Understanding emotions: origins and roles of the amygdala

Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences of these activations that contribute to neuronal networks mediating thoughts, language, and behavior, thus enhancing the ability to predict, learn, and reappraise stimuli and situations in the environment based on previous experiences. Contemporary theories of emotion converge around the key role of the amygdala as the central subcortical emotional brain structure that constantly evaluates and integrates a variety of sensory information from the surroundings and assigns them appropriate values of emotional dimensions, such as valence, intensity, and approachability. The amygdala participates in the regulation of autonomic and endocrine functions, decision-making and adaptations of instinctive and motivational behaviors to changes in the environment through implicit associative learning, changes in short- and long-term synaptic plasticity, and activation of the fight-or-flight response via efferent projections from its central nucleus to cortical and subcortical structures

Treatment of patients with spinal muscular atrophy in Croatia - positive results from the national registry and new challenges

Spinalna mišićna atrofi ja je autosomno recesivna, progresivna degenerativna bolest uzrokovana mutacijom gena SMN1 (survival of motor neuron 1) na kromosomu 5q. Djelotvorno zbrinjavanje bolesnika i utjecaj standardiziranog terapijskog pristupa radi postizanja kakvoće života zahtijeva multidisciplinski terapijski pristup i koordinaciju velikog broja stručnjaka - užih specijalista. Rana primjena neinvazivne ventilacije i aparata za potpomognuto iskašljavanje te ortopedski pristup rješavanju skolioze značajno povoljno utječu na prirodni tijek bolesti. Uspješan ishod terapijskih postupaka započinje ranom primjenom modifi cirajuće genetičke i genske terapije. Protusmjerni oligonukleotid nusinersen i mala molekula (risdiplam) usmjereni su na uključivanje egzona 7 u SMN2 mRNK te stvaranja stabilnog i funkcionalnog proteina, a genska terapija (onasemnogen abeparvovec) nadomjesna je terapija mutiranog gena SMN1. Rezultati primjene nusinersena upućuju na to da je napredak na testovima motoričkih funkcija najznačajniji u prvih 6 - 12 mjeseci primjene, osobito za spinalnu mišićnu atrofi ju tip 1, uz dobru podnošljivost s malim brojem nuspojava. Rana primjena modifi cirajuće terapije spinalne mišićne atrofi je, ponajprije u tipu 1, povezana je s promjenom prirodnog tijeka i ishoda bolesti u smislu zaustavljanja njene progresije i napretka u razvoju. Zasad nema međunarodno prihvaćenih kriterija za uključivanje bolesnika u gensku i genetičku terapiju prema tipovima, dobi, trajanju bolesti i ovisnosti o trajnoj mehaničkoj ventilaciji. Potrebna su dodatna ispitivanja radi procjene učinkovitosti terapije temeljem procjene motoričkih funkcija i stupnjeva motoričkog razvoja, terapijskog „prozora“, procjene ishoda pomoću biomarkera bolesti, trajanja liječenja, doze lijeka, nuspojava vezanih za dugotrajnu primjenu i ishoda terapije, ponajprije učinka na poremećaje ventilacije i gutanja, učinka na razvoj skolioze, kognitivnog razvoja te rasta i autonomnih funkcija te procjene objektivnosti ljestvica za procjenu motoričkih funkcija. Zaključak. Rano prepoznavanje kliničkih znakova, novorođenački probir i rana genetička dijagnoza, primjena ciljane terapije koja modifi cira tijek bolesti, redovito multidisciplinsko timsko praćenje i liječenje poremećaja disanja, ortopedskih i gastroenteroloških komplikacija bolesti, kao i rani početak tranzicijskog razdoblja neizostavan su dio skrbi o bolesnicima sa spinalnom mišićnom atrofi jom. Radi unapređenja zbrinjavanja i njege bolesnika, kao i standardizacije skrbi o njima značajna je kontinuirana evaluacija kriterija za uključivanje i prekid modifi cirajuće terapije te individualni pristup svakom bolesniku i poticanje osnivanja i redovitog obnavljanja registra bolesnika s neuromuskularnim bolestima s podatcima vezanim za ishod liječenja na nacionalnoj razini i u različitim zemljama širom svijeta, te njihovo međusobno povezivanje i suradnja.Spinal muscular atrophy is an autosomal recessive, progressive degenerative disease caused by mutation of the SMN1 (survival of motor neuron 1) gene on chromosome 5q. Eff ective patient care and success of standardized therapeutic approaches taken to achieve better quality of life require multidisciplinary therapeutic approach and coordination of a large number of specialists. Successful outcome of diagnostic and therapeutic procedures is based on the application of the standardized procedure. It begins with early recognition of clinical signs and symptoms, as well as the risk of complications. Early application of non-invasive ventilation and cough assist device together with orthopaedic approach to scoliosis signifi cantly alter the natural course of the disease. Antisense oligonucleotide (AON) nusinersen and small molecules are directed to enhancing inclusion of exon 7 in SMN2 mRNK and formation of a stable and functional protein, and gene therapy (onasemnogene abeparvovec) is an example of SMN1 gene replacement therapy. Results of treatment with nusinersen show improvement on motor function scales, which is most pronounced in the fi rst 6 to 12 months of therapy in spinal muscular atrophy type I, with good tolerability and safety. Earlier application of modifying therapy for spinal muscular atrophy, primarily for type I, may signifi cantly change of the natural course and outcomes of the disease in terms of halting disease progression, as well as establishing progress in motor development. There are currently no strict internationally accepted criteria for inclusion of diff erent genetic or gene therapies in patients according to disease type or duration, patient age and dependence on permanent mechanical invasive ventilation. Additional studies are required to evaluate therapeutic effi cacy, therapeutic window, duration of treatment, drug dose, side eff ects related to long-term use and treatment outcome, preferably eff ects on ventilation and swallowing, eff ect on cognitive development, scoliosis, growth and autonomic function, and objectivity of the rating scale for motor functions. In conclusion, early genetic diagnosis, neonatal screening and application of target therapy that modifi es the course of the disease, timely monitoring and treatment of respiratory, cardiologic and gastroenterological complications, as well as early onset of the transition period are crucial parts of the care for spinal muscular atrophy patients. In order to improve patient care, it is important to enable treatment possibilities according to standards of care, ongoing evaluation of the criteria for inclusion and termination of modifying therapy, relieving centres for tertiary level of care, reducing the number of disease related hospitalizations and individual access to each patient, along with encouraging the establishment of patient registries for neuromuscular disorders at the national level, as well as in diff erent countries around the world, and their interconnection and cooperation

Phenotypic diversity in patients with CACNA1 gene mutation

Kalcijevi kanali regulirani naponom široko su rasprostranjeni u središnjem živčanom sustavu gdje posreduju utok iona kalcija u stanicu u odgovoru na depolarizaciju. To omogućuje egzocitozu neurotransmitera, regulaciju ekspresije gena i brojne druge fiziološke funkcije. α - podjedinica tvori senzor napona i poru kanala kroz koju ulaze kalcijevi ioni. Poznato je 10 različitih α - podjedinica kodirano CACNA1 genima. Mutacije CACNA1 implicirane su u razvoju brojnih neuroloških poremećaja. Mutacije CACNA1A gena, koji kodira α - podjedinicu P/Q - tipa kalcijevog kanala, dosada su pokazale najveću raznolikost fenotipa. Uzrokuju familijarnu hemiplegičnu migrenu tip 1, vrstu migrene s aurom karakteriziranom hemiplegijom. Epizodička ataksija tip 2 i spinocerebelarna ataksija tip 6 bolesti su koje poglavito oslikavaju zahvaćenost cerebeluma, što nije neuobičajeno budući da su P/Q - kanali tamo široko rasprostranjeni. Epizodička ataksija karakterizirana je povremenim simptomima poremećaja cerebelarne funkcije na početku bolesti, no s vremenom simptomi postaju trajno prisutni, a bolest progresivna. Spinocerebelarna ataksija je sporo progresivna bolest, koja se, u većini slučajeva, javlja u srednjoj do starijoj životnoj dobi. Dostignuća molekularne tehnologije omogućila su identifikaciju ostalih fenotipova. Otkrivena je povezanost mutacija CACNA1A gena s razvojem epileptičke encefalopatije, što je u ovom radu dodatno naglašeno prikazom dvoje pacijenata s tom dijagnozom. Refraktorne epilepsije, zastoj u razvoju i ostali neuropsihijatrijski poremećaji najčešće su posljedica de novo mutacija. Osim CACNA1A, de novo mutacije ostalih CACNA1 gena povezane su s ekspresijom sličnih fenotipova i ukratko prikazane.Voltage-gated calcium channels are expressed abundantly throughout the central nervous system. They mediate calcium influx in cells in response to membrane depolarization. This step is crucial for neurotransmitter exocytosis, regulation of gene expression, and other physiological functions. 10 CACNA1 genes code for alpha subunits that incorporate the voltage sensor and channel pore. CACNA1 encodes the alpha subunit of P/Q - calcium channel. Mutations of many of CACNA1 genes cause neurological disorders. CACNA1A gene mutations hold the greatest phenotypic diversity. Hemiplegia in the aura phase defines familial hemiplegic migraine type 1. Cerebellar dysfunction, as a consequence of high P/Q - channel expression in cerebellum, is best represented by episodic ataxia type 2 and spinocerebellar ataxia type 6. Episodes of cerebellar dysfunction characterize the beginning of episodic ataxia, but symptoms progress and become permanent in the later course of the disease. Spinocerebellar ataxia begins at an older age and progresses slowly. Advances in molecular technology provided the establishment of more phenotypes. A correlation between epileptic encephalopathy and CACNA1A mutations has been observed. This paper presents two patients with the disease and confirms the association. De novo mutations are usually the cause of refractory epilepsy, developmental delay, and various neuropsychiatric disorders. De novo mutations in other CACNA1 genes give rise to similar phenotypes

Phenotypic diversity in patients with CACNA1 gene mutation

Kalcijevi kanali regulirani naponom široko su rasprostranjeni u središnjem živčanom sustavu gdje posreduju utok iona kalcija u stanicu u odgovoru na depolarizaciju. To omogućuje egzocitozu neurotransmitera, regulaciju ekspresije gena i brojne druge fiziološke funkcije. α - podjedinica tvori senzor napona i poru kanala kroz koju ulaze kalcijevi ioni. Poznato je 10 različitih α - podjedinica kodirano CACNA1 genima. Mutacije CACNA1 implicirane su u razvoju brojnih neuroloških poremećaja. Mutacije CACNA1A gena, koji kodira α - podjedinicu P/Q - tipa kalcijevog kanala, dosada su pokazale najveću raznolikost fenotipa. Uzrokuju familijarnu hemiplegičnu migrenu tip 1, vrstu migrene s aurom karakteriziranom hemiplegijom. Epizodička ataksija tip 2 i spinocerebelarna ataksija tip 6 bolesti su koje poglavito oslikavaju zahvaćenost cerebeluma, što nije neuobičajeno budući da su P/Q - kanali tamo široko rasprostranjeni. Epizodička ataksija karakterizirana je povremenim simptomima poremećaja cerebelarne funkcije na početku bolesti, no s vremenom simptomi postaju trajno prisutni, a bolest progresivna. Spinocerebelarna ataksija je sporo progresivna bolest, koja se, u većini slučajeva, javlja u srednjoj do starijoj životnoj dobi. Dostignuća molekularne tehnologije omogućila su identifikaciju ostalih fenotipova. Otkrivena je povezanost mutacija CACNA1A gena s razvojem epileptičke encefalopatije, što je u ovom radu dodatno naglašeno prikazom dvoje pacijenata s tom dijagnozom. Refraktorne epilepsije, zastoj u razvoju i ostali neuropsihijatrijski poremećaji najčešće su posljedica de novo mutacija. Osim CACNA1A, de novo mutacije ostalih CACNA1 gena povezane su s ekspresijom sličnih fenotipova i ukratko prikazane.Voltage-gated calcium channels are expressed abundantly throughout the central nervous system. They mediate calcium influx in cells in response to membrane depolarization. This step is crucial for neurotransmitter exocytosis, regulation of gene expression, and other physiological functions. 10 CACNA1 genes code for alpha subunits that incorporate the voltage sensor and channel pore. CACNA1 encodes the alpha subunit of P/Q - calcium channel. Mutations of many of CACNA1 genes cause neurological disorders. CACNA1A gene mutations hold the greatest phenotypic diversity. Hemiplegia in the aura phase defines familial hemiplegic migraine type 1. Cerebellar dysfunction, as a consequence of high P/Q - channel expression in cerebellum, is best represented by episodic ataxia type 2 and spinocerebellar ataxia type 6. Episodes of cerebellar dysfunction characterize the beginning of episodic ataxia, but symptoms progress and become permanent in the later course of the disease. Spinocerebellar ataxia begins at an older age and progresses slowly. Advances in molecular technology provided the establishment of more phenotypes. A correlation between epileptic encephalopathy and CACNA1A mutations has been observed. This paper presents two patients with the disease and confirms the association. De novo mutations are usually the cause of refractory epilepsy, developmental delay, and various neuropsychiatric disorders. De novo mutations in other CACNA1 genes give rise to similar phenotypes

Understanding emotions: origins and roles of the amygdala

Emotions arise from activations of specialized neuronal populations in several parts of the cerebral cortex, notably the anterior cingulate, insula, ventromedial prefrontal, and subcortical structures, such as the amygdala, ventral striatum, putamen, caudate nucleus, and ventral tegmental area. Feelings are conscious, emotional experiences of these activations that contribute to neuronal networks mediating thoughts, language, and behavior, thus enhancing the ability to predict, learn, and reappraise stimuli and situations in the environment based on previous experiences. Contemporary theories of emotion converge around the key role of the amygdala as the central subcortical emotional brain structure that constantly evaluates and integrates a variety of sensory information from the surroundings and assigns them appropriate values of emotional dimensions, such as valence, intensity, and approachability. The amygdala participates in the regulation of autonomic and endocrine functions, decision-making and adaptations of instinctive and motivational behaviors to changes in the environment through implicit associative learning, changes in short- and long-term synaptic plasticity, and activation of the fight-or-flight response via efferent projections from its central nucleus to cortical and subcortical structures

Personalizing the Care and Treatment of Alzheimer’s Disease: An Overview

Alzheimer's disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally, medications such as antipsychotic drugs, antidepressants, sedative, and hypnotic agents, and mood stabilizers are used for the management of behavioral and psychological symptoms of dementia (BPSD). Clinical research has been extensively investigated treatments focusing on the hallmark pathology of AD, including the amyloid deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes; however, so far without success, as all new potential drugs failed to show significant clinical benefit. The underlying heterogeneous etiology and diverse symptoms of AD suggest that a precision medicine strategy is required, which would take into account the complex genetic, epigenetic, and environmental landscape of each AD patient. The article provides a comprehensive overview of the literature on AD, the current and potential therapy of both cognitive symptoms as well as BPSD, with a special focus on gut microbiota and epigenetic modifications as new emerging drug targets. Their specific patterns could represent the basis for novel individually tailored approaches aimed to optimize precision medicine strategies for AD prevention and treatment. However, the successful application of precision medicine to AD demands a further extensive research of underlying pathological processes, as well as clinical and biological complexity of this multifactorial neurodegenerative disorder