Pappas et al. Reference Page Template Berkeley Pharma Tech Journal of Medicine Correspondence: isabelle.pappas02@gmail.com Keywords: PTSD Brain Development Stress Trauma Adolescents Neurodevelopment Neuroimaging Youth Published July 31, 2025 Full Open Access Creative Commons Attribution License 4.0 Abstract The developing adolescent brain is particularly susceptible to the effects of stress and trauma which can result in long-lasting morphological and psychological effects. This review paper aims to highlight the important changes caused by childhood stress and trauma, outline current treatments, and provide insight into future research directions. Studies suggest that exposure to stressors and traumatic events at a young age increases overall volume in the amygdala while decreasing volume in the hippocampus and frontocortical regions. However, due to a discrepancy in results, there is a need for future studies to control for age-based and trauma differences. Additionally, analysis of commonly used treatments reveals that a combination of therapeutic approaches, hormonal treatments, and lifestyle changes is generally most effective to address both underlying mechanisms and psychological effects. Ultimately, studies show that adolescent stress and trauma leads to significant hormonal and morphological changes in the brain that result in psychological changes such as anxiety and depressive symptoms. Adolescent Brain Development Under Stress and Trauma: Evidence-Based Treatments By: Isabelle Pappas, Tzung Yu, Olivia Liu and Nainika Srinivasan 1. Introduction Trauma is defined as an experience that triggers intense physical and psychological stress reactions, including heightened arousal, intrusive thoughts, and emotional numbness. The stress induced by trauma releases hormones like cortisol which can disrupt bodily systems and is associated with increased risk of anxiety, depression, and Post-Traumatic Stress Disorder (PTSD).1 Researchers often model trauma in test subjects using chronic variable or restraint stress, enabling the study of these impacts.2 A severe outcome of trauma is PTSD, characterized by abnormalities in frontolimbic circuitry that result in increased threat sensitivity and reduced emotional regulation.3 PTSD is linked to poor academic performance, higher rates of depression, suicide attempts, and substance abuse.3 In adults, PTSD manifests through symptoms like flashbacks, avoidance, hyperarousal, and mood changes.4 Adolescent development is a time of significant psychological and physiological vulnerabilities. For instance, there are significant volumetric increases in the hippocampus and amygdala in the early stages of puberty.2 Furthermore, there are periods of cortical thinning in the frontal and temporal cortical volumes during adolescence following the initial increase in volume during childhood.2 These are regions intimately involved in emotional and cognitive processes, and it can be inferred that alterations to the developmental process of these brain regions would affect the emotional and cognitive abilities of the individual; however, the precise nature of this structure-function relationship in the adolescent brain is unclear. 5 In animal models, particularly mouse models, adolescence is also marked by increased hippocampal volume and vulnerability to stress, making this period of development particularly vulnerable to the morphological changes that result from stress and trauma. Mouse models are particularly useful because of their genetic similarity to humans and the ability to control their environmental factors. Exposure to stressful stimuli in adolescent mice (between 5 and 7 weeks old) results in short term as well as long term morphological changes in their brains, suggesting similar results for Berkeley Pharma Tech Journal of Medicine | 37 https://www.zotero.org/google-docs/?9diot8 https://www.zotero.org/google-docs/?6TsMLW https://www.zotero.org/google-docs/?QpoUe5 https://www.zotero.org/google-docs/?ojZBQ4 https://www.zotero.org/google-docs/?b18Z0q https://www.zotero.org/google-docs/?SCkOOG https://www.zotero.org/google-docs/?C5u2in https://www.zotero.org/google-docs/?Js7v5K adolescent humans.6 Behaviorally, mice exhibit impaired cognitive functions and social withdrawal, which mirror the psychological effects of stress in adolescent humans. Thus, mouse models can allow researchers to identify biological indicators of disorders caused by stress. Additionally, the mouse models can aid physician scientists in developing the most effective treatment plans to mitigate the adverse effects of stress and trauma. The impact of trauma is most pronounced during adolescence, affecting critical brain regions at specific ages: the hippocampus at 14, the amygdala between 10 and 11, and the prefrontal cortex between 14 and 16.3 Adolescents exhibit higher stress reactivity, with stress hormones like ACTH and corticosterone taking longer to normalize post-stress compared to adults.2 This necessitates study and prevention of abuse and trauma for adolescents due to the vulnerable nature of that time period and the long term effects these changes can have on the psychology of these individuals. Figure 1. Physical changes characteristic of adolescence in humans. Berkeley Pharma Tech Journal of Medicine | 38 https://www.zotero.org/google-docs/?ylO0ox https://www.zotero.org/google-docs/?KYO530 https://www.zotero.org/google-docs/?ZYuG2F Figure 2. Physical characteristics of mice (left) vs. human (right) brains. Mice models are commonly used for the studies reviewed in this paper. 2. Morphological and Psychological Effects 2.1 Amygdala The amygdala, critical for emotional reactivity and cognitive processes such as memory, possesses a high concentration of glucocorticoid receptors that causes it to be susceptible to stress.7,8 During postnatal development, the amygdala undergoes a period of rapid growth which peaks during ages 9-11 and diminishes.9 These changes highlight the importance of the amygdala in studies regarding adolescent stress and trauma. Childhood trauma and adversity have been found to be correlated with heightened amygdala reactivity to negative stimuli in functional magnetic resonance imaging (fMRI) studies of both healthy and psychiatric youth.10–12 In addition, amygdala hyperactivation in youth with PTSD compared to healthy youth has also been reported, similar to the hyperactivation in adult PTSD.11,13–15 On the other hand, many studies also Berkeley Pharma Tech Journal of Medicine | 39 https://www.zotero.org/google-docs/?cUm479 https://www.zotero.org/google-docs/?d6xV1j https://www.zotero.org/google-docs/?z1q2aD https://www.zotero.org/google-docs/?OewurS report no difference in amygdala hyperactivation.16–18 This contrast in findings may be due to a delayed expression of amygdala hyperactivation until adulthood, as shown when analyzing amygdala activation using age-related differences demonstrates that typically developing youth show decreased activation with age whereas youth with PTSD have increased activation with age.19 The same authors established that amygdala activation in youth with PTSD was lower at ages below 15 years compared to healthy youth, possibly due to younger children compensating for stress by downregulating amygdala activity, but this becomes less effective as they age. Amygdala hypertrophy caused by childhood trauma is expressed in adulthood. In a longitudinal sample, adult subjects exposed to maltreatment had higher right and left amygdala volumes than healthy controls.20 Furthermore, by using the Maltreatment and Abuse Chronology of Exposure Scale, it was revealed that the right amygdala undergoes a sensitive period during 10-11 years, becoming prone to enlargement from exposure to maltreatment.21 Interestingly, even small amounts of maltreatment in healthy controls triggered hypertrophy during this sensitive period, despite not meeting the threshold for moderate exposure. Left amygdala volume was also shown to be correlated to attachment disruption at 18 months.1 This underscores the susceptibility of the amygdala to stress and trauma during youth development and highlights the need for further understanding in this topic. In rats, early life stress exposure led to increased amygdala volume and reactivity for prolonged periods of time.22–24 Developing rats exposed to restraint stress exhibited an increase in dendrite complexity and frequent, spontaneous neuron firing in the basolateral amygdala which resulted in amygdala hypertrophy.25,26 Further studies found that exposure to psychological stress or stress hormone lead to increased excitability and spine formation on pyramidal cells, a basis for exhibiting anxiety-like behaviors.27–29 Additionally, studies have shown that development of threat learning occurred earlier in rodents exposed to early life stress compared to the controls.30 This evidence supports previous trials indicating an association with early life stress and enhanced threat bias in youth.23 These findings suggest that hyperreactive amygdala in adolescents exposed to Berkeley Pharma Tech Journal of Medicine | 40 https://www.zotero.org/google-docs/?knRdja https://www.zotero.org/google-docs/?KG4G2O https://www.zotero.org/google-docs/?hdNANt https://www.zotero.org/google-docs/?HNqQB4 https://www.zotero.org/google-docs/?zTrsw0 https://www.zotero.org/google-docs/?dnogHg https://www.zotero.org/google-docs/?DmbdPL https://www.zotero.org/google-docs/?zvhXyc https://www.zotero.org/google-docs/?2YRzQ5 https://www.zotero.org/google-docs/?omWmTA trauma and stress may be of evolutionary advantage to detect threat. Similarly, chronic restraint stress during adolescence also resulted in short-term difficulties unlearning fear responses, such as freezing, which disappeared in the long term.26,31 However, when adolescent and adult rats were exposed to corticosterone as a chronic stressor, only adolescents had impaired extinction retention, showing the importance of sensitive periods during development.32 2.2 Hippocampus The hippocampus, which plays key roles in memory, learning, and emotion, grows rapidly during adolescence.33 Additionally, this region is densely populated with glucocorticoid receptors, causing it to be highly susceptible to the increased levels of glucocorticoids due to childhood maltreatment.34 Studies have shown that high exposure to glucocorticoids can lead to changes in hippocampus regions, such as reversible atrophy of dendritic processes in the cornu ammonis and suppression of neurogenesis in the dentate gyrus.35 Due to the rapid development and sensitivity to stress hormones of the hippocampus, this region is important in our understanding of the effects of childhood trauma and stress. Current literature proposes that childhood stress and trauma are associated with lower volume of the hippocampus, aligning with the reduced hippocampal volume present in adult PTSD.36 One study on patients with childhood PTSD concluded a significant 12% reduction in left hippocampal volume compared with typically developing controls.37 Another paper analyzing structural MRI images determined that childhood trauma was associated with less gray matter in the hippocampus.38 However, some report that hippocampal volume is not altered between youth with PTSD and typically developing youth. For example, multiple studies have found no significant reduction in hippocampal volume in children with PTSD.39–41 One possible explanation for the discrepancy between these studies is that, similar to the amygdala, the hippocampus has delayed onset of reduced volume. For instance, analyses show that subjects in studies reporting no significant reduction had a mean age of 11.26 years whereas studies reporting significant hippocampus reduction had a mean age of Berkeley Pharma Tech Journal of Medicine | 41 https://www.zotero.org/google-docs/?9kWOZY https://www.zotero.org/google-docs/?5Ysh3i https://www.zotero.org/google-docs/?sQeEfO https://www.zotero.org/google-docs/?jXBSPw https://www.zotero.org/google-docs/?Dr6usJ https://www.zotero.org/google-docs/?ozH8jN https://www.zotero.org/google-docs/?fEULWX https://www.zotero.org/google-docs/?S6hOTC https://www.zotero.org/google-docs/?4UFR4C 12.65 years, suggesting that there is a silent period between maltreatment and neurobiological effects.42 Additionally, when analyzing differences using age-related differences, hippocampal volume increased in typically developing youth but decreased in PTSD youth with age.3 Rodent studies have also shown impaired hippocampus growth. One study reported that chronic restraint stress on both male and female adolescent rats resulted in lowered dendrite complexity of pyramidal neurons in the hippocampus compared to controls.25 Rats exposed to stress also exhibited depressive behaviors. In another study, male rats that were exposed to chronic stress during adolescence exhibited short-term increase in hippocampal growth in the CA1 region only.43 However, a later examination revealed a significant long-term decrease in CA1 and DG regions and CA3 growth arrested. These structural changes correlated with impaired abilities in navigation which demonstrates that adolescent stress can significantly change brain structure and function in the long-term. 2.3 Frontocortical Regions 2.3.1 Prefrontal Cortex The prefrontal cortex (PFC) is a region of the brain that controls complex processes such as emotion, thought, and actions. Studies have analyzed MRI images and found that gray matter in the frontal lobe increased during adolescence.44 Growth peaked at 12.1 years for males and 11.0 years for females then decreased during post-adolescence. Additionally, past literature has stated that the PFC is particularly vulnerable to stress-induced morphological changes which makes it important to understand changes in the PFC from stress and trauma in developing youth.45 Youth with PTSD have shown a decreased volume in the PFC compared to typically developing youth. For example, multiple articles found decreased gray matter volume in the right ventromedial prefrontal cortex (vmPFC), bilateral ventrolateral prefrontal cortex (vlPFC), dorsomedial prefrontal cortex (dmPFC), and dorsolateral prefrontal cortex (dlPFC)11,46,47 while other studies report increased gray matter in the vmPFC, vlPFC, dmPFC, and dlPFC in individuals with childhood trauma.16,17,19,38,48 One possible explanation for this disparity could be differences in sample PTSD severity, Berkeley Pharma Tech Journal of Medicine | 42 https://www.zotero.org/google-docs/?cUKeHS https://www.zotero.org/google-docs/?kEM4KH https://www.zotero.org/google-docs/?xLwbtD https://www.zotero.org/google-docs/?R7gQAj https://www.zotero.org/google-docs/?YSkBLa https://www.zotero.org/google-docs/?I1SSyY https://www.zotero.org/google-docs/?RoXXpl https://www.zotero.org/google-docs/?ThNeg4 trauma-related factors, or age-related differences. Studies that report a decrease in gray volume also note that lower left ventral and left inferior prefrontal matter are associated with higher cortisol levels.49 Additionally, childhood PTSD was found to be associated with loss of neuronal integrity in the PFC.47 These results demonstrate the need to further investigate the underlying mechanisms and contributing factors to better understand the impact of PTSD on brain development and to develop targeted intervention strategies. Studies using rodent models have achieved similar results. When chronic restraint stress is applied to adolescent rats, those exposed to stress had reduced PFC dendrite complexity in pyramidal neurons.25 The same protocol combined with early weaning caused rats to show decreased PFC neuronal activity in stress-inducing environments.50 Furthermore, social isolation rearing led to decreased spine density, dendritic branching in pyramidal neurons, and volume in the PFC.51–54 Exposure to isolation stress also resulted in lasting lower concentrations of proteins spinophilin, synaptophysin, and myelin basic protein in the PFC of adolescent rats.55 Post-adolescent rats that were exposed to isolation stress in childhood exhibited down-regulation of immediate early genes and genes that regulate differentiation and apoptosis in the medial PFC.56 These genetic changes were associated with the degree of hyperlocomotion and social isolation in stressed rats which offers a molecular basis for anxiety-like behaviors expressed in individuals exposed to stress and trauma. 2.3.2 Anterior Cingulate Cortex The anterior cingulate cortex (ACC) regulates emotions, motivation, cognition, and motor abilities during conflict. Due to the importance of the ACC in body processes, it is crucial for us to further understand the effects of stress and trauma on its development during adolescence. Previous studies have found that the dorsal ACC becomes hyperactivated when exposed to threat and emotional pictures in youth with PTSD.18,19 However, this contrasts with dorsal ACC becoming hypoactivated in adults with PTSD which could be due to overcompensating for emotional regulation during adolescence which fades with age.57 Moreover, reduced gray matter in the ACC has been associated with maltreatment during Berkeley Pharma Tech Journal of Medicine | 43 https://www.zotero.org/google-docs/?3mJ8YQ https://www.zotero.org/google-docs/?riVk8b https://www.zotero.org/google-docs/?ChJ3Sj https://www.zotero.org/google-docs/?XykBXU https://www.zotero.org/google-docs/?YUmjbU https://www.zotero.org/google-docs/?Kk1wBn https://www.zotero.org/google-docs/?nHCqAD https://www.zotero.org/google-docs/?CIquKF https://www.zotero.org/google-docs/?1Xxupi adolescence.58 Since ACC volume has been correlated with depressive symptoms, there is an urgent need for more understanding of trauma effects on this region of the brain.59 2.4 Corpus Callosum The corpus callosum connects the left and right brain hemispheres and allows them to communicate and coordinate actions. Studies show that children who have PTSD or suffered abuse have a smaller corpus callosum than controls.4 For example, multiple studies have reported an association between maltreatment and a significant reduction in corpus callosum volume, specifically higher in adolescent male samples than females.39,60–63 This may be due to males having a larger sensitive period lasting throughout infancy and early childhood. Notably, one study reported that at corpus callosum segments II and III, adolescents with low risk of mental disorders had the greatest fractional anisotropy followed by controls then adolescents with high risk.64 These results demonstrate the possibility that corpus callosum size may indicate vulnerability to mental disorders. However, analysis on the Bucharest Early Intervention Project demonstrated that significant reductions in the corpus callosum were mitigated when orphans were placed in foster care compared to those who remained in institutions.65 These findings are particularly impactful since they demonstrate the potential irreversibility of the damage to the corpus callosum caused by stress and trauma. 2.5 Larger Scale Effects 2.5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis During adolescence, the Hypothalamic-Pituitary-Adrenal (HPA) axis undergoes significant growth and developmental changes. The HPA axis is intricately intertwined with the hypothalamic-pituitary-gonadal (HPG) axis which releases more gonadal steroids, triggering the onset of puberty. HPA activity is influenced by the HPG Axis, resulting in heightened activity along with an increase in mineralocorticoid and glucocorticoid receptors in the hippocampus during this particular period of development.66 Basal activity of the HPA axis, characterized as the resting rate of hormones associated with this axis, increases during adolescence. This increase in basal Berkeley Pharma Tech Journal of Medicine | 44 https://www.zotero.org/google-docs/?AYuqQQ https://www.zotero.org/google-docs/?aGyYka https://www.zotero.org/google-docs/?R8hq8t https://www.zotero.org/google-docs/?gx6BDx https://www.zotero.org/google-docs/?rbcTxL https://www.zotero.org/google-docs/?HdAr84 https://www.zotero.org/google-docs/?1tAyLZ activity results in hypersensitivity and reactivity to stimuli, which can make adolescents particularly vulnerable to traumatic experiences.67 In rodent models, stress results in higher levels of adrenocorticotropic hormone (ACTH) and cortisone which last longer during periods of adolescence than during adulthood. Studies have revealed sex-specific changes in the HPA axis due to stress in adolescent rodent models. For example, “males that have been subjected to adolescent isolation have lower corticosterone responses to restraint stress compared with controls, whereas females develop greater restraint-induced corticosterone responses.”67 Additionally, rats that are exposed to repeated stressful environments, such as prolonged isolation, exhibit an increase in hormonal reactivity after being paired with a foreign cagemate. Prolonged exposure to stress can also lead to habituation or desensitization of the HPA axis in rodent models, which suggests that the same can occur in adolescent humans under conditions of chronic stress and trauma. Maladaptive changes, such as hyperactivity or subdued activity of the HPA axis, can make adolescents more vulnerable to mental health disorders, such as anxiety and depression. 2.5.2 The Dopaminergic System The dopaminergic system is involved in the regulation of motor, cognitive, and motivational brain regions.68 Furthermore, dopamine (DA) modulates emotional processing at multiple levels, which affects the amygdala, medial temporal lobe, and prefrontal cortex.69 The dopaminergic system has three main dopaminergic pathways, affecting regions of the brain spanning the prefrontal cortex and midbrain.70 In rats, the development of this system has several maturation steps. Firstly, the activity and levels of DA and 3,4-dihydroxyphenylacetic acid rises in the nucleus accumbens and striatum at postnatal day (PD) 28, which remains constant until adulthood 71. DA synthesis and turnover increases in the PFC at approximately PD 30 but decreases after several days.72–75 DA fibers mature earlier in the striatum and nucleus accumbens (~PD 35) compared to projections in the PFC.76–78 D1 and D2 receptor densities peak at PD 28 in the nucleus accumbens and striatum, and peak in the PFC at around PD 40-60.78–83 Berkeley Pharma Tech Journal of Medicine | 45 https://www.zotero.org/google-docs/?qKunA2 https://www.zotero.org/google-docs/?MKpY8S https://www.zotero.org/google-docs/?OQSPw6 https://www.zotero.org/google-docs/?RuHK9T https://www.zotero.org/google-docs/?PNz8Lo https://www.zotero.org/google-docs/?iMvuc5 https://www.zotero.org/google-docs/?uwY2Rd https://www.zotero.org/google-docs/?wzDLMf https://www.zotero.org/google-docs/?ZkwtpD There are changes to the DA system during adolescence that make it particularly sensitive to the effects of stress.67 For example, extracellular DA levels in the dorsal and ventral striatum are lower during adolescence, while DA activity in the PFC peaks during adolescence.84 This can also be seen when rats were subjected to social isolation rearing, where several effects on the DA system were observed. There was an increase in the in vivo firing rate and burst-like activity of putative DA neurons in the ventral tegmental area (PD 25-90),85 DA release and DA transporter activity was increased in the nucleus accumbens and dorsomedial striatum (PD 28-77),86 and DA innervation and turnover decreased in the mPFC (starting from PD 21-28).76,87,88 Furthermore, during adolescent social isolation rearing, DA activity and turnover increased in the nucleus accumbens.76,77,89,90 DA levels declined in the PFC in adulthood after repeated prolonged social isolation episodes in periadolescent mice (PD 15-21).91 The predator odor model in adolescent mice also showed decreased levels of D2 receptors in the mPFC.92 There was also lower basal tissue and extracellular DA levels and upregulated DA transporters in the PFC as a result of social defeat stress.93–96 Restraint stress and footshock increased responsivity of VTA DA neurons in adults when adolescent rats (PD 31-40) were exposed to these stressors.97 Lastly, DA levels in the mPFC were elevated in adulthood as a result of chronic variable physical stressors during adolescence (PD 27-33).98 2.5.3 Default Mode, Salience, and Central Executive Networks Recent research has highlighted the significant impact of larger brain networks in PTSD, extending the frontolimbic model to include key networks such as the default mode network (DMN) for self-referential thought, the salience network (SN) for detecting relevant cues, and the central executive network (CEN) for goal-directed behavior and emotion regulation.99 Typically, the DMN and CEN function in opposition, switching between internal processing and external tasks. In adult PTSD, studies show increased SN activity, decreased DMN and CEN activity, and poor regulation between the CEN and DMN, which may explain symptoms like hypervigilance and poor emotion regulation.100 Berkeley Pharma Tech Journal of Medicine | 46 https://www.zotero.org/google-docs/?dSIcvh https://www.zotero.org/google-docs/?KIBqSD https://www.zotero.org/google-docs/?6m1iPR https://www.zotero.org/google-docs/?EpsXUv https://www.zotero.org/google-docs/?APOhWQ https://www.zotero.org/google-docs/?uLa038 https://www.zotero.org/google-docs/?Kzpdrg https://www.zotero.org/google-docs/?wdNVpB https://www.zotero.org/google-docs/?6oeC9o https://www.zotero.org/google-docs/?QUqaW1 https://www.zotero.org/google-docs/?AgzYni https://www.zotero.org/google-docs/?ePGjW0 https://www.zotero.org/google-docs/?7p9UND Pediatric PTSD research suggests a hyperactive SN and decreased CEN engagement as children age, though large-scale network function studies in this group are limited. Initial research in youth with PTSD indicates increased DMN connectivity and greater anti-correlation between the DMN and CEN/SN compared to adults.101 Stronger CEN/SN connectivity correlates with fewer re-experiencing symptoms, suggesting compensatory use of executive control systems, which might also contribute to dissociative symptoms. However, additional research is required to understand network function in pediatric PTSD and its development over time. During acute stress, connectivity increases between DMN and CEN regions while decreasing between the SN and both DMN and CEN.102 Greater polyvictimization is associated with reduced connectivity between the DMN and the left insula of the SN, potentially disrupting emotion regulation. Further studies are necessary to clarify these dynamics and their impact on PTSD symptoms in youth. 2.6 Brain Region Connectivity 2.6.1 Changes and importance of neuroplasticity Neuroplasticity is the ability for the brain to form and reorganize synaptic connections following learning, experience, or injury. This is particularly important during development since stress strongly impacts social interactions and behaviors in developing adolescents, magnifying negative effects on neuroplasticity due to social isolation.103 Studies have found stress to impact the ability to develop neurons during adolescence. In two experiments, female rats exposed to chronic restraint stress or social instability during adolescence exhibited lower levels of neurogenesis in contrast to another study that reported increased neurogenesis in males.104–106 Interestingly, levels of brain-derived neurotrophic factor as well as neurogenesis was reduced in mildly-stressed adult animals but increased in adolescents.106 Due to this discrepancy, more studies are needed to determine the short and long-term effects of stress and trauma on neuroplasticity in male and female adolescents. 2.6.2 Alterations in brain region connectivity Berkeley Pharma Tech Journal of Medicine | 47 https://www.zotero.org/google-docs/?HgXncw https://www.zotero.org/google-docs/?0g8Ck7 https://www.zotero.org/google-docs/?9b1CBS https://www.zotero.org/google-docs/?VsKtr6 https://www.zotero.org/google-docs/?ddblQM Previous studies have found changes in connectivity between various brain regions in adolescents exposed to stress and trauma. For example, less coupling occurred between the amygdala and the ACC/dmPFC in youth with PTSD, which is also inversely associated with the severity of PTSD.18,19,101 These results are of interest because adolescents exposed to adversity that downregulate amygdala and ACC/dmPFC coupling exhibit depressive and anxiety symptoms during late adolescence.57 Furthermore, coupling between the amygdala and the vmPFC decreased in youth with PTSD in contrast to increases shown in typically developing youth.18 However, similar to discrepancies discussed previously, age-related differences can also be seen. Compared to typically developing youth, younger adolescents with PTSD show greater connectivity between the amygdala and vmPFC which reverses as they age.18 Overall, when accounting for age differences, amygdala and ACC/PFC connectivity has been shown to decrease in adolescents exposed to stress and trauma. Additionally, studies have shown that adolescent PTSD patients have decreased connectivity between the vmPFC to amygdala and vlPFC to hippocampus during development compared to healthy youth.47 In the posterior cingulate cortex (PCC) of healthy individuals, activity was correlated with activity in regions of the default network such as the mPFC, precuneus, lateral parietal cortices, inferior and middle temporal cortices, thalamus, and cerebellum.107 However, patients with early life trauma expressed only correlation between the PCC and right superior frontal gyrus and left ventrolateral thalamus. Additionally, connectivity between the PCC and precuneus, right amygdala, right hippocampus, mPFC, right insula, and bilateral lateral parietal cortex was higher in healthy controls than those with early life trauma. These results suggest that early life trauma may strongly impact development of the right hemisphere and the default network. Berkeley Pharma Tech Journal of Medicine | 48 https://www.zotero.org/google-docs/?lLwsl8 https://www.zotero.org/google-docs/?8M5bJL https://www.zotero.org/google-docs/?LI3FKn https://www.zotero.org/google-docs/?UQxcXj https://www.zotero.org/google-docs/?JwlXHh https://www.zotero.org/google-docs/?R9PAD5 (A) (B) Figure 3. Morphological effects of stress and trauma on the adolescent (A) outer brain regions and (B) inner brain regions. Berkeley Pharma Tech Journal of Medicine | 49 Figure 4. Physiological effects of stress and trauma on adolescent brain connections. 3. Discussion 3.1 Overall Effects Adolescence is a period of significant volumetric increases in the hippocampus and amygdala, cortical thinning in the frontal and temporal lobe, as well as heightened sensitivity to stress. This is mirrored by the time periods in which different parts of the brain are the most vulnerable to change due to abuse as mentioned above, exacerbating the importance of the study, prevention, and treatment of trauma and PTSD of adolescents. The physiological changes to the brain caused by trauma present differently depending on parts of the brain, but they largely affect neural networks that are related to emotional processing and memory. It is worth noting that many of the studies investigating this topic have been unable to differentiate the effects of different kinds of trauma on the developing brain, as it is often the case that youth with PTSD are subject to multiple and repeated traumas instead.3 Furthermore, many symptoms common to adults with PTSD like reduced hippocampal volume and hyperactivity of the amygdala and insula do not consistently present themselves in adolescents with PTSD. This is due to the increased stress sensitivity of the developing neural system, as well as delayed developmental effects.3 Berkeley Pharma Tech Journal of Medicine | 50 https://www.zotero.org/google-docs/?awbD4I https://www.zotero.org/google-docs/?ueUxkd PTSD in youth exhibits changes to the frontolimbic circuits that contribute to the psychological changes like increased threat reactivity and reduced emotion regulation capacity as they age, which can persist well into adulthood.2,3 It has commonly been speculated that these changes to the brain caused by trauma and PTSD are adaptations to aversive and threatening environments, as the neural circuits affected by trauma in adolescents affect the brain’s capacity to detect threat, threat extinction, and threat reactivity.3,47 In particular, the increased volume and activity of the amygdala, as well as the abnormal connectivity between the amygdala and different parts of the prefrontal cortex are indicative of early maturation of these processes, at the potential cost of sustained hypervigilance and an inability inhibiting threat responses. This ultimately leads to an improved automatic detection of threat, increased responsivity of the hypothalamic-pituitary axis stress response, impaired threat regulation, etc.3 There are many parts of the PFC that get affected as a result of early life stress and trauma, including the dorsolateral PFC, ventrolateral PFC, ventromedial PFC, precentral gyrus, and dorsomedial PFC. As stated above, there are discrepancies in how trauma affects gray matter volume in these areas, which seem to be due to differences in age-related factors and trauma/PTSD severity. The abnormal development of the PFC also showed evidence of decreased intrinsic connectivity with the amygdala and hippocampus over time. Furthermore, there has been mixed evidence on the activation of these parts as a result of PTSD, including the ventrolateral PFC, ventromedialPFC/rostral ACC, and dorsomedial PFC. There are many possible reasons for this, including task differences, trauma-related factors, sex differences, and age differences in the studies. A particularly important region of the PFC for emotional processing is the ventromedial PFC. The ventromedial PFC has been associated with the top down modulation of the amygdala responses and threat response inhibition. Abnormal development of the ventromedial PFC and reduced ventromedial PFC-amygdala coupling we’ve seen in both youth and adults with PTSD contributes to the reduced threat extinction and negative emotional processing capabilities of these youth.3,47 Berkeley Pharma Tech Journal of Medicine | 51 https://www.zotero.org/google-docs/?CX10hT https://www.zotero.org/google-docs/?HhXlM6 https://www.zotero.org/google-docs/?MQapiP https://www.zotero.org/google-docs/?3jjYV6 Adult PTSD is characterized in the hippocampus with reduced volumes. However, this is not consistently found in youth with PTSD.47 A possible reason for this is the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of PTSD, which has been shown to increase hippocampal neurogenesis and increase hippocampal gray matter volume in adults with PTSD.47 This suggests that the use of SSRIs can counteract the effects of trauma on the hippocampus by preventing the reduction of hippocampal volume. Another reason is the delayed developmental effect mentioned above, where the physiological effects of trauma take time to present themselves. Both the ventrolateral PFC and dorsolateral PFC have shown decreased connectivity with the anterior hippocampus in adolescents with PTSD. This is significant as the anterior hippocampus has many projections into the amygdala, and is involved in unconditioned threat responses. Both of these PFC regions are heavily involved in emotional processes; the ventrolateral PFC is associated with selection and inhibition of cognitive appraisals, while the dorsolateral PFC is associated with explicit emotion regulation through cognitive reappraisal.47 It can be hypothesized that this reduction in connectivity between the two parts of the PFC and the anterior hippocampus can result in a loss of inhibitory control of unconditioned threat responses, increased threat acquisition, and impaired threat extinction. However, the study by Heyn et al. was unable to confirm this, and further study including threat learning and emotion regulation is required.47 The physiological changes in the hippocampus as a result of stress doesn’t just affect the emotional and threat responses of the individual, but spatial memory and navigation as well. This is evident by the reduced spatial navigation capabilities in rats tested using the Morris Water Maze, which coincides with reduced volumes of the cornu ammonis 1, 3, and dentate gyrus.2 These reductions in volume in different parts of the hippocampus as a result of stressors shows that early life trauma does not just affect the emotional and threat responses of individuals, but other parts of mental capacity as well, such as spatial navigation and memory. Berkeley Pharma Tech Journal of Medicine | 52 https://www.zotero.org/google-docs/?ogCUq6 https://www.zotero.org/google-docs/?Slb9Lj https://www.zotero.org/google-docs/?8hehfB https://www.zotero.org/google-docs/?vGz6VU https://www.zotero.org/google-docs/?bVcGyM Overall, the physiological changes in adolescent brains caused by trauma contribute to the symptoms of PTSD that persist through adulthood, such as improved threat detection, impaired threat extinction, and reduced negative emotion regulation. These changes include abnormal gray matter volumes and connectivities throughout different parts of the PFC, amygdala, and hippocampus. These changes do not immediately present themselves, however, and can take many years to appear. Furthermore, these changes affect not only the emotional and threat processing circuits, but other brain regions responsible for thinking and memory as well. These effects of these physiological changes on the brain and emotional capabilities on the individuals highlight the importance of studying, treating, and prevention of trauma in adolescents. 3.2 Therapeutic Treatments The most effective treatments for adolescents who have experienced stress and trauma include a combination of therapeutic, hormonal, and lifestyle changes. Medication alone may not be effective in treating a patient with severe psychological illness, but medication combined with therapy may be. Cognitive behavioral therapy (CBT) is one of the most effective methods for helping individuals cope with trauma. CBT focuses on the interplay between thoughts, feelings, and behaviors. This therapy helps individuals challenge negative thought patterns and develop problem-solving skills. CBT is particularly desirable for adolescents because it equips them with the skills to manage distressing behaviors and emotional reactions. Trauma-focused cognitive behavior therapy (TF-CBT) is a subset of CBT designed to help those who have experienced significant trauma in their lives. This form of therapy often focuses on controlled exposure to emotions associated with the trauma, the creation of a trauma narrative, and relaxation techniques.108 TF-CBT is a short-term treatment, lasting up to 16 sessions of this type of therapy, and its main focus is to address post traumatic stress. TF-CBT relies on the individual’s ability to master the therapeutic techniques learned during the session in order to practice them routinely after the sessions have ended.109 A meta-analysis of published and Berkeley Pharma Tech Journal of Medicine | 53 https://www.zotero.org/google-docs/?UiFPvF https://www.zotero.org/google-docs/?UqRfT5 unpublished data regarding the efficacy of CBT for PTSD in adolescents found that “participants who received CBTs-TF had lower mean post-traumatic stress symptoms after treatment than those who received the control conditions, after adjusting for post-traumatic stress systems before treatment.”110 According to an article by Evgenia Gkintoni et al. assessing the efficacy of different therapeutic interventions for PTSD in adolescents: “Among the array of therapeutic interventions analyzed, CBT and specifically TF-CBT emerge as the most effective and extensively employed methodologies for addressing PTSD in children and adolescents.”111 Eye movement desensitization and reprocessing (EMDR) is another popular form of therapy used to treat post traumatic stress. EMDR is based on the Adaptive Information Process (AIP) model of storing memories, which suggests that some traumatic events can remain “unprocessed” by the brain and stay “stuck” in the body, resulting in negative emotions and adverse responses to similar situations as the traumatic event. By having the individual “focus on external stimuli” while recalling these traumatic events, EMDR aims to desensitize the individual to their own traumatic experiences.112 EMDR helps to mitigate the effects of stress and trauma on the brain by using bilateral stimulation, in the form of guided eye movements, while the brain recalls traumatic events. The eye movements are thought to stimulate the information processing region of the brain, which enables the reprocessing of traumatic memories into less distressing ones. Bilateral stimulation allows the participant to reconstruct a more coherent traumatic narrative, reducing the emotional impact of the event itself.113 Significant research suggests that EMDR is beneficial for minimizing the effects of PTSD by desensitizing the participant, allowing the individual to think about their traumatic event without inciting an intense emotional response.114 While EMDR was originally meant to be used on adults, the therapy has been relatively recently extended to help children of all ages. EMDR would be beneficial for adolescents who have experienced any sort of trauma because it is a holistic approach to healing and provides them with the tools to manage distressing emotions that may arise in their future. 3.3 Hormonal Treatments Berkeley Pharma Tech Journal of Medicine | 54 https://www.zotero.org/google-docs/?7YuCUy https://www.zotero.org/google-docs/?EvIFqw https://www.zotero.org/google-docs/?ssPp8R https://www.zotero.org/google-docs/?ggQwsK https://www.zotero.org/google-docs/?yVM46q In addition to employing a myriad of therapeutic treatments, adolescent trauma survivors can also take medication to alleviate the psychological symptoms of PTSD. The hormonal treatments focus on addressing the dysregulation of the HPA axis which is often disrupted in adolescents who have experienced stress and trauma. Most recently, glucocorticoid-therapy based treatments have become popular for treating PTSD in individuals of all ages.115 The glucocorticoids are used to normalize levels of cortisol, commonly known as the stress hormone, in order to mitigate the physiological and psychological effects of stress on the individual. Glucocorticoids are thought to prevent the overactivation of the HPA axis which is commonly seen in individuals suffering from PTSD.116 Glucocorticoids impair memory consolidation and impairs the retrieval of adverse memories. Glucocorticoids have been used both as a treatment and preventative method for individuals that may be more susceptible to developing PTSD.115 Although the use of glucocorticoids presents promising results, there are some negative side effects that should be taken into consideration when choosing the most effective treatment plan for the patient. Some side effects of glucocorticoid use are insomnia, edema, and hypomania. These side effects, coupled with the daily struggles of adolescence, may make this relatively new form of therapy not entirely desirable for this age group. It may be a few years before biochemists and physician-scientists refine the treatment approach for this therapeutic drug, but the potential for glucocorticoids to prevent and treat PTSD is there.117 Psychedelic drugs, such as ketamine and MDMA, are being used as alternative hormonal therapies to treat PTSD and other stress-related disorders. Ketamine is a dissociative anesthetic which acts on the brain’s N-methyl-D-aspartate (NMDA) receptors involved in mood regulation and synaptic plasticity. Ketamine infusions are intravenous and have been most widely used to treat major depressive and anxiety disorders, specifically in previously treatment-resistant patients.118 There is a current clinical trial entitled “Ketamine-Assisted Psychotherapy for Adolescents PTSD (KAP)” that aims to investigate the efficacy of ketamine infusions for adolescents diagnosed with PTSD. The study is set to commence in August 2024 and conclude a year later. Participants will receive three intravenous ketamine administrations before receiving psychotherapy sessions over a six week Berkeley Pharma Tech Journal of Medicine | 55 https://www.zotero.org/google-docs/?fam0B4 https://www.zotero.org/google-docs/?LILuNF https://www.zotero.org/google-docs/?SyILw6 https://www.zotero.org/google-docs/?aTt3DP https://www.zotero.org/google-docs/?Wu2qUo course. Then, participants’ sleep will be monitored using SmartSleep EEG recording headset for seven consecutive days. The researchers hypothesize that, following the ketamine infusion therapy, the participants’ PTSD symptom severity will decrease.119 As opposed to psychedelics, selective serotonin reuptake inhibitors (SSRIs) are more widely accepted drugs that have been used since the late 1980s to treat major depressive disorders and anxiety, which can result from complex trauma and stress in adolescents. SSRIs function by increasing the amount of serotonin in the brain, a neurotransmitter responsible for feelings of happiness and mood regulation. SSRIs can often mitigate the symptoms of depression and anxiety by reducing the intensity of emotions and emotional responses.120 Some SSRIs include sertraline (Zoloft), paroxetine (Paxil), and fluoxetine, but only sertraline and paroxetine are currently FDA approved as treatments for PTSD.121,122 SSRIs are most effective when used alongside other therapeutic treatment methods, like CBT or EMDR. Additionally, this hormonal treatment is appealing to adolescents suffering from PTSD because it stabilizes mood and regulates complex emotions that arise from traumatic experiences. That being said, SSRIs can also have adverse side effects, such as significant weight gain and changes in appetite which can be particularly harmful to adolescents who already struggle with body dysmorphia and/ or disordered eating as a result of the stress and trauma. Finally, the use of SSRIs can result in dependency, which makes tapering off them an added challenge for adolescents who may not want to take them long term.123 In addition to SSRIs, alpha-adrenergic blockers (Prazosin) is also an effective hormonal treatment for PTSD in adolescents. Alpha-adrenergic blockers, also known as alpha-1 adrenergic receptor antagonists, block alpha-receptors on cells within the body, which can be used to treat high blood pressure and stress-related disorders like PTSD. Within the scope of this article, alpha-adrenergic blockers limit adrenergic activity which reduces the body’s stress response. Research suggests that alpha-adrenergic blockers are effective at minimizing hyperarousal symptoms associated with PTSD which can manifest in adolescents as extreme moodiness and heightened anxiety. By blocking the alpha-1 adrenergic receptor, the body decreases its Berkeley Pharma Tech Journal of Medicine | 56 https://www.zotero.org/google-docs/?tyvoBe https://www.zotero.org/google-docs/?mML1N0 https://www.zotero.org/google-docs/?J61V8Q https://www.zotero.org/google-docs/?AJ2ezl parasympathetic and sympathetic responses, which are responsible for activating the “fight or flight” feelings.124 Finally, PTSD can disrupt particular stages of the sleep cycle, like the rapid eye movement (REM) stage, and these alpha-adrenergic blockers are known to restore this sleep stage. While alpha-adrenergic blockers have been most suitable for treating PTSD in war veterans due to the high incidence of sleep disturbances and night terrors in this population, studies suggest that it may also be used for treating PTSD and other stress-related disorders in other groups as well.125 Maintaining proper sleep quality is essential for adolescents in particular as sleep regulates emotions and determines cognitive functioning during the day. The negative side effects of Prazosin include dizziness and headaches due to slight hypotension.125 Just as with other hormonal treatments, alpha-adrenergic blockers are most effective when used in combination with other therapeutic treatments discussed above. An ongoing clinical trial entitled “Sleep and Emotion Processing in Adolescent Post Traumatic Stress Disorder” explores the role of sleep in emotional processing and reactivity in adolescents with PTSD. Subject ages from 12 to 17 years old, and all have been previously diagnosed with PTSD. The researchers plan to use electroencephalogram (EEG) tests to determine the quality of sleep in their subjects. Using sleep enhancement algorithms, researchers hope to investigate if the deepest sleep, non-rapid-eye-movement (NREM), can be clinically enhanced in adolescents suffering from sleep disturbances due to PTSD.126 This study could potentially lead to targeted interventions for improving sleep and mitigating the effects of PTSD in adolescents. 3.4 Lifestyle Changes In addition to biochemical and therapeutic treatments, adolescents can also make lifestyle changes that may mitigate the effects of stress and trauma on the body and the brain. Perhaps the most important lifestyle change for treating PTSD is to engage in physical activity. Exercising releases endorphins, which reduce symptoms of anxiety and depression and is known to stabilize mood. Research suggests that “aerobic exercise, which improves cardiorespiratory fitness, is an effective treatment for depression, Berkeley Pharma Tech Journal of Medicine | 57 https://www.zotero.org/google-docs/?SZILuH https://www.zotero.org/google-docs/?7VXKp3 https://www.zotero.org/google-docs/?WkVbeH https://www.zotero.org/google-docs/?jYglqp anxiety, and schizophrenia through both physiological and psychological mechanisms, and may be comparable or superior to other common treatments, such as psychotherapy and pharmacology.”127 Additionally, a balanced diet plays an important role in maintaining emotional wellbeing. A diet rich in whole grains, vitamin D and B12, and lean proteins can minimize physiological and psychological effects of stress on the brain as well as regulate mood and emotions. In an article recently published by Harvard T.H. Chan School of Public Health, a study suggests that a mediterranean diet may help to mitigate the symptoms of PTSD.128 Additionally, caffeine in chocolate, coffee and other fountain drinks act as a stimulant, enhancing the body’s stress response and ultimately exacerbating PTSD symptoms. This is particularly important for this age group, as coffee and energy drinks are popular beverages among middle and high school students. Figure 5. Infographic for Effective Treatments for PTSD in Adolescents - Some effective therapeutic treatments for PTSD in adolescents include CBT, TF-CBT, and EMDR. Additionally, hormonal treatments, such as glucocorticoids and SSRIs can be used to mitigate symptoms from stress-related disorders. Finally, lifestyle changes like maintaining a well-balanced diet and a routine sleep schedule can help to normalize cortisol levels in the body.129–136 3.5 Future Research Future research on the effects of stress and trauma on adolescent brain development should focus on several key areas to enhance our understanding and ultimately improve health outcomes. For one, Berkeley Pharma Tech Journal of Medicine | 58 https://www.zotero.org/google-docs/?dnXhWX https://www.zotero.org/google-docs/?zFP7Bq https://www.zotero.org/google-docs/?HgtkcC physician-scientists could conduct long-term research that follows subjects from childhood, through adolescence, and into adulthood to investigate the long term effects of trauma on the mind and body. Additionally, these studies could investigate which period of development interventions are most effective. It would also be beneficial to explore resilience factors that may affect how trauma manifests itself in the body as well as the healing process. Factors like social support, coping mechanisms, and genetic predispositions all play significant roles in the body’s response to stress and trauma. Since this article is geared towards adolescents, it would be important to investigate how the use of social media might reduce or exacerbate the effects of stress and trauma on the brain. Additionally, there needs to be more research done on the socio-economic and cultural factors that might influence how adolescents process trauma and ultimately heal from it as well. Access to mental health resources may mitigate the effects of trauma on the adolescent brain, so this would be an important area to explore when determining health outcomes. Finally, it would be interesting to investigate how collective traumas like cultural diasporas and natural disasters affect the brain, morphologically and psychologically. This information could provide a point of comparison to how individual traumas, like experiences in childhood, affect the adolescent brain. 4. Conclusion 4.1 Summary of Main Ideas Adolescent trauma has been shown to induce severe physiological and psychological stress, including disorders such as PTSD, anxiety, and depression. Some regions in the adolescent brain have also been shown to be in a sensitive period during that time and are particularly vulnerable to stress and trauma. Studies in both animal and human models reflect this sensitivity since exposure to stressors during adolescence results in lasting brain changes and impaired cognitive function. This underscores the need for more research and treatment efforts to address stress and trauma in adolescents. Berkeley Pharma Tech Journal of Medicine | 59 Clinical trials as well as rodent studies have mapped the effects of stress and trauma on adolescent brain development. Most notably, individuals with exposure to stress or trauma exhibited altered volume in brain regions with increased volume in the amygdala, reduced volume in the hippocampus, and various changes in PFC matter according to specific location. Additionally, studies have shown reduction in corpus callosum volume, decreased brain connectivity, and changes in the HPA axis, DA levels, and larger brain networks. It is important to mention that many studies reported conflicting results; however, many of these discrepancies were eliminated when analyzing based on age-related effects. The most effective treatments for adolescent PTSD often combine hormonal, therapeutic, and lifestyle treatments. CBT, specifically TF-CBT, addresses negative thought patterns associated with PTSD and is one of the most common treatments for adolescents. Another therapeutic option, EMDR, helps those with PTSD process memories. Therapeutic treatments, which mitigate psychological symptoms, are often combined with hormonal treatments, including glucocorticoids, ketamine, SSRIs, and alpha-adrenergic blockers which target underlying biological processes. Additionally, lifestyle changes such as exercise, a balanced diet, and limited caffeine intake are commonly recommended. 4.2 Practical Applications This research article has several practical applications that may impact mental health treatment and public health policies. Understanding how stress and trauma affect the brain as well as how these morphological changes manifest themselves as emotional and behavioral changes is important for early detection of PTSD and other stress-related disorders. Early identification is necessary for timely intervention, which significantly improves health outcomes. Therefore, this article can be used as an informational guide for those who care for and work closely with adolescents, such as parents, pediatricians, and educators. In school settings, teachers can be trained to recognize the signs of trauma in their students, which would help early detection and prevention. Along with teachers, students could attend required educational sessions on trauma so that they, themselves, are aware of the effects of trauma and can spot warning signs Berkeley Pharma Tech Journal of Medicine | 60 well in advance of symptoms worsening. Finally, this review article could be used for the development of new and effective mental health treatments and policy advocacy. Public health policies could leverage the insights gained from this article to advocate for community-based initiatives that address several systemic causes of stress and trauma such as poverty and familial violence. 4.3 Acknowledgements We would like to thank Ms. Vanloan Nguyen for her guidance and support throughout the writing process of this paper. We would also like to thank Hayden Loc-Jun Wong, Aditi Shankar and Luke Wang for feedback on our manuscript. Figures were created with BioRender.com. Berkeley Pharma Tech Journal of Medicine | 61 References 1. Teicher MH, Samson JA. Annual Research Review: Enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry. 2016;57(3):241-266. doi:10.1111/jcpp.12507 2. Eiland L, Romeo RD. Stress and the Developing Adolescent Brain. Neuroscience. 2013;249:162-171. doi:10.1016/j.neuroscience.2012.10.048 3. Herringa RJ. Trauma, PTSD, and the Developing Brain. 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