018). In an fMRI study conducted by Falk and colleagues in 2010, participants observing arguments related to various topics (i.e., donating blood, listening to a topic by a persuasive/non-persuasive source) were asked to rate persuasiveness. When the subjects were reflective and mentalising about their strongest beliefs (typically from a persuasive source without much evidence), the VMPFC, observed in emotional reappraisal and selective memory, was activated. Subsequently, it is also involved in the long-term maintenance of message-consistent behaviour.
The somatic marker and default mode network hypotheses support well-established research regarding the PFC's role in cognitive flexibility, decision-making, and the corresponding neural networks of cortical and subcortical structures. Both hypotheses illuminate these highly coordinated networks wherein emotional coherence and biological homeostasis are constantly sought across multiple domains: sensory, memory and neuroendocrine structures. The cognitive inflexibility characteristic of a conspiracy may be due to these disrupted interoceptive and exteroceptive processes in response to the perceived threat of an essential human feature: protecting one's values. Whether a belief is right or wrong, this area of research is invaluable for dismantling global and relational conspiracy-related conflict, as the neurobiology presented commands that effective communication also be regulated from a somatic standpoint. However, it is also essential to acknowledge that the research presented is limited. Firstly, empirical research in neuroscience and conspiracy theories is relatively sparse. Hopefully, this will improve, given that it is a subject that will become increasingly relevant, as social media and the speed of sharing misinformation are more common than not. The above research also contains a bias in the assumption that all conspiracies are wrong and may mistakenly disregard someone who believes in a conspiracy as being emotionally unstable or at the peril of one's neurobiology. As well, self-report measurements in some of the material inevitably contain self-report bias (Falk et al., 2010). Furthermore, conspiracies are heterogenous in how they may be defined as threatening or harmless in neuroscience research versus the real world. Since the 2020 pandemic, future researchers must also keep an open mind to what is plausible and implausible, considering the current ethos of the tenuous climate, politics, and unpredictable global events.
References
:
Apperly, I. A., Samson, D., Chiavarino, C., & Humphreys, G. W. (2004). Frontal and temporoparietal lobe contributions to theory of mind: neuropsychological evidence from a false-belief task with reduced language and executive demands. Journal of cognitive neuroscience, 16(10), 1773-1784.
Bechara, A., & Damasio, A. R. (2005). The somatic marker hypothesis: A neural theory of economic decision. Games and economic behaviour, 52(2), 336-372.
Damasio, A. R. (1996). The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 351(1346), 1413-1420.
Döhnel, K., Schuwerk, T., Meinhardt, J., Sodian, B., Hajak, G., & Sommer, M. (2012). Functional activity of the right temporoparietal junction and of the medial prefrontal cortex associated with true and false belief reasoning. Neuroimage, 60(3), 1652-1661.
Duch, W. (2021). Memetics and neural models of conspiracy theories. Patterns, 2(11), 100353.
Dunn, B. D., Dalgleish, T., & Lawrence, A. D. (2006). The somatic marker hypothesis: A critical evaluation. Neuroscience & Biobehavioral Reviews, 30(2), 239-271.
Falk, E. B., Berkman, E. T., Mann, T., Harrison, B., & Lieberman, M. D. (2010). Predicting persuasion-induced behaviour change from the brain. Journal of Neuroscience, 30(25), 8421-8424.
Falk, E., & Scholz, C. (2018). Persuasion, influence, and value: Perspectives from communication and social neuroscience. Annual review of psychology, 69, 329-356.
Goel, V., & Dolan, R. J. (2003). Explaining modulation of reasoning by belief. Cognition, 87(1), B11-B22.
Harris, S., Kaplan, J. T., Curiel, A., Bookheimer, S. Y., Iacoboni, M., & Cohen, M. S. (2009). The neural correlates of religious and nonreligious belief. PLoS one, 4(10), e7272.
Harris, S., Sheth, S. A., & Cohen, M. S. (2008). Functional neuroimaging of belief, disbelief, and uncertainty. Annals of neurology, 63(2), 141-147.
Hattersley, M., Brown, G. D., Michael, J., & Ludvig, E. A. (2022). Of tinfoil hats and thinking caps: Reasoning is more strongly related to implausible than plausible conspiracy beliefs. Cognition, 218, 104956.
Kaplan, J. T., Gimbel, S. I., & Harris, S. (2016). Neural correlates of maintaining one’s political beliefs in the face of counterevidence. Scientific reports, 6(1), 1-11.
Orosz, G., Krekó, P., Paskuj, B., Tóth-Király, I., Bőthe, B., & Roland-Lévy, C. (2016). Changing conspiracy beliefs through rationality and ridiculing. Frontiers in Psychology, 1525.
Race, E., Tobin, H., & Verfaellie, M. (2023). Leveraging Prior Knowledge to Support Short-term Memory: Exploring the Role of the Ventromedial Prefrontal Cortex. Journal of Cognitive Neuroscience, 1-11.
Rollwage, M., Loosen, A., Hauser, T. U., Moran, R., Dolan, R. J., & Fleming, S. M. (2020). Confidence drives a neural confirmation bias. Nature communications, 11(1), 1-11.
Xue, G., He, Q., Lu, Z. L., Levin, I. P., Dong, Q., & Bechara, A. (2013). Agency modulates the lateral and medial prefrontal cortex responses in belief-based decision-making. PLoS One, 8(6), e65274.
Submitted by Julia McCabe
Feb 13, 2023
What can neuroscience contribute to our understanding of why conspiracy theories emerge and how they can be prevented or challenged?
Mindfulness-Based Stress Reduction (MBSR) has emerged over the last twenty years as a holistic, low-cost intervention beneficial for individuals experiencing chronic stress. Chronic stress is deleterious to the body's endocrine, nervous, and immune system functions yet has become contemporaneously normalized in Western culture. Allostatic overload hypothesizes homeostatic dysfunction due to incessant stress, increasing the likelihood of depression, anxiety, and somatic diseases (Reive, 2019). In addition, an overload posits that chronic psychological input of perceived stress dysregulates neuroendocrine system hormones, agitates pro-inflammatory responses and decreases phagocytic immune system activity (Marciniak et al., 2020). The techniques of MBSR introduced through the seminal work of Jon Kabat Zinn provide core tenets based on non-judgement, self-acceptance, and the observation of vitiating emotions (Janusek et al., 2019). The eight-week program postulates to act as a psychological salve, reducing chronic stress implications and the dysfunction of allostatic related biomarkers (Carlson et al., 2003). Biomarkers include autonomic measures like blood pressure (BP), immune system responses (cytokines and Natural Killer Cell Activity or NKCA) and dysregulation of the neurohormonal system (cortisol and the Hypothalamic Pituitary Adrenal Axis or HPA Axis) (Reive, 2019). The following may help clarify the utility of MBSR intervention, the essential role of stress mediators like cortisol, blood pressure and cytokine activity, and the discernment of biological data from psychometrics like the Perceived Stress Scale (PSS), Profile of Mood States (POMS) and Mindful Attention Awareness Scale (MAAS).
In 2009, Klatt and colleagues examined the efficacy of low doses of MBSR in fast-paced work environments, using the PSS and MAAS in conjunction with an assay of salivary cortisol. The authors hypothesized that reductions in salivary cortisol would also be reflected in the PSS and MAAS results (Klatt et al.,2009). Adrenocortical activity (when cortisol is released from the adrenal cortex in response to stress) has been cited as a reliable and objective biomarker compared to the criticized biases of metrics like the PSS and MAAS (Matousek et al., 2020). However, Klatt and colleagues critically illuminate that biomarker activity, including cortisol, does not necessarily guarantee similar findings in psychometric test results nor the improvement of symptoms like anxiety and depression (Klatt et al., 2009). Similarly, favourable self-report tests do not reflect an improvement in stress biomarkers outcomes. For example, salivary cortisol during short-bout workplace intervals of MBSR showed minimal change pre- and post-intervention. Despite randomization, there were no changes in average daily salivary cortisol levels in the control group or MBSR group (Klatt et al., 2009). However, the PSS scores showed encouraging results, reflecting a dissonance of biological results and the potential bias of self-reporting. Alternatively, lower doses of MBSR may be ineffective for concurrently shifting psychological and biological markers like cortisol (Klatt et al., 2009).
However, a study of forty-two healthcare professionals receiving a higher dose of the MBSR eight-week intervention revealed a similar outcome. Cortisol was considered an unreliable measurement for chronic stress as it is affected by the body's circadian rhythm (Matousek et al., 2020). Although salivary cortisol is advantageous over serum cortisol as it is non-invasive, the results depend on the subject's monitoring of time. Results can also be altered by food, smoking, caffeine, and exercise (Matousek et al., 2020). Therefore, cortisol in isolation as a biomarker for stress is recommended to be supported with measurements of cytokines, salivary amylase, and other glucocorticoids (Matousek et al., 2020). Salivary amylase, for example, is a secretory immunoglobin known to react more rapidly to stress than cortisol and is considered a more accurate measurement (Matousek et al., 2020). In addition, stress sustained at low levels can also increase cortisol, suggesting that populations experiencing low-grade versions of chronic stress are plausibly missed in MBSR research (Klatt et al., 2009).
Similarly, cytokine pro-inflammatory markers are associated with depression, anxiety and stress, and the macrophage migration inhibitory factor is an example of cytokine activity measured in MBSR research (Wang et al., 2018). Plasma levels of microRNA were measured after an eight-week trial with 168 individuals suffering from depression, anxiety, and stress. The macrophage migration inhibitory factor decreased with MBSR therapy (Wang et al., 2018). However, although inflammation was reduced, not all psychological symptoms of depression and anxiety improved, suggesting that MBSR alone may not suffice as a primary therapeutic intervention (Wang et al., 2018).
MBSR and cytokine activity have also been commonly studied in cases of early cancer diagnoses when stress is at its highest, as it is posited as beneficial for preventing cytotoxicity (Carlson et al., 2002). In 2002, an MBSR study of immune system parameters with breast and prostate cancer used the POMS, a questionnaire containing sixty-five words/statements to assess distinct mood states. Stress scores were used as well as immune cell count and cytokine activity. Post-MBSR, the POMS results correlated to longer disease-free intervals and was one of the first studies to indicate how timing is critical for mitigating early diagnosis stressors and disease proliferation (Carlson et al., 2002). NKC cytotoxicity is one of the most significant indicators of cancerous diseases, and NKC production of IL-10 was found to decrease post-MBSR, shifting pro-inflammatory profiles to anti-inflammatory ones (Carlson et al., 2002). In addition, there was a decrease in IFN-y from T-cells and decreased Th-1 type cytokines associated with pro-inflammatory effects (Carlson et al., 2002). They also found a three-fold increase in T-cell production of IL-4 cytokines that have an anti-inflammatory effect, suggesting that MBSR is an invaluable and natural intervention for IL-4 therapy (Carlson et al., 2002). However, the findings also suggest that MBSR only works when practised consistently. Long‐term follow‐up six months post-intervention revealed that biological markers tended not to improve (Carlson et al., 2002). The authors also emphasized a link between cytokines and cancer as emulating the pattern of depression and the importance of MBSR for emotional regulation (Carlson et al., 2002).
In 2019, a systematic review from 1985 to 2018, ten reports analyzed MBSR, and the autonomic measures of systolic and diastolic blood pressure associated with increased stress. BP was primarily unchanged during and after most MBSR interventions (Reive 2019). In contrast, a parallel study of MBSR and hypertension between 2012 and 2017 found favourable BP reductions; however, most data had been recorded from clinical office settings, and very few recorded daily-life ambulatory BP (Solano Lopez, 2018). Also, many studies did not rule out co-morbidities or pharmacological treatments that impact BP results. For example, many common medications have an anti-hypertensive effect or, like beta-blockers, change BP readings (Lopez, 2018). A common obstacle was a lack of funding, time, and resources to rule out such variables (Lopez, 2018).
Increased pro-inflammatory cytokines like IL-6, TNF and CRP have also been reported in mild cognitive impairment (MCI), a condition aggravated by chronic stress (Marciniak et al., 2020). MCI is a precursor for dementia that is predicted to double every twenty years and is plausibly a preventable disease (Marciniak et al., 2020). In 2020, Marciniak and colleagues measured subjects with MCI and their immunological profiles and cognitive functioning pre- and post-MBSR intervention. They concluded that MBSR should not be used as a primary cognitive intervention for patients with MCI despite the favourable immunological outcomes and phagocytic activity (Marciniak et al., 2020). Instead, it is implied that MBSR is most useful as a preventative measure or a tool in earlier stages of stress when it may garner a more significant long-term impact.
Many MBSR studies have historically depended on self-report scales, ignoring biological stress markers. Conflating definitions of mindfulness practices have proliferated as its popularity has increased, and many MBSR iterations lack gold standard definitions and methodology (Van Dam et al., 2019). Accuracy in information also depends on the types of mental processes and brain areas stimulated and the monitoring of how it is being taught. For example, focused attention, meta-awareness, and re-perceiving oneself are elements of MBSR that affect specific brain regions connected with neurohormonal or immune system activity. However, a home online phone app versus a group meditation practice may produce critical differences in efficacy and stress response biomarkers, yet both methods are grouped under the umbrella term of mindfulness. Also, questionnaires may lack validity due to social-desirability biases or the conflation of ones' desire to be mindful versus the actual state of mindfulness (Van Dam et al., 2019).
MBSR may also exclude and endanger suicidality and the presence of psychiatric disorders, including schizophrenia and bipolar disorder (Van Dam et al., 2019). Meditation-induced experiences of psychosis, mania and panic have been reported and exacerbated when individuals practise alone (Van Dam et al., 2019). Despite positive shifts in stress biomarkers and increased activity in the parietal cortex documented as an ideal outcome for most, MBSR may aggravate those susceptible to depersonalization, hallucinations, or disassociation. Much like the adverse effects of pharmacotherapy, MBSR also has contraindications that may be overlooked (Van Dam et al., 2019). fMRI techniques and measuring brain region activation may be helpful in current and future MBSR research; however, images from fMRI and errors due to artefacts have also resulted in oversimplification of the stress response and individuals with psychiatric disorders (Van Dam et al., 2019).
A multimodal approach with biomarkers and psychological metrics is the continued way forward for MBSR research by collecting first and third-person data and the assumption that neurobiological and behavioural assessments will continue to improve and inform one another (Van Dam et al., 2019). The error of isolating stress biomarkers like BP, cortisol, cytokine activity, or self-report metrics has unfortunately lessened the impact of research and this helpful intervention. As suggested, MBSR may be most effective if it is adopted early on in school settings with children to mitigate illness and prepare for inevitable life stresses. It may also be prudent to use it as a complementary tool for adults currently suffering from chronic stress rather than as a first-line intervention method where the immediacy of therapy, pharmaceuticals and other clinical interventions may be imminent.
References:
Carlson, L. E., Speca, M., Patel, K. D., & Goodey, E. (2003). Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress, and immune parameters in breast and prostate cancer outpatients. Psychosomatic medicine, 65(4), 571-581.
Danese, A., & McEwen, B. S. (2012). Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiology & behavior, 106(1), 29-39.
Klatt, M. D., Buckworth, J., & Malarkey, W. B. (2009). Effects of low-dose mindfulness-based stress reduction (MBSR-ld) on working adults. Health education & behavior, 36(3), 601-614.
Marciniak, R., Šumec, R., Vyhnálek, M., Bendíčková, K., Lázničková, P., Forte, G., ... & Sheardová, K. (2020). The effect of mindfulness-based stress reduction (MBSR) on depression, cognition, and immunity in mild cognitive impairment: A pilot feasibility study. Clinical Interventions in Aging, 15, 1365.
Matousek, R. H., Dobkin, P. L., & Pruessner, J. (2010). Cortisol as a marker for improvement in mindfulness-based stress reduction. Complementary therapies in clinical practice, 16(1), 13-19.
Nyklíček, Mommersteeg, P. M. C., Van Beugen, S., Ramakers, C., & Van Boxtel, G. J. (2013). Mindfulness-Based Stress Reduction and Physiological Activity During Acute Stress: A Randomized Controlled Trial. Health Psychology, 32(10), 1110–1113. https://doi.org/10.1037/a0032200
Reive, C. (2019). The biological measurements of mindfulness-based stress reduction: a systematic review. Explore, 15(4), 295-307.
Solano Lopez, A. L. (2018). Effectiveness of the mindfulness‐based stress reduction program on blood pressure: a systematic review of literature. Worldviews on Evidence‐Based Nursing, 15(5), 344-352.
Van Dam, N. T., Van Vugt, M. K., Vago, D. R., Schmalzl, L., Saron, C. D., Olendzki, A., ... & Meyer, D. E. (2018). Mind the hype: A critical evaluation and prescriptive agenda for research on mindfulness and meditation. Perspectives on psychological science, 13(1), 36-61.
Wang, X., Sundquist, K., Palmér, K., Hedelius, A., Memon, A. A., & Sundquist, J. (2018). Macrophage migration inhibitory factor and microRNA-451a in response to mindfulness-based therapy or treatment as usual in patients with depression, anxiety, or stress and adjustment disorders. International Journal of Neuropsychopharmacology, 21(6), 513-521.
In 2009, Klatt and colleagues examined the efficacy of low doses of MBSR in fast-paced work environments, using the PSS and MAAS in conjunction with an assay of salivary cortisol. The authors hypothesized that reductions in salivary cortisol would also be reflected in the PSS and MAAS results (Klatt et al.,2009). Adrenocortical activity (when cortisol is released from the adrenal cortex in response to stress) has been cited as a reliable and objective biomarker compared to the criticized biases of metrics like the PSS and MAAS (Matousek et al., 2020). However, Klatt and colleagues critically illuminate that biomarker activity, including cortisol, does not necessarily guarantee similar findings in psychometric test results nor the improvement of symptoms like anxiety and depression (Klatt et al., 2009). Similarly, favourable self-report tests do not reflect an improvement in stress biomarkers outcomes. For example, salivary cortisol during short-bout workplace intervals of MBSR showed minimal change pre- and post-intervention. Despite randomization, there were no changes in average daily salivary cortisol levels in the control group or MBSR group (Klatt et al., 2009). However, the PSS scores showed encouraging results, reflecting a dissonance of biological results and the potential bias of self-reporting. Alternatively, lower doses of MBSR may be ineffective for concurrently shifting psychological and biological markers like cortisol (Klatt et al., 2009).
However, a study of forty-two healthcare professionals receiving a higher dose of the MBSR eight-week intervention revealed a similar outcome. Cortisol was considered an unreliable measurement for chronic stress as it is affected by the body's circadian rhythm (Matousek et al., 2020). Although salivary cortisol is advantageous over serum cortisol as it is non-invasive, the results depend on the subject's monitoring of time. Results can also be altered by food, smoking, caffeine, and exercise (Matousek et al., 2020). Therefore, cortisol in isolation as a biomarker for stress is recommended to be supported with measurements of cytokines, salivary amylase, and other glucocorticoids (Matousek et al., 2020). Salivary amylase, for example, is a secretory immunoglobin known to react more rapidly to stress than cortisol and is considered a more accurate measurement (Matousek et al., 2020). In addition, stress sustained at low levels can also increase cortisol, suggesting that populations experiencing low-grade versions of chronic stress are plausibly missed in MBSR research (Klatt et al., 2009).
Similarly, cytokine pro-inflammatory markers are associated with depression, anxiety and stress, and the macrophage migration inhibitory factor is an example of cytokine activity measured in MBSR research (Wang et al., 2018). Plasma levels of microRNA were measured after an eight-week trial with 168 individuals suffering from depression, anxiety, and stress. The macrophage migration inhibitory factor decreased with MBSR therapy (Wang et al., 2018). However, although inflammation was reduced, not all psychological symptoms of depression and anxiety improved, suggesting that MBSR alone may not suffice as a primary therapeutic intervention (Wang et al., 2018).
MBSR and cytokine activity have also been commonly studied in cases of early cancer diagnoses when stress is at its highest, as it is posited as beneficial for preventing cytotoxicity (Carlson et al., 2002). In 2002, an MBSR study of immune system parameters with breast and prostate cancer used the POMS, a questionnaire containing sixty-five words/statements to assess distinct mood states. Stress scores were used as well as immune cell count and cytokine activity. Post-MBSR, the POMS results correlated to longer disease-free intervals and was one of the first studies to indicate how timing is critical for mitigating early diagnosis stressors and disease proliferation (Carlson et al., 2002). NKC cytotoxicity is one of the most significant indicators of cancerous diseases, and NKC production of IL-10 was found to decrease post-MBSR, shifting pro-inflammatory profiles to anti-inflammatory ones (Carlson et al., 2002). In addition, there was a decrease in IFN-y from T-cells and decreased Th-1 type cytokines associated with pro-inflammatory effects (Carlson et al., 2002). They also found a three-fold increase in T-cell production of IL-4 cytokines that have an anti-inflammatory effect, suggesting that MBSR is an invaluable and natural intervention for IL-4 therapy (Carlson et al., 2002). However, the findings also suggest that MBSR only works when practised consistently. Long‐term follow‐up six months post-intervention revealed that biological markers tended not to improve (Carlson et al., 2002). The authors also emphasized a link between cytokines and cancer as emulating the pattern of depression and the importance of MBSR for emotional regulation (Carlson et al., 2002).
In 2019, a systematic review from 1985 to 2018, ten reports analyzed MBSR, and the autonomic measures of systolic and diastolic blood pressure associated with increased stress. BP was primarily unchanged during and after most MBSR interventions (Reive 2019). In contrast, a parallel study of MBSR and hypertension between 2012 and 2017 found favourable BP reductions; however, most data had been recorded from clinical office settings, and very few recorded daily-life ambulatory BP (Solano Lopez, 2018). Also, many studies did not rule out co-morbidities or pharmacological treatments that impact BP results. For example, many common medications have an anti-hypertensive effect or, like beta-blockers, change BP readings (Lopez, 2018). A common obstacle was a lack of funding, time, and resources to rule out such variables (Lopez, 2018).
Increased pro-inflammatory cytokines like IL-6, TNF and CRP have also been reported in mild cognitive impairment (MCI), a condition aggravated by chronic stress (Marciniak et al., 2020). MCI is a precursor for dementia that is predicted to double every twenty years and is plausibly a preventable disease (Marciniak et al., 2020). In 2020, Marciniak and colleagues measured subjects with MCI and their immunological profiles and cognitive functioning pre- and post-MBSR intervention. They concluded that MBSR should not be used as a primary cognitive intervention for patients with MCI despite the favourable immunological outcomes and phagocytic activity (Marciniak et al., 2020). Instead, it is implied that MBSR is most useful as a preventative measure or a tool in earlier stages of stress when it may garner a more significant long-term impact.
Many MBSR studies have historically depended on self-report scales, ignoring biological stress markers. Conflating definitions of mindfulness practices have proliferated as its popularity has increased, and many MBSR iterations lack gold standard definitions and methodology (Van Dam et al., 2019). Accuracy in information also depends on the types of mental processes and brain areas stimulated and the monitoring of how it is being taught. For example, focused attention, meta-awareness, and re-perceiving oneself are elements of MBSR that affect specific brain regions connected with neurohormonal or immune system activity. However, a home online phone app versus a group meditation practice may produce critical differences in efficacy and stress response biomarkers, yet both methods are grouped under the umbrella term of mindfulness. Also, questionnaires may lack validity due to social-desirability biases or the conflation of ones' desire to be mindful versus the actual state of mindfulness (Van Dam et al., 2019).
MBSR may also exclude and endanger suicidality and the presence of psychiatric disorders, including schizophrenia and bipolar disorder (Van Dam et al., 2019). Meditation-induced experiences of psychosis, mania and panic have been reported and exacerbated when individuals practise alone (Van Dam et al., 2019). Despite positive shifts in stress biomarkers and increased activity in the parietal cortex documented as an ideal outcome for most, MBSR may aggravate those susceptible to depersonalization, hallucinations, or disassociation. Much like the adverse effects of pharmacotherapy, MBSR also has contraindications that may be overlooked (Van Dam et al., 2019). fMRI techniques and measuring brain region activation may be helpful in current and future MBSR research; however, images from fMRI and errors due to artefacts have also resulted in oversimplification of the stress response and individuals with psychiatric disorders (Van Dam et al., 2019).
A multimodal approach with biomarkers and psychological metrics is the continued way forward for MBSR research by collecting first and third-person data and the assumption that neurobiological and behavioural assessments will continue to improve and inform one another (Van Dam et al., 2019). The error of isolating stress biomarkers like BP, cortisol, cytokine activity, or self-report metrics has unfortunately lessened the impact of research and this helpful intervention. As suggested, MBSR may be most effective if it is adopted early on in school settings with children to mitigate illness and prepare for inevitable life stresses. It may also be prudent to use it as a complementary tool for adults currently suffering from chronic stress rather than as a first-line intervention method where the immediacy of therapy, pharmaceuticals and other clinical interventions may be imminent.
References:
Carlson, L. E., Speca, M., Patel, K. D., & Goodey, E. (2003). Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress, and immune parameters in breast and prostate cancer outpatients. Psychosomatic medicine, 65(4), 571-581.
Danese, A., & McEwen, B. S. (2012). Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiology & behavior, 106(1), 29-39.
Klatt, M. D., Buckworth, J., & Malarkey, W. B. (2009). Effects of low-dose mindfulness-based stress reduction (MBSR-ld) on working adults. Health education & behavior, 36(3), 601-614.
Marciniak, R., Šumec, R., Vyhnálek, M., Bendíčková, K., Lázničková, P., Forte, G., ... & Sheardová, K. (2020). The effect of mindfulness-based stress reduction (MBSR) on depression, cognition, and immunity in mild cognitive impairment: A pilot feasibility study. Clinical Interventions in Aging, 15, 1365.
Matousek, R. H., Dobkin, P. L., & Pruessner, J. (2010). Cortisol as a marker for improvement in mindfulness-based stress reduction. Complementary therapies in clinical practice, 16(1), 13-19.
Nyklíček, Mommersteeg, P. M. C., Van Beugen, S., Ramakers, C., & Van Boxtel, G. J. (2013). Mindfulness-Based Stress Reduction and Physiological Activity During Acute Stress: A Randomized Controlled Trial. Health Psychology, 32(10), 1110–1113. https://doi.org/10.1037/a0032200
Reive, C. (2019). The biological measurements of mindfulness-based stress reduction: a systematic review. Explore, 15(4), 295-307.
Solano Lopez, A. L. (2018). Effectiveness of the mindfulness‐based stress reduction program on blood pressure: a systematic review of literature. Worldviews on Evidence‐Based Nursing, 15(5), 344-352.
Van Dam, N. T., Van Vugt, M. K., Vago, D. R., Schmalzl, L., Saron, C. D., Olendzki, A., ... & Meyer, D. E. (2018). Mind the hype: A critical evaluation and prescriptive agenda for research on mindfulness and meditation. Perspectives on psychological science, 13(1), 36-61.
Wang, X., Sundquist, K., Palmér, K., Hedelius, A., Memon, A. A., & Sundquist, J. (2018). Macrophage migration inhibitory factor and microRNA-451a in response to mindfulness-based therapy or treatment as usual in patients with depression, anxiety, or stress and adjustment disorders. International Journal of Neuropsychopharmacology, 21(6), 513-521.
Submitted by Julia McCabe
June 12, 2023
A Critical Evaluation of the statement:
"All aggression is learned."
Submitted by Julia McCabe
Feb 14, 2022
— Student who'd like to remain secret :) 2026
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