Brainstem? Brainstem!

Revisiting brain regions, courtesy  of Pinky and the Brain.

 

(Incidentally, I named my first neuroscience review paper “Dyspnoea and the Brain” partly in honour of this comic, fully expecting the title to be dismissed by colleagues and journal alike. It wasn’t. Nobody has spotted the connection yet, sadly.)

Breathing on the brain

As easy as breathing? It may seem like it, but breathing is actually no easy process. It involves the precise integration of several systems, including, of course, the pulmonary and cardiovascular systems (gas exchange and transport, respectively). However, it also requires the direct involvement of the central nervous system: the brain.

The drive to breathe is generated in the brainstem. In a study published almost 100 years ago, the crucial role of the different parts of the brainstem was demonstrated in a somewhat gruesome way by sectioning the brainstem of an anaesthetised cat (Lumsden, 1923). The main areas of interest are in the medulla and pons. Cut above this, and the breathing continue. Cut below this, and it will cease.

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The brainstem is the part of the brain that connects to the spinal cord. The figure above shows an MRI image of a human brainstem, with the pons (A) and medulla (B) labelled.

The Medulla

On each side of the medulla we find neurons that are grossly organised in vertical columns. These can be divided into dorsal and ventral columns – that means columns situated towards the back of the medulla, and columns that are towards the front.

On the dorsal side of the medulla (towards the back), we find neurons that primarily govern inspiration (as opposed to expiration). These neurons fire when you breathe in. One of the most important clusters of neurons in this area is the nucleus tractus solitarius (NTS), which is an area that receives sensory input from the chest. It is thought that the NTS integrates sensory information from the body and relays this to other regions in the brainstem. In short, it could be viewed as a communication hub. The NTS is involved in a range of important functions as well as respiratory control, including for example the control of blood pressure.

On the ventral side of the medulla (towards the front), we find both inspiratory and expiratory neurons. We also find motor neurons that connect with muscles in the throat and chest. The respiratory column on the ventral side can be grossly divided into three regions: rostral (top/front), intermediate (middle) and caudal (bottom//back). The rostral part holds expiratory neurons. The intermediate part contains mostly inspiratory neurons plus the assumed ‘pacemaker’ of breathing: the pre-Bötzinger complex*. This complex contains pacemaker neurons capable of setting a breathing rhythm, and it can generate different rhythms depending on the level of oxygenation. We don’t yet know if the pre-Bötzinger complex sets the pace on its own, or if uses input from other regions as well. Typically, if not influenced by other factors, this region is ‘on’ for two seconds (inspiration) and ‘off’ for three seconds (expiration). Finally, the caudal regions hold expiratory neurons (that connect with motor neurons controlling expiration).

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So to summarise, it is thought that sensory  input relevant to respiration is received in the dorsal medulla, specifically the NTS, and relayed to the ventral side, where we find both expiratory and inspiratory neurons, a ‘pacemaker’ and motor neuron connections to the body. So far so good.

At normal, ‘relaxed’ breathing, we see heightened activity in inspiratory motor neurons during inspiration, but the expiratory phase is silent. This is because we normally exhale by passive recoil (i.e. by simply letting the lung return to its non-stretched state after breathing in). During heavy breathing, such as during exercise, expiration is active. This means that the expiratory muscle neurons will fire whenever we breathe out, forcing a faster and stronger expiration than normal (puffing). Which leads us to one crucial point: the activity in the medulla can be modulated, and even overridden.

The Pons

Further up in brainstem, we find clusters of respiratory neurons in the pons. If the brainstem is cut between the medulla and the pons, the breathing will (most likely) continue, but it will be irregular. The part of the pons involved in the control of breathing is the pneumotaxic centre (or, as it is currently often named: the pontine respiratory group). This is a selection of clusters that modulates breathing through connections to the medulla (i.e. through causing the medulla to change its activity). It controls the timing of breaths through switching the duration of the respiratory phases. For example, stimulation of the pontine respiratory groups can cause your breathing to switch more quickly from inspiration to expiration. It also receives input from receptors in the lung. This input acts to dampen its activity, so that the lungs aren’t made to inflate too much (or too little). In short, the pontine respiratory groups fine-tune how quick and deep you breathe.

A second region of the pons is also often discussed in terms of respiratory control, but this centre – the apneustic centre – has not been found yet. All we know is that cutting the pons in the general region where we believe the apneustic centre is located causes excessively long inspirations with only the occasional expiration (apneustic breathing). We therefore guess that this area is important for stopping inspirations (generating the inspiratory cut-off). Again, it is thought that this region acts by sending signals to the medulla.

So to summarise, the pons is necessary for the finer regulation of our breathing patterns to fit the needs of the body, say, for example, if we need to breathe faster or take deeper breaths. Without the pons, the medulla generates a rhythmic, but slightly gasping, type of breathing.

The higher brain regions

In addition, we have higher brain regions that can modulate breathing. Speaking, holding your breath, eating, being in pain or startled, emotional states – these can all change your breathing, either voluntarily or involuntarily. Generally speaking, voluntary breathing alterations (e.g. speaking, eating, holding your breath) bypass brainstem centres and act directly on spinal motor neurons, while involuntary breathing alterations (e.g. pain, startle) can act both on the spinal motor neurons and through the brainstem nuclei, thus changing the respiratory pattern generation directly.

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The higher brain regions involved in breathing modulation are not fully described, and it is likely that each of the situations mentioned above may recruit different higher brain regions. For example, being out of breath can induce activation in sensorimotor brain regions and/or emotional regions (like the limbic system) and/or areas associated with cognition (prefrontal regions), each to varying degrees, depending on the level and origin of the breathlessness (Herigstad et al. 2011).

 

In conclusion, we are still some way away from fully characterizing how the brain governs breathing, and it’s not likely to be a simple process. As with many of the important bodily functions, there are several layers of control, both to fine-tune our responses and make it possible for us to adapt to different environments and situations, but also to provide redundancies (‘backup systems’) to ensure that the body keeps on functioning even if one system is not working precisely the way it should. It’s never as easy as breathing.

 

Caveat: This is meant as a brief summary of breathing in the brain. It doesn’t include all the details, mechanisms or exceptions by a long stretch. Squeezing that kind of detail into a single blog post is not really feasible.

* The pre-Bötzinger complex is a projection of the Bötzinger complex, which was named after a bottle of reasonably-priced white wine that happened to be served at the scientific workshop when its discovery was discussed.

References: Lumsden, T. J Physiol (1923), 57: 153-160; Pattinson, K.T.S. Br J Anaesth (2008), 100(6): 747-758; Herigstad, M. et al. Respir Med (2011), 105(6): 809-18.

P-values for correlations in Excel

This is just a quick post to describe how to calculate p-values for two-variable correlations in Excel. Annoyingly, there is no direct way of doing this. Excel will give you the correlation, but not its associated p-value. It can be done, however, in a slightly roundabout way.

First, calculate the correlation between your groups:

=correl(variable1, variable2)

This gives you the sample test statistic r, which can be converted to t with the following formula:

temp2

where r is the correlation obtained above and n is your number of observations. Say you have 30 samples for two groups, and a r of 0.5. The calculation to obtain t is then (in excel terms):

=(0.5*sqrt(30-2))/(sqrt(1-0.5^2))
=3.05505

Then to assess the significance value associated with this t, simply use the tdist function (Student T distribution output):

=t.dist.2t(t, degrees of freedom)

This gives us results for a two-tailed distribution. Alternatively, the old tdist function can still be used, which requires the user to specify the number of tails (=tdist(t, degrees of freedom, #tails)).

Our calculation thus looks like this:

=t.dist.2t(3.05505, 30-2)
=0.0049

Which is the p-value for the correlation. Done!

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