ABSTRACT
The DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth Edition, text Revision) defines attention-deficit/hyperactivity disorder (ADHD) as a disorder usually first diagnosed during infancy. Its essential feature is a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than typically observed in individuals at a comparable level of development. It produces a significant impairment in social, academic, or occupational functioning. The prevalence of ADHD among the general population is between 5-10% in children and adolescents, and 1.2% to 7.3% in adults. In clinical samples, the prevalence in adults is higher: 1 6.80%. Less than 10% of the children diagnosed with ADHD reached a total functional remission when they became adults. Subjects with ADHD have a higher risk of suffering personality disorders and substance abuse. This disorder has a genetic basis. About 80% of the variance is explained by genetics. Some of the genes implied in this disorder are the dopamine transporter, the dopamine receptor 4, the beta-hydroxilase enzyme, the adrenergic receptor α2, the serotonin transporter and the serotonin receptor 1B. Environmental factors such as parental nicotine consumption during pregnancy, low birth weight, perinatal problems, parental psychiatric disorders, social adversity, and low parental education are related to a higher risk for ADHD. Several studies have shown that there are morphological brain abnormalities in subjects with ADHD. Structures like frontal lobe, cerebellar hemispheres and vermis, callosum splenium, cingulate anterior cortex and right caudate, are smaller in subjects with ADHD compared with healthy subjects. On the other hand, regarding the response to stimulants, studies with positron emission tomography (PET), among other techniques, suggest that the dopamine and noradrenergic systems play a role in the pathophysiology of ADHD. From 1990 to date, there are 41 morphological studies in ADHD, published in English, reporting volumetric abnormalities. However, the results are contradictory, so definitive conclusions about the brain structures being involved in ADHD remain unclear. Objective This article reviews the general neurobiology of ADHD providing an updated and comprehensive overview of the brain structural findings. The methodologies of morphological studies using magnetic resonance imaging (MRI) are reviewed in detail so as to find the source of the contradictory findings reported in the published studies. Method A literature search and review of the relevant published articles in MEDLINE and PsycINFO sites was made using the following key words: attention deficit hyperactivity disorder, neurobiology, morphological alteration, and MRI. In general, the literature supports the genetic basis of the disorder as well as the involvement of dopaminergic and noradrenergic systems in the pathophysiology. Nevertheless, regarding the structural abnormalities reported in ADHD, there is an enormously heterogeneous methodology in MRI scan acquisition and processing. Almost every study used a different image analysis to measure brain structures. Some works chose a hand user definition of the region of interest (ROI), which is prone to a user's bias. Other papers used a semi-automated analysis combining a user-defined ROI and segmentation techniques based only in intensity. These methodologies are prone to bias and to a deficient separation of grey and white matter. Finally, the automated methods where there is no user intervention are preferred because they are not a biased in the selection of ROI and use tissue probability maps to improve the segmentation. Unfortunately, none of these methods has been validated against histological and anatomopatological data. So, there is not a measure of validity and reliability of these methods. On the other hand, female subjects are extremely underrepresented in these studies: only around 20% of the individuals studied were females and only 50% of the ADHD samples included female subjects, whereas 95% included males. The number of reports done in ADHD adults is very scarce. Discussion Despite the multiple inconsistencies found in each MRI study as a consequence of limitations such as small samples size, and methodological differences across the studies such as lack of consistency in the acquisition and the image analysis, the structures more frequently and consistently reported to be smaller in ADHD subjects, compared to healthy subjects, are regions of the frontal lobe, the callosum splenium, the anterior cingulate gyrus, the vermis, the cerebral hemispheres and the right caudate. However, these findings are applicable to the most frequently studied samples: male children. Considering the prevalence and lack of complete remission of ADHD symptoms during adulthood, there is a need for structural studies in adults as well as in women. Conclusion The findings and results of MRI studies represent clear but insufficient advances in the knowledge of the anatomical structures involved in ADHD. There is a lack of research on the age-related changes imposed by neurodevelopment. The brain abnormalities and their gender differences in ADHD individual are subjects of future research.
El trastorno por déficit de atención e hiperactividad (TDAH) se caracteriza por un patrón persistente de inatención y/o hiperactividad e impulsividad y produce un deterioro en diversas áreas del funcionamiento del individuo. La prevalencia del TDAH en niños y adolescentes en la población general es de 5-10% y en adultos es de 1.2 a 7.3%. Menos del 10% de los niños que fueron diagnosticados con TDAH alcanzan una remisión funcional total en la edad adulta. Estos sujetos presentan más riesgo de sufrir un trastorno grave de la personalidad así como de dependencia a substancias. Cerca del 80% de la varianza del TDAH se explica por factores genéticos. Los genes que han sido asociados al TDAH con más frecuencia son aquellos que codifican al transportador de dopamina, al receptor de dopamina D4, a la enzima beta-hidroxilasa, al receptor adrenérgico a2, al transportador de serotonina y al receptor de serotonina 1B. Existen variables medioambientales asociadas al TDAH; como el consumo materno de tabaco durante el embarazo, las complicaciones perinatales, la psicopatología de los padres, y la adversidad psicosocial. Por otra parte, la respuesta a los estimulantes así como los estudios hechos con tomografía por emisión de positrones, sugieren que la dopamina y los sistemas noradrenérgicos tienen un papel en la fisiopatología del TDAH. Desde 1990 a la fecha, se han realizado 41 estudios morfológicos del TDAH que han reportado anormalidades volumétricas. Sin embargo, los resultados son contradictorios, lo que no permite obtener conclusiones definitivas acerca de las estructuras involucradas en el trastorno. Objetivo El presente artículo presenta una revisión general de la neurobiología del TDAH y una actualización de las anomalías estructurales encefálicas en los sujetos con TDAH por medio del uso de imágenes por resonancia magnética (IRM). Se han revisado en detalle las metodologías usadas en los estudios estructurales con el fin de conocer el origen de los hallazgos contradictorios en los estudios publicados hasta la fecha. Métodos Se realizó una búsqueda en la bibliografía médica de los artículos publicados en las bases MEDLINE y PsycINFO, con las siguientes palabras clave: TDAH, neurobiología, alteraciones morfológicas e imágenes por resonancia magnética. Resultados Los estudios sobre las anormalidades estructurales en el TDAH muestran una enorme heterogeneidad en la metodología de la adquisición y del procesamiento de las IRM. Por otro lado, la mayoría de los estudios se han realizado en niños del sexo masculino. Existen pocos artículos realizados en sujetos del sexo femenino y en adultos. Discusión A pesar de las inconsistencias encontradas en cada estudio de IRM, las estructuras encefálicas que se reportan reducidas en los sujetos TDAH son: el lóbulo frontal, el esplenio calloso, el cíngulo anterior, el vermis cerebeloso, los hemisferios del cerebelo y el núcleo caudado derecho. Dada la alta prevalencia del TDAH y la falta de remisión de síntomas en la población adulta, es necesario realizar más estudios estructurales en sujetos adultos y femeninos. Conclusión Los resultados obtenidos en los estudios de IRM constituyen avances claros pero insuficientes en el conocimiento de las estructuras anatómicas involucradas en el TDAH. Las anormalidades encefálicas entre los sujetos TDAH y las diferencias de edad y género entre estos sujetos deben ser los objetivos de futuras investigaciones.
ABSTRACT
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Abstract: The most recent technologies of cerebral imaging provide new data about cerebral abnormalities in patients with diverse psychiatric disorders. These methods include computed tomography (CT), magnetic resonance (MRI), electro magnetic (EMEKG), functional magnetic resonance (MRIf), positron emission tomography (PET), single photon emission computed tomography (SPECT), quantitative electroencephalography (QEEG), and evoked potentials (Eps), among others. Illnesses such as anxiety disorders, depressive disorders, dementing disorders, obsessive compulsive disorder, schizophrenia, bipolar disorder, learning disorders, and attention-deficit/ hyperactivity disorder (ADHD), are now considered the result of an interaction between environmental factors and abnormal function and structure of the brain. Data obtained from studies in ADHD subjects indicate a biological basis for this disorder. The specific anatomical and functional alterations of the brain in these patients, has been possible thanks to neuro-imaging. Satterfield & Dawson, in 1971, were pioneers proposing that the ADHD symptoms were related to a malfunction of the fronto-limbic circuits. They said that the normal fronto- cortical inhibitory control exerted over the limbic system is weak in patients with ADHD. This hypothesis was known as the "fronto limbic hypothesis of ADHD"; although, the results of the research derived from diverse disciplines such as neuropsychology, neuro-imaging, and neuro biochemistry, suggest that Satterfield & Dawson were partially right, in fact the neurobiology of ADHD would be more complex than they originally supposed. Almost every research done with neuropsychological methods in ADHD patients points to the same results: a malfunction in the frontal cortex. Damage in the orbital area of the human frontal cortex produ ces social disinhibition and impulsivity; also injury to dorsolateral prefrontal cortex (DLPFC), causes deficit in the ability of behavioral organization, planning, working memory and attention. The findings of neuropsychological research point toward dysfunction to the orbito frontal cortex and DLPFC in subjects with ADHD. With the advance of the new neuroimaging techniques, the results delivered from the clinical and neuropsychological observations can be validated; when used in combination they can give us detailed information about the anatomic areas involved. The early structural studies made in subjects with ADHD were done using CT. Unfortunately the poor resolution and the lack of quantitative measurement of the CT, besides of the small sample size of subjects using diverse methods of clinical diagnosis, and the difficulty to find healthy controls; made the results of these early studies with CT inconsistent. The results reported by different authors were contradictory, since some of them reported no abnormality at all in subjects with ADHD, and some others found frontal and cerebellar atrophy in patients with ADHD. The studies made with MRI improved the quality of the structural studies done in subjects with ADHD. At the same time, the improvement of the diagnostic tools in regard to validity and reliability, and the inclusion of adequate control groups; made the results obtained from these new studies to overcome the deficits of the studies that were made with CT. The studies made with MRI found a decrease in the size of corpus callosum, basal ganglia, particularly in left globus pallidus, and cerebellum; and atrophy of the right frontal cortex and a change in the total cerebral volume. On the other hand the studies made with techniques such as PET, SPECT and functional magnetic resonance, have found a decrease in cerebral blood flow (CBF) in the frontal lobes, striatum and cerebellum in subjects with ADHD. The studies with SPECT made by several groups of researchers have shown increase of the CBF frontal cortex and the caudate nucleus, and decrease of the CBF of the occipital cortex; however, almost all these studies included small sample sizes and used inadequate control groups. Other studies made with PET in adults with ADHD have shown a decrease of the metabolism of the frontal cortex; however, different groups of researchers have reported different findings, possibly due to methodological variations across the studies. Again the majority of these studies used small sample sizes. The studies made with MRIf show that the fronto-stratial circuits work differently in subjects with ADHD when they are compared with controls. Again almost all the published studies included a small sample size. In particular, the results from the studies done by Bush C. et al in 1999 using MRIf combined with a neuropsychological test named "Counting Stroop", showed a lack of activation of the anterior cingulate gyrus in subjects with ADHD compared with controls. The PET technology can study the brain chemistry invivo. Some researchers have found a decrease ofdopamine reuptake in the prefrontal and medial cortex and an increase in the mesencephalon in patients with ADHD. Some studies have found an increase of the dopamine transporter density in the striatum in subjects with ADHD. In conclusion: the neuropsychological studies and the studies of neuroimaging, suggest that the fronto-stratial circuit in the right side plus the cerebellar influence are involved in the neurobiology of ADHD. The cortex-striatum-thalamic circuit selects, starts and executes cognitive and motor complex responses, and the cerebellar circuits provide the guide for these functions. The hypothetical implications of the data contributed by the findings with neuroimaging techniques in ADAH are at this time only tentative. Reproduction of this data for independent researchers is needed. Besides, it is necessary to perform more detailed subdivisions of the brain areas implicated in ADHD. The low statistical power due to the cohort small size included in almost all of these studies is an important problem because of the high anatomical variability of brain measurements. Besides just a few of the published studies controlled the previous exposure to medications for ADHD. Finally, there are no studies in other circuits that play a role in the attention such as those formed by the thalamic pulvinar, the parietal inferior cortex, the primary sensory area, and the postero-inferior parietal cortex. However, the research using methods of structural and functional imaging surely will be valuable in the future, in order to improve our understanding of the anatomical and functional physiopathology ofADHD and ofthe other psychiatric disorders.