More about Locus Ceruleus

Deric Bownds at Mindblog posted about this new article today: Modafinil Shifts Human Locus Coeruleus to Low-Tonic, High-Phasic Activity During Functional MRI. Not exactly a catchy title, but what the abstract implies is pretty exciting - LC seems to be involved in cognition.

Cognition? Cognition. Fascinating.

Here is the abstract, viewable by clicking on Deric's post, How a cognition enhancing drug works.

"Models of cognitive control posit a key modulatory role for the pontine locus coeruleus–norepinephrine (LC-NE) system. In nonhuman primates, phasic LC-NE activity confers adaptive adjustments in cortical gain in task-relevant brain networks, and in performance, on a trial-by-trial basis. This model has remained untested in humans. We used the pharmacological agent modafinil to promote low-tonic/high-phasic LC-NE activity in healthy humans performing a cognitive control task during event-related functional magnetic resonance imaging (fMRI). Modafanil administration was associated with decreased task-independent, tonic LC activity, increased task-related LC and prefrontal cortex (PFC) activity, and enhanced LC-PFC functional connectivity. These results confirm in humans the role of the LC-NE system in PFC function and cognitive control and suggest a mechanism for therapeutic action of procognitive noradrenergic agents."

Thank you so much for bringing this to this reader's avid attention, Deric. I was interested in the pain-downregulating capacity of LC, its role in sleep, and its extensive connection to everything else in the brain. Now it looks like there may be a direct link between it and actual, functional cognition, not just anatomical noradrenergic pathways between it and parts of the brain one might be forgiven for having assumed were involved in actual, functional cognition.

Here is a link to posts I made earlier in the year, about locus ceruleus.

It has become one of those brain part names that leaps out at me, as does the insula.

"Sky-blue place" IV: Descending modulation

In reference to:
Locus Ceruleus: "Sky-blue place"
"Sky-blue place" II: Projections
"Sky-blue place" III: Input

This will be the last post in this series.
I think I've turned over most of the stones I could find learning about this cool little brain spot that seems to know just when to wake up the brain and when to be quiet.

I want to bring forward a few more juicy tidbits here, however, from Textbook of Pain 5th Ed.

1. The PAG (periaqueductal grey) and locus ceruleus seem to enhance one another's function: (p. 394:)

"Concurrent delivery".. (of "ethylketocyclazocine,""reported to have μ-agonist properties"), "at doses that together were less than injected in either site alone, produced a significant, naloxone-reversible increase in response latency. These observations were argued to reflect a synergic interaction between these two anatomically distinct systems (Bodnar et al 1991)."

If something is naloxone-reversible it means it has an opioid effect of some kind.

2. Anterior insular cortex projects to LC: (p. 127:)

"Dorsolateral pontine systems may also contribute to cortical control of spinal nociceptive transmission. Increasing GABA levels in the anterior insular cortex produces an analgesic effect that is blocked by intrathecal administration of α-adrenergic antagonists. Because this cortical region projects to the locus coeruleus as well as the RVM, it was suggested that inhibition of the insular outflow disinhibits noradrenergic neurons of the locus coeruleus (Jasmin et al 2003b). This could be through an action in the pons or via the RVM."

I missed this when I did the projections post.
(Note: RVM = rostral ventromedial medulla)

3. Linkage to affective states: (p. 234:)

"Chapman (2004) described how processing of nociceptive signals produces affect in multiple neurotransmitter pathways that project to the cortex. Noradrenergic, serotonergic, dopaminergic and acetylcholinergic fibres and pathways are involved. Drawing on an extensive literature on the biology of emotions (e.g. Gray 1987), noradrenergic pathways are recognized as linked most closely to negative emotional states. Of particular importance are nociceptive afferent systems operating and transmitting through the limbic brain-in particular the locus coeruleus, the dorsal noradrenergic bundle, the ventral noradrenergic bundle, and the hypothalamo-pituitary-adrenocortical axis-to all of the neocortex. These are not specific in their activation to nociception, but are also responsive to non-nociceptive, aversive emotional states. These systems are recognized as fostering survival by allowing biological vigilance to threatening and harmful stimuli, both external and internal. Chapman proposes that the affective dimensions of pain can best be conceptualized as involving a two-stage mechanism. The immediate experience would be akin to hypervigilance or fear, with this rapid response giving rise through efferent messages to visceral and other event-related, autonomic activity that creates a strong negative subjective experience and an affective response involving images and symbols."

4. Supraspinal analgesia: (p. 431:)

"Fibres descending from the RVM to the dorsal horn of the spinal cord are mostly serotonergic, enkephalinergic, glycinergic and GABAergic. The nucleus raphe magnus contained within the RVM and the noradrenergic nuclei (locus coeruleus, subcoeruleus, A5 and A7 cell groups) are major PAG relays for noradrenergic and serotonergic descending pathways, respectively, to the dorsal horn (Kwiat & Basbaum 1992). Rather than the RVM being a homogeneous population of serotonergic neurons, GABA- (and glycine-) releasing neurons are now thought to constitute a significant proportion of spinally projecting RVM fibres (Antal et al 1996). The pharmacology of noradrenergic and serotonergic modulation in the dorsal horn is complex but opioids can also interact with noradrenergic mechanisms and there are many studies showing that the effector mechanism and location for the major noradrenaline target receptor-the α2 adrenoceptor-is very similar to that of opioid receptors."

Here is a picture of where LC is to be found in the brain (see red arrow, image from Atlas of Functional Neuroanatomy and modified).

Look at how tiny it is. (I think if you click on the picture you can enlarge it some more.)

Here is a link to a set of notes I made on this little brain part.

"Sky-blue place" III: Input

In reference to "Sky-blue place" II: Projections:

In the post referenced above I provided a very very sketchy list of all the places LC fibers go to, what they affect, i.e., which parts hear the "alarm."

I now have pages and pages of info on that, but finding out which bits feed into LC is a bit harder. I guess the pathways are a bit less well worked out.

The Appenzeller source lists a couple of places, nucleus paragigantocellularis lateralis (of the rostral ventrolateral medulla), and nucleus prepositus hypoglossi of the rostral dorsomedial medulla.

Nucleus paragigantocellularis lateralis (what a name!) corresponds neuroanatomically to the neurochemical localization of C1 and A1 epinephrine and norepinephrine-containing cell bodies near the ventral surface of the brainstem. Nucleus prepositus hypoglossi corresponds to the localization of C3 adrenergic neurones near the dorsal surface of the medulla bordering on the 4th ventricle. (Riveting, I know..)

Other than that, apparently LC receives neurons from itself, with collaterals. Appenzeller says, p. 162:

"Both external and internal perturbations can activate the locus ceruleus, the latter after sensory processing in the medullary nuclei. Thus, if a stimulus were perceived as novel, severe or threatening, locus ceruleus activation could foster transmission of the signal to higher brain centers, facilitating active attention and memory consolidation and further orienting the organism to the stimulus."

The brain can perturb its own LC. Maybe it's the LC that becomes activated during times of cognitive dissonance.


New Territory

I looked into those two medullary or brainstem nuclei, which took me into the reticular formation, from which I'm yet to emerge. It is not an easy place to grasp. Gray's Anatomy (39th) says, (p. 347):

"The brain stem contains extensive fields of intermingled neurones and nerve fibres, which are collectively termed the reticular formation. The reticular regions are often regarded as phylogenetically ancient, representing a primitive nerve network upon which more anatomically organized, functionally selective, connections have developed during evolution. However, the most primitive nervous systems show both diffuse and highly organized regions, which cooperate in response to different demands.

"The general characteristics of reticular regions may be summarized as follows. They tend to be ill-defined collections of neurones and fibres with diffuse connections. Their conduction paths are difficult to define, complex and often polysynaptic, and they have ascending and descending components that are partly crossed and uncrossed. Their components subserve somatic and visceral functions. They include distinct chemoarchitectonic nuclear groups, including clusters of serotoninergic neurones (group B cells), which synthesize the indolamine 5-hydroxytryptamine (serotonin); cholinergic neurones (group Ch cells), which contain acetyltransferase, the enzyme which catalyses the synthesis of acetylcholine; and three catecholaminergic groups composed of noradrenergic (group A), adrenergic (group C), and dopaminergic (group A) neurones, which synthesize noradrenaline (norepinephrine), adrenaline (epinephrine) and dopamine respectively as neurotransmitters."

This seems daunting, but in persevering, I am learning quite a bit about the reticular formation system(s). They are generally grouped into three systems, raphe or median, medial (just to be confusing) located between the raphe and lateral, the third.


Are the neurons coming or going to LC?

The raphe system seems to connect to LC, but are the neurons afferent or efferent? From Gray's:

"the dorsal raphe nucleus, in addition to sending a large number of fibres to the locus coeruleus, projects to the dorsal tegmental nucleus and most of the rhombencephalic reticular formation, together with the central superior, pontine raphe and raphe magnus nuclei."

However, another source, an online book, Basic Neurochemistry, in its page on serotonin, says:

"The raphe nuclei also receive input from other cell body groups in the brainstem, such as the substantia nigra and ventral tegmental area (dopamine), superior vestibular nucleus (acetylcholine), locus ceruleus (norepinephrine) and nucleus prepositus hypoglossi and nucleus of the solitary tract (epinephrine)."

Regarding pain modulation

In Gray's this tantalizing bit appears: "Raphe spinal serotoninergic axons originate mainly from neurones in the raphe magnus, pallidus and obscurus nuclei. They project as ventral, dorsal and intermediate spinal tracts in the ventral and lateral funiculi, and terminate respectively in the ventral horns and laminae I, II and V of the dorsal horns of all segments, and in the thoracolumbar intermediolateral sympathetic and sacral parasympathetic preganglionic cell columns. The dorsal raphe spinal projections function as a pain-control pathway that descends from the mesencephalic pain-control centre, which is located in the periaqueductal grey matter, dorsal raphe and cuneiform nuclei. The intermediate raphe spinal projection is inhibitory, and, in part, modulates central sympathetic control of cardiovascular function. The ventral raphe spinal system excites ventral horn cells and could function to enhance motor responses to nociceptive stimuli and to promote the flight and fight response."

To be continued.

References:
1. Atlas of Functional Neurology (2006) Hendelman W (p. 114-19)
2. Gray's Anatomy (39th ed.) p. 347-350
3. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW, p. 155
4. Basic Neurochemistry (1999) Siegal G

Additional reading:
1. Brainstem (scholarpedia)

Locus Ceruleus: "Sky-blue place"

You must admit, the name is catchy.

I first read about this spot in the brain in a very entertaining and informative book called Beyond the Zonules of Zinn: a Fantastic Journey Through Your Brain, by David Bainbridge, a vet. I first heard about the book from Ginger Campbell of Brainscience podcast, in Episode 32.

Bainbridge, in his discussion about the tegmentum, has this to say about locus ceruleus;

"Also in this area is the wistful-sounding locus coeruleus, the "sky blue place." Its ethereal blue color probably results from the deposition of long chains of the chemical that its neurons release, norepinephrine. The coeruleus is in no way a restful place, however. It is probably important in driving the rest of your brain to be active when it needs to be, and it is involved in alertness, arousal, stress and ultimately panic. Its neurons send meandering tendrils to almost all other parts of your brain to jolt you into action - for example, it is almost certainly part of the fright-recognition pathway between the hillocks and the almonds. Intriguingly, it is also important in dreaming sleep - something to which we will return briefly in the final chapter of this book. Finally, and perhaps unsurprisingly when you consider what it does, many antidepressants are thought to act on areas with which the locus coeruleus communicates. Maybe depression is when the sky-blue place darkens into twilight."

I must admit I was captivated by the unabashedly poetic way he writes about this "sky-blue place" (along with everything else). He says elsewhere in the book that it was originally discovered and named by Félix Vicq d'Azyr, who was an anatomist, veterinarian, and personal physician to Marie Antoinette.

It sounded like a part that deserved to be checked out more deeply, and I'm glad I did. There are scads of interesting factoids about this brain part, which I will bring here to this blog over the next few days. Meanwhile, here is what is probably its main feature important from a pain perspective: it alerts the whole brain to novel stimuli via ascending (or rostrally projecting) fibers, while simultaneously dampening nociceptive relay neurons in the dorsal horn through descending (or caudally projecting) fibers. (Check out the image provided. Find LC, which is colored lime green in this image, not sky-blue. Trace the arrows projecting from LC. They go up and around the whole cortex, and down to the cord.)



This explains why, even if you have pain, if you were to see a bus coming at your toddler, you forget all about your pain, wouldn't even feel it probably, and would run out to snatch your toddler out of danger.

This makes the locus ceruleus sort of like a transmission that can change gears suddenly, or a switch box that can change the locus of one's attention in a flash. Kandel says (p. 895);

"The largest collection of noradrenergic neurons is in the pons in the locus ceruleus. Remarkably, although the locus ceruleus projects to every major region of the brain and spinal cord, in humans it contains only about 10,000 neurons on each side of the brain. The locus ceruleus maintains vigilance and responsiveness to novel stimuli. It therefore influences both arousal at the level of the forebrain and sensory perception and motor tone in the brain stem and spinal cord."

From the Encyclopedia, p. 639 Vol 3;

"LC activation can also produce potent anti-nociception by reducing the response of neurons of the dorsal horn of the spinal cord through the stimulation of α2- adrenergic receptors."

References:
1. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW
2. Gray's Anatomy (39th ed)
3. Encyclopedia of the Human Brain
4. Principles of Neural Science 4th Ed (Eric Kandel)
5. Image provided courtesy of CNSforum Brain Explorer image bank

Additional reading:
1. Brainstem (Scholarpedia)

Nervous System Basics VI: PURPOSEFULNESS

Angevine's fifth basic organizing principle, purposefulness:

"The Purposefulness of Neural Components
Every part of the nervous system has at least one function, often many more. Small parts of the CNS may play crucial roles, as in the extensive distribution and profound influence of axons from inconspicuous brain centers. The locus ceruleus ("blue spot") on each side of the fourth ventricle contains about 12,000 large melanin-pigmented neurons. These synthesize norepinephrine and release it in the cerebral cortex, cerebellum, and almost every other part of the CNS. Electrically, they are almost silent in sleep, hypoactive in wakefulness, and hyperactive in watchful or startling situations. They serve vigilance and attention to novel stimuli. They contribute, indirectly but no less crucially, to perceptual and cognitive functions. By contrast, immense structures make large but expensive contributions, as in the cognitive and motor abilities afforded us by the billions of neurons in our cerebral and cerebellar cortices."

I never have heard such attributes associated with the locus ceruleus before. Fascinating. Another tidbit on locus ceruleus, from Kandel, p. 483:

"...other descending inhibitory systems that suppress the activity of nociceptive neurons in the dorsal horn originate in the noradrenergic locus ceruleus and other nuclei of the medulla and pons. These descending projections block the output of neurons in laminae I and V by direct and indirect inhibitory actions. They also interact with endogenous opioid-containing circuits in the dorsal horn..."

So, locus ceruleus is involved in descending inhibition of pain. Doubly fascinating.

On another topic expanding from this organizing principle, i.e., preconscious genesis/control of conscious thought or action, of ordinary activities we "imagine" to be of our own "free will", much research has demonstrated that, in fact, non-conscious areas of the brain truly run all the decision making activities and simply provide us a grand illusion that we somehow have choice in what we are going to "do" in any given moment.

This can pose a problem if one's concept of the brain is
1. it is monolithic and singular, or
2. if one identifies conscious awareness with the brain itself
3. if one's experience is that when one wants to pick up one's hand, one can, and that's all there is to it.

It may seem odd that nonconscious parts of one's own brain control the behavior and timing of the "I" construct, instead of the other way round. Yet, this is more like how things actually are.

Antonio Damasio's book, The Feeling of What Happens, helps this all fall into place. Reading this book helped my own concept of the brain to change completely from thinking of it as some big homogenous blob up on the top of my body, to an appreciation of the brain as a community of discrete parts that communicate intensely and continuously, a predictor and simulator.

After reading this book, my image of the brain changed to one in which a main, nonconscious "brain", operating autonomously but with my best interests first and foremost, exists in space with two parts attached, a large mobile body attached to the back end, and something called "conscious awareness" affixed (sort of like a miner's head lamp, but easily swiveled) to the front end. The "brain" in the middle can coordinate these two parts easily. (It's a simplistic image but it works for me. In PT, it will take quite awhile before all of us switch from regarding the brain as that blob at the top of the body that is none of our business, to seeing the body as merely the big blob behind the brain, and the brain as the main focus of our interventions.)

There is a trail of research on the timing of conscious awareness as being an after-the-fact phenomenon leading back to Benjamin Libet's Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential): the unconscious initiation of a freely voluntary act. Note the extensive citation list.

Deric Bownds spoke of it recently on MindBlog. Here is a more recent paper he mentioned: Unconscious determinants of free decisions in the human brain.

Additional reading:

1. Books by Benjamin Libet
2. Review of Mind Time, one of the books
3. Publisher comment on another Libet book, The Volitional Brain
4. An analysis of Libet's work by John McCrone