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1.
Cell ; 184(24): 5886-5901.e22, 2021 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-34822784

RESUMEN

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Receptor Muscarínico M1/agonistas , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Inhibidores de la Colinesterasa/farmacología , Cricetulus , Cristalización , Modelos Animales de Enfermedad , Perros , Donepezilo/farmacología , Electroencefalografía , Femenino , Células HEK293 , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación de Dinámica Molecular , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Primates , Ratas , Receptor Muscarínico M1/química , Transducción de Señal , Homología Estructural de Proteína
2.
Mov Disord ; 36(8): 1879-1888, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33973693

RESUMEN

BACKGROUND: Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear. OBJECTIVE: To investigate spatial covariance patterns of cholinergic muscarinic M1 /M4 receptors in PD and their relationship with cognition and motor symptoms. METHODS: Some 19 PD and 24 older adult controls underwent 123 I-iodo-quinuclidinyl-benzilate (QNB) (M1 /M4 receptor) and 99m Tc-exametazime (perfusion) single-photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M1 /M4 spatial covariance patterns associated with PD. RESULTS: A cholinergic M1 /M4 pattern that converged onto key hubs of the default, auditory-visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F1,41  = 135.4, P < 0.001). In PD, we derived M1 /M4 patterns that correlated with global cognition (r = -0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M1 /M4 pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks. CONCLUSIONS: Cholinergic muscarinic M1 /M4 modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M1 /M4 binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Disfunción Cognitiva , Enfermedad de Parkinson , Anciano , Encéfalo , Colinérgicos , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único
3.
Br J Clin Pharmacol ; 87(7): 2945-2955, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33351971

RESUMEN

AIMS: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. METHODS: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects. RESULTS: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. CONCLUSION: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.


Asunto(s)
Enfermedad de Alzheimer , Adulto , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos
4.
Br J Clin Pharmacol ; 87(11): 4439-4449, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33891333

RESUMEN

AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.


Asunto(s)
Colinérgicos , Receptores Colinérgicos , Anciano , Área Bajo la Curva , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos
5.
Int J Obes (Lond) ; 43(3): 523-532, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30568264

RESUMEN

BACKGROUND: While gross measures of brain structure have shown alterations with increasing body mass index (BMI), the extent and nature of such changes has varied substantially across studies. Here, we sought to determine whether small-scale morphometric measures might prove more sensitive and reliable than larger scale measures and whether they might offer a valuable opportunity to link cortical changes to underlying white matter changes. To examine this, we explored the association of BMI with millimetre-scale Gaussian curvature, in addition to standard measures of morphometry such as cortical thickness, surface area and mean curvature. We also assessed the volume and integrity of the white matter, using white matter signal intensity and fractional anisotropy (FA). We hypothesised that BMI would be linked to small-scale changes in Gaussian curvature and that this phenomenon would be mediated by changes in the integrity of the underlying white matter. METHODS: The association of global measures of T1-weighted cortical morphometry with BMI was examined using linear regression and mediation analyses in two independent groups of healthy young to middle aged human subjects (n1 = 52, n2 = 202). In a third dataset of (n3 = 897), which included diffusion tensor images, we sought to replicate the significant associations established in the first two datasets, and examine the potential mechanistic link between BMI-associated cortical changes and global FA. RESULTS: Gaussian curvature of the white matter surface showed a significant, positive association with BMI across all three independent datasets. This effect was mediated by a negative association between the integrity of the white matter and BMI. CONCLUSIONS: Increasing BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults. Our results are consistent with a model whereby BMI-linked cortical changes are mediated by the effects of BMI on white matter microstructure.


Asunto(s)
Índice de Masa Corporal , Encéfalo/patología , Sustancia Blanca/patología , Adolescente , Adulto , Anisotropía , Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Obesidad/diagnóstico por imagen , Obesidad/epidemiología , Obesidad/patología , Sustancia Blanca/diagnóstico por imagen , Adulto Joven
6.
Hum Psychopharmacol ; 34(3): e2694, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31124194

RESUMEN

OBJECTIVE: This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. METHODS: Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. RESULTS: The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma ß-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. CONCLUSION: Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.


Asunto(s)
Cognición/efectos de los fármacos , Triglicéridos/farmacología , Ácido 3-Hidroxibutírico/sangre , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Método Doble Ciego , Electroencefalografía/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Neuronas/fisiología , Pruebas Neuropsicológicas , Triglicéridos/efectos adversos
7.
Nat Rev Neurosci ; 14(6): 401-16, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23674053

RESUMEN

Increasing evidence suggests that synaptic dysfunction is a key pathophysiological hallmark in neurodegenerative disorders, including Alzheimer's disease. Understanding the role of brain-derived neurotrophic factor (BDNF) in synaptic plasticity and synaptogenesis, the impact of the BDNF Val66Met polymorphism in Alzheimer's disease-relevant endophenotypes - including episodic memory and hippocampal volume - and the technological progress in measuring synaptic changes in humans all pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis. This article reviews the key issues in translating BDNF biology into synaptic repair therapies.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/fisiología , Factor Neurotrófico Derivado del Encéfalo/uso terapéutico , Terapia Molecular Dirigida/métodos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Humanos , Neurogénesis/genética , Plasticidad Neuronal/genética , Polimorfismo de Nucleótido Simple/fisiología , Receptor trkB/agonistas , Receptor trkB/metabolismo
8.
Hum Psychopharmacol ; 30(5): 341-9, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25900350

RESUMEN

OBJECTIVE: While the role of dopamine in modulating executive function, working memory and associative learning has been established; its role in word learning and language processing more generally is not clear. This preliminary study investigated the impact of increased synaptic dopamine levels on new-word learning ability in healthy young adults using an explicit learning paradigm. METHOD: A double-blind, placebo-controlled, between-groups design was used. Participants completed five learning sessions over 1 week with levodopa or placebo administered at each session (five doses, 100 mg). Each session involved a study phase followed by a test phase. Test phases involved recall and recognition tests of the new (non-word) names previously paired with unfamiliar objects (half with semantic descriptions) during the study phase. RESULTS: The levodopa group showed superior recall accuracy for new words over five learning sessions compared with the placebo group and better recognition accuracy at a 1-month follow-up for words learnt with a semantic description. CONCLUSIONS: These findings suggest that dopamine boosts initial lexical acquisition and enhances longer-term consolidation of words learnt with semantic information, consistent with dopaminergic enhancement of semantic salience.


Asunto(s)
Dopaminérgicos/farmacología , Lenguaje , Aprendizaje/efectos de los fármacos , Levodopa/farmacología , Adulto , Dopaminérgicos/administración & dosificación , Método Doble Ciego , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Levodopa/administración & dosificación , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Proyectos Piloto , Reconocimiento en Psicología/efectos de los fármacos , Adulto Joven
9.
Neuroimage ; 90: 280-9, 2014 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-24384148

RESUMEN

BACKGROUND: The brain-derived neurotrophic factor (BDNF) val66met polymorphism is associated with altered activity dependent secretion of BDNF and a variable influence on brain morphology and cognition. Although a met-dose effect is generally assumed, to date the paucity of met-homozygotes have limited our understanding of the role of the met-allele on brain structure. METHODS: To investigate this phenomenon, we recruited sixty normal healthy subjects, twenty in each genotypic group (val/val, val/met and met/met). Global and local morphology were assessed using voxel based morphometry and surface reconstruction methods. White matter organisation was also investigated using tract-based spatial statistics and constrained spherical deconvolution tractography. RESULTS: Morphological analysis revealed an "inverted-U" shaped profile of cortical changes, with val/met heterozygotes most different relative to the two homozygous groups. These results were evident at a global and local level as well as in tractography analysis of white matter fibre bundles. CONCLUSION: In contrast to our expectations, we found no evidence of a linear met-dose effect on brain structure, rather our results support the view that the heterozygotic BDNF val66met genotype is associated with cortical morphology that is more distinct from the BDNF val66met homozygotes. These results may prove significant in furthering our understanding of the role of the BDNF met-allele in disorders such as Alzheimer's disease and depression.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Encéfalo/anatomía & histología , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Alelos , Imagen de Difusión Tensora , Femenino , Genotipo , Heterocigoto , Homocigoto , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Adulto Joven
10.
Int J Neuropsychopharmacol ; 17(2): 199-209, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24160414

RESUMEN

It has been hypothesised that the mechanisms modulating social affiliation are regulated by reward circuitry. Oxytocin, previously shown to support affiliative behaviour and the processing of socio-emotional stimuli, is expressed in areas of the brain involved in reward and motivation. However, limited data are available that test if oxytocin is directly involved in reward learning, or whether oxytocin can modulate the effect of emotion on reward learning. In a double-blind, randomised, placebo-controlled, within-group study design, 24 typical male volunteers were administered 24 IU of oxytocin or placebo and subsequently completed an affective reward learning task. Oxytocin selectively reduced performance of learning rewards, but not losses, from happy faces. The mechanism by which oxytocin may be exerting this effect is discussed in terms of whether oxytocin is affecting identity recognition via affecting the salience of happy faces. We conclude that oxytocin detrimentally affects learning rewards from happy faces in certain contexts.


Asunto(s)
Expresión Facial , Relaciones Interpersonales , Aprendizaje/fisiología , Oxitocina/farmacología , Reconocimiento Visual de Modelos/fisiología , Recompensa , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Aprendizaje/efectos de los fármacos , Masculino , Reconocimiento Visual de Modelos/efectos de los fármacos , Estimulación Luminosa/métodos , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Adulto Joven
11.
Int J Neuropsychopharmacol ; 18(2)2014 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-25552432

RESUMEN

BACKGROUND: Evidence suggests that individuals with social anxiety demonstrate vigilance to social threat, whilst the peptide hormone oxytocin is widely accepted as supporting affiliative behaviour in humans. METHODS: This study investigated whether oxytocin can affect attentional bias in social anxiety. In a double-blind, randomized, placebo-controlled, within-group study design, 26 healthy and 16 highly socially anxious (HSA) male volunteers (within the HSA group, 10 were diagnosed with generalized social anxiety disorder) were administered 24 IU of oxytocin or placebo to investigate attentional processing in social anxiety. Attentional bias was assessed using the dot-probe paradigm with angry, fearful, happy and neutral face stimuli. RESULTS: In the baseline placebo condition, the HSA group showed greater attentional bias for emotional faces than healthy individuals. Oxytocin reduced the difference between HSA and non-socially anxious individuals in attentional bias for emotional faces. Moreover, it appeared to normalize attentional bias in HSA individuals to levels seen in the healthy population in the baseline condition. The biological mechanisms by which oxytocin may be exerting these effects are discussed. CONCLUSIONS: These results, coupled with previous research, could indicate a potential therapeutic use of this hormone in treatment for social anxiety.


Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Atención/efectos de los fármacos , Emociones/efectos de los fármacos , Oxitocina/farmacología , Psicotrópicos/farmacología , Adolescente , Adulto , Trastornos de Ansiedad/psicología , Método Doble Ciego , Cara , Expresión Facial , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento Visual de Modelos/efectos de los fármacos , Estimulación Luminosa , Tiempo de Reacción/efectos de los fármacos , Conducta Social , Adulto Joven
12.
Int J Neuropsychopharmacol ; 17(5): 705-13, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24405657

RESUMEN

The brain-derived neurotropic factor (BDNF) Val66Met polymorphism has been associated with abnormalities of synaptic plasticity in animal models, and abnormalities in motor cortical plasticity have also been described in humans using transcranial direct current stimulation. No study has yet been done on plasticity in non-motor regions, and the effect of two Met alleles (i.e. 'Met dose') is not well understood. We studied the effect of the BDNF Val66Met polymorphism on the after-effects of transcranial direct current stimulation and tetanic auditory stimulation in 65 subjects (23; Val66Val, 22; Val66Met and 20; Met66Met genotypes). In the first session, motor evoked potentials (MEP) were recorded under stereotaxic guidance for 90 min after 9 min of anodal transcranial direct current stimulation (TDCS). In the second session, auditory-evoked potentials (AEP) were recorded before and after 2 min of auditory 13 Hz tetanic stimulation. There was a difference in MEP facilitation post-TDCS comparing Met carriers with non-Met carriers, with Met carriers having a modest late facilitation at 30-90 min. There was no difference in responses between Val66Met genotype and Met66Met genotype subjects. Tetanic auditory stimulation also produced late facilitation of N1-P2 AEP at 25 min, but there was no apparent effect of genetic status. This study indicates that Met66Met carriers behave like Val66Met carriers for TDCS-induced plasticity, and produce a late facilitation of MEPs. Auditory cortical plasticity was not affected by the BDNF Val66Met polymorphism. This study sheds light on the differences between auditory and motor cortical plasticity and the role of the BDNF Val66Met polymorphism.


Asunto(s)
Corteza Auditiva/fisiología , Percepción Auditiva , Factor Neurotrófico Derivado del Encéfalo/genética , Corteza Motora/fisiología , Plasticidad Neuronal , Polimorfismo de Nucleótido Simple , Estimulación Acústica , Adulto , Alelos , Percepción Auditiva/genética , Estimulación Eléctrica , Potenciales Evocados Auditivos/genética , Potenciales Evocados Motores/genética , Femenino , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Plasticidad Neuronal/genética , Estimulación Magnética Transcraneal , Adulto Joven
13.
J Psychiatry Neurosci ; 39(4): 267-75, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24690370

RESUMEN

BACKGROUND: Acute neural effects of antidepressant medication on emotion processing biases may provide the foundation on which clinical outcomes are based. Along with effects on positive and negative stimuli, acute effects on neutral stimuli may also relate to antidepressant efficacy, yet these effects are still to be investigated. The present study therefore examined the impact of a single dose of the selective serotonin reuptake inhibitor escitalopram (20 mg) on positive, negative and neutral stimuli using pharmaco-fMRI. METHODS: Within a double-blind, randomized, placebo-controlled crossover design, healthy women completed 2 sessions of treatment administration and fMRI scanning separated by a 1-week washout period. RESULTS: We enrolled 36 women in our study. When participants were administered escitalopram relative to placebo, left amygdala activity was increased and right inferior frontal gyrus (IFG) activity was decreased during presentation of positive pictures (potentiation of positive emotion processing). In contrast, escitalopram was associated with decreased left amygdala and increased right IFG activity during presentation of negative pictures (attenuation of negative emotion processing). In addition, escitalopram decreased right IFG activity during the processing of neutral stimuli, akin to the effects on positive stimuli (decrease in negative appraisal). LIMITATIONS: Although we used a women-only sample to reduce heterogeneity, our results may not generalize to men. Potential unblinding, which was related to the subjective occurrence of side effects, occurred in the study; however, manipulation check analyses demonstrated that results were not impacted. CONCLUSION: These novel findings demonstrate that a single dose of the commonly prescribed escitalopram facilitates a positive information processing bias. These findings provide an important lead for better understanding effects of antidepressant medication.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Citalopram/farmacología , Emociones/efectos de los fármacos , Emociones/fisiología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Mapeo Encefálico , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Imagen por Resonancia Magnética , Estimulación Luminosa , Percepción Visual/efectos de los fármacos , Percepción Visual/fisiología
14.
BMC Psychiatry ; 14: 99, 2014 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-24693962

RESUMEN

BACKGROUND: Gray and white matter brain changes have been found in schizophrenia but the anatomical organizing process underlying these changes remains unknown. We aimed to identify gray and white matter volumetric changes in a group of patients with schizophrenia and to quantify the distribution of white matter tract changes using a novel approach which applied three complementary analyses to diffusion imaging data. METHODS: 21 patients with schizophrenia and 21 matched control subjects underwent brain magnetic resonance imaging. Gray and white matter volume differences were investigated using Voxel-based Morphometry (VBM). White matter diffusion changes were located using Tract Based Spatial Statistics (TBSS) and quantified within a standard atlas. Tracts where significant regional differences were located were examined using fiber tractography. RESULTS: No significant differences in gray or white matter volumetry were found between the two groups. Using TBSS the schizophrenia group showed significantly lower fractional anisotropy (FA) compared to the controls in regions (false discovery rate <0.05) including the genu, body and splenium of the corpus callosum and the left anterior limb of the internal capsule (ALIC). Using fiber tractography, FA was significantly lower in schizophrenia in the corpus callosum genu (p = 0.003). CONCLUSIONS: In schizophrenia, white matter diffusion deficits are prominent in medial frontal regions. These changes are consistent with the results of previous studies which have detected white matter changes in these areas. The pathology of schizophrenia may preferentially affect the prefrontal-thalamic white matter circuits traversing these regions.


Asunto(s)
Encéfalo/patología , Trastornos Psicóticos/patología , Esquizofrenia/patología , Sustancia Blanca/patología , Adulto , Anisotropía , Mapeo Encefálico , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto Joven
15.
Curr Neuropharmacol ; 12(3): 281-8, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24851092

RESUMEN

There has been a great deal of interest recently in genetic effects on neurocognitive performance in the healthy population. KIBRA -a postsynaptic protein from the WWC family of proteins- was identified in 2003 in the human brain and kidney and has recently been associated with memory performance and synaptic plasticity. Through genome-wide screening, a single nucleotide polymorphism (SNP) was detected in the ninth intron of KIBRA gene (T→ C substitution) and was implicated in human memory and the underlying neuronal circuitry. This review presents a synopsis of the current findings on the effects of the KIBRA SNP on human memory and synaptic plasticity. Overall the findings suggest impaired memory performance and less efficient or impaired hippocampal/medial temporal lobe (MTL) activation in CC homozygotes (in comparison to T carriers) with some differences between young and older subjects. This review also highlights limitations and potential sources for variability of studies' imaging findings along with future perspectives and implications for the role of KIBRA in memory-related brain systems.

16.
Aust N Z J Psychiatry ; 48(12): 1115-25, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24810870

RESUMEN

OBJECTIVE: Benefit from antidepressant treatment such as selective serotonin reuptake inhibitors (SSRIs) may depend on individual differences in acute effects on neural emotion processing. The short ('S') allele of the serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) is associated with both negative emotion processing biases and poorer treatment outcomes. Therefore, the aim of the present study was to explore the effects of 5-HTTLPR on the impact of the SSRI escitalopram during processing of positive and negative emotional images, as well as neutral stimuli. METHODS: The study employed a double-blind, randomised, placebo-controlled crossover design on 36 healthy Caucasian female participants who underwent functional magnetic resonance imaging (fMRI) scanning following placebo or escitalopram treatment, separated by a 7-day washout period. RESULTS: Changes in the left amygdala signal with escitalopram treatment during processing of emotional stimuli were linearly related to the 5-HTTLPR 'S' allele load such that the signal to positive stimuli decreased and the signal to negative stimuli increased with an increasing number of low-expressing 'S' alleles. While 5-HTTLPR subgroups were small in size, individual subject changes with treatment and task condition increase confidence in the findings. CONCLUSIONS: While preliminary, our findings comprise the first pharmacogenetic study demonstrating an effect of the 5-HTTLPR 'S' allele load on escitalopram-induced changes in amygdala activity during emotional processing, consistent with a 5-HTT expression dosage model. The present findings have implications for the impact of this polymorphism on antidepressant efficacy in patients with mood and anxiety disorders.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Citalopram/farmacología , Emociones/efectos de los fármacos , Genotipo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adolescente , Adulto , Alelos , Amígdala del Cerebelo/metabolismo , Mapeo Encefálico , Estudios Cruzados , Método Doble Ciego , Emociones/fisiología , Femenino , Neuroimagen Funcional , Dosificación de Gen , Humanos , Imagen por Resonancia Magnética , Polimorfismo de Nucleótido Simple , Adulto Joven
17.
J Neurosci ; 32(8): 2619-27, 2012 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-22357846

RESUMEN

How the brain monitors ongoing behavior for performance errors is a central question of cognitive neuroscience. Diminished awareness of performance errors limits the extent to which humans engage in corrective behavior and has been linked to loss of insight in a number of psychiatric syndromes (e.g., attention deficit hyperactivity disorder, drug addiction). These conditions share alterations in monoamine signaling that may influence the neural mechanisms underlying error processing, but our understanding of the neurochemical drivers of these processes is limited. We conducted a randomized, double-blind, placebo-controlled, cross-over design of the influence of methylphenidate, atomoxetine, and citalopram on error awareness in 27 healthy participants. The error awareness task, a go/no-go response inhibition paradigm, was administered to assess the influence of monoaminergic agents on performance errors during fMRI data acquisition. A single dose of methylphenidate, but not atomoxetine or citalopram, significantly improved the ability of healthy volunteers to consciously detect performance errors. Furthermore, this behavioral effect was associated with a strengthening of activation differences in the dorsal anterior cingulate cortex and inferior parietal lobe during the methylphenidate condition for errors made with versus without awareness. Our results have implications for the understanding of the neurochemical underpinnings of performance monitoring and for the pharmacological treatment of a range of disparate clinical conditions that are marked by poor awareness of errors.


Asunto(s)
Concienciación/efectos de los fármacos , Concienciación/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Estado de Conciencia/efectos de los fármacos , Estado de Conciencia/fisiología , Inhibición Psicológica , Adolescente , Adulto , Análisis de Varianza , Clorhidrato de Atomoxetina , Mapeo Encefálico , Citalopram/farmacología , Estudios Cruzados , Método Doble Ciego , Giro del Cíngulo/irrigación sanguínea , Giro del Cíngulo/efectos de los fármacos , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Metilfenidato/farmacología , Pruebas Neuropsicológicas , Oxígeno , Lóbulo Parietal/irrigación sanguínea , Lóbulo Parietal/efectos de los fármacos , Estimulación Luminosa , Propilaminas/farmacología , Tiempo de Reacción/efectos de los fármacos , Factores de Tiempo , Adulto Joven
18.
J Cogn Neurosci ; 25(4): 649-56, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23163418

RESUMEN

Response inhibition, comprising action cancellation and action restraint, and error awareness are executive functions of considerable clinical relevance to neuropsychiatric disorders. Nevertheless, our understanding of their underlying catecholamine mechanisms, particularly regarding dopamine, is limited. Here, we used the dopamine D2 agonist cabergoline to study its ability to improve inhibitory control and modulate awareness of performance errors. A randomized, double-blind, placebo-controlled, crossover design with a single dose of cabergoline (1.25 mg) and placebo (dextrose) was employed in 25 healthy participants. They each performed the stop-signal task, a well-validated measure of action cancellation, and the Error Awareness Task, a go/no-go measure of action restraint and error awareness, under each drug condition. Cabergoline was able to selectively reduce stop-signal RT, compared with placebo, indicative of enhanced action cancellation (p < .05). This enhancement occurred without concomitant changes in overall response speed or RT variability and was not seen for errors of commission on the Error Awareness Task. Awareness of performance errors on the go/no-go task was, however, significantly improved by cabergoline compared with placebo (p < .05). Our results contribute to growing evidence for the dopaminergic control of distinct aspects of human executive ability, namely, action cancellation and error awareness. The findings may aid the development of new, or the repurposing of existing, pharmacotherapy that targets the cognitive dysfunction of psychiatric and neurological disorders. They also provide further evidence that specific cognitive paradigms have correspondingly specific neurochemical bases.


Asunto(s)
Concienciación , Inhibición Psicológica , Desempeño Psicomotor/fisiología , Receptores de Dopamina D2/metabolismo , Adolescente , Adulto , Concienciación/efectos de los fármacos , Cabergolina , Agonistas de Dopamina/farmacología , Método Doble Ciego , Ergolinas/farmacología , Humanos , Masculino , Actividad Motora/efectos de los fármacos , Pruebas Neuropsicológicas , Desempeño Psicomotor/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Detección de Señal Psicológica/efectos de los fármacos , Factores de Tiempo , Adulto Joven
19.
Int J Neuropsychopharmacol ; 16(2): 255-60, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22647521

RESUMEN

The neuropeptide oxytocin (OXT) plays an important role in complex socio-affective behaviours such as affiliation, attachment, stress and anxiety. Previous studies have focused on the amygdala as an important target of OXT's effects. However, the effects of OXT on connectivity of the amygdala with cortical regions such as medial frontal cortex, an important mediator of social cognition and emotion regulation, remain unexplored. In a randomized, double-blind, cross-over design, 15 volunteers received intranasal OXT or placebo prior to resting-state functional magnetic resonance imaging. OXT significantly increased connectivity between both amygdalae and rostral medial frontal cortex (rmFC), while having only negligible effects on coupling with other brain regions. These results demonstrate that OXT is a robust and highly selective enhancer of amygdala connectivity with rmFC, a region critical to social cognition and emotion regulation, and add to our understanding of the neural mechanisms by which OXT modulates complex social and cognitive behaviours.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Oxitocina/farmacología , Descanso/fisiología , Adulto , Amígdala del Cerebelo/irrigación sanguínea , Método Doble Ciego , Lóbulo Frontal/irrigación sanguínea , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/irrigación sanguínea , Oxígeno/sangre , Adulto Joven
20.
Int J Neuropsychopharmacol ; 16(4): 721-31, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-22932339

RESUMEN

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.


Asunto(s)
Conducta Adictiva/psicología , Bencimidazoles/uso terapéutico , Trastornos del Conocimiento/psicología , Memoria Episódica , Receptor Muscarínico M1/agonistas , Cese del Hábito de Fumar/psicología , Adulto , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Conducta Adictiva/tratamiento farmacológico , Bencimidazoles/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Nicotina , Receptor Muscarínico M1/fisiología , Fumar/psicología , Adulto Joven
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