Student: Where have you been?
Professor: Well, I’ve gotten lost deep in the forest of pulmonary physiology. So, for dyspnea described as ‘breathing too deeply’, let me list the paths I’ve covered:
- Starting along the path from the brainstem respiratory centers ,
- through phrenic spinal cord motoneuron,
- and the contracting diaphragm;
- then traveled from its tendon organs up their afferents,
- passing the C4-C5 dorsal root ganglia to external cuneate nucleus,
- and to ventral posterior lateral thalamic nuclei (VPL),
- that acts as a gate for sensations,
- so that only some can become respiratory perceptions.
Student: Wow, what a sensory gating trip. I’m guessing you could go on talking for hours!
Professor: I sure could, and instead, a short, annotated reference list will do.
1. Ventroposterior thalamus and somatosensory gating
Professor: Evidence #1 for Sensory Gating:
a. Some individuals seem to be flooded more by background sound than others:
Kisley MA, Noecker TL, Guinther PM. (2004) Comparison of sensory gating to mismatch negativity and self-reported perceptual phenomena in healthy adults. Psychophysiology 41: 604–612.
- Individuals showing a less robust event related potential (ERP) positive wave at about 50 ms (P1) for the second click (P2) of a paired-click paradigm.
- These persons also showed a larger mismatch negativity (MMN) waveform that was associated with higher self-reports of being flooded by sounds, i.e., not being filtered.
- Attenuation of P1 wave in the paired-click paradigm has been interpreted as ‘‘gating out,’’ and enhancement of wave P1 in response to stimulus novelty in the MMN oddball paradigm as ‘‘gating in’’.
- An enhanced neural activity associated with a larger P1 could lead to a neural ‘‘call to attention,’’ which is recorded at the scalp as a MMN.
Student: Yes; indeed. Some people can screen out redundant or unnecessary or novel information much better than others.
Professor: Evidence #2 for Sensory Gating:
b. A Stroke that includes VPL allows flooding the sensory gate:
Staines WR, Black SE, Graham SJ, McIlroy WE. (2002) Somatosensory gating and recovery from stroke involving the thalamus. Stroke 33: 2642-2651.
- Stroke involving VPL thalamus results in impaired detection of contralateral vibration, when accompanied by competing ipsilateral vibration, early after stroke.
- They suggest that this is due to a decreased “ability to gate competing information” due to an impaired “prefrontal-thalamic system”.
Student: Aha. A stroke that impairs the VPL thalamus cannot prevent flooding the gate.
Professor: So, what prevents flooding the gate? Let’s first look at efferent mechanisms, including EFFERENCE COPIES, that could possibly gate feedback from respiratory motoneurons. This means starting with the mechanisms that control and regulate breathing.
2. Control of breathing
Professor: First of all, guess what!? No more brainstem pneumotaxic or apneustic centers. These are still described in some modern physiology books!
Student: Hey! Then! What’s new?
Professor: Some scientists probing around the pons and medulla discovered groups of cells that behaved differently according to the time from the beginning of the respiratory cycle.
a. Very recently Rybak group’s first model of a network controlling breathing was published:
Rybak IA, Shevtsova NA, Paton JFR, Dick TE, St.-John WM, Mörschel M, Dutschmann M. (2004) Modeling the ponto-medullary respiratory network. Respir Physiol Neurobiol 143: 307-319.
- These authors noted that this was “the first attempt of computational modeling” for the ponto-medullary network.
- It involves many, many excitatory and inhibitory neurons and interneurons in the medulla’s Bötzinger Complex (BötC), pre-Bötzinger Complex (pre-BötC), and rostral Ventral Respiratory Group (rVRG) plus centers above them in the rostral pons.
- They stated, “that during eupnea the respiration-related pontine structures control the medullary network mechanisms for respiratory phase transitions, suppress the intrinsic pacemaker-driven oscillations in the pre-BötC, and provide inspiration-inhibitory and expiration-facilatatory reflexes”.
Student: Very fascinating! And where did this term “Bötzinger” come from, like in the “Bötzinger Complex”?
Professor: Professor Jack Feldman used an “unremarkable white” wine, Bötzinger, to give a toast naming an anatomical area in the medulla, before other investigators could. (https://www.inkling.com/read/medical-physiology-boron-boulpaep-2nd/chapter-32/origin-of-the-terms-btzinger)
Professor: Now, while you read the next article,
b. Sniff very deeply, taking deep breaths using only the diaphragm:
Smith JC, Abdala APL, Borgmann A, Rybak IA, Paton JFR. (2012) Brainstem respiratory networks: Building blocks and microcircuits. Trends in Neurosciences 36: 152–162.
- This is an Awesome Review! Excellent illustrations of the compartmentalization involved for a diaphragmatic inspiration.
- Third Rybak model showed the controlling microcircuits, that now including input from chemoreceptors, sensorimotor, and peripheral afferents.
- Revised and clarified drawings of this model with ‘compartmentalized microcircuits’.
- The model was used to depict the three stages of entire respiratory cycle: Inspiration, Post-Inspiration, and Expiration.
Student: I totally agree. Awesome review!
Professor: To complete the possible stages for the respiratory cycle, I wonder if they could add a “Post-Expiratory” stage rather than noting some scientists naming Post-Inspiration as E1 and all of expiration as E2?
Student: Hmm, you make an interesting comment about staging; lately, while meditating on my back, I’ve noticed that I breath up into my belly, quick transition to breathing down out of my belly, and pause for the count of One and Two.
Professor: Thanks, and notice the emphasis so far in our review is feedforward control of breathing. The next research article emphasizes,
c. The feedback elements that can assist in regulating breathing:
Molkov YI, Bacak BJ, Dick TE, Rybak IA. (2013) Control of breathing by interacting pontine and pulmonary feedback loops. Front Neural Circuits doi: 10.3389/fncir.2013.00016, 1-18.
- Using a newer version of their model, Rybak and co- investigators used computational modeling of data from vagotomized cats. They elegantly showed how feedback from pulmonary stretch receptors via the vagus nerves serves as variable respiratory input.
- Then they simulated pharmacologically suppressed feedback control from higher pontine centers to demonstrate that their mechanism involves glutamate receptors.
Student: Yea! Now I can see the complete picture for control of breathing. Is it okay to put the revised model to use?
Professor: Yes. Now we can check to see if,
d. There is a definite order of actions for each inspiration:
Dutschmann M, Dick TE. (2012) Pontine mechanisms of respiratory control. Comprehensive Physiology 2: 2443–2469.
- A brilliant use of the earlier model by Mörschel & Dutschmann (2009) to demonstrate the sequence of neural actions that occur during a complete inspiration.
- This sequence,
- Begins with a burst from pre-Bötz pacemaker (I-driver) neurons, exciting pontine early-I neurons and inhibiting medullary aug-I neurons during the initiation of inspiration.
- The latter two neurons then block neurons involved with the inspiratory-expiration transition.
- For the activities of these cells and others at the end of inspiration and end of post-inspiration, please look at Figure 5 of their article.
- Importantly, the inspiration/expiration transition is a dynamic, gating (or switching) interaction:
- Of the peripheral, reflexive, afferent inputs into the medullary respiratory centers and
- Of central, intrinsic activity of the Kölliker-Fuse (KF) nuclei in the rostral pons involved with learning how to breathe when sniffing, sighing, etc.
- These researchers also designate two pathways:
- The pathway from the medullary I-driver to medullary aug-I neuron continuing to pontine early-I neuron and
- The pathway from the medullary aug-I neuron to pontine I/E neuron
as two efference copies happening during the inspiration sequence.
Student: At last, has this review found possible pathways for efferent copies for potential afferent mismatching?
Professor: Yes. In fact, the efference copies could continue to some gating comparator in the cerebellum (see earlier post). Another pathway might be via the afferent circuits from the inspiratory muscles?
Student: Is it okay just to trace the involvement of the diaphragm?
3. Descending drive to phrenic motoneurons
Professor: Sure. Let’s follow,
a. How the diaphragm’s motoneuron is activated via the phrenic nerve:
Dobbins EG, Feldman JL. (1994) Brainstem network controlling descending drive to phrenic motoneurons in rat. J Compar Neurol 347: 64-86.
- The “primary population” of second-order controlling phrenic motoneuron is from the rostral Ventral Respiratory Group; another important monosynaptic pathway is from the Solitary Tract Nucleus.
- Third-order neurons project from numerous lateral tegmental tract, the Kölliker-Fuse (KF) area, and the brainstem nuclei involved with homeostasis, directly to ponto-medullary respiratory premotoneurons.
Student: The phrenic nuclei really gets a variety of direct excitatory inputs!
Professor: And some of these are from peripheral feedback circuits and others are from central behaviorally driven pathways via,
b. The tuning of the excitatory inspiratory neuron chains:
Ott MM, Nuding SC, Segers LS, O’Connor R, Morris KF, Lindsey BG. (2012) Central chemoreceptor modulation of breathing via multipath tuning in medullary ventrolateral respiratory column circuits. J Neurophysiol 107: 603–617
- The investigators studied the alignment of integrated phrenic nerve EMG with bursts of medullary respiratory cell activity during CO2 challenge via vertebral artery injection.
- Spike frequency from BötC-rVRG neuron microarray electrodes showed peaks or troughs with or without offset from start of inspiration, and also phasic or tonic patterns.
- The mosaic of identified correlational subassemblies of neurons incorporating these patterns (Fig. 6B) offered a new perspective on respiratory network architecture that includes multiple sites for regulating the motor pattern for breathing.
- These researchers suggest that,
- “Transmission of chemoreceptor drive [is] via a multipath network architecture.
- “RTN-pF modulation of pre-BötC-rVRG … excitatory inspiratory neuron chains is tuned by feedforward and recurrent inhibition from other inspiratory neurons and from “tonic” expiratory neurons.”
Student: So this ‘architecture’ and ‘tuning’ is what powers ‘comfortable’ pulmonary ventilation breath-by-breath.
Professor: They sure do. But what about ‘ uncomfortable’ breathing?
4. Phrenic nerve afferents receptors and pathways
Student: So, now we can turn and follow the diaphragmatic efferents back up toward the CNS.
Professor: Yup. Let’s start with the
a. Diaphragmatic muscle spindles and tendon organs:
Balkowiec A, Kukula K, Szulczyk P. (1995) Functional classification of afferent phrenic nerve fibres and diaphragmatic receptors in cats. J Physiology 483: 759-768.
- Within and especially around the musculotendinous edge of the central tendon were receptors that were “vigorously activated by diaphragmatic contraction.” They inferred “that they may innervate tendon organs“.
- When the diaphragm was contracted, many receptors “suppressed” their high resting activity and were mostly found in the lumbar area of the diaphragm. They suggested that they “probably innervated muscle spindles“.
Student: Interesting that these receptors are relatively fewer than skeletal muscle.
Professor: But they are still quite important when they send signals,
b. To the spinal cord and on to external cuneate nuclei in medulla:
Marlot D, Macron J-M, Duron B. (1985) Projection of phrenic afferents to the external cuneate nucleus in the cat. Brain Res 327: 328-330.
- First-order afferents from diaphragmatic mechanoreceptors have cell bodies in dorsal root ganglion and send collaterals to other cells in spinal cord and send axons to rostral ventral spinocerebellar tract (rVSCT).
- Stimulation of the rVSCT “evoked a complex response” recorded from the ipsilateral external cuneate nucleus.
- Second-order afferents travel from the external cuneate nuclei,
- Go to cerebellum and
- Collaterals also go to some nuclei of the thalamus.
Student: these cuneocerebellar neurons could send information to be compared to efference copies coming from the medullary respiratory group.
Professor: Later, we will discuss the cerebellar comparator, since there is apparently,
c. A direct route to the VPL thalamic nuclei:
Zhang W, Davenport PW (2003) Activation of thalamic ventroposteriolateral neurons by phrenic nerve afferents in cats and rats. J Appl Physiol 94: 220–226.
- In cats, direct mechanical stimulation of the diaphragm elicited increased activity in the same VPL neurons that were also activated by electrical stimulation of the phrenic nerve.
- Some VPL neurons responded to both phrenic afferent stimulation and shoulder probing suggesting possible VPL involvement in referred pain.
- In rats, VPL neurons are also activated by inspiratory occlusion that also have responded to stimulation on phrenic afferents.
- These results,
- “Demonstrate that phrenic afferents can reach the VPL thalamus under physiological conditions and
- “Support the hypothesis that the thalamic VPL nucleus functions as a relay for the conduction of proprioceptive information from the diaphragm to the somatosensory cortex.”
Student: Having a merged pathways for shoulder and diaphragm sensations is a possible part of referred pain!
Professor: AND NOW Evidence #3 for Sensory Gating
d. Data from paired inspiratory occlusions demonstrate second occlusion is reduced:
Chan P-YS. Davenport PW. (2008) Respiratory-related evoked potentials of respiratory sensory gating. J Appl Physiol 105: 1106-1113.
- They tested if paired inspiratory occlusions in humans would result in a reduced (i.e., gated) amplitude of the second stimulation, indicating respiratory central neural gating.
- The negative EEG peak at about 100 ms (N1) of an respiratory-related evoked potential (RREP) represents early perceptual processing of respiratory sensory information that is similar to the N100 peak shown with tactile sensation.
- The first RREP N1 peak amplitude was significantly greater than the second, and the S2/S1 ratio was 0.43.
- These results are consistent with central neural gating of respiratory afferent input.
Student: It’s getting quite clear that there is sensory gating and that it related to thalamic functioning.
5. TPN and Searchlight
Professor: Right on! In fact, from 1984, here is Evidence #4 for Sensory Gating:
a. A function of the thalamus is focusing attention, like using a flashlight to look for ‘unusual’ activity:
Crick F. (1984) Function of the thalamic reticular complex: The searchlight hypothesis. PNAS 81: 4586-4590.
- Professor Crick “presents a set of speculative hypotheses concerning the functions of … the nucleus reticularis of the thalamus.”
- It is “as if the brain had an internal attentional searchlight [in the thalamic reticular nucleus (TRN)] that moved around from one … [highly active spot] to the next.”
- “It is believed that many of the axons that pass in both directions through the reticular complex give off collaterals that make excitatory synaptic contacts [with cells of the TRN] ….”
- “If the thalamus is the gateway to the cortex, the reticular complex might be described as the guardian of the gateway.”
Student: Whoa! Eh what! You said this was published in 1984! Who kept this hidden?!
Professor: I guess this is what happens when some ‘know it all’ researchers in sensory psychophysiology did not broaden their historical work. Well, so be it, and let’s look at
b. Newer research on the structure and function of the “skin” around the thalamus:
Guillery RW, Feig SL, Lozsádi DA. (1998) Paying attention to the thalamic reticular nucleus. Trends Neurosci 21: 28-32.
- The thalamic reticular nucleus (TRN) is a thin multilayer ‘skin’ more “like a sieve rather than a real shield.”
- They noted that, “It is divided into sectors, with one per sensory modality; each TPN sector maps topographically with the cortex.”
- Each TPN sector “serves as a nexus, where several functionally related cortical areas and thalamic nuclei can … interact to control thalamocortical transmission [into/out of] related thalamic [relay cells].”
Student: I never was taught about this!
Professor: This thalamic reticular nucleus is a well-kept secret.
c. How does it work like a searchlight, gating unnecessary information transfer to the cortex?
Lam Y-W, Sherman SM. (2011) Functional organization of the thalamic input to the thalamic reticular nucleus. J Neurosci 31: 6791-6799.
- The investigators show that “the thalamoreticular pathway is organized topographically for most neurons.
- For example, “The somatosensory region of the TRN can be organized into three tiers.
- “From the inner (thalamoreticular) border to the outer, in a manner roughly reciprocal to the reticulothalamic pathway, each of these tiers receives its input from one of the somatosensory relays of the thalamus—the posterior medial, ventroposterior medial, and ventroposterior lateral nuclei.
- “What is surprising is that approximately a quarter of the recorded neurons received input from multiple thalamic regions usually located in different nuclei. These neurons distribute evenly throughout the thickness of the TRN.
- “[These] results, therefore, suggest that there exist a subpopulation of TRN neurons that receive convergent inputs from multiple thalamic sources and engage in more complex patterns of inhibition of relay cells.
- “[They] propose these neurons enable the TRN to act as an externally driven “searchlight” that integrates cortical and subcortical inputs and then inhibits or disinhibits specific thalamic relay cells, so that appropriate information can get through the thalamus to the cortex.”
Student: So there is the mechanism for gating diaphragmatic activity from reaching the somatomotor cortex, unless the activity overwhelmes the TRN inihibition for mechanical feedback.
Student: So, there is the mechanism for blocking, i.e., gating, diaphragmatic activity from reaching the somatomotor cortex.
Professor: Yup. That is, unless breathing sensations overwhelm the TRN inhibition for mechanical feedback. See Sherman’s Scholarpedia review, referenced below, for more detail about thalamic cellular ionic disinhibiting mechanisms and gating circuitry.
Take Home: The thalamic reticular nucleus acts like searchlight to spot ‘unusual’ breathing or other thalamocortical sensory activities, I.e., a mismatch, to allow that information to travel upward and possible be perceived as uncomfortable.
Next: How do the higher CNS networks for Attention, Salience, Executive Control, Default Mode, and Vocalization handle breathing sensations that are uncomfortable?
Additional References:
Mörschel M, Dutchmann M. (2009) Pontine respiratory activity involved in Inspiratory / expiratory phase transition. Phil Trans R Soc B 364: 2517–2526.
Sherman, SM. Thalamus. (2006) Scholarpedia, 1(9):1583., revision #88881.
http://www.scholarpedia.org/article/Thalamus
