A Qualitative Study to Explore the Role of Olfactory Stimulant Plants in Modulating IL-6 in Post-Traumatic Stress Disorder (PTSD) and Traumatic Brain Injury (TBI)

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Samarth Kasaraneni
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Abstract

Background: Numerous research studies have confirmed that there are physical and mental benefits associated with performing therapeutic horticulture (TH) activities1. Studies have proven that therapeutic horticulture interventions successfully improved psychological wellbeing of patients living with PTSD, TBI, substance abuse, and depression2. However, there are no clear studies to show how the special characteristics of certain therapeutic plants initiate the changes in macrophages to modulate elevated IL-6 levels that are associated with PTSD and TBI in patients. The purpose of this study is to investigate the role of olfactory stimulant plants on macrophages in modulating IL-6 in PTSD and TBI induced neuroinflammation.
Method: At a local hospital in Charlotte, North Carolina, we built smell scape gardens and invited 15 patients between the ages of 50 to 85 to spend time with the olfactory and visual stimulant plants. The self-reported survey evaluated the effect of the physiological recovery effects of olfactory, visual, and tactile simulation associated with therapeutic plants on the psychological wellbeing of patients living with posttraumatic stress disorder, substance, alcohol abuse, and depression.
Results: The survey results supported the proposal that therapeutic horticulture (TH) is effective in increasing mental well-being, engagement, and a sense of meaningfulness and accomplishment of participants. All the participants in the focus group reported a reduction in stress and anxiety.
Conclusion: Although this study’s approach to gather qualitative feedback through interviews, limited focus group surveys and conversations was certainly a step in the right direction, no quantitative data gathering was undertaken driven by limitations in accessibility to patient data. To truly validate the impact of olfactory stimulating gardens on macrophages to modulate the elevated IL-6 levels in PTSD and TBI induced neuroinflammation, thorough quantitative research coupled with large scale studies must be conducted.

Introduction

Background & Context

Posttraumatic stress disorder (PTSD) and Traumatic Brain Injury (TBI) are devastating diagnoses which affect millions globally3,4. Nearly 69 million people are diagnosed with TBI around the world5. Interestingly, TBI and PTSD demonstrate high levels of comorbidity6. TBI and PTSD both show notable neuroinflammation and subsequent excitotoxicity, oxidative stress, and morphological changes7. Studies have been conducted to prove the role of elevated IL-6 in neuroinflammation8 ,9 This study focuses on the factors promoting neuroinflammation in PTSD. Given the role of IL-6 in neuroprotection acutely, compared to detrimental chronically, targeting this cytokine at specific time points may be beneficial in modulating neuroinflammation10. Present treatments for TBI or PTSD are variably effective11. Given the role of IL-6 in PTSD, ongoing research is required to establish non pharmaceutical treatments to modulate IL-6 in patients with PTSD, TBI, and other neurological disorders. This research study focuses on the impact of TH intervention in overall psychological well-being in the participating patients.

TBI is defined as a brain injury due to external force12, whereas PTSD is more related to emotional trauma involving intrusive thoughts, avoidant behavior, guilt, and apathy13. Due to the etiology of these diagnoses, however, they frequently occur together. Intriguingly, isolated PTSD and post-TBI patients have similar clinical presentations, with both showing anxiety, irritability, insomnia, and cognitive deficits6. This symptom overlap may be attributable to similar pathophysiology7.

Neuroinflammation in TBI and PTSD

TBI has been shown to increase levels of M1 microglia, which are pro-inflammatory derivations of myeloid precursor cells14,15 These microglia release inflammatory cytokines, including IL-1, IL-6, IL-12, TNF-α, and IFN-γ, which ultimately perpetuate a cyclic proliferation of M1 microglia16,17. While acute neuroinflammation can induce neurogenesis, increase spatial learning, and decrease infection risk, it can become detrimental if prolonged18,19 TBI presents with acute and chronic neuroinflammation20.

Similarly, pro-inflammatory microglia promote neuroinflammation in PTSD21. PTSD-related microglial proliferation, however, can be seen after stressful events, with chronic stressors further amplifying the differentiation of pro-inflammatory microglia22. PTSD also shows BBB damage, like TBI4. TBI and PTSD share many consequences of prolonged neuroinflammation, such as altered synaptic transmission, changes in morphology, and changes to neuronal plasticity23,24

Role of IL-6 in Neuroinflammation

The role of IL-6 in neuroinflammation is variable. However, two cell signaling pathways help to explain the dual-acting impact of IL-625.

In classical signaling, IL-6 binds to the membrane-bound IL-6 receptor (IL-6R) on the surface of target cells. This complex then associates with the signal-transducing receptor subunit gp130, initiating downstream signaling pathways26,27 Classical signaling is generally associated with regenerative and protective responses. It plays a crucial role in immune regulation, hematopoiesis, and tissue regeneration28,29

In trans-signaling, IL-6, as a modulator of inflammation25, binds to a soluble form of the IL-6 receptor (sIL-6R). This IL-6/sIL-6R complex can then interact with gp130 on the surface of cells that do not express IL-6R, thereby initiating signaling in a broader range of cells30.

Neuroinflammatory cells have gp130 but not membrane bound IL-6 receptors and thus require this soluble receptor/IL-6 complex to promote inflammation25. This differential signaling mechanisms offer niche therapeutic possibilities to reduce neuroinflammation. For TBI and PTSD, elevated IL-6 may offer novel treatment options given these findings on IL-6 signaling31.

IL-6 in patients with PTSD

Given the similar neuroinflammatory phenotypes between TBI and PTSD, it is not surprising that IL-6 is also reportedly elevated in PTSD32. In patients with PTSD compared to patients without, there were higher salivary pro-inflammatory cytokines, IL-2, IFN-γ, IL-6, and IL-17, and lower anti-inflammatory cytokines, IL-4 and IL-1033. This continuous hyperactivation may promote chronic inflammation detrimental to patients with PTSD. Health quality of life measurements was also notably decreased for patients with higher levels of IL-6 and PTSD34. Not only do elevations in IL-6 impact the pro-inflammatory cascade seen in PTSD, but it may also cause a plethora of devastating PTSD symptoms. Overall, IL-6 is clearly elevated in PTSD, likely contributing to symptoms and severity.

Treatments Targeting IL-6 for PTSD and TBI

Current treatments for PTSD and TBI are moderately, but inconsistently and incompletely successful. TBI treatment includes rest or surgery (in severe cases)11. While these treatments may be beneficial, they may not rectify the permanent neurological damage resulting from neuroinflammation31. PTSD treatments are broader, including psychological approaches, such as narrative exposure psychotherapy and pharmaceutical approaches, such as SSRIs35.

Underlying neuroinflammation in PTSD and TBI may explain the similarity in symptoms. Furthermore, a common therapeutic target may be capable of mitigating TBI and PTSD symptoms. A therapy to target both PTSD and TBI would be incredibly beneficial due to the comorbidity of these disorders31. A potential target for the neuroinflammatory cascade is IL-6, a cytokine involved in inflammation36. Unfortunately, about half of the patients do not benefit from current treatment modalities. Given IL-6′ s apparent role in the pathology of PTSD and TBI, it is a promising target for non- pharmaceutical methods.

Role of Olfactory Receptors & Macrophages in resolution of inflammation

Olfactory receptors (ORs) were initially described in 1991 by Linda Buck and Richard Axel. In their initial observation, they suggested that this new family of receptors was restricted to the olfactory epithelium (OE) of the nose37. These G-protein-coupled receptors (GPCRs) are activated by volatile chemical compounds also known as odorants38. ORs in humans are proposed to be able to discriminate between anywhere from 10,000 to more than one trillion different smells39. Intriguingly, ORs were found expressed also in macrophages in both mice and humans40 ,41

The olfactory system (in the brain) is closely connected to the limbic system, involving neural regions like the hippocampus, amygdala, and thalamus. Consequently, olfactory perception is also closely tied to emotional and stress processing and smell-related autobiographical memories; associated emotional encodings are also retrieved with stronger activation of the amygdala beyond non-emotional memories or emotional memories associated with other modalities. Consistently, perceived smells that are not actively attended to are also able to evoke emotional responses in individuals42.

Monocytes and macrophages have a highly specialized sensory system of pattern-recognition receptors, GPCRs, and tyrosine kinase receptors43. Among the GPCRs, ORs can “smell” metabolites and allow macrophages to respond to their environment. This response can, among others, mediate the activation of the inflammasome40 that is also highly conserved among vertebrates44

Macrophage origin can be broadly divided into tissue-resident macrophages and monocyte-derived macrophages45. Macrophages can have proinflammatory or anti-inflammatory features, defined often as classical M1 (proinflammatory) or alternative M2 (anti-inflammatory) polarization. During inflammation and damage, derived monocytes can populate the inflamed tissue, generating dendritic cells (DCs) and macrophages that impact the initiation, progression, and resolution of inflammation45.

Objective

Non-pharmaceutical treatments targeting IL-6 in patients suffering from PTSD

Therapeutic Horticulture (TH) has been applied as one of most common non-pharmaceutical intervention to enhance the health of elder people. TH is contacting with nature and associated physical activities such as growing and eating food together and TH has long been several ways to increase mood, improve nutritional status, reduce loneliness, and reduce the physical health impacts of mental illnesses such as post-traumatic stress disorder46

Extensive studies have proven that TH is associated with a reduction in the levels of biomarkers that measure the extent of T-cell exhaustion and inflammation in older adults. The positive effects of TH on T-cell exhaustion were associated with the reduction of IL-6 levels47.

Researchers have found that plant scents stimulate nerves in the brain through the olfactory sulci, inducing the central nervous system and endocrine system to secrete hormones, thereby affecting various physiological reactions42.

As shown in Table 1, all three types of stimulation affected the central nervous system, which can be seen from the ANOVA results for the α and β brainwave amplitudes. The ANOVA results suggest that during exposure to the olfactory, visual and olfactory–visual stimulus modes, the subjects’ alpha and beta brainwave amplitudes exhibited significant increases compared with the control group. Olfactory receptors in macrophages are a rich source of untapped opportunity for modulating inflammation and reducing elevated Il-6 levels associated with PTSD and other neurological disorders45. I hypothesize that special characteristics of certain therapeutic plants could initiate the changes in macrophages to modulate elevated IL-6 levels, and the modulated IL6 levels could potentially improve the wellbeing of patients with neurological problems such as PTSD and TBI.

  P (LSD) 
OVO&V
SCO&V0.004––
C–0.0010.000
α wavesO–0.006–
C0.0090.0000.001
β wavesV0.001–0.006
C0.0100.0000.001
p < 0.01 indicates an extremely significant difference; 0.01 < p < 0.05 indicates a significant difference; p > 0.05 indicates that the difference was not significant. Those not shown were a combination of p > 0.05. O: olfactory stimulation; V: visual stimulation; O&V: olfactory–visual stimulation; C: control; SC: skin conductance.
Table 1: Significance analysis of the influence of different stimulation methods on skin conductance (SC), α waves and β waves 52

Methodology

Therapeutic horticulture (TH) has only been recently introduced at the hospital which I conducted the study at. Under the guidance of a horticultural therapist, sensory gardens have been created with an intent to stimulate senses and create a multisensory healing experience at this hospital. A sensory garden is a garden that stimulates the senses of sight, smell, sound, taste, and touch. The goal of a sensory garden is to encourage visitors to interact with the garden and experience it with all their senses. Given the limited time and restricted access to patient data, self-reported survey was identified as the most appropriate methodology to test the hypothesis that olfactory stimulating plants on macrophages potentially play a significant role in modulating IL-6 in PTSD and TBI induced neuroinflammation. The emphasis of this research was more on personal narrative, interviews, patient feedback, and Horticultural Therapist’s observations.

Preparation and Material

The sensorygarden at the hospital was made possible because of the efforts of several volunteers, including staff, volunteers like myself, and patients – all contributing time, materials, equipment, and services needed to create the garden – a process which occurred over a 12-month period. Through this process of building the sensory garden, the horticultural therapist sought ideas and inspiration as well as practical advice on plant selection from both academic and popular literature. In addition, the horticultural therapist regularly talked with patients about the purpose of the garden to generate interest and involvement.

A couple of locations were identified for the creation of the garden primarily to meet two objectives. First, the garden should provide a positive retreat for patients and visitors. Second, a dedicated space was required where plant selection and therapeutic horticulture (TH) activities can be discussed with the participants. With these two criteria in mind, the open space next to and existing Green House in the hospital was narrowed down as the final location for the sensory garden.

Also, several key features were considered as part of the garden design, including plant selection and equipment selection to be appropriate for the patients suffering with PTSD, TBI, Substance Abuse, and/or depression (see Table 2).

Garden Design: The garden should be an attractive and interesting location for spatial engagement with below key considerations: Garden should encourage physical and passive engagement with the space.Most spaces should be accessible to patients of all abilities.Layer in some potential seating areas (in shady spots) for comfort and to encourage interactions.Different zones for one-to-one and group use by patients, families, and therapist-patient sessions.Raised garden beds at accessible heights for seated gardening. Raising the soil level three feet is a good height for both adult wheelchair users and standing veteran gardenersLevelled pathways (with minimal slope) for easy cane, walker or wheel chair maneuvering.  
Equipment Selection: Below are some equipment and accessories consideration to enable a therapeutic gardening experience for the veterans: Correct table heights for manual and power wheelchair access Appropriate height for chairs and benches to enable patient transfer to and from wheelchairs Light weight, brightly colored tools and watering cans that are inter-changeable, and adjustable to be used by veterans with a wide range of abilities. Hose spigots should 2-3 feet above the ground for ease of access by individuals using a wheelchairRetractable hose that covers entire area. Lever faucet handles are preferred over knob handles as they are easier to turn on and off.
Plant Selection: Overall, the plant palette should help patients narrate interesting stories about their life experiences, bring back beautiful memories, and make sense of current life experiences through optimal olfactory stimulation. Touching plants with unique and soft textures such as Lamb’s ear and Silver sage (Salvia argentea ‘Artemis’).Culinary plants (i.e. Tomatoes, bell peppers, mint, sage, lavender, thyme, zucchini) that provide patients with opportunities to be a part of the entire lifespan of these plants – from sowing seed to growing them in the garden, and then harvesting and eating – triggering a sense of accomplishment.Incorporate plants with bright colors like petunias, sunflowers, and cosmos to energize patients, while blue or white colored flowers like salvia, bluebells, hyacinth, jasmine, and chamomile can de-stress.Ornamental grasses (White Pampas, Pink Muhly, Bunny tail grass) gracefully respond to the breeze and help patients immerse in the gentle sound and texture of these delicate grasses.Plants for tranquility and relaxation such as Bonsai, Pothos, Jade, Wandering Dude, and Succulents.Flowering perennials (Roses, zinnias, lilies, hydrangeas, daisies, ornamental gaura) that not only are a visual treat but also attract bees, humming birds, and butterflies to flock to their nectar-rich blooms.  
Table 2: Key considerations in designing the sensory garden

Participants

In this study, 15 patients between the ages of 50 to 85 were interviewed at the hospital.The patients have been informed of the purpose of this study and have willingly contributed to report on the findings through focus group surveys and interviews. Further, the patients have been assured that confidentiality will be maintained on their personal information and medical conditions. The15 participating patients are geriatric, suffering from PTSD, depression, and alcohol/substance abuse. This assessment was taken after the participants visited the newly designed therapeutic sensory garden for at least once a week consistently over a period of 6 months.

Intervention

The therapeutic horticulture (TH) intervention was designed by the horticultural therapist at the medical center. Patients were directly involved in planting and maintaining the sensory garden. Tasks included planting and raising flowers, herbs, and vegetables from seeding, watering, mulching and weeding. Other horticultural activities such as pruning the Bonsai trees, watering the hanging baskets, and setting up climbing plants by trellis were also included to gauge and enhance patients’ engagement and interest. The patients were then encouraged to spend time at the Substance Abuse Recovery and Rehabilitation Treatment Program (SARRTP) garden to test the impact of olfactory stimulant plants such as White Gaura (Oenothera lindheimeri), Bee balm, and Lavender plants. Tactile stimulant Lamb ears plants were also planted in the garden to allow veterans to touch and feel those plants during the visits to the garden. It is to be noted that the horticultural therapist worked very closely with the participants to explain the various uses of plant species in the sensory gardens. Therefore, patients were fully aware of the smell sources, tactical stimulants and were voluntarily spending time at the garden and participating in the horticulture activities during the process of building the garden and through the study period of 6 months.

Patient interviews, conversations and reflections

As previously mentioned, due to constraints on availability of patient data combined with the exploratory nature of this project, qualitative data collection methods such as patient interviews, surveys, and reflectionswere used to evaluate the impact of sensory gardens as opposed to quantitative analysis. The participants who were involved in the sensory garden implementation and the participants who took part in the weekly sessions were asked to fill in surveys to provide information on why they came to these sessions, what they enjoyed most about the newly created garden(s), how they used this space, and the impact of the TH program on specifically their mental well-being. The horticultural therapist at the hospital also conducted in-depth conversations with the participants during the 6 months program to understand the impact of sensory gardens on stress and anxiety, engagement and participation, mental well-being and social exchange.

Study Results

The study results directly supported the hypothesis that spending time at the newly created sensory garden certainly had positive effects such as increasing mental well-being, engagement, and a sense of meaningfulness and accomplishment as reported by the participants. Many participants reported a reduction in stress and anxiety that allowed them to slow down and enjoy nature, trigger a memory, feel more positive and experience a sense of more balanced state. Intriguingly, the patients who do not like gardens are also the same people who sit indoors and do not seek out a social support. They are reluctant to make a change in their environment and are also the more likely to have repeat admission for the same issues such as drug rehabilitation treatment and other mental disorders.

When reviewing the feedback provided by the 15 participants over the 6-month period, several themes were identified across the interviews, surveys and personal reflections. Table 3 summarizes the survey results by the plant and stimulation type.

One major theme is that the sensory garden provided an opportunity for some patients to feel more capable:

            “I feel a sense of accomplishment from making art with my bonsai plant” (Patient with Depression).

Secondly, the horticultural activities provided an opportunity for new experiences and skills:

              “I have never gardened before, and I am finding that horticulture is fun” (Geriatric Patient).

Third, the smell scape garden(s) triggered old memories and had the patients longing for more:

“My mom has always gardened when I was younger; I feel like this is a great way to honor her memory” (Patient with PTSD).

Fourth, multiple participants reported feeling more hopeful and increased patience levels:

A participant with PTSD was particularly impressed with how simple yet so deeply satisfying it was to grow tomatoes right from the seeding stage and then patiently wait for them to be harvested.

And finally, the sensory garden activated the senses by providing exposure to fresh air, familiar touch, new smells and sunlight:

“I enjoy the outdoors, and I enjoy gardening and the smell of lavender reminds me of my childhood.” (Alcohol abuse patient).

“The gently touch of the Lamb’s ear reminds me of my daughter when she was a baby” (Geriatrics Patient).

PlantStimulationImpactPatient ConditionFrequency of visitObservations
GauraAttracts butterflies and sways in the windAttracts animals, such as butterflies, which the veterans enjoy watchingPTSD1/weekAllowed them to slow down and enjoy nature
Bonsai (Jade)Calming, meditativeTeaches patience, perseverance, and determinationAlcohol abuse, depressionEvery dayPatients keep them in their rooms and watch them grow every. Sense of accomplishment from making art with plants
Bea BalmOlfactory StimulationActivates sense of smell and allows the veterans to enjoy nature, such as bees visiting the plantTBI, Substance abuse1/weekAllowed them to slow down and enjoy nature, trigger a memory and think what other plants may smell like this
TomatoesMemory StimulationMost people have found memories gardening with familyTBI, Depression1/weekSee fruits of their labor, reminiscence about good times growing up with a garden
LavenderOlfactory StimulationActivates sense of smell: known for its ability to help relaxationPTSD1/weekAllowed them to slow down and enjoy nature, trigger a memory what other plants may smell like this
Lamb’s EarTactile StimulationActivate sense of TouchGeriatrics, Depression1/weekAllowed them to slow down and enjoy nature, trigger a memory what other plants or material they resemble in their lives, or something interesting
Succulents (Various species)HardinessRelatednessPTSD, Substance AbuseEvery dayPatients keep them in their rooms and watch them grow every day. Easy to grow, requires little water. Patients can relate to hardiness of plant and the possibility of overcoming an adversity.
Hanging Basket house plants (Pothos, wandering dude)Symbolize: hang in thereRelatednessTBI DepressionEvery dayPatients keep them in their rooms and watch them grow every day. Easy to grow, requires little water. Patients can relate to hardiness of plant and the possibility of overcoming an adversity.
 
Table 3: Summary of survey results by the plant and simulation type

Conclusion

As evidenced by the study results, therapeutic horticultural sensory garden has proven to make a significant positive contribution at the hospital. This review highlights that non-pharmaceutical interventions like therapeutic horticulture (TH) within an acute healthcare setting can improve the health outcomes for patients with psychiatric disorders. In addition, the findings from this review support the possibility that olfactory stimulation through healing gardens could potentially modulate inflammation and reduce elevated IL-6 levels in patients with neurological disorders such as PTSD and TBI.

However, this review is subject to some limitations. Due to constraints on time and data, only a limited pool of 15 patients were enrolled in this study. More patients should be included in future studies to further evaluate the results. Further, this study revealed positive outcomes for the participant pool based only on short-term TH activities. Future large-scale studies need to measure the long-term effects of sensory gardens on physical and mental health of the vulnerable veteran pool.

Furthermore, although this study’s approach to gather qualitative feedback through interviews, limited focus group surveys and conversations was certainly a step in the right direction, no quantitative data gathering was undertaken driven by limitations in accessibility to patient data. To truly validate the impact of olfactory stimulating gardens on macrophages to modulate the elevated IL-6 levels in PTSD and TBI induced neuroinflammation, thorough quantitative research couple with large-scale study must be conducted. It would be valuable to obtain access to participants’ neurological data and then analyze the IL6 levels in those participants both pre- and post- exposure to olfactory stimulation. Determining the connection between olfactory receptors, TH sensory gardens and impact on elevated IL6 levels associated with neurological disorders such as TBI and PTSD would be a great milestone in supporting communities.

Definitions

M1 microglia are a type of activated microglia that are pro-inflammatory and can cause neuronal damage and degeneration. They are one of two main phenotypes of microglia, the other being M2 microglia, which are anti-inflammatory

Myeloid progenitor cells are the precursors of red blood cells, platelets, granulocytes (polymorphonuclear leukocytes [PMNs]: neutrophils, eosinophils, and basophils), monocyte-macrophages, dendritic cells (DCs), and mast cells and osteoclasts.

Neurogenesis is the process by which new neurons are formed in the brain. Neurogenesis is crucial when an embryo is developing, but also continues in certain brain regions after birth and throughout our lifespan

Neuroinflammation is the process by which an organism attempts to remove an injurious stimulus in the central nervous system (CNS) and initiate the healing process to protect the cells and overall function of the brain.

Signaling pathway refers to a series of molecular interactions that occur within the nervous system to transmit signals and regulate various processes

Excitotoxicity This occurs when there is excessive activation of excitatory neurotransmitters, primarily glutamate. High levels of glutamate lead to prolonged activation of glutamate receptors, such as NMDA receptors, resulting in an excessive influx of calcium ions into neurons. This can cause neuronal damage and cell death.

The neuronal damage caused by excitotoxicity can trigger an inflammatory response in the brain. Microglia, the brain’s resident immune cells, become activated and release pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-62. This inflammation can further exacerbate neuronal damage and contribute to a cycle of ongoing neuroinflammation and excitotoxicity.

Oxidative Stress This occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these reactive intermediates or repair the resulting damage. ROS are highly reactive molecules that can damage cellular components, including lipids, proteins, and DNA. The damage caused by oxidative stress can activate microglia and astrocytes, the primary immune cells in the brain. These cells respond by releasing pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, leading to neuroinflammation.

Cytokines are small proteins that play a crucial role in cell signaling, particularly within the immune system. Interleukin-6 (IL-6) is a cytokine, a type of signaling molecule in the immune system, that plays a significant role in the body’s inflammatory response.

Microglial proliferation plays a significant role in the development and progression of post-traumatic stress disorder (PTSD). Studies have shown that microglia are the major brain immune cells responding to PTSD. Their numbers and the ratio of microglia to other immune cells significantly increase following traumatic events.

Blood-brain barrier (BBB) is a crucial protective layer that separates the brain from the bloodstream, maintaining the brain’s delicate environment. Damage to the BBB can have significant implications for brain health

Altered synaptic transmission refers to changes or disruptions in the normal process of communication between neurons. Changes can occur at different stages of synaptic transmission, including neurotransmitter release, receptor binding, and neurotransmitter reuptake or degradation.

Neuronal plasticity, also known as neuroplasticity or brain plasticity, is the brain’s remarkable ability to reorganize itself by forming new neural connections throughout life. In PTSD, neuroplasticity can be altered, leading to persistent changes in how these brain regions communicate. This can result in heightened fear responses, difficulty in distinguishing between past and present threats, and impaired emotional regulation

Glycoprotein 130 (gp130), also known as IL6ST, is a crucial transmembrane protein that acts as a signal transducer for the interleukin-6 (IL-6) family of cytokines. gp130 forms part of the receptor complex for several cytokines, including IL-6, IL-11, IL-27. When IL-6 binds to its receptor (IL-6R), the complex associates with gp130, leading to the formation of a hexametric signaling complex

Biomarker is a measurable substance in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure.

T-cell immunosenescence refers to the gradual deterioration of the immune system associated with aging, particularly affecting T cells. Senescent T cells tend to produce more pro-inflammatory cytokines, contributing to a state of chronic low-grade inflammation.

Macrophages are specialized cells involved in the detection, phagocytosis and destruction of bacteria and other harmful organisms. In addition, they can also present antigens to T cells and initiate inflammation by releasing molecules (known as cytokines) that activate other cells.

Monocytes are a type of white blood cell that play a key role in inflammation and the immune system. Monocytes differentiate into different types of cells depending on the local environment. For example, classical monocytes differentiate into pro-inflammatory macrophages, while non-classical monocytes differentiate into anti-inflammatory macrophages

Pattern recognition receptors (PRRs) are proteins that recognize patterns associated with pathogens or damage. They are part of the innate immune system and play a key role in the initial defense against infections.

G-protein-coupled receptors (GPCRs) are a large family of cell surface proteins that receive and transduce signals from the outside of the cell into physiological effects. They are the largest protein family in the human genome, making up over 3% of human genes. GPCRs are widely expressed in microglia, the resident immune cells of the central nervous system (CNS). Activation of certain GPCRs can regulate microglial responses to injury or disease, influencing the extent of neuroinflammation

α waves and β waves In the Central Nervous System (CNS), alpha waves are associated with a relaxed, resting state, typically occurring when eyes are closed and a person is not actively focusing on a task, while beta waves are linked to active thinking, alertness, and concentration, appearing when someone is actively engaged in a mental activity or under stress)

Tyrosine kinase receptors (TKRs) play a significant role in neuroinflammation, which is a common feature in various neurological disorders. RTKs such as EGFR and c-Abl are implicated in neurodegenerative diseases. Aberrant activity of these kinases can induce neuronal apoptosis and cell cycle arrest, contributing to neuroinflammation and neurodegeneration3.

Olfactory receptors (ORs) are specialized cells in the nose that detect odor molecules and allow us to perceive smell

The olfactory epithelium (OE) is a specialized tissue in the nasal cavity that detects odors and sends the information to the brain

References

  1. Lai, P., Li, C., Hung, S., Lee, A., Chang, C., & Tang, H. (2023). How Do Horticultural Activities Affect Brain Activation and Emotion? Scientific Evidence Based on Functional Connectivity. HortScience, 58(1), 67-78 [↩]
  2. Mottershead R and Ghisoni M. Horticultural therapy, nutrition and post-traumatic stress disorder in post-military veterans: developing non-pharmaceutical interventions to complement existing therapeutic approaches, F1000Research 2021, 10:885 [↩]
  3. S.A. Acosta, N. Tajiri, J. Hoover, Y. Kaneko, C.V. Borlongan, Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke, Stroke 46 (9) (2015) 2616–2627 [↩]
  4. R.C. Kessler, P. Berglund, O. Demler, R. Jin, K.R. Merikangas, E.E. Walters, Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication, Arch. Gen. Psychiatry 62 (6) (2005) 593–602 [↩]
  5. M.C. Dewan, A. Rattani, S. Gupta, et al., Estimating the global incidence of traumatic brain injury, J. Neurosurg. (2018) 1–18, Apr 1 [↩]
  6. J.J. Vasterling, S. Dikmen, Mild traumatic brain injury and posttraumatic stress disorder: clinical and conceptual complexities, J. Int Neuropsychol. Soc. 18 (3) (2012) 390–393 [↩] [↩]
  7. M. Monsour, D. Ebedes, C.V. Borlongan, A review of the pathology and treatment of TBI and PTSD, Exp. Neurol. 351 (2022), 114009 [↩] [↩]
  8. T. Woodcock, M.C. Morganti-Kossmann, The role of markers of inflammation in traumatic brain injury, Front Neurol. 4 (2013) 18 [↩]
  9. C.R. Schindler, T. Lustenberger, M. Woschek, et al., Severe Traumatic Brain Injury (TBI) modulates the kinetic profile of the inflammatory response of markers for neuronal damage, J. Clin. Med 9 (6) (2020). [↩]
  10. Molly Monsour a, Davide Marco Croci b, Siviero Agazzi, The role of IL-6 in TBI and PTSD, a potential therapeutic target? Clinical Neurology and Neurosurgery, Volume 218, July 2022, 107280. [↩]
  11. National Institute of Neurological Disorders and Stroke Traumatic Brain Injury: Hope Through Research [↩] [↩]
  12. M.B. Stein, T.W. McAllister, Exploring the convergence of posttraumatic stress disorder and mild traumatic brain injury, Am. J. Psychiatry 166 (7) (2009) 768–776 [↩]
  13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. vol 5. American Psychiatric Publishing; 2013 [↩]
  14. D. Lozano, G.S. Gonzales-Portillo, S. Acosta, et al., Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities, Neuropsychiatry. Dis. Treat. 11 (2015) 97–106 [↩]
  15. I. Shaked, D. Tchoresh, R. Gersner, et al., Protective autoimmunity: interferon-gamma enables microglia to remove glutamate without evoking inflammatory mediators, J. Neurochem. 92 (5) (2005) 997–1009 [↩]
  16. D.G. Hernandez-Ontiveros, N. Tajiri, S. Acosta, B. Giunta, J. Tan, C.V. Borlongan, Microglia activation as a biomarker for traumatic brain injury, Front Neurol. 4 (2013) 30 [↩]
  17. M. Das, S. Mohapatra, S.S. Mohapatra, New perspectives on central and peripheral immune responses to acute traumatic brain injury, J. Neuroinflamm. 9 (2012) 236 [↩]
  18. Y. Ziv, N. Ron, O. Butovsky, et al., Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood, Nat. Neurosci. 9 (2) (2006) 268–275 [↩]
  19. B. Giunta, D. Obregon, R. Velisetty, P.R. Sanberg, C.V. Borlongan, J. Tan, The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention, J. Neuroinflamm. 9 (2012) 185 [↩]
  20. P. Marcet, N. Santos, C.V. Borlongan, When friend turns foe: central and peripheral neuroinflammation in central nervous system injury, Neuroimmunol. Neuroinflamm. 4 (2017) 82–92 [↩]
  21. S. Sugama, M. Fujita, M. Hashimoto, B. Conti, Stress induced morphological microglial activation in the rodent brain: involvement of interleukin-18, Neuroscience 146 (3) (2007) 1388–1399 [↩]
  22. R.J. Tynan, S. Naicker, M. Hinwood, et al., Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions, Brain Behav. Immun. 24 (7) (2010) 1058–1068 [↩]
  23. G.B. Kaplan, K.A. Leite-Morris, L. Wang, et al., Pathophysiological bases of comorbidity: traumatic brain injury and post-traumatic stress disorder, J. Neurotrauma 35 (2) (2018) 210–225 [↩]
  24. T.D. Fischer, M.J. Hylin, J. Zhao, A.N. Moore, M.N. Waxham, P.K. Dash, P. M. Abdul–Muneer, N. Chandra, J. Haorah, Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury, Mol. Neurobiol. 51 (2015) 966–979 [↩]
  25. M. Rothaug, C. Becker-Pauly, S. Rose-John, The role of interleukin-6 signaling in nervous tissue, Biochim Biophys. Acta 1863 (6 Pt A) (2016) 1218–1227 [↩] [↩] [↩]
  26. M. Hibi, M. Murakami, M. Saito, T. Hirano, T. Taga, T. Kishimoto, Molecular cloning and expression of an IL-6 signal transducer, gp130, Cell 63 (6) (1990) 1149–1157 [↩]
  27. T. Taga, M. Hibi, Y. Hirata, et al., Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130, Cell 58 (3) (1989) 573–581 [↩]
  28. H. Hirota, H. Kiyama, T. Kishimoto, T. Taga, Accelerated Nerve Regeneration in Mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma, J. Exp. Med. 183 (6) (1996) 2627–2634 [↩]
  29. A.J. Chucair-Elliott, C. Conrady, M. Zheng, C.M. Kroll, T.E. Lane, D.J. Carr, Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells, Glia 62 (9) (2014) 1418–1434 [↩]
  30. Baran P, Hansen S, Waetzig GH, Akbarzadeh M, Lamertz L, Huber HJ, Ahmadian MR, Moll JM, Scheller J. The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem. 2018 May 4;293(18):6762-6775 [↩]
  31. Molly Monsour a, Davide Marco Croci b, Siviero Agazzi, The role of IL-6 in TBI and PTSD, a potential therapeutic target? Clinical Neurology and Neurosurgery, Volume 218, July 2022, 107280 [↩] [↩] [↩]
  32. I.C. Passos, M.P. Vasconcelos-Moreno, L.G. Costa, et al., Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression, Lancet Psychiatry 2 (11) (2015) 1002–1012 [↩]
  33. Z. Wang, H. Mandel, C.A. Levingston, M.R.I. Young, An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of Veterans with combat-related PTSD, Hum. Immunol. 77 (8) (2016) 652–657 [↩]
  34. J. Gill, H. Lee, T. Barr, et al., Lower health related quality of life in U.S. military personnel is associated with service-related disorders and inflammation, Psychiatry Res. 216 (1) (2014) 116–122 [↩]
  35. P. Tucker, W.D. Ruwe, B. Masters, et al., Neuroimmune and cortisol changes in selective serotonin reuptake inhibitor and placebo treatment of chronic posttraumatic stress disorder, Biol. Psychiatry 56 (2) (2004) 121–128 [↩]
  36. D.E. Cressman, L.E. Greenbaum, R.A. DeAngelis, et al., Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice, Science 274 (5291) (1996) 1379–1383 [↩]
  37. Buck L, Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell (1991) 65:175–87 [↩]
  38. Buck LB. Olfactory receptors and odor coding in mammals. Nutr Rev (2004) 62:S184–8; discussion S224-41 [↩]
  39. Drew L. Olfactory receptors are not unique to the nose. Nature (2022) 606:S14–7 [↩]
  40. Orecchioni M, Kobiyama K, Winkels H, Ghosheh Y, McArdle S, Mikulski Z, et al. Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production. Science (2022) 375:214–21 [↩] [↩]
  41. Vadevoo SMP, Gunasekaran GR, Lee C, Lee N, Lee J, Chae S, et al. The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc Natl Acad Sci U. S. A. (2021) 118(37): e2102434118. [↩]
  42. Zhang, X.; Guo, J.; Zhang, X.; Zhang, Q. Physiological Effects of a Garden Plant Smellscape from the Perspective of Perceptual Interaction.Int. J. Environ. Res. Public Health 2023,20, 5004 [↩] [↩]
  43. Ley K, Pramod AB, Croft M, Ravichandran KS, Ting JP. How mouse macrophages sense what is going on. Front Immunol (2016) 7:204 [↩]
  44. Maltez VI, Miao EA. Reassessing the evolutionary importance of inflammasomes. J Immunol (2016) 196:956–62 [↩]
  45. Orecchioni Marco, Matsunami Hiroaki, Ley Klaus, Olfactory receptors in macrophages and inflammation, Frontiers in Immunology, Vol=13, year=2022 [↩] [↩] [↩]
  46. Wong GCL, Ng TKS, Lee JL, Lim PY, Chua SKJ, Tan C, Chua M, Tan J, Lee S, Sia A, Ng MKW, Mahendran R, Kua EH, Ho RCM, Larbi A. Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial. J Gerontol A Biol Sci Med Sci. 2021 Jan 18;76(2):307-317. [↩]
  47. Wong GCL, Ng TKS, Lee JL, Lim PY, Chua SKJ, Tan C, Chua M, Tan J, Lee S, Sia A, Ng MKW, Mahendran R, Kua EH, Ho RCM, Larbi A. Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial. J Gerontol A Biol Sci Med Sci. 2021 Jan 18;76(2):307-317 [↩]

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