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All living creatures have to cope with environmental
demands and threats that challenge their physical
or emotional homeostasis.

Klodiana-Daphne Tona

Visualizing small brainstem nuclei involved in stress, important cognitive functions & neurological disorders

The locus coeruleus, a small brainstem nucleus, is the main source of noradrenaline in the brain and is involved in a number of cognitive functions as well as several neurological and psychiatric disorders.

The last decade, together with my supervisors, colleagues and students I have been studying the human locus coeruleus-noradrenergic system (LC-NE), the anatomy of this tiny brainstem nucleus and the involvement of the LC-NE system in stress, arousal, cognitive flexibility, memory and fear.

Here, I would like to showcase methodological developments in the visualization of brainstem nuclei (such as the LC) in vivo in humans. To this end, I will present two anatomical studies that examine this tiny brainstem nucleus.

In a nutshell

Explorers in the 15th century (e.g. Christopher Columbus & Amerigo Vespucci ) were mapping planet earth, but explorers in the 21st century (i.e. researchers) are still trying to map “planet brainstem”.

In the 21st century humans have created very detailed maps of planet earth, have mapped other planets, and are even in search of extraterrestrial life. Yet you might be surprised to hear that we have actually not yet succeeded in fully mapping the structures that are inside our own brain. This is particularly true for (small) structures that are located deep in the brain, especially on the brainstem. Surprising, isn’t it? 

What prevents us from looking inside our brainstem?

The challenges are of two kinds: technical and anatomical. Regarding the technical challenges, there is a need for specific technological advancements, and these have only recently taken place. This means that no matter how hard the researcher-explorers of the past tried to map these structures in living humans, such an enterprise was simply impossible because the timing was not right: one is dependent on technological advances that take quite some time to become feasible and be implemented in brain research. Regarding the anatomical challenges, some structures are difficult to map because they are small, their location and size varies a lot among different individuals and also in some cases are located in parts of the brain that cannot be easily visualized in living humans within the MRI scanner (e.g. they are located on brain tissue close to the vessels or the fourth ventricle and pulsate when blood or cerebrospinal fluid is rushing).

The individual differences in the location and size of these structures signify that in different people these brain structures can be a bit higher or lower, and the size and shape can also differ. Under these circumstances, the explorer- researcher, like a modern Christopher Columbus,  runs the risk of accidentally ending up to America (i.e. periaqueductal gray in our case) while the desired destination was India (i.e. locus-coeruleus in our case).

What would be the solution in this case?

Solution Nr 1: use a probabilistic map. To avoid mixing India with America in the brain, you can make use of a probabilistic map. This map aligns all the different brain structures, one on top of the other and quantifies the similarities and the differences. In this way the final output is a map that shows a representative image of the core structure (the core of India), but also some extra borders around it (to account for individuals where the structures are slightly bigger or smaller than the core). This helps to quantify the certainty of the structure localization (e.g., what percentage sure are you that you are in India and not in America)? This is exactly what we did in this study 1.  

Solution Nr 2: use a Google map filter (i.e. special MRI sequence) and camera with higher resolution (i.e. move from 3T to 7T MRI).

This is what we did in study 2.  We used special MRI sequences that have been shown to visualize structures that contain neuromelanine (the locus coeruleus is one of them), and we compared the effectiveness of these sequences using a “low resolution camera” (3 Tesla MRI) and a “camera with higher resolution” (7 Tesla MRI).

What is next?

The exploration continues of course. Both in terms of investigating the underlying mechanisms of stress and in visualizing brain structures which play an important role in stress. And of course this journey has higher impact and is more fun when researchers -explorers join powers. In the end, a “modern Christopher Columbus” researcher would always benefit from a colleague who – like a modern Amerigo Vespucci – would demonstrate that she was wrong to believe that she reached India when she had actually reached an unexplored, “New World”- America. So feel free to check Research Gate and contact me if you have any question or comment.


Study 1:

Tona, K.-D., et al. (2017). "In vivo visualization of the locus coeruleus in humans: quantifying the test–retest reliability." Brain Structure and Function.


Study 2:

Tona, K.-D., et al. (2019). "Quantifying the contrast of the human locus coeruleus in vivo at 7 Tesla MRI." PLoS One 14(2): e0209842.


Contact me:  

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Research Gate



Overview of LC probability atlas. The color intensity indicates the percentage overlap across the 17 participants (i.e. the “core” of India and the extra borders around it- in the example mentioned in the text above). The z coordinates are in MNI space.


429 2017 1464 Fig3 HTML


 Figure was previously published in Tona, K.-D., et al. (2017). "In vivo visualization of the locus coeruleus in humans: quantifying the test–retest reliability." Brain Structure and Function.