Friday, January 28, 2011

One Sad Day for Mankind

Today 25 years ago the Space Shuttle Challenger exploded high in the sky shortly after liftoff, taking the lives of seven astronauts on board, including a school teacher. In a congressional hearing on the causes of the tragic accident, the eminent physicist Richard Feynman would later elegantly demonstrate to the public that the O-ring seals in the booster rockets lost elasticity at freezing temperatures. He dropped a piece of the material into an ice water cup in front of him, letting it soak for a while. He then took it out and pinched it. The result was lasting indentations, affirming that the material changed its properties dramatically with dropping temperatures.

During the days before Columbia's liftoff, Florida endured a cold spell with freezing temperatures. The O-rings sealing the fuel into the booster rockets had turned stiff and leaky. Flames blasting sideways onto the main liquid fuel tank ignited the fuel, triggering the tank's explosion. The manufacturer's warning that the rings' strength would not withstand low temperatures had gone unheeded when the fateful decision for launch was cast.
Space Shuttle Decoy at Huntsville, AL, showing the white booster rocket and the brown fuel tank.
Projects as complex as the Space Shuttle program demand unprecedented care. Only a few nations are able to command the needed resources, infrastructure,  intellectual capital and economies sufficiently advanced to embark on such endeavors. The organizational challenges involved in the management of the risks inherent in such projects should teach us lessons. It may be true that great explorations are not for the faint of heart. Alas, the Challenger tragedy should serve as a lasting reminder to be prudent. Murphy's law does apply!

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Friday, January 7, 2011

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.

The notion that the brain is plastic is more than a century old. Eminent 19th-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.

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!

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