Volumetric parcellation methodology of the human hypothalamus in neuroimaging: Normative data and sex differences
Highlights
► A novel morphometric method for volumetric analysis of the in-vivo human hypothalamus. ► Anatomically driven morphometric method for measuring the human hypothalamus. ► Compared 2 high-resolution (7-T) ex-vivo datasets to their own histology. ► Normative data of in-vivo human hypothalamic volume. ► Sex differences in the overall hypothalamic volume and tuberal-region volumes.
Introduction
Traditionally it has been difficult to assess hypothalamic involvement in specific human behavior, affect, and cognition, given the difficulties of measuring this structure in vivo. However, current studies using in vivo structural and functional magnetic resonance imaging (s/fMRI) in humans have demonstrated potential hypothalamic roles in mood and arousal (Augustinack et al., 2005, Bao et al., 2005, Goldstein et al., 2010, Goldstein et al., 2005, Handa et al., 1994, Majdic and Tobet, 2011), and psychiatric disorders (Goldstein et al., 2007). MRI offers advantages over traditional anatomy and histopathology, such as capabilities of in vivo measurement and monitoring of structure and function in healthy and clinical conditions. Using sMRI, a volumetric and topological analysis of the healthy hypothalamus with results matching those derived from traditional anatomy was used to differentiate schizophrenia patients, their first-degree relatives and healthy controls (Goldstein et al., 2007). Although this was an advance in the measurement and usefulness of the hypothalamus for understanding disease, there are a number of methodological and technological challenges that have hindered the progress of this line of research.
Anatomically, the human hypothalamus is a relatively small-sized structure, yet is considered a critical center for drive-related activities (such as feeding, defense and sexual behavior), endocrine and autonomic function (Baroncini et al., 2010, Saper et al., 2002, Swaab, 2003, Swaab, 2004, Swanson, 2000). Currently, there is increasing evidence regarding the importance of the hypothalamus for understanding women's health and sex differences in relation to neurological, psychiatric, endocrine and sleep disorders. Although different in histology, physiology, connections and function, multiple nuclei of the hypothalamus subserve autonomic functions and are nodal points for the coordination of endocrine, emotional and somatic activities for the purpose of maintaining the organism within a healthy physiological equilibrium (i.e., homeostasis) (Saper et al., 2002, Swaab, 2003, Swaab, 2004, Swanson, 2000). Overall, endocrine functions are primarily related to hypothalamic neuronal secretions into the median eminence to reach the anterior pituitary and direct projections to the posterior pituitary. Motivated behaviors are related to connections with limbic structures, such as the cingulate and parahippocampal gyri, amygdala and hippocampus. Somatic responses are associated with hypothalamic connections with somatic and visceral nuclei located within the brainstem and spinal cord (Koh and Ricardo, 1978, Saper et al., 2002). In fact, even specific nuclei within the hypothalamus, such as the paraventricular nucleus, have specific neuronal components associated with endocrine and autonomic functions (Herman et al., 2005, Stratton et al., 2011, Swaab, 2003, Swaab, 2004, Swanson and Sawchenko, 1983). Hypothalamic regulation of the endocrine system plays a key role in the development of the sexual differentiation of the brain given the roles of hormones and genes on specific nuclei during particular gestational periods of development (Handa et al., 1994, Swaab, 2003, Swaab, 2004, Tobet et al., 2009). This role has been demonstrated for many years in model animals and more recently in humans (Bao and Swaab, 2011, Goldstein et al., 2001, Raznahan et al., 2010). Thus, given the critical importance of hypothalamic nuclei and their key roles in regulating numerous functions, it is important to develop the ability to conduct in vivo human studies of anatomic structure, volumetry, connectivity, and function of hypothalamic regions represented at the level of its characteristic cell groups or nuclei. However, this level of structural analysis has not been currently achieved in hypothalamic MRI research. Traditional histology and immunohistochemistry has elucidated this level of analysis and thus serves as the “gold standard” to validate, guide and assist us in the MRI-based assessment and mapping of hypothalamic structure. Currently, the level of quantitative structural analysis that has been achieved in hypothalamic MRI research is measuring the volume of the entire hypothalamus using an approach of morphometric analysis (Goldstein et al., 2007). This is a different and complementary approach to the qualitative morphological characterization of the human hypothalamus for atlas generation using MRI (Baroncini et al., 2012).
The goals of the present study were two-fold: (1) develop a novel method of semi-automated, volumetric parcellation for the human hypothalamus that could be used to investigate clinical conditions using MRI, and (2) demonstrate the method's applicability. The new method extends previous work in which MRI was used to measure the entire hypothalamus as a single volumetric unit (Goldstein et al., 2007). In an effort to analyze quantitatively the human hypothalamus at a more fine-grained level, the new method subdivides the hypothalamus into five measurable parcels (or parcellation units [PUs]) based on visible anatomic landmarks that are associated with specific nuclear groupings. To validate this method, two ex vivo hypothalami were imaged at high resolution in a 7 T scanner and then processed histologically. Imaging results were compared with the histological evaluation. The parcellation methodology was then used to analyze the hypothalami from 44 healthy adult subjects (26 men; 18 women) to derive normative volumetric data and assess sex differences in the hypothalamus in its entirety as well as in its five subdivisions and thus infer associations with more specific hypothalamic nuclear groupings.
Section snippets
Anatomic parcellation of the human hypothalamus using MRI and its validation
The hypothalamus is located in the diencephalon, ventrally to the thalamus and hypothalamic sulcus and surrounding the third ventricle. It extends rostrally from the anterior commissure and the lamina terminalis to the ventral tegmentum caudally just behind the mamillary bodies. Its ventral surface is exposed to the subarachnoid space and the cerebral spinal fluid covering a distance from the optic chiasm to the caudal edge of the mamillary bodies (see Fig. 1). The hypothalamus is constituted
Results
Results are organized in the following way: (1) parcellation of 7 T MRI datasets and their comparison against their own (ex vivo) histology to determine hypothalamic nuclei within each parcellation unit; (2) comparison of 7 T ex vivo to in vivo 1.5 T data; and (3) application of the novel method to hypothalamic volume assessment of 1.5 T MRI data in a healthy normative sample of men and women.
Discussion
This study created and confirmed a novel method for the study of the human hypothalamus in vivo. The hypothalamus was subdivided in five parcels and the analysis demonstrated the neurobiological meaning of each one of these subdivisions by identifying the structures (i.e., the nuclei) that are present within them. This was achieved by comparing imaged ex vivo human hypothalami with their histological data. The importance of this advance in hypothalamic research in the field of human
Conclusions
Here we have presented a unique and innovative methodology for the segmentation of the human hypothalamus, which subdivides the hypothalamus into five parcels based on visible anatomic landmarks associated with specific nuclear groupings. We provided an initial validation of the method using two ex vivo hypothalami imaged in a 7-T scanner and processed histologically, and applied it to 44 healthy men and women, comparable on age, handedness, ethnicity, and socioeconomic status. We reported
Acknowledgments
This study was primarily supported by ORWH-NIMH R21MH084041 (Makris, PI) and ORWH-NIMH SCOR P50MH082679, (Goldstein, Tobet, Handa, PI). Some of the methodological work related to addiction was in part supported by NIDA R01DA027804 (Makris, PI). The authors also thank Larry Seidman, Ph.D. [NIMH R01 MH63951 (Seidman, PI) and NIMH R01 MH56956 (Goldstein, PI)] for contributing to original collection of the healthy control subjects used in these analyses, Bruce Rosen, MD, PhD for his administrative
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