1 4339 86 MIGRAINE: A GENETIC DISEASE? MIGRAINES CARRY A SUBSTANTIAL GENETIC LIABILITY, AND IN FAMILIES AFFECTED WITH THE TYPICAL MIGRAINES (MIGRAINE WITH, MA, AND WITHOUT AURA, MO) LINKAGE TO SOME CHROMOSOMAL LOCI HAS BEEN REPORTED. AS YET HOWEVER, NO GENES ARE KNOWN FOR MA/MO, WHILE THE THREE GENES DISCOVERED AS RESPONSIBLE FOR FAMILIAL HEMIPLEGIC MIGRAINE (FHM) ARE NOT INVOLVED IN THE TYPICAL MIGRAINES. ACCORDINGLY, WE PROPOSE TO CONSIDER FHM AS A SYNDROMIC MIGRAINE AND NOT AS A VARIETY OF MA. MOREOVER, WE SUGGEST THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE DETERMINATION OF THE TYPICAL MIGRAINES, AND THAT THE PRIMARY HEADACHES REPRESENT BEHAVIOURAL RESPONSES (SICKNESS BEHAVIOUR, FIGHT-OR-FLIGHT RESPONSES), HAVING ADAPTIVE ADVANTAGE AND HAVING BEEN EVOLUTIONARY CONSERVED, IN WHICH PAIN REPRESENTS A SIGNAL OF HOMEOSTATIC IMBALANCE. EPIGENETIC MECHANISMS AND THIS PROPOSED GENETIC BEHAVIOURAL MODEL COULD BE USEFULLY INCORPORATED INTO HEADACHE GENETIC RESEARCH. 2008 2 2029 18 EPIGENETIC CHANGES IN HEADACHE. INTRODUCTION: MULTIPLE FACTORS, INCLUDING BOTH GENETIC AND ENVIRONMENTAL MECHANISMS, APPEAR TO PLAY A ROLE IN THE AETIOLOGY OF HEADACHE. AN INTERESTING AREA OF STUDY IS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN HEADACHE DEVELOPMENT AND THE TRANSFORMATION TO CHRONIC HEADACHE, AND THE POTENTIAL ROLE OF THESE FACTORS AS A THERAPEUTIC TARGET. METHODS: WE PERFORMED A LITERATURE REVIEW OF THE INVOLVEMENT OF DIFFERENT EPIGENETIC MECHANISMS IN HEADACHE, MAINLY USING THE MEDLINE/PUBMED DATABASE. TO THIS END, WE USED THE FOLLOWING ENGLISH SEARCH TERMS: HEADACHE, MIGRAINE, EPIGENETICS, DNA METHYLATION, HISTONES, NON-CODING RNA, AND MIRNA. RESULTS: A TOTAL OF 15 ENGLISH-LANGUAGE PUBLICATIONS RELATED TO THE ABOVE TERMS WERE OBTAINED. CONCLUSION: THERE IS LIMITED BUT CONSISTENT EVIDENCE OF THE RELATIONSHIP BETWEEN EPIGENETICS AND HEADACHE; IT IS THEREFORE ESSENTIAL TO CONTINUE RESEARCH OF EPIGENETIC CHANGES IN HEADACHE. THIS MAY HELP TO UNDERSTAND THE PATHOPHYSIOLOGY OF HEADACHE AND EVEN TO IDENTIFY CANDIDATE BIOMARKERS AND NEW, MORE EFFECTIVE, THERAPEUTIC TARGETS. 2021 3 1250 27 CURRENT PERSPECTIVES ON MITOCHONDRIAL DYSFUNCTION IN MIGRAINE. MITOCHONDRIA ARE AN AUTONOMOUS ORGANELLE THAT PLAYS A CRUCIAL ROLE IN THE METABOLIC ASPECTS OF A CELL. CORTICAL SPREADING DEPRESSION (CSD) AND FLUCTUATIONS IN THE CEREBRAL BLOOD FLOW HAVE FOR LONG BEEN MECHANISMS UNDERLYING MIGRAINE. IT IS A NEUROVASCULAR DISORDER WITH A UNILATERAL MANIFESTATION OF DISTURBING, THROBBING AND PULSATING HEAD PAIN. MIGRAINE AFFECTS 2.6% AND 21.7% OF THE GENERAL POPULATION AND IS THE MAJOR CAUSE OF PARTIAL DISABILITY IN THE AGE GROUP 15-49. HIGHER MUTATION RATES, IMBALANCE IN CONCENTRATION OF PHYSIOLOGICALLY RELEVANT MOLECULES AND OXIDATIVE STRESS BIOMARKERS HAVE BEEN THE MAIN THEMES OF DISCUSSION IN DETERMINING THE ROLE OF MITOCHONDRIAL DISABILITY IN MIGRAINE. THE CORRELATION OF MIGRAINE WITH OTHER DISORDERS LIKE HEMIPLEGIC MIGRAINE; MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS AND STROKE-LIKE EPISODES [MELAS]; TENSION-TYPE HEADACHE (TTH); CYCLIC VOMITING SYNDROME (CVS), ISCHAEMIC STROKE; AND HYPERTENSION HAS HELPED IN THE ASSESSMENT OF THE PHYSIOLOGICAL AND MORPHOGENETIC BASIS OF MIGRAINE. HERE, WE HAVE REVIEWED THE DIFFERENT NUANCES OF MITOCHONDRIAL DYSFUNCTION AND MIGRAINE. THE DIFFERENT MTDNA POLYMORPHISMS THAT CAN AFFECT THE GENERATION AND TRANSMISSION OF NERVE IMPULSE HAS BEEN HIGHLIGHTED AND SUPPORTED WITH RESEARCH FINDINGS. IN ADDITION TO THIS, THE GENETIC BASIS OF MIGRAINE PATHOGENESIS AS A CONSEQUENCE OF MUTATIONS IN NUCLEAR DNA THAT CAN, IN TURN, AFFECT THE SYNTHESIS OF DEFECTIVE MITOCHONDRIAL PROTEINS IS DISCUSSED ALONG WITH A BRIEF OVERVIEW OF EPIGENETIC PROFILE. THIS REVIEW GIVES AN OVERVIEW OF THE PATHOPHYSIOLOGY OF MIGRAINE AND EXPLORES MITOCHONDRIAL DYSFUNCTION AS A POTENTIAL UNDERLYING MECHANISM. ALSO, THERAPEUTIC SUPPLEMENTS FOR MANAGING MIGRAINE HAVE BEEN DISCUSSED AT DIFFERENT JUNCTURES IN THIS PAPER. 2022 4 63 19 A HIGH METHYLATION LEVEL OF A NOVEL -284 BP CPG ISLAND IN THE RAMP1 GENE PROMOTER IS POTENTIALLY ASSOCIATED WITH MIGRAINE IN WOMEN. MIGRAINE IS A COMPLEX NEUROVASCULAR DISORDER AFFECTING ONE BILLION PEOPLE WORLDWIDE, MAINLY FEMALES. IT IS CHARACTERIZED BY ATTACKS OF MODERATE TO SEVERE HEADACHE PAIN, WITH ASSOCIATED SYMPTOMS. RECEPTOR ACTIVITY MODIFYING PROTEIN (RAMP1) IS PART OF THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR, A PHARMACOLOGICAL TARGET FOR MIGRAINE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, PLAY A ROLE IN CLINICAL PRESENTATION OF VARIOUS DISEASES. DNA METHYLATION OCCURS MOSTLY IN THE GENE PROMOTER AND CAN CONTROL GENE EXPRESSION. WE INVESTIGATED THE METHYLATION STATE OF THE RAMP1 PROMOTER IN 104 FEMALE BLOOD DNA SAMPLES: 54 MIGRAINEURS AND 50 CONTROLS. WE TREATED DNA WITH SODIUM BISULFITE AND PERFORMED PCR, SANGER SEQUENCING, AND EPIGENETIC SEQUENCING METHYLATION (ESME) SOFTWARE ANALYSIS. WE IDENTIFIED 51 CPG DINUCLEOTIDES, AND 5 SHOWED METHYLATION VARIABILITY. MIGRAINEURS HAD A HIGHER NUMBER OF INDIVIDUALS WITH ALL FIVE CPG METHYLATED WHEN COMPARED TO CONTROLS (26% VS. 16%), ALTHOUGH NON-SIGNIFICANT (P = 0.216). WE ALSO FOUND THAT CPG -284 BP, RELATED TO THE TRANSCRIPTION START SITE (TSS), SHOWED HIGHER METHYLATION LEVELS IN CASES (P = 0.011). THIS CPG MAY POTENTIALLY PLAY A ROLE IN MIGRAINE, AFFECTING RAMP1 TRANSCRIPTION OR RECEPTOR MALFUNCTIONING AND/OR ALTERED CGRP BINDING. WE HOPE TO CONFIRM THIS FINDING IN A LARGER COHORT AND ESTABLISH AN EPIGENETIC BIOMARKER TO PREDICT FEMALE MIGRAINE RISK. 2022 5 1574 28 DNA METHYLATION PATTERNS OF CHRONIC EXPLOSIVE BREACHING IN U.S. MILITARY WARFIGHTERS. BACKGROUND: INJURIES FROM EXPOSURE TO EXPLOSIONS ROSE DRAMATICALLY DURING THE IRAQ AND AFGHANISTAN WARS, WHICH MOTIVATED INVESTIGATION OF BLAST-RELATED NEUROTRAUMA. WE HAVE UNDERTAKEN HUMAN STUDIES INVOLVING MILITARY "BREACHERS" -EXPOSED TO CONTROLLED, LOW-LEVEL BLAST DURING A 3-DAYS EXPLOSIVE BREACHING COURSE. METHODS: WE SCREENED EPIGENETIC PROFILES IN PERIPHERAL BLOOD SAMPLES FROM 59 SUBJECTS (IN TWO SEPARATE U.S. MILITARY TRAINING SESSIONS) USING INFINIUM METHYLATIONEPIC BEADCHIPS. PARTICIPANTS HAD VARYING NUMBERS OF EXPOSURES TO BLAST OVER THEIR MILITARY CAREERS (EMPIRICALLY DEFINED AS HIGH >/= 40, AND CONVERSELY, LOW < 39 BREACHING EXPOSURES). DAILY SELF-REPORTED PHYSIOLOGICAL SYMPTOMS WERE RECORDED. TINNITUS, MEMORY PROBLEMS, HEADACHES, AND SLEEP DISTURBANCES ARE MOST FREQUENTLY REPORTED. RESULTS: WE IDENTIFIED 14 SIGNIFICANTLY DIFFERENTIALLY METHYLATED REGIONS (DMRS) WITHIN GENES ASSOCIATED WITH CUMULATIVE BLAST EXPOSURE IN PARTICIPANTS WITH HIGH RELATIVE TO LOW CUMULATIVE BLAST EXPOSURE. NOTABLY, NTSR1 AND SPON1 WERE SIGNIFICANTLY DIFFERENTIALLY METHYLATED IN HIGH RELATIVE TO LOW BLAST EXPOSED GROUPS, SUGGESTING THAT SLEEP DYSREGULATION MAY BE ALTERED IN RESPONSE TO CHRONIC CUMULATIVE BLAST EXPOSURE. IN COMPARING LIFETIME BLAST EXPOSURE AT BASELINE (PRIOR TO EXPOSURE IN CURRENT TRAINING), AND TOP ASSOCIATED SYMPTOMS, WE IDENTIFIED SIGNIFICANT DMRS ASSOCIATED WITH TINNITUS, SLEEP DIFFICULTIES, AND HEADACHE. NOTABLY, WE IDENTIFIED KCNN3, SOD3, MUC4, GALR1, AND WDR45B, WHICH ARE IMPLICATED IN AUDITORY FUNCTION, AS DIFFERENTIALLY METHYLATED ASSOCIATED WITH SELF-REPORTED TINNITUS. THESE FINDINGS SUGGEST NEUROBIOLOGICAL MECHANISMS BEHIND AUDITORY INJURIES IN OUR MILITARY WARFIGHTERS AND ARE PARTICULARLY RELEVANT GIVEN TINNITUS IS NOT ONLY A PRIMARY DISABILITY AMONG VETERANS, BUT HAS ALSO BEEN DEMONSTRATED IN ACTIVE DUTY MEDICAL RECORDS FOR POPULATIONS EXPOSED TO BLAST IN TRAINING. ADDITIONALLY, WE FOUND THAT DIFFERENTIALLY METHYLATED REGIONS ASSOCIATED WITH THE GENES CCDC68 AND COMT TRACK WITH SLEEP DIFFICULTIES, AND THOSE WITHIN FMOD AND TNXB TRACK WITH PAIN AND HEADACHE. CONCLUSION: SLEEP DISTURBANCES, AS WELL AS TINNITUS AND CHRONIC PAIN, ARE WIDELY REPORTED IN U.S. MILITARY SERVICE MEMBERS AND VETERANS. AS WE HAVE PREVIOUSLY DEMONSTRATED, DNA METHYLATION ENCAPSULATES LIFETIME EXPOSURE TO BLAST. THE CURRENT DATA SUPPORT PREVIOUS FINDINGS AND RECAPITULATE TRANSCRIPTIONAL REGULATORY ALTERATIONS IN GENES INVOLVED IN SLEEP, AUDITORY FUNCTION, AND PAIN. THESE DATA UNCOVERED NOVEL EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISM UNDERLYING THE ETIOLOGICAL BASIS OF THESE SYMPTOMS. 2020 6 3334 24 HISTONE DEACETYLASE INHIBITORS COUNTERACT CGRP SIGNALING AND PRONOCICEPTIVE SENSITIZATION IN A RAT MODEL OF MEDICATION OVERUSE HEADACHE. CHRONIC TRIPTAN EXPOSURE IN RODENTS RECAPITULATES MEDICATION OVERUSE HEADACHE (MOH), CAUSING CEPHALIC PAIN SENSITIZATION AND TRIGEMINAL GANGLION OVEREXPRESSION OF PRONOCICEPTIVE PROTEINS INCLUDING CGRP. BECAUSE OF THESE TRANSCRIPTIONAL DERANGEMENTS, AS WELL AS THE EMERGING ROLE OF EPIGENETICS IN CHRONIC PAIN, IN THE PRESENT STUDY, WE EVALUATED THE EFFECTS OF THE HISTONE DEACETYLASE INHIBITORS (HDACIS) PANOBINOSTAT AND GIVINOSTAT, IN RATS CHRONICALLY EXPOSED TO ELETRIPTAN FOR 1 MONTH. BOTH PANOBINOSTAT AND GIVINOSTAT COUNTERACTED OVEREXPRESSION OF GENES CODING FOR CGRP AND ITS RECEPTOR SUBUNIT RAMP1, HAVING NO EFFECTS ON CLR AND RCP RECEPTOR SUBUNITS IN THE TRIGEMINAL GANGLION (TG) OF ELETRIPTAN-EXPOSED RATS. WITHIN THE TRIGEMINAL NUCLEUS CAUDALIS (TNC), TRANSCRIPTS FOR THESE GENES WERE NEITHER UPREGULATED BY ELETRIPTAN NOR ALTERED BY CONCOMITANT TREATMENT WITH PANOBINOSTAT OR GIVINOSTAT. HDACIS COUNTERACTED HYPERSENSITIVITY TO CAPSAICIN-INDUCED VASODILATATION IN THE TRIGEMINAL TERRITORY, AS WELL AS PHOTOPHOBIC BEHAVIOR AND CEPHALIC ALLODYNIAIN ELETRIPTAN-EXPOSED RATS. ELETRIPTAN DID NOT AFFECT CGRP, CLR, AND RAMP1 EXPRESSION IN CULTURED TRIGEMINAL GANGLIA, WHEREAS BOTH INHIBITORS REDUCED TRANSCRIPTS FOR CLR AND RAMP-1. THE DRUGS, HOWEVER, INCREASED LUCIFERASE EXPRESSION DRIVEN BY CGRP PROMOTER IN CULTURED CELLS. OUR FINDINGS PROVIDE EVIDENCE FOR A KEY ROLE OF HDACS AND EPIGENETICS IN MOH PATHOGENESIS, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE PREVENTION OF MIGRAINE CHRONIFICATION. PERSPECTIVE: THE PRESENT STUDY HIGHLIGHTS A KEY EPIGENETIC ROLE OF HDAC IN THE RODENT MODEL OF MEDICATION OVERUSE HEADACHE, FURTHERING OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS RESPONSIBLE FOR PRONOCICEPTIVE SENSITIZATION DURING HEADACHE CHRONIFICATION. 2022 7 5537 24 ROLE OF CALCITONIN GENE-RELATED PEPTIDE IN LIGHT-AVERSIVE BEHAVIOR: IMPLICATIONS FOR MIGRAINE. MIGRAINE IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRENT EPISODES OF SEVERE UNILATERAL THROBBING HEAD PAIN AND ASSOCIATED SYMPTOMS, SUCH AS PHOTOPHOBIA. OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING MIGRAINE HAS BEEN HAMPERED BY LIMITATIONS IN ASCERTAINING MIGRAINE SYMPTOMS IN ANIMAL MODELS. CLINICAL STUDIES HAVE ESTABLISHED THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A KEY PLAYER IN MIGRAINE. HERE, WE ESTABLISH A GENETIC MODEL OF PHOTOPHOBIA BY ENGINEERING INCREASED SENSITIVITY TO CGRP IN MICE. THESE TRANSGENIC MICE (NESTIN/HRAMP1) DISPLAY LIGHT-AVERSIVE BEHAVIOR THAT IS GREATLY ENHANCED BY INTRACEREBROVENTRICULAR INJECTION OF CGRP AND BLOCKED BY COADMINISTRATION OF THE CGRP RECEPTOR ANTAGONIST OLCEGEPANT. THIS BEHAVIOR APPEARS TO BE AN INDICATOR OF PHOTOPHOBIA AND CANNOT BE FULLY EXPLAINED BY GROSS ABNORMALITY OF OCULAR ANATOMY OR DIFFERENCES IN GENERAL ANXIETY OR MOTOR ACTIVITY. OUR FINDINGS DEMONSTRATE THAT A SINGLE GENE, RECEPTOR ACTIVITY-MODIFYING PROTEIN 1 (RAMP1), CAN BE A MODIFIER OF PHOTOPHOBIA AND, BY EXTENSION, SUGGEST THAT GENETIC OR EPIGENETIC MODULATION OF RAMP1 LEVELS MAY CONTRIBUTE TO MIGRAINE SUSCEPTIBILITY. MOREOVER, THEY VALIDATE CGRP HYPERSENSITIVE MICE AS A TOOL FOR EXPLORING THE NEUROBIOLOGY AND NOVEL THERAPIES FOR MIGRAINE AND OTHER DISORDERS INVOLVING PHOTOPHOBIA. 2009 8 1390 15 DIAGNOSING NOCIPLASTIC PAIN IN CANCER SURVIVORS: A MAJOR STEP FORWARD. NOCIPLASTIC PAIN SYNDROMES INCLUDE PARTICULAR FIBROMYALGIA, IRRITABLE BOWEL SYNDROME, HEADACHE, COMPLEX REGIONAL PAIN SYNDROME, AND IDIOPATHIC OROFACIAL PAIN. SEVERAL MECHANISMS HAVE BEEN PROPOSED TO ACCOUNT FOR NOCIPLASTIC PAIN INCLUDING CENTRAL SENSITISATION, ALTERATIONS OF PAIN MODULATORY CONTROLS, EPIGENETIC CHANGES, AND PERIPHERAL MECHANISMS. IMPORTANTLY, NOCIPLASTIC PAIN MIGHT ALSO BE PRESENT IN PATIENTS WITH CANCER PAIN, PARTICULARLY THOSE WITH PAIN RELATED TO COMPLICATIONS OF CANCER TREATMENT. INCREASED AWARENESS OF NOCIPLASTIC PAIN ASSOCIATED WITH CANCER SHOULD HAVE IMPORTANT IMPLICATIONS FOR MONITORING AND MANAGING SUCH PATIENTS. 2023 9 6916 24 [WHAT IS MIGRAINE?]. MIGRAINE IS A MULTIFACTORIAL AND HETEROGENEOUS DISORDER. DIAGNOSTIC CRITERIA HAVE BEEN ESTABLISHED BY THE INTERNATIONAL HEADACHE SOCIETY, HOWEVER THESE ARE ONLY SUPPORTIVE IN TERMS OF DEFINITION. THE PATHOPHYSIOLOGY INVOLVES NEURONAL AND VASCULAR PHENOMENA. THE FORMER IS SUPPORTED BY THE CORTICAL SPREADING DEPRESSION BEING THE AURA CORRELATE AND BY BRAINSTEM AND HYPOTHALAMIC ACTIVATION DURING THE PAIN PHASE; THE LATTER IS SUGGESTED BY THE ASSOCIATION BETWEEN MIGRAINE AND CARDIOVASCULAR DISEASE AND FINDINGS OF PATHOLOGICAL VASOREACTIVITY AND ENDOTHELIAL DYSFUNCTION. TRIPTANS AND CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONISTS SHOW ONLY A RELATIVE MIGRAINE-SPECIFIC ACTION; UP TO 30% OF PATIENTS ARE NONRESPONDERS. DESPITE A CLEAR GENETIC COMPONENT, THE DISCOVERY OF SPECIFIC GENES FOR COMMON FORMS OF MIGRAINE REMAINS ELUSIVE. ELECTROPHYSIOLOGICAL STUDIES CONSISTENTLY INDICATE A CHARACTERISTIC "DYSHABITUATION" CONCURRING WITH CLINICAL FEATURES OF ALTERED SENSORY PERCEPTION. THE AGE- AND SEX-SPECIFIC PATTERN ALONG WITH THE EFFECT OF EXTERNAL FACTORS ON THE COURSE OF MIGRAINE ARGUE IN FAVOR OF THE INVOLVEMENT OF EPIGENETIC MECHANISMS. KNOWLEDGE ABOUT MIGRAINE IS STILL LIMITED, WHICH HAMPERS A DEFINITION. 2009 10 2079 18 EPIGENETIC DNA METHYLATION CHANGES ASSOCIATED WITH HEADACHE CHRONIFICATION: A RETROSPECTIVE CASE-CONTROL STUDY. BACKGROUND THE BIOLOGICAL MECHANISMS OF HEADACHE CHRONIFICATION ARE POORLY UNDERSTOOD. WE AIMED TO IDENTIFY CHANGES IN DNA METHYLATION ASSOCIATED WITH THE TRANSFORMATION FROM EPISODIC TO CHRONIC HEADACHE. METHODS PARTICIPANTS WERE RECRUITED FROM THE POPULATION-BASED NORWEGIAN HUNT STUDY. THIRTY-SIX FEMALE HEADACHE PATIENTS WHO TRANSFORMED FROM EPISODIC TO CHRONIC HEADACHE BETWEEN BASELINE AND FOLLOW-UP 11 YEARS LATER WERE MATCHED AGAINST 35 CONTROLS WITH EPISODIC HEADACHE. DNA METHYLATION WAS QUANTIFIED AT 485,000 CPG SITES, AND CHANGES IN METHYLATION LEVEL AT THESE SITES WERE COMPARED BETWEEN CASES AND CONTROLS BY LINEAR REGRESSION ANALYSIS. DATA WERE ANALYZED IN TWO STAGES (STAGES 1 AND 2) AND IN A COMBINED META-ANALYSIS. RESULTS NONE OF THE TOP 20 CPG SITES IDENTIFIED IN STAGE 1 REPLICATED IN STAGE 2 AFTER MULTIPLE TESTING CORRECTION. IN THE COMBINED META-ANALYSIS THE STRONGEST ASSOCIATED CPG SITES WERE RELATED TO SH2D5 AND NPTX2, TWO BRAIN-EXPRESSED GENES INVOLVED IN THE REGULATION OF SYNAPTIC PLASTICITY. FUNCTIONAL ENRICHMENT ANALYSIS POINTED TO PROCESSES INCLUDING CALCIUM ION BINDING AND ESTROGEN RECEPTOR PATHWAYS. CONCLUSION IN THIS FIRST GENOME-WIDE STUDY OF DNA METHYLATION IN HEADACHE CHRONIFICATION SEVERAL POTENTIALLY IMPLICATED LOCI AND PROCESSES WERE IDENTIFIED. THE STUDY EXEMPLIFIES THE USE OF PROSPECTIVELY COLLECTED POPULATION COHORTS TO SEARCH FOR EPIGENETIC MECHANISMS OF DISEASE. 2018 11 404 26 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS. 2020 12 6779 16 [BIO-PSYCHO-SOCIAL THERAPY FOR STRESS-INDUCED CHRONIC PAIN]. BIO-PSYCHO-SOCIAL THERAPY FOR STRESS-INDUCED CHRONIC PAIN ABSTRACT. AGAINST THE BACKGROUND OF LATEST NEUROBIOLOGICAL AND EPIGENETIC FINDINGS THE BIO-PSYCHO-SOCIAL MODEL OF DISEASE IS OUTLINED OFTEN MISINTERPRETED IN THE CONTEXT OF CHRONIC PAIN. IT REPRESENTS THE BASIC PRINCIPLE FOR A PERSONALIZED TREATMENT OF STRESS-INDUCED CHRONIC PAIN. CONSEQUENCES FOR DIAGNOSTIC PROCEDURES ARE DELINEATED TO DETECT THIS PATHOGENETIC SUBGROUP OF CHRONIC PAIN PATIENTS (E.G. FIBROMYALGIA, BACK PAIN, TEMPOROMANDIBULAR DYSFUNCTION, TENSION HEADACHE). FINALLY, THE PRINCIPLES OF A BIO-PSYCHO-SOCIAL TREATMENT PROGRAM WITH HIGH EFFICIENCY ARE PRESENTED. 2020 13 5500 18 REVISITING MIGRAINE: THE EVOLVING PATHOPHYSIOLOGY AND THE EXPANDING MANAGEMENT ARMAMENTARIUM. MIGRAINE AFFECTS ABOUT ONE BILLION PEOPLE WORLDWIDE YEARLY AND IS ONE OF THE MOST COMMON NEUROLOGIC ILLNESSES, WITH A HIGH PREVALENCE AND MORBIDITY, PARTICULARLY AMONG YOUNG ADULTS AND FEMALES. MIGRAINE IS ASSOCIATED WITH MANY COMORBIDITIES, INCLUDING STRESS, SLEEP DIFFICULTIES, AND SUICIDAL IDEATION. MIGRAINE, DESPITE ITS WIDESPREAD OCCURRENCE, IS UNDERDIAGNOSED AND UNDERTREATED. BECAUSE OF THE COMPLICATED AND PRIMARILY UNKNOWN MECHANISMS OF MIGRAINE FORMATION, SEVERAL SOCIAL AND BIOLOGICAL RISK FACTORS, SUCH AS HORMONE IMBALANCES, GENETIC AND EPIGENETIC IMPACTS, AND CARDIOVASCULAR, NEUROLOGICAL, AND AUTOIMMUNE ILLNESSES, HAVE BEEN PROPOSED. THROUGH THE MID-20TH CENTURY DIVERSION OF THE NOW-DEFUNCT VASCULAR THEORY, THE PATHOPHYSIOLOGY OF MIGRAINE HAS DEVELOPED FROM A HISTORICAL STUDY OF THE "HUMOURS" TO A DISTINCT ENTITY AS A NEUROLOGICAL DISORDER. THE RANGE OF THERAPEUTIC TARGETS HAS BROADENED SIGNIFICANTLY, INCREASING THE NUMBER OF SPECIALIZED CLINICAL TRIALS. UNDERSTANDING THE BIOLOGY OF MIGRAINE THROUGH CAREFUL RESEARCH HAS RESULTED IN THE IDENTIFICATION OF MAJOR THERAPEUTIC CLASSES: (I) TRIPTANS, SEROTONIN 5-HT1B/1D RECEPTOR AGONISTS, (II) GEPANTS, CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR ANTAGONISTS, (III) DITANS, 5-HT1F RECEPTOR AGONISTS, (IV) CGRP MONOCLONAL ANTIBODIES, AND (V) GLURANTS, MGLU5 MODULATORS, WITH FURTHER TARGETS BEING EXPLORED. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE MOST RECENT LITERATURE ON EPIDEMIOLOGY AND RISK FACTORS AND EXPOSES KNOWLEDGE GAPS. 2023 14 638 29 BIOMARKERS ASSOCIATED WITH MIGRAINE AND THEIR POTENTIAL ROLE IN MIGRAINE MANAGEMENT. OBJECTIVE: THE FOCUS OF THIS REVIEW IS TO REVIEW POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKERS ASSOCIATED WITH MIGRAINE. BACKGROUND: MIGRAINE HEADACHE IS A COMMON DISEASE THAT AFFECTS MILLIONS OF INDIVIDUALS WORLDWIDE. ALTHOUGH WELL-ACCEPTED DIAGNOSTIC CRITERIA EXIST FOR MIGRAINE, IT IS STILL A COMPLEX DISORDER THAT REMAINS BOTH UNDERDIAGNOSED AND MISDIAGNOSED. THE CAUSES OF MIGRAINE ARE LIKELY A MIX OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT, TOGETHER WITH THE INDIVIDUAL'S LIFE HISTORY, TRANSLATE INTO THE OBSERVED CLINICAL HETEROGENEITY. INHERENT CLINICAL HETEROGENEITY IS AN OBSTACLE IN DEVELOPING MORE EFFECTIVE TREATMENTS. THE LACK OF APPROPRIATE BIOMARKERS IS ALSO AN IMPEDIMENT TO DEVELOPING MORE EFFECTIVE THERAPEUTIC/PREVENTIVE APPROACHES. ULTIMATELY, BIOMARKERS MAY FACILITATE THE GOAL OF INDIVIDUALIZED MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER TYPES OF HEADACHE. METHODS: A COMPREHENSIVE REVIEW WAS CONDUCTED OF PUBMED CITATIONS CONTAINING THE KEY WORD "MARKER" OR "BIOMARKER" COMBINED WITH "MIGRAINE" OR "HEADACHE." OTHER KEY WORDS INCLUDED "SERUM," "SALIVA," "CEREBROSPINAL FLUID," "GENES," "BLOOD," AND "INFLAMMATION." THE ONLY RESTRICTION WAS ENGLISH-LANGUAGE PUBLICATION. THE ABSTRACTS OF ALL ARTICLES MEETING THESE CRITERIA WERE REVIEWED, AND FULL TEXT WAS RETRIEVED AND EXAMINED FOR RELEVANT REFERENCES. RESULTS: DATA FROM HUMAN STUDIES HAVE BEGUN TO IDENTIFY GENETIC MUTATIONS/POLYMORPHISMS AND ALTERED LEVELS OF SPECIFIC PROINFLAMMATORY AND NEUROMODULATORY MOLECULES THAT STRONGLY CORRELATE WITH MIGRAINE AS WELL AS SYMPTOM SEVERITY. RESULTS FROM A SMALLER NUMBER OF STUDIES HAVE IDENTIFIED PARAMETERS, SUCH AS THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP), WHICH ARE SIGNIFICANTLY ASSOCIATED WITH RESPONSE TO SPECIFIC TREATMENTS FOR ACUTE MIGRAINE ATTACKS AND PROPHYLAXIS. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MIGRAINE, AND UNDERSTANDING ENVIRONMENTALLY INDUCED GENETIC CHANGES ASSOCIATED WITH THIS DISEASE MAY EVENTUALLY GUIDE THE DEVELOPMENT OF THERAPIES CAPABLE OF REVERSING THESE PATHOPHYSIOLOGICAL CHANGES IN GENE FUNCTION. CONCLUSIONS: THE UNDERSTANDING OF THE ETIOLOGY OF MIGRAINE IS INCOMPLETE. ALTHOUGH THE IDENTIFICATION AND VALIDATION OF BIOMARKERS HAS GREATLY ADVANCED DIAGNOSTIC PRECISION AND MEASURES OF THERAPEUTIC EFFICACY IN OTHER DISEASES, THERE ARE NO CURRENTLY ACCEPTED BIOMARKERS FOR CHRONIC OR EPISODIC MIGRAINE. HOWEVER, THE CONTINUED INVESTIGATION AND IDENTIFICATION OF GENETIC, EPIGENETIC, AND MOLECULAR BIOMARKERS IS LIKELY TO FACILITATE THE GOAL OF INDIVIDUALIZING MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER HEADACHE DISORDERS. 2013 15 847 22 CHILDHOOD MALTREATMENT AND HEADACHE DISORDERS. CHILDHOOD MALTREATMENT IS SUBSTANTIATED IN 12 % OF CHILDREN, BUT NEARLY 50 % ADULTS RECALL HAVING BEEN NEGLECTED OR ABUSED AS CHILDREN. MALTREATMENT, ESPECIALLY EMOTIONAL ABUSE, IS ASSOCIATED WITH MIGRAINE. DYSREGULATION OF THE HPA AXIS, AUTONOMIC, IMMUNE, AND METABOLIC SYSTEMS APPEARS TO BE A CONSEQUENCE OF MALTREATMENT, AND IS ALSO REPORTED IN MIGRAINE. AREAS OF THE BRAIN STRUCTURALLY AND FUNCTIONALLY AFFECTED BY CHILDHOOD ABUSE AND BY MIGRAINE ARE ALSO SIMILAR, AND INCLUDE THE LIMBIC SYSTEM STRUCTURES, WHICH CONNECT TO PAIN REGIONS IN THE BRAINSTEM. PUTATIVE MECHANISMS BY WHICH EARLY LIFE STRESS INCREASES THE LIKELIHOOD OF DEVELOPING MIGRAINE INCLUDE GENE X ENVIRONMENT INTERACTIONS, IN ADDITION TO EPIGENETIC MODIFICATIONS VIA DNA METHYLATION. THESE MODIFICATIONS ARE STABLE AND MAY BE TRANSFERRED ACROSS GENERATIONS, BUT THEY MAY ALSO BE REVERSED BY SOME MEDICATIONS COMMONLY USED IN MIGRAINE, INCLUDING VALPROIC ACID AND TOPIRAMATE. 2016 16 686 20 BRAIN-SPECIFIC GENES CONTRIBUTE TO CHRONIC BUT NOT TO ACUTE BACK PAIN. INTRODUCTION: BACK PAIN IS THE LEADING CAUSE OF DISABILITY WORLDWIDE. ALTHOUGH MOST BACK PAIN CASES ARE ACUTE, 20% OF ACUTE PAIN PATIENTS EXPERIENCE CHRONIC BACK PAIN SYMPTOMS. IT IS UNCLEAR WHETHER ACUTE PAIN AND CHRONIC PAIN HAVE SIMILAR OR DISTINCT UNDERLYING GENETIC MECHANISMS. OBJECTIVES: TO CHARACTERIZE THE MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO ACUTE AND CHRONIC PAIN STATES. METHODS: CROSS-SECTIONAL OBSERVATIONAL GENOME-WIDE ASSOCIATION STUDY. RESULTS: A TOTAL OF 375,158 INDIVIDUALS FROM THE UK BIOBANK COHORT WERE INCLUDED IN THE DISCOVERY OF GENOME-WIDE ASSOCIATION STUDY. OF THOSE, 70,633 (19%) AND 32,209 (9%) INDIVIDUALS MET THE DEFINITION OF CHRONIC AND ACUTE BACK PAIN, RESPECTIVELY. A TOTAL OF 355 SINGLE NUCLEOTIDE POLYMORPHISM GROUPED INTO 13 LOCI REACHED THE GENOME-WIDE SIGNIFICANCE THRESHOLD (5X10(-8)) FOR CHRONIC BACK PAIN, BUT NONE FOR ACUTE. OF THESE, 7 LOCI WERE REPLICATED IN THE NORD-TRONDELAG HEALTH STUDY (HUNT) COHORT (19,760 CHRONIC LOW BACK PAIN CASES AND 28,674 PAIN-FREE CONTROLS). SINGLE NUCLEOTIDE POLYMORPHISM HERITABILITY WAS 4.6% (P=1.4X10(-78)) FOR CHRONIC BACK PAIN AND 0.81% (P=1.4X10-8) FOR ACUTE BACK PAIN. SIMILAR DIFFERENCES IN HERITABILITY ESTIMATES BETWEEN ACUTE AND CHRONIC BACK PAIN WERE FOUND IN THE HUNT COHORT: 3.4% (P=0.0011) AND 0.6% (P=0.851), RESPECTIVELY. PATHWAY ANALYSES, TISSUE-SPECIFIC HERITABILITY ENRICHMENT ANALYSES, AND EPIGENETIC CHARACTERIZATION SUGGEST A SUBSTANTIAL GENETIC CONTRIBUTION TO CHRONIC BUT NOT ACUTE BACK PAIN FROM THE LOCI PREDOMINANTLY EXPRESSED IN THE CENTRAL NERVOUS SYSTEM. CONCLUSION: CHRONIC BACK PAIN IS SUBSTANTIALLY MORE HERITABLE THAN ACUTE BACK PAIN. THIS HERITABILITY IS MOSTLY ATTRIBUTED TO GENES EXPRESSED IN THE BRAIN. 2022 17 214 20 ACUTE AND CHRONIC MOLECULAR SIGNATURES AND ASSOCIATED SYMPTOMS OF BLAST EXPOSURE IN MILITARY BREACHERS. INJURIES FROM EXPOSURE TO EXPLOSIONS ROSE DRAMATICALLY DURING THE IRAQ AND AFGHANISTAN WARS, WHICH MOTIVATED INVESTIGATIONS OF BLAST-RELATED NEUROTRAUMA AND OPERATIONAL BREACHING. IN THIS STUDY, MILITARY "BREACHERS" WERE EXPOSED TO CONTROLLED, LOW-LEVEL BLAST DURING A 10-DAY EXPLOSIVE BREACHING COURSE. USING AN OMICS APPROACH, WE ASSESSED EPIGENETIC, TRANSCRIPTIONAL, AND INFLAMMATORY PROFILE CHANGES IN BLOOD FROM OPERATIONAL BREACHING TRAINEES, WITH VARYING LEVELS OF LIFETIME BLAST EXPOSURE, ALONG WITH DAILY SELF-REPORTED SYMPTOMS (WITH TINNITUS, HEADACHES, AND SLEEP DISTURBANCES AS THE MOST FREQUENTLY REPORTED). ALTHOUGH ACUTE EXPOSURE TO BLAST DID NOT CONFER EPIGENETIC CHANGES, SPECIFICALLY IN DNA METHYLATION, DIFFERENTIALLY METHYLATED REGIONS (DMRS) WITH COORDINATED GENE EXPRESSION CHANGES ASSOCIATED WITH LIFETIME CUMULATIVE BLAST EXPOSURES WERE IDENTIFIED. THE ACCUMULATIVE EFFECT OF BLAST SHOWED INCREASED METHYLATION OF PAX8 ANTISENSE TRANSCRIPT WITH COORDINATED REPRESSION OF GENE EXPRESSION, WHICH HAS BEEN ASSOCIATED WITH SLEEP DISTURBANCE. DNA METHYLATION ANALYSES CONDUCTED IN CONJUNCTION WITH REPORTED SYMPTOMS OF TINNITUS IN THE LOW VERSUS HIGH BLAST INCIDENTS GROUPS IDENTIFIED DMRS IN KCNE1 AND CYP2E1 GENES. KCNE1 AND CYP2E1 SHOWED THE EXPECTED INVERSE CORRELATION BETWEEN DNA METHYLATION AND GENE EXPRESSION, WHICH HAVE BEEN PREVIOUSLY IMPLICATED IN NOISE-RELATED HEARING LOSS. ALTHOUGH NO SIGNIFICANT TRANSCRIPTIONAL CHANGES WERE OBSERVED IN SAMPLES OBTAINED AT THE ONSET OF THE TRAINING COURSE RELATIVE TO CHRONIC CUMULATIVE BLAST, WE IDENTIFIED A LARGE NUMBER OF TRANSCRIPTIONAL PERTURBATIONS ACUTELY PRE- VERSUS POST-BLAST EXPOSURE. ACUTELY, 67 ROBUSTLY DIFFERENTIALLY EXPRESSED GENES (FOLD CHANGE >/=1.5), INCLUDING UFC1 AND YOD1 UBIQUITIN-RELATED PROTEINS, WERE IDENTIFIED. INFLAMMATORY ANALYSES OF CYTOKINES AND CHEMOKINES REVEALED DYSREGULATION OF MCP-1, GCSF, HGF, MCSF, AND RANTES ACUTELY AFTER BLAST EXPOSURE. THESE DATA SHOW THE IMPORTANCE OF AN OMICS APPROACH, REVEALING THAT TRANSCRIPTIONAL AND INFLAMMATORY BIOMARKERS CAPTURE ACUTE LOW-LEVEL BLAST OVERPRESSURE EXPOSURE, WHEREAS DNA METHYLATION MARKS ENCAPSULATE CHRONIC LONG-TERM SYMPTOMS. 2020 18 4139 26 MECHANISMS OF MIGRAINE AS A CHRONIC EVOLUTIVE CONDITION. UNDERSTANDING THE MECHANISMS OF MIGRAINE REMAINS CHALLENGING AS MIGRAINE IS NOT A STATIC DISORDER, AND EVEN IN ITS EPISODIC FORM MIGRAINE REMAINS AN "EVOLUTIVE" CHRONIC CONDITION. CONSIDERABLE PROGRESS HAS BEEN MADE IN ELUCIDATING THE PATHOPHYSIOLOGICAL MECHANISMS OF MIGRAINE, ASSOCIATED GENETIC FACTORS THAT MAY INFLUENCE SUSCEPTIBILITY TO THE DISEASE, AND FUNCTIONAL AND ANATOMICAL CHANGES DURING THE PROGRESSION OF A MIGRAINE ATTACK OR THE TRANSFORMATION OF EPISODIC TO CHRONIC MIGRAINE. MIGRAINE IS A LIFE SPAN NEUROLOGICAL DISORDER THAT FOLLOWS AN EVOLUTIVE AGE-DEPENDENT CHANGE IN ITS PREVALENCE AND EVEN CLINICAL PRESENTATIONS. AS A DISORDER, MIGRAINE INVOLVES RECURRENT INTENSE HEAD PAIN AND ASSOCIATED UNPLEASANT SYMPTOMS. MIGRAINE ATTACKS EVOLVE OVER DIFFERENT PHASES WITH SPECIFIC NEURAL MECHANISMS AND SYMPTOMS BEING INVOLVED DURING EACH PHASE. IN SOME PATIENTS, MIGRAINE CAN BE TRANSFORMED INTO A CHRONIC FORM WITH DAILY OR ALMOST DAILY HEADACHES. THE MECHANISMS BEHIND THIS EVOLUTIVE PROCESS REMAIN UNKNOWN, BUT GENETIC AND EPIGENETIC FACTORS, INFLAMMATORY PROCESSES AND CENTRAL SENSITIZATION MAY PLAY AN IMPORTANT ROLE. 2019 19 2052 20 EPIGENETIC CONNECTION OF THE CALCITONIN GENE-RELATED PEPTIDE AND ITS POTENTIAL IN MIGRAINE. THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) IS IMPLICATED IN THE PATHOGENESIS OF SEVERAL PAIN-RELATED SYNDROMES, INCLUDING MIGRAINE. TARGETING CGRP AND ITS RECEPTOR BY THEIR ANTAGONISTS AND ANTIBODIES WAS A BREAKTHROUGH IN MIGRAINE THERAPY, BUT THE NEED TO IMPROVE EFFICACY AND LIMIT THE SIDE EFFECTS OF THESE DRUGS JUSTIFY FURTHER STUDIES ON THE REGULATION OF CGRP IN MIGRAINE. THE EXPRESSION OF THE CGRP ENCODING GENE, CALCA, IS MODULATED BY EPIGENETIC MODIFICATIONS, INCLUDING THE DNA METHYLATION, HISTONE MODIFICATION, AND EFFECTS OF MICRO RNAS (MIRNAS), CIRCULAR RNAS, AND LONG-CODING RNAS (LNCRNAS). ON THE OTHER HAND, CGRP CAN CHANGE THE EPIGENETIC PROFILE OF NEURONAL AND GLIAL CELLS. THE PROMOTER OF THE CALCA GENE HAS TWO CPG ISLANDS THAT MAY BE SPECIFICALLY METHYLATED IN MIGRAINE PATIENTS. DNA METHYLATION AND LNCRNAS WERE SHOWN TO PLAY A ROLE IN THE CELL-SPECIFIC ALTERNATIVE SPLICING OF THE CALCA PRIMARY TRANSCRIPT. CGRP MAY BE INVOLVED IN CHANGES IN NEURAL CYTOARCHITECTURE THAT ARE CONTROLLED BY HISTONE DEACETYLASE 6 (HDAC6) AND CAN BE RELATED TO MIGRAINE. INHIBITION OF HDAC6 RESULTS IN REDUCED CORTICAL-SPREADING DEPRESSION AND A BLOCKADE OF THE CGRP RECEPTOR. CGRP LEVELS ARE ASSOCIATED WITH THE EXPRESSION OF SEVERAL MIRNAS IN PLASMA, MAKING THEM USEFUL PERIPHERAL MARKERS OF MIGRAINE. THE FUNDAMENTAL ROLE OF CGRP IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF CGRP SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE THERAPY. 2022 20 6323 25 THE ROLE OF A POTENTIAL BIOMARKER IN PATIENTS WITH MIGRAINE: REVIEW AND NEW INSIGHTS. INTRODUCTION: THE SEARCH FOR AN IDEAL BIOMARKER FOR MIGRAINE HAS PERSISTED FOR A LONG TIME. THERE IS PLENTIFUL EVIDENCE OF POTENTIAL BIOMARKERS FOR MIGRAINE FOUND IN CEREBROSPINAL FLUID, BLOOD, AND SALIVA.AREAS COVERED: HEREIN, THE AUTHORS HIGHLIGHT AND DISCUSS THE MOST PROMISING CANDIDATES IN THE LITERATURE. AN ELECTRONIC SEARCH WAS PERFORMED FOR STUDIES PUBLISHED BETWEEN 2010 AND 2020 IN MEDLINE, PUBMED, AND EMBASE, RELATED TO POTENTIAL BIOMARKERS IN MIGRAINE PATIENTS, FOUND IN CEREBROSPINAL FLUID, SALIVA, AND SERUM, FOCUSING ON BIOMARKERS THAT CAN BE RELATED TO TREATMENT AND CLINICAL OUTCOMES.EXPERT OPINION: AN IDEAL BIOMARKER, OR A PANEL OF BIOMARKERS, COULD REVOLUTIONIZE THE WAY WE ADDRESS AND PROPOSE TREATMENTS FOR THIS DISEASE. ONCE SEVERE PRESENTATIONS AND PHENOTYPES HAVE BEEN IDENTIFIED USING A RELIABLE BIOMARKER, PATIENTS COULD BE TREATED AT EARLIER DISEASE STAGES WITH MORE SPECIFIC MEDICATIONS. THE MOST IMPORTANT BIOMARKERS WITH THE MOST SIGNIFICANT LEVELS OF EVIDENCE COMPRISED CALCITONIN GENE-RELATED PEPTIDE (CGRP), GLUTAMATE, NERVE GROWTH FACTOR, SOME INFLAMMATORY (CRP, TNF-ALPHA, INTERLEUKINS) AND OXIDATIVE STRESS MARKERS. CGRP WAS ASSOCIATED WITH EPISODIC, CHRONIC MIGRAINE AND RESPONSE TO TREATMENT. PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE IS AN EMERGING NEUROPEPTIDE INVOLVED IN MIGRAINE DIAGNOSTICS AND SEVERITY. NEW GENETIC AND EPIGENETIC BIOMARKERS WILL BE CANDIDATES FOR FUTURE RESEARCH. 2021