Age-related differences in functional connectivity associated with pain modulation.

Growing evidence suggests that aging is associated with impaired endogenous pain modulation, and that this likely underlies the increased transition from acute to chronic pain in older individuals. Resting-state functional connectivity (rsFC) offers a valuable tool to examine the neural mechanisms behind these age-related changes in pain modulation. RsFC studies generally observe decreased within-network connectivity due to aging, but its relevance for pain modulation remains unknown. We compared rsFC within a set of brain regions involved in pain modulation between young and older adults and explored the relationship with the efficacy of distraction from pain. This revealed several age-related increases and decreases in connectivity strength. Importantly, we found a significant association between lower pain relief and decreased strength of three connections in older adults, namely between the periaqueductal gray and right insula, between the anterior cingulate cortex (ACC) and right insula, and between the ACC and left amygdala. These findings suggest that the functional integrity of the pain control system is critical for effective pain modulation, and that its function is compromised by aging.

Periaqueductal gray matter echogenicity as a marker of migraine chronification: a case control study.

BACKGROUND: Migraine is one of the most prevalent and disabling medical diseases in the world. The periaqueductal gray matter and the red nucleus play an important role in its pathogenesis. Our aim was to evaluate the echogenicity of the periaqueductal gray matter and the red nucleus in patients with migraine, by means of transcranial ultrasound. METHODS: In this cross-sectional study, a group of patients with migraine (according to the International Classification of Headache Disorders) and a group of control subjects with comparable age-and-sex distribution were prospectively included. We evaluated the area and echogenicity of the periaqueductal gray matter and the red nucleus by means of transcranial ultrasound, both bedside and posteriorly analyzed with the medical image viewer Horos. RESULTS: We included 115 subjects: 65 patients with migraine (39 of them with chronic migraine and 26 with episodic migraine), and 50 controls. Median disease duration in patients with chronic migraine was 29 (IQR: 19; 40) years, with a median of 18 (IQR: 14; 27) days of migraine per month. The area of the periaqueductal gray matter was larger in patients with chronic migraine compared to episodic migraine and controls (0.15[95%CI 0.12;0.22]cm2; 0.11[95%CI 0.10;0.14]cm2 and 0.12[95%CI 0.09;0.15]cm2, respectively; p = 0.043). Chronic migraine patients showed an intensity of the periaqueductal gray matter echogenicity lower than controls (90.57[95%CI 70.87;117.26] vs 109.56[95%CI 83.30;122.64]; p = 0.035). The coefficient of variation of periaqueductal gray matter echogenicity was the highest in chronic migraine patients (p = 0.009). No differences were observed regarding the area or intensity of red nucleus echogenicity among groups. CONCLUSION: Patients with chronic migraine showed a larger area of echogenicity of periaqueductal gray matter, a lower intensity of its echogenicity and a higher heterogenicity within this brainstem structure compared to patients with episodic migraine and controls. The echogenicity of the periaqueductal gray matter should be further investigated as a biomarker of migraine chronification.

Abnormally Increased Effective Connectivity of the Periaqueductal Gray in Migraine Without Aura Patients.

OBJECTIVES: The periaqueductal gray (PAG) is a key region in the descending pain modulatory system. We applied a Granger causality analysis-based approach to examine resting-state effective connectivity of the bilateral PAG regions in migraine patients without aura (MwoA). MATERIALS AND METHODS: Resting-state functional magnetic resonance imaging data were obtained from 28 MwoA patients and 17 healthy controls. The effective connectivity of the bilateral PAG was characterized using a voxel-wised Granger causality analysis method. The resulting effective connectivity measurements were assessed for correlations with other clinical features. RESULTS: Compared with the healthy controls, MwoA patients showed increased effective connectivity from the left PAG to the left anterior cingulate gyrus and right postcentral gyrus. Meanwhile, MwoA patients also showed increased effective connectivity from the right PAG to the left precentral gyrus and increased effective connectivity from the left caudate and right middle occipital gyrus to the right PAG. DISCUSSION: Abnormally increased effective connectivity between PAG and limbic system, primary sensorimotor cortex, and visual cortex may play a key role in neuropathological features, perception, and affection of MwoA. The current study provides further insights into the complex scenario of MwoA mechanisms.

Disruption of Periaqueductal Gray-default Mode Network Functional Connectivity in Patients with Crohn's Disease with Abdominal Pain.

Abdominal pain in Crohn's disease (CD) has been known to be associated with changes in the central nervous system. The periaqueductal gray (PAG) plays a well-established role in pain processing. However, the role of PAG-related network and the effect of pain on the network in CD remain unclear.Resting-state functional magnetic imaging (fMRI) data were collected from 24 CD patients in remission with abdominal pain, 24 CD patients without abdominal pain and 28 healthy controls (HCs). Using the subregions of PAG (dorsomedial (dmPAG), dorsolateral (dlPAG), lateral (lPAG) and ventrolateral (vlPAG)) as seeds, the seed-based FC maps were calculated and one-way analysis of variance (ANOVA) was performed to investigate the differences among the three groups.Results showed that the group differences were mainly involved in the FC of the vlPAG with the precuneus, medial prefrontal cortex (mPFC) as well as orbitofrontal cortex (OFC), and the FC of the right lateral PAG (lPAG) with the precuneus, inferior parietal lobule (IPL), angular gyrus and premotor cortex. The FC values of all these regions decreased successively in the order of HCs, CD without abdominal pain and CD with abdominal pain. The pain score was negatively correlated with the FC of the l/vlPAG with the precuneus, angular gyrus and mPFC in CD patients with abdominal pain.This study implicated the disrupt communication between the PAG and the default mode network (DMN). These findings complemented neuroimaging evidence for the pathophysiology of visceral pain in CD patients.

Modulation effects of different treatments on periaqueductal gray resting state functional connectivity in knee osteoarthritis knee pain patients.

BACKGROUND: The analgesic effect of acupuncture is widely recognized, but the mechanical characteristics of acupuncture for pain relief, compared to non-steroidal anti-inflammatory (NSAIDs) and placebo medication, remain unknown. AIMS: To compare the modulation effects of acupuncture treatment with NSAIDs and placebo medication on descending pain modulation system (DPMS) in knee osteoarthritis (KOA) patients. METHODS: This study recruited 180 KOA patients with knee pain and 41 healthy controls (HCs). Individuals with KOA knee pain were divided randomly into groups of verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), and waiting list (WT), with 36 patients in each group. VA and SA groups included ten sessions of puncturing acupoints or puncturing non-acupoints acupuncture treatment for two successive weeks. Celecoxib capsules were continuously given orally to patients in the SC group at a dosage of 200 mg daily for 2 weeks. In the PB group, patients received a placebo capsule once a day for 2 weeks at the same dosage as celecoxib capsules. In the WL group, patients did not receive any treatment. Patients underwent a resting-state BOLD-fMRI scan pre- and post-receiving the therapy, whereas HCs only underwent a baseline scan. Seed (ventrolateral periaqueductal gray, vlPAG, a key node in DPMS) based resting-state functional connectivity (rs-FC) was applied in the data analysis. RESULTS: All groups demonstrated improved knee pain scores relative to the initial state. There was no statistical difference between the VA and SA groups in all clinical outcomes, and vlPAG rs-FC alterations. KOA knee pain individuals reported higher vlPAG rs-FC in the bilateral thalamus than HCs. KOA knee pain patients in the acupuncture group (verum + sham, AG) exhibited increased vlPAG rs-FC with the right dorsolateral prefrontal cortex (DLPFC) and the right angular, which is associated with knee pain improvement. In contrast with the SC and PB group, the AG exhibited significantly increased vlPAG rs-FC with the right DLPFC and angular. Contrary to the WT group, the AG showed greater vlPAG rs-FC with the right DLPFC and precuneus. CONCLUSIONS: Acupuncture treatment, celecoxib, and placebo medication have different modulation effects on vlPAG DPMS in KOA knee pain patients. Acupuncture could modulate vlPAG rs-FC with brain regions associated with cognitive control, attention, and reappraisal for knee pain relief in KOA patients, compared with celecoxib and placebo medication.

Longitudinal differences in iron deposition in periaqueductal gray matter and anterior cingulate cortex are associated with response to erenumab in migraine.

OBJECTIVES: The objective of this longitudinal study was to determine whether brain iron accumulation, measured using magnetic resonance imaging magnetic transverse relaxation rates (T2*), is associated with response to erenumab for the treatment of migraine. METHODS: Participants (n = 28) with migraine, diagnosed using international classification of headache disorders 3rd edition criteria, were eligible if they had six to 25 migraine days during a four-week headache diary run-in phase. Participants received two treatments with 140 mg erenumab, one immediately following the pre-treatment run-in phase and a second treatment four weeks later. T2* data were collected immediately following the pre-treatment phase, and at two weeks and eight weeks following the first erenumab treatment. Patients were classified as erenumab responders if their migraine-day frequency at five-to-eight weeks post-initial treatment was reduced by at least 50% compared to the pre-treatment run-in phase. A longitudinal Sandwich estimator approach was used to compare longitudinal group differences (responders vs non-responders) in T2* values, associated with iron accumulation. Group visit effects were calculated with a significance threshold of p = 0.005 and cluster forming threshold of 250 voxels. T2* values of 19 healthy controls were used for a reference. The average of each significant region was compared between groups and visits with Bonferroni corrections for multiple comparisons with significance defined as p < 0.05. RESULTS: Pre- and post-treatment longitudinal imaging data were available from 28 participants with migraine for a total of 79 quantitative T2* images. Average subject age was 42 ± 13 years (25 female, three male). Of the 28 subjects studied, 53.6% were erenumab responders. Comparing longitudinal T2* between erenumab responders vs non-responders yielded two comparisons which survived the significance threshold of p < 0.05 after correction for multiple comparisons: the difference at eight weeks between the erenumab-responders and non-responders in the periaqueductal gray (mean ± standard error; responders 43 ± 1 ms vs non-responders 32.5 ± 1 ms, p = 0.002) and the anterior cingulate cortex (mean ± standard error; responders 50 ± 1 ms vs non-responders 40 ± 1 ms, p = 0.01). CONCLUSIONS: Erenumab response is associated with higher T2* in the periaqueductal gray and anterior cingulate cortex, regions that participate in pain processing and modulation. T2* differences between erenumab responders vs non-responders, a measure of brain iron accumulation, are seen at eight weeks post-treatment. Less iron accumulation in the periaqueductal gray and anterior cingulate cortex might play a role in the therapeutic mechanisms of migraine reduction associated with erenumab.

Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray with episodic and chronic migraine: a proton magnetic resonance spectroscopy study.

BACKGROUND: The pathogenesis of migraine chronification remains unclear. Functional and structural magnetic resonance imaging studies have shown impaired functional and structural alterations in the brains of patients with chronic migraine. The cerebellum and periaqueductal gray (PAG) play pivotal roles in the neural circuits of pain conduction and analgesia in migraine. However, few neurotransmitter metabolism studies of these migraine-associated regions have been performed. To explore the pathogenesis of migraine chronification, we measured gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the dentate nucleus (DN) and PAG of patients with episodic and chronic migraine and healthy subjects. METHODS: Using the MEGA-PRESS sequence and a 3-Tesla magnetic resonance scanner (Signa Premier; GE Healthcare, Chicago, IL, USA), we obtained DN and PAG metabolite concentrations from patients with episodic migraine (n = 25), those with chronic migraine (n = 24), and age-matched and sex-matched healthy subjects (n = 16). Patients with chronic migraine were further divided into those with (n = 12) and without (n = 12) medication overuse headache. All scans were performed at the Beijing Tiantan Hospital, Capital Medical University. RESULTS: We found that patients with chronic migraine had significantly lower levels of GABA/water (p = 0.011) and GABA/creatine (Cr) (p = 0.026) in the DN and higher levels of Glx/water (p = 0.049) in the PAG than healthy controls. In all patients with migraine, higher GABA levels in the PAG were significantly associated with poorer sleep quality (GABA/water: r = 0.515, p = 0.017, n = 21; GABA/Cr: r = 0.522, p = 0.015, n = 21). Additionally, a lower Glx/Cr ratio in the DN may be associated with more severe migraine disability (r = -0.425, p = 0.055, n = 20), and lower GABA/water (r = -0.424, p = 0.062, n = 20) and Glx/Water (r = -0.452, p = 0.045, n = 20) may be associated with poorer sleep quality. CONCLUSIONS: Neurochemical levels in the DN and PAG may provide evidence of the pathological mechanisms of migraine chronification. Correlations between migraine characteristics and neurochemical levels revealed the pathological mechanisms of the relevant characteristics.

Regional hypothalamic, amygdala, and midbrain periaqueductal gray matter recruitment during acute pain in awake humans: A 7-Tesla functional magnetic resonance imaging study.

Over the past two decades, magnetic resonance imaging (MRI) studies have explored brain activation patterns during acute noxious stimuli. Whilst these human investigations have detailed changes in primarily cortical regions, they have generally not explored discrete changes within small brain areas that are critical in driving behavioural, autonomic, and endocrine responses to pain, such as within subregions of the hypothalamus, amygdala, and midbrain periaqueductal gray matter (PAG). Ultra-high field (7-Tesla) MRI provides enough signal-to-noise at high spatial resolutions to investigate activation patterns within these small brain regions during acute noxious stimulation in awake humans. In this study we used 7T functional MRI to concentrate on hypothalamic, amygdala, and PAG signal changes during acute noxious orofacial stimuli. Noxious heat stimuli were applied in three separate fMRI scans to three adjacent sites on the face in 16 healthy control participants (7 females). Images were processed using SPM12 and custom software, and blood oxygen level dependent signal changes within the hypothalamus, amygdala, and PAG assessed. We identified altered activity within eight unique subregions of the hypothalamus, four unique subregions of the amygdala, and a single region in the lateral PAG. Specifically, within the hypothalamus and amygdala, signal intensity largely decreased during noxious stimulation, and increased in the lateral PAG. Furthermore, we found sex-related differences in discrete regions of the hypothalamus and amygdala. This study reveals that the activity of discrete nuclei during acute noxious thermal stimulation in awake humans.

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients.

Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.

Influence of periaqueductal gray on other salience network nodes predicts social sensitivity.

The intrinsic connectivity of the salience network (SN) plays an important role in social behavior, however the directional influence that individual nodes have on each other has not yet been fully determined. In this study, we used spectral dynamic causal modeling to characterize the effective connectivity patterns in the SN for 44 healthy older adults and for 44 patients with behavioral variant frontotemporal dementia (bvFTD) who have focal SN dysfunction. We examined the relationship of SN effective connections with individuals' socioemotional sensitivity, using the revised self-monitoring scale, an informant-facing questionnaire that assesses sensitivity to expressive behavior. Overall, average SN effective connectivity for bvFTD patients differs from healthy older adults in cortical, hypothalamic, and thalamic nodes. For the majority of healthy individuals, strong periaqueductal gray (PAG) output to right cortical (p < .01) and thalamic nodes (p < .05), but not PAG output to other central pattern generators contributed to sensitivity to socioemotional cues. This effect did not exist for the majority of bvFTD patients; PAG output toward other SN nodes was weak, and this lack of output negatively influenced socioemotional sensitivity. Instead, input to the left vAI from other SN nodes supported patients' sensitivity to others' socioemotional behavior (p < .05), though less effectively. The key role of PAG output to cortical and thalamic nodes for socioemotional sensitivity suggests that its core functions, that is, generating autonomic changes in the body, and moreover representing the internal state of the body, is necessary for optimal social responsiveness, and its breakdown is central to bvFTD patients' social behavior deficits.

Modulation effect of acupuncture treatment on chronic neck and shoulder pain in female patients: Evidence from periaqueductal gray-based functional connectivity.

AIMS: Chronic neck and shoulder pain (CNSP) is a common neurological disorder, which females are more likely to suffer from. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. This study aimed to investigate altered PAG-based functional connectivity (FC) in female patients with CNSP related to healthy controls (HCs) and the effect of acupuncture for female patients with CNSP using PAG-based FC biomarkers. METHODS: PAG-based FC value was calculated based on resting-state functional images and then compared between patients with CNSP at pre-acupuncture, post-acupuncture, and HCs. Then, correlational analyses were performed to examine the relationships between increased PAG-based FC strength and improved clinical parameters in patients after acupuncture treatment. RESULTS: Before acupuncture treatment, compared to HCs, patients with CSNP showed altered PAG-based FC with widely distributed brain regions, including the left medial superior frontal gyrus, bilateral posterior insula (pIns), and cingulate gyrus. After treatment, patients with CNSP exhibited specially improved PAG-pIns FC compared to that before treatment, and no significant difference was observed in the increased PAG-pIns FC strength between HCs and patients with CNSP after treatment. Furthermore, pain catastrophizing reduction was significantly correlated with the increased PAG-pIns FC strength in patients after treatment. CONCLUSION: The effect of acupuncture treatment may relate to the increased PAG-pIns FC, which significantly correlated with pain catastrophizing reduction after treatment. These findings shed important mechanistic information on the role of therapeutic approaches in treating chronic neck and shoulder pain.

A 7-Tesla MRI study of the periaqueductal gray: resting state and task activation under threat.

The periaqueductal gray (PAG) is a region of the midbrain implicated in a variety of behaviors including defensive responses to threat. Despite the wealth of knowledge pertaining to the differential functional roles of the PAG columns in nonhuman and human research, the basic functional connectivity of the PAG at rest has not been well characterized. Therefore, the current study utilized 7-Tesla magnetic resonance imaging (MRI) to characterize PAG functional connectivity at rest and task activation under uncertain threat. A sample of 53 neurologically healthy undergraduate participants (Mage = 22.2, s.d.age = 3.62) underwent structural and resting state functional MRI scans. Supporting previous work, voxel-wise analyses showed that the PAG is functionally connected to emotion regulation and fear networks. The comparison of functional connectivity of PAG columns did not reveal any significant differences. Thirty-five participants from the same sample also completed an uncertain threat task with blocks of three conditions-no shock, predictable shock and unpredictable shock. There were no robust activity differences within the PAG columns or the whole PAG across conditions although there was differential activity at the voxel level in the PAG and in other regions theoretically relevant to uncertain threat. Results of this study elucidate PAG connectivity at rest and activation in response to uncertain threat.

Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats.

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats.

Secondary cluster headache due to a contralateral demyelinating periaqueductal gray matter lesion.

OBJECTIVES/BACKGROUND: Tension-type headache and migraine without aura are the most common primary headaches occurring in people with demyelinating diseases, whereas cluster headache (CH) can be considered exceptional. The location of demyelinating lesions could be strategic in these cases, involving areas interacting with the trigeminovascular system. METHODS AND RESULTS: We report a case of a 54-year-old woman with right-sided CH as the initial manifestation of multiple sclerosis and showing a left dorsal brainstem lesion on magnetic resonance imaging, in the region of the dorsal longitudinal fasciculus (DLF). CONCLUSION: Our case seems to suggest a possible role of the DLF in the process that leads to CH attacks. Because neuroimaging clearly showed a lesion contralateral to CH pain, we hypothesize that some fibers from periaqueductal gray matter project to the contralateral side, besides the known ipsilateral connections.

Parcellation of human periaqueductal gray at 7-T fMRI in full and empty bladder state: The foundation to study dynamic connectivity changes related to lower urinary tract functioning.

AIMS: The periaqueductal gray (PAG) is a brain stem area involved in processing signals related to urine storage and voiding. The PAG is proposed to be responsible for projecting afferent information from the bladder to cortical and subcortical brain areas and acts as a relay station projecting efferent information from cortical and subcortical areas to the pons and spinal cord. Here, we use 7-Tesla functional magnetic resonance imaging to parcellate the PAG into functionally distinct clusters during a bladder filling protocol. METHODS: We assess the similarity between parcellation results in empty and full bladder states and show how these parcellations can be used to create dynamic response profiles of connectivity changes between clusters as a function of bladder sensations. RESULTS: For each of our six healthy female participants, we found that the agreement between at least one of the clusters in both states resulting from the parcellation procedure was higher than could be expected based on chance (p ≤ .05), and observed that these clusters are significantly organized in a symmetrical lateralized fashion (p ≤ .05). Correlations between clusters change significantly as a function of experienced sensations during bladder filling (p ≤ .05). CONCLUSIONS: This opens new possibilities to investigate the effects of treatments of lower urinary tract symptoms on signal processing in the PAG, as well as the investigation of disease-specific bladder filling related dynamic signal processing in this small brain structure.

[A case of oculomotor disorder and urinary retention due to a lower midbrain lesion].

We report an 86-year-old woman who suffered sudden onset of diplopia while cooking. The patient presented with binocular diplopia, bilateral adduction weakness, convergence disorder and bilateral abduction nystagmus. Although brain MRI on admission detected no abnormality, a repeat MRI examination on the following day demonstrated a focal hyperintense lesion in the tegmentum of the midbrain on diffusion-weighted images. At 36 hours after admission, lower abdominal distension became apparent, and about 1 liter of urine was drained via a urethral catheter. Bladder filling sensation was not present, and we considered that the midbrain lesion had been responsible for the oculomotor disorder and urinary retention. As cerebral infarction was the most likely pathology of this lesion, an antiplatelet agent was administered. At two months after onset, the eye movement disorder was resolved and there was no diplopia. Bladder voiding also resumed at normal intervals. We considered that the bilateral medial longitudinal fasciculi and subgroups of the oculomotor nucleus, which contain motor neurons supplying the medial rectus muscle, had been responsible for the oculomotor disorder. The urinary retention was thought to have been caused by a lesion in the periaqueductal gray, which is one structure controlling micturition. This was a rare case of urinary retention due to a small midbrain infarction.

Sensitivity of functional connectivity to periaqueductal gray localization, with implications for identifying disease-related changes in chronic visceral pain: A MAPP Research Network neuroimaging study.

Previous studies examining the resting-state functional connectivity of the periaqueductal gray (PAG) in chronic visceral pain have localized PAG coordinates derived from BOLD responses to provoked acute pain. These coordinates appear to be several millimeters anterior of the anatomical location of the PAG. Therefore, we aimed to determine whether measures of PAG functional connectivity are sensitive to the localization technique, and if the localization approach has an impact on detecting disease-related differences in chronic visceral pain patients. We examined structural and resting-state functional MRI (rs-fMRI) images from 209 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We applied three different localization techniques to define a region-of-interest (ROI) for the PAG: 1) a ROI previously-published as a Montreal Neurological Institute (MNI) coordinate surrounded by a 3 mm radius sphere (MNI-sphere), 2) a ROI that was hand-traced over the PAG in a MNI template brain (MNI-trace), and 3) a ROI that was hand-drawn over the PAG in structural images from 30 individual participants (participant-trace). We compared the correlation among the rs-fMRI signals from these PAG ROIs, as well as the functional connectivity of these ROIs with the whole brain. First, we found important non-uniformities in brainstem rs-fMRI signals, as rs-fMRI signals from the MNI-trace ROI were significantly more similar to the participant-trace ROI than to the MNI-sphere ROI. We then found that choice of ROI also impacts whole-brain functional connectivity, as measures of PAG functional connectivity throughout the brain were more similar between MNI-trace and participant-trace compared to MNI-sphere and participant-trace. Finally, we found that ROI choice impacts detection of disease-related differences, as functional connectivity differences between pelvic pain patients and healthy controls were much more apparent using the MNI-trace ROI compared to the MNI-sphere ROI. These results indicate that the ROI used to localize the PAG is critical, especially when examining brain functional connectivity changes in chronic visceral pain patients.

Depth relationships and measures of tissue thickness in dorsal midbrain.

Dorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distances from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for delineating depth for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.

Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation.

When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.