Human spirituality can be localized to a specific brain circuit – the periaqueductal gray (PAG)


More than 80 percent of people around the world consider themselves to be religious or spiritual. But research on the neuroscience of spirituality and religiosity has been sparse.

Previous studies have used functional neuroimaging, in which an individual undergoes a brain scan while performing a task to see what areas of the brain light up. But these correlative studies have given a spotty and often inconsistent picture of spirituality.

A new study led by investigators at Brigham and Women’s Hospital takes a new approach to mapping spirituality and religiosity and finds that spiritual acceptance can be localized to a specific brain circuit. This brain circuit is centered in the periaqueductal gray (PAG), a brainstem region that has been implicated in numerous functions, including fear conditioning, pain modulation, altruistic behaviors and unconditional love. The team’s findings are published in Biological Psychiatry.

“Our results suggest that spirituality and religiosity are rooted in fundamental, neurobiological dynamics and deeply woven into our neuro-fabric,” said corresponding author Michael Ferguson, Ph.D., a principal investigator in the Brigham’s Center for Brain Circuit Therapeutics. “We were astonished to find that this brain circuit for spirituality is centered in one of the most evolutionarily preserved structures in the brain.”

To conduct their study, Ferguson and colleagues used a technique called lesion network mapping that allows investigators to map complex human behaviors to specific brain circuits based on the locations of brain lesions in patients. The team leveraged a previously published dataset that included 88 neurosurgical patients who were undergoing surgery to remove a brain tumor. Lesion locations were distributed throughout the brain.

Patients completed a survey that included questions about spiritual acceptance before and after surgery. The team validated their results using a second dataset made up of more than 100 patients with lesions caused by penetrating head trauma from combat during the Vietnam War. These participants also completed questionnaires that included questions about religiosity, such as, “Do you consider yourself a religious person? Yes or No?”.

Of the 88 neurosurgical patients, 30 showed a decrease in self-reported spiritual belief before and after neurosurgical brain tumor resection, 29 showed an increase, and 29 showed no change. Using lesion network mapping, the team found that self-reported spirituality mapped to a specific brain circuit centered on the PAG.

The circuit included positive nodes and negative nodes – lesions that disrupted these respective nodes either decreased or increased self-reported spiritual beliefs. Results on religiosity from the second dataset aligned with these findings. In addition, in a review of the literature, the researchers found several case reports of patients who became hyper-religious after experiencing brain lesions that affected the negative nodes of the circuit.

Lesion locations associated with other neurological and psychiatric symptoms also intersected with the spirituality circuit. Specifically, lesions causing Parkinsonism intersected positive areas of the circuit, as did lesions associated with decreased spirituality. Lesions causing delusions and alien limb syndrome intersected with negative regions, associated with increased spirituality and religiosity.

“It’s important to note that these overlaps may be helpful for understanding shared features and associations, but these results should not be over-interpreted,” said Ferguson. “For example, our results do not imply that religion is a delusion, that historical religious figures suffered from alien limb syndrome, or that Parkinson’s disease arises due to a lack of religious faith. Instead, our results point to the deep roots of spiritual beliefs in a part of our brain that’s been implicated in many important functions.”

The authors note that the datasets they used do not provide rich information about the patient’s upbringing, which can have an influence over spiritual beliefs, and that patients in both datasets were from predominantly Christian cultures. To understand the generalizability of their results, they would need to replicate their study across many backgrounds.

The team is also interested in untangling religiosity and spirituality to understand brain circuits that may be driving differences. Additionally, Ferguson would like to pursue clinical and translational applications for the findings, including understanding the role that spirituality and compassion may have in clinical treatment.

“Only recently have medicine and spirituality been fractionated from one another. There seems to be this perennial union between healing and spirituality across cultures and civilizations,” said Ferguson. “I’m interested in the degree to which our understanding of brain circuits could help craft scientifically grounded, clinically-translatable questions about how healing and spirituality can co-inform each other.”

The periaqueductal gray (PAG) is a key structure in the propagation and modulation of pain, sympathetic responses as well as the learning and action of defensive and aversive behaviors. Most notably, the PAG is largely responsible for descending modulation of pain perception, both in inhibition and facilitation, as pain does not depend on peripheral stimulation alone.[1][2][3] Both suppression and facilitation of pain via these pathways is a major component of chronic pain, which can lead to further disease states such as depression and anxiety, thus guiding the focus of clinical studies and therapies.

The PAG also participates in risk assessment, and responses to threats, aiding in defensive behaviors. These pathways give rise to learned aversive behaviors by the involvement of sympathetic responses, motor responses, emotional reactions, and elevating levels of awareness. Mice and rat models demonstrating aversive memory formation to pain related to the PAG highlights the important implications of this structure in our interactions with the environment. Further, this highlights the integral effects the PAG can have not only on the modulation of pain but the subsequent long-term impact in behavioral and memory responses to painful stimuli.

The role of the PAG with autonomic excitability not only contributes to defensive behaviors but also disease states that are affected by this activation, including panic attacks and anxiety.[4][5] Through its complex relationship with pain processing, research has shown that the PAG to become activated in those with depression. More recently identified, the PAG is involved with migraines as a possible initiator of attacks.[6]

Structure and Function

The periaqueductal gray is aptly named as the gray matter structure surrounding the aqueduct of Sylvius in the midbrain. Along the caudal-rostral axis, the PAG extends from the level of the posterior commissure down to the level of the locus coeruleus. Internally, the PAG is delineated by columnal based boundaries: the dorsal PAG (dPAG), dorsolateral PAG (dlPAG), the lateral PAG (lPAG) and the ventrolateral PAG (vlPAG).[7][8] These columns are based on chemical pathways by which afferent and efferent tracts appear to travel, corresponding to functional pathways.[7]

Several neurotransmitters are involved in the transmission of signals to and from the PAG. Inhibitory serotonergic projections are considered the key component of descending pain pathways. However, norepinephrine, dopamine, enkephalin, glutamate, mu-opioid receptors, and GABAergic neurons contribute in this sense as well.[2][3][2][9] Serotonin, enkephalin, mu-opioid, and GABAergic receptors are involved in descending pain control pathways, mediated by interneurons.[1][2][10] Catecholamines (epinephrine and norepinephrine) are found in high concentrations in the vlPAG, contributing to heightened arousal in response to pain.[11]


The PAG plays a major role in the modulation and perception of pain. Initial recognition of this structure stemmed from the observation that stimulation of the PAG before surgery resulted in decreased anesthetic requirements.[12] Through both ascending and descending projections, the PAG can lessen or augment pain perception as it propagates nociceptive and analgesic stimuli in a bidirectional manner.[2] Initial pain signals ascend through the dorsal horn, specifically through lamina I (superficial dorsal horn), lamina II (substantia gelatinosa), and lamina V (deep dorsal horn).

Those signals, via the spinothalamic and spinobulbar pathways, further ascend to the PAG and other structures to be relayed to the non-specific medial thalamus.[1][2] Pain pathways have been extensively researched but remain complex. Specific higher structures identified in bidirectional control of pain include the cingulate gyrus, insular cortices, amygdala, periventricular and posterolateral hypothalamus, PAG, ventromedial medulla (VMM) and dorsolateral pontine tegmentum.[1][13][14]

The PAG has two major descending pathways involving the rostral ventromedial medulla (RVMM) and the locus coeruleus (LC). The PAG -LC pathway propagates by norepinephrine (NE), exerting an antinociceptive effect in the dorsal horn via the presynaptic alpha-2 receptor.[14][15] The serotonergic PAG- RVMM pathway is considered the key endogenous modulator of pain, constituting a primary target for supraspinal opioid analgesia.[3][15]

Specifically, the PAG activates the raphe nuclei via glutamate, and the raphe nuclei activate enkephalin neurons, causing inhibitory signals to c-fiber pain afferents [8]. Specific serotonin receptors have been implicated for their antinociceptive effects in the PAG, including 5-HT.[1]

Though the serotonergic pathway is the major influencer of pain, other key neurotransmitters have demonstrated involvement in these pathways. Glutamate, when applied to the central amygdala and PAG of rats in experimental settings, demonstrated analgesic properties via higher thresholds for paw withdrawal to pain. However, complexity in this system requires emphasis as activation of the “ON-cells” in the PAG has also shown pro-nociceptive effects.[10] Largely the vlPAG connected with the PFC, amygdala, and ventromedial nucleus (VMN) have been identified in the pain pathway.[8]


The PAG is a key component in defensive and aversive behavior, mediated by emotional and autonomic arousal. The PAG is the source of unpleasant sensations, including fear, anxiety, and danger.[15] Chemical stimulation of the dlPAG via NMDA in rodents demonstrates the manifestations of these sensations, such as freezing, running, and avoidance.[16][17] In addition to emotional arousal, autonomic and cardiopulmonary excitation are also elicited in this structure via sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM).

Projections from the vlPAG and dPAG to the RVLM, a component of the reticular formation and arousal pathway, are shown to illicit cardiopulmonary excitation with elevated blood pressure, heart rate, and alertness during stress responses.[11] Interestingly, specific neural subsets have appeared to relate to risk assessment before subsequent defensive behaviors.[17] This anticipation is a behavioral strategy aimed at decreasing future pain stimuli.[3]

The combination of these sensations contributes to learned aversive and defensive behaviors in response to stressful stimuli.[16][17][11] Mediation of the vlPAG-RVLM system occurs with 5-HT, as demonstrated by inhibition of defense responses with microinjections of 5-HT. Further, the stimulation of 5-HT on GABAergic neurons in the vPAG demonstrates anxiolysis.[15]

Overall, defensive behavior can subdivide into immediate and long-term responses. Stimulation of the dorsolateral and lateral PAG demonstrates short-term fight or flight with increases in heart rate and blood pressure, increased alertness, and transmission of non-opioid antinociceptive signals.[11] Stimulation of the vlPAG demonstrated more long term learned behaviors, including freezing and opioid-mediated antinociceptive signals.[11] The co-occurrence of fear and anti-nociceptive signals underlies future avoidance and learning.[18] Fear induced antinociception is evoked with stimulation of the dlPAG and superior colliculus.[15]


The PAG has been studied for even more specific functions, such as its role in migraines. Interestingly, the PAG has been implicated in the pathophysiology of migraines, possibly being the “generator” sites for migraine attacks. Increased non-heme iron deposition in the PAG for those with current migraines compared to those without a migraine relate to this evidence, although it is not clear if this is cause or consequence of the attacks.[6]

reference link :

More information: Michael A. Ferguson et al, A neural circuit for spirituality and religiosity derived from patients with brain lesions, Biological Psychiatry (2021). DOI: 10.1016/j.biopsych.2021.06.016


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