SCIENTISTS MAP MATURATION OF THE HUMAN BRAIN; MAKE ADVANCES IN UNDERSTANDING THE LASTING EFFECTS OF STRESS, NICOTINE AND ALCOHOL

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SCIENTISTS MAP MATURATION OF THE HUMAN BRAIN; MAKE ADVANCES IN UNDERSTANDING THE LASTING EFFECTS OF STRESS, NICOTINE AND ALCOHOL

NEW ORLEANS, Nov. 8 - For the first time, scientists have mapped the progressive maturation of the human brain in childhood and adolescence. In other studies, they have made advances in understanding during adolescence the effects of stress, nicotine, and alcohol.

Scientists at the National Institute of Mental Health (NIMH) in collaboration with the University of California, Los Angeles, developed a new brain mapping technique and applied it to high quality MRI scans of children scanned across ages 4 through 21. This allowed them to visualize the dynamics of brain development including the cortex. They also constructed the first three-dimensional movie of human brain development.

The cortex, or surface of the brain, is also called the “gray matter” where the neurons, or the main brain cells, reside along with their immediate connections or synapses. After birth, an initial overproduction of synapses- which are within the gray matter - is followed by their systematic pruning with maturation. For most of the cortex, this maturation begins right before puberty.

“While confirming that the cortical gray matter maturation is a temporally uneven process, we found that the normal gray matter loss begins first in the motor and sensory parts of the brain (the top-middle portion), slowly spreading downwards and forwards, over the entire brain surface,” says Nitin Gogtay, MD. “The surprising thing is that the sequence in which the cortex matures appears to agree with regionally relevant milestones in cognitive development, and also reflects the evolutionary sequence in which brain regions were formed,” he says.

Parts of the brain associated with more basic functions matured early: primary motor and sensory brain areas matured first followed by areas involved in spatial orientation, speech and language development, and attention (upper and lower parietal lobes), spreading to the areas involved in executive functioning, attention or motor coordination (frontal lobes). Further, the areas that integrate these functions matured the last in this age range (temporal lobe). Moreover, the parts of the brain that are evolutionarily older appear to mature early compared to the newer parts of the brain.

These findings have direct clinical relevance, says Gogtay. For example, autism, an early onset disorder, may occur because of faulty development early on. Childhood onset schizophrenia, with a somewhat later onset than autism, shows a back to front wave of gray matter loss, whereas later onset (the more typical form) schizophrenia seems to be more strongly associated with later maturing temporal and frontal regions. Thus the gray matter loss seen in schizophrenia could, at least in part, be an exaggeration of the normal “back to front” maturation process, and thus may also suggest excessive elimination of synapses (pruning) as a possible trigger of the disease.

Most prior studies of brain development were based on information from single (one time) MRI scans of subjects selected over a wide age range. The only study with repeatedly scanned children was done at the NIMH, but also included children with single scans. This study, an extension of a prior NIMH sample, permits more precise understanding of brain development in relation to its functional maturation, and provides the first video maps of brain development.

For this study, 13 healthy children were selected from the NIMH sample, who had 3-5 sequential MRI scans; each repeated at two-year intervals (a total of 52 MRI scans) and processed using the novel brain mapping technique. This technique, which the scientists developed at the UCLA School of Medicine, uses landmarks on the brain surface and then mathematically matches several brains. This creates a map of gray matter volume, at individual MRI point (voxel) over the entire brain surface. Using repeated scans it is then possible to map the changes in gray matter volume at each of these single MRI points (total 65,536 points) on the brain surface in extraordinary detail. Since some children are scanned many times, it is possible to extrapolate the points in between and make a time-lapse movie depicting the dynamic progression of brain changes over time.

The researchers are currently expanding these studies to examine the genetic factors that impact normal brain development, and to map brain changes in a variety of child psychiatric conditions.

Other reports describe the effects of environmental influences that occur during adolescence on later conditions that become apparent in the adult.

Studies by Susan Andersen, PhD, of McLean Hospital in Belmont, Mass., and colleagues show that stressful events experienced during adolescence can lead to enduring changes in brain structure in adulthood. This work is the first to demonstrate that exposure to a significant stress during adolescence can impact neuronal connections in the adult brain.

The researchers found that adult rats exposed to a social stress during adolescence (ages approximating 13 to 15 years in humans) showed a significant decrease in a specific protein found in the hippocampus, a brain region important for learning and memory. In fact, the loss of this protein, synaptophysin, is at least as great as that occurring in animals exposed to more severe stressors at a younger age, suggesting that adolescents may be more vulnerable to the effects of stress than younger animals.

Under typical conditions, synaptophysin, which is often used as an index of the number of neuronal connections, or synapses, reaches a peak during young adulthood (approximately ages 18 to 20), with the rise occurring primarily during adolescence. The team tested whether a social stress during this key developmental period might alter this pattern. A control group of rats was housed with their peers, and an experimental group of rats was housed individually during adolescence; individual housing in normally social animals such as rats is a stressful experience. The brains of both groups were then examined during young adulthood. The team found that rats exposed to the social stressor did not show the normal increase in synaptophysin during this period. These data suggest that social stress during adolescence causes either a loss of synapses or a decrease in the synaptophysin protein.

The researchers then compared the loss of synaptophysin in rats that were stressed during adolescence with rats that experienced significant stress during ages comparable to childhood. The stressor used for this age group was repeated maternal separation (RMS). The scientists found no significant difference in synaptic density between rats that had social stress during adolescence or rats that had early RMS. However, the density of synapses in the hippocampus of both groups was reduced significantly when compared with control rats.

These findings are the first to demonstrate that exposure to a significant stress during adolescence can have enduring consequences on the connections formed in the hippocampus in adulthood. These data may suggest why early traumatic stress, such as physical or sexual abuse or neglect, is associated with a decrease in the size of the hippocampus in adulthood.

“These preclinical data suggest that stress experienced early in life alters the normal developmental trajectory of the hippocampus, but that these changes are not apparent until later in life,” says Andersen.

In another study, non-smoking adolescents with attention deficit hyperactivity disorder (ADHD) showed significant improvement in their ability to inhibit a motor response following acute nicotine administration. Nicotine produced a short-term improvement that was as large as the improvement seen after giving them Ritalin, the standard drug used to treat ADHD, says Alexandra Potter, PhD, of the University of Vermont in Burlington.

"This is the first study we know of that specifically examines the positive effects that nicotine might have on inhibition in ADHD. Other researchers have shown that nicotine improves the global symptoms of ADHD and our study expanded on these findings by looking specifically at a certain part of cognition (inhibition) in an attempt to better understand the effects that nicotine has on these adolescents," says Potter.

"These data suggest that nicotine might ameliorate some of the cognitive symptoms associated with ADHD. It is already known that adolescents with ADHD have higher rates of smoking compared to adolescents without ADHD. Perhaps one reason why these adolescents are more vulnerable to becoming cigarette smokers is the relief nicotine provides in controlling their ADHD symptoms."

The findings raise other questions such as whether drugs that act at nicotinic acetycholine receptors could be used as treatments for ADHD, whether the effects we found are specific to people with ADHD, and how the gender of the subject might affect these findings, Potter says. Future studies are aimed at beginning to answer these questions.

The study focused on a cognitive phenomenon known as inhibition. Inhibition is the process which allows us to modify our behavior based on cues we get from the environment. Researchers over the last several years have hypothesized that the true central deficit of ADHD is not deficient attention, but is rather a problem of insufficient control of attention due to lack of inhibition.

In a pilot study that investigated 8 non-smoking adolescents with ADHD over three separate study days, subjects were administered nicotine, Ritalin, or placebo (sugar pill). Over three study days, each subject had one day with each medication. After the medication was given, the subject was tested on standard measures of inhibition (the stop signal and Stroop tasks). They also completed mood and behavior ratings, and had their vital signs monitored during the study.

The findings raise other questions such as whether nicotinic drugs could be used as treatments for ADHD, whether the effects we found are specific to people with ADHD, and how the gender of the subject might affect these findings, Potter says. Future studies are aimed at beginning to answer these questions.

In a study of alcohol, scientists found that binge alcohol exposure during adolescence in rats caused long-lasting tolerance to alcohol, and represent the first investigations into the long-term brain effects of chronic binge alcohol exposure during this age. The study was conducted by Douglas Matthews, PhD, of the University of Memphis.

Tolerance, a reduced effect of a drug following previous exposure to the drug, is a hallmark of chronic ethanol exposure in adults. Specifically, alcohol tolerance results from the loss of ethanol responses in individual brain neurons and the loss of the ability of ethanol to elevate brain steroid levels. In addition, chronic binge alcohol exposure altered specific GABA-A receptor and other brain protein levels, and these alterations persisted following an extended alcohol free period.

Chronic alcohol abuse during adolescence produces profound neurobiological changes that might last until adulthood. Adolescence, a critical period of neural development, is often marked by high levels of alcohol abuse in humans. For example, the 2000 National Household Study on Drug Abuse reported that 16.4 percent of adolescents used alcohol in the month prior to the survey, while 10.4 percent reported binge drinking (consumption of 5 or more drinks on one occasion), and 2.6 percent report heavy alcohol use (5 or more drinks on 5 or more occasions). Binge and heavy drinking peak at age 21 with 45.2 percent reporting binging, and 16.7 percent reporting heavy drinking.

While it has been known for several years that alcohol drinking during adolescence predicts future alcohol abuse, the underlying mechanisms have been unknown. “These new finding are novel and important as they represent the first investigations into the long-term brain effects of chronic binge alcohol exposure during adolescence,” says Matthews.

“The findings strongly suggest that binge alcohol exposure during adolescence alters the neurobiology of the brain in a manner that can be long lasting. These long-lasting changes highlight adolescence as a critical period when alcohol abuse can produce changes in the brain. These changes might represent a long-term state that leads to alcohol abuse.”

The present research supports the notion that chronic binge ethanol exposure produces changes in rat brain. The research also is the first to identify genetic and steroid changes that are directly associated with tolerance to the cognitive impairing effects of ethanol.

In the study, 16 male rats were treated with 5.0 grams/kilogram of ethanol every 48 hours from postnatal day 30 to postnatal day 50, the time period corresponding to adolescence in rats. Hippocampi were then collected on postnatal day 51 or postnatal day 65 and genetic changes were then measured.

Chronic binge alcohol exposure during adolescence was found to alter the expression pattern of several genes including genes that are known to change during ethanol tolerance. Changes in mRNA levels were then verified by similar changes in protein levels in the hippocampus in a unique group of 24 animals. Finally, changes in the function of the brain that might underlie tolerance were examined by recording the activity of single brain neurons in the hippocampus of 19 additional rats. It was revealed that chronic binge alcohol exposure during adolescences produced alcohol tolerance in single neurons of the brain. Finally, it was discovered that chronic binge alcohol exposure during adolescence produces tolerance to alcohol increases in brain steroid levels.

Future studies must identify whether such changes last throughout adulthood and if these changes drive increased alcohol drinking. If this is the case, then the current work will be the first to identify a mechanism that produces alcohol abuse in adults following exposure to high levels of alcohol during adolescence.