Periaqueductal Gray (Pag) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
The periaqueductal gray (PAG), also known as the central gray, is a column of gray matter surrounding the cerebral aqueduct (aqueduct of Sylvius) in the midbrain. The PAG is one of the most functionally diverse structures in the central nervous system, serving as a critical integration center for pain modulation, defensive behavior, autonomic regulation, vocalization, and sleep-wake control [1]. It receives input from descending cortical and limbic pathways and projects to brainstem and spinal cord circuits that control pain perception, autonomic function, and defensive behaviors [2].
In neurodegenerative diseases, the PAG shows alpha-synuclein-containing glial cytoplasmic inclusions in multiple system atrophy, and tau protein neurofibrillary tangles in progressive supranuclear palsy. PAG pathology contributes to the pain syndromes, autonomic dysfunction, sleep disturbances, and cardiovascular dysregulation that are prominent non-motor features of these conditions. The PAG extends caudally, spanning approximately 14 mm in the human brain [@benarroch1994].
The PAG is organized into four longitudinal columns, each with distinct functions, connectivity, and neurochemistry [2:1].
The PAG receives convergent input from multiple brain regions:
The PAG exerts its functions through projections to:
The PAG is the master control center for endogenous pain inhibition. Electrical stimulation of the vlPAG produces profound analgesia — sufficient for surgical procedures in experimental animals — through activation of the descending PAG-RVM-spinal cord pathway. This system is also affected in multiple system atrophy [5].
PAG neurons, particularly dopaminergic neurons in the vlPAG, contribute to wakefulness regulation. vlPAG dopaminergic neurons are wake-active, and their lesion increases sleep duration. The PAG is affected by Lewy body pathology (Braak stages 2–3), and its degeneration contributes to several prominent non-motor symptoms [6].
Pain: Chronic pain affects 60–85% of PD patients and is poorly understood. A 2023 study demonstrated that PAG dopaminergic neuron loss is a key contributor to PD-associated pain. Using the 6-OHDA model, researchers found reductions in dopaminergic (DRD5-expressing) neurons in the PAG, and pharmacological activation of D1-like receptors in the PAG alleviated mechanical hypersensitivity. The PAG shows prominent accumulation of alpha-synuclein-containing glial cytoplasmic inclusions (GCIs) across all columns. A systematic neuropathological study found significant loss of VGLUT2-immunoreactive neurons in the ventrolateral, lateral, and dorsomedial columns of MSA patients. Tau protein neurofibrillary tangles densely infiltrate the PAG, particularly in proximity to the oculomotor and trochlear nuclei, with loss of neurons in specific columns. The functional significance of PAG degeneration in AD is not fully understood but may contribute to the altered pain perception and autonomic changes observed in advanced AD (Parvizi et al., 2000).
PAG/periventricular gray (PVG) deep brain stimulation has been used to treat chronic, intractable pain conditions, particularly nociceptive and central pain syndromes. Stimulation of the vlPAG activates the descending analgesic pathway, producing long-term pain relief in selected patients. This approach has been explored for PD-related pain refractory to dopaminergic therapy.
Understanding PAG dopaminergic neuron loss in PD suggests that targeted D1/D5 receptor agonists acting on the PAG could provide analgesic benefits. Currently, levodopa partially ameliorates PD pain, likely through restoration of PAG dopaminergic function among other mechanisms.
This section links to atlas resources relevant to this brain region.
The study of Periaqueductal Gray (Pag) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Behbehani MM. Functional characteristics of the midbrain periaqueductal gray. 1995. ↩︎ ↩︎
Bandler R, Shipley MT. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci. 1994. ↩︎ ↩︎
Fields HL, Bry J, Hentall I, Zorman G. The activity of neurons in the rostral medulla of the brainstem during pain in rats. 1983. ↩︎
Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. 2010. ↩︎
Linnman C, Moulton E, Becerra L, Borsook D. Functional imaging of the periaqueductal gray during pain. 2012. ↩︎
Benarroch EE. Periaqueductal gray: an interface for behavioral control. 2012. ↩︎