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 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 3 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 4 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 5 6846 27 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 6 2815 27 FIBROMYALGIA: GENETICS AND EPIGENETICS INSIGHTS MAY PROVIDE THE BASIS FOR THE DEVELOPMENT OF DIAGNOSTIC BIOMARKERS. FIBROMYALGIA IS A DISEASE CHARACTERIZED BY CHRONIC WIDESPREAD PAIN WITH ADDITIONAL SYMPTOMS, SUCH AS JOINT STIFFNESS, FATIGUE, SLEEP DISTURBANCE, COGNITIVE DYSFUNCTION, AND DEPRESSION. CURRENTLY, FIBROMYALGIA DIAGNOSIS IS BASED EXCLUSIVELY ON A COMPREHENSIVE CLINICAL ASSESSMENT, ACCORDING TO 2016 ACR CRITERIA, BUT VALIDATED BIOLOGICAL BIOMARKERS ASSOCIATED WITH FIBROMYALGIA HAVE NOT YET BEEN IDENTIFIED. GENOME-WIDE ASSOCIATION STUDIES INVESTIGATED GENES POTENTIALLY INVOLVED IN FIBROMYALGIA PATHOGENESIS HIGHLIGHTING THAT GENETIC FACTORS ARE POSSIBLY RESPONSIBLE FOR UP TO 50% OF THE DISEASE SUSCEPTIBILITY. POTENTIAL CANDIDATE GENES FOUND ASSOCIATED TO FIBROMYALGIA ARE SLC64A4, TRPV2, MYT1L, AND NRXN3. FURTHERMORE, A GENE-ENVIRONMENTAL INTERACTION HAS BEEN PROPOSED AS TRIGGERING MECHANISM, THROUGH EPIGENETIC ALTERATIONS: IN PARTICULAR, FIBROMYALGIA APPEARS TO BE CHARACTERIZED BY A HYPOMETHYLATED DNA PATTERN, IN GENES IMPLICATED IN STRESS RESPONSE, DNA REPAIR, AUTONOMIC SYSTEM RESPONSE, AND SUBCORTICAL NEURONAL ABNORMALITIES. DIFFERENCES IN THE GENOME-WIDE EXPRESSION PROFILE OF MICRORNAS WERE FOUND AMONG MULTIPLE TISSUES, INDICATING THE INVOLVEMENT OF DISTINCT PROCESSES IN FIBROMYALGIA PATHOGENESIS. FURTHER STUDIES SHOULD BE DEDICATED TO STRENGTH THESE PRELIMINARY FINDINGS, IN LARGER MULTICENTER COHORTS, TO IDENTIFY RELIABLE DIRECTIONS FOR BIOMARKER RESEARCH AND CLINICAL PRACTICE. 2019 7 847 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 8 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 9 1524 19 DNA METHYLATION CHANGES IN CYSTIC FIBROSIS: CAUSE OR CONSEQUENCE? TWIN AND SIBLING STUDIES HAVE SHOWN THAT LUNG DISEASE SEVERITY IS VARIABLE AMONG CYSTIC FIBROSIS (CF) PATIENTS AND AFFECTED TO THE SAME EXTENT BY GENETIC AND NONHERITABLE FACTORS. GENETIC FACTORS HAVE BEEN THOROUGHLY ASSESSED, WHEREAS THE MOLECULAR MECHANISMS WHEREBY NONHERITABLE FACTORS CONTRIBUTE TO THE PHENOTYPIC VARIABILITY OF CF PATIENTS ARE STILL UNKNOWN. EPIGENETIC MODIFICATIONS MAY REPRESENT THE MISSING LINK BETWEEN NONHERITABLE FACTORS AND PHENOTYPIC VARIATION IN CF. HEREIN, WE REVIEW RECENT STUDIES SHOWING THAT DNA METHYLATION IS ALTERED IN CF AND WE ADDRESS THREE POSSIBLE FACTORS RESPONSIBLE FOR THESE VARIATIONS: (I) OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DEPLETION OF DNA METHYLATION COFACTORS AND (III) SUSCEPTIBILITY TO ACUTE AND CHRONIC BACTERIAL INFECTIONS. ALSO, WE HYPOTHESIZE THAT THE UNIQUE DNA METHYLATION PROFILE OF EACH PATIENT CAN MODULATE THE PHENOTYPE AND DISCUSS THE INTEREST OF IMPLEMENTING INTEGRATED GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC STUDIES TO FURTHER UNDERSTAND THE CLINICAL DIVERSITY OF CF PATIENTS (GRAPHICAL ABSTRACT). 2020 10 5038 19 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 11 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 12 1314 20 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 13 638 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 14 6137 22 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022 15 6159 26 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 16 6459 19 TIME TO CHANGE FROM A SIMPLE LINEAR MODEL TO A COMPLEX SYSTEMS MODEL. A SIMPLE LINEAR MODEL TO TEST THE HYPOTHESIS BASED ON ONE-ON-ONE RELATIONSHIP HAS BEEN USED TO FIND THE CAUSATIVE FACTORS OF DISEASES. HOWEVER, WE NOW KNOW THAT NOT JUST ONE, BUT MANY FACTORS FROM DIFFERENT SYSTEMS SUCH AS CHEMICAL EXPOSURE, GENES, EPIGENETIC CHANGES, AND PROTEINS ARE INVOLVED IN THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS DIABETES MELLITUS. SO, WITH AVAILABILITY OF MODERN TECHNOLOGIES TO UNDERSTAND THE INTRICATE NATURE OF RELATIONS AMONG COMPLEX SYSTEMS, WE NEED TO MOVE FORWARD TO THE FUTURE BY TAKING COMPLEX SYSTEMS MODEL. 2016 17 3418 22 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 18 5810 17 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 19 4370 19 MIRNAS AND THEIR ROLE IN THE CORRELATION BETWEEN SCHIZOPHRENIA AND CANCER (REVIEW). SCHIZOPHRENIA (SZ) AND CANCER (CA) HAVE A BROAD SPECTRUM OF CLINICAL PHENOTYPES AND A COMPLEX BIOLOGICAL BACKGROUND, IMPLICATING A LARGE NUMBER OF GENETIC AND EPIGENETIC FACTORS. SZ IS A CHRONIC NEURODEVELOPMENTAL DISORDER SIGNIFIED BY AN INCREASE IN THE EXPRESSION OF APOPTOTIC MOLECULAR SIGNALS, WHEREAS CA IS CONVERSELY CHARACTERIZED BY AN INCREASE IN APPROPRIATE MOLECULAR SIGNALING THAT STIMULATES UNCONTROLLED CELL PROLIFERATION. THE RATHER LOW RISK OF DEVELOPING CA IN PATIENTS SUFFERING FROM SZ IS A HYPOTHESIS THAT IS STILL UNDER DEBATE. RECENT EVIDENCE HAS INDICATED THAT MICRORNAS (MIRNAS OR MIRS), A LARGE GROUP OF SMALL NON?CODING OLIGONOUCLEOTIDES, MAY PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF CA AND MAJOR PSYCHIATRIC DISORDERS, SUCH AS SZ, BIPOLAR DISORDER, AUTISM SPECTRUM DISORDERS, SUICIDALITY AND DEPRESSION, THROUGH THEIR INTERFERENCE WITH THE EXPRESSION OF MULTIPLE GENES. FOR INSTANCE, THE POSSIBLE ROLE OF LET?7, MIR?98 AND MIR?183 AS BIOMARKERS FOR CA AND SZ WAS INVESTIGATED IN OUR PREVIOUS RESEARCH STUDIES. THEREFORE, FURTHER INVESTIGATIONS ON THE EXPRESSION PROFILES OF THESE REGULATORY, SMALL RNA MOLECULES AND THE MOLECULAR PATHWAYS THROUGH WHICH THEY EXERT THEIR CONTROL MAY PROVIDE A PLAUSIBLE EXPLANATION AS TO WHETHER THERE IS A CORRELATION BETWEEN PSYCHIATRIC DISORDERS AND LOW RISK OF DEVELOPING CA. 2016 20 6130 13 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015