Search Results (31)

Background/Objectives: Pediatric multiple sclerosis (MS) is a rare and complex neuroinflammatory disease characterized by demyelination and neurological dysfunction in individuals under 18 years of age. This systematic review and activation likelihood estimation (ALE) meta-analysis aimed to synthesize the existing literature on functional and structural brain alterations in pediatric MS patients. Methods: Following the PRISMA guidelines, we analyzed 21 studies involving 917 pediatric MS patients and 320 healthy controls, assessing brain structure and function using MRI and fMRI techniques. Results: The results reveal consistent alterations in brain regions critical for cognitive and motor functions, including reduced brain volume, increased lesion load, and disrupted functional connectivity, particularly in the thalamus, cerebellum, and hippocampus. The ALE meta-analysis identified significant activation clusters in the dorsal anterior cingulate cortex, angular gyrus, and superior parietal lobes, regions associated with cognition, attention, and working memory. Conclusions: These findings suggest that pediatric MS uniquely affects brain development, contributing to cognitive impairments that differ from those observed in adult MS. Our study underscores the importance of early diagnosis and tailored therapeutic interventions to mitigate neurodevelopmental disruptions and improve long-term outcomes in pediatric MS patients. Full article

Background/Objectives: Neuroimaging biomarkers could offer more objective measures of the pain experience. This study investigated rT1/T2 maps of the brain as a novel biomarker for chronic pain in patients with central post-stroke pain (PSP) and persistent spinal pain syndrome type 2 (PSPS-II). Methods: Patients with PSP and PSPS-II were retrospectively included alongside healthy controls. Bias correction and intensity normalization were applied to the T1-weighted and T2-weighted images to generate the rT1/T2 maps of the brain. Subsequently, rT1/T2 maps were spatially correlated with neurotransmitter atlases derived from molecular imaging. Results: In total, 15 PSPS-II patients, 11 PSP patients, and 18 healthy controls were included. No significant differences between patient and control demographics were found. Significant decreases in rT1/T2 signal intensity (p < 0.001) were observed in the dorsal and medial part of the thalamus, left caudate nucleus, cuneus, superior frontal gyrus, and dorsal cervicomedullary junction in PSP patients. No significant changes were found in rT1/T2 signal intensity in PSPS-II patients. Significant correlations were found with CB1-, 5HT2a-, and mGluR5-receptor maps (pFDR = 0.003, 0.030, and 0.030, respectively) for the PSP patients and with CB1-, 5HT1a-, 5HT2a-, KappaOp-, and mGluR5-receptor maps (pFDR = 0.003, 0.002, 0.002, 0.003, and 0.002, respectively) in PSPS-II patients. Conclusions: These findings suggest that microstructural alterations occur in the thalamus, cuneus, and dorsal cervicomedullary junction in patients with PSP. The lack of significant findings in rT1/T2 in PSPS-II patients combined with the significant correlations with multiple neurotransmitter maps suggests varying degrees of microstructural deterioration in both chronic pain syndromes, although further research is warranted. Full article

Background/Objectives: Cocaine use disorder (CUD) poses a worldwide health challenge, with severe consequences for brain function. However, the phase dynamics underlying CUD and the transitions between CUD and health remain poorly understood. Methods: Here, we used resting-state functional magnetic resonance imaging (fMRI) data from 43 CUD patients and 45 healthy controls (HCT). We performed empirical analysis to identify phase-coherence states and compared their probabilities of occurrence between conditions. To further explore the underlying mechanism, we employed computational modeling to replicate the observed state probabilities for each condition. These generated whole-brain models enabled us to simulate external perturbations and identify optimal brain regions mediating transitions between HCT and CUD. Results: We found that CUD was associated with a reduced occurrence probability of the state dominated by the default mode network (DMN). Perturbing the nucleus accumbens, thalamus, and specific regions within the default mode, limbic and frontoparietal networks drives transitions from HCT to CUD, while perturbing the hippocampus and specific regions within the visual, dorsal attention, and DMN facilitates a return from CUD to HCT. Conclusions: This study revealed altered DMN-related dynamics in CUD from the phase perspective and provides potential regions critical for state transitions. The results contribute to understanding the pathogenesis of CUD and the development of therapeutic stimulation strategies. Full article

Background: Fibromyalgia, a chronic condition that causes long-lasting pain over several months, is a global medical issue with both personal and societal implications. It is one of the hardest types of pain to heal, given the lack of objective parameters for diagnosis and progression evaluation. The main symptoms of fibromyalgia are long-lasting widespread pain alongside with anxiety, fatigue, sleep disorders, cognitive dysfunction, and obesity. Programmed cell death 1 ligand 1 (PD-L1) has been used as a target in cancer immunotherapy. It can inhibit acute and chronic pain by suppressing nociceptive neuron activity via PD-1 receptors. Methods: The current study aimed to investigate the role of PD-L1/PD1 in a mouse fibromyalgia pain model. Mice were exposed to intermittent cold stress (ICS) to produce a murine fibromyalgia model characterized using von Frey and Hargreaves tests. Results: The ICS-induced mice fibromyalgia pain model showed mechanical (2.26 ± 0.18 g) and thermal (4.36 ± 0.31 s) hyperalgesia. Nociceptive responses could be relieved with electroacupuncture, intracerebral PD-L1 injection, or Trpv1 deletion. We also identified a lower PD-1 level in the dorsal root ganglion, spinal cord, thalamus, and somatosensory cortex. In contrast, levels of pain-related kinases increased after fibromyalgia induction, an effect which could be reversed by EA, PD-L1, or Trpv1 deletion. Conclusions: Our findings shed light on the contribution of PD-L1/PD1 to EA and fibromyalgia pain, indicating its potential as a treatment target for fibromyalgia. Full article

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments. Full article

The dorsal raphe nucleus (DRN) has gained attention owing to its involvement in various physiological functions, such as sleep–awake, feeding, and emotion, with its analgesic role being particularly significant. It is described as the “pain inhibitory nucleus” in the brain. The DRN has diverse projections from hypothalamus, midbrain, and pons. In turn, the DRN is a major source of projections to diverse cortex, limbic forebrain thalamus, and the midbrain and contains highly heterogeneous neuronal subtypes. The activation of DRN neurons in mice prevents the establishment of neuropathic, chronic pain symptoms. Chemogenetic or optogenetic inhibition neurons in the DRN are sufficient to establish pain phenotypes, including long-lasting tactile allodynia, that scale with the extent of stimulation, thereby promoting nociplastic pain. Recent progress has been made in identifying the neural circuits and cellular mechanisms in the DRN that are responsible for sensory modulation. However, there is still a lack of comprehensive review addressing the specific neuron types in the DRN involved in pain modulation. This review summarizes the function of specific cell types within DRN in the pain regulation, and aims to improve understanding of the mechanisms underlying pain regulation in the DRN, ultimately offering insights for further exploration. Full article

Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5^−/− mice (peripheral) but increased in LPAR2^−/− and Prg1^−/− mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2^−/−) or Prg2 (PRG2^−/−). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5^−/− mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress “non-histaminergic” itch. Full article

Pain is a complex response to noxious stimuli. Upon detection of the nociceptive stimulus by first-order neurons or nociceptors, an action potential ascends to the spinal dorsal horn, a crucial site for synapsing with second-order neurons. These second-order neurons carry the nociceptive stimulus to supraspinal regions, notably the thalamus. Although extensive research has focused on spinal-level nociceptive mechanisms (e.g., neurotransmitters, receptors, and glial cells), the thalamus is still poorly elucidated. The role of the thalamus in relaying sensory and motor responses to the cortex is well known. However, a comprehensive understanding of the mechanisms in the synapse between the second-order and third-order neurons that transmit this impulse to the somatosensory cortex, where the response is processed and interpreted as pain, is still lacking. Thus, this review investigated the thalamus’s role in transmitting nociceptive impulses. Current evidence indicates the involvement of the neurotransmitters glutamate and serotonin, along with NMDA, P2X4, TLR4, FGR, and NLRP3 receptors, as well as signaling pathways including ERK, P38, NF-κB, cytokines, and glial cells at nociceptive synapses within the thalamus. Full article

Polysulfides are endogenously produced in mammals and generally associated with protective functions. Our aim was to investigate the effect of dimethyl trisulfide (DMTS) in a mouse model of acute stress. DMTS activates transient receptor potential ankyrin 1 (TRPA1) channels and leads to neuropeptide release, potentially that of substance P (SP). We hypothesize that DMTS might inhibit the degrading enzymes of endocannabinoids, so this system was also investigated as another possible pathway for mediating the effects of DMTS. Trpa1 gene wild-type (WT) and knockout (KO) mice were used to confirm the role of the TRPA1 ion channel in mediating the effects of DMTS. C57BL/6J, NK1 gene KO, and Tac1 gene KO mice were used to evaluate the effect of DMTS on the release and expression of SP. Some C57BL/6J animals were treated with AM251, an inhibitor of the cannabinoid CB1 receptor, to elucidate the role of the endocannabinoid system in these processes. Open field test (OFT) and forced swim test (FST) were performed in each mouse strain. A tail suspension test (TST) was performed in Trpa1 WT and KO animals. C-FOS immunohistochemistry was carried out on Trpa1 WT and KO animals. The DMTS treatment increased the number of highly active periods and decreased immobility time in the FST in WT animals, but had no effect on the Trpa1 KO mice. The DMTS administration induced neuronal activation in the Trpa1 WT mice in the stress-related brain areas, such as the locus coeruleus, dorsal raphe nucleus, lateral septum, paraventricular nucleus of the thalamus, and paraventricular nucleus of the hypothalamus. DMTS may have a potential role in the regulation of stress-related processes, and the TRPA1 ion channel may also be involved in mediating the effects of DMTS. DMTS can be an ideal candidate for further study as a potential remedy for stress-related disorders. Full article

The present study examined how P2X7 receptor knockout (KO) modulates central post-stroke pain (CPSP) induced by lesions of the ventrobasal complex (VBC) of the thalamus in behaviors, molecular levels, and electrical recording tests. Following the experimental procedure, the wild-type and P2X7 receptor KO mice were injected with 10 mU/0.2 μL type IV collagenase in the VBC of the thalamus to induce an animal model of stroke-like thalamic hemorrhage. Behavioral data showed that the CPSP group induced thermal and mechanical pain. The P2X7 receptor KO group showed reduced thermal and mechanical pain responses compared to the CPSP group. Molecular assessments revealed that the CPSP group had lower expression of NeuN and KCC2 and higher expression of GFAP, IBA1, and BDNF. The P2X7 KO group showed lower expression of GFAP, IBA1, and BDNF but nonsignificant differences in KCC2 expression than the CPSP group. The expression of NKCC1, GABAa receptor, and TrkB did not differ significantly between the control, CPSP, and P2X7 receptor KO groups. Muscimol, a GABAa agonist, application increased multiunit numbers for monitoring many neurons and [Cl⁻] outflux in the cytosol in the CPSP group, while P2X7 receptor KO reduced multiunit activity and increased [Cl⁻] influx compared to the CPSP group. P2X4 receptor expression was significantly decreased in the 100 kDa but not the 50 kDa site in the P2X7 receptor KO group. Altogether, the P2X7 hypothesis of CPSP was proposed, wherein P2X7 receptor KO altered the CPSP pain responses, numbers of astrocytes and microglia, CSD amplitude of the anterior cingulate cortex and the medial dorsal thalamus, BDNF expression, [Cl⁻] influx, and P2X4 expression in 100 kDa with P2X7 receptors. The present findings have implications for the clinical treatment of CPSP symptoms. Full article

The primary visual cortex (V1) is one of the most studied regions of the brain and is characterized by its specialized and laminated layer 4 in human and non-human primates. However, studies aiming to harmonize the definition of the cortical layers and borders of V1 across rodents and primates are very limited. This article attempts to identify and harmonize the molecular markers and connectional patterns that can consistently link corresponding cortical layers of V1 and borders across mammalian species and ages. V1 in primates has at least two additional and unique layers (L3b2 and L3c) and two sublayers of layer 4 (L4a and L4b) compared to rodent V1. In all species examined, layers 4 and 3b of V1 receive strong inputs from the (dorsal) lateral geniculate nucleus, and V1 is mostly surrounded by the secondary visual cortex except for one location where V1 directly abuts area prostriata. The borders of primate V1 can also be clearly identified at mid-gestational ages using gene markers. In rodents, a novel posteromedial extension of V1 is identified, which expresses V1 marker genes and receives strong inputs from the lateral geniculate nucleus. This V1 extension was labeled as the posterior retrosplenial cortex and medial secondary visual cortex in the literature and brain atlases. Layer 6 of the rodent and primate V1 originates corticothalamic projections to the lateral geniculate, lateral dorsal, and reticular thalamic nuclei and the lateroposterior–pulvinar complex with topographic organization. Finally, the direct geniculo-extrastriate (particularly the strong geniculo-prostriata) projections are probably major contributors to blindsight after V1 lesions. Taken together, compared to rodents, primates, and humans, V1 has at least two unique middle layers, while other layers are comparable across species and display conserved molecular markers and similar connections with the visual thalamus with only subtle differences. Full article

The thalamus plays a crucial role in ensuring the faithful transfer of sensory information, except olfactory signals, to corresponding cortical areas. However, thalamic function is not simply restricted to relaying information to and from the cerebral cortex. The ability to modulate the flow of sensory information is supported by a second abundant neuronal type in the prethalamus, the inhibitory gamma-aminobutyric acid (GABAergic) neurons, which project inhibitory GABAergic axons to dorsal thalamic glutamatergic neurons. Interestingly, during the trajectory of pioneer prethalamic axons, morphogen fibroblast growth factor (FGF)-3 is expressed in the ventral chick hypothalamus. Using in vitro analyses in chick explants, we identify a chemorepellent effect of FGF3 on nearby prethalamic GABAergic axons. Furthermore, inhibition of FGF3 guidance functions indicates that FGF3 signaling is necessary to navigate prethalamic axons correctly. Gene expression analyses and loss of function studies demonstrate that FGF3 mediates prethalamic axonal guidance through the downstream pathway of the FGF receptor (FGFR)-1. Together, these results suggest that FGF3 expressed in the hypothalamus functions as a chemorepellent molecule to direct the pathway selection of neighboring GABAergic axons. Full article

Parkinson’s disease (PD) is one of the leading neurodegenerative disorders. It is considered a movement disorder, although it is accepted that many nonmotor symptoms accompany the classic motor symptoms. PD exhibits heterogeneous and overlaying clinical symptoms, and the overlap of motor and nonmotor symptoms complicates the clinical diagnosis and management. Loss of modulation secondary to the absence of dopamine due to degeneration of the substantia nigra compacta produces changes in firing rates and patterns, oscillatory activity, and higher interneuronal synchronization in the basal ganglia–thalamus–cortex and nigrovagal network involvement in motor and nonmotor symptoms. These neurophysiological changes can be monitored by electrophysiological assessment. The purpose of this review was to summarize the results of neurophysiological changes, especially in the network oscillation in the beta-band level associated with parkinsonism, and to discuss the use of these methods to optimize the diagnosis and management of PD. Full article

The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies. Full article

Self-conscious emotions, such as shame and guilt, play a fundamental role in regulating moral behaviour and in promoting the welfare of society. Despite their relevance, the neural bases of these emotions are uncertain. In the present meta-analysis, we performed a systematic literature review in order to single out functional neuroimaging studies on healthy individuals specifically investigating the neural substrates of shame, embarrassment, and guilt. Seventeen studies investigating the neural correlates of shame/embarrassment and seventeen studies investigating guilt brain representation met our inclusion criteria. The analyses revealed that both guilt and shame/embarrassment were associated with the activation of the left anterior insula, involved in emotional awareness processing and arousal. Guilt-specific areas were located within the left temporo-parietal junction, which is thought to be involved in social cognitive processes. Moreover, specific activations for shame/embarrassment involved areas related to social pain (dorsal anterior cingulate and thalamus) and behavioural inhibition (premotor cortex) networks. This pattern of results might reflect the distinct action tendencies associated with the two emotions. Full article