Introduction

Post-Traumatic Stress Disorder (PTSD) is a prevalent psychiatric condition that can develop following exposure to a traumatic event. While PTSD presents with a wide range of clinical symptoms, it is primarily marked by disruptions in cognition, mood, physical sensations, and behaviour. The disorder can result in long-term dysfunctions, contribute to the development of additional psychiatric conditions, and heighten the risk of suicide (Miao et al., 2018).

PTSD symptoms typically begin within three months of a traumatic event but can emerge later, lasting more than a month for a diagnosis. These fall into several categories: re-experiencing (flashbacks and reliving the trauma), avoidance (steering clear of reminders), arousal and reactivity (feeling on edge, difficulty concentrating or sleeping), and cognition and mood changes (negative thoughts, memory issues, loss of interest) (The National Institute of Mental Health, 2023). Treatments include psychotherapy, especially trauma-focused CBT (Yehuda, 2002), and pharmacotherapy, such as SSRIs or prazosin (Wynn, 2015; Raskind et al., 2013; Schrader and Ross, 2021). Neuromodulation techniques such as ECT and DBS are options for severe or treatment-resistant cases (Youssef, McCall and Andrade, 2017; Langevin et al., 2016; Hamani et al., 2020). Combining therapies and early intervention often leads to better outcomes (Hetrick et al., 2010).

Early-life trauma is defined as subjective early experiences that overwhelm a person’s ability to maintain psychophysical integrity. Traumatic experiences in early life can cause neurobiological changes that alter brain development and cause significant changes in brain function. These changes in brain structures are responsible for cognitive and physical functioning, posing a significant risk factor for physical and mental health development distortion in later life. Furthermore, the effects of early-life trauma can extend into adulthood, influencing emotional regulation, stress responses, and social relationships. Early intervention and therapeutic support can mitigate some of these long-term impacts, promoting better health outcomes.

Early-life trauma has an impact on PTSD and other trauma disorders. Still, as with the majority of psychological illnesses, there is often a disparity in exact causation. To gain more empirical evidence, brain scans and anatomical testing can be used to provide quantitative evidence as to the exact effects of early-life trauma. Some of the regions of the brain found to be involved in PTSD and early-life trauma are the hippocampus, amygdala, and the prefrontal cortex. The connections between these regions are greatly impacted, with apparent changes in the neurochemistry and synaptic connection between neurons (De Klerk, 2006). Neurotransmitters and hormones are also affected, with many studies showing changes in norepinephrine, dopamine, serotonin, and cortisol (Cimesa, 2023).

During childhood, the brain has high neuroplasticity meaning brain development is more sensitive to its environment. Exposure to trauma or neglect can alter the structure and functions of brain areas, leading to difficulties with cognitive and emotional functioning, and increasing the risk of mental health disorders later in life, such as PTSD (Cimesa et al. 2023). Childhood trauma can cause the hippocampus, the learning and memory centre, to develop smaller, leading to the reduced formation and retrieval of memories, and difficulties with the emotive processing of information and memories (Sullivan and Opendak, 2020). Further, traumatic experiences early in life can cause the hypothalamic-pituitary-adrenal (HPA) axis, responsible for the production of cortisol, to be dysregulated, resulting in an excessive and prolonged stress response, which can lead to impaired development of brain regions such as the prefrontal cortex and amygdala, both of which are important for emotional regulation, resulting in increased risk of mental disorders (Perry et al., 1995).

Why do negative or traumatic experiences often persist in an individual’s memory? This research paper will provide insight into this topic by examining the brain’s mechanisms and further identifying how stress in the early stages of an individual’s life affects the brain and increases the risk of developing PTSD.

Early-Life Trauma and the Role in PTSD 

Early-Life Trauma and its Impact

Early-life trauma is the experience of an event, by a child, that is emotionally painful or distressful, often resulting in long-lasting mental and physical effects (Wang et al., 2018).

Traumatic experiences typically take place between ages 0-6, normally impacting brain regions such as the prefrontal cortex, hippocampus, and amygdala (Bremner, 2006). Due to this consequence, the affected child tends to behave abnormally, eventually leading to a diagnosis of PTSD (McLean, 2016).

Trauma is categorised into different types, with interpersonal trauma being the most common. This includes any harmful experiences within a relationship, such as abuse, neglect, violence, and bullying. It can also involve the sudden loss of a parent or caregiver due to events like death, divorce, forced adoption, separation, or imprisonment (Center for Substance Abuse Treatment (US), 2019). In some cases, children may even experience trauma inflicted by caregivers who are themselves struggling with unresolved trauma.

Parental Influence and Intergenerational Trauma

In most cases, caregivers affected by their own trauma do not intend to negatively influence their children; rather, they strive to provide typical parenting. However, due to their own struggles, such as past illnesses, accidents, or substance use, they may find it difficult to bond and connect with their children as in other parent-child relationships (Frosch, Schoppe-Sullivan and O’Banion, 2019). This can lead to misinterpretations of the child’s behaviour and parental difficulties in discussing trauma, which can negatively impact the child and potentially lead to PTSD (Williamson et al., 2016).

Neurobiological Effects of Early Trauma

The long-term effects of such early-life trauma often involve complex neurochemical and biological reactions, varying significantly based on factors such as the severity of the trauma, the closeness of the relationship, the caregiver’s reaction, and the support provided afterwards (Integrative Life Center, 2021). Research, including fMRI scans and childhood trauma questionnaires, has shown that individuals who experienced trauma, particularly related to abuse, often exhibit heightened efficiency in isolated brain regions responsible for visual, auditory, linguistic, and motor functions (Cai et al., 2023). These findings suggest that the relationship between trauma and brain development can increase the risk of psychiatric disorders later in life, underscoring the need for professional intervention to mitigate the chances of developing psychosis (National Institutes of Health, 2023).

Childhood Adversity and Long-Term Psychological Impact

This connection between trauma and brain development is particularly relevant when considering the various types of adversity that can shape vulnerability to PTSD. Adverse experiences range from more common events, such as parental separation and economic instability, to more severe traumas such as sexual assault and child neglect. These different types of adversity can trigger varying stress responses in children, depending on the individual, and contribute to the development of psychiatric disorders later in life (Nelson et al., 2020). However, maladaptive family functioning (MFF) childhood adversities — such as sexual abuse, physical abuse, neglect, and family violence — often have the highest association with trauma. For example, in the World Health Organization Survey, respondents reported a 9.5%, 9.7%, and 10.9% prevalence of exposure to parent psychopathology, family violence, and physical abuse during their childhood, respectively (McLaughlin et al., 2017).

Early adversity can hinder individuals’ behavioural and emotional development; consequences include the risk of developing stress-related psychopathology, negative behavioural consequences, and a dysfunctional cognition about themselves and others (Nelson et al., 2013). Furthermore, individuals who have experienced childhood adversity appear to have low self-esteem, deny the negative impact of the traumatic event, and develop psychiatric disorders (e.g. depression, substance addiction); consequently, the mentally vulnerable state of affected individuals raises the likelihood of PTSD formation (Downey and Crummy, 2022).

These psychological consequences of trauma, particularly PTSD, have been recognised historically, with formal medical recognition beginning during the American Civil War and the Franco-Prussian War. Austrian physician, Josef Leopold, described “nostalgia” in soldiers as marked by sadness, anxiety, and sleep problems, similar to what we now recognise as PTSD. Another model during the Civil War, known as “soldier’s heart”, attributed symptoms like rapid pulse and anxiety to overstimulation of the heart’s nervous system (Kéri, 2022). This idea was supported by European cases of “railway spine”, where railway accident victims displayed similar symptoms (Gasquoine, 2020). By World War I, these symptoms were labelled as “shell shock”, initially thought to result from brain damage caused by explosions. In World War II, the term evolved into “Combat Stress Reaction” (CSR), reflecting a broader understanding of combat’s psychological toll. PTSD then was formally recognised in 1980, influenced by studies of Vietnam War veterans and Holocaust survivors. This recognition extended PTSD’s relevance beyond military contexts, acknowledging its impact on civilians and children who experience trauma (Friedman, 2023). As the understanding of PTSD evolved, it became clear that trauma was not exclusive to combat situations. Studies began to show that PTSD could develop in response to various traumatic events, including those experienced during childhood. This broader understanding led to the recognition that childhood trauma could have long-lasting psychological effects similar to those observed in war veterans. Research into childhood PTSD continues to explore the unique ways in which trauma manifests in younger populations and the importance of early intervention (Bryant, 2019).

However, not everyone exposed to traumatic events develops PTSD. This is often due to a combination of resilience factors and the absence of certain risk factors (Voges and Romney, 2003). Resilience plays a crucial role, with individuals who seek and receive support from friends, family, or support groups being less likely to develop PTSD. Effective coping strategies and the ability to manage fear during stressful situations also contribute to this resilience. Additionally, coming to terms with one’s actions during the traumatic event can help mitigate the impact (Quan et al., 2022).

On the other hand, certain risk factors increase the likelihood of PTSD. These include prior exposure to trauma (particularly in childhood), experiencing injury or witnessing harm or death, and intense feelings of helplessness or extreme fear. A lack of social support, combined with stressors such as the loss of a loved one or home, and a personal or family history of mental illness or substance use, further elevate the risk. Therefore, the interplay between these resilience and risk factors explains why some individuals can endure traumatic events without developing PTSD (The National Institute of Mental Health, 2023).

Early-Life Trauma and Neurodevelopment

Early brain development is never-ending from the embryonic period to the infant and is distinguished by rapid structural and functional growth and changes. The following is a brief overview of brain development from the womb to early adulthood, which shall be immediately followed by more in-depth discussion (see below).

Development begins in the womb, and during the early ages neurons and networks are formed. By the time a child is born, the major brain structures are in place (Psychology Today, 2023). In the Sensorimotor Stage (birth-2 years old) there is an explosive growth in synaptic connections which is responsible for learning basic, and then increasingly complex, skills. This is because the different regions in our brain mature and become more and more specialised, and as we learn, the connections are constantly modified. In the beginning, genes play a significant role in organising the structures in the brain, but as the brain continues to develop, the factors affecting us change (Piaget, 1896–1980). During the first 2-7 years, the Preoperational Stage begins: children begin to use words and symbols, but have difficulty with logical thought processes and comprehending the viewpoints of others. Certain systems in the brain become specialised, creating a foundation for functions such as language, social behaviour and emotions; everything that goes right or wrong during this period of time will have consequences later. The Concrete Operational Stage occurs during the ages of 7-11 years as children develop an awareness of classification and conservation and existing events. The Formal Operational Stage begins at 12 years, with the emergence of advanced problem-solving abilities and abstract reasoning. Brain development reaches a major milestone between the ages of 22-25, by which point most areas are fully matured.

Our brain is adaptable, so not every harmful factor will lead to dysfunction, nor does the brain only need positive experiences to function properly (Piaget, 1950). Childhood trauma is characterised by rapid structural and functional changes, particularly in regions crucial for emotional regulation and stress response. The amygdala, responsible for processing emotions and fear, is particularly sensitive to early trauma. Overactivity in the amygdala due to trauma can lead to heightened fear responses and anxiety, which are common in PTSD (Šimić et al., 2021).

Prenatal Development

The brain undergoes rapid development from the prenatal period through early childhood, a time when it is particularly susceptible to external influences, including trauma. Early-life trauma can have profound and long-lasting effects on brain structure and function, particularly in regions involved in emotional processing, such as the amygdala. The development of the brain begins in the womb and is characterised by several key processes, including neurogenesis, migration, differentiation, and synaptogenesis. Neurogenesis, the formation of neurons, begins around the third week of gestation, with most neurons in place by the end of the second trimester. Following neurogenesis, neurons migrate to their designated locations within the brain and begin to differentiate into specific types, establishing the brain’s foundational architecture. Synaptogenesis, the formation of synapses, starts prenatally and continues into early childhood, playing a crucial role in the development of neural circuits responsible for sensory, motor, and cognitive functions (Stiles and Jernigan, 2010a).

Postnatal Development

After birth, the brain continues to develop rapidly, with significant processes including synaptic pruning and myelination. Synaptic pruning, which peaks between ages 2 and 10, involves the elimination of excess synaptic connections, making neural circuits more efficient. This process is essential for cognitive development, but also represents a period when the brain is highly impressionable and vulnerable to external influences such as trauma (Huttenlocher and Dabholkar, 1997). Myelination, the coating of axons with myelin to speed up neural transmission, continues into adolescence and is critical for efficient brain function. The brain undergoes critical periods during early childhood when it is particularly sensitive to environmental influences. These periods are crucial for acquiring essential skills, such as language and emotional regulation. Trauma during these sensitive periods can have profound impacts on brain development, leading to long-lasting changes in brain structure and function (Knudsen, 2004).

Impact of Early-Life Trauma on the Amygdala

The amygdala is a key structure in the brain’s emotional processing system, responsible for detecting threats and processing emotions such as fear and anxiety. Early-life trauma can lead to increased activity in the amygdala, which is associated with an exaggerated response to stress and a higher likelihood of developing anxiety disorders and PTSD later in life (Tottenham and Sheridan, 2009). This heightened activity indicates that the amygdala becomes more sensitive to negative stimuli, resulting in a hyper-vigilant state characteristic of PTSD. Research has demonstrated that early-life trauma can lead to structural changes in the amygdala, including alterations in its size. For example, studies have shown that children who have experienced severe early-life stress or trauma may exhibit a larger amygdala, correlating with increased anxiety and stress reactivity (Malter Cohen et al., 2013). These structural changes underscore the significant impact that trauma can have on the brain’s development and function.

The amygdala’s dysfunction due to early trauma can impair its ability to regulate emotions, leading to difficulties in controlling fear responses, emotional outbursts, and challenges in forming secure attachments. These emotional regulation issues can persist into adulthood, affecting interpersonal relationships and overall mental health (Teicher, Anderson and Polcari, 2012). The inability to regulate emotions effectively is a hallmark of PTSD and other anxiety-related disorders, highlighting the critical role of the amygdala in these conditions.

Early-life trauma has profound effects on the developing brain, particularly on the amygdala, which plays a crucial role in emotional processing. The brain’s rapid development and high plasticity during the prenatal period and early childhood make it especially vulnerable to external influences. Trauma during these critical periods can lead to heightened activity, structural changes, and dysfunction in the amygdala, contributing to the development of PTSD and other anxiety-related disorders. Understanding these processes is essential for developing interventions that can mitigate the long-term impact of trauma on mental health.

The Role of Neuroplasticity in PTSD

Structural Changes in the Brain Related to PTSD

Neuroplasticity refers to the brain’s ability to adapt to stimuli, a mechanism to repair or rework potential issues in structure and function. This is particularly seen during childhood, as at this time the brain has increased neuroplasticity to develop brain functions and areas important for learning and development (Mateos-Aparicio, 2019). Crucially, this high neuroplasticity means that the developing brain is more sensitive to its environment, so in cases of trauma such as abuse or neglect, plasticity leads to such changes in brain structure and function (known as functional plasticity), ultimately leading to an increased risk of developing PTSD later in life (Cimeša et al., 2023).

Neuroplasticity can be beneficial, such as in the case of restoring function after a brain injury; however, prolonged toxic stress from traumatic or adverse childhood experiences can cause neuroplasticity to be maladaptive, leading to negative effects (i.e. smaller brain areas such as the hippocampus and dysregulated systems such as the HPA axis). Neuroplasticity is multifaceted and its levels vary from synaptic and molecular to global neuronal network changes (Howell, 2024).

Synaptic plasticity is thought to be the underlying basis of learning and memory, and refers to the changes that take place at the synapse as a result of synaptic activity (Mahan and Ressler, 2011). Dysfunctional or maladaptive synaptic plasticity (when synaptic connections in the brain produce negative symptoms) may help explain how individuals with PTSD have impaired emotional regulation and stress responses. People suffering from PTSD have been found to have synaptic loss in the prefrontal cortex (Appelbaum et al., 2022) suggesting that the changes to brain areas are related to dysfunctional synaptic connections. Negative childhood experiences imprint, which may disturb neural pathways in the brain, and prolonged or repetitive stimulation of these pathways can exacerbate the harmful effects on the brain and their resulting symptoms, due to the synaptic connections being reinforced and strengthened (Schiraldi, 2022).

While neuroplasticity may be affected by childhood trauma leading to negative changes within the brain and its neural pathways, it can also be a useful tool for recovering from childhood trauma as patients in therapy may combat PTSD symptoms through rewiring of the brain by making new positive connections (Lovering, 2022).

Due to neuroplasticity, specific regions of the brain have been correlated with certain functions, a concept that has been backed by research for years. However, some of these regions are impacted or changed in response to early-life stress or trauma, which may lead to the development of PTSD. One such region of the brain is the prefrontal cortex, a region associated with higher-order thinking, impulse control, and emotional regulation. Studies found that there was decreased grey matter volume in the region following early childhood trauma (Bengeman, 2023). Another region associated with emotional regulation is the amygdala. In a magnetic resonance imaging (MRI) study of 137 subjects, researchers reported a potential dysregulation between the relationship of the orbitofrontal cortex and the amygdala. They found that subjects who reported childhood trauma had an imbalanced relationship between two regions: a reduction in orbitofrontal cortex volume and an increase in amygdala volume (Bounoua, 2020). The hippocampus, which is involved in memory, also has been reported to have been affected by childhood trauma. In a 2002 study on hippocampal volume, researchers contrasted MRIs from subjects who experienced trauma early in life compared to those who reported no trauma, and found a significant reduction in hippocampal volume in those who reported trauma (Vythilingam, 2002).

There are some treatment options available for those with PTSD or a change to their neuroanatomy. Firstly, there is an abundance of trauma-focused therapy options: cognitive processing therapy (CPT), eye movement desensitisation and restructuring (EMDR), written and narrative exposure therapy, and prolonged exposure therapy (Schrader, 2021). There are also many pharmacological treatments available aimed to particularly target neurochemistry changes or imbalances seen in those with PTSD or early childhood trauma. Most of the approved medications are SNRIs or SSRIs, like fluoxetine, paroxetine, sertraline, and venlafaxine (Schrader, 2021). These medications target symptoms of PTSD. One experimental treatment option is surgical treatment; some researchers have proposed ablation of the unilateral side of the amygdala. This seems to yield a reduction of certain PTSD symptoms like flashbacks. However, some risks have been established with this potential treatment, like changes in memory and emotional control (Teye-Botchway, 2023).

Neurochemical Changes in PTSD

As well as regional structure, the brain’s neurochemistry, and the chemical processes that occur in the nervous system, have been found to be altered during early-life trauma, leading to long-lasting defects that relate to those found in PTSD.

Neurotransmitters, the chemical messengers that allow for synaptic communication, have been shown to have varying levels during early-life trauma (Sheffler, 2023). Norepinephrine is a key neurotransmitter responsible for the body’s “fight-or-flight” response. During and after trauma or traumatic stress, norepinephrine levels increase, leading to a surplus of the neurotransmitters being produced; increased urinary and plasma levels of norepinephrine have been found, as well as an overactivation of the norepinephrine system (Geracioti et al. 2001). This over-stimulates the stress response, resulting in PTSD symptoms such as anxiety and hypervigilance (Hendrickson et al., 2018). This increase in norepinephrine levels found post-trauma suggests that early-life trauma is an evident cause of PTSD. To combat this, prazosin helps to block alpha-1 adrenoreceptors in the brain, which in turn decreases the ability for it to receive norepinephrine. This decreases the overactivity in the sympathetic nervous system, helping to reduce PTSD-related symptoms.

On the other hand, serotonin, a neurotransmitter responsible for mood regulation, is typically reduced in people with PTSD due to early-life trauma. It is found that individuals who are genetically more susceptible to stress (and so vulnerable to PTSD) had significantly lower serum serotonin levels compared to those who were not, signifying a correlation between reduced serotonin levels and PTSD (Ogłodek 2022). The reduction results in the overactivation of the HPA axis, causing an exaggerated response to stress and reduced emotional control. This is contradictory to the levels of serotonin found during trauma, where it is found elevated in many brain regions. However, the conditions during these elevated levels are described as “acute stress”, so may not be comparable to the more abusive environments associated with early-life trauma (Oglodrek, 2022). This can be treated via the use of antidepressant drugs sertraline (SSRI), paroxetine (SSRI), and venlafaxine (NSRI). They work by blocking the reuptake of serotonin into the presynaptic neuron, increasing the availability of serotonin in the synaptic cleft. This balances out the lowered serotonin levels. which helps improve mood and reduce anxiety.

Similarly, gamma-aminobutyric acid (GABA), responsible for the control over neural excitability, is also typically found in reduced levels in individuals with PTSD. This is because stress from trauma can suppress the expression of GABA receptors, reducing GABAergic activity in the brain. As the brain’s primary inhibitory neurotransmitter, this decrease in GABAergic activity causes insufficient inhibition control, which consequently results in many stress-related problems and PTSD symptoms such as insomnia and depression (Huang et al. 2023). Rate studies also provided evidence that GABA is decreased in adult rats that were exposed to shocked stress conditions in childhood, proving this relationship (Huang et al, 2023). GABA receptor function may be restored using medications gabapentinoids and muscimol.

Comparably, dopamine is a neurotransmitter that regulates moods, motivation, and reward systems. The role of dopamine in PTSD is complex: on the one hand, increased urinary and plasma levels of dopamine are found in individuals who suffered traumatic stress, and a significant positive correlation is recorded between dopamine levels and the severity of PTSD (Hamner et al. 1993). Elevated dopamine levels create a heightened state of arousal, leading to hypervigilance and anxiousness often seen in PTSD. However, low dopamine function has been associated with an increased risk for PTSD. In a study by Blum et al. (2012), veterans with genetic predispositions of reduced dopamine production or receptor functions are more prone to PTSD, highlighting a conflicting negative correlation between dopamine levels and PTSD symptoms. This reduced dopamine function impairs the brain’s reward system, making it harder to experience pleasure and motivation, hence leading to potential deficits such as depression and anhedonia. Dopamine may be regulated using aripiprazole, which balances out dopamine levels and reduces mood swings associated with the fluctuation in dopamine levels.

Hormonal patterns as well as neurotransmission have been found and linked closely to those used as diagnostic markers of PTSD. A study on hormone levels of adolescent rats who had experienced early-life trauma, such as a lack of maternal care, found decreased activity in the peripheral T3 thyroid hormone, one associated with decreased metabolic rate. These findings were later conducted within a case study format on 80 adolescent volunteers, finding that the amount of T4 hormone converted into T3 decreased with increasing reports of physical childhood abuse (Machado et al 2015). This has changed the ratios of T3:T4 hormone by 42%. Similar results were shown in other forms of abuse that occurred in childhood, with sexual assault victims showing decreased T3 ratios and decreased levels of thyroid-stimulating hormone (Friedman 2005). These changes in hormone levels alter the function of the HPA axis, leading to an increased stress response. A meta-analysis showed that this stress response also led to an increase in cortisol levels, with a 60% increase in levels in those who had experienced trauma. However, there has been inconsistent data with varying conclusions on the effect that childhood trauma has on cortisol levels. Saliva tests have shown decreased plasma cortisol and ACTH in acute PTSD, regardless of the source of trauma (Shalev et al 2008).

Brain-derived neurotrophic factor (BDNF) has also shown an association with PTSD, with an overexpression of the hormone found in the hippocampus in those experiencing a stress response who have previously been in stressful conditions. This increased BDNF has been shown to alter the hippocampus volume, increasing the likelihood of memory change and PTSD (Zhang, 2016). However, a decreased secretion of BDNF has been shown after early-life trauma, suggesting that BDNF levels may not provide a direct linkage between early-life trauma and PTSD development.

This malfunctioning of the HPA axis has been shown to increase the likelihood of PTSD in later life, with PTSD patients showing abnormally low levels of plasma cortisol. This connection between the hormonal effects of childhood trauma and those found in PTSD suggests an increased susceptibility to the disorder in those who have experienced early-life stressors.

The alteration of hormone levels within the brain during PTSD has been used as a graph for its possible treatment options. Base substances such as soy proteins have been used as carriers for hormone-based medication, such as the FSWW08 (used in clinical trials), and have been shown to increase the levels of testosterone and cortisol, with decreased levels of cholesterol. These changes were shown to reduce the mental-related symptoms of PTSD volunteer patients, including those who had been resistant to other treatment options (Gocan et al., 2011). This research leads to the promising possibility of hormone treatments being used outside of the trial setting for PTSD in the future.

These neurochemical changes relate to the overall alteration of the brain function and chemistry associated with PTSD, due to the brain’s neuroplasticity. The impact of early trauma prevents the development of the connection and transmission of information throughout the brain and body.

Discussion

Early-life trauma can cause a predisposition for traumatic disorders such as PTSD. There is clear evidence from twin studies, post-war intervention, and empirical data of changing brain structure and neurotransmission levels. However, it is unclear throughout the research where certain lines are drawn when it comes to defining early-life trauma and stress, perhaps creating a more correlational relationship between early-life events and the later development of PTSD.

Trauma has been divided into categories, which have been earlier described. Whilst this helps to define the exact events a person has gone through, it does not investigate the severity of a person’s trauma. This variable would have a great effect on the development of a post-traumatic disorder or illness. As previously stated, “the impact of early-life trauma in the long-term largely differs depending on the severity”, yet there is little evidence in the literature that shows the scale of trauma that has been investigated.

This issue still prevails in anatomical evidence, as contradicting results of neurotransmitter levels are found in case studies that use differing severity. Studies found different levels of serotonin in those experiencing PTSD compared with those who have experienced early-life trauma, a factor not commonly found when looking into other neurotransmitter or hormone levels (Oglodrek, 2022). The study describes the early-life traumas of the patients investigated within the study as “acute stress” suggesting minor severity. Despite defining the trauma of these individuals, the experiences of those diagnosed with PTSD were not explained, leaving it unclear as to whether these two groups that have been compared are related in terms of the traumas they have experienced, or whether they are simply correlational factors that are independent of one another.

There is also little evidence as to whether the kind of trauma someone experiences affects the later development of PTSD. It is clear from the research that was conducted that all known kinds of early-life trauma increase the likelihood of PTSD being developed in later life, due to varying psychological and physiological changes. However, the extent to which this likelihood is increased is not apparent in studies, nor is the kind of PTSD that may develop. The five main types of PTSD are not clearly defined in research, which leads to a lack of accuracy in the conclusions of many of these research papers. There is also a possibility that what presents as PTSD in some volunteers may be experiencing “normal reactions to abnormal circumstances”, rather than a diagnosable condition (Rockville, 2014).

Despite a certain lack of clarity within some of the research performed, the clear applicable use of the research in the treatment of PTSD provides validity to the literature that has been reviewed. Post-war studies have been used to create new therapies and preventative care for those going into war situations. Strategies such as critical incident stress management (CISM) and psychological debriefing (PD) have been recently implemented in the aftermath of conflict. This rapid therapy aims to prevent desensitisation or dissociation from an event, reducing the development of PTSD. The treatment has had much success after events such as the Afghanistan War and the Coconut Grove fires in Boston, “facilitating the early detection and treatment of post-trauma reactions and other psychological sequelae” (Regel, 2007).

Furthermore, perceiving PTSD as the cause of change in the brain’s neuroplasticity has allowed for further development in treatment options, not just for PTSD but also other trauma-related disorders. For example, the changes in the brain’s anatomy, such as changes in hippocampal volume, can be again altered using deep brain stimulation, which has shown promising effects in clinical practice in attempts to reduce the symptoms of PTSD. Although this has not yet been applied in full, accessible practice, preclinical data indicate that high-frequency stimulation delivered at specific time frames to various targets, including the amygdala, ventral striatum, hippocampus and prefrontal cortex, can enhance fear extinction and anxiety-like behaviours in rodents (Reznikov, 2017).

This changing view of PTSD has clearly allowed for great development in the treatments available for the disorder. However, an ethical debate within the research and new treatment options is posed. Much of the research investigating PTSD is done on animals, and although under regulated conditions, questions may still be asked as to its necessity. With new genetic findings regarding the factors of predisposition of PTSD, another ethical dilemma arises, as there is a question of the implementation of genetic screening within this aspect of the psychological field. The main point of debate is whether the somewhat clouded research is enough to support a counteracting argument against these newly found ethical challenges.

Acheson, D.T., Gresack, J.E. and Risbrough, V.B. (2012). Hippocampal Dysfunction Effects on Context memory: Possible Etiology for Posttraumatic Stress Disorder. Neuropharmacology, 62(2), pp.674–685. doi:https://doi.org/10.1016/j.neuropharm.2011.04.029.

Appelbaum, L.G., Shenasa, M.A., Stolz, L. and Daskalakis, Z. (2022). Synaptic plasticity and mental health: methods, challenges and opportunities. Neuropsychopharmacology, [online] 48(1), pp.1–8. doi:https://doi.org/10.1038/s41386-022-01370-w.

Arnsten, A.F.T. (2009). Stress Signalling Pathways That Impair Prefrontal Cortex Structure and Function. Nature Reviews Neuroscience, [online] 10(6), pp.410–422. doi:https://doi.org/10.1038/nrn2648.

Begemann, M.J.H., Schutte, M.J.L., Dellen, E. van, Abramovic, L., Boks, M.P., Haren, N.E.M. van, Mandl, R.C.W., Vinkers, C.H., Bohlken, M.M. and Sommer, I.E.C. (2021). Childhood trauma is associated with reduced frontal gray matter volume: a large transdiagnostic structural MRI study. Psychological Medicine, [online] 53(3), pp.1–9. doi:https://doi.org/10.1017/S0033291721002087.

Blue Knot (2021). What is Childhood Trauma? [online] Blue Knot Foundation. Available at: https://blueknot.org.au/resources/understanding-trauma-and-abuse/what-is-childhood-trauma/.

Blum, K. (2012). Diagnosis and Healing In Veterans Suspected of Suffering from Post- Traumatic Stress Disorder (PTSD) Using Reward Gene Testing and Reward Circuitry Natural Dopaminergic Activation. Journal of Genetic Syndromes & Gene Therapy, 03(04). doi:https://doi.org/10.4172/2157-7412.1000116.

Bounoua, N., Miglin, R., Spielberg, J.M., Johnson, C.L. and Sadeh, N. (2020). Childhood trauma moderates morphometric associations between orbitofrontal cortex and amygdala: implications for pathological personality traits. Psychological Medicine, 52(13), pp.1–10. doi:https://doi.org/10.1017/s0033291720004468.

Bremner, J.D. (2006). Traumatic stress: Effects on the Brain. Dialogues in Clinical Neuroscience, [online] 8(4), pp.445–61. doi:https://doi.org/10.31887/DCNS.2006.8.4/jbremner.

Bryant, R.A. (2019). Post‐traumatic stress disorder: a state‐of‐the‐art review of evidence and challenges. World Psychiatry, [online] 18(3), pp.259–269. doi:https://doi.org/10.1002/wps.20656.

Cai, J., Li, J., Liu, D., Gao, S., Zhao, Y., Zhang, J. and Liu, Q. (2023). Long‐term Effects of Childhood Trauma Subtypes on Adult Brain Function. Brain and Behavior, [online] 13(5). doi:https://doi.org/10.1002/brb3.2981.

Center for Substance Abuse Treatment (US) (2019). Trauma-Informed Care in Behavioral Health Services. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK207192/.

Downey, C. and Crummy, A. (2021). The Impact of Childhood Trauma on children’s Welbeing and Adult Behavior. European Journal of Trauma & Dissociation, 6(1), pp.1–8. doi:https://doi.org/10.1016/j.ejtd.2021.100237.

Finkelhor, D., Turner, H.A., Shattuck, A. and Hamby, S.L. (2013). Violence, crime, and Abuse Exposure in a National Sample of Children and youth: an Update. JAMA Pediatrics, [online] 167(7), pp.614–21. doi:https://doi.org/10.1001/jamapediatrics.2013.42.

Friedman, M. (2023). History of PTSD in Veterans: Civil War to DSM-5 – PTSD: National Center for PTSD. [online] Va.gov. Available at: https://www.ptsd.va.gov/understand/what/history_ptsd.asp.

Frosch, C.A., Schoppe-Sullivan, S.J. and O’Banion, D.D. (2019). Parenting and Child development: a Relational Health Perspective. American Journal of Lifestyle Medicine, [online] 15(1), pp.45–59. doi:https://doi.org/10.1177/1559827619849028.

Gasquoine, P.G. (2020). Railway spine: The advent of compensation for concussive symptoms. Journal of the History of the Neurosciences, 29(2), pp.234–245. doi:https://doi.org/10.1080/0964704x.2019.1711350.

Geracioti, T.D., Baker, D.G., Ekhator, N.N., West, S.A., Hill, K.K., Bruce, A.B., Schmidt, D., Rounds-Kugler, B., Yehuda, R., Keck, P.E. and Kasckow, J.W. (2001). CSF Norepinephrine Concentrations in Posttraumatic Stress Disorder. American Journal of Psychiatry, 158(8), pp.1227–1230. doi:https://doi.org/10.1176/appi.ajp.158.8.1227.

Hamani, C., Davidson, B., Levitt, A., Meng, Y., Corchs, F., Abrahao, A., Rabin, J.S., Giacobbe, P. and Lipsman, N. (2020). Patient With Posttraumatic Stress Disorder Successfully Treated With Deep Brain Stimulation of the Medial Prefrontal Cortex and Uncinate Fasciculus. Biological Psychiatry, [online] 88(11), pp.e57–e59. doi:https://doi.org/10.1016/j.biopsych.2020.05.018.

Hamner, M.B. and Diamond, B.I. (1993). Elevated plasma dopamine in posttraumatic stress disorder: A preliminary report. Biological Psychiatry, 33(4), pp.304–306. doi:https://doi.org/10.1016/0006-3223(93)90302-t.

Herringa, R.J. (2017). Trauma, PTSD, and the Developing Brain. Current Psychiatry Reports, [online] 19(10). doi:https://doi.org/10.1007/s11920-017-0825-3.

Hetrick, S.E., Purcell, R., Garner, B. and Parslow, R. (2010). Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD). Cochrane Database of Systematic Reviews, (7). doi:https://doi.org/10.1002/14651858.cd007316.pub2.

Howell, S.N. (2024). Neuroplasticity After Brain Injury: Principles and Methods for Postinjury Improvement. [online] https://www.psychiatrictimes.com/. Available at: https://www.psychiatrictimes.com/view/neuroplasticity-after-brain-injury-principles-and-methods-for-postinjury-improvement [Accessed 23 Aug. 2024].

Huang, J., Xu, F., Yang, L., Tuolihong, L., Wang, X., Du, Z., Zhang, Y., Yin, X., Li, Y., Lu, K. and Wang, W. (2023). Involvement of the GABAergic system in PTSD and its therapeutic significance. Frontiers in Molecular Neuroscience, 16. doi:https://doi.org/10.3389/fnmol.2023.1052288.

Hughes, K., Bellis, M.A., Hardcastle, K.A., Sethi, D., Butchart, A., Mikton, C., Jones, L. and Dunne, M.P. (2017). The Effect of Multiple Adverse Childhood Experiences on health: a Systematic Review and meta-analysis. The Lancet Public Health, 2(8), pp.356–366.

Huttenlocher, P.R. and Dabholkar, A.S. (1997). Regional differences in synaptogenesis in human cerebral cortex. The Journal of Comparative Neurology, 387(2), pp.167–178. doi:https://doi.org/10.1002/(sici)1096-9861(19971020)387:2%3C167::aid-cne1%3E3.0.co;2-z.

Johnson, S.B., Blum, R.W. and Giedd, J.N. (2019). Adolescent Maturity and the brain: the Promise and Pitfalls of Neuroscience Research in Adolescent Health Policy. Journal of Adolescent Health, [online] 45(3), pp.216–221. doi:https://doi.org/10.1016/j.jadohealth.2009.05.016.

Kéri, S. (2022). Trauma and Remembering: From Neuronal Circuits to Molecules. Life, 12(11), p.1707. doi:https://doi.org/10.3390/life12111707.

Knudsen, E.I. (2004). Sensitive Periods in the Development of the Brain and Behavior. Journal of Cognitive Neuroscience, 16(8), pp.1412–1425. doi:https://doi.org/10.1162/0898929042304796.

Laderer, A. (2023). This Is What PTSD From Childhood Abuse in Adults Looks Like. [online] Charlie Health. Available at: https://www.charliehealth.com/post/ptsd-from-childhood-abuse-in-adults#:~:text=Childhood%20trauma%20can%20also%20impact.

Langevin, J.-P., Koek, R.J., Schwartz, H.N., Chen, J.W.Y., Sultzer, D.L., Mandelkern, M.A., Kulick, A.D. and Krahl, S.E. (2016). Deep Brain Stimulation of the Basolateral Amygdala for Treatment-Refractory Posttraumatic Stress Disorder. Biological Psychiatry, 79(10), pp.e82–e84. doi:https://doi.org/10.1016/j.biopsych.2015.09.003.

Lovering, N. (2022). Neuroplasticity and Childhood Trauma: Effects, Healing, and EMDR. [online] Psych Central. Available at: https://psychcentral.com/ptsd/the-roles-neuroplasticity-and-emdr-play-in-healing-from-childhood-trauma [Accessed 23 Aug. 2024].

Mahan, A.L. and Ressler, K.J. (2011). Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends in Neurosciences, 35(1), pp.24–35. doi:https://doi.org/10.1016/j.tins.2011.06.007.

Malter Cohen, M., Jing, D., Yang, R.R., Tottenham, N., Lee, F.S. and Casey, B.J. (2013). Early-life stress has persistent effects on amygdala function and development in mice and humans. Proceedings of the National Academy of Sciences, [online] 110(45), pp.18274–18278. doi:https://doi.org/10.1073/pnas.1310163110.

Mateos-Aparicio, P., & Rodríguez-Moreno, A. (2019). The Impact of Studying Brain Plasticity. Frontiers in cellular neuroscience, 13, 66. https://doi.org/10.3389/fncel.2019.00066

McLaughlin, K.A., Koenen, K.C., Bromet, E.J., Karam, E.G., Liu, H., Petukhova, M., Ruscio, A.M., Sampson, N.A., Stein, D.J., Aguilar-Gaxiola, S., Alonso, J., Borges, G., Demyttenaere, K., Dinolova, R.V., Ferry, F., Florescu, S., de Girolamo, G., Gureje, O., Kawakami, N. and Lee, S. (2017). Childhood Adversities and post-traumatic Stress disorder: Evidence for Stress Sensitisation in the World Mental Health Surveys. British Journal of Psychiatry, [online] 211(5), pp.280–288. doi:https://doi.org/10.1192/bjp.bp.116.197640.

McLean, S. (2016). The Effect of Trauma on the Brain Development of Children | Australian Institute of Family Studies. [online] aifs.gov.au. Available at: https://aifs.gov.au/resources/practice-guides/effect-trauma-brain-development-children.

Miao, X.-R., Chen, Q.-B., Wei, K., Tao, K.-M. and Lu, Z.-J. (2018). Posttraumatic stress disorder: from diagnosis to prevention. Military Medical Research, [online] 5(1), pp.1–7. doi:https://doi.org/10.1186/s40779-018-0179-0.

Mladen, C., Sokić, A. and Cimeša, B.M. (2023). Childhood Trauma and its Effect on Brain Development: Neurobiological Mechanisms and Implications. [online] ResearchGate. Available at: https://www.researchgate.net/publication/370490619_Childhood_Trauma_and_its_Effect_on_Brain_Development_Neurobiological_Mechanisms_and_Implications [Accessed 17 Aug. 2024].

Nair, J. and Ajit, S.S. (2008). The Role of the Glutamatergic System in Posttraumatic Stress Disorder. CNS Spectrums, 13(07), pp.585–591. doi:https://doi.org/10.1017/s1092852900016862.

Nelson, C.A., Bhutta, Z.A., Burke Harris, N., Danese, A. and Samara, M. (2020). Adversity in Childhood Is Linked to Mental and Physical Health Throughout Life. The BMJ, [online] 371(371). doi:https://doi.org/10.1136/bmj.m3048.

Ogłodek, E.A. (2022a). Changes in the Serum Concentration Levels of Serotonin, Tryptophan and Cortisol among Stress-Resilient and Stress-Susceptible Individuals after Experiencing Traumatic Stress. International Journal of Environmental Research and Public Health, [online] 19(24), p.16517. doi:https://doi.org/10.3390/ijerph192416517.

Ogłodek, E.A. (2022b). Changes in the Serum Concentration Levels of Serotonin, Tryptophan and Cortisol among Stress-Resilient and Stress-Susceptible Individuals after Experiencing Traumatic Stress. International Journal of Environmental Research and Public Health, [online] 19(24), p.16517. doi:https://doi.org/10.3390/ijerph192416517.

Pearce, J., Murray, C. and Larkin, W. (2019). Childhood Adversity and trauma: Experiences of Professionals Trained to Routinely Enquire about Childhood Adversity. Heliyon, 5(7), p.e01900. doi:https://doi.org/10.1016/j.heliyon.2019.e01900.

Quan, L., Lü, B., Sun, J., Zhao, X. and Sang, Q. (2022). The Relationship between Childhood Trauma and post-traumatic Growth among College students: the Role of Acceptance and Positive Reappraisal. Frontiers in Psychology, 13. doi:https://doi.org/10.3389/fpsyg.2022.921362.

Rakofsky, J.J., Ressler, K.J. and Dunlop, B.W. (2011). BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity. Molecular Psychiatry, 17(1), pp.22–35. doi:https://doi.org/10.1038/mp.2011.121.

Raskind, M.A., Peterson, K., Williams, T., Hoff, D.J., Hart, K., Holmes, H., Homas, D., Hill, J., Daniels, C., Calohan, J., Millard, S.P., Rohde, K., O’Connell, J., Pritzl, D., Feiszli, K., Petrie, E.C., Gross, C., Mayer, C.L., Freed, M.C. and Engel, C. (2013). A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. The American journal of psychiatry, [online] 170(9), pp.1003–10. doi:https://doi.org/10.1176/appi.ajp.2013.12081133.

Regel, S. (2007). Post-trauma support in the workplace: the current status and practice of critical incident stress management (CISM) and psychological debriefing (PD) within organizations in the UK. Occupational Medicine, 57(6), pp.411–416. doi:https://doi.org/10.1093/occmed/kqm071.

Schechter, D.S., Kaminer, T., Grienenberger, J.F. and Amat, J. (2003). Fits and Starts: A Mother-Infant Case-Study Involving Intergenerational Violent Trauma and Pseudoseizures Across Three Generations. Infant mental health journal, [online] 24(5), pp.510–528. doi:https://doi.org/10.1002/imhj.10070.

Schiraldi, G.R. (2022). Adverse Childhood Experiences, Neuroplasticity, and Imagery. [online] Psychology Today. Available at: https://www.psychologytoday.com/gb/blog/hidden-wounds/202204/adverse-childhood-experiences-neuroplasticity-and-imagery?amp [Accessed 24 Aug. 2024].

Schrader, C. and Ross, A. (2021). A Review of PTSD and Current Treatment Strategies. Missouri Medicine, [online] 118(6), pp.546–551. Available at: https://pubmed.ncbi.nlm.nih.gov/34924624/.

Shalev, A.Y., Videlock, E.J., Peleg, T., Segman, R., Pitman, R.K. and Yehuda, R. (2007). Stress hormones and post-traumatic stress disorder in civilian trauma victims: a longitudinal study. Part I: HPA axis responses. The International Journal of Neuropsychopharmacology, [online] 11(03). doi:https://doi.org/10.1017/s1461145707008127.

Šimić, G., Tkalčić, M., Vukić, V., Mulc, D., Španić, E., Šagud, M., Olucha-Bordonau, F.E., Vukšić, M. and R. Hof, P. (2021). Understanding Emotions: Origins and Roles of the Amygdala. Biomolecules, [online] 11(6), p.823. doi:https://doi.org/10.3390/biom11060823.

Steffen, P.R., Hedges, D. and Matheson, R. (2022). The Brain Is Adaptive Not Triune: How the Brain Responds to Threat, Challenge, and Change. Frontiers in Psychiatry, 13. doi:https://doi.org/10.3389/fpsyt.2022.802606.

Stevens, J.S., van Rooij, S.J.H. and Jovanovic, T. (2016). Developmental Contributors to Trauma Response: the Importance of Sensitive Periods, Early Environment, and Sex Differences. Behavioral Neurobiology of PTSD, 38(1), pp.1–22. doi:https://doi.org/10.1007/7854_2016_38.

Stiles, J. and Jernigan, T.L. (2010a). The Basics of Brain Development. Neuropsychology Review, 20(4), pp.327–348. doi:https://doi.org/10.1007/s11065-010-9148-4.

Stiles, J. and Jernigan, T.L. (2010b). The Basics of Brain Development. Neuropsychology Review, 20(4), pp.327–348. doi:https://doi.org/10.1007/s11065-010-9148-4.

Taylor-Robinson, D.C., Straatmann, V.S. and Whitehead, M. (2018). Adverse Childhood Experiences or Adverse Childhood Socioeconomic conditions? The Lancet Public Health, 3(6), pp.e262–e263. doi:https://doi.org/10.1016/s2468-2667(18)30094-x.

Teicher, M.H., Anderson, C.M. and Polcari, A. (2012). Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proceedings of the National Academy of Sciences, 109(9), pp.E563–E572. doi:https://doi.org/10.1073/pnas.1115396109.

Teye-Botchway, L., Willie, J.T. and Rooij, van (2023). Unilateral amygdala ablation: a potential treatment option for severe chronic post-traumatic stress disorder (PTSD)? Expert Review of Neurotherapeutics, [online] 23(6), pp.483–486. doi:https://doi.org/10.1080/14737175.2023.2218034.

The National Institute of Mental Health (2023). Post-Traumatic Stress Disorder. [online] The National Institute of Mental Health. Available at: https://www.nimh.nih.gov/health/publications/post-traumatic-stress-disorder-ptsd.

Tottenham, N. and Sheridan, M.A. (2009). A review of adversity, the amygdala and the hippocampus: a consideration of developmental timing. Frontiers in Human Neuroscience, 3(68). doi:https://doi.org/10.3389/neuro.09.068.2009.

Vasung, L., Abaci Turk, E., Ferradal, S.L., Sutin, J., Stout, J.N., Ahtam, B., Lin, P.-Y. and Ellen Grant, P. (2019). Exploring Early Human Brain Development with Structural and Physiological Neuroimaging. NeuroImage, [online] 187, pp.226–254. doi:https://doi.org/10.1016/j.neuroimage.2018.07.041.

Voges, M.A. and Romney, D.M. (2003). Risk and Resiliency Factors in Posttraumatic Stress Disorder. Annals of General Hospital Psychiatry, [online] 2(1), p.4. doi:https://doi.org/10.1186/1475-2832-2-4.

Vythilingam, M., Heim, C., Newport, J., Miller, A.H., Anderson, E., Bronen, R., Brummer, M., Staib, L., Vermetten, E., Charney, D.S., Nemeroff, C.B. and Bremner, J.D. (2002). Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression. The American journal of psychiatry, [online] 159(12), pp.2072–2080. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230324/.

Wang, D., Lu, S., Gao, W., Wei, Z., Duan, J., Hu, S., Huang, M., Xu, Y. and Li, L. (2018). The Impacts of Childhood Trauma on Psychosocial Features in a Chinese Sample of Young Adults. Psychiatry Investigation, [online] 15(11), pp.1046–1052. doi:https://doi.org/10.30773/pi.2018.09.26.

Williamson, V., Creswell, C., Butler, I., Christie, H. and Halligan, S.L. (2016). Parental Responses to Child Experiences of Trauma following Presentation at Emergency departments: a Qualitative Study. BMJ Open, [online] 6(11), p.e012944. doi:https://doi.org/10.1136/bmjopen-2016-012944.

World Health Organisation (2020). Adverse Childhood Experiences International Questionnaire (ACE-IQ). [online] www.who.int. Available at: https://www.who.int/publications/m/item/adverse-childhood-experiences-international-questionnaire-(ace-iq).

Wynn, G.H. (2015). Complementary and Alternative Medicine Approaches in the Treatment of PTSD. Current Psychiatry Reports, 17(8). doi:https://doi.org/10.1007/s11920-015-0600-2.

Yehuda, R. (2002). Post-Traumatic Stress Disorder. New England Journal of Medicine, 346(2), pp.108–114. doi:https://doi.org/10.1056/nejmra012941.

Youssef, N.A., McCall, W.V. and Andrade, C. (2017). The role of ECT in posttraumatic stress disorder: A systematic review. Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists, [online] 29(1), pp.62–70. Available at: https://pubmed.ncbi.nlm.nih.gov/28207917/.

Zhang, L., Li, X.-X. and Hu, X.-Z. (2016). Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met. World Journal of Psychiatry, 6(1), p.1. doi:https://doi.org/10.5498/wjp.v6.i1.1.