Rejuvenation

Rejuvenation

At the beginning of the twentieth century the world's most outstanding neuroanatomist, Nobel Prize winner Santiago Ramon y Cajal, who laid the groundwork for our understanding of how neurons are structured, turned his attention to one of the most vexing problems of human brain anatomy. Unlike the brains of simpler animals, such as lizards, the human brain seemed unable to regenerate itself after an injury. This helplessness is not typical of all human organs. Our skin, when cut, can heal itself, by producing new skin cells; our fractured bones can mend themselves; lost blood can replenish itself because cells in our marrow can become red or white blood cells.

But our brains seemed to be a disturbing exception. It was known that millions of neurons die as we age. Whereas other organs make new tissues from stem cells, none could be found in the brain. The main explanation for the absence was that the human brain, as it evolved, must have become so complex and specialized that it lost the power to produce replacement cells. Besides, scientists asked, how could a new neuron enter a complex, existing neuronal network and create a thousand synaptic connections without causing chaos in that network? The human brain was assumed to be a closed system.Ramon y Cajal devoted the later part of his career to searching for any sign that either the brain or spinal cord could change, regenerate, or reorganize its structure. He failed.

In his 1913 masterpiece, Degeneration and Regeneration of the Nervous system, he wrote, “ In adult brain centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree.”

There matters stood.

The neuronal stem cells I see are vibrating with life. They are called “neuronal” stem cells because they can divide and differentiate to become neurons or glial cells, which support neurons in the brain. The ones I am looking at have yet to differentiate into either neurons or glia and have yet to “specialize,” so they all look identical. Yet what stem cells lack in personality, they make up for in mortality. For stem cells don't have to specialize but can continue to divide, producing exact replicas of themselves, and they can go on doing this endlessly without any signs of aging. For this reason stem cells are often described as the eternally young, baby cells of the brain. This rejuvenating process is called “neurogenesis,” and it goes on until the day that we die.

Paradoxically, sometimes losing neurons can improve brain function, as happens in the massive “pruning back” that occurs during adolescence when synaptic connections and neurons that have not been extensively used die off, in perhaps the most dramatic case of use it or lose it. Illustration by Elena.

Neuronal stem cells were long overlooked, in part, because they went against the theory that the brain was like a complex machine or computer, and machines don't grow new parts. When, in 1965, Joseph Altman and Gopal D. Das of the Massachusetts Institute of Technology discovered them in rats, their work was disbelieved.

Then in the 1980s Fernando Nottebohm, a bird specialist, was struck by the fact that songbirds sing new sons each season. He examined their brains and found that every year, during the season when the birds do the most singing, they grow new brain cells in the area of the brain re responsible for song learning. Inspired by Nottebohm's discovery, scientists began examining animals that were more like human beings. Elizabeth Gould of Princeton University was the first to discover neuronal stem cells in primates. Next, Eriksson and Gage found an ingenious way to stain brain cells with a marker, called BrdU, that gets taken into neurons only at the moment they are created and that lights up under the microscope. Erikson and Gage asked terminally ill patients for permission to inject them with the marker. When these patients died, Erikson and Gage examined their brains and found new, recently formed baby neurons in their hippocampi. Thus we learned from these dying patients that living neurons form in us until the very end of our lives.

The search continues for neuronal stem cells in other parts of the human brain. So far they've also been found active in the olfactory bulb (a processing area for smell) and dormant and inactive in the septum (which processes emotion), the striatum (which processes movement), and the spinal cord. Gage and others are working on treatments that might activate dormant stem cells with drugs and be useful if an area where they are dormant suffers damage. They are trying to find out whether stem cells can be transplanted into injured brain areas, or even induced to move to those areas.

To find out if neurogenesis can strengthen mental capacity, Gage's team has set out to understand how to increase the production of neuronal stem cells. Gage's colleague Gerd Kempermann raised aging mice in enriched environments, filled with mice toys such as balls, tubes, and running wheels, for only forty-five days. When Kempermann sacrificed the mice and examined their brains, he found they had a 15 percent increase in the volume of their hippocampi and forty thousand new neurons, also a 15 percent increase, compared with mice raised in standard cages.

Mice live to about two years. When the team tested older mice raised in the enriched environment for ten months in the second half of their lives, there was a fivefold increase in the number of neurons in the hippocampus. These mice were better at tests of learning, exploration, movement, and other measures of mouse intelligence than those raised in unenriched conditions. They developed new neurons, though not quite as quickly as younger mice, proving that long-term enrichment had an immense effect on prompting neurogenesis in an aging brain.

(Rejuvenation. The Brain That Changes Itself by Norman Doidge, M.D., excerpt).

Keeping unused neurons supplied with blood, oxygen, and energy is wasteful, and getting rid of them keeps the brain more focused and efficient. Illustration by Elena.

Content of Thought

Imagination : Content of Thought

One reason we can change our brains simply by imagining is that, from a neuroscientific point of view, imagining an act and doing it are not as different as they sound. When people close their eyes and visualize a simple object, such as the letter “a”, the primary visual cortex lights up, just as it would if the subjects were actually looking at the letter “a”. Brain scans show that in action and imagination many of the same parts of the brain are activated. That is why visualizing can improve performance. 

In an experiment that is as hard to believe as it is simple, Drs. Guang Yue and Kelly Cole showed that imagining one is using one's muscles actually strengthens them. The study looked at two groups, one that did physical exercise and one that imagined doing exercise. Both groups exercised a finger muscle, Monday through Friday, for four weeks. The physical group did trials of fifteen maximal contractions, with a twenty-second rest between each. The mental group merely imagined doing fifteen maximal contractions, with a twenty-second rest between each, while also imagining a voice shouting at them, “Harder! Harder! Harder!”

At the end of the study the subjects who had done physical exercise increased their muscular strength by 30 percent, as one might expect. Those who only imagined doing the exercise, for the same period, increased their muscle strength by 22 percent. The explanation lies in the motor neurons of the brain that “program” movements. During these imaginary contractions, the neurons responsible for stringing together sequences of instructions for movements are activated and strengthened, resulting in increased strength when the muscle are contracted.

The research has led to the development of the first machines that actually “read” people's thoughts. Thought translation machines tap into motor programs in a person or animal imagining an act, decode the distinctive electrical signature of the thought, and broadcast an electrical command to a device that puts the thought into action. These machines work because the brain is plastic and physically changes its state and structure as we think, in ways that can be tracked by electronic measurements.

Experiments show how truly integrated imagination and action ar, despite the fact that we tend to think of imagination and action as completely different and subject to different rules. Illustration by Elena.

These devices are currently being developed to permit people who are completely paralyzed to move objects with their thoughts. As the machines become more sophisticated, they may be developed into thought readers, which recognize and translate the content of a thought, and have the potential to be far more probing than lie detectors, which can only detect stress levels when a person is lying. 

These machines were developed in a few simple steps. In the mid-1990s, at Duke University, Miguel Nicolelis and John Chapin began a behavioral experiment, with the goal of learning to read an animal's thoughts. They trained a rat to press a bar, electronically attached to a water-releasing mechanism. Each time the rat pressed the bar, the mechanism released a drop of water for the rat to drink. The rat had a small part of its skull removed, and a small group of micro-electrodes were attached to its motor cortex. These electrodes recorded the activity of forty-six neurons in the motor cortex involved in planning and programming movements, neurons that normally send instructions down the spinal cord to the muscles. Since the goal of the experiment was to register thoughts, which are complex, the forty-six neurons had to be measured simultaneously. Each time the rat moved the bar, Nicolelis and Chapin recorded the firing of its forty-six motor-programming neurons, and the signals were sent to a small computer. Soon the computer “recognized” the firing pattern for bar pressing.

After the rat became used to pressing the bar, Nicolelis and Chapin disconnected the bar from the water release. Now when the rat pressed the bar, no water came. Frustrated, it pressed the bar a number of times, but to no avail. Next the researchers connected the water release to the computer that was connected to the rat's neurons. In theory, now, each time the rat had the thought “press the bar,” the computer would recognize the neuronal firing pattern and send a signal to the water release to dispense a drop.

After a few hours, the rat realized it didn't have to touch the bar to get water. All it had to do was to imagine its paw pressing the bar, and water would come. Nicolelis and Chapin trained four rats to perform the task.

(Imagination. The Brain That Changes Itself by Norman Doidge, M.D., excerpt).

If the brain is easily altered, how are we protected from endless change? Photograph by Elena.

Gray and White Matter

Gray and White Matter in Our Brain

Neurons are connected to one another in their billions. Building on this, we must add that the cell bodies tend to group together, rather like debris on the surface of an expanse of water. When cell bodies clump together like this, the resultant tissue appears somewhat grayish The stringy connections between gray tissues, formed principally by the axons interconnecting the cell bodies, appear white by contrast (mainly because axons are surrounded by a sheath of fatty tissue, and fat has a white appearance). This is the basis of the famous distinction between gray matter and white matter. Collections of cell bodies are gray; the fiber connections between them are white.

The cell bodies forming the gray matter group together in one or two ways – either as nuclei or in layers. The nuclei are simply balls of cell bodies, lumped together. The layers are more complicated. They are formed when the cell bodies line up in rows. The resultant sheets of cells are typically found on the outer surface of the brain – and form its cortex (“cortex” means outer layer). There is a shortage of space in the human cranium, because the amount of cortex has expanded dramatically in recent evolution; so the brain saves space by folding the layers in upon themselves, in a wavelike pattern. This  is what gives the outer surface of the brain its well-known convoluted appearance. The nuclei lie deeper within the brain, underneath these layers of cortex – and the white matter is located between the two. The white matter – principally axons – thereby connects the cell bodies of the nuclei and cortical layers with one another. The precise anatomy of the resultant systems is enormously complex, but these basic principles are easier to understand.

Mind and brain are entwined like yin and yang. Illustration by Elena.

Brainstem and forebrain

A further basic division of the brain is that between the brainstem and the forebrain. This is a distinction of great importance for understanding some of the psychological functions. These two structures are, in turn, intricately subdivided. There are innumerable terms for the various regions within them – often (and quite confusingly) more than one term for the same structure. The terms we mention here form the standard (or most widely accepted) terminology.

The brainstem is a direct extension of the spinal cord into the skull, and it is phylogenetically (i.e., in evolutionary terms) the most ancient part of the brain. The best way to depict it is by slicing the brain down the midline to produce a medial view. The lowest portion of the brainstem, the part immediately adjoining the spinal cord, is the medulla oblongata (Latin for “oblong core”) - a structure that has little to do with what is traditionally conceived of as “the mind” (the medulla contains nuclei that govern heartbeat, breathing, etc.) Above the medulla oblongata is the pons (Latin for “bridge”). Hanging behind the pons is the cerebellum (“little brain”). The top of the brainstem proper is the midbrain.

Above this region are structures that are not technically part of the brainstem (opinions on this point have changed over the years), but they are very closely connect in functional terms to the medulla oblongata, pons, and midbrain. These structures are referred to as the diencephalon. There is no generally accepted English word for this region of the brain, although at one time it was called the “twixt-brain,” which conveyed the essential fact that it lies between the brainstem and the forebrain. There are two main parts to the diencephalon. The largest, the upper portion, is the thalamus. Below the thalamus lies the hypothalamus, which is directly connected to the pituitary gland. All of these brainstem and diencephalic structures contain nuclei that are connected to one another (and to the forebrain structures) in intricate patterns.

The forebrain is phylogenetically younger than the brainstem. It consists principally of the two great cerebral hemispheres that fill the vault of the cranium. The outer surface of these hemispheres is the cerebral cortex, made up of folded layers of gray matter. Within the cerebral hemispheres, and hidden from view, are various forebrain nuclei.

Each hemisphere is divided into four lobes. At the back of the head is the occipital lobe; in the center is the parietal lobe (situated above and slightly behind the ears); below and in front of the parietal lobe is the temporal lobe (at the temples); the reminder of the hemisphere is the large frontal lobe, which lies over the eyes and is perhaps our greatest (and, in parts, uniquely human) phylogenetic acquisition. Buried between these lobes, if one pulls the temporal lobe down and lifts the frontal and parietal lobes up, lies a further region of cerebral cortex known as the insula.

Inside the cerebral hemispheres are the forebrain nuclei. The most substantial such nuclei are the basal ganglia. Close to the basal ganglia, nestled within the lower half of the frontal lobe, are the basal forebrain nuclei. Behind them, inside the anterior ((I.e.front) part of the temporal lobe, is the amygdala (Latin for “almond,” which this group of nuclei resembles in shape).

The Brain and the Inner World, Introduction to Basic Concepts. Mark Solms, Oliver Turnbull.

Although neuroscience and psychiatry/psychology have struggled to illuminate mind and brain in its own way, it is now clear that both need to work together intimately for any comprehensive understanding to emerge. Illustration by Elena.

Neuropathic Pain

Neuropathic Pain

There are a whole host of haunting pains that torment us for reasons we do not understand and that arrive from we know not where – pains without return address. Lord Nelson, the British admiral, los his right arm in an attack on Santa Cruz de Tenerife in 1797. Soon afterward, Ramachandran points out, he vividly began to experience the presence of his arm, a phantom limb that he could feel but not see. Nelson concluded that its presence was “direct evidence for the existence of the soul,” reasoning that if an arm can existe after being removed so then might the whole person exist after the annihilation of the body.

Phantom limbs are troubling because they give rise to a chronic “phantom pain” in 95 percent of amputees that often persists for a lifetime. But how do you remove a pain in an organ that isn't there?

Phantom pains torment soldiers with amputations and people who lose limbs in accidents, but they are also part of a larger class of uncanny pains that have confused doctors for millennia, because they had no known source in the body. Even after routine surgery, some people are left with equally mysterious postoperative pains that last a lifetime. The scientific literature on pain includes stories of women who suffer menstrual cramps and labor pains even after their uteruses have been removed, of men who still feel ulcer pain after the ulcer and its nerve have been cut out, and of people who are left with chronic rectal and hemorrhoidal pain after their rectums were removed. There are stories of people whose bladders were removed who still have an urgent, painful chronic need to urinate. These episodes are comprehensible if we remember that they too are phantom pains, the result of internal organs being “amputated”.

Normal pain, “acute pain,” alerts us to injury or disease by sending a signal to the brain, saying, “This is where you are hurt – attend to it.” But sometimes an injury can damage both our bodily tissues and the nerves in our pain systems, resulting in “neuropathic pain,” for which there is no external cause. Our pain maps get damaged and fire incessant false alarms, making us believe the problem is in our body when it is in our brain. Long after the body has healed, the pain system is still firing and the acute pain has developed an afterlife.

The phantom limb was first proposed by Silas Weir Mitchell, an American physician who tended the wounded at Gettysburg and became intrigued by an epidemic of phantoms. 

Physicians have long known that a patient who expects to get pain relief from a pill often does, even though it is a placebo containing no medication. Illustration by Megan Jorgensen.

Civil War soldiers' wounded arms and legs often turned gangrenous, and in an age before antibiotics, the only way to save the soldier's life was to amputate the limb before the gangrene spread. Soon amputees began to report that their limbs had returned to haunt them. Mitchell first called these experiences “sensory ghosts,” then switched to calling them “phantom limbs.”

They are often very lively entities. Patients who have lost arms can sometimes feel them gesticulating when they talk, waving hello to friends, or reaching spontaneously for a ringing phone.

A few doctors thought the phantom was the product of wishful thinking – a denial of the painful loss of a limb. But most assumed that the nerve endings on the stump end of the lost limb were being stimulated or irritated by movement. Some doctors tried to deal with phantoms by serial amputations, cutting back the limbs – and nerves – farther and father, hoping the phantom might disappear. But after each surgery it reemerged.

Ramachandran had been curious about phantoms since medial school. Then in 1991 he read the paper by Tim Pons and Edward Taub about the final operations on the Silver Spring monkeys. Pons mapped the brains of the monkeys who had had all the sensory input from their arms to their brains eliminated bu deafferentation and found that the brain map for the arm, instead of wasting away, had become active and now processed input from the face – which might be expected because, as Wilder Penfield has shown, the hand and facial maps are side by side.

Ramachandran immediately thought that plasticity might explain phantom limbs because Taub's monkeys and patients with phantom arms were similar. The brain maps for both the monkeys and the patients had been deprived of stimuli from their limbs. Was it possible that the face maps of amputees had invaded the maps for their missing arms, so that when the amputee was touched on the face, he felt his phantom arm? And where, Ramachandran wondered, did Taub's monkeys feel it when their faces were stroked – on their faces, or in their “deafferented” arm?

Pain, like the body image, is created by the brain and projected onto the body. This assertion is contrary to common sense and the traditional neurological view of pain that says that when we are hurt, our pain receptors send a one-way signal to the brain's pain center and that the intensity of pain perceived is proportional to the seriousness of the injury. We assume that pain always files an accurate damage report. This traditional view dates back to the philosopher Descartes, who saw the brain as a passive recipient of pain. But that view was overturned in 1965, when neuroscientists Ronald Melzack (a Canadian who studied phantom limbs and pain) and Patrick Wall (an Englishman who studied pain and plasticity) wrote the most important article in the history of pain. Wall and Melzack's theory asserted that the pain system is spread throughout the brain and spinal cord, and far from being a passive recipient of pain, the brain always controls the pain signals we feel. 

Their “gate control theory of pain” proposed a series of controls, or “gates”, between the site of injury and brain. When pain messages are sent from damaged tissue through the nervous system, they pass through several “gates”, starting in the spinal cord, before they get to the brain. But these messages travel only if the brain gives them “permission,” after determining they are important enough to be let through. If permission is granted, a gate will open and increase the feeling of pain by allowing certain neurons to turn on and transmit their signals. The brain can also close a gate and block the pain signal by releasing endorphins, the narcotics made by the body to quell pain. How much pain we feel is determined in significant part by our brains and minds – our current mood, our past experiences of pain, our psychology, and how serious we think our injury is.

When a mother soothes her hurt child, by stroking and talking sweetly to her, she is helping the child's brain turn down the volume on its pain. Illustration by Megan Jorgensen.

Constrained-Induced Therapy

Constrained-Induced Therapy

The principles of constraint-induced therapy have been applied by a team headed by Dr. Friedemann Pulvermüller in Germany, which worked with Dr. Taub to help stroke patients who have damage to Broca's area and have lost the ability to speak. About 40 percent of patients who have a left hemisphere stroke have this speech aphasia. Some, like Broca's famous aphasia patient, “Tan”, can use only one word; others have more words but are still severely limited. Some do get better spontaneously or get some words back, but it has generally been thought that those who didn't improve within a year couldn't.

What is the equivalent of putting a mitt on the mouth or a sling on speech? Patients with aphasia, like those with arm paralysis, tend to fall back on the equivalent of their “good”arm. They use gestures or draw pictures. If they can speak at all, they tend to say what is easiest over and over.

The “constraint” imposed on aphasiacs is not physical, but it's just as real: a series of language rules. Since behaviour must be shaped, these rules are introduced slowly. Patients play a therapeutic card game. Four people play with thirty-two card, made up of sixteen different pictures, two of each picture. A patient with a card with a rock on it must ask the others for the same picture. At first, the only requirement is that they not point to the card, so as not to reinforce learned nonuse. They are allowed to use any kind of circumlocution, as long as it is verbal. If they want a card with a picture of the sun cnd can't find the word, they are permitted to say “The thing that makes you hot in the day” to get the card they want. Once they get two of a kind, they can discard them. The winner is the player who gets rid of his cards first.

Therapy is always useful. Illustration by Elena.

The next stage is to name the object correctly. Now they must ask a precise question, such as “Can I have the dog card?” Next they must add the person's name and a polite remark: “Mr. Schmidt, may I please have a copy of the sun card?” Later in the training more complex cards are used. Colors and numbers are introduced – a card with three blue socks and two rocks, for instance. At the beginning patients are praised for accomplishing simple tasks; as they progress, only for more difficult ones.

The German team took on a very challenging population – patients who had had their strokes on average 8.3 years before, the very ones whom most had given up on. They studied seventeen patients. Seven in a control group got conventional treatment, simply repeating words; the other ten got CI therapy for language and had to obey the rules of the language game, three hours a day for ten days. Both groups spent the same numbers of hours, then were given standard language tests. In the ten days of treatment, after only thirty-two hours, the CI therapy group had a 30 percent increase in communication. The conventional treatment group had none.

Based on his work with plasticity, Dr. Taub has discovered a number of training principles: training is more effective if the skill closely relates to everyday life; training should be done in increments; and work should be concentrated into a short time, a training technique Dr. Taub calls “massed practice,” which he has found far more effective than long-term but less frequent training.

Many of these same principles are used in “immersion” learning of a foreign language. How many of us have taken language courses over years and not learned as much as when we went to the country and “immersed” ourselves in the language for a far shorter period? Our time spent with people who don't speak our native tongue, forcing us to speak theirs, is the “constraint.” Daily immersion allows us to get “massed practice.” Our accent suggests to others that they may have to use simpler language with us; hence we are incrementally challenged, or shaped. Learned nonuse is thwarted, because our survival depends on communication.

(Midnight Resurrections, The Brain That Changes Itself, by Norman Doidge, M.D., excerpt).

I can see what you want to say. Illustration by Elena.