September 2004

CROSSROADS UPDATE

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UCSD scientists study electrical stimulation to brain Chemical imbalances might be alleviated By Bruce Lieberman UNION-TRIBUNE STAFF WRITER June 18, 2004 Altering the electrical activity in brain cells can change the chemicals they use to communicate with one other – a finding that someday may lead to new treatments for mood and learning disorders, UCSD scientists say. Their study, which appeared this month in the journal Nature, suggests that chemical imbalances in the brain that lead to depression, phobias, schizophrenia, bipolar disorder and other conditions could be alleviated not by drugs but by direct electrical stimulation to specific areas of the brain. "These drugs have side effects, and they don't work in all cases," said Nicholas Spitzer, a UCSD neuroscientist whose lab conducted the study. "We are beginning to think . . . that there might be another way." Neuroscientists have long believed that the connection between a brain cell and the neurotransmitter it generates is hard-wired in the genes. A host of drugs, including Prozac and others, are designed to artificially boost or slow down the flow of neurotransmitters between neurons. Depression, for example, is associated with low levels of the neurotransmitter serotonin. And there is strong, although not conclusive, evidence that schizophrenia is fueled by the flood of the neurotransmitter dopamine between neurons. Other treatments to alter the flow of neurotransmitters have included electroconvulsive therapy, called ECT, and Transcranial Magnetic Stimulation, or TMS – both of which induce the flow of electrical currents through the brain in an attempt to alter the flow of neurotransmitters. But researchers are not certain why these treatments work, said Spitzer. The UCSD study and other basic research into how neurons generate neurotransmitters – and how to alter what they make – could lead to much more precise treatments using technology such as TMS, Spitzer said. In the UCSD study, scientists found that they could actually alter the kind of neurotransmitter a neuron generates by fine tuning the electrical signals flowing through it. "Different frequencies of signals lead to the appearance of different neurotransmitters," said Spitzer. "The concept then would be to stimulate the nervous system (through treatments like TMS) with the relevant frequencies of electrical stimulation to try to alter the balance of transmitters." In their study, Spitzer and his colleagues altered the electrical current flowing through the nerve cells in the spinal cords of frog embryos. Increases in electrical activity boosted the levels of neurotransmitters that inhibit connections between nerve cells. Decreasing electrical activity had the opposite effect. More basic research over the next several years will be needed before clinical trials in humans can begin, said Spitzer. Neurons use between 50 and 100 kinds of neurotransmitters to communicate with one another, and the UCSD scientists did not study two important ones implicated in many mood and learning disorders – serotonin and dopamine. "We're just starting experiments now to try to understand what are the relevant frequencies of stimulation for serotonin and dopamine," said Spitzer. "The goal will be to find those frequencies, and do tests in (animals) . . . more relevant than the frog embryo." Scientists will also have to determine whether the results they've seen in early developing organisms – in the UCSD case, frog embryos – hold up in adult organisms with mature nervous systems, said Gabrielle Leblanc, program director for neurogenetics and development at the National Institute of Neurological Disorders and Stroke, which helped fund the UCSD study. If they do hold up, scientists will make important advances toward finding alternatives to drugs for treating neurotransmitter imbalances, she said. "If we could find a way to stimulate the function (of neurons) electrically instead of with drugs, that may actually be a much more . . . natural remedy," Leblanc said. Young Brains on Alcohol The brain images show how alcohol may harm teen mental function. Compared with a young non-drinker, a 15-year-old with an alcohol problem showed poor brain activity during a memory task. This finding is noted by the lack of pink and red coloring. Clearly, experimentation with alcohol during youth is bad news.But now research shows it's even worse than you think. Recent studies suggest that drinking harms the developing brains of adolescents and teens possibly even more than it does adults. The repercussions may include learning and memory problems,among others. If confirmed, the results provide additional evidence that young people should avoid alcohol.   Acting like a fool, vomiting and a day-after headache are a few common side effects. More seriously, it may lead to an arrest or, in excess amounts, spur an accidental injury, even death.   Yet many young people consume alcohol. Approximately 9.7 million Americans aged 12 to 20 reported drinking alcohol in the month prior to a recent survey by the Substance Abuse and Mental Health Services Administration.   Converging lines of research, however, now provide additional evidence that the young should steer clear of beer, wine and other alcoholic beverages. Although the work is still in an early stage, it appears that drinking can launch a damaging brain assault in teens and adolescents that may even surpass its effects in adults.   Findings on brain development provided some of the first clues that young brains may be more vulnerable to alcohol than adults.   Researchers thought that the brain's key development finished within the first few years of life. Then recently they discovered that important brain regions continue to undergo refinement at least into a person's early twenties. For example, one study compared the brain structure of kids aged 12 to 16 with young adults aged 23 to 30. Several brain areas showed signs that their circuits pare down and fine tune between adolescence and young adulthood. Included is the frontal cortex,which helps process highly complex information. Another study examined molecular changes in the memory brain area, known as the hippocampus, and found that it is stillmaturing in rats equivalent in age to human teenagers.   The findings imply that introducing alcohol during this developmental stage can potentially harm the growing system and associated brain functions, such as learning and memory. Several, more specific studies, back this idea.   In one report, the equivalent of about five drinks in people impairs the ability of adolescent rats, but not adults, to learn a memory task. Other research examined two molecular processes tied to memory, termed long-term potentiation and N-methyl-D-aspartate receptor activity. Adolescent rats that received the equivalent of about one to two drinks experience more interference with these processes than do adults.   Perhaps most troublesome is work suggesting long-lasting alterations. One study found that the equivalent of about 10 drinks produces more extensive brain damage in adolescent rats than in adults.   Findings are hard to confirm in humans because scientists can't provide underage children with alcohol and then dissect their brains. Some evidence, however, is in line with the animal work.   For example, a study of young people indicates that those who start drinking during adolescence have smaller hippocampal memory areas than non-drinkers. Another study finds that following the consumption of about two to three drinks, people in their early twenties perform worse on memory tests than people in their late twenties. More recently researchers examined subjects aged 18 to 25 who reported a history of drinking about a six-pack on weekend nights. Compared with non-drinkers, they perform somewhat worse onmemory tasks. Furthermore, their performance correlates with poor brain activity. Preliminary findings show similar results with younger teens who drink heavily (see images). Their brain response is also diminished, although they manage to perform okay on the tasks. The researchers plan to investigate further how various drinking histories affect different age groups.   Some scientists also believe that the immature young brain may put kids at a disadvantage when they encounter situations involving alcohol. Possibly, their brains can't provide the foresight that they should avoid drinking because it's dangerous. Also, once experimentation begins, brain areas that make a person feel good and want to drink again may be in an underdeveloped state and more easily influenced.   Overall, the research adds fire to an often-repeated message: Just say no. Humor, Laughter and the Brain While comedians have spent a great deal of time focusing on humor and laughter, scientists mostly ignored the subject. In recent years, however, several groups of researchers started to scrutinize this form of merriment. Their investigations are shedding light on how the brain processes humor and prompts laughter. Researchers believe that uncovering the brain and body's specific response to positive stimuli like humor and laughter may lead to new therapies. What do you get if you cross a student with an alien? Something from another universe-ity!   You'll also get unique activity in the brain if you think this joke is funny, according to increasing evidence.   While many researchers have tracked the brain mechanisms of depression, fear and anger, they mostly ignored positive emotions. In recent years, however, a troupe of scientists has started to take laughter and humor much more seriously. Some new work teases out how the brain processes a funny experience. While it's still in an early phase, studies suggest that on a simple level the complex process involves three main brain components. One part, a cognitive thinking part, helps you get the joke. A second movement part helps move the muscles of the face to smile and laugh. And a third emotional part helps produce the happy feelings that accompany a mirthful experience.   In one of the new studies, researchers used imaging equipment to photograph the brain activity of healthy volunteers while they underwent a sidesplitting assignment of reading written jokes, viewing cartoons from The New Yorker magazine as well as Gary Larson's "The Far Side" and listening to digital recordings of laughter. Preliminary results indicate that the humor-processing pathway includes parts of the frontal lobe brain area, important for cognitive processing; the supplementary motor area, important for movement; and the nucleus accumbens, associated with pleasure.   Other work also supports the notion that parts of the frontal lobe are involved in humor appreciation. One study that imaged people while they listened to jokes found that an area of the frontal lobe activated only when they thought a joke was funny. Another study found that compared with healthy individuals, people who had damage to their frontal lobe areas were more likely to choose a wrong punch line to written jokes and didn't laugh or smile as much at funny cartoons or jokes.   Additional findings also back the idea that the supplementary motor area triggers smile and laughter movements. For example, one new study imaged the brains of individuals and recorded the movement of the main muscles involved in laughter while they watched scenes from the British comic series "Mr. Bean." High muscle activity from laughter linked to high activity in the supplementary motor area. In another example, researchers accidentally found proof of the area's role while using electrical stimulation to search for the cause of a young girl's seizures. Electrically stimulating her motor area triggered peals of mirthful laughter.   Currently, researchers are trying to further understand the precise roles that different brain areas play and how their functions may overlap. They also want to determine how the processing may tie to disease. For example, scientists plan to examine the activity of depressed people to see if their humor processing ability is impaired. If it is, then boosting the system’s activity may help depression.   Already some small studies hint that the brain activity from humor may have a medical benefit. For example, human tests have found some evidence that humorous videos and tapes can reduce feelings of pain, prevent negative stress reactions and boost the brain's biological battle against infection. Studies continuing this work are underway. Researchers hope to uncover whether humor or some other component, such as distraction, is the predominant factor in the results.   While much more needs to be known in this area, at least humor doesn't seem to spur any harmful effects.   Seinfeld reruns never looked so good. Researchers believe we process humor and laughter through a complex pathway of brain activity. Paring it down to a simple level, studies suggest that there are three main brain components. Cognitive areas, such as sections of the frontal lobe near the forehead, help you get the joke. Another component involved in the processing is a movement area, likely the supplementary motor area. It is thought to trigger the muscle movements tied to smiling and laughing. Last, researchers believe an emotional component elicits the happiness you feel after a funny experience. One study suggests that the nucleus accumbens, a small area deep in the brain, holds this duty. Brain anti-anxiety switch found Scientists have found a switch in the brain that appears to control anxiety and wakefulness. In tests on rodents, the University of California team found a protein called NPS was active in areas of the brain governing arousal and anxiety. This switch could be a target for drugs to treat sleep and anxiety disorders and attention deficit hyperactivity disorder, they hope. The findings appear in the journal Neuron. Scientists had recently discovered the brain protein neuropeptide S (NPS), but had not fully explored its actions. Dr Rainer Reinscheid and colleagues looked at the activity of NPS in the brains of rodents and found it was produced in a few discrete brain regions. One of these was a region of the brain stem which is known to be important in regulating sleep and anxiety. Neurons in this area fire signals to promote arousal and are inactive during periods of sleep. When the scientists injected mice with NPS they became more active and showed fewer anxiety responses to stressful situations. When rats were injected with NPS they became more alert, sleeping less. By identifying where NPS is active and how it affects the brain the researchers said it might now be possible to target the same pathways. Dr Rainer Reinscheid said: "We've found NPS to be so active with sleep and anxiety behaviour that it can be a very attractive drug target, both to enhance and to suppress its function." It might lead to treatments for a condition called narcolepsy that causes excessive daytime sleepiness attacks, or anxiety disorders, he said. "It's an important step to describe such a fundamental process because we spend a third of our time sleeping," he said. But he added: "This is at a very early stage. Treatments would be five to 10 years down the road." He said their next step was to investigate what would happen if someone was lacking this switch. They could do this by looking at animal models, he said. Alison Cobb, spokewoman for Mind, said: " Any advance in understanding brain chemistry and function is welcome, but as this research is still based on mice it is at a much earlier stage than drug development. "If treatments are developed which improve on current sleeping pills, it is important that they are still used with caution as it takes time for a full profile of side effects to emerge. "Sleep problems are very common, and although they can be severe and intractable, talking up the potential of new drug therapies risks medicalising a problem that can be tackled in other ways."

ALZHEIMER/DEMENSIA NEWS

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Vitamin B(12) deficiency in elderly patients. CMAJ. 2004 Aug 3;171(3):251-259. Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, Noblet-Dick M, Maloisel F, Schlienger JL, Blickle JF. Departments of Internal Medicine and of Diabetes and Metabolic Diseases, Medical Clinic B (Andres, Loukili, Noel, Abdelgheni, Blickle), Internal Medicine and Geriatrics (Kaltenbach, Noblet-Dick), Internal Medicine and Nutrition (Perrin, Schlienger), and the Oncology and Hematology Department (Maloisel), Strasbourg University Hospitals, Strasbourg, France. VITAMIN B(12) OR COBALAMIN DEFICIENCY occurs frequently (> 20%) among elderly people, but it is often unrecognized because the clinical manifestations are subtle; they are also potentially serious, particularly from a neuro-psychiatric and hematological perspective. Causes of the deficiency include, most frequently, food-cobalamin malabsorption syndrome (> 60% of all cases), pernicious anemia (15%-20% of all cases), insufficient dietary intake and malabsorption. Food-cobalamin malabsorption, which has only recently been identified as a significant cause of cobalamin deficiency among elderly people, is characterized by the inability to release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or both. We review the epidemiology and causes of cobalamin deficiency in elderly people, with an emphasis on food-cobalamin malabsorption syndrome.

AUTISM NEWS

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EEG spectral analysis of wakefulness and REM sleep in high functioning autistic spectrum disorders. Clin Neurophysiol. 2004 Jun;115(6):1368-73. Daoust AM, Limoges E, Bolduc C, Mottron L, Godbout R. Neurodevelopmental Disorders Program, Laboratoire du Sommeil, Centre de Recherche Fernand-Seguin, Hopital Riviere-des-Prairies, Montreal, Quebec, Canada OBJECTIVE: The aim of this study was to investigate the involvement of temporo-occipital regions in the pathophysiology of autistic spectrum disorders (ASD) by using REM sleep and waking EEG. METHODS: The EEG recordings of 9 persons with ASD and 8 control participants were recorded using a 12-electrode montage. Spectral analysis (0.75-19.75 Hz) was performed on EEG activity recorded upon two activated states: REM sleep and wakefulness. RESULTS: During REM sleep, persons with ASD showed a selective, significantly lower absolute beta (13.0-19.75 Hz) spectral amplitude over the primary (O(1), O(2)) and associative (T(5), T(6)) cortical visual areas compared to controls. Persons with ASD showed significantly higher absolute theta (4.0-7.75 Hz) spectral amplitude over the left frontal pole region (Fp1) compared to controls during evening wakefulness, but not during morning wakefulness. SIGNIFICANCE: The results of waking EEG are consistent with previously reported observations of neuropsychological signs of frontal atypicalities in ASD; results from REM sleep are the first EEG evidence to support the hypothesis of abnormal visuoperceptual functioning in ASD. Altogether, these results point toward atypical thalamo-cortical mechanisms subserving the neural processing of information in ASD. Trends in autism. Int J Adolesc Med Health. 2004 Jan-Mar;16(1):75-8. Merrick J, Kandel I, Morad M. National Institute of Child Health and Human Development, Office of the Medical Director, Division for Mental Retardation, Ministry of Social Affairs, Jerusalem, Israel. Leo Kanner described autism in 1943, and Hans Asperger described the syndrome in 1944. The term Pervasive Developmental Disorders (PDD) was first used in the 1980s to describe a class of disorders that include (1) Autistic disorder, (2) Rett disorder or syndrome, (3) Childhood Disintegrative Disorder, (4) Asperger's disorder or syndrome, and (5) Pervasive Developmental Disorder Not Otherwise Specified, or PDDNOS. Autism prevalence studies published before 1985 showed prevalence rates of 4 to 5 per 10,000 children for the broader autism spectrum, and about 2 per 10,000 for the classic autism definition. Since 1985 there have been higher rates of autism reported from several countries. From the UK a prevalence rate of 16.8 per 10,000 children for autistic disorder was reported, and 62.6 per 10,000 for the entire autistic spectrum disorders. Sweden reported a prevalence of 36 per 10,000 for Asperger and 35 per 10,000 for social impairment, or a total prevalence of 71 per 10,000 for suspected and possible cases. From the US, 40 per 10,000 in three to ten year old children for autistic disorder and 67 per 10,000 children for the entire autism spectrum was reported. From the north region in Israel for children born between 1989-93 in the Haifa area, an incidence rate of 10 per 10,000 was found for autism. In recent years concern has been shown about the possible increase in the prevalence of autistic spectrum disorders. Studies have shown an increase, but during these last twenty years diagnostic criteria and definition have also changed. Although many factors are at play, it is evident that there has been an increase.

BRAIN INJURY

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EEG alpha power changes reflect response inhibition deficits after traumatic brain injury (TBI) in humans. Neurosci Lett. 2004 May 13;362(1):1-5. Roche RA, Dockree PM, Garavan H, Foxe JJ, Robertson IH, O'Mara SM. Department of Psychology and Trinity College Institute of Neuroscience, University of Dublin, Trinity College, Brain damage due to traumatic brain injury (TBI) has been associated with deficits in executive functions and the dynamic control of behaviour. Event-related brain potentials and spectral power data were recorded from eight TBI participants and eight matched controls while they completed a Go/NoGo response inhibition task. The TBI group was found to be significantly impaired at the task compared to controls, and exhibited abnormal N2 and P3 waveform components in response to NoGo stimuli relative to controls. Significant correlations were also found between alpha power, Go-trial RT and errors. We conclude that abnormal activity in the structures damaged in this group may render such patients less capable of maintaining a state of alpha desynchronisation compared to controls, resulting in poorer performance on the task.

BRAIN RESEARCH

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Gender differences in hemispheric organization during divergent thinking: an EEG investigation in human subjects. Neurosci Lett. 2004 May 27;362(3):193-5 Razumnikova OM. Cognitive Physiology Laboratory, State Research Institute of Physiology, Siberian Branch Russian Academy of Medical Sciences, Timakov str., 4, 630117, Novosibirsk, Russia. This study examined the gender-related differences in EEG patterns during the experimental condition of divergent thinking. The EEG of 36 males and 27 females was recorded from 16 scalp electrodes in rest and while students were solving a creative problem. The spectral power density along with EEG coherence estimates were analyzed in each of the six frequency bands in the 4-30 Hz range. Gender-related differences in the EEG patterns were found during successful divergent thinking. Creative men were characterized by massive increases of amplitude and interhemispheric coherence in the beta2 whereas creative women showed more local increases of the beta2 power and coherence. On the contrary, the task-induced desynchronization of the alpha1 rhythm in creative women was topographically more expanded as compared with men who demonstrated greater interhemispheric coherence than women did. Our results propose a different hemispheric organization in men and women during creative thinking. Diet and the Brain Your snack choice is more important than you think. New research indicates that in addition to affecting your waistline, food also can influence your brain. Some diets appear to aid mental functioning while others harm it. Altogether the studies show the importance of diet on mental health and also may have implications for those who suffer from certain brain ailments. Loathe anything leafy and green? Obsess over cream-filled cupcakes? Junk food junkies take notice. What you eat does more than influence your gut. It also may affect your brain. Increasing evidence shows that certain fruits and veggies produce brain benefits, while some types of fat appear to cause harm. Mentally healthy foods include strawberries, blueberries and spinach, according to some of the work. In one example, researchers fed aging rats the daily equivalent of a pint of strawberries, pint of blueberries or a spinach salad for two months. Compared with aging rats on a regular diet, molecular measures of brain cell communications showed that the supplemented animals had better cell function. They also performed better on a memory test. In addition, preliminary findings indicate that the food possibly may have an effect on Alzheimer’s disease (AD), a memory-impairing disorder that hits in old-age. Mice bred to develop AD perform better on a memory task when they receive a blueberry supplement. Their brain cell communication also enhances. Plans to study supplements of the foods in humans are under way. Researchers surmise that the benefits of these produce items stem, at least in part, from their high antioxidant content. In the brain, antioxidant molecules wage war against troops of molecules, known as free radicals, which can harm brain cells and brain function (see illustration). Many scientists believe that, as we age and during various disease-related circumstances, our internal antioxidant defenses can become overpowered by the free radical force. The antioxidant-rich foods are thought to offer brain protection during these times by providing an extra boost in defense, keeping the free radicals in check. General diets rich in antioxidants also have benefits. By following a group of people aged 65 and over for about four years, researchers recently found that a diet packed with high levels of the antioxidant, vitamin E, was associated with a lower risk of developing AD in some people. On the other end of the spectrum, a crop of studies finds evidence that gorging on foods that contain high levels of saturated fat—think french fries and donuts—can hinder brain function. Even though some fat is important for health, many Americans go overboard, especially with the saturated form. Studies indicate that rats kept on a comparable diet, where approximately 40 percent of their daily calories come from saturated fats, perform poorly on tests of memory and learning. Human studies also report negative effects. In one study researchers examined the food intake of some 5,000 participants. People who ate diets high in saturated fat had an increased risk of dementia. It’s not clear how excessive saturated fat harms the brain, but there are many theories. Some blame its effect on glucose, a sugar that provides energy to the body and brain. While a short-term supply of glucose can help the brain, excess fat may create a situation where brain cells receive a long-term, harmful exposure to glucose. Research on people with diabetes, a disease marked by problems with glucose, fits with this idea. For example, one report found that diabetics perform poorly on memory tests. Other research indicates that excess fat affects certain brain memory molecules. One of the studies on rats found that the high fat diet cut levels of brain-derived neurotrophic factor and other related molecules in the brain, which are thought to aid the formation of memories. More research is needed to sort out all the complicated effects of food, but scientists hope eventually to develop specific dietary guidelines that aid brain health. For now, researchers say it can’t hurt to eat more fruits and veggies and cut down on saturated fat. One way certain foods may help the brain is by fighting off harmful free radical molecules (A), which roam around anxiously looking to combine with other molecules. Their rush for a mate is thought to cause cell damage or even cell death (B) and contribute to a variety of brain function problems. Researchers believe that foods, such as strawberries, blueberries and spinach, provide the brain with extra platoons of antioxidants. These protective molecules can take the free radicals out of commission, ending their assault. "the anatomical projections from the medial cerebellum to the prefrontal cortex (PFC) were investigated in healthy human subjects, using high frequency repetitive transcranial magnetic (rTMS) stimulation and electroencephalography (EEG). Medial cerebellar rTMS, compared to placebo induced a significant shift in anterior asymmetry, from left to right dominance in the fast (30-50 Hz) EEG spectrum, whereas occipital and lateral cerebellum stimulation did not show such an effect. Moreover elevations in mood and alertness were reported again after medial cerebellar stimulation only. Taken together, these data confirm and further specify the assumed cerebellar modulation of PFC activity and affect." Activation of human cerebral and cerebellar cortex by auditory stimulation at 40 Hz. J Neurosci. 2002 Dec 1;22(23):10501-6. Maria A. Pastor1, Julio Artieda1, Javier Arbizu2, Josep M. Marti-Climent2, Ivan Peñuelas2, and Jose C. Masdeu1 Departments of 1 Neurology and 2 Nuclear Medicine, University of Navarra School of Medicine, 31080 Pamplona, Spain "...Additionally, we found that, compared with other stimulation frequencies, 40 Hz selectively activated the auditory region of the pontocerebellum, a brain structure with important roles in cortical inhibition and timing." ABSTRACT We used functional brain imaging with positron emission tomography (PET)-H2 15O to study a remarkable neurophysiological finding in the normal brain. Auditory stimulation at various frequencies in the gamma range elicits a steady-state scalp electroencephalographic (EEG) response that peaks in amplitude at 40 Hz, with smaller amplitudes at lower and higher stimulation frequencies. We confirmed this finding in 28 healthy subjects, each studied with monaural trains of stimuli at 12 different stimulation rates (12, 20, 30, 32, 35, 37.5, 40, 42.5, 45, 47.5, 50, and 60 Hz). There is disagreement as to whether the peak in the amplitude of the EEG response at 40 Hz corresponds simply to a superimposition of middle latency auditory evoked potentials, neuronal synchronization, or increased cortical synaptic activity at this stimulation frequency. To clarify this issue, we measured regional cerebral blood flow (rCBF) with PET-H2 15O in nine normal subjects at rest and during auditory stimulation at four different frequencies (12, 32, 40, and 47 Hz) and analyzed the results with statistical parametric mapping. The behavior of the rCBF response was similar to thesteady-state EEG response, reaching a peak at 40 Hz. This finding suggests that the steady-state amplitude peak is related to increased cortical synaptic activity. Additionally, we found that, compared with other stimulation frequencies, 40 Hz selectively activated the auditory region of the pontocerebellum, a brain structure with important roles in cortical inhibition and timing. INTRODUCTION In humans, auditory stimulation at different gamma frequencies elicits an electroencephalographic (EEG) steady-state response (SSR) that cycles at the stimulation frequency and has the greatest amplitude when the stimulus is given at 40 Hz (Galambos et al., 1981). Lower or higher frequencies produce a response of smaller amplitude. These oscillatory responses seem to be generated at the level of the auditory cortex, although modulated bythalamocortical systems (Makela and Hari, 1987; Steriade et al., 1991). The significance and origin of the steady-state potentials continue to be debated (Basar et al., 1987; Santarelli et al., 1995; Gutschalk et al., 1999). It is unclear whether the power increment of the steady-state auditory response at 40 Hz results merely from the temporal coherence (phase summation) of "middle latency" evoked responses, phase synchronization of a pool of cortical neurons, or a true increase in cortical synaptic activity at 40 Hz. Synaptic activity causes an increment in regional cerebral blood flow (rCBF). To test the hypothesis that the enhanced response at 40 Hz reflects increased synaptic cortical activity, we measured rCBF with positron emission tomography (PET) in the auditory cortex and other brain regions during auditory stimulation at different frequencies. A rise in rCBF at 40 Hz stimulation would suggest that the enhanced EEG response corresponds toincreased synaptic activity at this frequency. Most studies of oscillatory behavior have concentrated on the activity of the cortex and thalamus. PET allowed us to study the effect of gamma frequency stimulation on other brain structures, to test a second hypothesis: namely, that given the singular behavior of the EEG response to auditory stimulation at 40 Hz, brain regions outside the auditory cortex are activated specifically by stimulation at 40 Hz and not at other gamma frequencies. RESULTS Neurophysiological study The steady-state, auditory-evoked response, phase locked with the presented click frequency, was recorded at 12, 20, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, and 60 Hz. As a result of a rapidly repeated auditory stimulus application, an initial transient response evolved into an oscillatory EEG response having the same frequency as the stimulus (SRLR). The oscillatory response reached the greatest amplitude at ~40 Hz and subsequently decreased at higher click rates. Figure 1B represents the grand average of steady-state fast FFTs at 12, 20, 30, 40, 50, and 60 Hz stimulation frequencies. The fast Fourier transforms analysis revealed three major components. A first component peaked at 10 Hz and had an occipital predominance. It is possibly related to EEG activity. A second component peaked at the rate of auditory stimulation and was time locked with the stimulus rate (SRLR). Its amplitude (square root of the power) depended on the stimulation frequency, reaching a maximum at ~40 Hz (37.75; SD of 1.84) . We extracted the mean value at 12, 32, 40, and 47 Hz for the group of nine subjects who had PET to compare them with rCBF values (12 Hz = 22.23; 32 Hz = 35.4; 40 Hz = 50.59; 47 Hz = 10.99). The third component was observed at 40 Hz when the stimulation frequency was at one of its subharmonic rates, 10 and 20 Hz. Because we used binaural reference electrodes, the largest positive and negative potentials of the steady-state, auditory-evoked responses at 40 Hz were recorded in the frontal region contralateral to the side stimulated (at the F3 electrode with right ear stimulation) For this reason, in all subjects, we chose the activity recorded at F3 to compare it with rCBF changes. Compared with stimulation at other frequencies, 40 Hz stimulation elicited an increased rCBF in the cortex of the posterior aspect of both cerebellar hemispheres, predominantly on the side contralateral to auditory stimulation (Table 2, Fig. 4). The activated area, lateral to the paravermian region, was located on crus II using Schmahmann's nomenclature (Schmahmann et al., 1999). At the voxel maximally activated in these areas, rCBF clearly peaked during 40 Hz stimulation compared with other stimulation frequencies (Fig. 4). Regions with increased rCBF during 40 Hz auditory stimulation compared with stimulation at other frequencies. The activated areas, larger in the cerebellar hemisphere contralateral to the stimulated ear, are projected on a canonical image of the human brain obtained with T1-weighted MRI in the coronal, sagittal, and transverse planes. The chart depicts the effect size of the parameter estimates weighted for the amplitude of the EEG steady-state auditory response in the voxels of greatest activation (x, 30; y, 82; z, 42; and x, 28; y, 80; z, 48) at rest and during stimulation at each of the four frequencies. The left cerebellar hemisphere is on the left of the image. In the third contrast, derived from the SRLR values, both the temporal auditory cortex and cerebellar auditory clusters showed a pattern of rCBF activation similar to that of the EEG SRLRs at the different frequencies, with the highest activation induced by 40 Hz. However, although all stimulation frequencies increased rCBF at the temporal cortex, stimulation frequencies other than 40 Hz actually depressed or failed to significantly change rCBF at the cerebellar clusters. The difference can be seen comparing Figure 3 (the parameter estimates at the temporal cortex cluster) with Figure 4 (the parameter estimates at the cerebellar clusters). Neurophysiological study The results of our electrophysiological study agree with those of Galambos et al. (1981) and Azzena et al. (1995). The SRLRs increased in amplitude in the 30-40 Hz range and decreased at rates of >40 Hz. The topography of the EEG steady-state response in our study, with greatest amplitude in contralateral frontal electrodes, is a standard finding when the recording is performed with balanced earlobe reference electrodes (Azzena et al., 1995; Maiste et al., 1995). Using a noncephalic reference, the recordings show phase reversals in temporal regions (Johnson et al., 1988). This tangential dipole is better defined by magnetoencephalography (MEG) studies, which demonstrate the source in the primary auditory cortex, with a projection to central fields (Engelien et al., 2000). Because the amplitude of the EEG response obtained with our study design was greatest at F3, it seemed logical to use data from this electrode to compare them with rCBF data. Auditory cortex We found an asymmetry in temporal lobe activation, with a larger rCBF increase in the region of the contralateral primary auditory cortex. Studies using monaural auditory stimulation have shown a strong contralateral temporal lobe activation (Hirano et al., 1997). We also found a second smaller activated area in the superior temporal gyrus, surrounding the primary auditory cortex. This area has been enhanced in studies using complex auditory patterns of stimulation, such as music or speech, suggesting that it may have a role in temporal auditory pattern detection (Creutzfeldt and Ojemann, 1989; Zatorre et al., 1992). SSRs show maximum amplitude when tone pulses are presented at repetition rates near 40 Hz. To explain this finding, it has been postulated that the SSR consists of superimposed transient middle latency responses that display wave periods near 40 Hz and summate with one another when phase locked by 40 Hz steady-state stimulation. Some neurophysiologial data, however, seemed to contradict this postulate. Using tones and MEG-recording techniques, Pantev et al. (1996) studied the cortical sources of the 40 Hz auditory steady-state fields (SSFs) and middle latency auditory-evoked potentials. They found that these two types of responses arise in different locations at the auditory area, suggesting a diverse origin for the 40 Hz SSF and entrained middle latency responses. However, direct evidence of increased temporal cortex synaptic activity specific to 40 Hz stimulation was lacking. We worked with the hypothesis that rCBF in the auditory area of the temporal lobe would follow a similar pattern to the amplitude of the electrical steady-state response, increasing as the stimulus rate climbed to 30-40 Hz and decreasing at higher rates. The results support our hypothesis: the rCBF in the voxel with the greatest activation of the cluster located in the auditory cortex increased at auditory stimulation rates from 12 to 40 Hz, decreasing at 47 Hz. This finding suggests that the enhanced EEG response to stimulation at 40 Hz is not just the result of increased neuronal synchronization but reflects an overall increase in auditory cortex synaptic activity at this frequency. Thus, our study contributes to clarification of an ongoing controversy regarding the origin of the steady-state potentials (Basar et al., 1987; Santarelli et al., 1995; Gutschalk et al., 1999). Region of the head of the left caudate nucleus and right posterior cingular cortex Compared with rest, repetitive auditory stimulation produced a significant decrement in rCBF at the head of the left caudate nucleus and right posterior cingulate cortex. The caudate is activated to a similar degree by auditory stimulation during wakefulness and non-rapid-eye-movement sleep (Portas et al., 2000). Thus, even a stimulation paradigm such as ours, not specifically requiring any attention or any other perceptual or cognitive effort, is likely to activate the caudate nucleus. There is ample evidence that this structure participates in the processing of more complex auditory tasks. For instance, target detection of auditory stimuli activates the caudate nuclei and posterior cingulate regions (Kiehl et al., 2001). Posterior cingulate gyrus activation has been described even with simple auditory stimulation paradigms, and a decrement in rCBF occurred with high-intensity stimuli, similarly to what happened in our study (Lockwood et al., 1999). Activation by 40 Hz compared with other stimulation frequencies Compared with stimulation at lower or higher frequencies, auditory stimulation at 40 Hz caused bilateral activation of the cerebellar hemispheres, with some contralateral dominance. The activated area was in the posterolateral portion of the hemisphere, lateral to the paravermian region, in crus II using Schmahmann's nomenclature (Schmahmann et al., 1999). A similar location in the cerebellum was activated in other PET studies exploring temporal auditory processing (Penhune et al., 1998; Lockwood et al., 1999; Griffiths, 2000; Ramnani et al., 2000). The anatomical coincidence emphasizes the important role of this cerebellar region in the processing of information related to auditory stimuli. This region differs from the vermian and floccular areas that receive direct cochlear and collicular input. It corresponds to an area receiving auditory, visual, and somesthetic information. Connectivity studies, performed primarily in the cat and in rodents, have determined that the main bulk of afferents to this area originates in the temporal lobe and has a relay in the pontine nuclei before reaching the cerebellar cortex. In the primate, Schmahmann and Pandya (1991) found that projections from the primary auditory area are lacking. Instead, corticopontine auditory fibers originate in the second auditory area AII and adjacent association areas, but the most important bulk of corticopontocerebellar afferents is from multimodal areas in the upper bank of the superior temporal sulcus. These neurons project to the dorsolateral and lateral nuclei of the pons, which, in turn, project to the cerebellar area activated in our study (Brodal, 1979). It could be argued that cerebellar activation by 40 Hz stimuli simply represents an enhancement of the spontaneous baseline frequency discharge of Purkinje neurons, from 30 to 50 Hz (Strahlendorf et al., 1984). Although possible, this explanation does not seem likely, because this baseline frequency is found in the Purkinje neurons of the entire cerebellar cortex and is not restricted to the area activated in our study. Examples include neurons placed more superiorly in the cerebellar hemisphere, with a somatosensory receptive field (Fu et al., 1997), floccular neurons processing vestibular-oculomotor interactions (Fukushima et al., 1999), or visually responsive Purkinje neurons located higher in the cerebellar hemisphere (Marple-Horvat et al., 1998). To explain why auditory cortex was activated by all stimulation frequencies, whereas cerebellar activation was only detected comparing 40 Hz with the other frequencies, we could postulate that the cerebellum becomes more active to inhibit excessive cortical firing at some stimulation frequencies. For auditory stimuli, the critical stimulation frequency seems to be ~40 Hz. Perhaps, this is an indirect indication of the propensity of some brain regions to resonate at this frequency (Kapoor et al., 1991). Widespread cortical synchronization at the gamma band, ~40 Hz, may precede photically induced seizures (Parra et al., 2001). Other data suggest a cortical inhibitory role for the cerebellum. Small amplitude electrical stimulation of the cerebellar cortex in humans reduces cortical excitability (Ugawa et al., 1991). Some patients with cortical myoclonus have predominantly cerebellar pathology, suggesting that the enhanced cortical excitability may arise from deficient cerebellar control (Artieda and Obeso, 1993; Tijssen et al., 2000). Both the neurophysiological studies confirmed by our data and the novel findings of auditory cortex synaptic activation and of specific cerebellar activation at 40 Hz suggest that this frequency plays a distinct role in the brain mechanisms involved in auditory processing.

CHINESE MEDICINE

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Acupuncture points to post-op comfort New Scientist 31 July 2004, page 15 ACUPUNCTURE is a cheap and safe way of preventing people who have just had an operation from being sick or feeling nauseous. That is the conclusion of a review of 26 trials involving over 3000 patients. Anna Lee of the Chinese University of Hong Kong and Mary Done of the New Children's Hospital in Sydney, Australia, focused on trials that studied the effects of "P6" treatment - stimulation of the "pericardium" (P6) acupuncture point on the wrist. Patients receiving P6 acupuncture were 28 per cent less likely to feel nauseous and 29 per cent less likely to be sick than patients receiving sham treatments, such as insertion of the needle at the wrong place or pretended stimulation of P6. They were also 24 per cent less likely to ask for anti-sickness drugs. Without treatment, post-operative nausea and vomiting is estimated to affect four out of five people who have had anaesthetics. In head-to-head comparisons with routine anti-sickness drugs, acupuncture was equally good at preventing nausea and vomiting. The authors, whose review appears in The Cochrane Database of Systematic Reviews 2004, (DOI: 10.1002/14651858.CD003281.pub2), report that there were minimal side effects, and advocate P6 acupuncture as a safe and effective means of preventing post-operative sickness and nausea.

CHRONIC FATIGUE/FIBROMYALGIA

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Nutritional Supplement, Creatine, Linked to Increased Metabolic Energy Temple University College of Health Professions NEWSWISE Medical News, 23-Aug-2004 -- A Temple University researcher seeking physiological evidence of chronic fatigue syndrome (CFS) has found a link between creatine and metabolic energy. The findings, which hold promise for future CFS treatments, were published in a recent issue of the Journal of Applied Physiology. "We found that creatine affects mitochondria - the parts of the cells that produce energy for all biological functioning - in normal human subjects. Now that we have established this baseline evidence, we are looking at the link between creatine and energy production in CFS patients," said lead author Sinclair Smith, Sc.D., assistant professor of occupational therapy in Temple´s College of Health Professions. Creatine, thought to build muscle and improve performance, is a popular over-the-counter supplement used by athletes. Smith and his colleagues wondered if creatine could also be used to help relieve the extreme physical and mental fatigue that strikes CFS sufferers. "Many physicians still don´t believe that CFS exists, making it important to investigate possible physiologic differences and to determine if we can impact metabolic function in CFS patients," explained Smith. "In addition to improving muscle metabolic function, recent studies show that creatine supplementation may improve nervous system function as well. Given that cognitive fatigue is a frequent symptom of CFS, we thought that creatine may enhance both muscle and neural metabolic status in people with CFS," said Smith. In the study, "Use of phosphocreatine kinetics to determine the influence of creatine on muscle mitochondrial respiration: an in vivo 31P-MRS study of oral creatine ingestion," the researchers analyzed the effect of naturally -produced and supplemental creatine on the rate of muscle metabolism using non-invasive magnetic resonance imaging (MRI) techniques during exercise and rest. While previous studies have evaluated the link between creatine and mitochondria in animals and human muscle samples, Smith´s was the first lab to test in people. Smith collaborated in this research with the U.S. Army Research Institute of Environmental Medicine, Brigham and Women´s Hospital and Harvard Medical School, Boston University and Sargent College of Health and Rehabilitatiotos of Smith in Temple´s Neuromuscular Function Lab are available at: http://mdev.temple.edu/photoarchive/photoinfo.asp?pidy0 A targeted newswire featuring breaking medical news stories from over 200 leading academic and research institutions including: Johns Hopkins, Stanford, Harvard, and the Mayo Clinic.

EEG/QEEG/ERP

A source-imaging (LORETA) study of the EEGs from unmedicated males with depression. Psychiatry Res. 2004 Feb 15;130(2):191-207. Flor-Henry P, Lind JC, Koles ZJ. Clinical Diagnostics and Research Center, Alberta Hospital Edmonton, Edmonton, Alta., Canada. Imaging studies and quantitative EEG have often, but not consistently, implicated the right hemisphere and the left prefrontal cortex in depression. To help clarify this picture, a spatial filter shown to be effective for enhancing differences between EEG populations was combined with an electrical tomographic approach called low-resolution electromagnetic tomography and used to compare the source-current densities from a group of 25 male subjects with depression and a group of 65 matched controls. To elicit differences, comparisons were made during resting conditions and during verbal and spatial cognitive challenges to the subjects. Estimates of the source-current density were derived from 43-electrode recordings of the EEG reduced to the delta, alpha and beta frequency bands. The depressed subjects were unmedicated and selected according to DSM IV criteria. Regions of significantly increased current density in depression compared to controls were generally right hemispheric, while regions of significantly decreased current density were generally frontal and left hemispheric. A within-group comparison of the depressed subjects during the two cognitive challenges suggested a left anterior functional hypoactivation in depression. Retrospective classification of the two groups indicated that the spatial challenge best separated the groups irrespective of frequency band. Relative left-frontal activity is associated with increased depression in high reassurance-seekers. Biol Psychol. 2004 Oct;67(1-2):145-55. Minnix JA, Kline JP, Blackhart GC, Pettit JW, Perez M, Joiner TE. Department of Psychology, Florida State University Excessive reassurance-seeking, which has been associated with depression in many studies, can be defined as the relatively stable tendency to seek assurance perseveratively from others. We hypothesized that although depression has been associated with left-frontal EEG hypoactivity, reassurance-seekers may possess a unique diathesis that is more likely to be associated with increased left-frontal activity. Data were collected from 12 volunteers who were receiving therapeutic services from a University Clinic. EEG asymmetry scores were averaged over two measurement occasions at least 3 weeks apart. As predicted, stable relative right-frontal activity was associated with increased depression in those who were low on reassurance-seeking, while stable relative left-frontal activity was associated with increased depression among high reassurance-seekers. Perhaps those who seek reassurance excessively do so because of their inability to alter their behavior even when environmental cues are no longer reinforcing, which can maintain or exacerbate their depressive symptoms. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8174-9. Epub 2004 May 17 Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM. Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4-21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8-10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse "movies" reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism. PTSD arousal and depression symptoms associated with increased right-sided parietal EEG asymmetry. J Abnorm Psychol. 2004 May;113(2):324-9. Metzger LJ, Paige SR, Carson MA, Lasko NB, Paulus LA, Pitman RK, Orr SP. Veterans Affairs Medical Center Research Service, Manchester, NH Researchers have proposed that depression and particular types of anxiety are associated with unique patterns of regional brain activation. The authors examined the relationship among posttraumatic stress disorder (PTSD), anxiety, and depressive symptoms and frontal, temporal, and parietal EEG alpha asymmetry in female Vietnam War nurse veterans. The results indicate that PTSD arousal symptoms are associated with increased right-sided parietal activation. However, the combination of arousal, depression, and their interaction explain more than twice the variance in parietal asymmetry compared with arousal alone. The results support the contention that the association between anxiety and right-sided posterior activation is specific to the anxious arousal subtype. These findings underscore the importance of isolating, both theoretically and statistically, emotional subcomponents in studies of regional brain activation. Seventy-five Years of EEG Investigation Reprinted from Spectrum EEG Newsletter The field of cognitive neuroscience is said to have begun last decade ago with the advances in magnetic resonance imaging, but EEG has been providing psychiatrists and neurologists functional correlates since the 1930s. Like all imaging techniques, quantitative EEG required computer advances before blooming; and it wasn't until the mid-1960s until a reasonably quick method of computing spectral magnitudes (fast fourier transform, or FFT) was developed and the promise of this technique took stride. Prior to this, even with only eyeballs and rulers, important conclusions were made using EEG for a variety of conditions. Below is a list of the earliest research paper for each disorder. FIRST PAPERS IN TOPIC (and approximate years of research): Animal EEG: 1875 (125 years) Human EEG 1929 (75) Fourier analysis of EEG: 1932 (70) Children: 1932 (70) In English: 1934 (70) Sleep: 1935 (70) Aviation: 1941 (65) Military: 1942 (60) Disorders Epilepsy: 1933 (70) Schizophrenia: 1937 (65) Narcolepsy: 1939 (65) Migraine: 1941 (60) Alcoholism: 1941 (60) OCD: 1947 (55) Anxiety: 1948 (55) Brain Injuries Head injury: 1931 (70) Frontal lobotomy: 1936 (65) Mental deficiency: 1937 (65) Brain lesions: 1938 (65) Tremor: 1941 (60) Concussion: 1942 (60) Multiple sclerosis: 1944 (60) Behavior problems Stuttering: 1936 (55) Conduct disorder: 1937 (55) Aggression: 1942 (60) Delinquency: 1943 (60) Misc. Heredity: 1934 (70) Hypnosis: 1936 (65) Consciousness: 1937 (65) Personality: 1938 (65) Deafness: 1941 (60) Pregancy: 1942 (60) Operant conditioning: 1969 (35) Citations are below: First EEG paper (in animals): Caton R (1875). The electric currents of the brain. British Medical Journal, 2, 278. First human EEG paper: Berger H. (1929). Ueber das Elektroenkephalogramm des Menschen. Archiv für Psychiatrie und Nervenkrankheiten, 87, 527-570. First to use fourier analysis: Dietsch, G. (1932). Fourier-analyse von Elektrenkephalogrammen des Menschen. Pflüger's Arch. Ges. Physiol., 230, 106-112. Children: Berger, H. (1932). Über das Elektren-kephalogramm des Menschen. Fünfte Mitteilung. (Fifth Report) Archiv für Psychiatrie und Nervenkrankheiten, 98, 231-254. First EEG paper in English: Adrian ED & Matthews BHC (1934). The interpretation of potential waves in the cortex. Journal of Physiology, 81, 440-471. (and same year: Adrian E & Mathews BHC (1934). The Berger Rhythm. Brain, 57, 355-385.) Aviation [beat me by nearly 50 years]: Minderman E (1941). Pilots tested by brain wave analysis. Medical Records, 153, 292. Military service: Harty JE, Gibbs EL & Gibbs FA (1942). An EEG study of 274 candidates for military service, Journal of nervous mental disease, 96, 435-440. Epilepsy: Berger (1933) and F.A. Gibbs, H. Davis and W.G. Lennox. (1935). The electro-encephalogram in epilepsy and in conditions of impaired consciousness. Archives of Neurology and Psychiatry, 34, 1133-1148. Sleep: Loomis AL, Harvey EN, Hobart GA (1935). Potential rhythms of the cerebral cortex during sleep. Science, 81, 597-598. Alcoholism: Davis PA, Gibbs FA, Davis H, Jetter WW, & Trowbridge LS. (1941). The effects of alcohol upon the electroencephalogram (brain waves). Quarterly Journal of Studies on Alcohol, 1, 626-637. Migraine: Strauss H & Selinsky H. (1941). EEG changes in patients with migrainous syndrome. Transactions of the American Neurological Assoc., 67, 205-208. Narcolepsy: Janzen R. (1939). Hiernbioelektrische Untersuchungen uber den physiologischen Schlaf und den Schlaganfall bei Kranken mit genuiner Narkolepsie. Deutsch. Z. Nervenheilk. 149, 93-106. Head injury: Berger (1931) and Jasper HH, Kershman J, & Elvidge AR (1940). EEG studies of injury to the head. Archives of Neurology and Psychiatry, 44, 328-348. Frontal lobotomy (sign of the times): Marinesco G, Sager O, & Kreindler A (1936). Etudes EEG: EEG chez une malade avec extirpation du lobe frontal. Bulletin of Acad Med, 115, 873-877. Brain lesions: Case TJ & Bucy PC (1938). Localization of cerebral lesions by EEG. Journal of Neurophysiology, 1, 245-261. Tremor: Lindquist T. (1941). Finger tremor and alpha waves on the EEG. Acta Med Scand., 108, 580-585. Concussion: Anderson EW (1942). Psychiatric syndromes following blast, Journal of Mental Science, 88, 328-340. Multiple sclerosis: Hoefer PFA & Guttman SA (1944). The EEG in multiple sclerosis. Transactions of the American Neurological Assoc., 70, 70-73. Heredity: Perkins FT. (1934) Genetic study of cerebral action currents. Science, 79, 418. Aggression: Gibbs FA, Bloomberg W & Bagchi BK (1942). An EEG study of adult criminals. Transactions of the American Neurological Assoc., 68, 87-90 Delinquency: Jenkins RL & Pacella BL (1943). EEG studies of delinquent boys, American Journal of Orthopsychiatry, 13, 107-120. Hypnosis: Loomis AL, Harvey EN, & Hobart G (1936). Brain potentials during hypnosis. Science, 83, 239. Personality: Gottlober AB (1938). The relationship between brain potentials and personality. Journal of Experimental Psychology, 22, 67-74. Consciousness: Travis LE (1937). Brain potentials and the temporal course of consciousness, Journal of Experimental Psychology, 21, 302-309. Stuttering: Travis LE & Knott JR. (1936). Brain potentials from normal speakers and stutterers. Journal of Psychology, 2, 137-150. Schizophrenia: Travis LE & Malamud W (1937). Brain potentials from normal subjects, stutterers, and schizophrenics. American Journal of Psychiatry, 93, 927-936. and, Hoagland H (1937). Encephalography in schizophrenia. Archives of Neurology and Psychiatry, 39, 210-213. Behavior problems in children: Solomon P, Jasper HH & Braley C. (1937). Studies in behavior problem children. American Neurology and Psychiatry, 38, 1350-1351. Mental deficiency: Kreezer G & Smith FW (1937). Brain potentials in the hereditary type of mental deficiency. Psychological Bulletin, 34, 535-536. OCD: Rockwell FV & Simons DJ (1947). The electroencephalogram and personality organization in the obsessive-compulsive reactions. Archive of Neurology and Psychiatry, 57, 71-77. Anxiety: Schipp E, Dugan P, Kennard MA, & Welsh L. (1948). Effects of pathological anxiety in childhood on EEG and conditioned PGR. American Psychologist, 3, 371. Pregancy: Gibbs FA & Reid DE (1942). The EEG in pregnancy. American Journal of Obstetrics, 44, 672-675. Deafness: Bagchi BK (1941). The brain potentials of the deaf and dumb. Psychological Bulletin, 38, 591. Operant conditioning: Kamiya J, Callaway E, Yeager CL. (1969). Visual evoked responses in subjects trained to control alpha rhythms. Psychophysiology, 5, 683-95 The above doesn't include the numerous physiological investigations into vision, sensory stimulation, electrical stimulation, effects of drugs like anticonvulsants and anaesthetics, anoxia, hyperventilation, cardiovascular, blood sugar, animal research, etc. In all, functional neuroimaging has a 75 year history with over 250,000 peer reviewed papers to its name (fMRI has the majority, 125,000 papers published since its inception, EEG 87,000, PET 33,000, SPECT 17,000, and MEG or magnetoencephalography 3,500. Seventy-five years and computers are just now allowing the most pertinent and thorough investigations into the mind.

IMMUNOLOGY NEWS

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The Mind-Body Link Many scientists once rejected the idea that the immune system, traditionally thought of as the prime internal defense system, worked closely with the nervous and endocrine systems to carry out its task. Such a finding would suggest that our mind could influence illness. Now an increasing amount of evidence is showing that the three systems are indeed working together. Sometimes everything seems against you. You slip on the ice. Your dog bites you. Then, only a week before finals, you catch your sister's cold. A fever and the blahs compound your feelings of ill fate. These symptoms, however, are a sign that something is on your side. The immune system. And your brain too, according to an increasing number of studies.       The immune system battles countless enemies. Its wrath is unleashed on viruses, bacteria, parasites and other foreign molecules that make it past body borders and try to stake a claim. Immune defenses also combat abnormalities that arise inside the body, such as cancer cells.       Many researchers once believed that the immune system was an entirely independent entity in the body.       Now an increasing number of studies show that the immune system is tightly connected to the nervous system, as well as to another communication network known as the endocrine system. It appears that their three-way communication is vital for an adequate defense of the body and brain. The discovery of the strong connection is leading to: * Insight on how emotions can influence illness. * A clearer understanding of how the immune system fights foreign invaders and how disturbances in the circuit lead to disease. * Earlier diagnosis of diseases that might be influenced by communication between the systems. Starting in the 1980s researchers found evidence of strong connections between the immune, nervous and endocrine systems. First they identified direct links between nerve fibers and immune organs.       More recently researchers determined that hormones of the endocrine system help the immune and nervous systems defend the body. For example, stress hormones can initiate actions in the brain and immune system in response to injury or germs. This stress response acts as an immune system regulator. It can dampen down the immune system so it doesn't go overboard.       Scientists also recently discovered that immune molecules, known as cytokines, can initiate brain actions. For example, some cytokines help the body recuperate by sending messages to the brain that set off a series of sickness responses, such as fever. The high body temperature of a fever is thought to create an unfavorable environment for the foreign invaders. The immune molecules also can trigger feelings of sluggishness, sleepiness and loss of appetite. The behaviors can keep sick people out of harm's way until they feel better.       Researchers found that cytokines can activate certain nerves for quick brain activation or set off actions from posts in the blood (see illustration). Scientists also discovered that some cytokines are produced directly in the brain.       The increasing number of links that researchers are discovering between the immune, nervous and endocrine systems is leading them to investigate whether excess stress or too little stress can abnormally alter the immune defenses. Others are examining how defects in this intricate system possibly can lead to autoimmune disorders, in which the immune system attacks the body.       In addition, scientists are continuing to map the cross-communication network to identify new ways to improve diagnosis and head off disease.       For example, researchers recently found that a dramatic increase in one member of the defense team molecules can signal blood poisoning. This condition occurs when bacteria from an infected site such as a burn invades the blood stream. Diagnosis often comes too late, leading to a mortality rate as high as 51 percent. The researchers found larger than normal quantities of the defense molecule, nitric oxide, in the brains of rats soon after the onset of blood poisoning. This rise was detected in the spinal fluid. The scientists now are studying humans to see if this molecular signal will provide earlier diagnosis and treatment of the disease. Researchers found that one way immune molecules talk to the brain is through the blood. The large molecules are too big to cross from the blood to the brain but they may be able to slip across leaky junctions. Another way they get their message across is by attaching to special areas on blood vessels, called receptors, and triggering the production of molecules such as nitric oxide and prostaglandins. These molecules then directly relay messages to brain cells.

MEMORY

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Scientists study brain's wiring to learn how we remember, forget By Robert S. Boyd Knight Ridder Newspapers WASHINGTON - After decades of studying how memory works, scientists are trying to figure out how we forget. Their goal is to help people: - Forget painful things they don't want to remember, from an embarrassing moment in high school or a stupid mistake at work on up to a traumatic rape or accident. - Not forget things they do want to remember, such as where they left their keys or the name of the boss's spouse all the way, and slow the devastation of Alzheimer's disease. Instead of just giving memory tests to people, neuroscientists are using recent technologies that observe the living brain at work, such as fMRI (functional magnetic resonance imaging) and PET (positron emission tomography). In addition, legions of flies, snails and mice have given up their lives to provide insight into how people remember and forget, since some brain structures and functions are similar in humans and lowly pests. Forgetting is basically the reverse of remembering. Memories form when new physical and chemical links, called synapses, are created between brain cells, called neurons, or when old synaptic links are strengthened. An elaborate network of connections, rather like a computer wiring diagram, assembles a memory from separate parts of the brain that process the myriad sights, sounds, words, people, motions and emotions that crowd the senses every waking moment. This step is known as "consolidation." It occurs when a memory is moved from a short-term holding room - a mental scratchpad called working memory that lasts a few seconds or minutes - to long-term storage elsewhere in the neural network. When a memory is recalled, the process is called "retrieval." The memory isn't stored in a single place, but reassembled from bits and pieces scattered across the neural network. It never comes back exactly the way it went in because new experiences have reshaped the brain in the interim. Mistaken or garbled memories are common, as detectives and trial jurors learn to their sorrow. Forgetting can be a failure of either consolidation or of retrieval. In addition, memories may fade or decay over time, or be wiped out by interference from other memories. For example, you probably remember what you had for breakfast yesterday, but not last year. Too many breakfasts have come in between. Steven Schmidt, a psychologist at Middle Tennessee State University in Murfreesboro, likens forgetting to what happens when a stone is thrown into a lake. "The lake `remembers' the input of the rock as a series of waves on its surface," he explained in an e-mail. "Consolidation is a process that `holds' that pattern of waves. If consolidation is disrupted, the wave patterns are not retained." Like a water-skier breaking up the pattern of waves, the release of certain hormones in the brain may halt the process of consolidation. "The memory is simply not fully laid down," Schmidt said. Interference results when a pattern of activated neurons no longer can be sustained, perhaps because a flood of new information has overwritten the original memory. An analogy would be throwing many rocks into the lake near where the first one hit the water. "The wave patterns of the more numerous set of rocks will make it difficult to see the waves created by the first rock," Schmidt said. Failure to retrieve a memory is the inability to access information previously stored in the brain. "In my lake metaphor," he said, "I throw a rock in on one shore and notice the pattern of activation. At a later date I may have difficulty recognizing that pattern on the water if I am standing on the other side of the lake." Loss of memory also can result from emotional or physical causes, such as a blow to the head, a stroke, an infection or surgery. The brains of Alzheimer's patients are destroyed by plaques and tangles of alien material invading once-healthy neural networks. This kind of damage "could make old memories inaccessible because the fragments would be present in the cortex, but not connected, so the episode could no longer be reassembled," Joseph LeDoux, a neuroscientist at New York University, wrote in his new book, "Synaptic Self." "Patients lose memories because they lose the cells and synapses that lead to, or contain, those memories," Ivan Izquierdo, a Brazilian biochemist, said in an e-mail interview from Rio Grande do Sul. Mansuo Hayashi, a brain researcher at the Massachusetts Institute of Technology in Cambridge, used mutant mice to show what happens when short-term memory isn't consolidated in long-term storage. By altering a gene, she created a mouse with fewer, but bigger, synapses in the cortex, but left the hippocampus, a region where short-term memories are processed, alone. As a result, her mice learned the location of a platform in their cage, but after a few days they couldn't remember where it was. "We showed their formation of memories is fine," Hayashi said. "However, their long-term storage is impaired." In another intriguing experiment, Alison Barth, a neuroscientist at Carnegie Mellon University in Pittsburgh, found a way to make individual mouse neurons glow when they're processing a memory. To accomplish this feat, Barth attached a green fluorescent chemical to a gene that turns on when a nerve cell is activated. "Our mouse is a novel tool that can be used to visualize, in living brain tissue, a single neuron that has been activated in response to an animal's experience," Barth reported in the July 21 issue of The Journal of Neuroscience. By observing precisely where a memory is forming, she said, scientists will be better able to understand and treat neurological diseases. Forgetting, or at least reducing, painful memories - known as "therapeutic forgetting" - can be helpful to people such as soldiers or accident or rape victims. A drug called propranolol can blunt the memory of a trauma, according to James McGaugh, the director of the Center for Neurobiology of Learning and Memory at the University of California, Irvine. "The drug does not remove the memory - it just makes the memory more normal," McGaugh said in an e-mail report. "It prevents the excessively strong memory from developing, the memory that keeps you awake at night." "The original memory is not erased," Izquierdo said. "It is literally pushed backstage by other connections. Animals and humans must preserve the memory of frightening events in order to be able to react to them if required, but must keep them sufficiently less accessible if they want to live any life worthy of the name from then on." Michael Anderson, a psychologist at the University of Oregon in Eugene, used fMRI to find out what happens when people make a conscious effort - without drugs - to forget some words. He discovered that high-level areas of the cortex send signals to suppress low-level activity in the hippocampus, blocking recovery of the words. "Memory suppression requires people to override or stop the retrieval process," Anderson reported in the Jan. 9 edition of the journal Science. "This work confirms the existence of an active process by which people can prevent awareness of an unwanted past experience. This process causes forgetting."

NEUROTRANSMITTER NEWS

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Tourette's Syndrome and Dopamine Once dismissed as a behavior flaw, Tourette's syndrome is now known to be an inherited neurological disease. New research is mapping the chemical origin of the disorder characterized by tics, yelps and utterances. Advances may lead to improved treatments that can curb the disruptive symptoms without causing the harsh side effects often seen in today's remedies. A surgeon. A grocery store bagger. A professional athlete. A writer. A construction worker. Each experiences eruptions of tics - repeated, involuntary movements and uncontrollable utterances. Six nose twitches, three foot stomps, a series of eye blinks and a few neck stretches. Some hoot, bark, cough. Some swear.       The diagnosis? Bad habits. Nervousness. Demonic possession. For years the affliction, now known as Tourette's syndrome (TS), was regarded as a "moral" disease. The prescription was a dose of internal will to stop.       Then researchers discovered that a drug, haloperidol, which acts on the brain chemical dopamine, could calm the patient. This suggested that TS was a disorder rooted in altered brain chemistry. Now an increasing number of studies, including imaging research on humans, is providing clues on how dopamine and other factors mediate TS.       An estimated 100,000 Americans have full-blown TS. And more than 1 million people are suspected to have milder forms of the disease.       Currently there is no medication that can clear up all of the symptoms of TS. In addition, the side effects of the wide-acting therapies, such as haloperidol, can be worse than the disorder in some patients. But the deciphering of dopamine's role in the disease is helping to pave the way toward targeted treatments.       Research started to take off in the early 1960s. Scientists found that haloperidol suppressed tics by blocking the receiving areas on cells, or receptors, where dopamine normally passes on messages. Later researchers discovered that dopamine-stimulating drugs can trigger tics. Other research on human spinal fluid also pointed a finger at dopamine.       Today scientists are uncovering how the chemical specifically relates to TS.       New studies have led some researchers to believe that tics are related to dopamine receptors that are "supersensitive" to the chemical in specific brain areas.       One study of identical twins with TS found that extreme cases are related to a souped-up activity of dopamine receptors in the caudate nucleus.       This brain area normally acts as a brake on the movements that are made on purpose. When a movement is needed, however, dopamine can provide a password to the receptors that will release the urge to move. The research suggests that patients with severe symptoms have exceptionally sensitive receptors that take any subtle sign from dopamine as a reason to let urges loose. The result is a deluge of tics.       Other research indicates that tics are related to higher than normal levels of dopamine production and use. Perhaps there is a larger than normal number of dopamine-producing brain cells. Maybe the individual cells have an abundance of sites, or terminals, that release dopamine.       A new imaging study examined tic severity by comparing younger individuals with TS to older patients. Tics often become milder as patients age. The researchers found that in specific brain areas, the younger group had a greater number of molecules known as dopamine transporters than did controls. Once dopamine carries out a task, a dopamine transporter, which resides at the terminals, shuttles the chemical back into the cell that produced it so it can be used again. Since the number of dopamine transporters indicates the number of terminals that produce or release dopamine, these results suggest that tics may be related to an excess amount - too many dopamine cells or terminals - or release of dopamine.       Other research indicates that dopamine is not the only TS instigator. For example, one new study compared individuals with TS to those without the disease and found a difference in the number of transporters for another chemical, serotonin, but no significant difference in the density of dopamine transporters. Some scientists think that dopamine alterations may be more subtle in the disease and that serotonin plays a larger role.       Additional research, including the identification of the genetic basis of the disease, will provide more clear-cut clues. In one study, scientists are probing the complete set of human genes in order to find a TS-inducing gene or genes.       The hope is that, together, the research will result in improved treatments for those affected by the disorder. Stuttering and Dopamine   Society for Neuroscience Brain Briefings Even though many well-respected people have a history of stuttering, including actress Marilyn Monroe, actor Bruce Willis and singer Carly Simon, the speech condition has had a bad rap. Many people have long blamed emotional or personality factors as the cause and believed that it could be easily overcome with a change in attitude. But now accumulating research indicates that stuttering actually erupts from disturbances in brain function. The new work, based on studies that image the brain, finds that brain anatomy and brain activity is awry in stutterers. Methods that counter these biological disturbances might mend the underlying deficits and treat a large number of people. “On Aaaaaaaapril 30, 1789, George Washington was in-in-inaugurated first pres-pres-pres-pres . . . ,” the student reads aloud. “My gosh, just spit it out,” interrupts another pupil. Many people have assumed that nerves or some flaw in disposition causes stuttering speech, characterized by awkward pauses, dragging out parts of words and repeating certain sounds. Their solution? Snap out of it. But now a spate of recent scientific studies provides evidence that this simplistic view is false. Stuttering appears to erupt from an array of troubles in the brain. In past years, studies that focused on genes provided the first major hint that biology was behind stuttering. Passed along from our parents, genes hold the codes that guide the production of proteins, which build and run our body and brain. In one study, researchers compared twins who share the exact same genetic makeup with twins who on average share only half of their genes. If one twin stuttered, the other twin was more likely also to stutter if they shared the same genetic makeup. This suggests that genes—a biological factor—help spur stuttering. As part of their role, these genes may trigger problems in brain function. In recent years, imaging technologies that help scientists peer inside the head uncovered evidence that the brains of stutterers differ from the brains of fluent speakers. Some research highlights anatomical variations. One imaging study reveals that nerve fiber tracts in the rolandic operculum are less densely packed in adult stutterers, compared to nonstutterers. Since this brain area connects structures involved in the articulation and planning of utterances, alterations in its makeup may disturb signal transmission and prevent fluid speech. Also, part of a region near the rolandic operculum, termed Wernicke’s area, which is responsible for the comprehension of language and the production of meaningful speech, is larger in adult stutterers, according to another imaging study. In addition, the surface areas of additional brain regions important for language have an irregular, extra bumpy appearance. Researchers believe that these anatomical variations reflect differences in cellular networks that may impair speech and language processing in stutterers. Scientists also used imaging techniques to examine the activity of the brain while adult stutterers completed speech tasks. Results show that the stutterers’ overall activity patterns differ from nonstutterers, providing more evidence that their brains have problems with language and speech. Specific brain areas that act unusually include sections that help process sound and movement to produce utterances. Currently researchers are testing whether various therapies can target the irregular brain areas and activity patterns and improve speech. Preliminary findings from one group indicate that an intensive behavioral treatment program, which focuses on speech articulation, followed by a year of maintenance therapy, helps normalize brain activity and speech. Other scientists used imaging techniques to look at brain activity on a chemical level. Their study indicates that the activity of dopamine in stutterers is higher than normal. The brain’s cells use this chemical to transmit signals. Another study finds that a drug that blocks dopamine’s actions aided stuttering in a small number of patients tested. Early results from a larger study that tested a related compound are promising. It’s likely, however, that no single treatment would help all stutterers across the board. Researchers believe that many variations of stuttering exist and are investigating how assorted symptoms and factors such as age relate to brain differences. Ideal treatments would target the irregularities in brain anatomy and activity that are specific to each case. For the more than 3 million Americans who stutter, such treatments could help ease speaking in class and other day-to-day communications, making life run more smoothly. Normal speech is produced through a series of actions carefully orchestrated and monitored by the brain. Air from the lungs passes through bands of tissue, dubbed vocal cords. They vibrate and produce your voice. The palate, tongue, jaw and lips move to modify the sound and create speech. Feedback to the brain from senses such as hearing may trigger adjustments to the movements if necessary. In stutterers, among other irregularities, differences in the perisylvian brain region, which houses the rolandic operculum and Wernicke's area, may affect the processing of language and this system, creating stumbling speech. SIDS and Serotonin Once inexplicable, new studies now uncover some of the brain mechanisms that may underlie SIDS, a term used to describe the death of a seemingly healthy infant during sleep. These discoveries, including those that implicate a brain system that involves the chemical serotonin, could help researchers develop methods to identify babies at risk for SIDS and find new ways to prevent death. Also known as sudden infant death syndrome, SIDS describes the death of a child under the age of one that occurs during a sleep period and that can’t be explained by a complete autopsy. A leading cause of infant death, it killed some 2,500 babies in 2000, according to the most recent data from the National Center for Health Statistics. The unexpected loss of life has long perplexed parents, physicians, and scientists alike. How? Why? Now, new studies provide some insight into what may underlie these abrupt deaths. One line of work suggests that flaws in a brain system that communicates using the chemical serotonin may make some babies more susceptible to SIDS. In past years scientists identified some outside factors that increase the risk of SIDS. For example, they determined that infants who sleep on their stomachs are more likely to die of SIDS than those who sleep on their backs. Unfortunately, the biological mechanisms behind the condition have been harder to uncover, especially since many likely exist. Recently, however, researchers made some headway. One set of studies points a finger at a serotonin-based messaging system. Certain brain cells that contain serotonin release it when they become stimulated. The chemical attaches or binds to molecules on nearby brain cells, termed receptors, and triggers message transmission. Researchers examined brain tissue from SIDS victims and found that their serotonin receptor binding was lower than normal in the brain stem, an area that helps control vital functions like breathing. More recently scientists found that SIDS cases were more likely to have a certain variation of a gene that produces the serotonin transporter. This cell component can pump the serotonin back into the brain cell to mute the messaging process. The researchers suspect that people with the variation harbor more effective transporters than other people. Preliminary examinations of brain stem tissue also suggest that some SIDS victims have an excess of these more effective serotonin transporters. Together these results could mean that the serotonin communication system in some infants does not work properly, perhaps sending out fewer messages than normal. Possibly the faulty system prevents children from responding to life-threatening events during sleep, such as increased levels of carbon dioxide, a harmful waste product eliminated by the lungs during breathing. Babies can experience excessive levels of the gas when they rebreathe air trapped in bedding, for instance. Normally, the serotonin system may help sense the problem and trigger mechanisms that increase breathing to expel the carbon dioxide. Animal research supports this idea. For example, scientists discovered that normally an increase in carbon dioxide strongly stimulates cells that contain serotonin in the brain stem. Also early evidence indicates that a drug used for depression, which inhibits the transporter’s activities and increases messaging in the serotonin system, enhances the response of rats to carbon dioxide. In ongoing research, scientists also find that they can decrease an animal's response to carbon dioxide by killing cells that contain serotonin in the brain stem. In addition, mice bred to lack most of their serotonin cells have abnormal breathing and some die during infancy. Researchers plan to further define serotonin’s role in SIDS. Ultimately they would like to use the information to devise a test that predicts which children have the greatest risk of dying from SIDS and to find better ways to prevent death. Brain cells that contain serotonin, may play an important role in sudden infant death syndrome or SIDS. Some researchers suspect that these cells, situated in the brain near large arteries, are part of a system that normally monitors the blood for high levels of carbon dioxide, which can be harmful. Through a release of serotonin, the brain cells are thought to increase breathing and keep carbon dioxide levels low. This system, however, may not work properly in some babies and could help contribute to SIDS. Serotonin and Judgement Depression can hit at any age. More than the blues, the overall feeling of doom can trigger some people to kill themselves. Researchers now are looking at this behavior from a new angle. Studies show that low levels of the brain chemical serotonin can in part lead to an overall insensitivity to future consequences, setting off impulsive and aggressive behaviors and perhaps culminating in suicide. By selectively restoring the chemicals' activity researchers hope to prevent destructive behavior as well as head off suicide -- the eighth leading cause of death in the U.S.       Grades are posted. Alex . . . 98 percent. Pam ... 85 percent. Nick...91 percent. Your grade? 20 percent. You're upset so you talk to your teacher to find out where you went wrong.       But what if your feelings went out of control? You rip up the posted mid-term grades and glare at your teacher as you exit the classroom. In the days that follow you experience overwhelming feelings of sadness and thoughts of ending your life.       Why would a person behave one way rather than another? For years, scientists have agreed that some behavior flaws can arise from environmental influences including how your parents raised you or from a traumatic life crisis such as the death of a loved one. Now a growing body of evidence suggests that a chemical dubbed serotonin (ser-oh-TOE-nin) also may play a part. Some scientists believe that low activity of the chemical in the brain can lead to an underlying inability to handle powerful feelings, which can result in impulsive acts, aggressive behaviors and suicidal tendencies. This new line of research may lead to: * The use of brain imaging techniques for identifying those who may be impulsively aggressive or suicidal. * A method to monitor the serotonin medications given to suicidal depressed patients. * New insights on the mechanisms of serotonin.       Serotonin is one of a group of chemical messengers known as neurotransmitters that carry out communication in the brain and body. The message molecules flow from a nerve cell or neuron onto other neurons that act as receivers. There, they attach to a distinctly shaped area on the neuron called a receptor site. This union, which is like a key fitting into a lock, triggers signals that either allow the message to be passed on to other cells or prevent the message from being forwarded. Since the discovery of serotonin in the 1950s, researchers are finding evidence that one of its roles is to mediate emotions and judgment.       For example, in animal studies, scientists discovered that low serotonin levels may be associated with impulsive or risky behavior. Researchers observed monkeys and found that the ones who took more dangerous leaps traveling from tree to tree had lower serotonin levels and more injuries from falling. Other scientists examined rats and found the ones with low serotonin levels chose a small immediate reward instead of waiting for a bigger prize.       Scientists also have compiled studies that show serotonin is implicated in aggressive acts. One example involves mice who lack one type of receptor that responds to serotonin. These defective mice attack intruders faster and more intensely. Other researchers examined the spinal fluid of murderers in Finland. Their results indicate that these individuals have abnormally low levels of serotonin.       Some researchers now believe that suicide may be the ultimate act of inwardly directed impulsive aggression.       In one new area of