




































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 

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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. 
 
 

 

 

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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 

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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 

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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 

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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, 

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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 

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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 

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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  
 

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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 

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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 

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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. 

 

 
 

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(A) 

 
(B) 

Figure 3. Morphological effects of stress and trauma on the adolescent (A) outer 
brain regions and (B) inner brain regions. 

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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  

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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  

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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. 

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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 

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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 

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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 

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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 

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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, 

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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, 

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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. 
 

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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. 

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