Brain Plasticity & The Mind

Brain plasticity has become a major buzz word when we talk about our brain today. A week ago on New Year's Eve, the neurologist and popular writer Oliver Sacks enthusiastically championed in his OP-ED contribution to The New York Times with the title "This Year, Change Your Mind" our brain's striking ability of learning new skills even at advanced age and of adjusting to new, unprecedented conditions. Brain plasticity provides the foundation for this ability. Dr. Sacks, who faces deterioration of vision himself, encourages us in his New Year message to take the fullest advantage of the formidable powers of the plastic brain to enhance our quality of life.

History
The notion that the brain is plastic is more than a century old. Eminent 19^th-century neurologists with a passion for research like Auguste Forel (see my post entitled "Auguste Forel & Brain Plasticity" from Aug. 1, 2008) and Constantin von Monakow (see my post entitled "Constantin von Monakow & Brain Plasticity" from Nov. 4, 2009) already suspected that nerve cell connections in the brain must be dynamic and able to repair themselves and re-organize to facilitate the recovery from loss of function observed after brain injury. The recruitment of hitherto unused areas in cerebral cortex was presumed to underlie functional compensation. Moreover, it was speculated that cortical areas could be rededicated to entirely new uses. However, how the nerve cells in the brain actually accomplished such feats remained obscure.

Specificity in the Face of Plasticity
In frogs and fish, the optic nerves connecting the retina to visual midbrain known as optic tectum are crossed; the visual field of the eye is topographically mapped on the lobe of the optic tectum on the other side. In the 1940s, Roger Sperry observed in an elegant series of experiments with frogs (Sperry, 1945), and later repeated in fish (Sperry, 1948), that after he surgically removed an eye and implanted it reversed or upside down on the other side, vision was restored, but the original map of the visual field appeared preserved despite the change in the eye's orientation. The animals moved in the wrong direction, when presented with bait. Regenerating retinal nerve fibers must have reoccupied their original sites of termination in the brain, because the frogs saw the world either reversed or upside down. Sperry reasoned that fixed chemical cues in the optic tectum would guide arriving retinal nerve fibers to terminate at their topographically appropriate original locations, restoring the old map. His idea became known as the chemoaffinity hypothesis (Todman, 2008).

Sperry further predicted that the visual field inversion would not happen, if the surgery was carried out in tadpoles before connective specificity had been established. Hence, the brain possessed the capacity for restoration, but was not plastic to the degree that it could accommodate the novel orientation of the eye once the frog had matured. Alas, the severed optic nerve did successfully regenerate in adult lower vertebrates. In higher vertebrates, by contrast, most nerve cell connections in the central nervous system were known to grow only during development, but appeared to lose this ability in maturity. Santiago Ramón y Cajal observed vigorous outgrowth of nerve fibers from severed peripheral nerve stumps throughout life (DeFelipe and others, 1991). Reinnervation of peripheral muscle and skin restoring function was possible when the nerves were only crushed and the nerve sheaths remained intact. By contrast, nerve cells in central nervous system did not appear to possess this power. A severed spinal cord did not repair itself. The nerve cells did not proliferate after injury, cell division had come to a halt in most brain regions, and dying cells could not be replaced. The observation that disconnected nerve cells degenerated gave rise to the notion that they need to be connected and stimulated to survive.

Animal Behavior Suggests a Critical Period for Plasticity
Consistent with the observed limitations of brain repair in maturity, observations on animal behavior provided evidence that the essential framework of connections were laid early in development in response to sensory stimulation provided by the environment. The imprinting behavior observed by Konrad Lorenz in the 1940s suggested that once the layout had been finished, it could not be modified anymore (see my post entitled "Konrad Lorenz, Imprinting & Functional Brain Imaging" from Jun. 29, 2009). It seemed that the brain was most plastic, molding its connectivity according to experience, only for a limited period of time during development which became known as the critical period.

Evidence for a Neural Basis of the Critical Period
With the discovery of the plasticity of ocular dominance domains in cat visual cortex about 1960, Torsten Wiesel and David Hubel were able to provide a nerve cell basis for the critical period (Wiesel and Hubel, 1963). They found with recording of electrical nerve cell responses from wire electrodes lowered into visual cortex of cats that the cells receiving input from one or the other eye clustered together, functionally dividing the cortical surface into alternating domains of ocular dominance embedded in the map of the visual field. If one eye was permanently occluded in kittens early during postnatal development the domain with the cells responding to the stimulation of the open eye enlarged at the expense of the domain of the occluded eye. The enlargement could be reversed when the occlusion was switched. Furthermore, the changes in eye representation could be produced only during a limited time after birth. Therefore, the cortical domains representing each eye were plastic, but the plasticity depended on active inputs during a critical period.

Later work with anatomical tract tracers showed that the endings of the inputs from each eye on the cortical nerve cells strongly overlapped early in development, but proceeded to be pruned into separate domains under ordinary conditions. However, when one eye was shut, the endings of the silenced inputs would wither, while the endings of the active inputs from the intact eye consolidated (LeVay and others, 1978). The findings could be confirmed in primates (Hubel and others, 1977). It seemed that in our developing brain inputs compete for their targets based on nerve cell activity.

Hebb's Principle
This concept resonated well with an idea that the psychologist Donald Hebb had borne in the 1940s based on his observations on animal learning (Hebb, 1949). According to his hypothesis, excitatory nerve cell connections would strengthen when the cells were activated together. Reinforcement with treats during learning, for example, would provide the necessary co-activation. The strngthened nerve cell connection would constitue the substrate for memory and learning.

A possible nerve cell mechanism for Hebb's idea was eventually discovered in the hippocampus in which the excitability of nerve cells was observed to increase after their inputs had been synchronously and repeatedly activated over an extended period of time (Lømo, 2003). This long-term potentiation (LTP) of the nerve cell response was understood as a sign of synaptic strengthening. Moreover, researchers observed an increase in dendritic spines on nerve cells processes, that is protrusions on which excitatory inputs terminate.

Cellular and Molecular Mechanisms in Support of Hebb's Idea
Glutamate is the most prominent excitatory neurotransmitter in the brain. The inputs of ocular dominance domains make glutamatergic synapses, that is electrochemical contacts, with cortical nerve cells. The conclusive evidence for a molecular basis of Hebb's principle arrived with the discovery of an ionotropic type of postsynaptic glutamate receptor known as N-methyl-D-aspartate (NMDA) receptors.

NMDA receptors are comprised of four subunits that form voltage-gated ion channels. When the nerve cell is at rest, Mg⁺⁺ ions block the channel pores. However, when glutamate binds to its receptors and the cell is excited, the voltage across the cell membrane changes, the channel pores widen, and the Mg⁺⁺-block is released. Ca⁺⁺ and smaller cations can pass into the cell. As more glutamate binds to NMDA receptors, more channels are unblocked, resulting in an increased electric excitatory postsynaptic potential. As a consequence, concomitant excitation evokes a greater nerve cell response as Hebb's principle requires. The rise of intracellular Ca⁺⁺ triggers molecular pathways that regulate the synthesis of proteins instrumental to the strengthening of nerve cell connections. For example, Ca⁺⁺ stimulates CREB proteins that regulate the transcription of genes shown to be involved in establishing LTP, long-term memory, and the neurotrophin-mediated growth of dendritic spines (see review by Barko and others, 2006). 

Adult Plasticity
LTP has been observed also in the mature brains of higher vertebrates, suggesting that sensory representation in cerebral cortex might remain plastic to some degree throughout life. For example, in adult primates the denervation of a finger led to an expansion of the cortical representations of the unaffected fingers in somatic sensory cortex into the deprived territory (Merzenich and others, 1983). Similarly, focal lesions in the retina of adult primates resulted in an expansion of the representation of the visual field adjacent to the lesion into the area of visual cortex with the scotoma (Kaas and others, 1990; Darian-Smith and Gilbert, 1994).

My own research mouse somatic sensory cortex strikingly demonstrated such sensory map plasticity and differences between the developing and the mature rain.  The whiskers on the snout of the mouse constitute complex sensory organs equipped with multifarious types of touch receptors. The long whiskers are arrayed in five rows named A to E; four whiskers straddle the rows at the back end (see my post with the title "The Power of Instruction & The Brain" from Dec. 24, 2008). The row whiskers are numbered from cheek to nose beginning with 1. The orderly spatial organization of the whiskers on the snout is maintained by their representations in the brain.  In somatic sensory cortex, cytoarchitectonic units of cell body dense sides surrounding cell-sparse hollows represent the whiskers topographically. The units are called barrels. Cajal divided the cerebral cortex into six layers according to nerve cell types. The layers are distinguished by their in- and outputs. The barrels are situated in layer IV which receives the greatest sensory input from the whiskers via a crossed pathway relayed by stations in the brainstem and in the diencephalon.

The Barrels in Mouse Somatic Sensory Cortex: Micrograph of a section cut tangentially through the right cortical hemisphere of the mouse brain. The section is stained for cell bodies, showing the rows of barrels that represent the whiskers on the snout (the nose is right; the midline is up).

The micrograph above shows the barrels. The five rows can be recognized. Row A begins at the left corner of the barrelfield; rows B, C, D and E follow successively on top, curving down as they proceed toward the nose while the barrels diminish in size (right). The cluster of small barrels on the right represents the short whiskers near the lips.

Barrels develop during the first postnatal week. If whisker follicles are removed or severely damaged shortly after birth, the corresponding barrels do not develop and the adjacent barrels enlarge into the vacant territory. The changes can only be observed, when the damage occurs before the barrels are detectable, corroborating the idea of a critical period for brain plasticity. Mouse somatic sensory cortex therefore constitutes an appropriate model to study brain plasticity.

Combining histological staining techniques with a metabolic functional imaging method called the quantitative autoradiographic deoxyglucose method, I was able to distinguish plasticity of functional and cytoarchitectonic whisker representation. Whisker follicle removal in neonates changed the barrels and the associated whisker-activated areas dramatically. The entire region vacated of sensory input was highly activated when intact whiskers adjacent to the removed whiskers were stimulated. By contrast, the same lesion in adults did not affect the corresponding barrels structurally, but still resulted in an enlargement of the functional representations of the whiskers adjacent to the removed ones into the whisker-deprived barrels. The differential effect of neonatal and adult whisker follicle removal suggests that although the brain may be plastic beyond the critical period, the changes are more limited and subtle in adults. The experiments are described in detail below.

Whisker follicles intact.

Neonatal lesion.

Adult Lesion.

Neurofunctional Imaging of Plasticity in Mouse Somatic Sensory Cortex during Development and in Maturity: The color-coded images show energy metabolism in sections cut tangentially through the right cortical hemisphere. The quantitative autoradiographic deoxyglucose method was employed for neurofunctional imaging. Outlines of the barrels in somatic sensory cortex are superimposed on the images (The nose is to the right; the midline is up). When six whiskers, that is whiskers B1-3 and D1-3, on the left side were stimulated, focal regions of increased metabolic nerve cell activity (red) were found co-localized with the corresponding barrels B1-3 and D1-3 (top image; row A is outside the plane of section; the arrow points at barrel E1). The distinct gap of low activity between the highly activated regions comprises barrels C1-3. When the follicles of whiskers C1-3 were removed on the day of birth, the barrels that would have represented these whisker did not develop and the adjacent barrels enlarged into the territory deprived by the removal (center image, outlines). Stimulating whiskers B1-3 and D1-3 produced profound activation in the reorganized territory (Melzer and others, 1993). By contrast, when whiskers B1-3 and D1-3 were stimulated in mice that had the follicles of whiskers C1-3 removed in adulthood, the structure of the corresponding barrels was unchanged (bottom image). Despite, nerve cell activation extended into deprived barrels C1-3 (Melzer and Smith, 1995). Though the critical period for barrel development had long ended at the time of whisker follicle removal, nerve cell connectivity was apparently still plastic, be it with diminished outcome.

The mouse experiments above help visualize brain plasticity as a result of the absence of sensory input. Also increased use of inputs associated with reward has been shown to produce enlargement of sensory representation, particularly in auditory cortex (Polley and others, 2006). Increased stimulation increases  dendritic spines on pyramidal neurons of cerebral cortex. However, these spines have been shown to be more dynamic than previously thought (see my post with the title "Genes, Brain Plasticity & Memory" dated May 7, 2009), and the gains may prove temporary.

Conclusion
Much has been made of brain plasticity. Functional imaging studies revealed that regions of the occipital lobe that process vision in sighted people were activated, when people with severe visual disability read Braille with their fingertips (Melzer and others, 2001); otherwise visual regions of occipital cortex were activated during spatial hearing (Renier and others, 2010). Such activations commonly comprise areas of association cortex that are known to receive polymodal sensory input. For example, an association area involved in the visual discrimination of the orientation gratings was also activated when blindfolded sighted participants were asked to determine the orientation of gratings etched into a surface with their fingertips (Sathian and Zangaladze, 2002); visual and haptic information on objects of the same types appear to be processed in the same cortical regions. The activation of areas hitherto recognized as visual in blind people executing tactile tasks may therefore be the result of unmasking of inputs that gain prevalence as visual input ceases. Moreover, when we are blindfolded for a while or lose eyesight late in life, imagining our surroundings in front of our mind's eye may suffice to activate the cortical regions that are usually involved in the processing of visual spatial features. Without visual input, mental imagery-related activation gains prominence.

Unmasking weak inputs requires only small-scale reorganization of nerve cell connections. Our brain need not be as plastic as we might surmise. Despite, it is comforting to know that the nerve cells in our brain can strengthen existing connections and develop new ones throughout our lives, be it to lesser extent than in our younger years. Dr. Sacks rightly suggests in his New Year message that we must take advantage of this gift and resolve not to resist learning new skills as we go forward. The oldest mouse I tested for adult plasticity was 15 months of age; mice live perhaps 24. We may be able to keep learning and enjoy the fruits of our labor for a long time. If our vision fades, we shall always be able to learn Braille, if we are willing to make the effort. Even faced with greater adversity, we can rely on our brain's resilience. It sure does a heck of a job with filling in extraordinary gaps in a formidable effort to present us with a meaningful world.
Happy New Year!

References

• Barco A, Bailey C, Kandel E (2006) Common molecular mechanisms in explicit and implicit memory. J Neurochem 97:1520–1533.
• Darian-Smith C, Gilbert CD (1994) Axonal sprouting accompanies functional reorganization in adult cat striate cortex. Nature 368:737-740.
• DeFelipe J, Jones EG, May RM (1991) Cajal's Degeneration and Regeneration of the Nervous System. Oxford University Press, New York.
• Hebb DO (1949) The Organization of Behavior: A Neuropsychological Theory, 1st Edition. Wiley and Sons, New York.
• Hubel DH, Wiesel TN, LeVay S (1977) Plasticity of ocular dominance columns in monkey striate cortex. Philos Trans R Soc Lond B Biol Sci 278:377-409.
• Kaas JH, Krubitzer LA, Chino YM, Langston AL, Polley EH, Blair N (1990) Reorganization of retinotopic cortical maps in adult mammals after lesions of the retina. Science 248:229-231.
• LeVay S, Stryker MP, Shatz CJ (1978) Ocular dominance columns and their development in layer IV of the cat's visual cortex: a quantitative study. J Comp Neurol 179:223-244.
• (Lømo, T (2003) The discovery of long-term potentiation. Philos Trans R Soc Lond B Biol Sci 358:617–620.
• Melzer P, Smith CB (1995) Whisker follicle removal affects somatotopy and innervation of other follicles in adult mice. Cereb Cortex 5:301-306.
• Melzer P, Morgan VL, Pickens DR, Price RR, Wall RS, Ebner FF (2002) Cortical activation during Braille reading is influenced by early visual experience in subjects with severe visual disability: a correlational fMRI study. Hum Brain Mapp 14:186-195.
• Melzer P, Crane AM, Smith CB (1993) Mouse barrel cortex functionally compensates for deprivation produced by neonatal lesion of whisker follicles. Eur J Neurosci 5:1638-1652.
• Merzenich MM, Kaas JH, Wall J, Nelson RJ, Sur M, Felleman D (1983) Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation. Neurosci 8:33-55.
• Polley DB, Steinberg EE, Merzenich MM (2006) Perceptual learning directs auditory cortical map reorganization through top-down influences. J Neurosci 26:4970-4982.
• Wiesel TN, Hubel DH (1963) Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophysiol 26:1003-1017.
• Renier LA, Anurova I, De Volder AG, Carlson S, VanMeter J, Rauschecker JP (2010) Preserved functional specialization for spatial processing in the middle occipital gyrus of the early blind. Neuron 68:138-148.
• Sathian K, Zangaladze A (2002) Feeling with the mind's eye: contribution of visual cortex to tactile perception. Behav Brain Res 135:127-132.
• Sperry RW (1948) Patterning of central synapses in regeneration of the optic nerve in teleosts. Physiol Zool 21:351-361.
• Sperry RW (1945) Restoration of vision after crossing of optic nerves and after contralateral transplantation of eye. J Neurophysiol 8:15-28.
• Todman D (2008) History of Neuroscience: Roger Sperry (1913-1994), IBRO History of Neuroscience.

Related Posts

• Constantin von Monakow & Brain Plasticity
• Konrad Lorenz, Imprinting & Functional Brain Imaging
• Genes, Brain Plasticity & Memory
• The Power of Instruction & The Brain
• Auguste Forel & Brain Plasticity

Addendum

• The interested reader may wish to view the slide show of a presentation I gave on the topic (01/16/11):

About People with Visual Disability and the Usefulness of Braille

I had the privilege to meet people with severe visual disability in a study I conducted to examine the brain regions involved in Braille reading by touch. I am interested in brain plasticity. That is, I am studying the brains ability to reorganize after a change in input from the sensory periphery, e.g. the loss of eye sight. With positron emission tomography and functional magnetic resonance imaging, brain regions can be visualized that are activated during the exposure to sensory stimuli or the execution of tasks. Recent studies report that regions in the occipital lobes of the cerebral cortex that are known to process visual information in sighted people become activated in people with severe visual disability reading Braille with their fingertips. My colleagues and I at Vanderbilt University embarked on a study with Braille readers to examine specifically the role that the loss of vision may play in the recruitment of “visual” cerebral cortex for the processing of touch information. The movie shows typical cortical activation in a Braille reader with visual disability. At the beginning and the end of the rotation, the brain regions processing touch are at the top and the activated areas in "visual" cortex are at the bottom.

We could not determine in what cortical area the loss of vision was necessary for the recruitment. We could not find sighted readers who read Braille with their fingertips as proficient as people with severe visual disability. Hence, we could not exclude that visual cortex was recruited merely in the process of learning to read Braille, regardless of the presence or the absence of input from the eyes.

However, intriguingly we identified a number of cortical regions known to be involved in the processing of language. Careful analyses of the cerebral activation may help shed a light on the fashion in which occipital cortex processes information detached from a specific sensory modality, providing deeper insight into the workings of the human mind. Ford Ebner and I recently described the findings of our study comprehensively in a chapter of a book entitled "Blindness and Brain Plasticity in Navigation and Object Perception."


The study was a great learning experience for me. I had not met people with disabilities personally before.

• I was very impressed with the ease with which most coped with the challenges of daily life, e.g. crossing a street. Next time when you stand at the lights of a busy intersection, close your eyes and decide when to go. You will understand immediately what I am saying.

• I met many professionals with college degrees raising families. I asked one youngster whose parents are both blind, how they could possibly manage to keep track of him and his siblings. I have trouble with mine and I can see. He answered flatly: “It has never been a problem. My parents always know where we are and what we are up to.”

• People with disabilities possess great wisdom of life. I once walked down the sidewalk with a participant, returning from a study. We were joking around fueled by the elation that we had a good session. The scanner had worked and nothing else had failed that day. A young man came up. He looked sullen. He called out: “Excuse me! May I ask a question?” “Yes,” my friend replied. “I see you walking down the street a blind man. Yet, you seem happy and content. I can see. But I am depressed. I have got to take pills to get me through the day. There is no happiness in my life. Would you trade with me?” My friend answered: “Of course, I would rather see. But I learned to live without. Take a day at a time and make the best of it.”

• I was impressed with the physical abilities of people with visual disability. Many actively pursue sports. There are skiing programs in Colorado like Foresight that take people with visual disability to the slopes on weekends. Small groups are assigned to sighted guides whom they follow down the trails. I am a passionate skier. When I heard of the program, I imagined something quaint. Not at all! I happened to meet a group once on a black diamond tackling the moguls at awesome clip. I still cannot fathom, how you acquire this level of skill. My performance drops considerably in the fog. I was so impressed!

• They have got great talent for music and dance. Many are commercially successful. Just to name a few: Andrea Bocelli, Ray Charles, Stevie Wonder, Jose Feliciano, The Blind Boys of Alabama, Ginny Owens, and La Singla.

Finally, I learned about the meaning of Braille. A stencil with Braille cells is as essential as a notebook. The software that translates text to voice is improving at rapid rate. All major operating systems offer assistive technologies these days. Doubt is cast on the necessity of Braille in the future. However, many professionals prefer to use electronic Braille displays to be able to read the output from their computer most expediently and efficiently. Unfortunately, the gadgets are expensive compared with the voice programs, and not every employer is willing to make the investment.

Another problem is printing or, more correctly put, embossing. When I carried out my study, we attempted to emboss consent forms in Braille. It was a very cumbersome process. The software we had was rudimentary at best. The printer was highly mechanical and slow. The Braille dots were embossed in thick paper with metal pins. The noise reminded me of a machine gun and was quite unnerving. The gadget was huge, unwieldy and too expensive for personal use. I do not blame the engineers. They came up with a solution that is solid and works. However, in our day and age there must be faster, quieter and more affordable ways to emboss Braille.

I can only encourage development. Apart from the fascinating question how our brain processes Braille, Braille is here to stay for practical reasons. Who wants to depend on a computer during a black out?

Addenda

• Driving a Prius people with visual disability may have great difficulty in hearing you coming. Please be considerate (09/27/08)!
• New touch screen technology promises useful assistive technologies for smart phones. In his article published on The New York Times site on Jan. 4, 2009, Miguel Helft describes the work of T.V. Raman on applications tailored for people with severe visual disability using google's Android smart phone operating system.