Periaqueductal Gray Research Articles

Deep learning modelling of structural brain MRI in chronic head and neck pain after mild TBI.

Chronic headache is a common complication after mild traumatic brain injury (mTBI), which affects close to 70 million individuals annually worldwide. This study aims to test the utility of a unique, early predictive magnetic resonance imaging (MRI)-based classification model using structural brain MRI scans, a rarely used approach to identify high-risk individuals for post-mTBI chronic pain. We recruited 227 patients with mTBI after a vehicle collision, between March 30, 2016 and December 30, 2019. T1-weighted brain MRI scans from 128 patients within 72 hours postinjury were included and served as input for a pretrained 3D ResNet-18 deep learning model. All patients had initial assessments within the first 72 hours after the injury and performed follow-ups for 1 year. Chronic pain was reported in 43% at 12 months postinjury; remaining 57% were assigned to the recovery group. The best results were achieved for the axial plane with an average accuracy of 0.59 and an average area under the curve (AUC) of 0.56. Across the model's 8 folds. The highest performance across folds reached an AUC of 0.78, accuracy of 0.69, and recall of 0.83. Saliency maps highlighted the right insula, bilateral ventromedial prefrontal cortex, and periaqueductal gray matter as key regions. Our study provides insights at the intersection of neurology, neuroimaging, and predictive modeling, demonstrating that early T1-weighted MRI scans may offer useful information for predicting chronic head and neck pain. Saliency maps may help identify brain regions linked to chronic pain, representing an initial step toward targeted rehabilitation and early intervention for patients with mTBI to enhance clinical outcomes.

Common neural correlates of chronic pain - A systematic review and meta-analysis of resting-state fMRI studies.

Common neural correlates of chronic pain - A systematic review and meta-analysis of resting-state fMRI studies.

Deep Brain Stimulation and Brain–Spine Interface for Functional Restoration in Spinal Cord Injury

Background/Objectives: Spinal cord injury (SCI) presents significant challenges in restoring motor function, with limited therapeutic options available. Recent advancements in neuromodulation technologies, such as brain-spine interface (BSI), epidural electrical stimulation (EES), and deep brain stimulation (DBS), offer promising solutions. This review article explores the integration of these approaches, focusing on their potential to restore function in SCI patients. Findings: DBS has shown efficacy in SCI treatment with several stimulation sites identified, including the nucleus raphe magnus (NRM) and periaqueductal gray (PAG). However, transitioning from animal to human studies highlights challenges, including the technical risks of targeting the NRM in humans instead of rodent models. Additionally, several other regions have shown potential for motor rehabilitation, including the midbrain locomotor region (MLR) pathways, cuneiform nucleus (CnF), pedunculopontine nucleus (PPN), and lateral hypothalamic. DBS with EES further supports motor recovery in SCI; however, this approach requires high-DBS amplitude, serotonergic pharmacotherapy, and cortical activity decoding to attenuate stress-associated locomotion. BSI combined with EES has recently emerged as a promising novel therapy. Although human studies are limited, animal models have provided evidence supporting its potential. Despite these advancements, the effectiveness of DBS and combined systems remains limited in cases of complete central denervation. Conclusions: The integration and combination of DBS, BSI, and EES represent a transformational approach to treating and restoring function in patients with SCI. While further research is needed to optimize these strategies, these advancements hold immense potential for improving the quality of life in SCI patients and advancing the field of neuromodulation.

Consciousness disturbance in patients with chronic kidney disease: Rare but potentially treatable complication. Clinical and neuroradiological review.

Consciousness disturbance in patients with chronic kidney disease: Rare but potentially treatable complication. Clinical and neuroradiological review.

An intra-brainstem circuitry for pain-induced inhibition of itch.

An intra-brainstem circuitry for pain-induced inhibition of itch.

Possible brain regions involved in parturition in mice.

Parturition is a vital physiological process in the reproduction of female mammals, regulated by neurohumoral mechanisms coordinated by the central nervous system. The uterus is essential for this process; however, the neural pathways connecting the brain to the uterus remain poorly understood. In this study, we combined the pseudorabies virus (PRV) tracing tool with c-Fos immunofluorescence staining to identify brain regions that may regulate uterine muscle activity during parturition. We observed that the paraventricular nucleus (PVN), periaqueductal gray (PAG), and locus coeruleus (LC) were colabeled with PRV and c-Fos. Subsequently, we focused on the PVN to determine whether its activity correlated with parturition behavior. We used fiber photometry to record Ca2+ activity in the PVN during parturition in freely behaving mice and found a strong correlation between PVN activity and parturition behavior. Our results demonstrate that this method is both accessible and reliable for studying the roles of central-peripheral neural pathways involved in parturition behavior and suggest that PVN may be a key brain node for parturition.NEW & NOTEWORTHY Parturition is a vital physiological process in the reproduction of female mammals. Here, the authors established a method that combined retrograde tracing, c-Fos immunofluorescence staining, and fiber photometry to study the roles of central-peripheral neural pathways involved in parturition. Our method is simple and reliable to investigate the roles of central-peripheral neural pathways involved in a range of physiological processes in freely moving animals.

Neuroscience-based relational art therapy and deep brain reorienting in the treatment of dissociative identity disorder.

Art therapy (AT) has been proposed as a treatment for post-traumatic conditions, potentially by providing somatic sensory input that can (i) enhance the client's sense of self and embodiment, (ii) modulate arousal, and (iii) aid in rethinking and reframing traumatic memories. However, evidence supporting AT as a treatment for dissociative disorders remains limited. The theoretical basis for the efficacy of AT is discussed in relation to findings regarding the traumatized person's brain and mindset, as well as its altered functional network connectivity. It is crucial to consider specific alterations in brain networks associated with trauma, particularly those occurring in the deep brain regions, which include the midbrain, the brainstem, and the cerebellum. The hypothesis suggests that early or severe trauma can impair the brain's higher regulatory functions, as explained by the cascade theory. This theory explains how diverse activation patterns within the midbrain's periaqueductal gray (PAG) of the midbrain influence the limbic system and cortices, thereby modulating states of being and behavior. Phase-specific, resource-oriented, and long-term therapy for complexly traumatized and dissociative individuals can benefit from novel insights from neuroimaging studies to inform and enhance therapeutic methods. This is illustrated in a clinical vignette with a client diagnosed with dissociative identity disorder (DID), where deep brain reorienting (DBR) was combined with relational AT. The AT component is hypothesized to have facilitated a sense of grounding in the present moment and enhanced the client's access to her neurophenomenological self. Moreover, changes may have occurred at implicit and non-verbal levels. DBR is believed to have helped the client remain present with her previously avoided and unbearable internal experience. To validate these assumptions, the second author conducted a semi-structured interview that focused on the client's experiences of being dissociative and in psychotherapy, including the effect of DBR when introduced after AT. The client's experiences were articulated through a thematic analysis of the interview, which yielded the following themes: Loneliness, getting help, and moving towards togetherness. Further research on and development of therapy methods that enhance the neuroplasticity necessary for highly dissociative clients to change and heal are highly recommended.

Neural mechanisms underlying strain preference behaviour and plasticity in mice

All social animals, including humans, have different social identities that generate unique social interactions. Social preference behaviours, including social integration, prosocial behaviour, and cooperation, have a wide impact on an individual’s social life. However, the neural mechanisms underlying social preferences are not yet clear. In this study, using mice as model animals, we investigated strain preference, which is a social preference based on social identification. We revealed, for the first time, that the social behaviour strain preference of mice is heterogeneous; that is, C57 mice prefer to interact with mice of the same strain, whereas KM mice prefer to interact with mice of a different strain. We further confirmed that strain preference in mice can be plastically altered by changing the nurturing environment and increasing social exposure to mice of other strains. Finally, we screened brain regions related to mouse strain preference and revealed that the activity of the periaqueductal grey (PAG) was not only consistent with the social preference of both C57 and KM mice but also coordinated with the alteration in social preference. We subsequently used muscarine to inhibit the PAG in C57BL/6J mice and found that the strain-specific social preference in C57 mice disappeared. These results showed that the PAG is a key brain region for regulating strain preference and its plasticity. This work fills a gap in the study of strain preferences in social preference research.

Cortical representations of affective pain shape empathic fear in male mice

Affect sharing, the ability to vicariously feel others’ emotions, constitutes the primary component of empathy. However, the neural basis for encoding others’ distress and representing shared affective experiences remains poorly understood. Here, using miniature endoscopic calcium imaging, we identify distinct and dynamic neural ensembles in the anterior cingulate cortex (ACC) that encode observational fear across both excitatory and inhibitory neurons in male mice. Notably, we discover that the population dynamics encoding vicarious freezing information are conserved in ACC pyramidal neurons and are specifically represented by affective, rather than sensory, responses to direct pain experience. Furthermore, using circuit-specific imaging and optogenetic manipulations, we demonstrate that distinct populations of ACC neurons projecting to the periaqueductal gray (PAG), but not to the basolateral amygdala (BLA), selectively convey affective pain information and regulate observational fear. Taken together, our findings highlight the critical role of ACC neural representations in shaping empathic freezing through the encoding of affective pain.

NMDA glutamatergic receptor-signalling in the ventrolateral columns of the periaqueductal grey matter mediates riparin A-induced antinociception to noxious heat stimulation.

Riparin A, a synthetic form of natural riparins, has been shown to produce antinociception. However, little is known regarding the neural mechanisms and structures that mediate its pain-supressing effects. Glutamatergic neurons in the ventrolateral columns of the periaqueductal grey matter (vlPAG) are implicated in modulating spinally projecting pain inhibitory pathways. The aim of this work was to examine the antinociceptive effect of systemic treatment with riparin A at increasing doses and then investigate whether riparin A-induced antinociception is mediated by vlPAG glutamatergic NMDA receptors. Male Wistar Hannover rats were intraperitoneally treated with riparin A at different doses (5, 10 or 20mg/kg), and after 60min, they were submitted to either tail-flick or Hargreaves' plantar tests. After the specification of the most effective dose of riparin A (20mg/kg), independent groups of animals were pretreated with the NMDA receptor selective antagonist LY235959 (0.1nmol/0.2 μL) in vlPAG. Ten minutes later, these animals received intraperitoneal injections of riparin A, and after 60min, they were subjected to the same nociceptive tests. Intraperitoneal injections of riparin A caused antinociception in all laboratory rats. In contrast, previous intra-vlPAG microinjections of the LY235959 decreased the analgesic effect produced by riparin A. Our findings suggest that NMDA receptor-signalling in the vlPAG is critical for the antinociceptive effect produced by riparin A.

Top-down control of the descending pain modulatory system drives placebo analgesia.

In placebo analgesia, prior experience and expectations lead to pain suppression by the administration of an inert substance, but causal evidence for its neural basis is lacking. To identify the underlying neural circuits, we reverse-translated a conditioned placebo protocol from humans to mice. Surprisingly, the placebo effect suppresses both nociception and unconditioned emotional-motivational pain-related behavior. Descending pain modulatory neurons in the periaqueductal gray (PAG) are critical for both morphine and placebo antinociception. The placebo effect depends on input to the PAG from the medial prefrontal and anterior cingulate cortices, but not anterior insular cortex. Conditioning enhances noxious stimulus-evoked endogenous opioid release in the PAG to produce analgesia. Our results suggest that cortical control of the descending pain modulatory system (DPMS) is gated by rapid endogenous opioid signaling in the PAG during placebo trials. This study bridges clinical and preclinical research, establishing a central role for the DPMS in placebo analgesia.

Periaqueductal gray passes over disappointment and signals continuity of remaining reward expectancy.

Animals navigate environments with multiple objects to find rewards. We previously found that phasic activities of lateral habenula (LHb) neurons encode step-by-step changes in reward predictions induced by the series of multiple objects and errors. However, to obtain the reward, another important source would be to maintain their mind at the beginning and tolerate capricious errors in following steps to continue the sequence of actions. We found that periaqueductal gray (PAG) neurons, LHb downstream brain area, transport reward expectation from one step to the next step, affecting subsequent behaviors. The tonic PAG activities correlated with animal behavior responding to a cue and also contextually affected subsequent behaviors (vigorous reaching and holding). This research suggests that phasic and tonic signaling in the LHb-PAG pathway plays a crucial role in deciding the continuation versus discontinuation of reward-seeking behaviors in the sequential steps and enables animals to search complex environments and find rewards.

Peripartum buprenorphine and oxycodone exposure impair maternal behavior and increase neuroinflammation in the brains of new mother rats

Peripartum buprenorphine and oxycodone exposure impair maternal behavior and increase neuroinflammation in the brains of new mother rats

Fibromyalgia and the painful self: A meta-analysis of resting-state fMRI data.

Fibromyalgia (FM) is a complex medical condition. The nested hierarchical model of self and its extension to the pain matrix could represent an integrated theoretical framework that might comprehensively captures FM clinical feautres. A multi-level meta-analysis was conducted. Resting-state functional connectivity (RS-FC) studies that compared patients with FM and healthy controls (HCs) were included. The association between RS-FC among self-related brain regions and pain intensity was also explored in the FM group. Eleven studies were eligible for meta-analytic procedures. Patients with FM, compared to HCs, were characterized by an increased RS-FC between the default mode network (DMN) and areas ascribed to interoceptive (e.g., insula) and exteroceptive (e.g., premotor, visual/auditory cortices) self layers. The clinical group also showed a reduced RS-FC among regions of the pain matrix (i.e., periaqueductal gray matter, somatosensory areas) involved in pain modulation. An increased RS-FC within DMN together with a heightened RS-FC between DMN and interoceptive self areas were positively associated to pain intensity reported by patients with FM. The nested hierarchical model of self and its extension to the pain matrix might represent comprehensive neurobiological backgrounds for clarifying core mind-body clinical features of FM.

Activation of the periaqueductal gray controls respiratory output through a distributed brain network.

The periaqueductal gray (PAG) has been previously established to play a key role in producing the vital changes in respiration occurring in response to threat. However, it is not fully understood how PAG activation alters the ongoing respiratory output, nor it is understood which pathways mediate these effects, as several regions have been previously identified to influence respiratory activity. We used optogenetic tools in conjunction with EMG recordings of inspiratory and expiratory musculature to determine how PAG activation on short (250ms) and longer (10-15s) timescales alters respiratory muscle activity. Through cFOS mapping, we also identified key downstream brain regions which were likely modulated by PAG activation including the preBötzinger Complex (preBötC) and the lateral parafacial area (pFL). We then stimulated PAG terminals in those regions to determine whether their activity can account for the observed effects of PAG stimulation. Directly stimulating the PAG resulted in prominent changes to all recorded muscle activities and reset the breathing rhythm in either a phase-independent or phase-dependent manner. In contrast, stimulating PAG terminals in either preBötC or pFL with long or shorter timescale stimuli could not completely replicate the effects of direct PAG stimulation and also did not produce any respiratory reset. Our results show that the effects of PAG activity on respiration are not mediated solely by PAG inputs to either the preBötC or pFL and more likely involve integration across a larger network of brainstem areas.

Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats.

Psychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brain's hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (n=16, 8/sex), footshock stress (n=12, 6/sex), or a no-stress control condition (n=12, 6/sex) immediately after the session's conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking, perhaps in a sex-dependent manner.

A rare case of paralytic rabies presented with acute flaccid transverse myelitis in case of inadequate post-exposure prophylaxis

Rabies is a fatal infectious disease caused by rabies lyssavirus, mainly transmitted to humans by the bite of rabid mammals. Rabies can present in encephalitic and paralytic types. Paralytic rabies presents with acute flaccid transverse myelitis. We report a rare case of paralytic rabies with inadequate post-exposure prophylaxis (PEP). A 19-year-old male was admitted with paraplegia and associated bladder and bowel incontinence for 2 days. He had history of Category III bite by a street stray dog and received inadequate PEP 3 months back which was revealed later. On imaging of dorsal spinal cord magnetic resonance imaging, there was a long-segment T2 and short-tau inversion recovery (STIR) hyperintense signal in central gray matter of dorsal cord with involvement up to part of conus medullaris. Cerebrospinal fluid analysis showed elevated microprotein with lymphocyte predominance. Clinical and laboratory findings supported diagnosis of rabies induced acute transverse myelitis. Incomplete PEP has been frequently reported in cases developing paralytic rabies. Adequate PEP according can easily prevent this disease.

A molecularly distinct cell type in the midbrain regulates intermale aggression behaviors in mice.

Rationale: The periaqueductal gray (PAG) is a central hub for the regulation of aggression, whereas the circuitry and molecular mechanisms underlying this regulation remain uncharacterized. In this study, we investigate the role of a distinct cell type, Tachykinin 2-expressing (Tac2+) neurons, located in the dorsomedial PAG (dmPAG) and their modulation of aggressive behavior in mice. Methods: We combined activity mapping, in vivo Ca2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. Results: We revealed that dmPAGTac2 neurons are selectively activated by fighting behaviors. Chemogenetic activation of these neurons evoked fighting behaviors, while inhibition or genetic ablation of dmPAGTac2 neurons attenuated fighting behaviors. TRAP profiling of dmPAGTac2 neurons revealed an enrichment of serotonin-associated transcripts in response to fighting behaviors. Finally, we validated these effects by selectively administering pharmacological agents to the dmPAG, reversing the behavioral outcomes induced by chemogenetic manipulation. Conclusions: We identify dmPAGTac2 neurons as critical modulators of aggressive behavior in mouse and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence.

Periaqueductal gray passes over disappointment and signals continuity of remaining reward expectancy.

Disappointment is a vital factor in the learning and adjustment of strategies in reward-seeking behaviors. It helps them conserve energy in environments where rewards are scarce, while also increasing their chances of maximizing rewards by prompting them to escape to environments where richer rewards are anticipated (e.g., migration). However, another key factor in obtaining the reward is the ability to monitor the remaining possibilities of obtaining the outcome and to tolerate the disappointment in order to continue with subsequent actions. The periaqueductal gray (PAG) has been reported as one of the key brain regions in regulating negative emotions and escape behaviors in animals. The present study suggests that the PAG could also play a critical role in inhibiting escape behaviors and facilitating ongoing motivated behaviors to overcome disappointing events. We found that PAG activity is tonically suppressed by reward expectancy as animals engage in a task to acquire a reward outcome. This tonic suppression of PAG activity was sustained during a series of sequential task procedures as long as the expectancy of reward outcomes persisted. Notably, the tonic suppression of PAG activity showed a significant correlation with the persistence of animals' reward-seeking behavior while overcoming intermittent disappointing events. This finding highlights that the balance between distinct tonic signaling in the PAG, which signals remaining reward expectancy, and phasic signaling in the LHb, which signals disappointment, could play a crucial role in determining whether animals continue or discontinue reward-seeking behaviors when they encounter an unexpected negative event. This mechanism would be essential for animals to efficiently navigate complex environments with various reward volatilities and ultimately contributes to maximizing their reward acquisition.

DBS in the restoration of motor functional recovery following spinal cord injury.

The landscape of therapeutic deep brain stimulation (DBS) for locomotor function recovery is rapidly evolving. This review provides an overview of electrical neuromodulation effects on spinal cord injury (SCI), focusing on DBS for motor functional recovery in human and animal models. We highlight research providing insight into underlying cellular and molecular mechanisms. A literature review via Web of Science and PubMed databases from 1990 to May 29, 2024, reveals a growing body of evidence for therapeutic DBS in SCI recovery. Advances in techniques like optogenetics and whole-brain tractogram have helped elucidate DBS mechanisms. Neuronal targets sites for SCI functional recovery include the mesencephalic locomotor region (MLR), cuneiform nucleus (CNF), and nucleus raphe magnus (NRG), with pedunculopontine nucleus (PPN), periaqueductal gray (PAG), and nucleus ventroposterolateral thalami (VPL) for post-injury functional recovery treatment. Radiologically guided DBS optimization and combination therapy with classical rehabilitation have become an effective therapeutic method, though ongoing interventional trials are needed to enhance understanding and validate DBS efficacy in SCI. On the pre-clinical front, standardization of pre-clinical approaches are essential to enhance the quality of evidence on DBS safety and efficacy. Mapping brain targets and optimizing DBS protocols, aided by combined DBS and medical imaging, are critical endeavors. Overall, DBS holds promise for neurological and functional recovery after SCI, akin to other electrical stimulation approaches.