Early Trauma, Brain Development, and a Novel Therapeutic Approach

Abstract

Trauma can result from an event that is perceived as life-threatening or as having the potential of seriously harming oneself or others. Such experiences, often accompanied by intense fear, terror, and helplessness, can lead to the development of PTSS and PTSD. Response to trauma depends on trauma feature characteristics and specific personal factors. In clinical literature, PTSD is often accompanied by severe functional impairment and includes well-described symptoms. These create behavior that limits the person and causes functional damage over time. Moreover, PTSS in early age may lead to adverse structural and functional changes in the development of brain neural circuits. PTSD has been one of the most investigated themes in medicine, psychiatry, neurophysiology, and rehabilitation over the last years. HPA axis, neural inflammation, and the neural mitochondrial oxidative stress are involved in the molecular mechanism of PTSD, reducing neuroplasticity and synapse proliferation. Here, current data on PTSD causes and symptoms, and the mechanisms and functions of the mitochondrial stress response, are reviewed, leading to 3LT novel scientifically and clinically based therapeutic approach. 3LT tool, aimed to the neural molecular mechanism of PTSS, targets mitochondrial dysfunction for the prevention and correction of neural lesions associated with PTSD.

1. Introduction

The risk of PTSD after a traumatic incident is between 1% to above 50% [1]. Worldwide, about 8% of all people encounter PTSD, with a lifetime incidence of PTSD between 1.3–12.2% [2]. Yet, the ICD defines PTSD as a psychiatric syndrome, linked with several others having resembling symptoms.

As a major public health problem, post-traumatic stress disorder (PTSD) has a substantial impact on individuals and society. The total excess economic burden of PTSD in the US is estimated to be more than $232.2 billion a year [3].

Early/child trauma is universally widespread with high prevalence, and more than 2/3 of the children report at least one traumatic event by the age of 16. Traumatic events involve: Psychological, physical, or sexual abuse; community/school violence; witnessing/experiencing national violence; national disasters/terrorism; commercial sexual abuse; unexpected/violent loss of a dear one; refugee/war experiences; military family-related stressors (deployment, parent loss/injury); Physical/sexual attack; negligence; serious accidents/life-threatening disease.

The main symptoms of trauma may change from one child to another and depend a lot on the child’s age, and young kids may respond differently from older ones.

Preschool children are very vulnerable to traumatic events, and they usually show fear of being separated from their parent/caregiver; cry/yell a lot; eat poorly/lose weight; and have bad dreams. Elementary school children mainly become worried/fearful; feel guilt/shame; have a hard time concentrating, and have difficulty to sleep. Middle and high school children usually report feeling depressed/lonely; develop eating disorders/self-hurting actions; begin abusing alcohol/drugs; and become involved in risky sexual behavior.

According to the DSM-5 childhood trauma is defined as: “exposure to actual or threatened death, injury, or sexual violence” [4]. These may include direct experience, witnessing trauma, or learning about trauma that happened to an acquaintance.

When signs are present for more than a month after the traumatic event, the main symptom categorization that creates PTSD diagnosis is [5, 6, 7]:

1. flashbacks, intrusive thoughts, and nightmares.

2. hyperarousal, insomnia, restlessness, irritability, impulsivity, and anger.

3. Numbness, avoidance, withdrawal, confusion, dissociation, and depression.

Each of these reactions is a diagnostic criterion and is related to alterations in physiological routes and brain circuits, which contribute to neurodevelopmental deficits and cognitive–emotional dysregulation in children with early trauma [8].

PTSD is often correlated with certain physiologic biomarkers, and these include elevated blood glucose, insulin, and creatinine; elevated activity levels of certain genes, metabolites involved in energy processing, circulating microRNAs, and blood key proteins [9]. In addition, decreased plasma levels of fatty acids involved in neuroprotection were observed in PTSD patients [10]. These fatty acids block the action of the NFĸB transcription factor (NFĸB – Nuclear Factor-kappa B) and decrease production of reactive oxygen species (ROS) [11, 12] (hence, lower levels of fatty acids in PTSD lead to high ROS). Additional, PTSD biomarkers include high expression of mitochondrial nuclear gene chaperones, proteases, and antioxidant enzymes to repair mitochondria damaged organelles and restore functional activity in defective mitochondria [13]. Indeed, these biomarkers reflect intrinsic multilevel pathophysiologic process, including cellular metabolic changes that will chronically influence body and brain development and function.

Concerning PTSD outcomes, trauma is a risk factor for nearly all behavioral health and substance use disorders. Early trauma has difficult outcomes for the child, and for his family, as childhood trauma may develop into failure of mental processes [14, 15, 16], and various pathologies (i.e., distress, depression, disruptive behaviors, suicidality, substance use disorders, and more) [17, 18, 19, 20, 21, 22]. Yet, only recently, we learn about trauma’s physiologic effects in children’s brains, and how these processes lie behind trauma’s immediate and longstanding mental health outcomes.

2. Etiology of early trauma: enhanced neuroendocrine, and immune-inflammatory activity

HPA axis is strongly influenced by PTSD, causing neuroendocrine functional changes, structural abnormalities, and neurochemical alterations. These pathological changes negatively feedback on the brain activity via lateral amygdala, prefrontal cortex, and hippocampus.

Specifically, glucocorticoid activity inhibits lymphocyte proliferation, as a result, levels of pro-inflammatory cytokines IL-6, IL-12, IFN-γ, and TNF-α are significantly increased [23]. Additionally, rise in hypothalamic CRH (corticotrophin-releasing hormone) and pituitary ACTH (adreno corticotrophin hormone) hormone in PTSD were linked to severity of PTSD, psychosis, destructive personality disorders, and even suicide. Parallel to activity changes of HPA axis in PTSD, there is hyperactivity in the sympathetic noradrenergic and cholinergic neural circuits.

Research showed additional changes in immune system activity: higher levels of pro-inflammatory cytokines (IL-1β, TNFα, IL-2, IL-6, IL-17), interferon-gamma (INF-γ), C-reactive protein (CRP), and reduction in IL-4 concentration damage normal immune activity [24]. Such inflammatory processes are strongly correlated with mitochondria function: mitochondrial abnormalities result in ROS overproduction, causing broken mitochondrial DNA. Pro-inflammatory cytokines may also downregulate ATP (adenosine triphosphate) synthesis by IL-1β, TNFα, and IL-6. IL-6 enhanced activity causes amygdala and anterior cingulate cortex neuroinflammation [25, 26] and elevates amygdala and hippocampal dopamine concentration, resulting in dysregulation of normal HPA axis activity and stimulating the development of PTSD.

Altogether, PTSD is characterized by an increase in inflammatory neurohormones (corticosteroids, prostaglandins, etc.), and NFĸB, which damage mitochondrial function and plasticity [12, 27, 28], decreased cellular energy production, and further neural deterioration.

3. Brain development and downregulation of neural plasticity due to early trauma

Until recently, the specific brain circuits, that make persons who experienced a trauma vulnerable to permanent clinical signs, were not clear. New studies showed that under stressful conditions Amygdala neural circuits release norepinephrine, that increase heart rate and interfere with regulation of emotions [29]. Moreover, high cortisol levels during trauma, are known to harm hippocampal cells neural activity [30], and typically cause reduction in hippocampal size and function [31].

Additionally, cortical thinning in brain areas correlated with surviving attempts, and resistance has an important function in PTSD signs. It was found that cortical thinning in the superior frontal cortex (SFC), insula, superior temporal cortex, dorsolateral prefrontal cortex, superior parietal cortex, and precuneus, correlated with persistent PTSD [32]. Specifically, they found that in people who experienced trauma, cortical thinning in the SFC was correlated with maladaptive coping approach, and thinner insula layers are linked with lower resistance ability. These findings are especially important in the context of cortex neural proliferation and synapse formation during brain development.

4. Neural components of early emotional trauma: mitochondria and oxidative stress

A lot of energy is required for brain cells daily vitality, survival, and functioning. Mitochondria are cellular organelles, which are the cellular “powerhouses,” i.e. mitochondria are responsible for supplying energy for function and growth in the living cell. In addition to energy supply, the mitochondria participate in the cellular iron metabolism and in cellular calcium balance. Moreover, mitochondria are associated with normal and defective cell proliferation and participate in “programmed cell death.” Each eukaryotic cell may have hundreds to tens of thousands of mitochondria, depending on cellular function and its energy consumption.

Mitochondria are inherited from the mother through the ovum, may develop mutations as they reproduce, and have almost no repair mechanisms. Most of the proteins that make up the mitochondria are encoded in the cell nucleus, and since the mitochondria are inherited from the mother, they have no “backup” from the father’s genome when mutations or damage to the mitochondria occur. However, since the ovum contains a lot of mitochondria to begin with, some may be damaged without it being clinically apparent. This “hidden injury” may exist over several generations until a stage is achieved when there are only very few normal mitochondria, and then a neural problem may be revealed in the form of a defect or a strong tendency to emotional or mental injury.

Genetic changes in mitochondria may be caused not only by maternal inheritance (when cells divide to form the embryo) but also by a coding change called a “de novo mutation” (a new mutation in the mitochondria in fetal cells), which may happen due to an environmental/epigenetic cause.

Mitochondria are an important source of ROS in mammalian cells. Mitochondrial response to early emotional trauma consists of several continuous pathways: first – the HPA axis, which is a most important neuroendocrine rout implicated in stress response through release of hormones and prohormones. At the end point of HPA axis, glucocorticoids, released by adrenal gland into bloodstream, regulate mitochondrial transcription in target tissues. Then, mitochondrial stress response includes changes in mitochondrial dynamics, retrograde signaling, mitochondrial unfolded protein response, mitochondrial selective autophagy/apoptotic cell death. Finally, cellular stress response results in excitotoxicity when frequent and powerful membrane potential changes cause excessive synaptic release of glutamate, which binds to NMDA receptor, leading to excess calcium influx, failure of mitochondrial membrane potential, decreased ATP creation, and boosted ROS production.

As the genes involved in PTSD mechanism are shared by other prevalent mental syndromes (depression, anxiety, and more), it was believed until recently that several mental syndromes may be risk factors for PTSD. However, recently, the molecular mechanism of depression [33] and the molecular mechanism of PTSD focus us to basic molecular constituents of the eukaryote cell – the mitochondria.

Studies show that the etiology of PTSD involves processes of inflammation and stimulation of the immune system, which cause damage to the neural mitochondria [34, 35, 36, 37, 38], which, in turn, causes damage to the neural circuits – damage to the proliferation of contact points (= synapses) between neural cells and damage to neural circuits architecture plasticity.

Mitochondrial disorders include a decrease or increase in mitochondrial function, depending on the cause and the developmental time window, and may lead to neuronal damage. It was found that neurodevelopmental impairment, or susceptibility to mental–emotional injury, may be the result of mitochondrial disorder and abnormal mitochondrial physiology [39, 40, 41, 42].

To summarize, an increase in inflammatory neurohormones in PTSD may damage mitochondrial function, causing decreased cellular energy production, and further neural deterioration. This is especially significant for the cells of the nervous system – neurons and glial cells as it has been found that impaired neural mitochondrial function in stress is linked to the development of diverse brain mental and emotional pathologies [43, 44, 45].

Mitochondrial function is greatly affected by environmental factors, and impaired mitochondrial function is linked to environmental triggers [46, 47, 48, 49, 50, 51, 52]. Therefore, it is important to focus PTSD therapy on improving patient’s mitochondrial function, using a safe and noninvasive tool that has been scientifically proven to overcome the environmental impact.

5. Novel therapeutic tool

An important factor for children’s recovery is having access to effective therapy.

Today, first-line healing approaches for PTSD include psychotherapy and pharmacotherapy. In psychotherapy, we include mainly CBT (cognitive behavioral therapy), CRT (cognitive remediation therapy), and EMDR (eye movement desensitization and reprocessing). In pharmacotherapy, we mainly refer to the drugs paroxetine, sertraline, and venlafaxine, which are FDA-approved for PTSD [53, 54]. However, it was shown that these approaches either have only partial effectiveness or have a mechanism, which is not clear. Furthermore, data show that psychological treatment is primarily dependent on the patient’s psychological tolerance and is likely to cause secondary harm to the patient [55].

In recent years, the use of additional therapeutic tools has increased, including therapies based on East Asian ancient knowledge combined with modern clinical empirical scientific knowledge [56, 57, 58, 59, 60].

Employing 3LT, we use an innovative and well-known scientific therapeutic approach to solve the neural damage caused by early trauma.

Our 3LT therapeutic protocol consists of: A. specific physical properties of laser energy chosen according to the patient’s clinical picture (including clinically proven specific wavelength and frequency). B. specific skin points over, which the laser is activated. These skin points are chosen according to western clinically proven auricular therapy and according to Traditional Chinese Korean and Japanese Medicine and our knowledge and experience in neuroanatomy and neurophysiology, relating to the patient’s clinical picture.

5.1 Physical characteristics of low power/cold laser tool

Low-power laser therapy has evolved in recent years into a clinical procedure used for three main purposes: (1) To reduce inflammation, edema, and chronic injuries; (2) To promote healing of wounds, deep tissues, and nerves; (3) To treat neurological injuries and pain.

Our goal is to alleviate the trauma, utilizing low-level laser therapy (3LT = Low-Level Laser Therapy) tool. This approach is aimed at the injury mechanism following a traumatic experience and is based on research and clinical evidence.

Low-power laser heals neurological injuries, including PTSD by reducing the activity of the HPA axis, lowering the concentration of inflammatory proteins, regulating the energy-yielding activity of mitochondria, and increasing the production of ATP and nerve growth factors.

LASERs (Light Amplification by Excitation of Radiation emission) are electromagnetic radiation producing devices. LASER radiation has uniform wavelength, phase, and polarization. A low-power laser device (Low-Level Laser = 3 L) is a special type of laser that affects living tissues and biological systems by nonthermal means [61]. Our low-power laser system uses wavelengths in the range of red and blue light. Studies have found that red to NIR (near-infrared) light has a healing effect on local and systemic injuries and can affect the functioning of the brain and other organs.

Low-power laser therapy applies a noninvasive therapeutic laser for stimulation over specific skin body points. This technique is safe and noninvasive and has become an important tool for the treatment of patients at risk, including premature newborns [62, 63, 64]. For example, stimulation of Specific skin body points for pain relief using a low-power laser creates a local photochemical effect [65] that causes specific changes in brain neuron activity [66, 67], which are perceived by the patient as a reduction in pain intensity. These changes can be measured and quantified by brain imaging [68, 69].

A “photochemical effect” means that when the right parameters are employed (power, wavelength, frequency, duration, and location), the laser beam reduces tissue oxidative stress and increases ATP levels in cells, improves cell metabolism, and reduces inflammation [70, 71, 72].

Because 3LT is targeted at the very basic building blocks of eukaryote cells, it has shown beneficial effects for various clinical conditions and processes, i.e.:

It was found that 3LT improves the healing of soft tissues, reduces inflammation, and relieves chronic and acute physical and mental pain [73, 74, 75, 76, 77, 78, 79, 80].

3LT has been shown to alter axonal conduction, opioid receptor binding, and endorphin production [81, 82, 83].

In clinical studies, it was found that 3LT causes an immediate decrease in acute and chronic pain perception and functional enhancement [84, 85, 86].

3LT showed promising results for myocardial function [87], mesenchymal stem cell regeneration [88], skin injuries [89, 90, 91, 92], brain trauma, TBI [93, 94, 95, 96], diabetic retinopathy [97], oncology [98], and more.

We employ a combination of specific scientifically proven skin points/locations, frequencies, and wavelengths according to the patient’s characteristics.

3LT is a noninvasive tool that involves the projection of specific wavelengths, over the surface of the skin, at selected points. Infrared waves can produce diverse biological reactions in the body such as increasing the formation of ATP, the release of NO (nitric oxide) and CCO (cytochrome c oxidase), regulation and reduction of ROS, a change in membrane activity of intracellular organelles, (mainly the mitochondria), a change in transmembrane calcium flux, in the production of stress proteins, and more [57, 70, 99, 100, 101, 102].

In eukaryote cells, 3LT creates a shift toward higher oxidation in the total redox potential of the mitochondria [103] and briefly increases the level of ROS [90]. This change in the redox state of the mitochondria regulates several cellular proteins and protein genes. As a result, ATP levels and blood flow increase, and the availability of oxygen in damaged areas of the brain is improved [104].

Our laser device has three therapeutically proven wavelength ranges, 670 nm, 808 nm, and 915 nm. These wavelengths are within the “optical window” that allows optimal tissue penetration depth (lowest absorption of water, hemoglobin, and melanin).

The treatment reaches all relevant tissue layers because the visible red spectrum wavelength range penetrates the upper tissue layers, and the infrared wavelength range (not visible to the human eye) penetrates deeper tissue layers. As a result of the activity of these laser wavelengths, ATP synthesis, (which is the main cause of cell excitation and energetic activity increase), through the wavelengths of cytochrome-C-oxidase, is perfectly activated. In particular, the wavelengths of 670 nm, 808–830 nm, and 905–915 nm were found to be suitable for photobiomodulation and are now available at high power in the therapeutic laser device.

In addition, our 3LT device includes a laser source with a blue range wavelength because it was found that despite its low tissue penetration ability, involvement of a blue wavelength laser source brings the best results in terms of energy. A blue wavelength is absorbed by NADH (nicotinamide adenine dinucleotide + hydrogen) – the first complex of the cellular respiratory chain; blue and red laser wavelengths are absorbed by the complex of cytochrome C, with a blue wavelength (405 nm) showing five times higher absorption compared to red laser wavelength [105, 106]. Hence, it was found that bichromate laser radiation (red and blue wavelength range) yields a bigger change in the mitochondria redox potential by increased oxidation of NADH. This way, the proton-motive force increases (the force that drives the flow of protons into the mitochondrial matrix), and thereby ATP cycle is enhanced [107]. In addition, electron transfer is accelerated, and both effects cause an increase of ATP synthesis. This change at the cellular-molecular level is manifested clinically and functionally.

5.2 Clinical considerations – skin points over which the laser is activated

Acupuncture, an ancient therapy, has been long employed all over the world for the treatment of chronic and acute medical situations [108, 109], using invasive metal needles. World Health Organization advocated acupuncture for at least 20 pathologies [110], including for coping with pain in elder people [111, 112], children [113, 114, 115, 116, 117], and neonates [118, 119, 120, 121, 122]. For example, it was found that acupuncture increases the secretion of the natural neuromodulator adenosine, also known as anti-inflammatory and pain relief substance [123, 124]. In addition, acupuncture has been shown to have potential benefits for a variety of mental disorders [125, 126], and acupuncture for PTSD in adults was found to help with core symptoms [127, 128]; it was found that acupuncture can alleviate the anxiety behavior, as well as the recognition and memory ability of PTSD rats [129].

However, recent studies show that the main efficient acupuncture points for mature patients with PTSD [129], or earthquake survivors with major psychiatric disorder (MPD) [130], are near vertex skull points, located on fontanels (Fonticuli cranii) cranial suture lines (Suturae cranii). These acupuncture points named – Baihui, Sishencong, and Shenting, were punctured to depth of 20–25 mm obliquely [131] for a duration of 20 min per session [132]. Such a protocol, even after necessary adjustment, would not be appliable for children, toddlers, or infants. With young age patients, we should avoid skull acupuncture points and keep away from open suture fontanels. Using 3LT tool, we may combine suitable distal acupuncture skin points with selected auricular points and under-knee or under-tung laser applicator instead of over-fontanelle skull direct needle acupuncture points.

Auriculotherapy is an ancient technique initially used to treat pain. It was rediscovered in the 1940s and developed by French physician Dr. Paul Nogier and his colleagues. He showed that the ear contains a representation map of the body so that any pathology will be associated with a compatible modification of specific ear points. The therapeutic technique involves modifying of the dysfunctional ear point activity, which generates an impulse that is transmitted to the brain. Specific parts of the ear are innervated by specific branches of four cranial nerves and plexus (V, VII, IX, X). These nerves carry impulses between the body the brain and the ear. The ear point map is validated using fMRI [133, 134].

In low-Level Laser therapy, we employ an accurate laser beam, over suitable skin/ear points, to regulate mitochondrial function and create the required therapeutic effect according to specific clinical considerations.

6. Conclusion and recommendation

3LT is a suitable therapeutic tool for all populations without exclusion. 3LT is noninvasive, flexible, and diverse, yet always based on the physical characteristics of the laser beam and its therapeutic effects on human body cells through specific somatotopic skin points. Hence, even patients at risk, including old and sick or fragile babies with childhood trauma, may be suitable for laser therapy, using evidence-based protocols tailored for their needs.

Patients with childhood trauma usually have an already challenged immune system (because of trauma path physiology) and already exhibit a lot of stress. Using real needles (as with needle-based auricular therapy, or needle acupuncture), in repetitive ~20-minute sessions, with old patients having health complications or young patients in trauma may be dangerous, not efficient, and not practical.

Employing 3LT therapeutic tool, which we know exactly its molecular and cellular mechanism and has been proven to cause no damage or pain, is the most efficient and kind therapy we may offer these patients.

We recommend to further amplify the assimilation of evidence-based 3LT in medical training and to further encourage clinical studies to identify additional pathologies for which 3LT may be suitable, especially for the benefit of high-risk patients.