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.

Descending pain modulatory efficiency in healthy subjects is related to structure and resting connectivity of brain regions.

The descending pain modulatory system in humans is commonly investigated using conditioned pain modulation (CPM). Whilst variability in CPM efficiency, i.e., inhibition and facilitation, is normal in healthy subjects, exploring the inter-relationship between brain structure, resting-state functional connectivity (rsFC) and CPM readouts will provide greater insight into the underlying CPM efficiency seen in healthy individuals. Thus, this study combined CPM testing, voxel-based morphometry (VBM) and rsFC to identify the neural correlates of CPM in a cohort of healthy subjects (n =40), displaying pain inhibition (n = 29), facilitation (n = 10) and no CPM effect (n = 1). Clusters identified in the VBM analysis were implemented in the rsFC analysis alongside key constituents of the endogenous pain modulatory system. Greater pain inhibition was related to higher volume of left frontal cortices and stronger rsFC between the motor cortex and periaqueductal grey. Conversely, weaker pain inhibition was related to higher volume of the right frontal cortex - coupled with stronger rsFC to the primary somatosensory cortex, and rsFC between the amygdala and posterior insula. Overall, healthy subjects showed higher volume and stronger rsFC of brain regions involved with descending modulation, while the lateral and medial pain systems were related to greater pain inhibition and facilitation during CPM, respectively. These findings reveal structural alignments and functional interactions between supraspinal areas involved in CPM efficiency. Ultimately understanding these underlying variations and how they may become affected in chronic pain conditions, will advance a more targeted subgrouping in pain patients for future cross-sectional studies investigating endogenous pain modulation.

Blockade of GPR55 in dorsal periaqueductal gray produces anxiety-like behaviors and evocates defensive aggressive responses in alcohol-pre-exposed rats.

GPR55 is a receptor expressed in several central nervous system areas, including the periaqueductal gray (PAG). Current knowledge of GPR55 physiology in PAG only covers pain integration, but it is involved in other actions such as anxiety, panic, motivated behaviors, and alcohol intake. In the present study, juvenile male Wistar rats were unexposed (alcohol-naïve group; A-naïve) or exposed to alcohol for 5 weeks (alcohol-pre-exposed group; A-pre-exposed). Posteriorly, animals received intra dorsal-PAG (D-PAG) injections of vehicle (10% DMSO), LPI (1 nmol/0.5 µl) and ML-193 (1 nmol/0.5 µl, a selective GPR55 antagonist). Finally, defensive burying behavior (DBB) paradigm and alcohol preference were evaluated. Compared to the A-naïve group, the A-pre-exposed vehicle group had higher (p < 0.05): (i) time of immobility; (ii) latency to and duration of burying; and (iii) alcohol consumption. In both groups (i.e., A-naïve and A-pre-exposed) treatment with LPI: (i) decreased duration of burying (p < 0.05); (ii) suppressed time of immobility; and (iii) increased alcohol intake (p < 0.05). On the other hand, treatment with ML-193: (i) decreased duration of immobility in A-pre-exposed (but not in A-naïve rats); (ii) promoted an aggressive response against the shock-probe in A-pre-exposed rats (p < 0.05); and (iii) increased alcohol intake (p < 0.05). Our results suggest that blockade of GPR55 in D-PAG is associated with anxiety-like behaviors, defensive aggressive behaviors, and higher alcohol intake, whereas LPI in D-PAG produced anxiolytic-like effects (probably GPR55-mediated), but not prevention of alcohol intake.

Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction.

The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Neurons and Astrocytes in Ventrolateral Periaqueductal Gray Contribute to Restraint Water Immersion Stress-Induced Gastric Mucosal Damage via the ERK1/2 Signaling Pathway.

BACKGROUND: The restraint water immersion stress (RWIS) model includes both psychological and physical stimulation, which may lead to gastrointestinal disorders and cause gastric mucosal damage. The ventrolateral periaqueductal gray (VLPAG) contributes to gastrointestinal function, but whether it is involved in RWIS-induced gastric mucosal damage has not yet been reported. METHODS: The expression of glial fibrillary acidic protein, neuronal c-Fos, and phosphorylated extracellular signal regulated kinase 1/2 in the VLPAG after RWIS was assessed using western blotting and immunocytochemical staining methods. Lateral ventricle injection of astrocytic toxin L-a-aminoadipate and treatment with extracellular signal-regulated kinase (ERK)1/2 signaling pathway inhibitor PD98059 were further used to study protein expression and distribution in the VLPAG after RWIS. RESULTS: The expression of c-Fos, glial fibrillary acidic protein, and phosphorylated extracellular signal regulated kinase 1/2 in the VLPAG significantly increased following RWIS and peaked at 1 hour after RWIS. Lateral ventricle injection of the astrocytic toxin L-a-aminoadipate significantly alleviated gastric mucosal injury and decreased the activation of neurons and astrocytes. Treatment with the ERK1/2 signaling pathway inhibitor PD98059 obviously suppressed gastric mucosal damage as well as the RWIS-induced activation of neurons and astrocytes in the VLPAG. CONCLUSIONS: These results suggested that activation of VLPAG neurons and astrocytes induced by RWIS through the ERK1/2 signaling pathway may play a critical role in RWIS-induced gastric mucosa damage.

Nociception alterations precede motor symptoms in a progressive model of parkinsonism induced by reserpine in middle-aged rats.

Nociception alterations are frequent non-motor symptoms of the prodromal phase of Parkinson's disease (PD). The period for the onset of symptoms and the pathophysiological mechanisms underlying these alterations remain unclear. We investigated the course of nociception alterations in a progressive model of parkinsonism induced by reserpine (RES) in rats. Male Wistar rats (6-7 months) received 5 or 10 subcutaneous injections of RES (0.1 mg/kg) or vehicle daily for 20 days. Motor evaluation and nociceptive assessment were performed throughout the treatment. At the end of the treatment rats were euthanized, the brains removed and processed for immunohistochemical analysis (TH and c-Fos). The RES-treated rats exhibited an increased nociceptive response to mechanical and chemical stimulation in the electronic von Frey and formalin tests, respectively. Moreover, these alterations preceded the motor impairment observed in the catalepsy test. In addition, the RES treatment reduced the TH-immunoreactivity in the ventral tegmental area (VTA) and increased the c-Fos expression in the ventral-lateral periaqueductal gray (vlPAG), rostral ventral medulla (RVM) and dorsal raphe nucleus (DRN) after noxious stimuli induced by formalin. Taken together, our results reinforce that nociceptive changes are one of the early signs of PD and monoamine depletion in basal ganglia can be involved in the abnormal processing of nociceptive information in PD.

The Distinct Functions of Dopaminergic Receptors on Pain Modulation: A Narrative Review.

Chronic pain is considered an economic burden on society as it often results in disability, job loss, and early retirement. Opioids are the most common analgesics prescribed for the management of moderate to severe pain. However, chronic exposure to these drugs can result in opioid tolerance and opioid-induced hyperalgesia. On pain modulation strategies, exploiting the multitarget drugs with the ability of the superadditive or synergistic interactions attracts more attention. In the present report, we have reviewed the analgesic effects of different dopamine receptors, particularly D1 and D2 receptors, in different regions of the central nervous system, including the spinal cord, striatum, nucleus accumbens (NAc), and periaqueductal gray (PAG). According to the evidence, these regions are not only involved in pain modulation but also express a high density of DA receptors. The findings can be categorized as follows: (1) D2-like receptors may exert a higher analgesic potency, but D1-like receptors act in different manners across several mechanisms in the mentioned regions; (2) in the spinal cord and striatum, antinociception of DA is mainly mediated by D2-like receptors, while in the NAc and PAG, both D1- and D2-like receptors are involved as analgesic targets; and (3) D2-like receptor agonists can act as adjuvants of µ-opioid receptor agonists to potentiate analgesic effects and provide a better approach to pain relief.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats.

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

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.

Resting state hypothalamic and dorsomedial prefrontal cortical connectivity of the periaqueductal gray in cocaine addiction.

Cocaine-dependent (CD) individuals demonstrate significant anxiety and dysphoria during withdrawal, a negative emotional state that may perpetuate drug seeking and consumption. An extensive body of work has focused on characterizing reward circuit dysfunction, but relatively little is known about the pain circuit during cocaine withdrawal. In an earlier study, we highlighted how cue-elicited functional connectivity between the periaqueductal gray (PAG), a subcortical hub of the pain circuit, and ventromedial prefrontal cortex supports tonic craving in recently abstinent CD. The functional organization of the brain can be characterized by intrinsic connectivities, and it is highly likely that the resting state functional connectivity (rsFC) of the PAG may also be altered in association with cocaine use variables. Here, we examined this issue in 52 CD and 52 healthy control (HC) participants. Imaging data were processed with published routines, and the findings were evaluated with a corrected threshold. In a covariance analysis, CD as compared with HC showed higher PAG rsFC with the hypothalamus, dorsomedial prefrontal, and inferior parietal cortices. Further, these connectivities were correlated negatively with tonic cocaine craving and recent cocaine use, respectively. Higher hypothalamic and frontoparietal rsFC with the PAG may reflect a compensatory process to regulate craving and compulsive drug use. The findings provide additional evidence in humans implicating the PAG circuit and may help research of the role of negative reinforcement in sustaining habitual drug use in cocaine addiction.

[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.

Early adolescent adversity alters periaqueductal gray/dorsal raphe threat responding in adult female rats.

Early adolescent adversity increases adult risk for anxiety disorders. The ventrolateral periaqueductal gray (vlPAG) and neighboring dorsal raphe (DR) are integral to threat prediction, and are responsive to acute stressors. Here, we tested the hypothesis that early adolescent adversity reshapes vlPAG/DR threat-related cue activity and threat probability signaling. Female, Long Evans rats experienced a battery of adverse adolescent experiences (n = 12), while controls did not (n = 8). Single-unit activity was recorded 50 + days following the final adverse experience, when the adult rats received fear discrimination consisting of danger, uncertainty and safety cues. Despite achieving fear discrimination that was equivalent to controls, vlPAG/DR threat responding was altered in adverse-experienced rats. Early adolescent adversity resulted in a greater proportion of cue-responsive neurons. Cue-excited neurons showed greater increases in firing and cue-inhibited neurons showed greater decreases. Even more, early adversity reduced flexible, threat probability signaling by cue-excited neurons and promoted more rigid, fear output signaling by cue-inhibited neurons. The results reveal long-lasting changes in vlPAG/DR threat responding resulting from early adolescent adversity.

Persistent Activity of Metabotropic Glutamate Receptor 5 in the Periaqueductal Gray Constrains Emergence of Chronic Neuropathic Pain.

Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.

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.

Cue-elicited functional connectivity of the periaqueductal gray and tonic cocaine craving.

BACKGROUND: Withdrawal 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. METHODS: Here 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. RESULTS: CD 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. CONCLUSION: The 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.

Peripheral nerve injury reduces the excitation-inhibition balance of basolateral amygdala inputs to prelimbic pyramidal neurons projecting to the periaqueductal gray.

Cellular and synaptic mechanisms underlying how chronic pain induces maladaptive alterations to local circuits in the medial prefrontal cortex (mPFC), while emerging, remain unresolved. Consistent evidence shows that chronic pain attenuates activity in the prelimbic (PL) cortex, a mPFC subregion. This reduced activity is thought to be driven by increased inhibitory tone within PL circuits. Enhanced input from the basolateral amygdala (BLA) to inhibitory neurons in PL cortex is one well-received mechanism for this circuit change. In mice, we used retrograde labeling, brain slice recordings, and optogenetics to selectively stimulate and record ascending BLA inputs onto PL neurons that send projections to the periaqueductal gray (PAG), which is a midbrain structure that plays a significant role in endogenous analgesia. Activating BLA projections evoked both excitatory and inhibitory currents in cortico-PAG (CP) neurons, as we have shown previously. We measured changes to the ratio of BLA-evoked excitatory to inhibitory currents in the spared nerve injury (SNI) model of neuropathic pain. Our analysis reveals a reduced excitation-inhibition (E/I) ratio of BLA inputs to PL-CP neurons 7 days after SNI. The E/I ratio of BLA inputs to CP neurons in neighboring infralimbic (IL) cortex was unchanged in SNI animals. Collectively, this study reveals that the overall E/I balance of BLA inputs to PL neurons projecting to the PAG is reduced in a robust neuropathic pain model. Overall, our findings provide new mechanistic insight into how nerve injury produces dysfunction in PL circuits connected to structures involved in pain modulation.

Deficits in ascending and descending pain modulation pathways in patients with postherpetic neuralgia.

Postherpetic Neuralgia (PHN), develops after the resolution of the herpes zoster mucocutaneous eruption, is a debilitating chronic pain. However, there is a lack of knowledge regarding the underlying mechanisms associated with ascending and descending pain modulations in PHN patients. Here, we combined psychophysics with structural and functional magnetic resonance imaging (MRI) techniques to investigate the brain alternations in PHN patients. Psychophysical tests showed that compared with healthy controls, PHN patients had increased state and trait anxiety and depression. Structural MRI data indicated that PHN patients had significantly smaller gray matter volumes of the thalamus and amygdala than healthy controls, and the thalamus volume was negatively correlated with pain intensity (assessed using the Short-form of the McGill pain questionnaire) in PHN patients. When the thalamus and periaqueductal gray matter (PAG) were used as the seeds, resting-state functional MRI data revealed abnormal patterns of functional connectivity within ascending and descending pain pathways in PHN patients, e.g., increased functional connectivity between the thalamus and somatosensory cortices and decreased functional connectivity between the PAG and frontal cortices. In addition, subjective ratings of both Present Pain Index (PPI) and Beck-Depression Inventory (BDI) were negatively correlated with the strength of functional connectivity between the PAG and primary somatosensory cortex (SI), and importantly, the effect of BDI on PPI was mediated by the PAG-SI functional connectivity. Overall, our results provided evidence suggesting deficits in ascending and descending pain modulation pathways, which were highly associated with the intensity of chronic pain and its emotional comorbidities in PHN patients. Therefore, our study deepened our understanding of the pathogenesis of PHN, which would be helpful in determining the optimized treatment for the patients.

Altered resting-state functional connectivity and effective connectivity of the habenula in irritable bowel syndrome: A cross-sectional and machine learning study.

Irritable bowel syndrome (IBS) is a disorder involving dysfunctional brain-gut interactions characterized by chronic recurrent abdominal pain, altered bowel habits, and negative emotion. Previous studies have linked the habenula to the pathophysiology of negative emotion and pain. However, no studies to date have investigated habenular function in IBS patients. In this study, we investigated the resting-state functional connectivity (rsFC) and effective connectivity of the habenula in 34 subjects with IBS and 34 healthy controls and assessed the feasibility of differentiating IBS patients from healthy controls using a machine learning method. Our results showed significantly enhanced rsFC of the habenula-left dorsolateral prefrontal cortex (dlPFC) and habenula-periaqueductal grey (PAG, dorsomedial part), as well as decreased rsFC of the habenula-right thalamus (dorsolateral part), in the IBS patients compared with the healthy controls. Habenula-thalamus rsFC was positively correlated with pain intensity (r = .467, p = .005). Dynamic causal modeling (DCM) revealed significantly decreased effective connectivity from the right habenula to the right thalamus in the IBS patients compared to the healthy controls that was negatively correlated with disease duration (r = -.407, p = .017). In addition, IBS was classified with an accuracy of 71.5% based on the rsFC of the habenula-dlPFC, habenula-thalamus, and habenula-PAG in a support vector machine (SVM), which was further validated in an independent cohort of subjects (N = 44, accuracy = 65.2%, p = .026). Taken together, these findings establish altered habenular rsFC and effective connectivity in IBS, which extends our mechanistic understanding of the habenula's role in IBS.

Acute Posttrauma Resting-State Functional Connectivity of Periaqueductal Gray Prospectively Predicts Posttraumatic Stress Disorder Symptoms.

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by hyperarousal, avoidance, and intrusive/re-experiencing symptoms. The periaqueductal gray (PAG), which generates behavioral responses to physical and psychological stressors, is also implicated in threat processing. Distinct regions of the PAG elicit opposing responses to threatening or stressful stimuli; the ventrolateral PAG evokes passive coping strategies (e.g., analgesia), whereas the dorsolateral PAG (dlPAG) promotes active responses (e.g., fight or flight). We investigated whether altered PAG resting-state functional connectivity (RSFC) prospectively predicted PTSD symptoms. METHODS: A total of 48 trauma-exposed individuals underwent an RSFC scan 2 weeks posttraumatic injury. Self-report measures, including the visual analog scale for pain and the Impact of Event Scale, were collected at 2 weeks and 6 months posttrauma. We analyzed whether acute bilateral PAG RSFC was a marker of risk for total 6-month symptom severity and specific symptom clusters. In an exploratory analysis, we investigated whether dlPAG RSFC predicted PTSD symptoms. RESULTS: After adjusting for physical pain ratings, greater acute posttrauma PAG-frontal pole and PAG-posterior cingulate cortex connectivity was positively associated with 6-month total PTSD symptoms. Weaker dlPAG-superior/inferior parietal lobule connectivity predicted both higher hyperarousal and higher intrusive symptoms, while weaker dlPAG-supramarginal gyrus RSFC was associated with only hyperarousal symptoms. CONCLUSIONS: Altered connectivity of the PAG 2 weeks posttrauma prospectively predicted PTSD symptoms. These findings suggest that aberrant PAG function may serve as a marker of risk for chronic PTSD symptoms, possibly by driving specific symptom clusters, and more broadly that connectivity of specific brain regions may underlie specific symptom profiles.

Brain activation patterns of female multiple sclerosis patients with voiding dysfunction.

AIMS: We compared brain activation patterns between female multiple sclerosis (MS) patients with voiding dysfunction (VD) and those without. We aim to expand current knowledge of supraspinal correlates of voiding initiation within a cohort of female MS patients with and without VD. MATERIALS AND METHODS: Twenty-eight ambulatory female MS patients with stable disease and lower urinary tract dysfunction were recruited for this study. Subjects were divided into group 1, without VD (n = 14), and group 2, with VD (n = 14), defined as postvoid residual urine of ≥40% of maximum cystometric capacity or need for self-catheterization. We recorded brain activity via functional magnetic resonance imaging (fMRI) with simultaneous urodynamic testing. Average fMRI activation maps (the Student t test) were created for both groups, and areas of significant activation were identified (P < .05). A priori regions of interest (ROIs), identified by prior meta-analysis to be involved in voiding, were selected. RESULTS: Group-averaged blood-oxygen level-dependent (BOLD) activation maps demonstrated significant differences between groups 1 and 2 during initiation of voiding with group 2 showing significantly lower levels of activation in all ROIs except for the left cerebellum and right cingulate gyrus. Interestingly, group 2 displayed negative BOLD signals, while group 1 displayed positive signals in the right and left pontine micturition center, right periaqueductal gray, left thalamus, and left cingulate gyrus. The activation map of group 1 was similar to healthy controls. CONCLUSIONS: Our results support the hypothesis that distinct supraspinal activation patterns exist between female MS patients with VD and those without.