Thalamocortical bistable switch as a theoretical model of fibromyalgia pathogenesis inferred from a literature survey

Fibromyalgia (FM) is an unsolved central pain processing disturbance. We aim to provide a unifying model for FM pathogenesis based on a loop network involving thalamocortical regions, i.e., the ventroposterior lateral thalamus (VPL), the somatosensory cortex (SC), and the thalamic reticular nucleus (TRN). The dynamics of the loop have been described by three differential equations having neuron mean firing rates as variables and containing Hill functions to model mutual interactions among the loop elements. A computational analysis conducted with MATLAB has shown a transition from monostability to bistability of the loop behavior for a weakening of GABAergic transmission between TRN and VPL. This involves the appearance of a high-firing-rate steady state, which becomes dominant and is assumed to represent pathogenic pain processing giving rise to chronic pain. Our model is consistent with a bulk of literature evidence, such as neuroimaging and pharmacological data collected on FM patients, and with correlations between FM and immunoendocrine conditions, such as stress, perimenopause, chronic inflammation, obesity, and chronic dizziness. The model suggests that critical targets for FM treatment are to be found among immunoendocrine pathways leading to GABA/glutamate imbalance having an impact on the thalamocortical system

Vestibular disability/handicap in Fibromyalgia : a questionnaire study

Fibromyalgia (FM) is a poorly understood, central pain processing disorder characterized by a broad range of symptoms, such as chronic pain, sleep disruption, chronic fatigue, and psychosomatic symptoms. In addition, recent studies have shown that FM patients also experience dizziness. We aimed to establish a prevalence rate of vestibular symptoms in a population of FM patients through a battery of questionnaires investigating socio-demographic, clinical and psychological characteristics, combined with the Dizziness Handicap Inventory (DHI) and the Situational Vertigo Questionnaire (SVQ). A total of 277 respondents, officially diagnosed with FM, completed the full study, while 80 controls were also included for DHI and SVQ questionnaires. We found that FM participants were significantly affected by vestibular symptoms, which correlated with FM-associated pain and non-pain symptoms. The dizziness reported by FM participants showed peculiar features suggesting an FM-intrinsic mechanism of vestibular dysfunction, possibly linked to migraine and dysautonomia conditions. Correlations between dizziness and depressive mood (or neuroticism), revealed an impact of dizziness on psychological status, leading to depressive reactions and interpersonal difficulties, and possibly involving a noxious, self-sustained stress condition. In conclusion, data showed a manifesting dizziness condition in FM patients that warrants careful clinical attention due to its possible inherent role in the syndrome

Models of Neurological Diseases based on Feedback Loop dynamics

Fibromyalgia (FM) is an unsolved central pain processing disturbance. We aim to provide a unifying model for FM pathogenesis based on a loop network involving thalamocortical regions, i.e., the ventroposterior lateral thalamus (VPL), the somatosensory cortex (SC), and the thalamic reticular nucleus (TRN). The dynamics of the loop have been described by three differential equations having neuron mean firing rates as variables and containing Hill functions to model mutual interactions among the loop elements. A computational analysis conducted with MATLAB has shown a transition from monostability to bistability of the loop behavior for a weakening of GABAergic transmission between TRN and VPL. This involves the appearance of a high-firing-rate steady state, which becomes dominant and is assumed to represent pathogenic pain processing giving rise to chronic pain. Our model is consistent with a bulk of literature evidence, such as neuroimaging and pharmacological data collected on FM patients, and with correlations between FM and immunoendocrine conditions, such as stress, perimenopause, chronic inflammation, obesity, and chronic dizziness. The model suggests that critical targets for FM treatment are to be found among immunoendocrine pathways leading to GABA/glutamate imbalance having an impact on the thalamocortical system.Fibromyalgia (FM) is a poorly understood, central pain processing disorder characterized by a broad range of symptoms, such as chronic pain, sleep disruption, chronic fatigue, and psychosomatic symptoms. In addition, recent studies have shown that FM patients also experience dizziness. We aimed to establish a prevalence rate of vestibular symptoms in a population of FM patients through a battery of questionnaires investigating socio-demographic, clinical and psychological characteristics, combined with the Dizziness Handicap Inventory (DHI) and the Situational Vertigo Questionnaire (SVQ). A total of 277 respondents, officially diagnosed with FM, completed the full study, while 80 controls were also included for DHI and SVQ questionnaires. We found that FM participants were significantly affected by vestibular symptoms, which correlated with FM-associated pain and non-pain symptoms. The dizziness reported by FM participants showed peculiar features suggesting an FM-intrinsic mechanism of vestibular dysfunction, possibly linked to migraine and dysautonomia conditions. Correlations between dizziness and depressive mood (or neuroticism), revealed an impact of dizziness on psychological status, leading to depressive reactions and interpersonal difficulties, and possibly involving a noxious, self-sustained stress condition. In conclusion, data showed a manifesting dizziness condition in FM patients that warrants careful clinical attention due to its possible inherent role in the syndrome.Fibromyalgia (FM) is a chronic pain syndrome with an unclear etiology. In addition to pain, FM patients suffer from a diverse array of symptoms and comorbidities, encompassing fatigue, cognitive dysfunction, mood disorders, sleep deprivation, and dizziness. Due to the complexity of FM, the diagnosis and treatment of it are highly challenging. The aim of the present work was to investigate some clinical and psychological characteristics of FM patients, and to uncover possible correlations with pharmacological and non-pharmacological therapies. We conducted a cross-sectional, questionnaire-based study aimed at evaluating pain, psychological traits, and the self-perceived effectiveness of pharmacological and non-pharmacological treatments in an Italian population of FM patients. Descriptive statistics, correlation, and inference analyses were performed. We found a prevalence of a neuropathic/nociplastic type of pain, which correlated with psychological traits such as anxiety, low mood, psychophysical discomfort, and the inability to relax. The pain type and psychological traits proved to play a role in determining the self-perceived effectiveness of therapeutic interventions. Patients revealed a better response to non-pharmacological therapies, particularly dietary interventions, relaxation techniques, and psychotherapy rather than pharmacological interventions. The sum of our data indicates that for better outcomes, the type of pain and psychological traits should be considered for tailor-made treatments considering non-pharmacological protocols as a complement to the use of drugs.Understanding the brain functioning is essential for governing brain processes with the aim of managing pathological network dysfunctions. Due to the morphological and biochemical complexity of the central nervous system, the development of general models with predictive power must start from in vitro brain network engineering. In the present work, we realized a micro-electrode array (MEA)-based in vitro brain network and studied its emerging dynamical properties. We obtained four-neuron-clusters (4N) assemblies by plating rat embryo cortical neurons on 60-electrode MEA with cross-shaped polymeric masks and compared the emerging dynamics with those of sister single networks (1N). Both 1N and 4N assemblies exhibited spontaneous electrical activity characterized by spiking and bursting signals up to global activation by means of network bursts. Data revealed distinct patterns of network activity with differences between 1 and 4N. Rhythmic network bursts and dominant initiator clusters suggested pacemaker activities in both assembly types, but the propagation of activation sequences was statistically influenced by the assembly topology. We proved that this rhythmic activity was ivabradine sensitive, suggesting the involvement of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and propagated across the real clusters of 4N, or corresponding virtual clusters of 1N, with dominant initiator clusters, and nonrandom cluster activation sequences. The occurrence of nonrandom series of identical activation sequences in 4N revealed processes possibly ascribable to neuroplasticity. Hence, our multi-network dissociated cortical assemblies suggest the relevance of pacemaker neurons as essential elements for generating brain network electrophysiological patterns; indeed, such evidence should be considered in the development of computational models for envisaging network behavior both in physiological and pathological conditions

Studio dell'andamento di Torqueteno virus in pazienti sottoposti a trapianto di organo solido e validazione dell'uso della viremia come marcatore predittivo della disfunzione del sistema immunitario dell'ospite infettato

Risulta sempre più evidente che la viremia di Torquetenovirus (TTV) nel sangue dell'individuo infetto può essere un solido e utile indicatore dell'efficienza del sistema immunitario. La cinetica di TTV è stata studiata in 280 pazienti che hanno ricevuto un trapianto di organo solido (fegato e rene) e diversi regimi di terapia immunosoppressiva di mantenimento. Durante l'anno di follow-up post trapianto, la viremia di TTV oscillava in base al tipo di immunosoppressore somministrato. Questo studio fornisce prove per l'uso della viremia di TTV nel monitoraggio e nella creazione su misura di una terapia immunosoppressiva di manteniment

Valutazione morfofunzionale del pavimento pelvico con Risonanza Magnetica Nucleare in pazienti sottoposti ad intervento di "Advance male sling" per incontinenza urinaria

L'incontinenza urinaria maschile da sforzo rappresenta una delle più importanti complicanze della Prostatectomia radicale.La sua prevalenza varia dall'1% all'87%.Il nostro studio ha lo scopo di analizzare e correlare, con l'ausilio della RMN 3 Tesla, le differenze anatomiche del pavimento pelvico dopo Advance male sling sia nei pazienti continenti che in quelli incontinenti.Le informazioni ottenute con la RMN sono indirette nel senso che lo sling essendo in propilene non risulta visibile all’imaging. Quella che risulta visibile è invece l’incisura del margine inferiore del bulbo uretrale corrispondente allo sling.Questo studio dimostra per la prima volta una correlazione significativa tra la continenza e la lunghezza del bulbo uretrale posteriore allo sling(LB).La RMN postoperatoria rappresenta, quindi, uno strumento utile per valutare e decidere un successivo intervento terapeutico nei pazienti in cui l'Advance non ha portato risultati soddisfacenti.E’ risultato infatti che se la lunghezza del bulbo uretrale posteriore allo sling non è sufficiente (< 8 mm) può essere indicato un nuovo riposizionamento, mentre se la lunghezza è adeguata, ma tuttavia il riposizionamento dell'uretra non è sufficiente a compensare una grave deficienza sfinterica si deve pensare ad una trattamento chirurgico compressivo, come lo sfintere artificiale AMS 800

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease

Online Questionnaire with Fibromyalgia Patients Reveals Correlations among Type of Pain, Psychological Alterations, and Effectiveness of Non-Pharmacological Therapies

Fibromyalgia (FM) is a chronic pain syndrome with an unclear etiology. In addition to pain, FM patients suffer from a diverse array of symptoms and comorbidities, encompassing fatigue, cognitive dysfunction, mood disorders, sleep deprivation, and dizziness. Due to the complexity of FM, the diagnosis and treatment of it are highly challenging. The aim of the present work was to investigate some clinical and psychological characteristics of FM patients, and to uncover possible correlations with pharmacological and non-pharmacological therapies. We conducted a cross-sectional, questionnaire-based study aimed at evaluating pain, psychological traits, and the self-perceived effectiveness of pharmacological and non-pharmacological treatments in an Italian population of FM patients. Descriptive statistics, correlation, and inference analyses were performed. We found a prevalence of a neuropathic/nociplastic type of pain, which correlated with psychological traits such as anxiety, low mood, psychophysical discomfort, and the inability to relax. The pain type and psychological traits proved to play a role in determining the self-perceived effectiveness of therapeutic interventions. Patients revealed a better response to non-pharmacological therapies, particularly dietary interventions, relaxation techniques, and psychotherapy rather than pharmacological interventions. The sum of our data indicates that for better outcomes, the type of pain and psychological traits should be considered for tailor-made treatments considering non-pharmacological protocols as a complement to the use of drugs

Multiple neuron clusters on Micro-Electrode Arrays as an in vitro model of brain network

Abstract Understanding the brain functioning is essential for governing brain processes with the aim of managing pathological network dysfunctions. Due to the morphological and biochemical complexity of the central nervous system, the development of general models with predictive power must start from in vitro brain network engineering. In the present work, we realized a micro-electrode array (MEA)-based in vitro brain network and studied its emerging dynamical properties. We obtained four-neuron-clusters (4N) assemblies by plating rat embryo cortical neurons on 60-electrode MEA with cross-shaped polymeric masks and compared the emerging dynamics with those of sister single networks (1N). Both 1N and 4N assemblies exhibited spontaneous electrical activity characterized by spiking and bursting signals up to global activation by means of network bursts. Data revealed distinct patterns of network activity with differences between 1 and 4N. Rhythmic network bursts and dominant initiator clusters suggested pacemaker activities in both assembly types, but the propagation of activation sequences was statistically influenced by the assembly topology. We proved that this rhythmic activity was ivabradine sensitive, suggesting the involvement of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and propagated across the real clusters of 4N, or corresponding virtual clusters of 1N, with dominant initiator clusters, and nonrandom cluster activation sequences. The occurrence of nonrandom series of identical activation sequences in 4N revealed processes possibly ascribable to neuroplasticity. Hence, our multi-network dissociated cortical assemblies suggest the relevance of pacemaker neurons as essential elements for generating brain network electrophysiological patterns; indeed, such evidence should be considered in the development of computational models for envisaging network behavior both in physiological and pathological conditions

Mal de Debarquement Syndrome explained by a vestibulo–cerebellar oscillator

Mal de Debarquement Syndrome (MdDS) is a puzzling central vestibular disorder characterized by a long-lasting perception of oscillatory postural instability that may occur after sea travels or flights. We have postulated that MdDS originates from the post-disembarking persistence of an adaptive internal oscillator consisting of a loop system, involving the right and left vestibular nuclei, and the Purkinje cells of the right and left flocculonodular cerebellar cortex, connected by GABAergic and glutamatergic fibers. We have formulated here a mathematical model of the vestibulo–cerebellar loop system and carried out a computational analysis based on a set of differential equations describing the interactions among the loop elements and containing Hill functions that model input–output firing rates relationships among neurons. The analysis indicates that the system acquires a spontaneous and permanent oscillatory behavior for a decrease of threshold and an increase of sensitivity in neuronal input–output responses. These results suggest a role for synaptic plasticity in MdDS pathophysiology, thus reinforcing our previous hypothesis that MdDS may be the result of excessive synaptic plasticity acting on the vestibulo–cerebellar network during its entraining to an oscillatory environment. Hence, our study points to neuroendocrine pathways that lead to increased synaptic response as possible new therapeutic targets for the clinical treatment of the disorder