Influence of Estradiol and Progesterone on Neural Circuits: A Diffusion-Weighted MRI Study

2128 

Abstract Submission 

Daniel Güllmar^1,2, Jürgen R. Reichenbach^1,2,3,4,5, Christian Gaser^6,4,5,7, Feliberto de la Cruz⁸, Ann-Christine Buck⁹, Carina Koeppel⁹, Lejla Colic^7,4,5, Michael Kiehntopf¹⁰, Zora Kikinis¹¹, Martin Walter^12,4,5, Ilona Croy^9,4,5, Carina Heller^9,7,4,11,5

¹Medical Physics Group, Inst. of Diagnostic and Interventional Radiology, Jena University Hospital, Jena, Germany, ²Michael Stifel Center Jena for Data-Driven and Simulation Science, Jena, Germany, ³Center of Medical Optics and Photonics (CeMOP), Jena, Germany, ⁴Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health, Jena, Germany, ⁵German Center for Mental Health (DZPG), Jena, Germany, ⁶Department of Neurology, Jena University Hospital, Jena, Germany, ⁷Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany, ⁸Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Jena University Hospital, Jena, Germany, ⁹Department of Clinical Psychology, Friedrich Schiller University Jena, Jena, Germany, ¹⁰Institute of Clinical Chemistry and Laboratory Diagnostics, Centralised Diagnostic Lab. Service, Jena, Germany, ¹¹Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard, Boston, MA, ¹²Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Thuringia

Daniel Güllmar  
Medical Physics Group, Inst. of Diagnostic and Interventional Radiology, Jena University Hospital|Michael Stifel Center Jena for Data-Driven and Simulation Science
Jena, Germany|Jena, Germany

Jürgen R. Reichenbach  
Medical Physics Group, Inst. of Diagnostic and Interventional Radiology, Jena University Hospital|Michael Stifel Center Jena for Data-Driven and Simulation Science|Center of Medical Optics and Photonics (CeMOP)|Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health|German Center for Mental Health (DZPG)
Jena, Germany|Jena, Germany|Jena, Germany|Jena, Germany|Jena, Germany

Christian Gaser  
Department of Neurology, Jena University Hospital|Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health|German Center for Mental Health (DZPG)|Department of Psychiatry and Psychotherapy, Jena University Hospital
Jena, Germany|Jena, Germany|Jena, Germany|Jena, Germany

Feliberto de la Cruz  
Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Jena University Hospital
Jena, Germany

Ann-Christine Buck  
Department of Clinical Psychology, Friedrich Schiller University Jena
Jena, Germany

Carina Koeppel  
Department of Clinical Psychology, Friedrich Schiller University Jena
Jena, Germany

Lejla Colic  
Department of Psychiatry and Psychotherapy, Jena University Hospital|Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health|German Center for Mental Health (DZPG)
Jena, Germany|Jena, Germany|Jena, Germany

Michael Kiehntopf  
Institute of Clinical Chemistry and Laboratory Diagnostics, Centralised Diagnostic Lab. Service
Jena, Germany

Zora Kikinis  
Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard
Boston, MA

Martin Walter  
Department of Psychiatry and Psychotherapy, Jena University Hospital|Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health|German Center for Mental Health (DZPG)
Jena, Thuringia|Jena, Germany|Jena, Germany

Ilona Croy  
Department of Clinical Psychology, Friedrich Schiller University Jena|Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health|German Center for Mental Health (DZPG)
Jena, Germany|Jena, Germany|Jena, Germany

Carina Heller  
Department of Clinical Psychology, Friedrich Schiller University Jena|Department of Psychiatry and Psychotherapy, Jena University Hospital|Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health|Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard|German Center for Mental Health (DZPG)
Jena, Germany|Jena, Germany|Jena, Germany|Boston, MA|Jena, Germany

Estradiol (E2) and progesterone (P4) are pivotal in modulating neural circuits throughout a female's lifespan (1,2). However, the precise mechanistic underpinnings of sex hormonal modulation on these neural circuits remain elusive. A growing body of cross-sectional neuroimaging studies has endeavored to unravel the intricate relationship between sex hormones and neural circuitry, employing structural and functional MRI techniques (2). Recent research has also begun to emphasize the importance of densely sampled longitudinal tracking (3) of hormonal rhythmic nature alongside dynamic changes in brain activity (4). This approach enriches our insights into the multifaceted hormone-brain interactions by detecting also subtle changes that could be unnoticed in less frequent sampling. However, notably absent from the existing literature is an investigation utilizing diffusion-weighted MRI, a modality known for its sensitivity to microstructural tissue changes (5). This study addresses this knowledge gap, aiming to provide a more comprehensive and nuanced understanding of the intricate interplay between sex hormones and neural circuits.

Three females and one man underwent extensive brain imaging across five weeks. Data collection took place mostly on weekdays in the morning. All three women were measured during their natural menstrual cycle, covering the follicular and luteal phases. One of the women underwent another complete measurement cycle while using an oral contraceptive. Hormonal E2 and P4 levels were measured daily after MRI. The dwMRI protocol consisted of a measurement with 394 volumes using a fast SMS-enabled sequence variant (6) (1.5 mm iso res, max bvalue: 2700 s/mm2. Data preprocessing included denoising, determination of the frequency offset map, and the subsequent correction of susceptibility-based artifacts, eddy-current-based distortions, and rigid motion. The preprocessed data was then masked and spatially rigidly aligned to the MNI template. Subsequently, so-called peaks were calculated from the diffusion data, from which we segmented into 50 different white matter tract structures for each data set separately (7). Tractograms for the diffusion properties fractional anisotropy (FA) and mean diffusivity (MD) were generated based on these tracts (8) (cf Fig. 1). The changes in these tractograms over time were compared with the respective corresponding individual time courses of E2 and P4 using a permutation test.

We found that the hormone level of P4 in many tracts can be used as a predictor for the temporal change of the diffusion parameter MD. This is particularly true for the tracts of the anterior thalamic radiation (ATR), fronto-pontine tract (FPT), and thalamic-premotor tract (T_PREM), where we observed very similar spatial distributions of areas between subjects (cf Fig. 2). However, we could not make this observation for the male and the female on the oral contraceptive measurement series. A correlation between the time course of the E2 level and the diffusion parameter MD could only be found in individual tracts and not consistently across the three female subjects with a natural menstrual cycle. Interestingly, no correlation of the temporal change in FA could be found with the hormones E2 and P4.

In summary, extensive brain imaging and venipuncture across the natural menstrual cycle have shown that changes in hormone levels are associated with measurable changes in diffusion parameters. Notably, the absence of correlations in the male and the female on oral contraceptives, when hormones are low or suppressed emphasizes the importance of considering the impact of hormonal dynamics on potential modulatory effects in future studies. This research contributes to a more comprehensive understanding of the nuanced dynamics between sex hormones and neural circuit microstructure, paving the way for further investigations that may elucidate the underlying mechanisms of hormonal modulation on brain connectivity.

Cortical Anatomy and Brain Mapping ¹

Subcortical Structures

White Matter Anatomy, Fiber Pathways and Connectivity

Diffusion MRI ²

ADULTS

Blood

Data analysis

MRI

STRUCTURAL MRI

Tractography

White Matter

WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC

Other - gonadal hormones