Affective neuroscience of ADHD: current data and future directions

Universidad de MálagaEl trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno de origen neurobiológico complejo y heterogéneo que se caracteriza no sólo por sus disfunciones cognitivas sino también por la existencia de importantes alteraciones afectivas, tanto motivacionales como emocionales. Sin embargo, los correlatos neurobiológicos que subyacen a las disfunciones afectivas del TDAH apenas han sido explorados, en comparación con la extensa investigación llevada a cabo sobre los mecanismos neurales implicados en sus principales déficit cognitivos (atención, inhibición de respuesta y memoria de trabajo). Este trabajo revisa las recientes investigaciones que han explorado las bases neurales involucradas en las alteraciones motivacionales y emocionales mostradas por las personas con TDAH. Asimismo, se discuten las implicaciones prácticas derivadas de los resultados de estos estudios y se proponen nuevas líneas de investigación desde la Neurociencia afectiva.Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder that is characterized not only by cognitive deficits but also by affective dysfunctions, both motivational and emotional. Nevertheless, the neural bases of affective dysfunctions have barely been explored in relation to this disorder, in contrast to extensive research that examined the neural correlates of its main cognitive deficits (attention, response inhibition and working memory). This article reviews the available data regarding the neurobiological substrates of motivational and emotional alterations showed by children, adolescents and adults with ADHD. Practical implications derived from these data are discussed and future research directions from affective neuroscience are suggested.Estudio financiado por el Ministerio de Ciencia e Innovación (PSI2008-03688) y la Comunidad de Madrid/Universidad Autónoma de Madrid (CCG08-UAM/SAL-4463)

Genetics applied to clinical practice in neurodevelopmental disorders

Las evidencias genéticas de los trastornos del neurodesarrollo están ampliamente sustentadas en la literatura médica. Los avances en la genética y la tecnología han incrementado la rentabilidad diagnóstica de los estudios actuales de un 3-5% a un 30-40% en los pacientes con discapacidad intelectual o trastornos del espectro autista. En este sentido, los estudios por microarrays cromosómicos muestran un mayor poder diagnóstico que las técnicas convencionales (cariotipo, análisis de subtelómeros…). Los protocolos más recientes en el apartado biomédico del estudio genético de estos trastornos sitúan los microarrays cromosómicos como análisis de primera línea, recomendando otros estudios específicos según las características clínicas del paciente (síndrome X frágil, mutación en PTEN...). En la evaluación de otros trastornos del neurodesarrollo (trastorno por déficit de atención/hiperactividad, trastornos del aprendizaje...), la realización de pruebas genéticas está limitada y condicionada a las características clínicas o antecedentes familiares o personales del paciente; incluso en estas situaciones, no existen protocolos de evaluación o derivación genéticaThe medical literature contains a wide body of evidence supporting genetic involvement in neurodevelopmental disorders. Advances made in genetics and technology have increased the diagnostic cost-effectiveness of current studies from 3-5% to 30-40% in patients with intellectual disability or autism spectrum disorders. In this regard, chromosomal microarray studies display greater diagnostic power than conventional techniques (karyotype, subtelomeric analyses, etc.). The latest protocols in the biomedical field of the genetic study of these disorders cite chromosomal microarrays as the first-line analysis, while also recommending other specific studies depending on the patient’s clinical features (fragile X syndrome, PTEN mutation, etc.). In the evaluation of other neurodevelopmental disorders (attention deficit hyperactivity disorder, learning disorders, etc.), the number of genetic tests carried out is limited and conditioned by the clinical characteristics or the patient’s familial or personal history. Even in these situations, there are no genetic referral or evaluation protocol

Neurociencia afectiva del TDAH: Datos existentes y direcciones futuras

Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder that is characterized not only by cognitive deficits but also by affective dysfunctions, both motivational and emotional. Nevertheless, the neural bases of affective dysfunctions have barely been explored in relation to this disorder, in contrast to extensive research that examined the neural correlates of its main cognitive deficits (attention, response inhibition and working memory). This article reviews the available data regarding the neurobiological substrates of motivational and emotional alterations showed by children, adolescents and adults with ADHD. Practical implications derived from these data are discussed and future research directions from affective neuroscience are suggested.El trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno de origen neurobiológico complejo y heterogéneo que se caracteriza no sólo por sus disfunciones cognitivas sino también por la existencia de importantes alteraciones afectivas, tanto motivacionales como emocionales. Sin embargo, los correlatos neurobiológicos que subyacen a las disfunciones afectivas del TDAH apenas han sido explorados, en comparación con la extensa investigación llevada a cabo sobre los mecanismos neurales implicados en sus principales déficit cognitivos (atención, inhibición de respuesta y memoria de trabajo). Este trabajo revisa las recientes investigaciones que han explorado las bases neurales involucradas en las alteraciones motivacionales y emocionales mostradas por las personas con TDAH. Asimismo, se discuten las implicaciones prácticas derivadas de los resultados de estos estudios y se proponen nuevas líneas de investigación desde la Neurociencia afectiva

The development of selective stopping: qualitative and quantitative changes from childhood to early adulthood

Although progress has been made in elucidating the behavioral and neural development of global stopping across the lifespan, little is known about the development of selective stopping. This more complex form of inhibitory control is required in real-world situations where ongoing responses must be inhibited to certain stimuli but not others, and can be assessed in laboratory settings using a stimulus selective stopping task. Here we used this task to investigate the qualitative and quantitative developmental changes in selective stopping in a large-scale cross-sectional study with three different age groups (children, preadolescents, and young adults). We found that the ability to stop a response selectively to some stimuli (i.e., use a selective strategy) rather than non-selectively to all presented stimuli (i.e., use a global, non-selective strategy) is fully mature by early preadolescence, and remains stable afterwards at least until young adulthood. By contrast, the efficiency or speed of stopping (indexed by a shorter stop-signal reaction time or SSRT) continues to mature throughout adolescence until young adulthood, both for global and selective implementations of stopping. We also provide some preliminary findings regarding which other task variables beyond the strategy and SSRT predicted age group status. Premature responding (an index of “waiting impulsivity”) and post-ignore slowing (an index of cognitive control) were among the most relevant predictors in discriminating between developmental age groups. Although present results need to be confirmed and extended in longitudinal studies, they provide new insights into the development of a relevant form of inhibitory controlThis work was supported by grants PSI2017-84922-R (Ministerio de Economía y Competitividad (MINECO, Spain) and SI1/PJI/2019-00061 (Comunidad de Madrid, Spain; V PRICIT

Diurnal source apportionment of organic and inorganic atmospheric particulate matter at a high-altitude mountain site under summer conditions (Sierra Nevada; Spain)

This work was supported by the CuanTox (CTM2015-71832-P), Intempol (PGC2018-102288-B-I00) and BioCloud project (RTI2018.101154.A.I00) funded by MCIN/AEI/10.13039/501100011033 and FEDER "ERDF a way of making Europe" and NUCLEUS project (PID2021-128757OB-I00) funded by MCIN/AEI/10.13039/501100011033 and the "European Union NextGenerationEU/PRTR". The study was partially funded by the European Union's Horizon 2020 research and innovation program through project ACTRIS.IMP (grant agreement No 871115) and ATMO_ACCESS (grant agreement No 101008004), by the Spanish Ministry of Science and Innovation through projects ELPIS (PID2020-120015RB-I00), and ACTRIS-Espana (RED2022-134824-E), by the Junta de Andalucia Excellence project ADAPNE (P20-00136) and AEROPRE (P-18-RT -3820). This research was partially supported by University of Granada Plan Propio through Singular Laboratory AGORA (LS2022-1) and Scientific Units of Excellence Program (grant no. UCE-PP2017-02). IDAEA-CSIC is a Severo Ochoa Centre of Research Excellence (Spanish Ministry of Science and Innovation, CEX2018-000794-S). Funding from Generalitat de Catalunya, Research Group 2021SGR00986, is acknowledged. C.J. thanks the financial support from a Training of University Teachers (FPU 19/06826) grant from the Ministry of Science and Innovation (Spain).High-altitude mountain areas are sentinel ecosystems for global environmental changes such as anthropogenic pollution. In this study, we report a source apportionment of particulate material with an aerodynamic diameter smaller than 10 μm (PM10) in a high-altitude site in southern Europe (Sierra Nevada Station; SNS (2500 m a.s.l.)) during summer 2021. The emission sources and atmospheric secondary processes that determine the composition of aerosol particles in Sierra Nevada National Park (Spain) are identified from the concentrations of organic carbon (OC), elemental carbon (EC), 12 major inorganic compounds, 18 trace elements and 44 organic molecular tracer compounds in PM10 filter samples collected during day- and nighttime. The multivariate analysis of the joint dataset resolved five main PM10 sources: 1) Saharan dust, 2) advection from the urbanized valley, 3) local combustion, 4) smoke from a fire-event, and 5) aerosol from regional recirculation with high contribution of particles from secondary inorganic and organic aerosol formation processes. PM sources were clearly associated with synoptic meteorological conditions, and day- and nighttime circulation patterns typical of mountainous areas. Although a local pollution source was identified, the contribution of this source to PM10, OC and EC was small. Our results evidence the strong influence of middle- and long-range transport of aerosols, mainly from anthropogenic origin, on the aerosol chemical composition at this remote site.CuanTox CTM2015-71832-PIntempol PGC2018-102288-B-I00MCIN/AEI RTI2018.101154.A.I00, PID2021-128757OB-I00Marie Curie ActionsEuropean Union (EU)European Union's Horizon 2020 research and innovation program through project ACTRIS.IMP 871115ATMO_ACCESS 101008004Spanish Government PID2020-120015RB-I00ACTRIS-España RED2022-134824-EJunta de Andalucia P20-00136AEROPRE P-18-RT -3820University of Granada Plan Propio LS2022-1Scientific Units of Excellence Program UCE-PP2017-02Severo Ochoa Centre of Research Excellence (Spanish Ministry of Science and Innovation) CEX2018-000794-SGeneralitat de Catalunya 2021SGR00986Spanish Government FPU 19/0682

Functional and structural deficiencies of Gemin5 variants associated with neurological disorders

Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)-like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protei

Attention deficit/hyperactivity disorde: Study habits

El trastorno por déficit de atención/hiperactividad (TDAH) es uno de los trastornos más prevalentes en la población infanto-juvenil, con un impacto ya conocido sobre el aprendizaje y rendimiento escolar. La falta de atención, la disfunción ejecutiva asociada y los problemas comórbidos –particularmente los relacionados con el aprendizaje y la ansiedad–, condicionan marcadamente este dominio conceptual. Los jóvenes afectos, tienen más problemas para la toma de apuntes, finalización de trabajos, programación escolar y menor motivación al estudio. A pesar de una mayor dedicación al estudio y mayor uso de recursos de apoyo, el fracaso escolar y la no consecución de objetivos curriculares son más frecuentes en estos pacientes. El diagnóstico temprano del TDAH y sus comorbilidades, la intervención psicoeducativa y farmacológica adecuada e individualizada, han demostrado mejorar el pronóstico académico a corto y largo plazo. Para este propósito, es imprescindible la participación activa de profesionales de la salud y la educaciónAttention deficit / hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child-youth population, with a known impact on learning and school performance. Lack of attention, associated executive dysfunction and comorbid problems –particularly those related to learning and anxiety–, strongly determine this conceptual domain. Affected youths have more problems for taking notes, completion of homework, school programming and less motivation to study. Despite greater dedication to homework and greater use of support resources, school failure and nonachievement of curricular objectives are more frequent in these patients. The early diagnosis of ADHD and its comorbidities, the adequate and individualized psychoeducational and pharmacological intervention, have been shown to improve academic prognosis in the short and long term. For this purpose, the active participation of health and education professionals is essential.Este estudio fue financiado por el Ministerio de Economía, Industria y Competitividad (proyecto PSI2017-84922-R

Eficacia de una vía de alta resolución en la evaluación del cólico renoureteral no complicado en un servicio de urgencias hospitalario: un ensayo clínico aleatorizado (Estudio STONE).

Objetivo. Evaluar una vía de alta resolución (vía POC) que utiliza análisis en el punto de atención (point-of-care testing –POCT–) y ecografía en el punto de atención (point-of-care ultrasonography –POCUS–) en la sospecha del cólico renoureteral (CRU) no complicado y compararla con la vía estándar (vía STD). Método. Ensayo clínico aleatorizado, controlado, no ciego, realizado en un servicio de urgencias hospitalario (SUH). Incluyó pacientes con sospecha clínica de CRU agudo y se aleatorizaron 1:1 a seguir vía POC o vía STD. Se analizó el tiempo de estancia en el SUH, el tratamiento administrado, la proporción de diagnósticos alternativos a CRU y las complicaciones a 30 días. Resultados. Entre noviembre de 2018 y octubre de 2019, se reclutaron 140 pacientes de los que se analizaron 124. El tiempo de estancia total en el SUH de la vía POC fue de 112 minutos (DE 45) y en la vía STD 244 minutos (DE 102) (p < 0,001). No hubo diferencias en el tratamiento administrado en urgencias, en el número de diagnósticos alternativos, ni en las complicaciones a 30 días. Conclusiones. La utilización de una vía de alta resolución del manejo del CRU en un SUH es eficaz, segura y reduce el tiempo de estancia en urgencias.post-print225 K

Mutations in phospholipase C eta-1 ( PLCH1 ) are associated with holoprosencephaly

Funder: NIHR Cambridge Biomedical Research centreBackground: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. Methods: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. Results: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. Conclusion: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype

Mutations in phospholipase C eta-1 ( PLCH1 ) are associated with holoprosencephaly

Funder: NIHR Cambridge Biomedical Research centreBackground: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. Methods: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. Results: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. Conclusion: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype