The mammillothalamic tracts: Age-related conspicuity and normative morphometry on brain magnetic resonance imaging.

The mammillothalamic tract (MTT, bundle of Vicq d'Azyr) is a white-matter projection from each mammillary body to the anterior nucleus of the thalamus (ANT). Deep brain stimulation of the MTTs or ANTs is a treatment option for medically refractory focal epilepsy. Since the ANTs may be atrophied in epilepsy, targeting of the MTT terminations could be used as a proxy for ANT locations. However, MTT conspicuity and morphometry on MRI have not been evaluated to date. We investigated normative age- and sex-related MRI morphometrics of the MTTs in healthy individuals. We retrospectively analyzed magnified axial T2-weighted images of 80 subjects for bilateral MTT conspicuity, diameters, areas, shapes, precise locations, and symmetry. We statistically tested the effects of independent variables (sex and MTT side) on measured dependent variables using two-way ANOVA; and performed linear regressions with age as the independent variable for each of the dependent variables. Subjects were F:M = 44:36, with mean age 45.3 years. Only one (0.63%) MTT was inconspicuous. Mean MTT diameter was 1.8 mm, area was 2.0 mm2 , and distance from third ventricle was 3.1 mm. MTTs were mostly bilaterally symmetrical in shape, equally round, or ovoid. The right MTT diameter was larger than the left, and males had larger MTT areas than females. We found no statistical difference between MTT diameters and areas in young, middle-aged, and older adults. We report normative axial MRI morphometrics of the MTTs to guide neuromodulation treatments. Future detailed analyses will determine if the MTTs atrophy in proportion to the ANTs in refractory epilepsy.

Accessory mammillary bodies formed by the enlarged lateral mammillary nuclei: cytoarchitecture.

Post mortem examination of the hypothalamus of a 79-year-old woman, deceased in cardiac arrest without recorded neurological symptoms, revealed well-defined spherical protrusions located rostro-laterally to the mammillary bodies that appear to be regular size when compared to normal. Cytoarchitectonically, these accessory mammillary bodies are formed by the enlarged lateral mammillary nucleus that is normally a thin shell over the medial. The mammillary nuclei appear to function synergistically in memory formation in rats; however, the functional consequences of the present variation are difficult to interpret due to lack of human data. Most importantly, in addition to the possible functional consequences, lateral mammillary bodies can be falsely identified as various neuropathological processes of the basal diencephalon including gliomas; therefore, it is extremely important to disseminate this unique morphological variant among clinicians.

Diffusion tensor tractography of the mammillothalamic tract in the human brain using a high spatial resolution DTI technique.

The mammillary bodies as part of the hypothalamic nuclei are in the central limbic circuitry of the human brain. The mammillary bodies are shown to be directly or indirectly connected to the amygdala, hippocampus, and thalami as the major gray matter structures of the human limbic system. Although it is not primarily considered as part of the human limbic system, the thalamus is shown to be involved in many limbic functions of the human brain. The major direct connection of the thalami with the hypothalamic nuclei is known to be through the mammillothalamic tract. Given the crucial role of the mammillothalamic tracts in memory functions, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the mammillothalamic tract in the human brain. Fifteen healthy adults were studied after obtaining written informed consent. We used high spatial resolution diffusion tensor imaging data at 3.0 T. We delineated, for the first time, the detailed trajectory of the mammillothalamic tract of the human brain using deterministic diffusion tensor tractography.

Neurosurgical relevance of the dissection of the diencephalic white matter tracts using the Klingler technique.

OBJECTIVE: The Klingler fiber dissection technique is a relevant and reliable method for neurosurgery to identify with accuracy the fine structure of the brain anatomy highlighting white matter tracts. In order to demonstrate the significance of the application of this technique, we aimed to observe the course and relations of the mammillothalamic and habenulo-interpeduncular tracts as there are very few papers showing these important diencephalic tracts. MATERIAL AND METHODS: Twelve formalin-fixed brains were dissected using the Klingler technique in order to expose the medial diencephalic surface. Diencephalic white matter tracts, particularly the mammillothalamic and habenulo-interpeduncular tracts, were dissected using wooden spatulas and metallic dissectors with different sizes and tips. Several measurements were performed in both dissected hemispheres relative to the mammillothalamic and habenulo-interpeduncular tracts. RESULTS: The course and length of these two tracts were visualized and the relations with other fiber systems and with the neighboring gray matter structures quantified and registered. The mammillothalamic tract approximately marks the anteroposterior coordinate of the anterior pole of the subthalamic nucleus in the anterior commissure - posterior commissure plane. CONCLUSION: The present study helps to understand the three-dimensional architecture of the white matter systems of tracts when the Klingler technique is used. The numerical data obtained may be helpful to neurosurgeons while approaching brain paraventricular and ventricular lesions and deep brain stimulation. Finally, the anatomical knowledge can lower surgical complications and improve patient care particularly in the field of neurosurgery.

Complementary subicular pathways to the anterior thalamic nuclei and mammillary bodies in the rat and macaque monkey brain.

The origins of the hippocampal (subicular) projections to the anterior thalamic nuclei and mammillary bodies were compared in rats and macaque monkeys using retrograde tracers. These projections form core components of the Papez circuit, which is vital for normal memory. The study revealed a complex pattern of subicular efferents, consistent with the presence of different, parallel information streams, whose segregation appears more marked in the rat brain. In both species, the cells projecting to the mammillary bodies and anterior thalamic nuclei showed laminar separation but also differed along other hippocampal axes. In the rat, these diencephalic inputs showed complementary topographies in the proximal-distal (columnar) plane, consistent with differential involvement in object-based (proximal subiculum) and context-based (distal subiculum) information. The medial mammillary inputs, which arose along the anterior-posterior extent of the rat subiculum, favoured the central subiculum (septal hippocampus) and the more proximal subiculum (temporal hippocampus). In contrast, anterior thalamic inputs were largely confined to the dorsal (i.e. septal and intermediate) subiculum, where projections to the anteromedial nucleus favoured the proximal subiculum while those to the anteroventral nucleus predominantly arose in the distal subiculum. In the macaque, the corresponding diencephalic inputs were again distinguished by anterior-posterior topographies, as subicular inputs to the medial mammillary bodies predominantly arose from the posterior hippocampus while subicular inputs to the anteromedial thalamic nucleus predominantly arose from the anterior hippocampus. Unlike the rat, there was no clear evidence of proximal-distal separation as all of these medial diencephalic projections preferentially arose from the more distal subiculum.

MRI anatomical variants of mammillary bodies.

The mammillary bodies (MBs) are classically defined as a pair of small round structures located on the undersurface of the diencephalon. The systematic observation of MR brain images of patients with neurological diseases, but also of healthy subjects enrolled in research protocols, reveals, however, a greater anatomical variability. The aim of the present study was to define the spectrum of such variability using spatial normalized 3D TFE T1-weighted MR images in a group of 151 healthy right-handed young subjects (78 females, age range 16-39 years). The MBs were identified on reformatted coronal and axial images and classified according to morphological, positional and numerical criteria. On the basis of coronal images, MBs were first divided into symmetrical (86.1 %) and asymmetrical (13.9 %), depending on their respective height. Symmetrical MBs were further subdivided into three variants [type A (2.7 %), B (76.2 %), C (7.3 %)] according to the depth of the intermammillary sulcus. Two morphological variants were defined on axial images, depending on whether the MBs were circular (63.6 %) or elliptic (36.4 %). This latter group was further divided in two subgroups, depending on whether the MBs were parallel (21.9 %) or convergent (14.6 %). Finally, two subjects (1.3 %) presented a supernumeral MB. The transverse size of the third ventricle was greater in the type A compared to the type B and C groups. Gender did not significantly affect the frequency of MBs variants, except for the three symmetrical subgroups in which the variants A and C were more frequent in males than in females. These findings suggest the presence of an anatomical variability of the MBs, in contrast to their classical definition. Therefore, atypical presentation of MBs can be the expression of this variability rather than a marker of neurological disorders (i.e. cerebral malformation, mesial temporal sclerosis, Wernicke-Korsakoff syndrome).

Premio Sixto Obrador 2013. Modelo topográfico de 3 ejes para el tratamiento quirúrgico de los craneofaringiomas. Parte II: Evidencias anatómicas y neurorradiológicas que definen el modelo de clasificación de 3 ejes y su utilidad para predecir el riesgo quirúrgico individual / The 2013 Sixto Obrador Award. A triple-axis topographical model for surgical planning of craniopharyngiomas. Part II: Anatomical and neuroradiological evidence to define triple-axis topography and its usefulness in predicting individual surgical risk

INTRODUCCIÓN Y OBJETIVOS: Este estudio analiza las evidencias patológicas y de imagen de resonancia magnética que definen la topografía de los craneofaringiomas y permiten una clasificación de las lesiones según el riesgo de daño hipotalámico que estas asocian. MATERIAL Y MÉTODOS: Se ha realizado un análisis sistemático de los métodos de clasificación topográfica empleados en las series quirúrgicas de craneofaringiomas descritas en la literatura (n = 145 series, 4.588 craneofaringiomas). También se analizaron las relaciones topográficas de casos individuales intervenidos y bien descritos de la literatura (n = 224 casos) y de casos estudiados en autopsias (n = 201 casos). Finalmente, se analizaron y compararon los estudios prequirúrgicos y posquirúrgicos de imagen de resonancia magnética de craneofaringiomas bien descritos (n = 130) para establecer un modelo diagnóstico topográfico en 3 ejes de la lesión, que permite anticipar cualitativamente el riesgo quirúrgico asociado de daño hipotalámico. RESULTADOS: Las 2 principales variables pronósticas que definen la topografía del craneofaringioma son su posición con respecto al diafragma selar y la afectación del suelo del tercer ventrículo. Un modelo diagnóstico de 5 variables, que son: edad del paciente, existencia de hidrocefalia o de alteraciones del comportamiento, posición relativa de los hipotálamos y el valor del ángulo mamilar, permiten diferenciar craneofaringiomas supraselares que comprimen el tercer ventrículo (craneofaringiomas seudointraventriculares) de lesiones estrictamente intraventriculares o aquellas con un crecimiento primario en el suelo del tercer ventrículo (craneofaringiomas infundibulotuberales o no estrictamente intraventriculares). CONCLUSIONES: Un modelo de clasificación topográfica de los craneofaringiomas en 3 ejes que incluya el grado de infiltración del hipotálamo es útil para la planificación del abordaje y el grado de resección. Los craneofaringiomas infundibulotuberales representan un 42% de los casos y muestran una adherencia fuerte y circunferencial al suelo del tercer ventrículo, asociando un riesgo de daño hipotalámico del 50%. El abordaje transesfenoidal endoscópico permite valorar la adherencia tumoral hipotalámica bajo visión directa

INTRODUCTION AND OBJECTIVES: This study evaluates the pathological and magnetic resonance imaging evidence to define the precise topographical relationships of craniopharyngiomas and to classify these lesions according to the risks of hypothalamic injury associated with their removal. MATERIAL AND METHODS: An extensive, systematic analysis of the topographical classification models used in the surgical series of craniopharyngiomas reported in the literature(n = 145 series, 4,588 craniopharyngiomas) was performed. Topographical relationships of well-described operated craniopharyngiomas (n = 224 cases) and of non-operated cases reported in autopsies (n = 201 cases) were also analysed. Finally, preoperative and postoperative magnetic resonance imaging studies displayed in craniopharyngiomas reports (n = 130) were compared to develop a triple-axis model for the topographical classification of the selesions with qualitative information regarding the associated risk of hypothalamic injury. RESULTS: The 2 major variables with prognostic value to define the topography of a craniopharyngioma are its position relative to the sellar diaphragm and its degree of invasion of the third ventricle floor. A multivariate diagnostic model including 5 variables -patient age, presence of hydrocephalus and/or psychiatric symptoms, the relative position of the hypothalamus and the mammillary body angle- makes it possible to differentiate suprasellar craniopharyngiomas displacing the third ventricle upwards (pseudointraventricular craniopharyngiomas) from either strictly intraventricular craniopharyngiomas or lesions developing primarily within the third ventricle floor (infundibulo-tuberal or not strictly intraventricular craniopharyngiomas). CONCLUSIONS: A triple-axis topographical model for craniopharyngiomas that includes the degree of hypothalamus invasion is useful in planning the surgical approach and degree of resection. Infundibulo-tuberal craniopharyngiomas represent 42% of all cases. These lesions typically show tight, circumferential adhesion to the third ventricle floor, with their removal being associated with a 50% risk of hypothalamic injury. The endoscopically-assisted extended transsphenoidal approach provides a proper view to assess the degree and extension of craniopharyngioma adherence to the hypothalamus

The habenulo-interpeduncular and mammillothalamic tracts: early developed fiber tracts in the human fetal diencephalon.

PURPOSE: The habenulo-interpeduncular (HI) and mammillothalamic (MT) tracts are phylogenetically ancient. The clinical relevance of these tracts has recently received attention. In this work, we map the anatomy the developing HI and MT. METHODS: To investigate the topographical anatomy of developing fiber tracts in and around the diencephalon, we examined the horizontal, frontal, and sagittal serial paraffin sections of 28 human fetuses at 8-12 weeks of gestation. RESULTS: In all specimens, eosinophilic early fiber bundles were limited to the bilateral HI and MT tracts in contrast to pale-colored later developing fibers such as the thalamocortical projections and optic tract. The HI and MT tracts ran nearly parallel and sandwiched the thalamus from the dorsal and ventral sides, respectively. The nerve tract course appeared to range from 5-7 mm for the HI tract and 3-5 mm for the MT tract in 15 specimens at 11-12 weeks. The HI tract was embedded in, adjacent to, or distant from the developing parvocellular red nucleus. CONCLUSIONS: In early human fetuses, HI and MT tracts might be limited pathways for primitive cholinergic fiber connections between the ventral midbrain and epithalamic limbic system.

The mamillothalamic tract is a good landmark for the anterior border of the subthalamic nucleus on axial MR images.

BACKGROUND: Identification of the subthalamic nucleus (STN) on MR images is difficult, and the use of external landmarks could be of interest for STN targeting in deep brain stimulation (DBS). OBJECTIVES: Our aim was to explore the relationship between the anteroposterior coordinates of (1) the center of the mamillothalamic tract and (2) the anterior border of the STN on axial MR images. PATIENTS AND METHODS: The brains of 16 healthy volunteers were imaged on a 3T MR system. Four millimeters under the anterior-posterior commissure plane, we noted the y coordinates of (1) the center of the mamillothalamic tract and (2) the anterior border of the STN. RESULTS: The coordinates were y(STN) = 14.7 ± 1.23 mm and y(Tmth) = 14.3 ± 1.13 mm from the posterior commissure for the STN and the mamillothalamic tract, respectively. The mean difference was 0.4 mm (range 0-1 mm). Pearson's coefficient was 0.97 (p < 0.01). CONCLUSION: We observed a strong correlation between the anteroposterior coordinates of the mamillothalamic tract and the anterior border of the STN (which is located between 0 and 1 mm in front of the mamillothalamic tract). The mamillothalamic tract could be a good anterior landmark for STN targeting. It could also be tested for target determination in DBS for severe obsessive-compulsive disorder.

Mammillotegmental tract in the human brain: diffusion tensor tractography study.

INTRODUCTION: Several animal studies have been conducted for the identification of the mammillotegmental tract (MTT); however, no study has been reported in the human brain. METHODS: In the current study, using diffusion tensor tractography (DTT), we attempted to identify the MTT in the human brain. We recruited 31 healthy volunteers for this study. Diffusion tensor images were acquired using 1.5 T, and the MTT was obtained using a probabilistic tractography method based on a multi-fiber model. Values of fractional anisotropy, mean diffusivity, and tract volume of the MTT were measured. RESULTS: MTTs of all subjects, which originated from the mammillary body, ascended posteriorly to the bicommissural level along the third ventricle and then turned caudally and terminated at the tegmentum of the midbrain. No significant differences were observed in terms of fractional anisotropy, mean diffusivity, and tract volume according to hemisphere and sex (P < 0.05). Using DTT, we identified the MTT in the human brain. CONCLUSION: We believe that the methodology and results of this study would be helpful in research on the MTT in the human brain.

Heterogeneity of the supramammillary-hippocampal pathways: evidence for a unique GABAergic neurotransmitter phenotype and regional differences.

The supramammillary nucleus (SuM) provides substantial projections to the hippocampal formation. This hypothalamic structure is involved in the regulation of hippocampal theta rhythm and therefore the control of hippocampal-dependent cognitive functions as well as emotional behavior. A major goal of this study was to characterize the neurotransmitter identity of the SuM-hippocampal pathways. Our findings demonstrate two distinct neurochemical pathways in rat. The first pathway originates from neurons in the lateral region of the SuM and innervates the supragranular layer of the dorsal dentate gyrus and, to a much lesser extent, the ventral dentate gyrus. This pathway displays a unique dual phenotype for GABAergic and glutamatergic neurotransmission. Axon terminals contain markers of GABAergic neurotransmission, including the synthesizing enzyme of GABA, glutamate decarboxylase 65, and the vesicular GABA transporter and also a marker of glutamatergic neurotransmission, the vesicular glutamate transporter 2. The second pathway originates from neurons in the most posterior and medial part of the SuM and innervates exclusively the inner molecular layer of the ventral dentate gyrus and the CA2/CA3a pyramidal cell layer of the hippocampus. The axon terminals from the medial part of the SuM contain the vesicular glutamate transporter 2 only. These data demonstrate for the first time the heterogeneity of the SuM-hippocampal pathways, not only from an anatomical but also a neurochemical point of view. These pathways, implicated in different neuronal networks, could modulate different hippocampal activities. They are likely to be involved differently in the regulation of hippocampal theta rhythm and associated cognitive functions as well as emotional behavior.

Mammillothalamic tract in human brain: diffusion tensor tractography study.

The mammillothalamic tract (MTT) is a part of the Papez circuit and connects the mammillary body and anterior thalamus. No studies of the MTT have been performed using diffusion tensor tractography (DTT). In the current study, we attempted to identify the MTT in the human brain using DTT. We recruited 25 healthy volunteers for this study. Diffusion tensor images (DTIs) were scanned using 1.5-T, and the MTT was obtained using FMRIB software. Values of fractional anisotropy (FA), mean diffusicity (MD), and tract volume of the MTT were measured. The location of the highest probability point of the MTT was measured at the bicommissural level. MTTs of all subjects, which originated from the mammillary body, ascended posteriorly to the bicommissural level, along the third ventricle, and then ascended to the anterior thalamus in the antero-lateral direction. Average location of the MTT was 37.15% from the most posterior border of the anterior commissure to the most posterior border of the third ventricle at the bicommissural level. We identified the MTT in the human brain using DTT. These methods and results would be helpful to both clinicians and researchers in this field.

Hippocampal-anterior thalamic pathways for memory: uncovering a network of direct and indirect actions.

This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal-anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal-diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal-anterior thalamic systems for recollective rather than familiarity-based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimulation studies showing how the properties of the direct hippocampal-anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal-anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.

Parallel but separate inputs from limbic cortices to the mammillary bodies and anterior thalamic nuclei in the rat.

The proposal that separate populations of subicular cells provide the direct hippocampal projections to the mammillary bodies and anterior thalamic nuclei was tested by placing two different fluorescent tracers in these two sites. In spite of varying the injection locations within the mammillary bodies and within the three principal anterior thalamic nuclei and the lateral dorsal thalamic nucleus, the overall pattern of results remained consistent. Neurons projecting to the thalamus were localized to the deepest cell populations within the subiculum while neurons projecting to the mammillary bodies consisted of more superficially placed pyramidal cells within the subiculum. Even when these two cell populations become more intermingled, e.g., in parts of the intermediate subiculum, almost no individual cells were found to project to both diencephalic targets. In adjacent limbic areas, i.e., the retrosplenial cortex, postsubiculum, and entorhinal cortex, populations of cells that project to the anterior thalamic nuclei and mammillary bodies were completely segregated. This segregated pattern included afferents to those nuclei comprising the head-direction system. The sole exception was a handful of double-labeled cells, mainly confined to the ventral subiculum, that were only found after pairs of injections in the anteromedial thalamic nucleus and mammillary bodies. The projections to the anterior thalamic nuclei also had a septal-temporal gradient with relatively fewer cells projecting from the ventral (temporal) subiculum. These limbic projections to the mammillary bodies and anterior thalamus comprise a circuit that is vital for memory, within which the two major components could convey parallel, independent information.

Re-evaluating the role of the mammillary bodies in memory.

Although the mammillary bodies were among the first brain regions to be implicated in amnesia, the functional importance of this structure for memory has been questioned over the intervening years. Recent patient studies have, however, re-established the mammillary bodies, and their projections to the anterior thalamus via the mammillothalamic tract, as being crucial for recollective memory. Complementary animal research has also made substantial advances in recent years by determining the electrophysiological, neurochemical, anatomical and functional properties of the mammillary bodies. Mammillary body and mammillothalamic tract lesions in rats impair performance on a number of spatial memory tasks and these deficits are consistent with impoverished spatial encoding. The mammillary bodies have traditionally been considered a hippocampal relay which is consistent with the equivalent deficits seen following lesions of the mammillary bodies or their major efferents, the mammillothalamic tract. However, recent findings suggest that the mammillary bodies may have a role in memory that is independent of their hippocampal formation afferents; instead, the ventral tegmental nucleus of Gudden could be providing critical mammillary body inputs needed to support mnemonic processes. Finally, it is now apparent that the medial and lateral mammillary nuclei should be considered separately and initial research indicates that the medial mammillary nucleus is predominantly responsible for the spatial memory deficits following mammillary body lesions in rats.