RESUMEN
Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.
Asunto(s)
Antipsicóticos/administración & dosificación , Benzodiazepinas/administración & dosificación , Mapeo Encefálico/métodos , Haloperidol/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/patología , Adulto , Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiología , Progresión de la Enfermedad , Femenino , Haloperidol/efectos adversos , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Olanzapina , Esquizofrenia/fisiopatología , Adulto JovenRESUMEN
In this study, a computational mapping technique was used to examine the three-dimensional profile of the lateral ventricles in autism. T1-weighted three-dimensional magnetic resonance images of the brain were acquired from 20 males with autism (age: 10.1+/-3.5 years) and 22 male control subjects (age: 10.7+/-2.5 years). The lateral ventricles were delineated manually and ventricular volumes were compared between the two groups. Ventricular traces were also converted into statistical three-dimensional maps, based on anatomical surface meshes. These maps were used to visualize regional morphological differences in the thickness of the lateral ventricles between patients and controls. Although ventricular volumes measured using traditional methods did not differ significantly between groups, statistical surface maps revealed subtle, highly localized reductions in ventricular size in patients with autism in the left frontal and occipital horns. These localized reductions in the lateral ventricles may result from exaggerated brain growth early in life.
Asunto(s)
Trastorno Autístico/diagnóstico , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Ventrículos Laterales/patología , Imagen por Resonancia Magnética , Adolescente , Mapeo Encefálico , Niño , Dominancia Cerebral/fisiología , Lóbulo Frontal/patología , Humanos , Masculino , Lóbulo Occipital/patología , Valores de ReferenciaRESUMEN
The N-aryl carbamate URB602 (biphenyl-3-ylcarbamic acid cyclohexyl ester) is an inhibitor of monoacylglycerol lipase (MGL), a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Here, we investigated the mechanism by which URB602 inhibits purified recombinant rat MGL by using a combination of biochemical and structure-activity relationship (SAR) approaches. We found that URB602 weakly inhibits recombinant MGL (IC(50) = 223 +/- 63 microM) through a rapid and noncompetitive mechanism. Dialysis experiments and SAR analyses suggest that URB602 acts through a partially reversible mechanism rather than by irreversible carbamoylation of MGL. Finally, URB602 (100 microM) elevates 2-AG levels in hippocampal slice cultures without affecting levels of other endocannabinoid-related substances. Thus, URB602 may provide a useful tool by which to investigate the physiological roles of 2-AG and explore the potential interest of MGL as a therapeutic target.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Compuestos de Bifenilo/farmacología , Encéfalo/efectos de los fármacos , Glicéridos/metabolismo , Monoacilglicerol Lipasas/antagonistas & inhibidores , Amidas , Animales , Ácidos Araquidónicos/química , Ácidos Araquidónicos/farmacología , Compuestos de Bifenilo/química , Encéfalo/metabolismo , Catálisis/efectos de los fármacos , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Endocannabinoides , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Etanolaminas , Células HeLa , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Cinética , Masculino , Monoacilglicerol Lipasas/genética , Monoacilglicerol Lipasas/metabolismo , Organofosfonatos/química , Organofosfonatos/farmacología , Ácidos Palmíticos/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Ratas , Ratas Wistar , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , TransfecciónRESUMEN
The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome, 22q11.2DS) involves cardiac and craniofacial anomalies, marked deficits in visuospatial cognition, and elevated rates of psychosis. Although the mechanism is unknown, characteristic brain alterations may predispose to development of psychosis and cognitive deficits in 22q11DS. We applied cortical pattern matching and new methods for measuring cortical thickness in millimeters to structural magnetic resonance images of 21 children with confirmed 22q11.2 deletions and 13 demographically matched healthy comparison subjects. Thickness was mapped at 65 536 homologous points, based on 3-dimensional distance from the cortical gray-white matter interface to the external gray-cerebrospinal fluid boundary. A pattern of regionally specific cortical thinning was observed in superior parietal cortices and right parietooccipital cortex, regions critical for visuospatial processing, and bilaterally in the most inferior portion of the inferior frontal gyrus (pars orbitalis), a key area for language development. Several of the 30 genes encoded in the deleted segment are highly expressed in the developing brain and known to affect early neuronal migration. These brain maps reveal how haploinsufficiency for such genes can affect cortical development and suggest a possible underlying pathophysiology of the neurobehavioral phenotype.
Asunto(s)
Corteza Cerebral/anatomía & histología , Deleción Cromosómica , Cromosomas Humanos Par 22/fisiología , Envejecimiento/fisiología , Mapeo Encefálico , Niño , Discapacidades del Desarrollo/genética , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/genética , Trastornos Mentales/psicologíaRESUMEN
We mapped the profile of neocortical thickness and complexity in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Thirty preoperative high-resolution magnetic resonance imaging scans were acquired from 15 right (mean age: 31.9 +/- 9.7 standard deviation [SD] years) and 15 left (mean age: 30.8 +/- 8.4 SD years) MTLE patients who were seizure-free for 2 years after anteriomesial temporal resection. Nineteen healthy controls were also scanned (mean age: 24.8 +/- 3.9 SD years). A cortical pattern matching technique mapped thickness across the entire neocortex. Mesial temporal structures were not included in this analysis. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity). Both MTLE groups showed up to 30% bilateral decrease in cortical thickness, in the frontal poles, frontal operculum, orbitofrontal, lateral temporal, and occipital regions. In both groups, cortical complexity was decreased in multiple lobar regions. Significant linkages were found relating longer duration of epilepsy to greater cortical thickness reduction in the superior frontal and parahippocampal gyrus ipsilateral to the side of seizure onset. The pervasive extrahippocampal structural deficits may result from chronic seizure propagation or may reflect other causes such as initial precipitating factors leading to MTLE.
Asunto(s)
Epilepsia del Lóbulo Temporal/patología , Hipocampo/patología , Neocórtex/patología , Adulto , Algoritmos , Mapeo Encefálico , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis , Convulsiones/patología , Convulsiones/fisiopatologíaRESUMEN
Applying a recently developed method to analyze gyrification with excellent spatial resolution across thousands of points across the lateral and medial cortical surface, we mapped differences in cortical surface anatomy between subjects with Williams syndrome (WS; n=42) and an age-matched sample of healthy subjects (n=40). WS subjects showed increased gyrification bilaterally in occipital regions and over the cuneus. Differences were more pronounced in the left hemisphere than in the right, with additional regions of increased gyrification in WS in the left precuneus, posterior and anterior cingulate, paracentral and mesial frontal lobe. No cortical area was significantly more convoluted in healthy subjects relative to the WS subjects. On the lateral surfaces, the direction and pattern of gyrification asymmetries were similar in WS subjects and controls; posterior brain regions had greater gyrification in the left hemisphere, while anterior brain regions showed greater gyrification in the right hemisphere. On the medial surfaces, control subjects and WS individuals differed considerably with respect to the degree but also direction of gyrification asymmetry. Our findings confirm and extend previous studies measuring cortical complexity at the global whole-brain or hemispheric levels. The observed gyrification abnormalities in individuals with WS might be related to dysfunctions in neuronal circuits and consequently contribute to the distinct cognitive and behavioral profile accompanying the disorder.
Asunto(s)
Corteza Cerebral/patología , Síndrome de Williams/patología , Adolescente , Adulto , Algoritmos , Niño , Femenino , Lóbulo Frontal/patología , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Lóbulo Occipital/patologíaRESUMEN
BACKGROUND: Volumetric studies have reported reductions in the size of the corpus callosum (CC) in autism, but the callosal regions contributing to this deficit have differed among studies. In this study, a computational method was used to detect and map the spatial pattern of CC abnormalities in male patients with autism. METHODS: Twenty-four boys with autism (aged 10.0 +/- 3.3 years) and 26 control boys (aged 11.0 +/- 2.5 years) underwent a magnetic resonance imaging (MRI) scan at 3 Tesla. Total and regional areas of the CC were determined using traditional morphometric methods. Three-dimensional (3D) surface models of the CC were also created from the MRI scans. Statistical maps were created to visualize morphologic variability of the CC and to localize regions of callosal thinning in autism. RESULTS: Traditional morphometric methods detected a significant reduction in the total callosal area and in the anterior third of the CC in patients with autism; however, 3D maps revealed significant reductions in both the splenium and genu of the CC in patients. CONCLUSIONS: Statistical maps of the CC revealed callosal deficits in autism with greater precision than traditional morphometric methods. These abnormalities suggest aberrant connections between cortical regions, which is consistent with the hypothesis of abnormal cortical connectivity in autism.
Asunto(s)
Trastorno Autístico/diagnóstico , Trastorno Autístico/fisiopatología , Mapeo Encefálico/métodos , Cuerpo Calloso/fisiopatología , Adolescente , Análisis de Varianza , Niño , Cuerpo Calloso/anatomía & histología , Cuerpo Calloso/patología , Humanos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Valores de ReferenciaRESUMEN
CONTEXT: We previously detected a dynamic wave of gray matter loss in childhood-onset schizophrenia that started in parietal association cortices and proceeded frontally to envelop dorsolateral prefrontal and temporal cortices, including superior temporal gyri. OBJECTIVE: To map gray matter loss rates across the medial hemispheric surface, including the cingulate and medial frontal cortex, in the same cohort studied previously. DESIGN: Five-year longitudinal study. SETTING: National Institute of Mental Health, Bethesda, Md. Subjects Twelve subjects with childhood-onset schizophrenia, 12 healthy controls, and 9 medication- and IQ-matched subjects with psychosis not otherwise specified. INTERVENTIONS: Three-dimensional magnetic resonance imaging at baseline and follow-up. MAIN OUTCOME MEASURES: Gyral pattern and shape variations encoded by means of high-dimensional elastic deformation mappings driving each subject's cortical anatomy onto a group average; changes in cortical gray matter mapped by computing warping fields that matched sulcal patterns across hemispheres, subjects, and time. RESULTS: Selective, severe frontal gray matter loss occurred bilaterally in a dorsal-to-ventral pattern across the medial hemispheric surfaces in the schizophrenic subjects. A sharp boundary in the pattern of gray matter loss separated frontal regions and cingulate-limbic areas. CONCLUSION: Frontal and limbic regions may not be equally vulnerable to gray matter attrition, which is consistent with the cognitive, metabolic, and functional vulnerability of the frontal cortices in schizophrenia.
Asunto(s)
Mapeo Encefálico/métodos , Lóbulo Frontal/patología , Giro del Cíngulo/patología , Esquizofrenia/patología , Adolescente , Factores de Edad , Atrofia , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/patología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Estudios Longitudinales , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Factores SexualesRESUMEN
BACKGROUND: Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. METHODS: We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology. RESULTS: Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. CONCLUSIONS: Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.
Asunto(s)
Nivel de Alerta/fisiología , Encéfalo/metabolismo , Estimulantes del Sistema Nervioso Central/efectos adversos , Glucosa/metabolismo , Metanfetamina/efectos adversos , Pruebas Neuropsicológicas/estadística & datos numéricos , Síndrome de Abstinencia a Sustancias/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Adulto , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico , Femenino , Fluorodesoxiglucosa F18 , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/metabolismo , Giro del Cíngulo/fisiopatología , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Síndrome de Abstinencia a Sustancias/diagnóstico por imagen , Síndrome de Abstinencia a Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/rehabilitaciónRESUMEN
We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of approximately 20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 x 192 x 124 volumes) of 42 subjects with genetically confirmed WS (mean +/- SD, 29.2 +/- 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 +/- 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.
Asunto(s)
Mapeo Encefálico , Corteza Cerebral/anomalías , Corteza Cerebral/patología , Síndrome de Williams/patología , Adolescente , Adulto , Factores de Edad , Estudios de Casos y Controles , Niño , Femenino , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
We visualize, for the first time, the profile of structural deficits in the human brain associated with chronic methamphetamine (MA) abuse. Studies of human subjects who have used MA chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities. Using magnetic resonance imaging (MRI) and new computational brain-mapping techniques, we determined the pattern of structural brain alterations associated with chronic MA abuse in human subjects and related these deficits to cognitive impairment. We used high-resolution MRI and surface-based computational image analyses to map regional abnormalities in the cortex, hippocampus, white matter, and ventricles in 22 human subjects who used MA and 21 age-matched, healthy controls. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of MA abusers (averaging 11.3% below control; p < 0.05). On average, MA abusers had 7.8% smaller hippocampal volumes than control subjects (p < 0.01; left, p = 0.01; right, p < 0.05) and significant white-matter hypertrophy (7.0%; p < 0.01). Hippocampal deficits were mapped and correlated with memory performance on a word-recall test (p < 0.05). MRI-based maps suggest that chronic methamphetamine abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. MA may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, inducing neuroadaptation, neuropil reduction, or cell death. Prominent white-matter hypertrophy may result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage. These brain substrates may help account for the symptoms of MA abuse, providing therapeutic targets for drug-induced brain injury.