Thursday, August 14, 2008

Cortical Development & Schizophrenia

In its Health Guide section of June 13, 2008, The New York Times published a comprehensive article entitled "Schizophrenia and the Brain" (the article has been found irretrievable on Jan. 29, 2011, but the animations can be found in the NIMH Science Update of Oct. 30, 2008, with the title "Brain's Wiring Stunted, Lopsided in Childhood Onset Schizophrenia"). The article includes a series of fascinating time lapse movies showing the maturation of cerebral cortex from early childhood (4 years of age) to young adulthood (21 years of age). The normal developmental profile was compared to that of people with early-childhood schizophrenia, the symptoms of which can manifest themselves as early as 8 years of age. A commentator explains the changes in the movies and an accompanying interview with P.M. Thompson, a principal investigator of this research, provides further perspective on the findings. The intriguing dynamics of cortical maturation shown in the time-lapse movies give pause to the close observer and evoke the desire for more information.

The human cerebrum consists of gray and white matter in roughly equal proportions. The gray matter comprises deep structures as well as the cerebral cortex containing the nerve cells and nerve cell processes that connect these cells locally. The cerebral white matter underlying the cortex is composed of the nerve cell processes known as axons that connect the cortical cells with distant regions in the same hemisphere, the other hemisphere, the deep gray matter structures and the spinal cord. It also contains the axons of ascending projections that terminate in the cerebral cortex. The axons are wrapped in sheeths of a fatty substance known as myelin. The myelination gives the white matter the color of cream.

Dr. Thompson and his colleagues measured the density of cortical gray matter repeatedly in the same people with nuclear resonance imaging in two-year intervals. The changes across the samples are projected in false colors and time lapse on virtual reconstructions of cerebral cortex. The studies providing the data for normal development have been described in detail by Gogtay and others (2004) and for early-onset schizophrenia by Gogtay (2008) and Thompson and others (2001). Some of the cited studies can be accessed for free, others need a subscription.
Dr. Thompson and his colleagues attribute the diminutions in gray matter density to enhanced myelination in the white matter and/or the loss of nerve cells, nerve cell processes known as neuropil and nerve cell contacts known as synapses in the gray matter. Myelination of axons accelerates nerve cell signal conduction at increased efficiency and is believed to continue into advanced age. The loss of synapses in the cerebral cortex may result from the pruning of neural networks in which used nerve cell connections are spared whereas idle connections are eliminated.

Based on his observations on animal behavior in the 1940s, the psychologist Donald O. Hebb was the first to suggest that the strengthening of synapses that are activated together may provide a neural mechanism for learning and memory. In the 1960s and 1970s, the Nobel Prize-laureates T. Wiesel, D. Hubel and their colleagues observed that the arbors of the endings of inputs to visual cortex from the eyes overlap at first, but separate into distinct, eye-specific domains during brain maturation (LeVail and others, 1980). As an important affirmation of the validity of Hebb's hypothesis, the development of the ocular dominance domains was plastic and depended on active input. When input from one eye was deprived, most endings of the idled input were pruned, whereas the endings of the functional, active input remained extended, claiming the cortical territory of the deprived eye. During a critical period the effect could be reversed when the inputs from the intact eye were deprived and the hitherto deprived inputs were reactivated. The experiments demonstrated elegantly that the development of connections between nerve cells can be highly dynamic and particularly sensitive to sensory stimulation during a critical period. 

In the 1980s, Hebb's hypothesis was validated on the cellular level with the discovery that repeated stimulation of the input of particular types of cortical nerve cells strengthened their response to stimulation. The effect is known as long-term potentiation or LTP for short. Subsequently, researchers identified the molecular mechanism for LTP. A particular type of receptor for the excitatory neurotransmitter glutamate plays a key role. Glutamatergic synapses are the most abundant in cerebral cortex. The receptor involved in LTP is known as N-methyl-D-aspartic acid receptor or NMDA-receptor for short. The receptor channels positively charged ions through the nerve cell membrane, increasing the the postsynaptic excitatory potential or EPSP for short. This voltage initiates electric spiking known as action potentials in the nerve cell's axon. The action potentials travel along the axon to the nerve cell endings and trigger the release of neurotransmitter into the cleft of the next synapse. NMDA-receptors can enhance synaptic transmission and thereby strengthen synapses because the opening of the ion channels is voltage dependent and multiple receptor activation facilitates the opening of disproportionately more channels. It is widely accepted today that via this mechanism Hebb's rule applies to the experience-dependent strengthening of glutamatergic synapses, and synaptic stabilization and loss are understood as basic mechanisms for the refinement of cortical nerve cell circuitry. 

In support of this concept, nerve cell connections between and within the cortical hemispheres have been shown to develop in steps of exuberance and elimination (for review see Innocenti, 1995). In harmony, P.R. Huttenlocher was the first to report a waxing and waning of nerve cell contact density in the maturing human cerebral cortex (see Huttenlocher and others, 1982-83). The exact time course appeared to differ among cortical areas. In accord, local peaks of energy metabolism were observed (Chugani and others, 1987). Eventually, comprehensive synaptic counts in the cortex of non-human primates affirmed the initial increase and the subsequent decrease in the number of synapses as fundamental steps in the maturation of cerebral cortex (Rakic and others, 1994).

In the time-lapse movies shown in The New York Times, Dr. Thompson and his colleagues use measurements of gray matter density to track the maturation of cerebral cortex. Gray matter density may indeed be closely associated with synaptic density. W.T. Greenough and colleagues showed that exposure to an enriched environment and the ensuing enhanced sensory stimulation increases myelination, cortical synaptic density and, notably, cortical thickness in rats (for review see Markham and Greenough, 2004).  In separate studies, Thompson and colleagues could establish that cortical gray matter density tightly correlates with cortical thickness (Sowell and others, 2004). The thickness varies regionally between 1.5 and 5.5 mm and diminished by as much as 0.3 mm in a year during development. In accord, the time-lapse movies on normal development show that the gray matter density in cerebral cortex diminishes on both hemispheres with advancing age. The diminution progresses in waves originating in the parietal lobes and sweeping toward the frontal lobes.

Exuberance of synapses in human cortex commonly peaks before the age of 4 years and the range of the time-lapse movies may not cover the synaptic build up. However, taking the findings reviewed above into consideration, it is reasonable to suggest that the reductions in gray matter density reflect synaptic elimination following exuberance and the dynamic in the movies may be accurately labeled as cortical maturation. By contrast, the changes in gray matter density visible in the time-lapse movie shown for childhood-onset schizophrenia are more complex. The color scale of maturation seems inverse. Despite the bright colors, the changes seem subtle. Thompson and others (2001) report that they observed more rapid and, in some areas, greater than normal decreases in gray matter density on both cortical hemispheres, suggesting a loss of synapses in addition to the normal pruning of underutilized connections.

The most striking diminutions of gray matter density were found in the parietal lobes. Large swaths of parietal cortex receive multi-modal sensory input. The information from multiple senses is integrated here. In humans, parietal areas process language. In my studies on cortical responses to Braille reading, distinct foci of activation were found in posterior parietal cortex near the borders of regions that predominantly receive visual, auditory or somatic sensory input (Melzer and others, 2001). Information that establishes our  identity may be processed in parietal cortex. In order to be able to interpret the gray matter density decrease in early-childhood schizophrenia more rigorously, it is essential to disambiguate the causes for the diminution and perhaps establish a relationship with synapse formation.

In my own research on developmental plasticity in mice, I observed considerable thinning of somatic sensory cortex in addition to cytoarchitectonic alterations after the deprivation of tactile input by neonatal whisker follicle removal (Melzer and others, 1993). The cortical layer that shrank the most normally receives the densest tactile input and synapses are lost when the input is disrupted. The cortex was not fully developed at the time of follicle removal. It takes the entire first week after birth for somatic sensory cortex to mature to a degree that the structural alterations visibly manifest themselves. Mouse somatic sensory cortex is considered fully mature three weeks after birth. That is, the effects of the deprivation of input take about the third of time for postnatal maturation to become obvious. In analogy, the cause for the gray matter loss observed in schizophrenia most likely affects cortical development well in advance of the manifestation of the loss.

In the search for the mechanisms underlying the gray matter loss, the time-lapse movies on the development of cortical gray matter density provide invaluable information. They allow us to begin the search in the cortical areas with the greatest loss. The movies represent group results. In order to select the best suited areas, it would be helpful to examine whether some cases in the sample contribute substantially more to the mapped averages of gray matter density loss than the rest of the sample and whether those cases share common factors in their medical histories.


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