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. 2012 Mar;60(1):505-22.
doi: 10.1016/j.neuroimage.2011.11.095. Epub 2011 Dec 14.

Neuroimaging of the Periaqueductal Gray: State of the Field

Free PMC article

Neuroimaging of the Periaqueductal Gray: State of the Field

Clas Linnman et al. Neuroimage. .
Free PMC article


This review and meta-analysis aims at summarizing and integrating the human neuroimaging studies that report periaqueductal gray (PAG) involvement; 250 original manuscripts on human neuroimaging of the PAG were identified. A narrative review and meta-analysis using activation likelihood estimates is included. Behaviors covered include pain and pain modulation, anxiety, bladder and bowel function and autonomic regulation. Methods include structural and functional magnetic resonance imaging, functional connectivity measures, diffusion weighted imaging and positron emission tomography. Human neuroimaging studies in healthy and clinical populations largely confirm the animal literature indicating that the PAG is involved in homeostatic regulation of salient functions such as pain, anxiety and autonomic function. Methodological concerns in the current literature, including resolution constraints, imaging artifacts and imprecise neuroanatomical labeling are discussed, and future directions are proposed. A general conclusion is that PAG neuroimaging is a field with enormous potential to translate animal data onto human behaviors, but with some growing pains that can and need to be addressed in order to add to our understanding of the neurobiology of this key region.


Figure 1
Figure 1. Methods and behaviors in review
Arrows indicate that a method (for example volumetric studies) has demonstrated involvement in a behavior (i.e. pain, emotion, cardiovascular and bowel function).
Figure 2
Figure 2
Schematic illustration of the dorsomedial, dorsolateral, lateral and ventrolateral neuronal columns within (from left to right) the rostral periaqueductal gray (PAG), the intermediate PAG (two sections) and the caudal PAG. Injections of excitatory amino acids (EAA) within the dorsolateral (dlPAG)/lateral (lPAG; green) vs. ventrolateral (vlPAG; orange) columns evoke fundamentally opposite, active vs. passive emotional coping strategies. EAA injections made within the rostral portions of dlPAG and lPAG columns evoke a confrontational defensive reaction, tachycardia, and hypertension (associated with decreased blood flow to limbs and viscera and increased blood flow to extracranial vascular beds). EAA injections made within the caudal portions of the dlPAG and lPAG evoke flight, tachycardia and hypertension (associated with decreased blood flow to visceral and extracranial vascular beds and increased blood flow to limbs). In contrast, EAA injections made within the vlPAG evoke cessation of all spontaneous activity (quiescence), a decreased responsiveness to the environment (hyporeactivity), hypotension and bradycardia. A nonopioid-mediated vs. an opioid-mediated analgesia is evoked from the dlPAG/lPAG vs. vlPAG. Adapted from Bandler et al. (1994) Fig. 1 and Bandler et at. (2000), Fig. 1 with permission.
Figure 3
Figure 3. Anatomical Organization of the PAG
Schematic overview of the organization of the PAG afferent and efferent connections. Represented on the left are the connections forming the descending limbic system and on the right are the connections forming the ascending sensory system. The two systems interact in the PAG. Structures indicated in bold are connected to either the dorsomedial, lateral or ventrolateral columns, or two of them or all of them. Structures indicated in italic are connected to the dorsolateral column. Structures indicated in bold and italic are connected to all four columns. The specific connections of the structures indicated in regular style have not been established. Adapted from (Paxinos and Mai, 2004), Figure 12.13 with permission.
Figure 4
Figure 4. Functional Activations in the PAG across Studies
Regions reported as the PAG. Red dots represent individual peaks projected to the sagittal and axial plane. The activation likelihood estimate for all included studies is illustrated on the right.
Figure 5
Figure 5. PAG Connections based on DTI
Schematic representation of regions connected to the PAG identified in diffusion-weighted tractography studies. ACC=anterior cingulate cortex, Cerebell=cerebellum, dmPFC=dorsomedial prefrontal cortex, vmPFC=ventromedial prefrontal cortex, vlPFC=ventrolateral prefrontal cortex, WM=white matter.
Figure 6
Figure 6. Activation likelihood estimates of regions found to be functionally connected to the PAG
Also, the amygdala and putamen displayed connectivity peaks.
Figure 7
Figure 7. Activation likelihood estimates across behavioral domains
The activation likelihood peaks are indicated in a sagittal slice of the MNI template.
Figure 8
Figure 8. PAG in the literature
Cumulative number of PubMed citations mentioning various brain structures in the title/abstract. Notably, the PAG neuroimaging literature reviewed here compose less than 10% of the entire PAG literature.
Figure 9
Figure 9. PAG at 7 Tesla
A single functional EPI slice at 0.85 mm isotropic resolution from one subject obtained at 7 tesla with a 32-channel head coil. The midbrain anatomical illustration is adapted from (Gray and Lewis, 1918).

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