Search Results (22)

Traumatic brain injury (TBI) is a major global health problem and a leading cause of long-term neurological disability. TBI produces a spectrum of persistent symptoms, including cognitive impairment, mood and behavioral disturbances, sleep disruption, fatigue, and autonomic dysregulation. Chronic pain is among the most debilitating sequelae, affecting physical, emotional, and social functioning. The etiology of post-TBI pain is multifactorial, arising from initial structural and biochemical injury to the nervous system, maladaptive neuroplastic changes, neuroinflammation, and psychological comorbidities that amplify pain perception and chronicity. This review explores the complex pathophysiology of post-TBI pain and outlines a multidisciplinary framework for management. Pain syndromes are classified according to the International Association for the Study of Pain’s mechanistic framework as nociceptive pain (resulting from tissue injury and inflammation), neuropathic pain (due to lesion or disease of the somatosensory nervous system), and nociplastic pain (arising from altered nociceptive processing without clear evidence of tissue or nerve damage). Many patients exhibit mixed pain phenotypes driven by neuroinflammation and central sensitization. Pharmacologic approaches, including anti-inflammatory agents, anticonvulsants, and antidepressants, require cautious titration due to TBI-related comorbidities. Equally essential are non-pharmacologic strategies such as physical and occupational therapy, cognitive behavioral therapy, and neuromodulation techniques, which target both biomechanical and psychosocial contributors. Emerging innovations, machine learning for prognostication, blood biomarkers for structural injury, and neuro-reparative agents, represent the next frontier in personalized management. Effective care for post-TBI pain requires an integrated strategy that combines mechanistic classification, multidisciplinary treatments, and advancing diagnostic technologies. Full article

Neuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective response to tissue injury, neuropathic pain arises from maladaptive signaling within the nervous system. In this context, the spinal endocannabinoid system (ECS) has emerged as a pivotal modulator of nociceptive processing. However, its precise role in neuropathic pain remains debated due to its dual effects. Numerous studies report antinociceptive and neuroprotective effects; however, emerging data indicate that under specific pathological conditions, ECS activation may paradoxically facilitate pain transmission. This review examines spinal ECS context dependence, uncovering its bidirectional antinociceptive and pronociceptive effects in neuropathic pain. By integrating current evidence on cellular, molecular, and pathophysiological mechanisms, we delineate the factors that determine whether ECS modulation inhibits or promotes pain. A comprehensive understanding of these mechanisms is essential for optimizing cannabinoid-based strategies to maximize therapeutic benefits while minimizing adverse outcomes. Finally, we highlight the spinal cord’s centrality as the principal site for the initiation and maintenance of neuropathic pain and advocate for rigorous translational research to clarify the therapeutic potential of spinal ECS-targeted interventions. Full article

Psychedelic compounds are gaining renewed attention across disciplines for their profound psychological and neurobiological effects. Emerging research highlights their efficacy in treating mood disorders, PTSD, and addiction by enhancing neuroplasticity and disrupting maladaptive cognitive patterns. From a psychological standpoint, psychedelics facilitate introspection, emotional processing, and therapeutic breakthroughs. Neuroscientific findings reveal altered brain network dynamics, while anthropological and philosophical perspectives contextualize their cultural and existential significance. In medicine, they offer novel interventions for chronic pain and palliative care. The present review article underscores the need for rigorous, ethically grounded research to explore psychedelics’ potential in reshaping mental health paradigms and cognitive science from a multidisciplinary perspective. Full article

Chronic pain is a complex and persistent condition involving sustained nociceptive input, maladaptive neuroplastic changes, and neuroimmune interactions. Central to its pathophysiology is the dysregulation of neuromodulatory signaling pathways, including neurotransmitters (e.g., dopamine, serotonin, norepinephrine), neuropeptides (e.g., substance P, CGRP), and neurotrophic factors (e.g., BDNF), which modulate both central and peripheral sensitization mechanisms. In disorders such as fibromyalgia, altered monoaminergic transmission has been implicated in the attenuation of descending inhibitory control, thereby enhancing pain perception and reducing responsiveness to conventional therapies. Concurrently, neuroinflammation, driven by glial cell activation and cytokine release, further exacerbates neuronal excitability and reinforces maladaptive signaling loops. Recent technological advances, including transcriptomic profiling, functional neuroimaging, and single-cell RNA sequencing, have provided new insights into patient-specific patterns of neuromodulatory dysfunction, highlighting potential biomarkers for disease stratification and therapeutic targeting. These developments support the hypothesis that dysregulated neuromodulatory circuits not only underlie diverse chronic pain phenotypes but may also serve as intervention points for precision medicine. This narrative review synthesizes current evidence on the roles of neuromodulatory systems in chronic pain, focusing on synaptic plasticity, nociceptor sensitization, and neuroimmune crosstalk. By integrating preclinical findings with clinical observations, we propose a mechanistic framework for understanding pain chronification and guiding future therapeutic strategies. Harnessing neuromodulatory targets, whether pharmacologically or via neuromodulation technologies, could offer more personalized and effective approaches to chronic pain management. Full article

Background: Transcranial direct current stimulation (tDCS) has emerged as a promising neuromodulatory tool for language rehabilitation in chronic aphasia. However, the effects of bi-hemispheric, multisite stimulation remain largely unexplored, especially in people with chronic and treatment-resistant language impairments. The goal of this study is to look at the effects on behavior and brain activity of an individualized language training program that combines bi-hemispheric multisite anodal tDCS with personalized language training for Albert, a patient with long-standing, treatment-resistant non-fluent aphasia. Methods: Albert, a right-handed retired physician, had transcortical motor aphasia (TCMA) subsequent to a left-hemispheric ischemic stroke occurring more than six years before the operation. Even after years of traditional treatment, his expressive and receptive language deficits remained severe and persistent despite multiple rounds of traditional therapy. He had 15 sessions of bi-hemispheric multisite anodal tDCS aimed at bilateral dorsal language streams, administered simultaneously with language training customized to address his particular phonological and syntactic deficiencies. Psycholinguistic evaluations were performed at baseline, immediately following the intervention, and at 1, 2, 3, and 6 months post-intervention. Resting-state fMRI was conducted at baseline and following the intervention to evaluate alterations in functional connectivity (FC). Results: We noted statistically significant enhancements in auditory sentence comprehension and oral reading, particularly at the 1- and 3-month follow-ups. Neuroimaging showed decreased functional connectivity (FC) in the left inferior frontal and precentral regions (dorsal stream) and in maladaptive right superior temporal regions, alongside increased FC in left superior temporal areas (ventral stream). This pattern suggests that language networks may be reorganizing in a more efficient way. There was no significant improvement in phonological processing, which may indicate reduced connectivity in the left inferior frontal areas. Conclusions: This case underscores the potential of combining individualized, network-targeted language training with bi-hemispheric multisite tDCS to enhance recovery in chronic, treatment-resistant aphasia. The convergence of behavioral gains and neuroplasticity highlights the importance of precision neuromodulation approaches. However, findings are preliminary and warrant further validation through controlled studies to establish broader efficacy and sustainability of outcomes. Full article

Ketamine, originally developed as an anesthetic, is gaining increasing attention due to its multifaceted pharmacological properties. In addition to its use in anesthesia, ketamine exerts potent analgesic effects via N-methyl-D-aspartate (NMDA) receptor antagonism, modulating pain perception and reducing central sensitization, particularly in chronic and neuropathic pain conditions. Emerging evidence also supports ketamine’s potential in the treatment of substance use disorder, where it may disrupt maladaptive reward-related memories and promote neuroplasticity which facilitates behavioral change. Moreover, in recent years, S-ketamine has shown rapid and potent antidepressant effects, especially in treatment-resistant depression (TRD), probably due to increased glutamatergic signaling, synaptic plasticity and the release of neurotrophic factors. This heterogeneous therapeutic profile positions ketamine as a unique agent at the interface of anesthesia, pain management, addiction medicine and psychiatry, warranting further exploration into its mechanism and long-term effectiveness. Full article

Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article

This review explores pain neuroscience education (PNE) in the context of opioid dependence among Caucasian and African American populations, addressing disparities and sociocultural influences in the opioid epidemic. Von Bertalanffy’s general systems theory and Bronfenbrenner’s ecological systems theory comprise the underlying theoretical frameworks behind the review, emphasizing the importance of biopsychosocial perspectives of chronic pain and ecological systems on individual development. Within these frameworks, the study objective is to summarize relevant and contemporary literature among African American and Caucasian populations regarding opioid dependency, neuroplasticity in chronic pain, and PNE. Peer-reviewed articles published within the last 10 years were reviewed for relevance. Limitations include a lack of research on the intersection of ethnicity and PNE, a lack of studies investigating interdisciplinary input regarding PNE, and a focus on only two ethnic groups. This narrative review finds that African Americans face systemic barriers to effective treatment for pain and opioid use disorder (OUD), while Caucasians are more likely to be overprescribed with higher rates of OUD. From a systems and ecological perspective, maladaptive neuroplasticity in chronic pain (biologic subsystem) intersects with ethnic disparities in prescribing access and pain beliefs (psychosocial subsystem) to influence opioid use and the chronic pain experience. PNE shows promise as an adjunct to traditional physical therapy in reducing nociplastic pain, potentially affecting opioid dependency. Future research should incorporate readiness-to-change models, generational and ethnocultural perspectives, and neuroimaging with PNE to optimize the delivery of PNE to individuals of different backgrounds. Full article

Background/Objectives: Lower-limb amputation (LLA) leads to disability, impaired mobility, and reduced quality of life, affecting 1.6 million people in the USA. Post-amputation, motor cortex reorganization occurs, contributing to phantom limb pain (PLP). Transcranial magnetic stimulation (TMS) assesses changes in cortical excitability, helping to identify compensatory mechanisms. This study investigated the association between TMS metrics and clinical and neurophysiological outcomes in LLA patients. Methods: A cross-sectional analysis of the DEFINE cohort, with 59 participants, was carried out. TMS metrics included resting motor threshold (rMT), motor-evoked potential (MEP) amplitude, short intracortical inhibition (SICI), and intracortical facilitation (ICF). Results: Multivariate analysis revealed increased ICF and rMT in the affected hemisphere of PLP patients, while SICI was reduced with the presence of PLP. A positive correlation between SICI and EEG theta oscillations in the frontal, central, and parietal regions suggested compensatory mechanisms in the unaffected hemisphere. Increased MEP was associated with reduced functional independence. Conclusions: SICI appears to be a key factor linked to the presence of PLP, but not its intensity. Reduced SICI may indicate impaired cortical compensation, contributing to PLP. Other neural mechanisms, including central sensitization and altered thalamocortical connectivity, may influence PLP’s severity. Our findings align with those of prior studies, reinforcing low SICI as a marker of maladaptive neuroplasticity in amputation-related pain. Additionally, longer amputation duration was associated with disrupted SICI, suggesting an impact of long-term plasticity changes. Full article

Background/Objectives: Complex regional pain syndrome (CRPS) is characterized by severe pain and reduced functionality, which can significantly affect an individual’s quality of life. The current treatment of CRPS is challenging. However, recent advances in diagnostic and treatment methods show promise for improving patient outcomes. This review aims to place the question of CRPS in a broader context and highlight the objectives of the research for future directions in the management of CRPS. Methods: This study involved a comprehensive literature review. Results: Research has identified three primary pathophysiological pathways that may explain the clinical variability observed in CRPS: inflammatory mechanisms, vasomotor dysfunction, and maladaptive neuroplasticity. Investigations into these pathways have spurred the development of novel diagnostic and treatment strategies focused on N-Methyl-D-aspartate Receptor Antagonists (NMDA), Toll-like receptor 4 (TLR-4), α1 and α2 adrenoreceptors, as well as the identification of microRNA (miRNA) biomarkers. Treatment methods being explored include immune and glial-modulating agents, intravenous immunoglobulin (IVIG) therapy, plasma exchange therapy, and neuromodulation techniques. Additionally, there is ongoing debate regarding the efficacy of other treatments, such as free radical scavengers, alpha-lipoic acid (ALA), dimethyl fumarate (DMF), adenosine monophosphate-activated protein kinase (AMPK) activators such as metformin, and phosphodiesterase-5 inhibitors such as tadalafil. Conclusions: The controversies surrounding the mechanisms, diagnosis, and treatment of CRPS have prompted researchers to investigate new approaches aimed at enhancing understanding and management of the condition, with the goal of alleviating symptoms and reducing associated disabilities. Full article

Background: Spinal cord injury (SCI) frequently leads to pain, leading to significant disability. Pain sensitization, a key feature of SCI, is commonly assessed via quantitative sensory testing like the Pressure Pain Threshold (PPT), though the factors influencing PPT changes remain unclear. This study hypothesizes that specific clinical and neurophysiological factors modulate PPT in SCI patients. The primary objective is to identify predictors of PPT in SCI patients. Methods: We conducted a cross-sectional analysis of neurophysiological, clinical, and demographic data from 102 SCI patients in an ongoing prospective cohort study called “Deficit of Inhibition as a Marker of Neuroplasticity” (DEFINE study). Multivariable regression analyses were used to evaluate demographic, clinical, and functional variables associated with PPT, the primary outcome measure. Results: The sample comprised 87.9% males with an average age of 41. Trauma was the leading cause of SCI (77.45%), predominantly affecting the cervical and thoracic levels. Pain was reported by 44% of participants, and the mean PPT was 8.3 kPa, measured bilaterally. Multivariate analysis of PPT in the left, right, and bilateral thenar regions revealed consistent trends. Significant negative associations were found between bilateral PPT and low beta EEG frequency in the central area (β = −14.94, p = 0.017), traumatic lesion etiology (β = −1.99, p = 0.038), and incomplete lesions by the American Spinal Injury Association classification (β = −1.68, p = 0.012). In contrast, positive associations were observed with age (β = 0.08, p < 0.001). Conclusions: Our findings show that increased beta oscillations and traumatic brain injury having a lower PPT indicate that factors associated with maladaptive plasticity are associated with decreased and likely less functional PPT. On the other hand, increased motor function may help to regulate PPT in a more functional status. Full article

Many stroke survivors experience persistent upper extremity impairment that limits performance in activities of daily living. Upper limb recovery requires high repetitions of task-specific practice. Stroke survivors are often prescribed task practices at home to supplement rehabilitation therapy. A poor quality of task practices, such as the use of compensatory movement patterns, results in maladaptive neuroplasticity and suboptimal motor recovery. There currently lacks a tool for the remote monitoring of movement quality of stroke survivors’ task practices at home. The objective of this study was to evaluate the feasibility of classifying movement quality at home using a wearable IMU. Nineteen stroke survivors wore an IMU sensor on the paretic wrist and performed four functional upper limb tasks in the lab and later at home while videorecording themselves. The lab data served as reference data to classify home movement quality using dynamic time warping. Incorrect and correct movement quality was labeled by a therapist. The home task practice movement quality was classified with an accuracy of 92% and F1 score of 0.95 for all tasks combined. Movement types contributing to misclassification were further investigated. The results support the feasibility of a home movement quality monitoring system to assist with upper limb rehabilitation post stroke. Full article

Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF’s pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain. Full article

Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study investigates the role of pain-modulatory brainstem pathways in CRPS using the nociceptive blink reflex (nBR), which not only provides a direct read-out of brainstem excitability and habituation to painful stimuli but may also be suitable for use as a diagnostic biomarker for CRPS. Thirteen patients with CRPS and thirteen healthy controls (HCs) participated in this prospective case-control study investigating the polysynaptic trigemino-cervical (R2) nBR response. The R2 area and its habituation were assessed following repeated supraorbital electrical stimulation. Between-group comparisons included evaluations of diagnostic characteristics as a potential biomarker for the disease. Patients with CRPS showed a substantial decrease in habituation on the stimulated (Cohen’s d: 1.3; p = 0.012) and the non-stimulated side (Cohen’s d: 1.1; p = 0.04). This is the first study to reveal altered nBR habituation as a pathophysiological mechanism and potential diagnostic biomarker in CRPS. We confirmed previous findings of altered nBR excitability, but the diagnostic accuracy was inferior. Future studies should investigate the nBR as a marker of progression to central mechanisms in CRPS and as a biomarker to predict treatment response or prognosis. Full article

A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals. Full article