Review Article | Published:

Biological studies of post-traumatic stress disorder

Nature Reviews Neuroscience volume 13, pages 769787 (2012) | Download Citation


Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

Key points

  • Perhaps the most well-replicated biological finding in post-traumatic stress disorder (PTSD) is higher autonomic (heart rate and skin conductance) and facial electromyography responding during internal, mental imagery of the traumatic event and upon exposure to external, trauma-related cues.

  • Higher heart rate responding to sudden loud tones in PTSD probably reflects an acquired sensitization of the nervous system.

  • Diminished volumes of the hippocampus and anterior cingulate cortex are the most frequently replicated neuroanatomic findings in patients with PTSD. These do not appear to be fully explained by comorbid conditions such as substance abuse and depression.

  • Some evidence exists to support both pre-existing vulnerability and neurotoxicity as origins of brain volume reductions in PTSD. On the basis of present data, it is going too far to say that stress damages the brain, but there is no doubt that it changes it.

  • Functional neuroimaging studies suggest that the amygdala and dorsal anterior cingulate cortex are hyper(re)active, whereas the ventral medial prefrontal cortex is hypo(re)active, in PTSD. These abnormalities are likely to underlie the attentional bias towards threat, impaired emotion regulation and persistence of fear memories in this disorder.

  • The classic model of stress based on chronic hyperactivity of the hypothalamus–pituitary–adrenal cortical axis does not characterize PTSD.

  • A number of neurotransmitters and neuroendocrinological factors interact to influence PTSD risk, symptom profiles and severity. These factors vary across individuals owing to genetic and epigenetic factors, as well as within individuals over time in response to environmental influences, including exposure to psychological trauma.

  • As with other mental disorders, genetic vulnerability to PTSD is likely to involve the sum of contributions from multiple alleles, each with small effects.

  • The full range of molecular genetic factors, which include genotype, methylation, histone deacetylation and gene expression, probably influence or accompany the development of PTSD. However, at this time, there are no definitive findings for any one gene or gene system in the aetiology of the disorder.

  • Animal models have identified important molecular pathways that are likely to contribute to the pathophysiology of PTSD and may constitute promising therapeutic targets.

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Author information


  1. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Roger K. Pitman
    • , Lisa M. Shin
    • , Scott P. Orr
    •  & Mohammed R. Milad
  2. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Roger K. Pitman
    • , Scott P. Orr
    • , Mark W. Gilbertson
    •  & Mohammed R. Milad
  3. Veterans Affairs Boston Healthcare System and National Center for PTSD, Women's Health Science Division, Boston, Massachusetts 02130, USA.

    • Ann M. Rasmusson
  4. Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

    • Ann M. Rasmusson
  5. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.

    • Karestan C. Koenen
  6. Department of Psychology, Tufts University, Boston, Massachusetts 02155, USA.

    • Lisa M. Shin
  7. Research Service, Veterans Affairs Medical Center, Manchester, New Hampshire 03104, USA.

    • Mark W. Gilbertson
  8. Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

    • Mark W. Gilbertson
  9. Psychiatry Service, Veterans Affairs Medical Center, Ann Arbor, Michigan 48105, USA.

    • Israel Liberzon
  10. Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48103, USA.

    • Israel Liberzon


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The authors declare no competing financial interests.

Corresponding author

Correspondence to Roger K. Pitman.

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  1. 1.

    Supplementary information S1 (table)

    Summary of Candidate Genes Studied in Relation to Posttraumatic Stress Disorder


Skin conductance

A measure of sweat activity recorded from two adjacent fingers and/or the thenar and hypothenar eminences of the palm of the hand. It is thought to be primarily under sympathetic nervous system influence.

Event-related potentials

(ERPs). Electrical potentials that are generated in the brain as a consequence of the synchronized activation of neuronal networks by external stimuli. These evoked potentials are recorded at the scalp and consist of precisely timed sequences of waves or 'components'.


A procedure by which a conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, resulting in diminution of the conditioned response.


An electroencephalographic event-related potential response that is positive and reaches its maximum deflection approximately 300ms after a stimulus is presented. It is thought to reflect the amount of attentional resources allocated to the stimulus.

Fear conditioning

An experimental paradigm that teaches an animal or human to associate a previously neutral conditioned stimulus (CS; for example, a light or a tone) with an aversive unconditioned stimulus (for example, an electric shock), the latter of which produces an aversive unconditioned response. Eventually, because of the association, the CS alone comes to elicit a fear response.

Extinction retention

Memory that a conditioned stimulus has been previously extinguished, expressed as a continuing reduction of the conditioned response. It is also called extinction recall.

Fear-potentiated startle

An increased electromyographic responsiveness to a startling stimulus that occurs when an animal or human is afraid.


An electroencephalographic event-related potential response that is positive and reaches its maximum deflection approximately 200ms after a stimulus is presented. It is thought to reflect 'tuning' of a mechanism that regulates the amount of sensory input to the cortex.

Conditioned fear

Fear that is elicited by a conditioned stimulus (or cue) following fear conditioning. Typical measures include freezing in rodents, skin conductance in humans and potentiated startle in both.

Corrugator EMG

A measure of electromyographic activity associated with contraction of the corrugator supercilii muscle, which draws the inner brow inward and downward during negatively valenced emotion.

Structural MRI

(sMRI). A non-invasive diagnostic and research procedure that uses a magnetic field and radio waves to create detailed sectional images of the internal structure of the body, including the brain.

Ventromedial prefrontal cortex

(vmPFC). A region within the medial wall of prefrontal cortex that roughly corresponds to Brodmann area 10. Some studies treat portions of adjacent Brodmann areas as part of the vmPFC.


A sector of the cornu ammonis subfield of the hippocampus and a major target of glucocorticoids.

Dentate gyrus

A subfield of the hippocampus that contains adult neural stem cells and is an important site of neurogenesis.

Magnetic resonance spectroscopic imaging

(MRSI). A non-invasive research and diagnostic technique that is similar to MRI but uses a stronger field to detect regional body chemistry at the cellular level. It is also called 1H-nuclear magnetic resonance spectroscopic imaging and proton magnetic resonance spectroscopic imaging.


A putative marker of neuronal integrity thought to be present predominantly in neuronal cell bodies. It emits the largest signal in magnetic resonance spectroscopic imaging of the human brain.

Dorsal anterior cingulate cortex

(dACC). A cortical area that roughly corresponds to Brodmann area 24. It may also be called anterior the mid-cingulate cortex.

Voxel-based morphometry

An automated neuroimaging analytic technique that allows the investigation of focal differences in brain anatomy using the statistical approaches of statistical parametric mapping and smoothing applied to structural images.

Diffusion tensor imaging

A structural MRI-based technique that tracks the diffusion of water molecules within a closed space, usually a tube such as a neural axon. It is useful in revealing white matter fibre structure and providing information regarding regional brain connectivity.

Positron emission tomography

(PET). A functional neuroimaging technique that uses radioactive isotopes to quantify regional cerebral blood flow, glucose metabolism or receptor occupancy.

Functional MRI

(fMRI). A functional neuroimaging technique that uses a magnetic field and radio waves to measure the blood-oxygenation-level-dependent signal, which serves as an index of regional brain activation.


Designating intermittent signalling, usually in response to a stimulus.


The splitting off of a mental process or group of mental processes from the main body of consciousness.


Designating continuous, steady or baseline signalling.


Located outside the synapse. Extrasynaptic receptors can be accessed by neuromodulatory factors derived from the periphery and circulating in the cerebrospinal fluid.


Capable of being passed from one generation to the next via DNA.

Single-nucleotide polymorphism

(SNP). A variation in a DNA sequence in which a single nucleotide (A, C, G or T) at a specific locus differs between members of the same biological species or between paired chromosomes of an individual.


An alteration in the response of a neuron induced by a substance that would not, by itself, affect neuronal firing rate.

DNA methylation

The modification of a strand of DNA in which a methyl group is added to a cytosine molecule that stands directly before a guanine molecule in the same chain. It has the effect of reducing gene expression.


One or more alternative forms of a genetic locus or a gene.


One or more mechanisms that regulate gene function without altering the underlying DNA sequence.

Face validity

The degree to which a model or a term appears to measure what it is supposed to measure.

Construct validity

The degree to which a model or a term corresponds to or reflects an underlying theory.

Glucocorticoid negative feedback

A negative-feedback phenomenon by which cortisol reduces its own release through inhibition of the hypothalamus–pituitary–adrenal cortical axis.

Brain-derived neurotrophic factor

(BDNF). A protein that is often released from a neuron, and that is involved in growth and the differentiation of new neurons and synapses.


A membranous tyrosine kinase receptor that binds brain-derived neurotrophic factor and other neurotrophic factors (also known as neurotrophins).

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