In Search for Novel and More Effective Psychological Treatments for Chronic Pain: The “Algea” Research Project

The aim of this paper isto present the objectivesand current state of anongoing multilevelcollaborative researchproject for the study ofpain. “Algea”, the painand suffering deity inancient Greek mythology,was the name given tothis project, which aimsto investigate criticalfactors involved in theexperience of pain, andsuffering. Moreover, theproject will examine theeffects of a novelapproach to treatmentbased on Acceptance andCommitment Therapy.This is a collaborativeproject between theUniversity of Cyprus, theUniversity of Crete, andthe Cyprus Institute ofNeurology and Genetics.Algea is the first systematic effort to examine painrelated parameters and evaluate a noveltherapeutic approach aimed at alleviating thesuffering and interference in living experienced byindividuals with one or more chronic painconditions (e.g., rheumatoid arthritis). The specificobjectives of the “Algea” project include:a) understanding the contributing factors involvedin the experience of pain in individuals withchronic pain (CP) conditions, their dyadicinteractions with their partners, and differenceswith individuals suffering from other chronicillnesses not involving pain; b) designing aculturally sensitive intervention based on newempirical findings stemming from third-wave CBTsfor use in clinical settings (i.e., CP organizations,CP rehabilitation and outpatients units, etc.); c)evaluating via randomized clinical trials theacceptability and effectiveness of this interventionespecially in reducing suffering, interference ofpain and medical utilization in various chronic painconditions; d) training interested healthprofessionals in this new approach and widelydisseminating it into clinical settings; and e)translating the intervention into a digitally-basedintervention so as to be more accessible and reacha wider audience of CP sufferers

Neural correlates of pain acceptance and the role of the cerebellum:Functional connectivity and anatomical differences in individuals with headaches versus matched controls

Background: Despite functional connectivity network dysfunction among indi-viduals with headaches, no studies have examined functional connectivity neuralcorrelates and anatomical differences in coping with headaches.Methods: This study investigated inter-individual variability in whole-brainfunctional connectivity and anatomical differences among 37 individuals withprimary headaches and 24 age- and gender-matched controls, and neural cor-relates of psychological flexibility (PF) that was previously found to contributeto headache adjustment. Participants (84% women; M headache severity = 4/10;M age = 43 years) underwent functional magnetic resonance imaging scans andcompleted questionnaires to examine global and subnetwork brain areas, andtheir relations with PF components, controlling for age, gender, education, andhead- motion.Results: Seed and voxel-based contrast analyses between groups showed atypicalfunctional connectivity of regions involved in pain matrix and core resting-statenetworks. Pain acceptance was the sole PF component that correlated with thecerebellum (x, y, z: 28, −72, −34, p-false discovery rate <0.001), where individualswith headaches showed higher grey matter density compared to controls.Conclusions: The cerebellum, recently implicated in modulating emotional andcognitive processes, was indicated to process information resembling what indi-viduals do when practicing pain acceptance. Our findings establish for the firsttime this connection of the cerebellum and its role in pain acceptance. We pro-pose that pain acceptance might be a behavioural biomarker target that couldmodulate problematic headache perceptions and brain networks abnormalities

Mild Phenotype in a Patient with a De Novo

We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes

Pathogenic and low-frequency variants in children with central precocious puberty

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP

Mitochondrial superclusters influence age of onset of Parkinson’s disease in a gender specific manner in the Cypriot population: A case-control study

Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson's disease (PD).To test this hypothesis for the Greek-Cypriot population, a cohort of 230 PD patients and 457 healthy matched controls were recruited. Mitochondrial haplogroup distributions for cases and controls were determined. Association tests were carried out between mitochondrial haplogroups and PD.Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. After pooling mitochondrial haplogroups together into haplogroup clusters and superclusters, association tests demonstrated a significantly protective effect of mitochondrial haplogroup cluster N (xR) and supercluster LMN for PD risk only in females. In addition, for female PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for female cases with an H haplogroup.Statistically significant associations regarding PD risk and PD age of onset were mostly detected for females thus suggesting that gender is a risk modifier between mitochondrial haplogroups and PD status / PD age of onset. The biological mechanisms behind this gender specificity remain to be determined

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Sarcoidosis in a case of MuSK-positive myasthenia gravis

Whereas the coexistence of different autoimmune or rheumatologic diseases with myasthenia gravis is well documented, the combination of myasthenia with sarcoidosis is extremely rare. There very few case reports of patients suffering from these two immune-mediated diseases. Nearly all had acetylcholine receptor antibodies. As far as we know myasthenia gravis with antibodies to muscle-specific tyrosine kinase-MuSK-has not been associated with any form of sarcoidosis. We present probably the first case of MuSK-positive myasthenia gravis with concurrent, asymptomatic pulmonary sarcoidosis. (c) 2008 Published by Elsevier B.V

Mechanisms of change in acceptance and commitment therapy for primary headaches

Background: Despite the demonstrated effectiveness of behavioural headache interventions, it is not yet known which intervention processes account for treatment responses. Acceptance and commitment therapy (ACT), an emerging behavioural intervention for headaches, proposes psychological flexibility (PF) processes as the mechanisms via which intervention change occurs. This is the first study examining these processes of change variables on headache-related disability and quality of life (treatment outcome). Methods: Data originated from a Randomized Clinical Trial evaluating the efficacy of ACT for primary headaches. Ninety-four individuals with primary headaches (M = 43 y; 84% females; M headache frequency/month = 9.30) were randomized to either an ACT-based or a Wait-list control group (N = 47 in each). Participants completed questionnaires related to their headache experiences and PF processes at pre- (T1), post-treatment (T2), and 3-month follow-up (T3). Results: Following a bootstrapped cross product of coefficients approach, results demonstrated mediating effects of headache acceptance, cognitive defusion, avoidance of headache, and mindfulness in the ACT group compared to control on parameters of headache-related disability and quality of life at post and 3-month follow-ups. Conclusions: These findings demonstrate that changes in certain PF processes lower disability and improve quality of life in headache sufferers, supporting that ACT works via its proposed mechanisms of change. Interventions for headache management may be optimized if they target increases in headache acceptance, defusion from thoughts, and mindfulness. Significance: Psychological flexibility (PF) guides the ACT approach, an emerging behavioral headache intervention that focuses on optimizing head pain adjustment via flexible responses to pain. It targets at increasing daily functioning rather than preventing or controlling headache episodes. Pain acceptance, cognitive defusion, and mindfulness act as processes of functional change in ACT, lowering disability and increasing daily functioning and quality of life. These components can upgrade the established effectiveness of behavioral headache interventions with personalized, modularized therapeutic targets that can help headache sufferers re-establish optimal daily functioning even in fluctuating and persistent headache episodes

Mild Phenotype in a Patient with a De Novo 6.3 Mb Distal Deletion at 10q26.2q26.3

We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes