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. In fact, hypothalamic nuclei, key regulators of autonomic and endocrine functions, are some of the most highly sexually dimorphic nuclei in the brain and implicated in psychiatric and medical disorders with known sex differences. We would argue that an understanding of hormonal effects on the brain and the regulation of other organs and/or systems, such as the cardiovascular and reproductive systems, are critical as downstream effects of hypothalamic activity. Thus an understanding of the neuroanatomy of hypothalamic nuclei and how they are differentially disrupted in men and women in specific disorders will contribute to elucidating sex differences in clinical medicine. However, the identification of hypothalamic nuclei in-vivo in humans has not been realized. This is important since studies have shown the association of the hypothalamus, endocrine dysfunction and sex differences in psychiatric disorders. In fact, the paraventricular hypothalamic nucleus (PVN) is enlarged in patients with major depressive disorder (MDD), in PVN neurons that are dense in corticotropin releasing hormone (CRH) and estrogen receptor (ER)1. In our recent work in schizophrenia (SCZ) we identified structural abnormalities using MRI in the hypothalamus particularly in the PVN in women. Furthermore, in healthy women we showed, using functional MRI, regulation of brain activity in hypothalamic nuclei such as the PVN, dependent on gonadal hormone changes over the menstrual cycle. The principal focus of this study is to use a new in-vivo methodology for the assessment of the hypothalamus comparing neuroimaging data using 7 Tesla magnetic resonance imaging (MRI) and human postmortem validation. The proposed study aims to identify the PVN in-vivo and ex-vivo in the human hypothalamus using high field MRI, to investigate the relationship of the MRI methodology and the histological technique, and to establish the correlates of the histological structures with the MRI representations. In addition to the PVN, which is critical for its role within the hypothalamic-pituitary-adrenal (HPA) axis and its dysfunction in MDD and SCZ, we will identify the supraoptic nucleus (SON), which will be used as a control region. High-resolution 7 Tesla MRI will be carried out in thirty healthy subjects, and four ex-vivo human hypothalamic samples. Our overarching goal is an innovative methodological one: to identify the PVN of the human hypothalamus in healthy adult women and men in-vivo. We expect this method, once defined, to be applied clinically in subjects with MDD and SCZ.

Public Health Relevance

Hypothalamic nuclei will be identified in living humans using high field magnetic resonance imaging (MRI) (i.e., a 7 Tesla scanner) and in ex-vivo human hypothalamic tissue. The MRI results will be compared with postmortem human tissue to assure methodological validation. These hypothalamic nuclei are key regulators of autonomic and endocrine functions implicated in numerous psychiatric and medical disorders with known sex differences such as depression and schizophrenia. Understanding sex differences and the hypothalamic involvement in relation to neurological, psychiatric, cardiovascular, endocrine and sleep disorders is very relevant for public health in general and women's health in particular.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rumsey, Judith M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Makris, Nikos; Liang, Lichen; Biederman, Joseph et al. (2015) Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naïve Adults. J Atten Disord 19:944-53
Yang, Jimmy C; Ginat, Daniel T; Dougherty, Darin D et al. (2014) Lesion analysis for cingulotomy and limbic leucotomy: comparison and correlation with clinical outcomes. J Neurosurg 120:152-163
Iacono, Maria Ida; Makris, Nikos; Mainardi, Luca et al. (2013) MRI-based multiscale model for electromagnetic analysis in the human head with implanted DBS. Comput Math Methods Med 2013:694171
Makris, N; Preti, M G; Asami, T et al. (2013) Human middle longitudinal fascicle: variations in patterns of anatomical connections. Brain Struct Funct 218:951-68
Asami, Takeshi; Saito, Yukiko; Whitford, Thomas J et al. (2013) Abnormalities of middle longitudinal fascicle and disorganization in patients with schizophrenia. Schizophr Res 143:253-9
Makris, Nikos; Swaab, Dick F; van der Kouwe, Andre et al. (2013) Volumetric parcellation methodology of the human hypothalamus in neuroimaging: normative data and sex differences. Neuroimage 69:1-10
Delgado, Mauricio R; Dickerson, Kathryn C (2012) Reward-related learning via multiple memory systems. Biol Psychiatry 72:134-41
Makris, Nikos; Seidman, Larry J; Brown, Ariel et al. (2012) Further understanding of the comorbidity between Attention-Deficit/Hyperactivity Disorder and bipolar disorder in adults: an MRI study of cortical thickness. Psychiatry Res 202:1-11
Agam, Yigal; Hamalainen, Matti S; Lee, Adrian K C et al. (2011) Multimodal neuroimaging dissociates hemodynamic and electrophysiological correlates of error processing. Proc Natl Acad Sci U S A 108:17556-61
Iacono, Maria I; Makris, Nikos; Mainardi, Luca et al. (2011) Atlas-based segmentation for globus pallidus internus targeting on low-resolution MRI. Conf Proc IEEE Eng Med Biol Soc 2011:5706-9

Showing the most recent 10 out of 13 publications