Periaqueductal Gray

Anatomy

• Gray matter encircling the cerebral aqueduct (of Sylvius) in the mesencephalon; extends rostrally to the third ventricle and caudally to the fourth ventricle.
• Four longitudinal columns: dorsomedial, dorsolateral, lateral and ventrolateral.
• Input: central nucleus of the amygdala, hypothalamus, mPFC/ACC, insula. Output: rostral ventromedial medulla (RVM), brainstem autonomic nuclei, thalamus.
• Blood supply: branches of the posterior cerebral and superior cerebellar arteries.
• The columns can be imaged in humans: at 7 T fMRI (0.75 mm), emotional images activated lateral and dorsomedial regions in rostral PAG and ventrolateral regions in caudal PAG; lateral and ventrolateral regions grouped with different emotions (anger, sadness) (Satpute et al., 2013). The column model from animals appears to hold in humans. B

Functions

• Active defense (dorsolateral/lateral column): fight-or-flight, tachycardia, raised blood pressure.
• Passive defense (ventrolateral column): freezing, immobility, bradycardia, hypotension.
• Endogenous pain control: opioid-mediated descending inhibition (PAG → RVM → dorsal horn of the spinal cord); stress analgesia. Placebo analgesia uses the same route: naloxone reduced the placebo effect and abolished rostral ACC–PAG coupling (Eippert et al., 2009). The biological counterpart of expectation and safety reducing pain. B
• Emotional vocalization: crying, separation calls.
• Tuning breathing and autonomic responses to the emotional state.

Connections and chemistry

• Central nucleus of the amygdala → PAG (defensive output)
• Hypothalamus ↔ PAG
• vmPFC/ACC → PAG (top-down regulation)
• PAG → RVM → spinal cord (descending pain control)
• Endogenous opioids, GABA, glutamate, endocannabinoids

Development

Developmental course through childhood and adolescence.

• A phylogenetically old structure that is functional at birth; the infant’s separation cry and basic defensive reflexes are organized at this level.
• Top-down regulation from the vmPFC/ACC matures over years; in young children regulation relies largely on the caregiver.

Clinical

• Panic disorder: dorsal PAG stimulation produces panic-like symptoms (a smothering sensation, the urge to flee).
• PTSD and dissociation: the dorsolateral PAG drives active defense (fight-or-flight), the ventrolateral PAG passive defense (freezing, autonomic blunting). In PTSD and its dissociative subtype, PAG resting connectivity with regions of emotional reactivity and defense is widely increased; the dissociative subtype shifts toward passive defense (Harricharan et al., 2016). B
• Chronic and functional pain: weakened descending pain inhibition.
• Selective mutism: a defensive stage linked to the freezing response (a theoretical model).

Treatment

This region from the perspective of medication, psychotherapy and neuromodulation. Letter badges are evidence levels.

• Opioid analgesics act partly through μ-opioid receptors in the PAG and RVM; the same circuit carries placebo and expectation effects (Eippert et al., 2009). B
• The psychotherapeutic counterpart: safety signals and expectation can change pain and the defensive response (rostral ACC → PAG). A biological rationale for cognitive-behavioral approaches in children with chronic pain.
• Deep brain stimulation (periventricular/periaqueductal gray): in an adult series about two thirds of patients with refractory neuropathic pain benefited (Boccard et al.). Adults only, experimental. C

Assessment

Neuropsychological tasks and measures that probe this region's function.

• Threat proximity paradigms (fMRI): as threat approaches, activity shifts from the vmPFC to the PAG (Mobbs et al., 2007)
• Conditioned pain modulation
• Measuring freezing responses with heart rate, skin conductance and startle

Lesions and damage

Clinical findings expected with damage or dysfunction.

• In animal studies, loss of emotional vocalization and defensive behaviors.
• Dorsal midbrain lesions may come with Parinaud syndrome and hydrocephalus from aqueductal stenosis.

In the model

How this structure is defined in the 3D model, and the data source.

Harvard AAN v2.0 PAG label (Edlow and Kinney, 2023). The atlas is on the FSL MNI152 1 mm grid; because its left–right pairs are symmetric about x = +0.5 mm, it was shifted by 0.5 mm and transferred to the ICBM 2009c template with world coordinates (no nonlinear registration). 99–100% of the transferred nuclei fall within the template’s brainstem (PPN 90%); PAG voxels lie a median 2.7 mm from the aqueduct line.

References

Full citations for the card; links go to the paper (DOI) or a PubMed search.

1. Satpute AB et al. Identification of discrete functional subregions of the human periaqueductal gray. PNAS 2013;110(42):17101–6. Search PubMed
2. Eippert F et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 2009. Search PubMed
3. Harricharan S et al. fMRI functional connectivity of the periaqueductal gray in PTSD and its dissociative subtype. Brain Behav 2016. Search PubMed
4. Boccard SGJ et al. Long-term outcomes of deep brain stimulation for neuropathic pain. Neurosurgery 2013. Search PubMed