Catecholamines are a group of neurotransmitters that include dopamine, norepinephrine, also called noradrenaline, and epinephrine, also called adrenaline. The sympathetic nervous system stimulates the release of catecholamines to mediate adaptive responses to acute stress. Catecholamines are also linked to long-term memory of events that induce strong emotions, including fear. Stress-responsive neurotransmitters released during emotional arousal are thought to enhance the consolidation of fear memory. Hyperresponsiveness in the dopaminergic system is common in individuals who have been exposed to stress, which was associated with PTSD symptoms such as restlessness, nightmares, fear memory, and impulsivity. Over activation of noradrenaline receptors could be associated with the flashbacks, and nightmares frequently experienced by those with persistence of PTSD symptoms.

What is the evidence for changes in catecholamines in people with PTSD?

Moderate to high quality evidence found a small increase in plasma or urinary norepinephrine levels in people with PTSD, with no differences in epinephrine or dopamine levels compared to controls without PTSD. Containing the epinephrine analysis to urine samples showed increased epinephrine in people with PTSD compared to controls.

August 2021

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Electroencephalography (EEG) has been used to study changes in brain functioning in people with PTSD. It uses electrodes on the scalp to measure electrical activity from the brain. Quantitative spectral EEG investigates several waveforms so the activity can be measured. However, EEG also gives rise to event related potentials (ERP). These measure the EEG activity directly evoked by a stimulus, often using cognitive or perceptual stimuli.

P300, also referred to as P3, may be the ERP most suitable for the assessment of PTSD. This is because it is well documented, and with the appropriate stimulus can convey information about attention and working memory. P300 refers to a spike in activity approximately 300ms following presentation of a target stimulus. The target stimulus is alternated with standard stimuli to create an ‘oddball’ paradigm, which is most commonly auditory. In this paradigm, the subject must respond only to the infrequent target stimulus rather than the frequent standard stimulus. The amplitude of the P300 response is proportional to the amount of attentional resource devoted to the task and the degree of information processing required. The latency is considered a measure of stimulus classification speed, unrelated to behavioural response time.

What is the evidence for changes in electroencephalography (EEG) readings in people with PTSD?

Moderate quality evidence found large increases in P3a (involuntary attention) amplitude with trauma-related distractors in people with PTSD compared to trauma-exposed people without PTSD. Medium-sized effects showed P3b (voluntary attention) amplitude was also increased with trauma-related distractors in people with PTSD. This was found in frontal and central brain regions, but not in parietal brain regions.

There were medium-sized reductions in P3b amplitude with neutral distractors in people with PTSD compared to healthy controls. There were also small reductions in P3wm (working memory) amplitude with neutral distractors in parietal, but not in frontal and central regions of people with PTSD.

August 2021

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Functional magnetic resonance imaging (fMRI) measures blood flow to determine activation and deactivation of specific brain regions. Positron emission tomography (PET) is a nuclear based imaging technique that utilises a radioactive tracer to visualise functional brain activity. The radioisotope tracers are coupled with a biological molecule such as glucose, which is used during cellular metabolism and can be used to highlight areas with changes in metabolic activity. Single-photon emission computed tomography (SPECT) offers more limited spatial and temporal resolution than PET but is less expensive as it does not require a cyclotron in close proximity.

What is the evidence for changes in brain functioning in PTSD?

Compared to non-trauma-exposed controls, moderate to high quality evidence found clusters of increased activation in PTSD during resting state or task processing in bilateral anterior insula, left amygdala, left putamen, left precuneus, right hippocampus, right middle frontal gyrus fusiform gyrus, and right postcentral gyrus. Clusters of decreased activation were found in bilateral precentral gyrus, left angular gyrus, left supramarginal gyrus, left middle frontal gyrus, right posterior cingulate cortex, right medial prefrontal cortex, and right caudate nucleus.

Compared to trauma-exposed controls, people with PTSD showed clusters of increased activation in the left fusiform gyrus, right precuneus, right thalamus, dorsal anterior cingulate cortex, and lateral medial temporal lobe. Clusters of decreased activation were found in the left thalamus, left parahippocampal gyrus, right medial prefrontal cortex, right orbitofrontal cortex, right precentral gyrus, left frontal pole, bilateral inferior frontal gyrus, bilateral middle frontal gyrus, and dorsal anterior cingulate cortex.

During trauma-related autobiographical memory tasks, moderate quality evidence found increased clusters of activation in PTSD compared to trauma-exposed controls in the left posterior cingulate extending into the precuneus and the mid-cingulate cortex, right parahippocampal gyrus, and the right dorsal anterior cingulate cortex. There were clusters of decreased activation in PTSD in the right ventromedial prefrontal cortex extending into the orbitofrontal and the perigenual anterior cingulate, and the left midline nucleus of the thalamus extending into the medial and the lateral dorsal nuclei and the left angular gyrus.

Compared to people with major depressive disorder, there was more activation in the PTSD group during negative affect processing in the left inferior frontal gyrus (including ventrolateral prefrontal cortex), bilateral amygdala and hippocampus, left superior frontal gyrus, dorsolateral prefrontal gyrus, and right middle frontal gyrus.

Compared to people with borderline personality disorder, moderate to low quality evidence found more activation in the PTSD group during negative affect processing in the left inferior frontal gyrus, left middle temporal gyrus, right striatum, bilateral middle frontal gyrus (including parts of the left superior frontal gyrus, dorsolateral), ventral premotor cortex, and the right posterior parietal cortex.

August 2021

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GABA is the most important inhibitor of neurotransmitters in the central nervous system and is often dysfunctional in people with mood disorders. It has also been investigated in people with PTSD. GABA can be measured via peripheral levels in plasma, via central levels in cerebrospinal fluid, and in brain regions using proton magnetic resonance spectroscopy.

What is the evidence for changes in GABA in people with PTSD?

Moderate to low quality evidence found no significant differences in brain GABA levels between people with PTSD and controls.

August 2021

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The biological response to stress is mediated through the Hypothalamic-Pituitary-Adrenal (HPA) axis and the sympathetic nervous system. Cortisol and the steroid hormone dehydroepiandrosterone (DHEA) and its sulfate form DHEA-S are important for elucidating the role of HPA dysfunctions in PTSD. Stress is a threat to the body’s ability to regulate internal processes following exposure to an adverse event. People adapt physiologically and behaviourally in response to stress to re-establish internal balance. Altered HPA axis activity can be detrimental to physical and psychological health.

What is the evidence for HPA dysfunction in people with PTSD?

Moderate to high quality evidence found small decreases in morning and 24-hour cortisol levels in people with PTSD compared to controls. The effect was larger in studies with non-trauma-exposed controls than in studies with trauma-exposed controls. Moderate quality evidence found no significant changes in cortisol levels or in the cortisol awakening response following psychosocial treatments for PTSD.

Moderate to high quality evidence found no significant differences in DHEA or DHEA-S levels compared to controls, apart from higher evening DHEA levels in people with PTSD when compared to non-trauma exposed controls.

August 2021

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The immune system is the body’s first line of defence. It uses proteins called cytokines that are secreted by immune cells to allow cell-to-cell communication. Cytokines include interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), transforming growth factors (TGF), and chemokines. These have influence over many cell types, including T helper lymphocytes (Th cells, or white blood cells). Cytokines act to regulate immunological and inflammatory responses to pathogens. They function as intermediaries between the immune system and the central nervous system. C-reactive protein (CRP) is released by the body during inflammation. Increased CRP blood levels are not only suggestive of infection, but also chronic inflammatory conditions, including cardiovascular disease, diabetes, and metabolic dysfunction. Alterations to the immune system have been found in bipolar disorder and schizophrenia, and it has also been investigated in people with PTSD.

What is the evidence for changes in the immune system in people with PTSD?

Moderate to high quality evidence found large increases in IFN-γ, IL-2, IL-1β, and IL-6, and medium-sized increases in TNF-α, WBC, and CRP in people with PTSD compared to controls. There were no differences in IL-4, IL-8, IL-10, lymphocyte, B lymphocyte, CD3+ T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, or NK cell. The effect sizes became non-significant in medicated patients for IL-1β, IL-2, and IL-6. The effect for CD8+ T lymphocyte became significant when using only trauma-exposed controls (reduced levels in patients). When using only non-trauma-exposed controls, the effect for IL-1β became non-significant, while the effect for IL-10 became significant (increased levels in patients). In patients without comorbid major depression, the effect sizes for IL-8 and CD4+ T lymphocyte became significant (increased levels in patients).

August 2021

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Metabolites include N-acetylaspartate (NAA), creatine (Cr), trimethylamines/ choline containing compounds (Cho) and glutamine (Gln). These derivatives are indirect indicators of biochemical activity. Alteration in levels of NAA/Cr ratio is associated with reduction in the protective myelin sheath surrounding neurons. Decreased levels of NAA are associated with neuron death, or injury to the part of the neuron that connects to other cells, the axon. Alterations in some neurometabolites have been found in bipolar disorder and schizophrenia, and these have been investigated in PTSD.

What is the evidence for neurometabolite alterations in people with PTSD?

Moderate quality evidence found medium-sized reductions in NAA concentration in the hippocampus and the anterior cingulate cortex of people with PTSD compared to controls. NAA/Cr ratio may also be reduced.

August 2021

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Neuropeptides are a class of molecules that can modulate the activity of neurotransmitters to increase or decrease the strength of synaptic signalling. Different neuropeptides are involved in different brain functions such as reward, food intake, metabolism, reproduction, social behaviours, and learning. Peripherally, they function like peptide hormones and modulate many bodily functions.

What is the evidence for neuropeptides in people with PTSD?

Moderate quality evidence found a large effect of lower neuropeptide Y levels in people with PTSD compared to controls without PTSD. This effect was also found in non-medicated samples.

High quality evidence found no significant differences in oxytocin levels between people with PTSD and controls.

August 2021

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Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor, are altered in bipolar disorder and schizophrenia. They regulate neuronal survival and growth during development. Effects of neurotrophins on neuronal transmission in the hippocampus, cortex, cerebellum, and basal forebrain are important for learning and memory processes.

What is the evidence for changes in neurotrophins in people with PTSD?

Moderate to low quality evidence found no significant differences in BDNF levels between people with PTSD and controls without PTSD.

August 2021

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