Evaluating the effectiveness of neurofeedback in chronic pain management: a narrative review

The prevalence and impact of chronic pain in individuals worldwide necessitate effective management strategies. This narrative review specifically aims to assess the effectiveness of neurofeedback, an emerging non-pharmacological intervention, on the management of chronic pain. The methodology adopted for this review involves a meticulous search across various scientific databases. The search was designed to capture a broad range of studies related to neurofeedback and chronic pain management. To ensure the quality and relevance of the included studies, strict inclusion and exclusion criteria were applied. These criteria focused on the study design, population, intervention type, and reported outcomes. The review synthesizes the findings from a diverse array of studies, including randomized controlled trials, observational studies, and case reports. Key aspects evaluated include the types of neurofeedback used (such as EEG biofeedback), the various chronic pain conditions addressed (like fibromyalgia, neuropathic pain, and migraines), and the methodologies employed in these studies. The review highlights the underlying mechanisms by which neurofeedback may influence pain perception and management, exploring theories related to neural plasticity, pain modulation, and psychological factors. The results of the review reveal a positive correlation between neurofeedback interventions and improved pain management. Several studies report significant reductions on pain intensity, improved quality of life, and decreased reliance on medication following neurofeedback therapy. The review also notes variations in the effectiveness of different neurofeedback protocols and individual responses to treatment. Despite the promising results, the conclusion of the review emphasizes the need for further research. It calls for larger, well-designed clinical trials to validate the findings, to understand the long-term implications of neurofeedback therapy, and to optimize treatment protocols for individual patients

Structural and functional studies on human DNA Topoisomerase IB: interation with supercoiled DNA and the antitumor drug Camptothecin

DNA Topoisomerases are essentials enzymes in biological process involving the relaxation of the superhelical tension of the DNA molecules. Human DNA topoisomerase I (hTop1p) is a monomeric conserved enzyme of 91 KDa, subdivided into four domains: the N-terminal; the core constituted by three subdomains; the C-terminal domain containing the catalytic residue Tyr723; the linker connecting the core with the C-terminal domain, locating the active site in the catalytic pocket, and characterized by two protruding coiled coil α-helices. DNA relaxation occured with a mechanism of DNA strand rotation in a multiple step process where the 5’-OH end is free to rotate around the intact strand. Two conformational changes are involved in this dynamic process: the enzyme binding the DNA through an open shape, then closed clamp that completely embraces the DNA. No external energy source occurred, but arises from the release of the superhelical tension. In addition hTop1p is of great interest since is the cellular target of the antitumor drug camptothecin (CPT). The reversible binding of the drug to the covalent complex DNA-Top1p brings to lethality due to religation inhibition and double strand breaks formation in a S-phase dependent manner. Different data supported the “controll rotation mechanism” to explain how this enzyme can relax both positevely and negatevely supercoiled substrates. First of all crystal structures [17] of human Top1 with a 22 bp oligonucleotide reported no sufficient space inside the clamp for a free rotation. Moreover a mutant isoform of the protein with 2 cysteines produced opposetely to the lips domains, locked the clamp through a disulfide bridge and reported that an opening conformation was not required for the relaxation activity [21] [135]. Also single-molecule experiments suggested that friction and torque are necessary for the relaxation process and the number of supercoils removed per cleavage-religation cycle is strictly dependent from the number of supercoils of the DNA substrate. The aim of this project is focused on the contribute of key residues located al the level of the hinge and involved in the control rotation mechanism during DNA relaxation. In my experiments Saccharomyces cerevisiae strains were used as a model organism to investigate a series of topoisomerase IB mutants: Pro431Gly; Arg434Ala; Arg434Cys; Trp205Cys. These substitutions are interesting because of their position in the enzyme three-dimensional structure. The flexible hinge (429-436 residues) facilitating clamp opening by a stretching or bending motion pivoting around Pro-431 and the cluster of large aromatic residues around the top of the hinge, probably are involved in controlling the movements of the α-helix and the proper closing of the clamp. In 2005 Sari and Andricioaei simulation analyses reported the possible role of the lips for the relaxation of the positive supercoils and the strechting of the hinge for the negative supercoils removal. Yeast strains lacking for endogenous topoisomerase I gene were transformed with YCpGAL1-hTOP1, YCpGAL1-hTOP1Pro431Gly, YCpGAL1-hTOP1Arg434Cys, YCpGAL1-hTOP1Arg434Ala, YCpGAL1-hTOP1Trp205Cys plasmids and viability was verified in a drug yeast sensitivity assay. Transformants were spotted in presence and absence of camptothecin at different concentrations. Moreover CPT sensitivity for each mutant was analyzed through measures of the stability of the covalent complex formation. Results are congruents and are also supported by Frohlich and Knudsen data, in 2007, suggesting a role for the Trp-205 and surrounding residues in the control of strand rotation during negative but not positive supercoiled removal, and reported a more CPT sensitivity during relaxation of positively versus negatevely supercoils. EKY3 strains expressing htop1W205Cp showed a partial resistance phenotype, and top1R434A, top1R434C mutants are not sensitive to lower drug dose (0.01<ug/ml<0.5). Processivity and distributivity of the catalytic activity for purified proteins was also tested at low (50mM), optimal (150mM) and high (500 and 1000 mM) salt concentration with both negative and positive supercoils. This allowed revealing mutant behaviors and its DNA affinity under stressed non-physiological conditions. The top1R434A mutant showed an interesting relaxation activity also in presence of high salt concentration up to 1000 mM KCl and reported a faster ability in realeasing positevely than negatevely supercoiled if compared to the wild-type and other mutants. The association/dissociation is rate limiting for DNA relaxation but the mutation R434 showed residue a stronger affinity for DNA. This data was obtained by the ability of the mutant to relax two topologically different DNAs in a two step relaxation experiment. Dynamic modeling simulation analyses for the top1R434A mutant in comparison with the WT enzyme was performed to better understand the real contribute of the protein domains in the mechanism of supercoils relaxation.Le DNA topoisomerasi sono enzimi essenziali in tutti i processi biologici in cui è necessario un riarrangiamento topologico della doppia elica. La DNA topoisomerasi IB umana (hTop1p) è una proteina monomerica di 91KDa, caratterizzata da 4 domini: uno N-terminale; uno “core” costituito a sua volta da 3 subdomini; un C-terminale contenente il residuo catalitico in posizione Tyr723 e una regione linker costituita da 2 α-eliche sporgenti e che connette il dominio core con il C-terminale. Il meccanismo di rilassamento del DNA è un processo multiplo attraverso il quale un filamento di DNA con un’estremità libera al 5’-OH è in grado di ruotare intorno a quello rimasto intatto. L’enzima lega la doppia elica dapprima assumendo una conformazione aperta, e successivamente si richiude attorno al substrato, in questo modo l’energia necessaria per la reazione di topoisomerizzazione è fornita dallo srotolamento della superelica e il rilascio di energia torsionale. hTop1p è anche target specifico di un farmaco antitumorale noto come camptotecina (CPT). Il legame reversibile tra CPT e il complesso DNA-enzima è dipendente dalla fase S del ciclo cellulare e porta ad apoptosi in seguito all’inibizione della fase di riligazione e alla formazione di frammenti a doppio filamento (noti come DSBs double strand breaks). Il meccanismo che spiega come questo enzima sia in grado di rilassare sia superavvolgimenti positivi che negativi è definito “meccanismo di controllo della rotazione” e vi sono diversi dati a suo supporto. La struttura cristallografica della hTop1p in complesso con un frammento di DNA di 22pb, ottenuta nel 1998 da Stewart e i suoi collaboratori ha evidenziato che non vi è spazio sufficiente per una rotazione libera all’interno della “tasca enzimatica”. Inoltre mediante un mutante della hTop1p con 2 residui terminali delle regioni delle “lips” sostituiti da 2 cisteine in modo da ottenere un ponte disolfuro, è stato possibile bloccare l’enzima nella conformazione chiusa e dimostrare comunque l’attività di rilassamento da parte della proteina [21] [135]. Vi sono inoltre esperimenti di “single-molecule” che evidenziano come il numero di superavvolgimenti rimossi per ciclo di taglio e riligazione sia direttamente proporzionale al numero di avvolgimenti del DNA substrato e che durante la topoisomerizzazione si registrano attriti e forze rotatorie derivanti dal meccanismo di rotazione del DNA durante il suo rilassamento. Lo scopo di questo progetto di ricerca verte sull’indagine di residui chiave localizzati nella regione hinge (residui 429-436) e coinvolti in tale meccanismo. Negli esperimenti è stato utilizzato l’organismo modello Saccharomyces cerevisiae, nel quale sono state introdotte le seguenti mutazioni: Pro431Gly; Arg434Ala; Arg434Cys; Trp205Cys. Tali sostituzioni risultano di grande interesse per quanto concerne la struttura tridimensionale: il residuo 431 caratterizzato da una prolina si è ipotizzato essere coinvolto in movimenti flessori e di stretching dell’hinge attraverso cui l’enzima medierebbe l’apertura/chiusura e l’interazione con i residui aromatici situati nel suo intorno. Sari e Andricioaei nel 2005 attraverso studi di dinamica molecolare evidenziarono il contributo della regione delle lips nel rilassamento dei superavvolgimenti positivi, mentre riportarono uno stretching dell’hinge per quelli negativi. Dapprima sono stati utilizzati ceppi di lievito deleti della topoisomerasi I endogena per trasfettare i plasmidi con all’interno la sequenza di espressione per la hTop1p mutata ed è stata analizzata la capacità di formare colonie nonché la loro vitalità in presenza di camptotecina a diverse concentrazioni. La sensibilità al farmaco è stata inoltre analizzata mediante saggio di equilibrio taglio-riligazione e valutando la formazione dei complessi di taglio per ciascun mutante in presenza e assenza di camptotecina. I risultati si sono rivelati congruenti con quanto già riportato nel 2007 dal laboratorio di Knudsen, secondo cui il residuo Trp205 e l’intorno aromatico regolano il meccanismo di rotazione durante il rilassamento di superavvolgimenti negativi e riportando una maggior sensibilità al farmaco durante la rimozione di substrati positivi piuttosto che del segno opposto. Il mutante htop1W205Cp nei miei esperimenti ha mostrato un fenotipo parzialmente resistente mentre per i mutanti top1R434A e top1R434C si è riportata una maggior sensibilità e capacità di formare colonie a dosi inferiori a 0.5ug/ml. Per ciascuna proteina è stata misurata la sua attività catalitica nel rilassare superavvolgimenti positivi e negativi, in condizioni di processività e distributività a forza ionica bassa (50 mM), a 150 mM (condizione ottimale) e a forza ionica elevata (500 mM e 1000 mM). In questo modo è stato possibile valutare l’affinità di legame di ciascun mutante per il DNA ed evidenziare aspetti biochimici funzionali legati alla mutazione specifica. Per quanto riguarda il mutante top1R434A è stata riportata attività catalitica ad alte concentrazioni saline, fino a 1000 mM KCl, ed è stata misurata una velocità maggiore nel rilassare substrati positivi piuttosto che negativi, e in ogni caso più performanti sia rispetto l’enzima wild type che gli altri mutanti. La sostituzione dell’arginina (R434) con un’alanina ha migliorato l’affinità di legame per il DNA dell’enzima e questo è stato ancor più evidenziato da saggi di rilassamento in cui top1R434A mostrava capacità di rilassamento, a basse e alte forze ioniche, di due DNA topologicamente diversi, ma contemporaneamente presenti nella miscela di reazione. L’enzima è perciò in grado di staccarsi e riassociarsi ad una nuova molecola di DNA. Inoltre tramite analisi di modelling molecolare è stato possibile indagare il contributo reale dei diversi domini della proteina wild type a confronto con quella mutata nel residuo R434, durante il processo di topoisomerizzazione

Perceived Pain in Athletes: A Comparison between Endurance Runners and Powerlifters through a Cold Experimental Stimulation and Two Sessions of Various Physical Activation

Few studies in the literature have illustrated cold hypoalgesia induced by strength training. Objectives of this contribution were to compare the ratings of perceived pain in endurance running (n = 22) and powerlifting (n = 22) male athletes and controls (n = 22) at baseline and after two bouts of 40 min aerobic/strength training respectively, using the Cold Pressor Test (CPT) and simultaneously monitoring changes in blood pressure (BP), heart rate (HR), and body temperature. A two-way repeated measures ANOVA was conducted to examine the effects of training sessions in endurance runners vs. powerlifting athletes vs. controls on the intensity of perceived pain at CPT. A statistically significant two-way interaction between the group and training resulted in p &lt; 0.001, &eta;p2 = 0.513. A simple main effects analysis showed that as the participants went through the strength training session, pain perception at CPT was significantly lower in powerlifters compared to runners and controls. Considering the physiological parameters, powerlifters reported significantly higher values of BP and HR. This difference was present at baseline but after training as well, and before and after CPT, despite a slight hypotensive effect. The differences reported after CPT at baseline, but very significantly after the strength activation session in the powerlifters, provide interesting insights into the hypoalgesic effect of high-intensity strength training

Both Gender and Agonistic Experience Affect Perceived Pain during the Cold Pressor Test

Background. Differences in pain perception in athletes have recently been highlighted in the literature. Objectives. To compare gender ratings of perceived pain in athletes with low and high agonistic experiences (N = 200) using the Cold Pressor Test (CPT). Methods. A three-way repeated measures ANOVA to assess both the effects of the athletes&rsquo; gender and lower vs. higher agonistic experiences in the intensity of perceived pain at the beginning of the cold box hand immersion (L0) and after a 90 s interval (L1). Results. There was a statistically significant interaction effect between the level of the agonistic experience and gender in the two moments: p &lt; 0.001; &eta;p2 = 0.266; F(1,49) = 9.771. Simple main effects analysis showed a significative difference for females at L0: F(1,99) = 93.567, p &lt; 0.025, partial &eta;2 = 0.302) and for males at L1: F(1,99) = 173.420, p &lt; 0.025, partial &eta;2 = 0.666. At the initial moment of CPT, the female athletes showed significantly higher perceived intensity than males, regardless of their experience level. After a 90 s interval, a significantly lower pain perception effect associated with the increased competitive experience of male athletes was observed. Female athletes did not appear to benefit from the experience effect on their pain tolerance. Conclusions. The study confirmed a significant difference in pain perception associated with the athletes&rsquo; gender and agonistic experience. Separate explanations related to the pattern of pain inhibition and the acquired reduction in pain sensitivity are reported