1 6736 239 WHAT IS A PSYCHOSIS AND WHERE IS IT LOCATED? KRAEPELIN'S DICHOTOMY, MANIC-DEPRESSIVE INSANITY AND DEMENTIA PRAECOX, ARE CONTRASTING AND TRUE ENDOGENOUS DISEASE ENTITIES WHICH AFFECT EXCITABILITY, THE FUNDAMENTAL PROPERTY OF THE CNS. KRAEPELIN WANTED TO ESTABLISH A VALID CLASSIFICATION AND HIT THE EXTREMES IN BRAIN STRUCTURE AND FUNCTION AT A TIME WHEN WE HAD NO KNOWLEDGE OF BRAIN DYSFUNCTION IN "FUNCTIONAL" PSYCHOSES. THE AETIOLOGY IS NOW KNOWN: THE PSYCHOSES ARE PART OF HUMAN GROWTH AND MATURATION AND MIGHT BE CLASSIFIED ACCORDING TO THEIR BRAIN DYSFUNCTION, WHICH IS EXACTLY WHAT KRAEPELIN WANTED. HOWEVER, PRESUMABLY TO REDUCE THE STIGMA ATTACHED TO THE WORD "PSYCHOSIS", THERE IS CURRENTLY A STRONG INITIATIVE TO ELIMINATE THE CONCEPT. BUT KNOWLEDGE OF WHAT IS HAPPENING IN THE BRAIN IN A PSYCHOSIS MIGHT BE MORE HELPFUL IN REDUCING STIGMA. IT IS SUGGESTED THAT PSYCHOSIS IS DUE TO AN AFFECTION OF THE SUPPLEMENTARY MOTOR AREA (SMA), LOCATED AT THE CENTRE OF THE MEDIAL FRONTAL LOBE NETWORK. THE SMA IS ONE OF THE RARE UNIVERSALLY CONNECTED AREAS OF THE BRAIN, AS SHOULD BE THE CASE FOR SUCH A KEY STRUCTURE THAT MAKES DECISIONS AS TO THE RIGHT MOMENT FOR ACTION. THIS IMPORTANT NETWORK, WHICH PARTLY HAS CONTINUOUS NEUROGENESIS, HAS SUFFICIENTLY WIDESPREAD CONNECTIONS. THE SMA, A PREMOTOR AREA LOCATED ON THE MEDIAL SIDE OF THE FRONTAL LOBES, IS ONE OF THE LAST REGIONS TO REACH A CONCURRENCE OF SYNAPTOGENESIS. AN AFFECTION OF THE SMA, A DEFICIENT OR ABOLISHED DELAYED RESPONSE TASK, SERIOUSLY DISTURBS OUR RELATION AND ADAPTATION TO THE SURROUNDINGS. WE USUALLY MASTER THE DELAYED RESPONSE TASK AROUND THE AGE OF 7 MONTHS, A TIME AT WHICH THE SECOND CNS REGRESSIVE EVENT TAKES PLACE, WHICH PROCEEDS FROM THE POSTERIOR TO THE ANTERIOR OF THE BRAIN. IN VERY LATE MATURATION, A PERSISTENT AFFECTION OF THE SMA MIGHT OCCUR. WE EXPERIENCE A CHRONIC PSYCHOSIS: INFANTILE AUTISM (IA), A CHRONIC INABILITY TO ACT CONSCIOUSLY, WHICH CONTRASTS WITH THE EPISODIC SMA AFFECTION POST-PUBERTY, WHEN EXCITATION IS REDUCED DUE TO EXCESSIVE PRUNING OF EXCITATORY SYNAPSES. SILENT SPOTS ARE THE RESULT OF INSUFFICIENT FILL-IN MECHANISMS FOLLOWING A BREAKDOWN OF CIRCUITRY. THEY MAY AFFECT THE SMA IN THE CASE OF VERY LATE PUBERTY. AN ACUTE REDUCTION IN EXCITATION AND CONCOMITANTLY A MARKED INCREASE IN SILENT SPOTS MIGHT LEAD TO AN ACUTE PSYCHOSIS. A FRONTAL PREFERENCE IS LIKELY, GIVEN THAT A REDUCTION MIGHT OCCUR ANYWHERE IN THE CORTEX, BUT PARTICULARLY IN THE AREAS MATURING LATEST. THE VARYING LOCALISATIONS PROBABLY EXPLAIN THE DIFFICULTY IN ACCEPTING SCHIZOPHRENIA AS A DISEASE ENTITY. THE MULTIFACTORIAL INHERITANCE OF THE DICHOTOMY IMPLIES THAT THE GENETICS ARE NOT FATE, A PSYCHOTIC DEVELOPMENT MIGHT BE PREVENTED GIVEN ENOUGH EPIGENETIC FACTORS: BRAIN FOOD (OMEGA 3). MIGHT THE PRESENT DIETARY ADVERSITY, WITH ITS LACK OF BRAIN FOOD, BE RESPONSIBLE FOR A RISING INCIDENCE IN PSYCHOSIS? A PSYCHOSIS IS AN UNDERSTANDABLE AND PREVENTABLE DYSFUNCTION OF THE BRAIN, AND ITS MECHANISMS ARE KNOWN. PRIMARILY A DISORDER OF REDUCED EXCITATION IN AN ATTENUATED CNS, THIS EXPLAINS WHY ALL THE NEUROLEPTICS ARE CONVULSANTS, RAISING EXCITATION, IN CONTRAST TO ALL ANTIDEPRESSIVES, WHICH ARE ANTI-EPILEPTIC. 2008 2 38 36 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003 3 1736 32 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 4 1796 38 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 5 6184 33 THE IMPACT OF ENVIRONMENTAL FACTORS IN SEVERE PSYCHIATRIC DISORDERS. DURING THE LAST DECADES, SCHIZOPHRENIA HAS BEEN REGARDED AS A DEVELOPMENTAL DISORDER. THE NEURODEVELOPMENTAL HYPOTHESIS PROPOSES SCHIZOPHRENIA TO BE RELATED TO GENETIC AND ENVIRONMENTAL FACTORS LEADING TO ABNORMAL BRAIN DEVELOPMENT DURING THE PRE- OR POSTNATAL PERIOD. FIRST DISEASE SYMPTOMS APPEAR IN EARLY ADULTHOOD DURING THE SYNAPTIC PRUNING AND MYELINATION PROCESS. META-ANALYSES OF STRUCTURAL MRI STUDIES REVEALING HIPPOCAMPAL VOLUME DEFICITS IN FIRST-EPISODE PATIENTS AND IN THE LONGITUDINAL DISEASE COURSE CONFIRM THIS HYPOTHESIS. APART FROM THE INFLUENCE OF RISK GENES IN SEVERE PSYCHIATRIC DISORDERS, ENVIRONMENTAL FACTORS MAY ALSO IMPACT BRAIN DEVELOPMENT DURING THE PERINATAL PERIOD. SEVERAL ENVIRONMENTAL FACTORS SUCH AS ANTENATAL MATERNAL VIRUS INFECTIONS, OBSTETRIC COMPLICATIONS ENTAILING HYPOXIA AS COMMON FACTOR OR STRESS DURING NEURODEVELOPMENT HAVE BEEN IDENTIFIED TO PLAY A ROLE IN SCHIZOPHRENIA AND BIPOLAR DISORDER, POSSIBLY CONTRIBUTING TO SMALLER HIPPOCAMPAL VOLUMES. IN MAJOR DEPRESSION, PSYCHOSOCIAL STRESS DURING THE PERINATAL PERIOD OR IN ADULTHOOD IS AN IMPORTANT TRIGGER. IN ANIMAL STUDIES, CHRONIC STRESS OR REPEATED ADMINISTRATION OF GLUCOCORTICOIDS HAVE BEEN SHOWN TO INDUCE DEGENERATION OF GLUCOCORTICOID-SENSITIVE HIPPOCAMPAL NEURONS AND MAY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF AFFECTIVE DISORDERS. EPIGENETIC MECHANISMS ALTERING THE CHROMATIN STRUCTURE SUCH AS HISTONE ACETYLATION AND DNA METHYLATION MAY MEDIATE EFFECTS OF ENVIRONMENTAL FACTORS TO TRANSCRIPTIONAL REGULATION OF SPECIFIC GENES AND BE A PROMINENT FACTOR IN GENE-ENVIRONMENTAL INTERACTION. IN ANIMAL MODELS, GENE-ENVIRONMENTAL INTERACTION SHOULD BE INVESTIGATED MORE INTENSELY TO UNRAVEL PATHOPHYSIOLOGICAL MECHANISMS. THESE FINDINGS MAY LEAD TO NEW THERAPEUTIC STRATEGIES INFLUENCING EPIGENETIC TARGETS IN SEVERE PSYCHIATRIC DISORDERS. 2014 6 4642 47 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 7 6174 50 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 8 5649 21 SEX DIFFERENCES IN PSYCHOSTIMULANT ABUSE: IMPLICATIONS FOR ESTROGEN RECEPTORS AND HISTONE DEACETYLASES. SUBSTANCE ABUSE IS A CHRONIC PATHOLOGICAL DISORDER THAT NEGATIVELY AFFECTS MANY HEALTH AND NEUROLOGICAL PROCESSES. A GROWING BODY OF LITERATURE HAS REVEALED GENDER DIFFERENCES IN SUBSTANCE USE. COMPARED TO MEN, WOMEN DISPLAY DISTINCT DRUG-USE PHENOTYPES ACCOMPANIED BY RECOVERY AND REHABILITATION DISPARITIES. THESE OBSERVATIONS HAVE LED TO THE NOTION THAT SEX-DEPENDENT SUSCEPTIBILITIES EXIST ALONG THE PROGRESSION TO ADDICTION. WITHIN THIS SCOPE, NEUROADAPTATIONS FOLLOWING PSYCHOSTIMULANT EXPOSURE ARE THOUGHT TO BE DISTINCT FOR EACH SEX. THIS REVIEW SUMMARIZES CLINICAL FINDINGS AND ANIMAL RESEARCH REPORTING SEX DIFFERENCES IN THE SUBJECTIVE AND BEHAVIORAL RESPONSES TO COCAINE, METHAMPHETAMINE, AND NICOTINE. THIS DISCUSSION IS FOLLOWED BY AN EXAMINATION OF EPIGENETIC AND MOLECULAR ALTERATIONS IMPLICATED IN THE ADDICTION PROCESS. SPECIAL CONSIDERATION IS GIVEN TO HISTONE DEACETYLASES AND ESTROGEN RECEPTOR-MEDIATED GENE EXPRESSION. 2022 9 6257 31 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 10 679 23 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021 11 6846 37 [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 12 4277 35 MICROGLIA SEQUELAE: BRAIN SIGNATURE OF INNATE IMMUNITY IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A PSYCHIATRIC DISORDER WITH SIGNIFICANT IMPACT ON INDIVIDUALS AND SOCIETY. THE CURRENT PHARMACOLOGIC TREATMENT, WHICH PRINCIPALLY ALLEVIATES PSYCHOSIS, IS FOCUSED ON NEUROTRANSMITTERS MODULATION, RELYING ON DRUGS WITH SEVERE SIDE EFFECTS AND INEFFECTIVENESS IN A SIGNIFICANT PERCENTAGE OF CASES. THEREFORE, AND DUE TO DIFFICULTIES INHERENT TO DIAGNOSIS AND TREATMENT, IT IS VITAL TO REASSESS ALTERNATIVE CELLULAR AND MOLECULAR DRUG TARGETS. DISTINCT RISK FACTORS - GENETIC, DEVELOPMENTAL, EPIGENETIC, AND ENVIRONMENTAL - HAVE BEEN ASSOCIATED WITH DISEASE ONSET AND PROGRESSION, GIVING RISE TO THE PROPOSAL OF DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS AND PUTATIVE PHARMACOLOGICAL TARGETS. IMMUNITY IS INVOLVED AND, PARTICULARLY MICROGLIA - INNATE IMMUNE CELLS OF THE CENTRAL NERVOUS SYSTEM, CRITICALLY INVOLVED IN BRAIN DEVELOPMENT - HAVE CAPTURED ATTENTION AS CELLULAR PLAYERS. MICROGLIA UNDERGO MARKED MORPHOLOGIC AND FUNCTIONAL ALTERATIONS IN THE HUMAN DISEASE, AS WELL AS IN ANIMAL MODELS OF SCHIZOPHRENIA, AS REPORTED IN SEVERAL ORIGINAL PAPERS. WE CLUSTER THE MAIN FINDINGS OF CLINICAL STUDIES BY GROUPS OF PATIENTS: (1) AT ULTRA-HIGH RISK OF PSYCHOSIS, (2) WITH A FIRST EPISODE OF PSYCHOSIS OR RECENT-ONSET SCHIZOPHRENIA, AND (3) WITH CHRONIC SCHIZOPHRENIA; IN TRANSLATIONAL STUDIES, WE HIGHLIGHT THE TIME WINDOW OF APPEARANCE OF PARTICULAR MICROGLIA ALTERATIONS IN THE MOST WELL STUDIED ANIMAL MODEL IN THE FIELD (MATERNAL IMMUNE ACTIVATION). THE ORGANIZATION OF CLINICAL AND TRANSLATIONAL FINDINGS BASED ON SCHIZOPHRENIA-ASSOCIATED MICROGLIA CHANGES IN DIFFERENT PHASES OF THE DISEASE COURSE MAY HELP DEFINING A TEMPORAL PATTERN OF MICROGLIA CHANGES AND MAY DRIVE THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES. 2022 13 2412 51 EPIGENETIC SIDE-EFFECTS OF COMMON PHARMACEUTICALS: A POTENTIAL NEW FIELD IN MEDICINE AND PHARMACOLOGY. THE TERM "EPIGENETICS" REFERS TO DNA AND CHROMATIN MODIFICATIONS THAT PERSIST FROM ONE CELL DIVISION TO THE NEXT, DESPITE A LACK OF CHANGE IN THE UNDERLYING DNA SEQUENCE. THE "EPIGENOME" REFERS TO THE OVERALL EPIGENETIC STATE OF A CELL, AND SERVES AS AN INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME. THE EPIGENOME IS DYNAMIC AND RESPONSIVE TO ENVIRONMENTAL SIGNALS NOT ONLY DURING DEVELOPMENT, BUT ALSO THROUGHOUT LIFE; AND IT IS BECOMING INCREASINGLY APPARENT THAT CHEMICALS CAN CAUSE CHANGES IN GENE EXPRESSION THAT PERSIST LONG AFTER EXPOSURE HAS CEASED. HERE WE PRESENT THE HYPOTHESIS THAT COMMONLY-USED PHARMACEUTICAL DRUGS CAN CAUSE SUCH PERSISTENT EPIGENETIC CHANGES. DRUGS MAY ALTER EPIGENETIC HOMEOSTASIS BY DIRECT OR INDIRECT MECHANISMS. DIRECT EFFECTS MAY BE CAUSED BY DRUGS WHICH AFFECT CHROMATIN ARCHITECTURE OR DNA METHYLATION. FOR EXAMPLE THE ANTIHYPERTENSIVE HYDRALAZINE INHIBITS DNA METHYLATION. AN EXAMPLE OF AN INDIRECTLY ACTING DRUG IS ISOTRETINOIN, WHICH HAS TRANSCRIPTION FACTOR ACTIVITY. A TWO-TIER MECHANISM IS POSTULATED FOR INDIRECT EFFECTS IN WHICH ACUTE EXPOSURE TO A DRUG INFLUENCES SIGNALING PATHWAYS THAT MAY LEAD TO AN ALTERATION OF TRANSCRIPTION FACTOR ACTIVITY AT GENE PROMOTERS. THIS STIMULATION RESULTS IN THE ALTERED EXPRESSION OF RECEPTORS, SIGNALING MOLECULES, AND OTHER PROTEINS NECESSARY TO ALTER GENETIC REGULATORY CIRCUITS. WITH MORE CHRONIC EXPOSURE, CELLS ADAPT BY AN UNKNOWN HYPOTHETICAL PROCESS THAT RESULTS IN MORE PERMANENT MODIFICATIONS TO DNA METHYLATION AND CHROMATIN STRUCTURE, LEADING TO ENDURING ALTERATION OF A GIVEN EPIGENETIC NETWORK. THEREFORE, ANY EPIGENETIC SIDE-EFFECT CAUSED BY A DRUG MAY PERSIST AFTER THE DRUG IS DISCONTINUED. IT IS FURTHER PROPOSED THAT SOME IATROGENIC DISEASES SUCH AS TARDIVE DYSKINESIA AND DRUG-INDUCED SLE ARE EPIGENETIC IN NATURE. IF THIS HYPOTHESIS IS CORRECT THE CONSEQUENCES FOR MODERN MEDICINE ARE PROFOUND, SINCE IT WOULD IMPLY THAT OUR CURRENT UNDERSTANDING OF PHARMACOLOGY IS AN OVERSIMPLIFICATION. WE PROPOSE THAT EPIGENETIC SIDE-EFFECTS OF PHARMACEUTICALS MAY BE INVOLVED IN THE ETIOLOGY OF HEART DISEASE, CANCER, NEUROLOGICAL AND COGNITIVE DISORDERS, OBESITY, DIABETES, INFERTILITY, AND SEXUAL DYSFUNCTION. IT IS SUGGESTED THAT A SYSTEMS BIOLOGY APPROACH EMPLOYING MICROARRAY ANALYSES OF GENE EXPRESSION AND METHYLATION PATTERNS CAN LEAD TO A BETTER UNDERSTANDING OF LONG-TERM SIDE-EFFECTS OF DRUGS, AND THAT IN THE FUTURE, EPIGENETIC ASSAYS SHOULD BE INCORPORATED INTO THE SAFETY ASSESSMENT OF ALL PHARMACEUTICAL DRUGS. THIS NEW APPROACH TO PHARMACOLOGY HAS BEEN TERMED "PHAMACOEPIGENOMICS", THE IMPACT OF WHICH MAY BE EQUAL TO OR GREATER THAN THAT OF PHARMACOGENETICS. WE PROVIDE HERE AN OVERVIEW OF THIS POTENTIALLY MAJOR NEW FIELD IN PHARMACOLOGY AND MEDICINE. 2009 14 6159 39 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 15 5133 41 POTENTIAL EPIGENETIC MECHANISM(S) ASSOCIATED WITH THE PERSISTENCE OF PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN RECEIVING CHEMOTHERAPY FOR BREAST CANCER: A HYPOTHESIS. DUE TO RECENT TREATMENT ADVANCES, THERE HAVE BEEN IMPROVEMENTS IN THE PROPORTION OF WOMEN SURVIVING A DIAGNOSIS OF BREAST CANCER (BC). HOWEVER, MANY OF THESE SURVIVORS REPORT PERSISTENT ADVERSE SIDE EFFECTS FOLLOWING TREATMENT, SUCH AS COGNITIVE DYSFUNCTION, DEPRESSIVE SYMPTOMS, ANXIETY, FATIGUE, SLEEP DISTURBANCES, AND PAIN. INVESTIGATORS HAVE EXAMINED CIRCULATING LEVELS OF INFLAMMATORY MARKERS, PARTICULARLY SERUM CYTOKINES, FOR A POTENTIAL CAUSAL RELATIONSHIP TO THE DEVELOPMENT/PERSISTENCE OF THESE PSYCHONEUROLOGICAL SYMPTOMS (PNS). WHILE INFLAMMATORY ACTIVATION, RESULTING FROM PERCEIVED STRESS OR OTHER FACTORS, MAY DIRECTLY CONTRIBUTE TO THE DEVELOPMENT OF PNS, WE OFFER AN ALTERNATIVE HYPOTHESIS, SUGGESTING THAT THESE SYMPTOMS ARE AN EARLY STEP IN A CASCADE OF BIOLOGICAL CHANGES LEADING TO EPIGENETIC ALTERATIONS AT THE LEVEL OF DEOXYRIBONUCLEIC ACID (DNA) METHYLATION, HISTONE MODIFICATIONS, AND/OR CHROMATIN STRUCTURE/CHROMOSOMAL INSTABILITY. GIVEN THAT EPIGENETIC PATTERNS HAVE PLASTICITY, IF THIS CONJECTURED RELATIONSHIP BETWEEN EPIGENOMIC/ACQUIRED GENOMIC ALTERATIONS AND THE DEVELOPMENT/PERSISTENCE OF PNS IS CONFIRMED, IT COULD PROVIDE FOUNDATIONAL KNOWLEDGE FOR FUTURE RESEARCH LEADING TO THE RECOGNITION OF PREDICTIVE MARKERS AND/OR TREATMENTS TO ALLEVIATE PNS IN WOMEN WITH BC. IN THIS ARTICLE, WE DISCUSS AN EVOLVING THEORY OF THE BIOLOGICAL BASIS OF PNS, INTEGRATING KNOWLEDGE RELATED TO INFLAMMATION AND DNA REPAIR IN THE CONTEXT OF GENETIC AND EPIGENETIC SCIENCE TO EXPAND THE PARADIGM FOR UNDERSTANDING SYMPTOM ACQUISITION/PERSISTENCE FOLLOWING CHEMOTHERAPY. 2014 16 5047 44 PHARMACOLOGICAL AND THERAPEUTIC APPROACHES IN THE TREATMENT OF EPILEPSY. EPILEPSY AFFECTS AROUND 50 MILLION PEOPLE ACROSS THE GLOBE AND IS THE THIRD MOST COMMON CHRONIC BRAIN DISORDER. IT IS A NON-COMMUNICABLE DISEASE OF THE BRAIN THAT AFFECTS PEOPLE OF ALL AGES. IT IS ACCOMPANIED BY DEPRESSION, ANXIETY, AND SUBSTANTIALLY INCREASED MORBIDITY AND MORTALITY. A LARGE NUMBER OF THIRD-GENERATION ANTI-EPILEPTIC DRUGS ARE AVAILABLE, BUT THEY HAVE MULTIPLE SIDE-EFFECTS CAUSING A DECLINE IN THE QUALITY OF LIFE. THE INHERITANCE AND ETIOLOGY OF EPILEPSY ARE COMPLEX WITH MULTIPLE UNDERLYING GENETIC AND EPIGENETIC MECHANISMS. DIFFERENT NEUROTRANSMITTERS PLAY INTRICATE FUNCTIONS TO MAINTAIN THE NORMAL PHYSIOLOGY OF VARIOUS NEURONS. IF THERE IS ANY DYSREGULATION OF NEUROTRANSMISSION DUE TO ABERRANT TRANSMITTER LEVELS OR THEIR RECEPTOR BIOLOGY, IT CAN RESULT IN SEIZURES. IN THIS REVIEW, WE HAVE DISCUSSED THE ROLES PLAYED BY VARIOUS NEUROTRANSMITTERS AND THEIR RECEPTORS IN THE PATHOPHYSIOLOGY OF EPILEPSY. DRUG-RESISTANT EPILEPSY (DRE) HAS REMAINED ONE OF THE FOREFRONT AREAS OF EPILEPSY RESEARCH FOR A LONG TIME. UNDERSTANDING THE MECHANISMS UNDERLYING DRE IS OF UTMOST IMPORTANCE BECAUSE OF ITS HIGH INCIDENCE RATE AMONG EPILEPSY PATIENTS AND INCREASED RISKS OF PSYCHOSOCIAL PROBLEMS AND PREMATURE DEATH. HERE WE HAVE ENUMERATED VARIOUS HYPOTHESES OF DRE. FURTHER, WE HAVE DISCUSSED DIFFERENT NON-CONVENTIONAL THERAPEUTIC STRATEGIES, INCLUDING COMBINATION THERAPY AND NON-DRUG TREATMENT. THE RECENT STUDIES SUPPORTING THE MODERN APPROACHES FOR THE TREATMENT OF EPILEPSY HAVE BEEN DELIBERATED WITH PARTICULAR REFERENCE TO THE MTOR PATHWAY, BREAKDOWN OF THE BLOOD-BRAIN BARRIER, AND INFLAMMATORY PATHWAYS. 2021 17 6889 36 [S-ADENOSYL L-METHIONINE IN CNS DISEASES]. S-ADENOSYL L-METHIONINE (SAME) IS THE NATURAL, UNIVERSAL METHYL GROUP DONOR, PARTICIPATING IN TRANSMETHYLATION REACTIONS, KNOWN AND COMMONLY USED AS A DIETARY SUPPLEMENT SINCE 1952. IT PLAYS AN IMPORTANT ROLE IN THE SYNTHESIS OF NEUROMEDIATORS AND MELATONIN AND MECHANISMS OF EPIGENETIC REGULATION. THE AIM OF THIS ARTICLE IS TO REVIEW THE LITERATURE ABOUT POSSIBILITIES OF SAME APPLICATION IN THE THERAPY OF CNS DISEASES: DEPRESSION, DEMENTIA SYNDROMES, SCHIZOPHRENIA AND SOMATIC DISORDERS. SAME IS THE PROMISING DIETARY SUPPLEMENT, WHICH MAY BE SUCCESSFULLY USED AS A SUBSTANCE INCREASING EFFECTIVENESS OF THE TREATMENT OF DEPRESSION, WITH ANTIDEPRESSANTS IN MONOTHERAPY IN MILD DEPRESSIVE STATES OR DEPRESSIVE SYMPTOMS. SAME ADDITION TO ANTIPSYCHOTIC DRUG, MAY LEAD TO THE IMPROVEMENT OF THE QUALITY OF LIFE AND REDUCTION OF AGGRESSIVENESS OF PATIENTS. SAME MAY BE AN EFFECTIVE SUBSTANCE IN THE THERAPY AND PROPHYLAXIS OF MILD COGNITIVE IMPAIRMENTS AND MILD DEMENTIA SYNDROME. SAME POSSESSES SOME HEPATOPROTECTIVE ACTION, SO IT MAY DECREASE THE RISK OF THE DEVELOPMENT OF NEOPLASM, ALCOHOL-INDUCED LIVER DISEASE (ALD) AND CIRRHOSIS. SAME IMPROVES THE FUNCTIONS OF JOINTS AND DECREASES THE EXPERIENCE OF PAIN IN RHEUMATOID ARTHRITIS (RA). 2011 18 682 37 BRAIN ON STRESS: HOW THE SOCIAL ENVIRONMENT GETS UNDER THE SKIN. STRESS IS A STATE OF THE MIND, INVOLVING BOTH BRAIN AND BODY AS WELL AS THEIR INTERACTIONS; IT DIFFERS AMONG INDIVIDUALS AND REFLECTS NOT ONLY MAJOR LIFE EVENTS BUT ALSO THE CONFLICTS AND PRESSURES OF DAILY LIFE THAT ALTER PHYSIOLOGICAL SYSTEMS TO PRODUCE A CHRONIC STRESS BURDEN THAT, IN TURN, IS A FACTOR IN THE EXPRESSION OF DISEASE. THIS BURDEN REFLECTS THE IMPACT OF NOT ONLY LIFE EXPERIENCES BUT ALSO GENETIC VARIATIONS AND INDIVIDUAL HEALTH BEHAVIORS SUCH AS DIET, PHYSICAL ACTIVITY, SLEEP, AND SUBSTANCE ABUSE; IT ALSO REFLECTS STABLE EPIGENETIC MODIFICATIONS IN DEVELOPMENT THAT SET LIFELONG PATTERNS OF PHYSIOLOGICAL REACTIVITY AND BEHAVIOR THROUGH BIOLOGICAL EMBEDDING OF EARLY ENVIRONMENTS INTERACTING WITH CUMULATIVE CHANGE FROM EXPERIENCES OVER THE LIFESPAN. HORMONES ASSOCIATED WITH THE CHRONIC STRESS BURDEN PROTECT THE BODY IN THE SHORT RUN AND PROMOTE ADAPTATION (ALLOSTASIS), BUT IN THE LONG RUN, THE BURDEN OF CHRONIC STRESS CAUSES CHANGES IN THE BRAIN AND BODY THAT CAN LEAD TO DISEASE (ALLOSTATIC LOAD AND OVERLOAD). BRAIN CIRCUITS ARE PLASTIC AND REMODELED BY STRESS TO CHANGE THE BALANCE BETWEEN ANXIETY, MOOD CONTROL, MEMORY, AND DECISION MAKING. SUCH CHANGES MAY HAVE ADAPTIVE VALUE IN PARTICULAR CONTEXTS, BUT THEIR PERSISTENCE AND LACK OF REVERSIBILITY CAN BE MALADAPTIVE. HOWEVER, THE CAPACITY OF BRAIN PLASTICITY TO EFFECTS OF STRESSFUL EXPERIENCES IN ADULT LIFE HAS ONLY BEGUN TO BE EXPLORED ALONG WITH THE EFFICACY OF TOP-DOWN STRATEGIES FOR HELPING THE BRAIN CHANGE ITSELF, SOMETIMES AIDED BY PHARMACEUTICAL AGENTS AND OTHER TREATMENTS. 2012 19 2700 42 EXCESS IRON: CONSIDERATIONS RELATED TO DEVELOPMENT AND EARLY GROWTH. WHAT EFFECTS MIGHT ARISE FROM EARLY LIFE EXPOSURES TO HIGH IRON? THIS REVIEW CONSIDERS THE SPECIFIC EFFECTS OF HIGH IRON ON THE BRAIN, STEM CELLS, AND THE PROCESS OF ERYTHROPOIESIS AND IDENTIFIES GAPS IN OUR KNOWLEDGE OF WHAT MOLECULAR DAMAGE MAY BE INCURRED BY OXIDATIVE STRESS THAT IS IMPARTED BY HIGH IRON STATUS IN EARLY LIFE. SPECIFIC AREAS TO ENHANCE RESEARCH ON THIS TOPIC INCLUDE THE FOLLOWING: LONGITUDINAL BEHAVIORAL STUDIES OF CHILDREN TO TEST ASSOCIATIONS BETWEEN IRON EXPOSURES AND MOOD, EMOTION, COGNITION, AND MEMORY; ANIMAL STUDIES TO DETERMINE EPIGENETIC CHANGES THAT REPROGRAM BRAIN DEVELOPMENT AND METABOLIC CHANGES IN EARLY LIFE THAT COULD BE FOLLOWED THROUGH THE LIFE COURSE; AND THE ESTABLISHMENT OF HUMAN EPIGENETIC MARKERS OF IRON EXPOSURES AND OXIDATIVE STRESS THAT COULD BE MONITORED FOR EARLY ORIGINS OF ADULT CHRONIC DISEASES. IN ADDITION, EFFORTS TO UNDERSTAND HOW IRON EXPOSURE INFLUENCES STEM CELL BIOLOGY COULD BE ENHANCED BY ESTABLISHING PLATFORMS TO COLLECT BIOLOGICAL SPECIMENS, INCLUDING UMBILICAL CORD BLOOD AND AMNIOTIC FLUID, TO BE MADE AVAILABLE TO THE RESEARCH COMMUNITY. AT THE MOLECULAR LEVEL, THERE IS A NEED TO BETTER UNDERSTAND STRESS ERYTHROPOIESIS AND CHANGES IN IRON METABOLISM DURING PREGNANCY AND DEVELOPMENT, ESPECIALLY WITH RESPECT TO REGULATORY CONTROL UNDER HIGH IRON CONDITIONS THAT MIGHT PROMOTE INEFFECTIVE ERYTHROPOIESIS AND IRON-LOADING ANEMIA. THESE INVESTIGATIONS SHOULD FOCUS NOT ONLY ON FACTORS SUCH AS HEPCIDIN AND ERYTHROFERRONE BUT SHOULD ALSO INCLUDE NEWLY IDENTIFIED INTERACTIONS BETWEEN TRANSFERRIN RECEPTOR-2 AND THE ERYTHROPOIETIN RECEPTOR. FINALLY, DESPITE OUR UNDERSTANDING THAT SEVERAL KEY MICRONUTRIENTS (E.G., VITAMIN A, COPPER, MANGANESE, AND ZINC) SUPPORT IRON'S FUNCTION IN ERYTHROPOIESIS, HOW THESE NUTRIENTS INTERACT REMAINS, TO OUR KNOWLEDGE, UNKNOWN. IT IS NECESSARY TO CONSIDER MANY FACTORS WHEN FORMULATING RECOMMENDATIONS ON IRON SUPPLEMENTATION. 2017 20 6065 34 THE DEVELOPMENTAL ORIGINS OF CHRONIC PHYSICAL AGGRESSION: BIOLOGICAL PATHWAYS TRIGGERED BY EARLY LIFE ADVERSITY. LONGITUDINAL EPIDEMIOLOGICAL STUDIES WITH BIRTH COHORTS HAVE SHOWN THAT PHYSICAL AGGRESSION IN HUMANS DOES NOT APPEAR SUDDENLY IN ADOLESCENCE AS COMMONLY THOUGHT. IN FACT, PHYSICALLY AGGRESSIVE BEHAVIOUR IS OBSERVED AS EARLY AS 12 MONTHS AFTER BIRTH, ITS FREQUENCY PEAKS AROUND 2-4 YEARS OF AGE AND DECREASES IN FREQUENCY UNTIL EARLY ADULTHOOD. HOWEVER, A MINORITY OF CHILDREN (3-7%) MAINTAIN A HIGH FREQUENCY OF PHYSICAL AGGRESSION FROM CHILDHOOD TO ADOLESCENCE AND DEVELOP SERIOUS SOCIAL ADJUSTMENT PROBLEMS DURING ADULTHOOD. GENETIC FACTORS AND EARLY SOCIAL EXPERIENCES, AS WELL AS THEIR INTERACTION, HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF CHRONIC AGGRESSIVE BEHAVIOUR. HOWEVER, THE BIOLOGICAL MECHANISMS UNDERLYING THESE ASSOCIATIONS ARE JUST BEGINNING TO BE UNCOVERED. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ARE RESPONSIVE TO ADVERSE ENVIRONMENTS AND COULD BE INVOLVED IN THE DEVELOPMENT OF CHRONIC AGGRESSION. USING BOTH GENE CANDIDATE AND GENOMIC APPROACHES, RECENT STUDIES HAVE IDENTIFIED EPIGENETIC MARKS, SUCH AS DNA METHYLATION ALTERATIONS IN GENES INVOLVED IN THE STRESS RESPONSE AND THE SEROTONIN AND IMMUNE SYSTEMS TO BE PARTLY RESPONSIBLE FOR THE LONG-LASTING EFFECTS OF EARLY ADVERSITY. FURTHER LONGITUDINAL STUDIES WITH BIOLOGICAL, ENVIRONMENTAL AND BEHAVIOURAL ASSESSMENTS FROM BIRTH ONWARDS ARE NEEDED TO ELUCIDATE THE SEQUENCE OF EVENTS THAT LEADS TO THESE LONG-LASTING EPIGENETIC MARKS ASSOCIATED WITH EARLY ADVERSITY AND AGGRESSION. 2015