Monkey Robotics

Mo at Neurophilosophy posted this today: Monkey controls robotic arm with brain-computer interface. It's a great post, full of great links. Check it out.

Other posts here that refer to monkeys and/or robotics:
1. Smart Prosthetics, Smart Nerves, Smart Brains
2. More Smartness

"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)

"Sky-blue place" II: Projections

In reference to: Locus Ceruleus: "Sky-blue place";

Noradrenergic neurons of LC project to:

1. thalamus
-especially anteroventral nucleus

2. hypothalamus nuclei (although most noradrenergic projections in this area come from norepinephrine-containing cells in the medulla)
-paraventricular
-periventricular
-supraoptic
-dorsomedial

3. hippocampus
noradrenergic activation of the hippocampus may facilitate long-term memory of distressing events

4. septal area
-basal nucleus of the stria terminalis
-central and basolateral nuclei of amygdala
-olfactory bulb

5. cerebellum

6. neocortex

7. several brainstem nuclei thought to function as primary sensory or association centers


Some features of this projection system

Apparently the arborization is very extensive - very few cells project very widely. This means that this little sky-blue spot has a lot of leverage. It doesn't take very many cells to get a big effect if those cells have a multiply-branched communication system in place.

It must be emphasized that this system is entirely inside the brain and spinal cord. LC directs its messaging only to other brain parts. It stays away from the body department - leaves communication of alerting and alarming to a different system; it does not project much directly to sympathetic preganglionic neurons, and probably participates only indirectly in regulation of sympathoneural outflow. Its job seems to be to "alarm" the hypothalamus which in turn "alarms" the adrenals which then prepare the body for an encounter with danger.

It might seem roundabout to have different systems running different parts differently, but a lot of things in the nervous system work like this. Bits that evolved ahead of other bits kept their operating systems and merely linked up to or completely enclosed other systems. They all still work, in parallel, separately and together. And it's not so bad from an organism point of view. Better for survival to have many systems (in case one should be knocked out) than to rely completely on just one perfected one.

The LC doesn't just magically know what's going on outside - special senses are involved, and must register input which must in turn be relayed to the LC before the LC can perform its alarm bell duty. So, next, I'll address where the LC gets its information from.

NOTES

*Innervation that travels from one part of the brain to another part or parts.

**"Noradrenergic"refers to a neurotransmitter, noradrenaline, also called norepinephrine, that stimulates a nervous system out of ordinary function into super function. (Here is a wikipedia entry about it.) In the brain it is thought to be recycled out of another neurotransmitter called dopamine. In the body it is secreted by the adrenal glands (which sit on top of the kidneys).

REFERENCES

1. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW, p. 155

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 IX: CHEMICAL CODING

Angevine's eighth and last organizing principle:

"Chemical Message Coding
The basic function of the nervous system, from which all others derive, is communication, performed (with unsung neuroglial support) by neurons. It depends on special electrical, structural,and chemical properties of these diversified cells with their long processes, on their exploitation and refinement of two basic protoplasmic properties, irritability and conductivity, on their external and internal neuronal morphology featuring multipolar shape and integrative design, almost infinite modes of dendritic and axonal branching, widespread, diversified connections, and specialized organelles, and on their use of chemical substances to encode, deliver and decipher messages of their own and other neurons.

Neural circuits are chemically coded. Neuroanatomy encompasses interneuronal connections and also chemical mediators and transmitters. Neuroactive substances comprise neurotransmitters, neuromodulators, and neurohormones. Their definition in contexts other than site of action, postsynaptic neuronal activity, and corelease of one or more additional neuroactive substances can be misleading. Neurotransmitters are small molecules acting swiftly, locally, and briefly on target cells. Neuromodulators are very small (peptides), regulating but not effecting transmission, and neurohormones are also small, with intrinsic activity mediated by neuronal and other cells, exerting slow, widespread, and enduring influence via the extracellular fluid or bloodstream.

Neurons releasing hormones are quasi-endocrine cells, liberating secretory products from axonal endings into the perivascular space to be conveyed to blood vessels and thence to target organs. The provincial concerns of neurophysiology and endocrinology have fused into neuroendocrinology, as psychoneuroimmunology has united psychobiology, molecular neurobiology, and immunology."

This area of study, neurophysiology, is something I haven't tackled yet to any large extent, still don't know the transmitters from the neurohormones from the chemical neuromodulators, but I'm working on it.

What I like about Angevine's little chemical coding summary is that it is succinct and clear.

Here is more, from Gray's Anatomy:

"Neurohormones
Neurohormones are included in the range of transmitter activities. They are synthesized in neurones and released into the blood circulation by exocytosis at synaptic terminal-like structures. As with classic endocrine gland hormones, they may act at great distances from their site of secretion. Neurones secrete into the cerebrospinal fluid or local interstitial fluid to affect other cells, either diffusely or at a distance. To encompass this wide range of phenomena the general term neuromediation has been used, and the chemicals involved are called neuromediators".

"Neuromodulators
Some neuromediators do not appear to affect the postsynaptic membrane directly, but they can affect its responses to other neuromediators, either enhancing their activity (increasing the immediate response in size, or causing a prolongation), or perhaps limiting or inhibiting their action. These substances are called neuromodulators. A single synaptic terminal may contain one or more neuromodulators in addition to a neurotransmitter, usually (though not always) in separate vesicles. Neuropeptides are nearly all neuromodulators, at least in some of their actions. They are stored within dense granular synaptic vesicles of various sizes and appearances."

"Neurotransmitters
Until recently the molecules known to be involved in chemical synapses were limited to a fairly small group of classic neurotransmitters, e.g. ACh, noradrenaline, adrenaline, dopamine and histamine, all of which had well-defined rapid effects on other neurones, muscle cells or glands. However, many synaptic interactions cannot be explained on the basis of classic neurotransmitters, and it now appears that other substances, particularly some amino acids such as glutamate, glycine, aspartate, GABA and the monoamine, serotonin, also function as transmitters. Substances first identified as hypophyseal hormones or as part of the dispersed neuroendocrine system of the alimentary tract, can be detected widely throughout the CNS and PNS, often associated with functionally integrated systems. Many of these are peptides: more than 50 (together with other candidates), function mainly as neuromodulators and influence the activities of classic transmitters."

More than 50. Looks like I'll be catching up on this for awhile. We must add to this the fact that ATP itself (the molecule which supplies metabolic energy) has been found to be a global (purinergic) neurotransmitter as well. Here is what Gray's Anatomy says about this recent upset to the way the data base on this was once arranged:

"The traditional concept of autonomic neurotransmission is that preganglionic neurones of both sympathetic and parasympathetic systems are cholinergic and that postganglionic parasympathetic neurones are also cholinergic while those of the sympathetic nervous system are noradrenergic. The discovery of neurones which do not use either acetylcholine or noradrenaline (norepinephrine) as their primary transmitter, and the recognition of a multiplicity of substances in autonomic nerves which fulfil the criteria for a neurotransmitter or neuromodulator, have greatly complicated neuropharmacological concepts of the autonomic nervous system. Thus, adenosine 5'-triphosphate (ATP), numerous peptides and nitric oxide have all been implicated in the mechanisms of cell signalling in the autonomic nervous system. The principal cotransmitters in sympathetic nerves are ATP and neuropeptide Y, vasoactive intestinal polypeptide (VIP) in parasympathetic nerves and ATP, VIP and substance P in enteric nerves."

My bold.

Geoffrey Burnstock, who has researched the autonomic nervous system for decades, suspected ATP long ago. Enough other researchers have drawn the same conclusion that it has become accepted, and he wrote a lengthy (140 page) detailed review paper on the history of the discovery. (Physiology and Pathophysiology of Purinergic Neurotransmission 2007).

He's currently (among other things) working on unraveling purinergic mechanosensory transduction and pain with a Swiss company, Roche Bioscience in Palo Alto. Here is an interview with this apparently irrepressible man.

Nervous System Basics VIII: PLASTICITY

Angevine's 7th attribute is plasticity:

"Plasticity
Highly reliable in a healthy person, the human nervous system has inherent modifiability, though in adulthood this attribute cannot approach that in invertebrates (moths and snails) or certain other vertebrates (teleosts and amphibians). In mammalian development, neural plasticity is striking. In continues postnatally. Abnormal visual experience at certain sensitive periods profoundly affects ocular dominance and orientation columns in the visual cortex. If an eye is closed at birth, ocular dominance columns for the other eye enlarge at the expense of adjacent blind eye columns, with thalamic fibers arriving in the cortex expanding terminal fields into them. If, shortly after birth, visual stimuli are restricted for a few weeks or even days to stripes of one orientation, cortical cells develop a response preference to lines of that orientation.

In humans, PET imaging studies of cortical blood flow show that tasks requiring tactile discrimination activate visual cortex in people blind at birth or having lost sight in childhood. This suggests that cortical connections reorganize after blindness: that afferent fibers to nearby cortical areas serving polymodal sensory integration usurp the bereft visual cortex. Such plasticity may explain the well-known tactile acuity of the blind.

In later development, neural plasticity operates on many levels, as in fine-tuning circuits to changing body dimensions. Depth perception is recalibrated as the skull enlarges and interpupillary distance increases. Even in adulthood, plasticity persists. Vilayanur Ramachandran has shown that a stroke with a cottonswab on the cheek of a young man who had accidentally lost his left arm led him to feel touch on his missing left hand. Later, the whole hand could be mapped on his face. The findings suggest that the deprived somatosensory cortical region for the hand becomes innervated by fibers from the adjacent face areas and that secondary input to a cortical neuron's broad receptive field becomes functional when primary input is lost.

After injury to the CNS, intact neurons form new terminals, by axon sprouting, to replace those of other neurons lost to trauma and thus reoccupy vacated synapses. Such reactive synaptogenesis, the clinically proven effectiveness of long-range regrowth of PNS axons, and the evident potential for axon regeneration in the CNS (as in teleosts and amphibia) hold promise for circuit reestablishment. But in mammals, these factors are thwarted by myelin debris, glial scarring, usurpation of sprouts, unresponsive injured neurons, and complex central connections. Developmental neuroscience now focuses on the cerebral cortex. The human nervous system appears to learn very rapidly by using preconstructed circuits and by locking neurons into specific types and functions after cell origin."

About that last paragraph suggesting that deliberate neurogenesis is difficult in mammals, check out this new blogpost Growing new neurons by Kevin McHenry at painonline.com:

"Wernig et al in Proc Natl Acad Sci U S A May (2008) have achieved a real breakthrough. They have been able to convert fibroblasts to neurons. These converted cells form into neurons, glia, and even dopaminergic cells. There has always been concern that converted cells might form tumors, but these scientists painstakingly separated the cells turned into neurons from pluripotential cells with fluorescent stains."

Seems like ordinary cells can be turned into neurons if they can be recoded, using appropriate transcription factors, "Oct4, Sox2, Klf4, and c-Myc"

Also, work by Peter Eriksson and Fred Gage showed that neurogenesis is intrinsic to the human brain, even in elderly people on the brink of death (see this history module, The Growth of New Neurons in the Adult Human Brain).

Neuroplasticity has been a favorite topic on this blog. It's starting to dawn on a few of us PTs that this is what "improved outcomes", be they pain reduction or increased function, strength etc, have always been all about. Here are some old posts with extensive links:

1. Neuroplasticity Dec 11/07
2. Learning Dec 12/07
3. History of neuroplasticity Dec 12/07
4. About mirror therapy Dec 16/07
5. The devil is in the details Dec 18/07
6. A few types of learning Dec 18/07
7. Cart ruts: More about UN-doing something Dec 29/07
8. It's all about movement Dec 30/07
9. And it's about brain parts: like Hippocampus Dec 30/07
10. Function only Jan 15/08
11. Smart Prosthetics, smart nerves, smart brains Feb 10/08

Nervous System Basics VII: UNIFORMITY WITH VERSATILITY

Here is Angevine's 6th attribute:

"Uniformity with Versatility
The vertebrate nervous system is accurately and reproducibly assembled. In animals of like genus and species it appears almost identical, although this is not absolute when genetic histories differ. Minor variations in the size of components and arrangements of cells are seen between species, striking ones between classes, orders and families. Yet basic regions and properties, cells and circuits, and overall organization are sufficiently alike to permit instant recognition off the basic brain plan and insights as to what these parts and cells contribute to function. Humans show increases in brain size and regional elaboration, numbers of neurons and prominence of certain connections, variations in cerebral sulcation, hemispheric asymmetry, and long projections."

Once nature came up with a way to do something at a cellular level and this cellular model survived all the predatory and thermodynamic slings and arrows, it became handed down more less intact. Neurons are highly useful, but expensive metabolically; once a working model became established it became highly conserved, replicated endlessly in all manner of species filling all manner of niches, each species phenotype using the basic neuron model in endlessly inventive ways.

As creatures evolved, bits got added to the nervous system, but nothing was ever really deleted from it. As a result, we share basic neuron structure design with animals that date back to the days prior to the division that occurred between vertebrates and our invertebrate cousins on the planet - everything considered "animal" has neurons, except for sponges. The list includes radially symmetric jelly fish, starfish, etc., insects... - all have neurons (i.e., we humans are not "special" for having neurons, but our neuron number and arrangement is - "specie-al" to humans).

As evolution proceeded our (really ancient animal) ancestors found their neuronally equipped selves becoming bilaterally symmetrical, better for getting a grip on the world to haul a little body physically perhaps, but requiring more hard drive to coordinate two sides. So the nervous system found itself clumped up a bit at one end. After that it was probably just more economical for special senses to evolve where there was already extra hard drive built in.

Everything after that, all the way to us, is a result of addition rather than truly different body plan. Apparently no other types of body plan were able to make it in the real world of predation and thermodynamic forces. So we share our bilaterally symmetric body plan with all other primates, quadrupeds, land vertebrates, and sea vertebrates including fish, who "invented" backbones and spinal cords, and everything else all the way back through time to whatever represents the fork in the road that led to worms on one side and fish ancestors on the other. Although worms lack a vertebral arrangement or any bones for that matter, they do have a bilaterally symmetric body plan, neurons, and a little "brain", up in front, to run all of it.

Additional reading:
1. Principles of Brain Evolution, Georg F. Streidter
2. Brain Architecture: Understanding the Basic Plan, Larry W. Swanson
3. Development of the Nervous System, Sanes, Reh and Harris

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

Nervous System Basics V: SPECIALIZATION

Here is Angevine's 4th vantage point:

"Specialization
Reflecting its diverse tasks, the nervous system is specialized, from the single neuron to each brain region. Specialized subsystems analyze sensations. They differ in some ways, but data processing is progressive and networked in all. Neurons and the neuroglia have special shapes and roles, but both enjoy all criteria for cells and work in concert. Less obvious but equally specialized are subsystems for other functions: sleep-wakefulness, alertness, attention, affect, collating pages of a report, reading out loud from a book, self-awareness, brain damage control, and so on ad infinitum.

Ubiquitous specializations include those for high nerve conduction velocity (large axon diameter, thick myelin sheath), space-saving bundling (small-axon diameter, thin myelin sheath, shared sheaths), short latency response (monosynaptic reflex), staggered, persistent latencies (parallel side chaining of long-axoned neurons), dependability (neuron redundancy), feature analysis (parallel processing), effect monitoring (feedback circuits), and force multiplication (feed-forward circuits). The neurons performing such tasks and the neuroglia backing them up are as specialized as these many diversified services. For neurons and the neuroglia, form indeed reflects function."

I think each of these features listed in the second paragraph could be a book in itself; I will list them out again:
1. high nerve conduction velocity (large axon diameter, thick myelin sheath)
2. space-saving bundling (small-axon diameter, thin myelin sheath, shared sheaths)
3. short latency response (monosynaptic reflex)
4. staggered, persistent latencies (parallel side chaining of long-axoned neurons)
5. dependability (neuron redundancy)
6. feature analysis (parallel processing)
7. effect monitoring (feedback circuits)
8. force multiplication (feed-forward circuits)

Specialization also applies to microglia.

Additional reading from Scholarpedia:
1. neuron
2. neuronal cable theory
3. Rall model on cable properties of dendritic trees

Nervous System Basics IV: CENTRALIZATION

Angevine's third basic organizing principle of the nervous system:

Centralization
"The key feature of the nervous system is centralization. It offers few circuits for local interactions of body parts. The CNS is almost always involved even if the distance, as from thumb to index finger, is slight. Intercession of the brain and spinal cord ensures integrated and coordinated activity.

Exceptions are instructive. The local cutaneous response to irritating stimuli (raking a blunt probe over the skin) has three components: local reddening (vasodilation from injury), wheal formation (transient edema from tissue fluid extrusion), and ensuing vasodilation (flare) with lowered thresholds and increased sensitivity to pain (pinprick). The flare and hyperalgesia represent an axon reflex. Nociceptive (pain) nerve endings are activated by substances released by injured tissue cells, and nerve impulses are conducted a short way centrally along nociceptive axons and then distally over branches of these axons to nearby arterioles, causing them to dilate. Advanced or primitive (it is sluggish, starting in about 20 sec. and developing fully in around 3 min), this reflex involves local nerve fibers only, not the CNS.

The "triple response" illustrates three concepts. Pain receptors sense chemical, as well as mechanical and thermal stimuli. Their sensitivity is increased by substances accumulating in the damaged area. Their response includes a neuroeffector component. They release substances (peptides) that initiate further events, providing further protection and favoring local tissue repair.

Studies in invertebrate neural systems show extensive local control of visceral function. Exceptions to central control are also found in the mammalian ANS. Near-normal interaction of bowel segments persists in the absence of CNS innervation. Sensory fibers from the gut exert feedback in intramural autonomic ganglia on visceral motor neurons regulating smooth muscle in the intestinal wall. The nervous system has pattern generators, both central and peripheral: systems with cellular, synaptic, and network properties (cyclic firing rhythms, reciprocal inhibition of cell pairs, leader and follower cells) that provide automated mechanisms for generating rhythmic movements (breathing, walking) or periodic activities (sleeping, waking). Regulated by neural (sensory feedback, volitional override) or neuroendocrine influences, pattern generators are pithy examples of neural endogenous activity."

This is a very instructive passage, particularly in its clear explanation of the peripherality of the axon reflex, but I would be so bold as to quibble with Angevine over his use of the term, "pain receptors." Some pain researchers part company with this terminology, preferring instead to refer to peripheral receptors that register chemical, mechanical and temperature stimuli which could be harmful (but aren't necessarily), as nociceptors, not "pain receptors." They are quite clear that strictly speaking, incoming information to the CNS is not "pain" until the brain decides it is, at which point it will make it so. It may seem a small point, but depending on context, the brain may choose to ignore nociception entirely to deal with a completely different, but from its perspective, more pertinent or immediate threat. Numerous examples of this are in the pain literature dating back to the Civil War. Also, the brain is capable of making "pain" in the absence of any noxious input (Derbyshire 2004).


Additional reading

For axon reflex:

1. Axon Reflex (3-page pdf)
2. Excerpts from book, Clinical Motor Electroneurography: Evoked Responses Beyond the M-wave on axon reflex
3. Axon reflex as discussed in book, Biology of Skin
4. Caselli A; Validation of the nerve axon reflex for the assessment of small fibre dysfunction JNNP 2006 (abstract)

For pain without nociception:

5. Derbyshire SW Cerebral activation during hypnotically induced and imagined pain 2004 (10-page pdf)

For pattern generators:

6. Hooper, SL Central pattern generators, 2000: 16-page pdf

Nervous System Basics III: UNITY

Here is the second organizing principle of the human nervous system;

"Unity
As in epithelium, all parts of the nervous system are physically coherent and functionally linked by nerves, tracts, and specified cell to cell contacts. Potentially each part communicates with all others. Some connections are direct (a two-neuron, monosynaptic reflex), whereas others involve myriad interposed neurons. Though complex, neural circuits offer total connectivity: fast, body-wide communication. Nerve impulses may originate in sensory nerve endings in any part of the body or anywhere in the system itself. Responsive activity complements endogenous activity, which is always evident in the human nervous system with its startling capacity to generate patterns of behavior and initiate events on its own. Sensory impulses, triggered by PNS primary sensory neurons, race over its nerves to the CNS, there diverging to clusters of secondary sensory neurons. Analysis begins. New impulses pass to central neurons on which related messages converge, which is a recombinant process providing integration. Other messages on stimulus modality, intensity, location, affective quality, body position and movement, visceral activity, fatigue, experience, and expectations are all integrated. Huge numbers of impulses are generated; untold numbers of synapses are activated. Almost instantly, nerve impulses that will elicit bodily responses stream out of the CNS to muscles and glands."

David Butler PT says in his book, The Sensitive Nervous System, p. 19;

"Each neuron is studded with approximately 5000 spines on which other neurons connect. Most of these connections will be part of feedback loops from neighboring neurons. Only a small percentage will come directly from the associated sense organs. "Every neuron is plumbed into a sea of feedback" (McCrone 1997). This gives the nervous system a recursive structure that allows the system to repeat itself again and again.This will allow a continual check/recheck on its actions.

The numbers are hard to get a feel for and popular texts are useful to try to get the message over. Kotulak (1996) based on evidence from electron microscopy research, says that there are about 350 million connections in a pinhead size speck of brain tissue. But the big numbers are just the start. It is the combination of connections possible which is awesome. Edelman (1992) reasoned that there were more possible combinations of connections than positively charged particles in the universe. There must be an extraordinary density of coding behind connections and combinations, allowing patterns of activity which can all be replayed if needed or quickly adapted for future responses. Our ultimate behavior is a result of this coding. There is surely enough space for the memories of a lifetime including all painful experiences, their contexts, the actual and possible responses at the time and future responses."

A number as big as something in the entire universe is all packed up inside the human skull, every human skull. I very much like to remember this when I find myself bogged down by some little annoyance. It makes the small stuff go back to smallness.

References:
1. The Sensitive Nervous System (2006) David Butler PT
2. Inside the Brain, 1997, Ron Kotulak
3. Encyclopedia of the Human Brain 2002, edited by VS Ramachandran
4. The Dynamics of Brain Processing: Top-down Effects of Consciousness, 1997, John McCrone
5. Brilliant Air, Bright Fire, 1994, Gerald Edelman (lots of more recent books)

Nervous System Basics: Part II: UBIQUITY

There are 8 considerations presented by the author on how to contemplate the nervous system. They are,
1. Ubiquity
2. Unity
3. Centralization
4. Specialization
5. Purposefulness
6. Uniformity with Versatility
7. Plasticity
8. Chemical Message Coding

This is the first. From p. 331, Vol III, Encyclopedia of the Human Brain, author Jay B. Angevine:

"Ubiquity
With 100,000 miles of nerve fibers the nervous system rivals the vascular system. Both pervade the body and function in harmony. By nerve impulses or circulating red and white cells, glucose, hormones and immune principles, they integrate body activity, protect the body, enhance its performance to met stress or demand, promote its growth and nutrition, and maintain its tone and vigor. The trunk and branches of both systems reflect body form. If either system and no other part of a person were visible, he or she would be recognizable. Density of innervation varies as the value of parts to sensory discrimination or motor control. In well-innervated areas (lips, fingertips) stimuli are sharply discriminated as to modality, intensity, and location, but in sparsely innervated areas (flanks, legs) these are less defined. Similarly, muscles vary in the ratio of motor neurons to muscle fibres. The higher the ratio, the more precise the control of the muscle and the movement it serves (a motor neuron may excite 2000 muscle fibers in a limb muscle or as few as 5 in extrinsic ocular muscles)."

I don't know what else to say. To me this is a beautiful image of a filamentous system which comprises only 2% of our physicality, but which regulates 100% of our function.

Nervous System Basics: Part I

In this series of posts I intend to bring out information found in one (just one) section of the 4-volume Encyclopedia of the Human Brain, 2002, edited by V.S. Ramachandran.

The section in question is written by Jay B. Angevine at the U. of Arizona, and begins page 313 in Vol. 3. He states the nervous system has:

*100 billion neurons of 10,000 types,
*1-10 trillion neuroglial cells,
*100 trillion chemical synapses,
*160,000 km. of neuronal processes,
*thousands of neuronal clusters and fiber tracts,
*hundreds of functional systems,
*dozens of functional subsystems,
*7 central regions, and
*three main divisions.

One hundred and sixty thousand kilometers, or about 100,000 miles of nerve fiber: the Bodyworlds Exhibit states that there are 72.5 kilometers (45 miles) of nerves, which are macro bundles of many fibers.. and that seemed a big number...

Angevine says, "... all of these parts form a coherent, bodily pervasive, diversified, complex epithelium with interdependent connectivity of neurons", most of which are interneurons rather than sensory or motor. The key organizing principles are centralization and integration (although there are many others as we will find out).

The nervous system performs the dual roles of regulation and initiation.

"In the first, it counteracts: responsively and homeostatically, gathering stimuli from outside and inside the body (including the brain), assessing their short-term and long-range significance, generating activity from faster breathing to stock trading, even to functional plasticity in learning or after brain damage.

In the other, it acts: endogenously, not so homeostatically, replacing one state of neural activity with another, generating activity from doing nothing at all to creative thinking and extraordinary achievement, even taking steps toward understanding how itself, the nervous system, works."

Angevine examines the overall organization of the nervous system from a number of perspectives in this section that runs 58 pages, and here I will delve into the third of ten sections he outlines, basic organizing principles, of which there are 8. I want to give each one of these principles some time and thought here.