Functional organization of the midbrain periaqueductal gray for regulating aversive memory formation.
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ABSTRACT:
SUBMITTER: Yeh LF
PROVIDER: S-EPMC8424891 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The periaqueductal gray matter (PAG) is a key brain region of the descending pain modulation pathway. It is also involved in cardiovascular functions, anxiety, and fear; however, little is known about PAG subdivisions in humans. The aims of this study were to use resting-state fMRI-based functional connectivity (FC) to parcellate the human PAG and to determine FC of its subregions. To do this, we acquired resting-state fMRI scans from 79 healthy subjects and (1) used a data-driven method to parcellate the PAG, (2) used predefined seeds in PAG subregions to evaluate PAG FC to the whole brain, and (3) examined sex differences in PAG FC. We found that clustering of the left and right PAG yielded similar patterns of caudal, middle, and rostral subdivisions in the coronal plane, and dorsal and ventral subdivisions in the sagittal plane. FC analysis of predefined subregions revealed that the ventolateral(VL)-PAG was supfunctionally connected to brain regions associated with descending pain modulation (anterior cingulate cortex (ACC), upper pons/medulla), whereas the lateral (L) and dorsolateral (DL) subregions were connected with brain regions implicated in executive functions (prefrontal cortex, striatum, hippocampus). We also found sex differences in FC including areas implicated in pain, salience, and analgesia including the ACC and the insula in women, and the MCC, parahippocampal gyrus, and the temporal pole in men. The organization of the human PAG thus provides a framework to understand the circuitry underlying the broad range of responses to pain and its modulation in men and women.
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Project description:The midbrain periaqueductal gray (PAG) region is organized into distinct subregions that coordinate survival-related responses during threat and stress [Bandler R, Keay KA, Floyd N, Price J (2000) Brain Res 53 (1):95-104]. To examine PAG function in humans, researchers have relied primarily on functional MRI (fMRI), but technological and methodological limitations have prevented researchers from localizing responses to different PAG subregions. We used high-field strength (7-T) fMRI techniques to image the PAG at high resolution (0.75 mm isotropic), which was critical for dissociating the PAG from the greater signal variability in the aqueduct. Activation while participants were exposed to emotionally aversive images segregated into subregions of the PAG along both dorsal/ventral and rostral/caudal axes. In the rostral PAG, activity was localized to lateral and dorsomedial subregions. In caudal PAG, activity was localized to the ventrolateral region. This shifting pattern of activity from dorsal to ventral PAG along the rostrocaudal axis mirrors structural and functional neurobiological observations in nonhuman animals. Activity in lateral and ventrolateral subregions also grouped with distinct emotional experiences (e.g., anger and sadness) in a factor analysis, suggesting that each subregion participates in distinct functional circuitry. This study establishes the use of high-field strength fMRI as a promising technique for revealing the functional architecture of the PAG. The techniques developed here also may be extended to investigate the functional roles of other brainstem nuclei.
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Project description:BackgroundWithdrawal from chronic cocaine use leads to anxiety and dysphoria that may perpetuate habitual drug use. The pain circuit is widely implicated in the processing and manifestations of negative emotions. Numerous studies have focused on characterizing reward circuit dysfunction but relatively little is known about the pain circuit response during cocaine withdrawal.MethodsHere we examined the activity and connectivity of the periaqueductal gray (PAG), a hub of the pain circuit, during cocaine cue exposure in 52 recently abstinent cocaine dependent participants (CD, 42 men). Imaging data were processed with published routines, and the results were evaluated at a corrected threshold.ResultsCD showed higher activation of the PAG and connectivity of the PAG with the ventromedial prefrontal cortex (vmPFC) during cocaine as compared to neutral cue exposure. PAG-vmPFC connectivity was positively and negatively correlated with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire, in male and female CD, respectively, and the sex difference was confirmed by a slope test. Granger causality analyses showed that the PAG Granger caused vmPFC time series in men and the reverse was true in women, substantiating sex differences in the directional interactions of the PAG and vmPFC.ConclusionThe findings provide the first evidence in humans implicating the PAG circuit in cocaine withdrawal and cocaine craving and advance our understanding of the role of the pain circuit and negative reinforcement in sustaining habitual drug use in cocaine addiction.
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Project description:Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG-vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG-insula and PAG-amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest.
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Project description:BACKGROUND:Posttraumatic stress disorder (PTSD) is associated with hyperarousal and active fight or flight defensive responses. By contrast, the dissociative subtype of PTSD, characterized by depersonalization and derealization symptoms, is frequently accompanied by additional passive or submissive defensive responses associated with autonomic blunting. Here, the periaqueductal gray (PAG) plays a central role in defensive responses, where the dorsolateral (DL-PAG) and ventrolateral PAG (VL-PAG) are thought to mediate active and passive defensive responses, respectively. METHODS:We examined PAG subregion (dorsolateral and ventrolateral) resting-state functional connectivity in three groups: PTSD patients without the dissociative subtype (n = 60); PTSD patients with the dissociative subtype (n = 37); and healthy controls (n = 40) using a seed-based approach via PickAtlas and SPM12. RESULTS:All PTSD patients showed extensive DL- and VL-PAG functional connectivity at rest with areas associated with emotional reactivity and defensive action as compared to controls (n = 40). Although all PTSD patients demonstrated DL-PAG functional connectivity with areas associated with initiation of active coping strategies and hyperarousal (e.g., dorsal anterior cingulate; anterior insula), only dissociative PTSD patients exhibited greater VL-PAG functional connectivity with brain regions linked to passive coping strategies and increased levels of depersonalization (e.g., temporoparietal junction; rolandic operculum). CONCLUSIONS:These findings suggest greater defensive posturing in PTSD patients even at rest and demonstrate that those with the dissociative subtype show unique patterns of PAG functional connectivity when compared to those without the subtype. Taken together, these findings represent an important first step toward identifying neural and behavioral targets for therapeutic interventions that address defensive strategies in trauma-related disorders.
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Project description:Background: Parkinson’s disease (PD) is a progressive, degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet, the underlying pathology mediating these significant voice deficits is unknown. The Pink1-/- rat is a valid model of early-onset PD that presents with analogous vocal communication deficits (e.g. reduced loudness). Previous work shows abnormal α-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1-/- rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence expression of genes that interact with Pink1, (2) highlight other key genes that relate to Mendelian PD, and (3) catalog molecular targets important for the production of rat vocalizations. Results: Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats. Pathway analysis highlighted several significant metabolic pathways. Weighted gene co-expression network analysis (WGCNA) was used to identify gene nodes and their interactions in (A) males, (B) females, and (C) combined-sexes datasets. For each analysis, within the module containing the Pink1 gene, Pink1 itself was the central node with the highest number of interactions with other genes including solute carriers, glutamate metabotropic receptors, and genes associated with protein localization. Strong connections between Pink1 and Krt2 and Hfe were found in both males and female datasets. In females a number of modules were significantly correlated with vocalization traits. Of interest, gene enrichment of the key vocal Cyan module in females showed a significant number of neuromodulatory genes including Nts, Slc6a4, Slc10a4, Ndnf, and Gpr160, that may be responsible for the modulation of rat vocalizations. The top biological pathways within the female Cyan vocal module included the regulation of membrane depolarization, indolalkylamine metabolic process, and monoamine transport. Conclusions: Overall, this work supports the premise that gene expression changes in the PAG may contribute to the vocal behavioral and deficits observed in this PD rat model. Additionally, this dataset identifies genes that represent new therapeutic targets for PD voice disorders.
2020-05-21 | GSE150939 | GEO