RESUMEN
The climate warming implies an increase of stress of plants (drought and torrential rainfall). The understanding of plant behavior, in this context, takes a major importance and sap flow measurement in plants remains a key issue for plant understanding. Magnetic Resonance Imaging (MRI) which is well known to be a powerful tool to access water quantity can be used to measure moving water. We describe a novel flow-MRI method which takes advantage of inflow slice sensitivity. The method involves the slice selectivity in the context of multi slice spin echo sequence. Two sequences such as a given slice is consecutively inflow and outflow sensitive are performed, offering the possiblility to perform slow flow sensitive imaging in a quite straigthforward way. The method potential is demonstrated by imaging both a slow flow measurement on a test bench (as low as 10 µm.s-1) and the Poiseuille's profile of xylemian sap flow velocity in the xylematic tissues of a tomato plant stem.
Asunto(s)
Imagen por Resonancia Magnética , Solanum lycopersicum/metabolismo , Cambio Climático , Solanum lycopersicum/fisiología , Estrés Fisiológico , Agua/metabolismoRESUMEN
Nuclear Magnetic Resonance spectroscopy and imaging can be classified as inductive techniques working in the near- to far-field regimes. We investigate an alternative capacitive detection with the use of micrometer sized probes positioned at sub wavelength distances of the sample in order to characterize and model evanescent electromagnetic fields originating from NMR phenomenon. We report that in this experimental configuration the available NMR signal is one order of magnitude larger and follows an exponential decay inversely proportional to the size of the emitters. Those investigations open a new road to a better understanding of the evanescent waves component in NMR with the opportunity to perform localized spectroscopy and imaging.
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Capacidad Eléctrica , Electrodos , Campos Electromagnéticos , Espectroscopía de Resonancia Magnética/instrumentaciónRESUMEN
Hemidystonia is usually 'secondary' to structural lesions within the cortico-striato-pallido-thalamic or the cerebello-thalamo-cortical loops. Globus pallidus internus Deep Brain Stimulation (GPi DBS) is a validated technique in the treatment of primary dystonia and still under assessment for secondary dystonia. Results of DBS in hemidystonia are limited and heterogeneous. Further knowledge concerning motor network organization after focal brain lesions might contribute to the understanding of this mitigated response to DBS and to the refinement of DBS indications and techniques in secondary dystonia. This study aimed to identify movement-related functional magnetic resonance imaging (fMRI) activation patterns in a group of hemidystonic patients in comparison to healthy controls (HC). Further analysis assessed recruitment pattern in different patient subgroups defined according to clinical and radiological criteria relevant to GPi DBS eligibility (hyperkinetic/hypokinetic and prepallidal/postpallidal). Eleven patients and nine HC underwent fMRI with a block-design alternating active and rest conditions. The motor paradigm consisted of self-paced elbow flexion-extension movements. The main results were as follows: single-subject studies revealed several activation patterns involving motor-related network regions; both ipsilesional and contralesional hemispheres showed abnormal patterns of activity; compared with HC, hemidystonic patients showed decreased brain activity in ipsilesional thalamus, pallidal and temporal areas during affected arm task execution; 'hypokinetic' subgroup was commonly related to widespread bilateral overactivity. This study provides additional arguments for case-by-case assessment of DBS surgery indication and target selection in hemidystonia. Single-lead approach might be unable to modulate a highly disorganized network activity in certain patients with this clinical syndrome.
Asunto(s)
Encéfalo/fisiopatología , Estimulación Encefálica Profunda , Trastornos Distónicos/fisiopatología , Trastornos Distónicos/terapia , Actividad Motora/fisiología , Adulto , Anciano , Niño , Vías Eferentes/fisiopatología , Codo/fisiopatología , Femenino , Lateralidad Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Plasticidad Neuronal , Descanso , Adulto JovenRESUMEN
BACKGROUND: No reliable biomarkers are identified in KLS. However, few functional neuroimaging studies suggested hypoactivity in thalamic and hypothalamic regions during symptomatic episodes. Here, we investigated relative changes in regional brain metabolism in Kleine-Levin syndrome (KLS) during symptomatic episodes and asymptomatic periods, as compared to healthy controls. METHODS: Four drug-free male patients with typical KLS and 15 healthy controls were included. 18-F-fluorodeoxy glucose positron emission tomography (PET) was obtained in baseline condition in all participants, and during symptomatic episodes in KLS patients. All participants were asked to remain fully awake during the whole PET procedure. RESULTS: Between state-comparisons in KLS disclosed higher metabolism in paracentral, precentral, and postcentral areas, supplementary motor area, medial frontal gyrus, thalamus and putamen during symptomatic episodes, and decreased metabolism in occipital and temporal gyri. As compared to healthy control subjects, KLS patients in the asymptomatic phase consistently exhibited significant hypermetabolism in a wide cortical network including frontal and temporal cortices, posterior cingulate and precuneus, with no detected hypometabolism. In symptomatic KLS episodes, hypermetabolism was additionally found in orbital frontal and supplementary motor areas, insula and inferior parietal areas, and right caudate nucleus, and hypometabolism in the middle occipital gyrus and inferior parietal areas. CONCLUSION: Our results demonstrated significant hypermetabolism and few hypometabolism in specific but widespread brain regions in drug-free KLS patients at baseline and during symptomatic episodes, highlighting the behavioral state-dependent nature of changes in regional brain activity in KLS.
Asunto(s)
Encéfalo/metabolismo , Síndrome de Kleine-Levin/metabolismo , Adolescente , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Neuroimagen Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Síndrome de Kleine-Levin/diagnóstico por imagen , Masculino , CintigrafíaRESUMEN
PURPOSE: To determine whether the range of normal variation of human olfactory functional magnetic resonance imaging (fMRI) activations in healthy single subjects is compatible with the detection of atypical patterns. MATERIALS AND METHODS: In an event-related olfactory experiment, the variability of fMRI activation in six bilateral olfactory areas known to be affected in neurodegenerative diseases was measured in a region of interest (ROI) analysis in terms of intensity, localization, and overlap on 51 subjects. fMRI measurements were compared against measurements from a visual experiment performed on 25 subjects. RESULTS: Olfaction induced activations with low intensity, high variability, and a 4-fold lower contrast-to-noise ratio (CNR) than vision. Even in the best case (piriform cortex), mean pairwise activation overlap was still less than 40%. None of the olfactory ROIs showed significant activation for all subjects at the permissive threshold of P < 0.001. A gender-dependent significantly stronger activation was found in the bilateral piriform cortex of male subjects. CONCLUSION: Linking t-statistics and CNR showed that for all olfactory ROIs, CNR is either near or below the estimated threshold of 0.73 found to be necessary to obtain significant activations. In our experimental conditions the low reliability of olfactory activations should prompt major reservations over using fMRI of human olfaction as a diagnostic tool in single subjects.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Olfato/fisiología , Adolescente , Adulto , Encéfalo/patología , Encéfalo/fisiología , Mapeo Encefálico/métodos , Estudios de Cohortes , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Vías Olfatorias/fisiología , Reproducibilidad de los Resultados , Relación Señal-RuidoRESUMEN
OBJECTIVE: To improve diagnosis of early Alzheimer's disease (AD), i.e., prodromal AD, by an automated quantitative tool combining brain perfusion single-photon emission computed tomography (SPECT) images and memory tests scores in order to be applied in clinical practice. PATIENTS AND METHODS: In this prospective, longitudinal, multi-centric study, a baseline (99m)Tc-ECD perfusion SPECT was performed in 83 patients with memory complaint and mild cognitive impairment (MCI). After a 3-year follow-up, 11 patients progressed to Alzheimer's disease (MCI-AD group), and 72 patients remained stable (MCI-S group), including 1 patient who developed mild vascular cognitive impairment. After comparison between the MCI-S and MCI-AD groups with a voxel-based approach, region masks were extracted from the statistically significant clusters and used alone or in combination with Free and Cued Selective Reminding Test (FCSRT) scores for the subject's categorization using linear discriminant analysis. Results were validated using the leave-one-out cross-validation method. RESULTS: Right parietal and hippocampal perfusion was significantly (p<0.05, corrected) decreased in the MCI-AD group as compared to the MCI-S group. The patients' classification in the MCI group using the mean activity in right and left parietal cortex and hippocampus yielded a sensitivity, specificity, and accuracy of 82%, 90%, and 89%, respectively. Combination of SPECT results and FCSRT free recall scores increased specificity to 93%. CONCLUSION: The combination of an automated quantitative tool for brain perfusion SPECT images and memory test scores was able to distinguish, in a group of amnestic MCI, patients at an early stage of AD from patients with stable MCI.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Encéfalo/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Mapeo Encefálico , Circulación Cerebrovascular , Trastornos del Conocimiento/patología , Cisteína/análogos & derivados , Cisteína/efectos de los fármacos , Diagnóstico por Computador/métodos , Progresión de la Enfermedad , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Compuestos de Organotecnecio , Perfusión/métodosRESUMEN
OBJECTIVE: To investigate brain changes in both basal and cataplectic conditions in awake patients with narcolepsy-cataplexy. BACKGROUND: Recent insights in pathophysiology have demonstrated that narcolepsy-cataplexy is caused by early loss of hypothalamus hypocretin neurons. However, the neurophysiological mechanisms underlying sleepiness and the dramatic cataplexy reaction to positive emotion remain unclear. METHODS: Twenty-one patients with narcolepsy-cataplexy and 21 age- and sex-matched controls were included. Diagnosis of narcolepsy was fully confirmed by polysomnography, HLA DQB1*0602 and CSF hypocretin levels (n=9). Seven patients were free of all drugs, and 14 were treated with psychostimulant and/or anticataplectic drugs. (18)-F-fluorodeoxy glucose positron emission tomography procedures were performed at baseline in all subjects and during cataplexy attacks (n=2). RESULTS: The authors found significant hypermetabolism in narcolepsy-cataplexy in fully awake condition in the limbic cortex specifically in the anterior and mid cingulate cortex, in the right cuneus and lingual gyrus. In contrast, no hypometabolism was found. Hypermetabolism was detected in the cerebellum and pre-postcentral gyri in treated compared with untreated patients. During cataplectic attacks, cerebral metabolism significantly increased in the bilateral pre-postcentral gyri, primary somatosensory cortex, with a marked decrease in the hypothalamus. CONCLUSION: Hypermetabolism was found in the executive network in narcolepsy at baseline in fully awake condition. Wake state assessment during scanning appears critical to avoid results showing altered functional neurocircuitry secondary to sleepiness and not to the underlying neurological disorder per se. Finally, cataplexy attacks were characterised by a hypometabolism in the hypothalamus associated with wide bilateral brain area hypermetabolisms.
Asunto(s)
Glucemia/metabolismo , Encéfalo/diagnóstico por imagen , Cataplejía/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Narcolepsia/diagnóstico por imagen , Tomografía de Emisión de Positrones , Adulto , Encéfalo/fisiopatología , Mapeo Encefálico , Cataplejía/fisiopatología , Dominancia Cerebral/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Narcolepsia/fisiopatología , Polisomnografía , Vigilia/fisiología , Adulto JovenRESUMEN
Neuroimaging studies investigating the neural correlates of verbal fluency (VF) focused on sex differences without taking into account behavioural variation. Nevertheless, group differences in this verbal ability might account for neurocognitive differences elicited between men and women. The aim of this study was to test sex and performance level effects and the combination of these on cerebral activation. Four samples of 11 healthy students (N=44) selected on the basis of sex and contrasted VF scores, high fluency (HF) versus low fluency (LF), performed a covert phonological VF task during scans. Within- and between-group analyses were conducted. Consistent with previous studies, for each sample, the whole-group analysis reported activation in the inferior frontal gyrus (IFG), insula, anterior cingulate cortex (ACC), medial frontal gyrus (mFG), superior (SPL) and inferior parietal lobules (IPL), inferior visual areas, cerebellum, thalamus and basal ganglia. Between-group analyses showed an interaction between sexes and performances in the right precuneus, left ACC, right IFG and left dorsolateral prefrontal cortex (dlPFC). HF men showed more activation than LF ones in the right precuneus and left dlPFC. LF men showed more activation in the right IFG than HF ones and LF women elicited more activation in the left ACC than HF ones. A sex main effect was found regardless of performance in the left inferior temporal gyrus (ITG), cerebellum, anterior and posterior cingulate cortexes and in the right superior frontal gyrus (SFG) and dlPFC, lingual gyrus and ACC, with men eliciting significantly greater activations than women. A performance main effect was found for the left ACC and the left cerebellum regardless of sex. LF subjects had stronger activations than HF ones in the ACC whereas HF subjects showed stronger activations in the cerebellum. Activity in three discrete subregions of the ACC is related to sex, performance and their interaction, respectively. Our findings emphasize the need to consider sex and performance level in functional imaging studies of VF.
Asunto(s)
Encéfalo/fisiología , Imagen por Resonancia Magnética , Desempeño Psicomotor/fisiología , Caracteres Sexuales , Habla/fisiología , Aprendizaje Verbal/fisiología , Adolescente , Adulto , Anciano , Ganglios Basales/fisiología , Encéfalo/anatomía & histología , Cerebelo/fisiología , Corteza Cerebral/fisiología , Niño , Femenino , Lóbulo Frontal/fisiología , Lateralidad Funcional/fisiología , Giro del Cíngulo/fisiología , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Lóbulo Parietal/fisiología , Valores de Referencia , Tálamo/fisiología , Adulto JovenRESUMEN
Positron emission tomography (PET) and its recent update PET/CT are very effective diagnostic tools for non-invasive imaging of metabolic or functional disorders in target tissues. The clinical usefulness of fluorodeoxyglucose-(18F) (FDG) has been now widely accepted. Recently, the clinical usefulness of fluoroDOPA-(18F) or FDOPA, an aminoacid labelled with the same positron emitter fluorine-18, has been evaluated and recognised in France and subsequently in several EU countries. FDOPA is diagnostic PET agent, which has been used for decades in imaging the loss of dopaminergic neurons in Parkinson's disease, and more recently to detect, stage and restage neuroendocrine tumours and to search for recurrence of viable glioma tissue. The present article summarises the body of evidence that led the French Medicines Agency (AFSSAPS) to grant a marketing authorisation to IASOdopa, a commercial preparation of FDOPA. Brief case reports and figures illustrate the diagnostic performance of FDOPA PET or PET/CT in the different settings that are currently approved in oncology.
Tomografia por emissão de positrons (PET) e sua recente atualização PET/CT são ferramentas de diagnóstico muito eficientes para imagens não invasivas de desordens metabólicas ou funcionais em tecido alvo. A utilidade clínica da fluordesoxiglicose-(18F)(FDG) tem sido agora largamente aceita. Recentemente, a utilidade clinica de fluoroDOPA-(18F) ou FDOPA, um aminoácido marcado com o mesmo emissor de pósitron, flúor-18, tem sido avaliado e reconhecido na França e subsequentemente em alguns países da União Européia. FDOPA é o radiofármaco para diagnóstico em PET, o qual tem sido usado por décadas para obtenção de imagens da perda de neurônios dopaminérgicos na doença de Parkinson e, mais recentemente, para identificar inicialmente o estágio e a reavaliação de tumores neuroendócrinos e para a pesquisa da recorrência de glioma viável. O presente artigo resume o conjunto de evidências que levarão a Agência Médica Francesa (AFSSAPS) garantir uma autorização de divulgação da IASOdopa, uma preparação comercial da FDOPA. O relato breve de caso e figuras que ilustram um padrão de imagem de diagnóstico usando FDOPA em PET ou PET/CT em diferentes configurações que são aceitas em oncologia.
Asunto(s)
Corazón/diagnóstico por imagen , Ácido Pentético/análogos & derivados , Radiofármacos , Vasculitis/diagnóstico por imagen , Corticoesteroides/uso terapéutico , Adulto , Antiinflamatorios/uso terapéutico , Femenino , Humanos , Angiografía por Radionúclidos , Vasculitis/tratamiento farmacológicoRESUMEN
BACKGROUND: The management and prognosis of a glioma depend on the tumour's histological grade. Thus, preoperative prediction of the grade is routinely needed to indicate whether surgery or biopsies are required. It has been proposed that thallium single photon emission computed tomography (SPECT), in a relative short series, will aid this prediction. AIM: To confirm the correlation between the results of preoperative thallium SPECT and grade of tumour as well as patient survival, and to define the cut-off value of the optimal thallium index for the detection of high grade gliomas in a large series of patients. METHODS: One hundred and eighteen patients treated for glioma were retrospectively included in this study. All patients underwent preoperative 201Tl SPECT upon initial presentation and were referred for neurosurgery. Initial scintigraphic findings were correlated with the histological grade of the tumour and overall patient survival. RESULTS: Thallium uptake was highly correlated with histological grade; the mean thallium indices for low grade and high grade gliomas were 1.8 and 4.9, respectively. On the basis of receiver operating characteristic analysis, the optimal cut-off value of the thallium index for the detection of high grade glioma was determined. By using 2.2 as the value for the threshold thallium index, the sensitivity and specificity were 93% and 72%, respectively. Kaplan-Meier estimates of the overall survival curves, as a function of the thallium index, indicated that it was correlated with the overall survival (P<0.001). CONCLUSION: Thallium SPECT provides useful information about the histological grade of the tumour and overall patient survival. Additionally, in spite of its relatively weak resolution, it appears to be a powerful routine clinical tool for the management of gliomas.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/epidemiología , Glioma/diagnóstico por imagen , Glioma/epidemiología , Talio , Tomografía Computarizada de Emisión de Fotón Único/estadística & datos numéricos , Neoplasias Encefálicas/patología , Francia/epidemiología , Glioma/patología , Incidencia , Pronóstico , Radiofármacos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Sensibilidad y Especificidad , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
UNLABELLED: The aim of the present study was to determine the clinical feasibility of integration of stereotactic SPECT (sSPECT) with 201Tl in the stereotactic MRI (sMRI)-based planning of brain tumor biopsy. Furthermore, the predictive value of the integrated techniques was analyzed by comparison with the corresponding histologically determined metabolic activity. METHODS: Ten patients underwent combined 201Tl SPECT- and MRI-guided stereotactic biopsy of intracranial lesions according to a previously described technique. An area of abnormal 201Tl uptake was used to guide the stereotactic biopsy trajectory. Several samples were taken along the trajectory above and beneath the target. An extensive histologic diagnosis (tumor grade, mitotic index [MI], and Ki67 index) and the 201Tl index were obtained for all samples and compared statistically. RESULTS: Combined 201Tl sSPECT- and sMRI-guided biopsy could be performed on all patients. Ki67 index, MI, and tumor grade correlated significantly. The correlations between MI or Ki67 index and 201Tl index were not significant (0.18 and 0.09, respectively). A trend to significance existed between tumor grade and 201Tl index (R = 0.31; P = 0.06). Mean 201Tl index for grade III tumors (3.27 +/- 1.89 [SD]) was significantly different from that for grade IV tumors (4.34 +/- 1.29). The sample position on the trajectory correlated with the MI (R = 0.39; P = 0.01). In 4 of the 10 patients, a variation in tumor grade could be observed along the trajectory. In all patients, the highest proliferative activity was within 5-10 mm of the target. CONCLUSION: These results support the view that 201Tl SPECT may contribute to the successful management of brain tumor patients requiring stereotactic biopsy, without causing a significant increase in discomfort or morbidity. The development of similar techniques integrating sSPECT data in the planning of stereotactic biopsy should be considered by centers performing stereotactic surgery and having access to SPECT technology. In the long term, this technique could become a support for focused gene therapy and cell transfer.
Asunto(s)
Biopsia con Aguja/métodos , Neoplasias Encefálicas/patología , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Técnicas Estereotáxicas , Técnica de Sustracción , Talio , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto , Anciano , Algoritmos , Neoplasias Encefálicas/diagnóstico , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Radiofármacos , Cirugía Asistida por Computador/métodosRESUMEN
MR or CT images acquired under stereotactic conditions are often used to plan and guide brain tumor biopsies. The objective of this study was to design and test a methodology to increase target selection reliability by acquiring stereotactic 201Tl-SPECT data and by integrating them into the surgical planning. The three-headed Philips gamma camera system (Prism 3000) was adapted to stereotactic acquisitions (patient pallet, headholder). A software was developed for the stereotactic target determination based on SPECT images (pixel with the highest metabolic activity inside the tumor). The whole system accuracy was tested with the Elekta phantom adapted to SPECT imaging. The methodology was applied to one brain tumor biopsy. Comparison of the specific phantom coordinates evaluated in SPECT with the theoretical ones did not reveal any significant difference. In this way, our methodology including our homemade software (identification of the stereotactic frame, determination of the pixel with highest metabolic activity within the tumor in the stereotactic coordinate system) was validated. No significant geometric deformations were detected. Clinical feasibility was confirmed in 1 patient with a brain glioma. This study illustrates the feasibility and the accuracy of SPECT acquisitions with the stereotactic Leksell G-frame. The clinical relevance of this methodology is under evaluation. This definition of the target, based on the point with the highest metabolic activity within the tumor, might lead to improved diagnosis in biopsies and patient management. Furthermore, it might prepare the future for therapy aimed at delivering a therapeutic agent within a tumor.
Asunto(s)
Neoplasias Encefálicas/patología , Lóbulo Parietal/patología , Técnicas Estereotáxicas , Radioisótopos de Talio , Tomografía Computarizada de Emisión de Fotón Único/métodos , Biopsia , Neoplasias Encefálicas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Lóbulo Parietal/diagnóstico por imagen , Técnicas Estereotáxicas/instrumentación , Tomografía Computarizada de Emisión de Fotón Único/instrumentaciónRESUMEN
Deep Brain Stimulation is an effective treatment of generalized dystonia. Optimal stimulation parameters vary between patients. This article investigates the influence of electrical brain impedance and delivered current on the brain response to stimulation. Twenty-four patients were bilaterally stimulated in the globus pallidus internus through two implanted four-contact electrodes. The variation of brain impedance and current measurements was correlated with stimulation parameters, time course, and clinical outcome. When a contact was activated, a statistically significant and reversible decrease of brain impedance was found. Impedance and current values and their variations with time significantly differed between patients. The absolute impedance did not significantly correlate with the final outcome. We conclude that the reversible decrease of impedance reflects an adaptive long-term mechanism, which could be due to a plasticity phenomenon, but has no prognostic value. Impedance and current measurements give new complementary information for parameter adjustment and trouble shooting and should therefore be included in all patients' follow-up.
RESUMEN
A solution for discrete multi-exponential analysis of T(2) relaxation decay curves obtained in current multi-echo imaging protocol conditions is described. We propose a preprocessing step to improve the signal-to-noise ratio and thus lower the signal-to-noise ratio threshold from which a high percentage of true multi-exponential detection is detected. It consists of a multispectral nonlinear edge-preserving filter that takes into account the signal-dependent Rician distribution of noise affecting magnitude MR images. Discrete multi-exponential decomposition, which requires no a priori knowledge, is performed by a non-linear least-squares procedure initialized with estimates obtained from a total least-squares linear prediction algorithm. This approach was validated and optimized experimentally on simulated data sets of normal human brains.