The hunt for the basal forebrain

Contents

• Introduction
• Where that leads me
• Back to Wikipedia
• Migration
• Some other sources
• Visual and other aids
• Conclusions

Introduction

For some time now I have been worrying away at reference 1, included chasing the hares noticed at reference 16 and 17, and the new hare started just a few days ago was the basal forebrain, one of the regions of interest listed in reference 1. Asking both Bing and Google, did not produce much of use to the novice, apart from a low frontal location. So I tried reference 11, a rather loud anatomy resource turned up a few weeks ago. This led to:

Figure 1

In which the neural tube is where it all starts, perhaps 20 days after conception, and which made some sense of all the cephalons that get bandied about, hyphenated here for exposition. I also learned that the brain is not the only organ to have a cortex, derived from the Latin for bark amongst other things. Bones, kidneys, ovaries and sundry glands have one too.

But it also left me with the impression that while things might have six layers and be nice and tidy across most of the cerebral hemispheres, particular the upper and outer surfaces, things probably get a bit more untidy down below, particularly near the junction with the brain stem, which is where I started.

Then I came across the excellent reference 2 which gave me the expanding neural tube:

Figure 2

Where E number is days after conception, not the food additives. So the brain is just the end of a tube which develops some lumps, named as in Figure 1. With an optic vesicle which becomes less prominent as time goes on.

Figure 3

So while the adult brain is both protected and supported by the bony skull, one supposes that a fair bit of interior pipework stills runs along embryonic lines, rather in the way of the alimentary canal, this last being formed very early on, about, as it happens, at the same time as the neural tube. Eventually, after a fair bit of poking around on the Internet, I open up my copy of reference 3, which in the series of sectional pictures at the front, confirms that this is the case. 

What we think of as the brain is just a rather convoluted, red and yellow bulge sitting on top of the green brain stem, the trunk as it were. A stem which splits into a left hand path and a right hand path just below the third ventricle, in pink. That is to say, the lower blade of the pink, three bladed propellor. One path for each of the two hemispheres.

From where I associate to the rather simpler pipe work of trees of references 4, 5 and 6. Then to cotyledons, walnuts and cauliflowers.

Cotyledons turned out to be a red herring, but I have learned that the cotyledons are the false leaves which first appear from a seed, before the true leaves kick in. Monocotyledons like grasses have one of them, dicotyledons or dicots like cucumbers have two of them and some plants have more.

Contrary to what I had thought, the fact that many seeds, like walnuts, broad beans and peanuts, split neatly into two halves has nothing to do with it. Although, given that the small peanut embryo sits at the bottom, between the two halves, maybe they do have some point of contact with hemispheres?

Figure 4

Notwithstanding, walnuts rather less of a red herring, with a hard shell in two parts, or less often in three parts, and the meat inside is usually in two halves, separated by a thin woody partition. With the convolutions of each half having something in common with a brain. No idea why the meat might maximise its surface area inside the hard shell, why it needs to behave like the growing cerebral cortex. Nor do I have any idea whether the convolutions of a walnut are all much the same from one walnut to another, in the way that the convolutions of a human brains are all much the same from one brain to another.

Figure 5

While cauliflowers are more of a counter-example. Their brain like appearance is just one stage in their growth, somewhere between being a speck on the end of a shoot to a large inflorescence, with an early stage of this last being shown top left in the snap above.

Figure 6

Furthermore, as became apparent later, cauliflowers grow from their tips, in the same way as trees mostly grow from their terminal shoots. Probably in the same way as the dendritic arbours grow, with the figure above lifted from reference 2. But brains as a whole are not like that at all.

Where that leaves me

Figure 7

I have attempted to summarise where all this left me in the figure above. On the left we have the cerebrum planted firmly on top of the brain stem, rather as the cauliflower is planted firmly on top of its stalk. Plus the cerebellum below, plus various odd and ancient (in evolutionary terms) bodies in red tucked under the cerebrum. 

In the middle, the brain with its two hemispheres shown from the front, in small, a little squashed.

And a sagittal (that is to say, front to back) section through the middle of the brain on the right, highlighting the tricky junction between the brain stem – a busy enough piece of machinery in its own right – and the brain. The black line is a zone of uncertainty where the mostly six layered cortex proper which covers the rest of the cerebrum gives way to something else. The blue rectangle is another zone of uncertainty where the brain stem gives way to the middle of the brain proper. The pale blue just visible behind a reminder that the cerebrum folds over the top of the brain stem. And the red rectangle is the mass of nerve fibres providing direct connections between the two hemispheres. 

Maybe these zones of uncertainty are not uncertain at all under a microscope. Maybe there are clear boundaries at the level of cells, the sort of thing that Brodmann used when he defined his areas.

With the basal forebrain being the bottom right hand portion of the cerebrum, just to the right of the red bodies.

Back to Wikipedia

Figure 8

I had not been very comfortable with the location graphic supplied by Wikipedia included above: I dare say it is accurate enough, but I did not understand the geometry.

But I am now a bit more comfortable about the location of the basal forebrain. And reference 6 makes it sound quite important: ‘… The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging…’. It best known for its cholinergic neurons which provide much of the brain with the neurotransmitter acetylcholine, a neurotransmitter which plays an important role in arousal, attention, memory and motivation. 

Both reference 7 and reference 8 go on to identify four relevant areas in the basal forebrain: Ch1, Ch2, Ch3 and Ch4 – this last being the one that interests the authors of reference 1, where I started.

Figure 9

A helpful view of the underside of the brain, well over a hundred years old now, from Gray’s Anatomy, via Wikipedia on Broca’s diagonal band, one of the structures to be found in the basal forebrain.

Figure 10

The figure above is taken from reference 9 and includes two of the structures listed in Wikipedia for the basal forebrain, the nucleus accumbens and Broca’s diagonal band. The section right only shows only the middle quarter of the lower brain, the underside of the two frontal lobes, between the two temporal lobes, which last are not shown.

Another reminder that old diagrams still have their uses. Do we still have draughtsmen that can produce such? Can we afford to put their work into scientific papers and books?

Figure 11

Which brings me to the development version of Figure 7.

Migration

Figure 12

Many plants grow from the tips of their growing shoots and once a cell is born it does not tend to move about. It is locked in. While animal cells, in particular neurons, do not necessarily start out where the growing is going on and do move about.

The figure above is a schematic section through the front half of a neural tube. Most cerebral neurons are born from stem cells on the inner, on the ventricular surface. While most of them end up on the outer, on the pial surface, having travelled through the wall of the neural tube to get there.

So a form of growth quite unlike anything that plants – for example cauliflowers – manage and the details of which have occupied the energies of many scientists.

Figure 13

This more complicated version of the story is taken from reference 10, with the left half being recycled in Figure 8 of reference 2 – where, as it happens, it is not made clear that it is a mouse rather than a human. Mice, it seems, are used for a lot of research on the vertebrate brain.

The caption to original of Figure 12 goes: ‘rodent and human fetal forebrains at the peak of corticogenesis. Diagrams of cross sections of half of a rodent (a) and a human (b) fetal forebrain are shown to scale (a zoom in of the rodent section is also provided for legibility). In rodents, the main source of interneurons is the ganglionic eminence (GE) — which is comprised of the lateral ganglionic eminence (LGE) and the medial ganglionic eminence (MGE) — of the ventral telencephalon. These neurons migrate tangentially to the neocortex in the dorsal telencephalon. By contrast, interneurons in the human forebrain originate both in the GE as well as locally in the ventricular … DF, dorsal forebrain; VF, ventral forebrain’.

The right half illustrating the two sorts of migration involved: radial (top two arrows) and tangential (bottom arrow). In the first, the migrating neuron cuts more or less straight across the wall of what was the neural tube. In the second, they take a rather longer route around the growing cerebral mantle. With the mid blue and its stepping stones being part of what becomes the basal forebrain.

Some other sources

It is all too easy to go wandering around all over the place, turning up all kinds of stuff of interest, but perhaps little to the point. References 8, 9 and 10 are just three of the places visited.

So reference 8 is about using optogenetics on mice to study the basal forebrain and its cholinergic neurons. No pictures and nothing about optogenetics, which Wikipedia suggests is an intrusive technique, only suitable for animals, but some useful introductory material at the beginning about what the basal forebrain does. 

Reference 9 contains a useful picture of a section through the basal forebrain, included above. There are other useful pictures, and even without attempting to read the paper through, one does get something of the position and anatomy of some parts of the basal forebrain. Something of what relevant slices of brain actually look like. The string ‘fmri’ does not appear at all and ‘mri’ just four times in this 15 page paper.

Reference 10 is a review of brain development more generally from the point of view of evolution. Something of a push back from the camp that believes that the study of evolution could do more to inform the study of development. ‘… the old and controversial, now generally discredited Haeckel’s law that “Ontogeny is the brief and rapid recapitulation of phylogeny”. Evo-Devo reflects…’. Some more useful pictures.

Visual and other aids

Ken Hub of reference 11 might be a bit loud, but also appears to be a sophisticated tool for learning about human anatomy. You get a fair bit for free, but there appears to be quite a lot more if you pay. I have found the free stuff helpful and have been tempted to stump up the £160 asked for lifetime access to the rest of it. In the meantime, Ken sends me lots of emails.

Ken’s visual aids prompts the thought that there is room for some kind of interactive, three dimensional atlas and Google quickly turns up four of them, references 12, 13, 14 and 15. All of which are easy enough to start up, but I have yet to find a user guide for any of them. That said, the third, from the Allen Brain Institute, looks more like a research tool than a teaching aid. It also does mice as well as men.

Without having looked very hard, it seems that it has not been worthwhile for anyone to build a proper computer package, perhaps to be sold at £500 a time, to provide interactive access to pictures of brains. Despite such packages being available to, for example, people who want to learn to play the piano and people who design or manage buildings. Despite neuroscience being one of the growth industries of the new millennium.

I am also impressed by the difficulty of producing easy, two dimensional diagrams of complicated three dimensional structures with complicated – possibly unstable – vocabularies. Which reminds me that my mother, a teacher of English, was a firm believer in there being no royal road to learning, no yellow brick road to knowledge. Easy diagrams might help, but were not a substitute for engaging the brain in the details, engagement which took time and effort.

And perhaps there is still a place here for real brains, in the way of medical students, certainly of old. Which reminds me that my father, a dentist, had to dissect at least one as part of his basic training. I remember him observing that it gave him a funny feeling to be holding in his hand something which once thought and felt in much the same way as he did.

Conclusions

So while I do not pretend to grasp the detail, I do now feel that I know roughly where the basal forebrain is and how it connects to the rest of the brain, even if it is not much like the connection of a head of cauliflower to its stalk. With the bonus that I also have some idea of why it would interest the authors of reference 1. All of which is enough for me and I shall now have another go at said reference 1.

References

Reference 1: Anterior insula regulates brain network transitions that gate conscious access - Zirui Huang, Vijay Tarnal, Phillip E. Vlisides, Ellen L. Janke, Amy M. McKinney, Paul Picton, George A. Mashour, Anthony G. Hudetz – 2021. 

Reference 2: The Basics of Brain Development - Joan Stiles and Terry L. Jernigan – 2010. Stiles is also the author of a standard text on the subject – ‘Fundamentals of Brain Development: Integrating Nature and Nurture’ – which fetches a good price second hand at both eBay and Abebooks. The present freebie being by way of a trailer.

Reference 3: The Brain Book – Carter, Aldridge, Page and Parker – 2009. A Dorling Kindersley picture book – and a rather useful one at that.

Reference 4: https://psmv2.blogspot.com/2014/09/botanic-problem-3.html. 

Reference 5: https://psmv2.blogspot.com/2014/09/botanic-problem-2.html. 

Reference 6: https://psmv2.blogspot.com/2014/09/botanic-problem-1.html. 

Reference 7: https://en.wikipedia.org/wiki/Basal_forebrain. 

Reference 8: Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition – Shih-Chieh Lin, Ritchie E. Brown, Marshall G. Hussain Shuler, Carl C.H. Petersen and Adam Kepecs – 2015.

Reference 9: Review: revisiting the human cholinergic nucleus of the diagonal band of Broca – A. K. L. Liu, E. J. Lim, I. Ahmed, R. C. C. Chang, R. K. B. Pearce and S. M. Gentleman – 2018.

Reference 10: Evolution of the neocortex: Perspective from developmental biology – Pasko Rakic – 2010.

Reference 11: https://www.kenhub.com/. 

Reference 12: http://da.si.washington.edu/da.html. Includes a series of images – sections, dissections and scans – optionally labelled.

Reference 13: https://www.brainfacts.org/3d-brain#intro=true. Mapping part elementary.

Reference 14: http://human.brain-map.org/static/brainexplorer. Looks a lot more sophisticated – but yet to find my way around.

Reference 15: http://www.thehumanbrain.info/. Different again. Whole head, not just the brain.

Reference 16: https://psmv4.blogspot.com/2021/07/teach-myself-all-about-fmri.html. 

Reference 17: https://psmv4.blogspot.com/2021/08/more-statistics.html.