Functional connectivity, ha ha ha.

 

If you do resting-state fMRI and you do any sort of functional connectivity analysis, you should probably read this new paper from Blaise Frederick:

https://www.nature.com/articles/s41562-024-01908-6

I've been banging the drum on systemic LFOs for some time. Here's another example of how not properly thinking through the physiology of the entire human can produce misleading changes in so-called FC in the fMRI data. That said, I don't think Blaise has the full story here, either. For one thing, the big dips in his Fig 1b suggest that something is being partially offset with the on-resonance adjustment that is conducted automatically at the start of each EPI time series, so I have a residual concern that there are magnetic susceptibility effects contributing here somewhere. (Perhaps the magnetic susceptibility effects are what's left to drift higher after RIPTiDe correction, as in Fig 6b, for example.) The point is that not having independent measures of things like arousal, or proper models of physiologic noise components like sLFOs, or a full understanding of what's happening in the scanner hardware (including head support) during the experiment can lead to an assumption that things are neural when there are better explanations available. 

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Link added on 6/23/2024: Blaise Frederick discussing systemic LFOs on "Coffee Break!"

 

Core curriculum - Cell biology: synapses and neurotransmitters

 

The action potential from one neuron may or may not trigger further action potentials in neurons it connects to via synapses. A typical neuron with its single axon may make thousands of synapses to the dendrites of these "downstream" neurons. The locations of the synapses matter, in the sense that position relative to the downstream neuron's cell body provides a sort of weighted importance to any one synapse, as does the type of synapse. For fMRI we don't need to get too deep into the details of these connections, but we do need a basic understanding of the differences between excitatory and inhibitory connections. For the most part, whether a connection is excitatory or inhibitory is determined by the type of neurotransmitter released at the synapse.

First, let's get an overview of types of synapse and neurotransmitter, and the difference between excitatory and inhibitory neurotransmission:

Next, a little more detail and some context: 

In case it wasn't already clear, here's a nice explanation linking the pre-synaptic neuron's electrical potential to neurotransmitter release at the synapse:

Categorizing any one neurotransmitter as excitatory or inhibitory is a reflection of its usual effect on the electrochemical potential in post-synaptic neurons. The actual effect on any one post-synaptic neuron - whether that neuron is rendered closer to or farther away from its threshold voltage - can depend on the location of the synapse as well as the neurotransmitter(s) released in the synaptic cleft. Still, we can usefully categorize neurotransmitters according to their broadly different functions around the body:

In case you're interested in the structure of these neurotransmitters - perhaps because you are researching the effects of exogenous compounds ("drugs") on brain activity - here's a little more biochemistry:

Most of the videos above have focused on the neurotransmitter in the synaptic cleft. Naturally, the receptors on the post-synaptic neuron are critical to signaling. So let's take a slightly closer look at receptor types: 

And finally, a little more detail on the importance of synaptic location, not just type, in determining the type of action produced by a neural circuit:

That should suffice as a basic introduction to neurotransmission for the bulk of fMRI experiments, where we are looking at the collective effects of millions of neurons and trillions of synapses in any given voxel. Additional videos suggested by YouTube should provide good branches for those of you wanting more detail.

At this point, I want to shift to looking at the axon structure and its myelin sheath because this is an important distinction at the level of the fMRI voxel. We will tend to categorize any given voxel as containing mostly white matter (myelinated axons) or mostly gray matter (cell bodies). We will look at these in turn.

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Post-publication bonus video! I came across this video on some recent discoveries on dendritic activity while hunting for introductions to myelin structure. It's well worth a watch.

 

 

Core curriculum - Cell biology: the neuron's action potential

 

The last post reviewed the origins and properties of the resting membrane potential. Specifically, we are most interested in the membrane potential of neurons because they have an activated state that leads to signaling between neurons. Signaling from one neuron is achieved via an action potential from the cell body (soma) down its axon to synapses with other neurons. There are several good summary videos available online. Try them all to reinforce your knowledge.

Finally, in this post we get our first real look at synapses and excitatory and inhibitory neurotransmitters as part of a graded potential:

Now that you've seen the electrochemical action potential, in the next couple of posts we can dig more into neuron-neuron signaling, including synapses and the role of chemical neurotransmitters.

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BONUS: a speedy review. All familiar stuff now, right?

Core curriculum - Cell biology: cell membranes and the resting potential

 

A lot of the important functions of neurons (and glia) happen at their cell membranes. In the case of neurons, in addition to the membrane around the cell body (the soma), we also need to understand what happens along the neuronal processes (aka neurites): the dendrites (inputs) and the neuron's axon (the output). 

Let's begin this section by reviewing the structure of the cell membrane.

 

 

Transport across the cell membrane was introduce above. There are different mechanisms of membrane transport, each establishing certain behaviors of a cell.

The sodium-potassium pump is one of the most important membrane transport mechanisms for neural signaling. Let's take a closer look.

 

The cell's resting membrane potential was mentioned in the last two videos. The resting potential is an important starting point for understanding neuronal signaling via action potentials. For the last part of this post, we will look in more detail at the origins of the electrical potentials and electrostatic gradients across a cell membrane at rest.

In the next post we can start to look at cell signaling. Specifically, we are most interested in a neuron's action potential, which is the main way neurons communicate with each other.

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Core curriculum - Cell biology: taxonomy

 

Most of the biology we need to learn can be treated orthogonal to the mathematics, whereas the mathematics underlies all the physics and engineering to come. As a change of pace, then, I'm going to start covering some of the biology so I can jump back and forth between two separate tracks. One track will involve Mathematics, then Physics, then Engineering, the other will be Cell Biology, Anatomy, Physiology and then Biochemistry.

 

Let's begin with a simple overview of cell structure:

 https://www.youtube.com/watch?v=0xe1s65IH0w

The owner prohibits embedding this video in other media so you'll have to click through the link to watch.

Next, a little more detail on what's in a typical mammalian cell:

All well and good, but we are primarily interested in the types of cells found in neural tissue, whether central nervous system (CNS) or peripheral nervous system (PNS):

A little more taxonomy before we get into the details of neurons and astrocytes. In this video, we start to encounter the chemical and electrical signaling properties in cells, something we will get into in more detail in a later post. Still, it's timely to introduce the concepts.

As we move towards the neural underpinnings of fMRI signals, we need to know a lot more about neurons and astrocytes. Let's do neurons first.

While this next video repeats a lot of what you've already seen, there is enough unique information to make it worth watching.

Finally, a little more taxonomy that relates types of neurons to parts of the body, something that could be very important for fMRI when we are considering an entire organism.

To conclude this introduction to cell biology and types of neural cells, let's look at glial cells in more detail.

 Another simple introduction, to reinforce the main points:

And a nice review to wrap up.

We will look far more closely at astrocytes in a later video, once we've learned more about blood flow and control. For now, just remember that those astrocyte end feet are going to be extremely important for the neurovascular origin of fMRI signals.

 

That will do for this primer. The next post in this series will concern the resting and action potentials, signaling and neurotransmission.

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