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Neuroscientists have long been banging their heads on their desks over exaggerated reports of brain scanning studies. Media stories illustrated with coloured scans, supposedly showing how the brain works, are now a standard part of the science pages and some people find them so convincing that they are touted as ways of designing education for our children, evaluating the effectiveness of marketing campaigns and testing potential recruits. Recently, to the chagrin of French scientists,politicians called for neuro-imaging to be used in the courts to decide on the guilt of criminals, after the technology made its dubious debut in the legal systems of India, Italy and the US.
This misplaced enthusiasm often stems from a misunderstanding about what brain scans tell us. The interpretation seems straightforward according to the popular press – the coloured blobs represent a “pleasure centre”, an “art centre” or perhaps a “love centre” – but none of this is true.
All of our experiences and abilities rely on a distributed brain network and nothing relies on a single “centre”. More than anything, the conclusions depend on the tasks volunteers undertake in the scanner and what each study tells us is limited. This small print has been repeated many times over by scientists. They bemoan how people misunderstand the subtleties and draw unwarranted conclusions. But now neuroscientists have had to come to terms with the fact that many of the methods on which brain scan studies are based have been flawed.
To understand where these flaws come from it’s important to know something about how data from the most common technique, functional Magnetic Resonance Imaging or fMRI, is analysed. The scanner creates a 3D map of the brain split up into tens of thousands of tiny blocks calledvoxels (like pixels but for volume) and each has a value that describes blood flow – used as a proxy for brain activity as more active areas need more oxygen. What you want to know is which bits of the brain are more active in certain tasks. Of course, the brain is changing all the time so scientists use statistics to check that changes in blood flow are due to the experimental tasks and not because of unrelated brain changes. The statistical problem is huge, however, as each scan has about 50,000 data points and thousands of scans are made in a single study.
When we’re talking about millions of comparisons, a big problem is false positives. Imagine you are playing two roulette wheels. Clearly, the result of one doesn’t affect the outcome of the other but sometimes they’ll both come up with the same number just due to chance. Now imagine you have a roulette wheel for every point or voxel in the brain. A comparison of any two scans could look like some areas show linked activity when really there is no relationship. Ideally, the analysis should separate roulette wheels from genuine activity, but you may be surprised that hundreds if not thousands of studies have been conducted without such corrections. To illustrate the problem, Craig Bennett and his colleagues at the University of California did a spoof experiment on a dead salmon. The standard techniques showed “brain activity” in the deceased fish.
Further illustrating the issue, Edward Vul and Hal Pashler from the University of California showed that some researchers were producing conclusions by first picking out the best results and then seeing if there was a relationship between them. To return to our roulette analogy, it would be like discarding any results that weren’t in the range of numbers 1-5 and then using only these selected results to see if any of the same numbers came up, something that is suddenly much more likely. A recent study by Anders Eklund and colleagues from Linköping Universityin Sweden found that they could find spurious “brain activity” related to non-existent tasks with standard settings on the most popular fMRI analysis software.
Recent advances have tried to control these problems but researchers have become much more cautious. “Our default attitude to any new and interesting fMRI finding should be scepticism,” says Tal Yarkoni, a neuroscientist at the University of Colorado. “What’s particularly problematic,” he says, “is the amount of flexibility researchers have when performing their analyses… you have no idea how many things the researchers tried before they got something to work.” Psychologist Russ Poldrack, from the University of Texas, who has been at the forefront of correcting these issues, also highlights cultural issues. This flexible approach “also includes methods that are known by experts to be invalid, but unfortunately these still get into top journals, which only helps perpetuate them”. Yarkoni explains that “researchers have a big incentive to come up with exciting new findings”, meaning scientists are motivated to “torture” the data and journals are attracted by the media-friendly results.
In this light of this, stories about the discovery of “brain centres” fall flat and efforts to base public policy on brain scans become nothing short of ridiculous. But perhaps the most important problem is not that brain scans can be misleading, but that they are beautiful. Like all other neuroscientists, I find them beguiling. They have us enchanted and we are far from breaking their spell.
You are given a frequent buyer card for your local coffeeshop. Each time you buy a cup of coffee you get a stamp on your card. When the card is filled you get a free cup of coffee. Here are two different scenarios:
Card A: The card has 10 boxes for the stamps, and when you get the card all the boxes are blank.
Card B: The card has 12 boxes for the stamps, and when you get the card the first two boxes are already stamped.
Question: How long will it take you to get the card filled up? Will it take longer or shorter for scenario A vs. scenario B? After all, you have to buy 10 cups of coffee in both scenarios in order to get the free coffee. So does it make a difference which card you use?
The answer apparently is yes. You will fill up the card faster with Card B than with Card A. And the reason is called the “goal-gradient” effect.
The goal-gradient effect was first studied in 1934 by Hull with rats. He found that rats that were running a maze to get food at the end would run faster as they got to the end of the maze.
The goal-gradient effect says that you will accelerate your behavior as you progress closer to your goal. The scenarios I describe above were part of a research study by Ran Kivetz, Oleg Urminsky, and Yuhuang Zheng (full reference is below). They decided to see if humans would behave like the rats. And the answer is, yes they do.
Here are some important things to keep in mind about the goal-gradient effect:
The shorter the distance to the goal the more motivated people will be to reach it.
You can get this extra motivation even with the illusion of progress, as in Scenario B above. There really isn’t any progress (you still have to buy 10 coffees), but it seems like there is some progress so it has the same effect
People enjoy being part of the reward program. When compared to customers who were not part of the program, the customers with the reward cards smiled more, chatted longer with café employees, said “thank you” more often and left a tip more often (all statistically significant for you research buffs out there).
In a related experiment the same researchers showed that people would visit a web site more frequently and rate more songs during each visit as they got closer to a reward goal at the site. So this goal-gradient effect appears to be generalizable across many situations.
Motivation and purchases plummet right after the goal is reached. This is called a “post-reward resetting phenomenon”. If you have a 2nd reward level people will initially not be very motivated to reach that 2nd reward. Right after a reward is reached is when you are most at risk of losing your customer.
And for those of you who want to read the original research:
Ran Kivetz, Oleg Urminsky, and Yuhuang Zheng, The Goal-Gradient Hypothesis Resurrected:Purchase Acceleration, Illusionary Goal Progress, and Customer Retention, Journal of Marketing Research, 39 Vol. XLIII (February 2006), 39–58.
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May 5, 2012
In an effort to identify the underlying causes of neurological disorders that impair motor functions such as walking and breathing, UCLA researchers have developed a novel system to measure the communication between stem cell-derived motor neurons and muscle cells in a Petri dish.
When brain cells start oozing too much of the amyloid protein that is the hallmark of Alzheimer’s disease, the astrocytes that normally nourish and protect them deliver a suicide package instead, researchers report.
Amyloid is excreted by all neurons, but rates increase with aging and dramatically accelerate in Alzheimer’s. Astrocytes, which deliver blood, oxygen and nutrients to neurons in addition to hauling off some of their garbage, get activated and inflamed by excessive amyloid.
Now researchers have shown another way astrocytes respond is by packaging the lipid ceramide with the protein PAR-4, which independently can do damage but together are a more “deadly duo,” said Dr. Erhard Bieberich, biochemist at the Medical College of Georgia at Georgia Health Sciences University.
“If the neuron makes something toxic and dumps it at your door, what would you do?” said Bieberich, corresponding author of the study published in the Journal of Biological Chemistry. “You would probably do something to defend yourself.”
The researchers hypothesize that this lipid-coated package ultimately kills them both, which could help explain the brain-cell death and shrinkage that occurs in Alzheimer’s. “If the astrocytes die, the neurons die,” Bieberich said, noting studies suggest that excess amyloid alone does not kill brain cells. “There must be a secondary process toxifying the amyloid; otherwise the neuron would self-intoxicate before it made a big plaque,” he said. “The neuron would die first.”
One of many avenues for future pursuit include whether a ceramide antibody could be a viable Alzheimer’s treatment. In the researchers’ studies of brain cells of humans with Alzheimer’s as well as an animal model of the disease, antibodies to ceramide and Par-4 prevented astrocytes’ amyloid-induced death.
Ceramide and Par-4 get packaged in lipid-coated vesicles called exosomes; all cells secrete thousands of these vesicles but scientists are only beginning to understand their normal function. When exosomes become deadly, they are called apoxosomes.
Ceramide and Par-4 are typically not in a vesicle, rather in two distinct parts of a cell. Ceramide appears to take the lead in bringing the two together when confronted with amyloid. Bieberich and colleagues at the University of Georgia reported in 2003 that the deadly duo helps eliminate duplicate brain cells that occur early in brain development when their survival could result in a malformed brain. They suspected then that the duo might also have a role in Alzheimer’s.
Risk factors for Alzheimer’s include aging, family history and genetics, according to the Alzheimer’s Association. Increasing evidence suggests that Alzheimer’s also shares many of the same risk factors for cardiovascular disease, such as high cholesterol, high blood pressure and inactivity.
Drs. Guanghu Wang, research scientist, and Michael Dinkins, postdoctoral fellow, are co-first authors on the study funded by the National Institutes of Health.
ScienceDaily (May 19, 2012) — University of Iowa neuroscientist John Wemmie, M.D., Ph.D., is interested in the effect of acid in the brain. His studies suggest that increased acidity or low pH, in the brain is linked to panic disorders, anxiety, and depression. But his work also suggests that changes in acidity are important for normal brain activity too.
“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, a UI associate professor of psychiatry. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”
Wemmie’s studies have shown that these acid-sensing proteins are required for normal fear responses and for learning and memory in mice. However, while you can buy a kit to measure the pH (acidity) of your garden soil, there currently is no easy way to measure pH changes in the brain.
Wemmie teamed up with Vincent Magnotta, Ph.D., UI associate professor of radiology, psychiatry, and biomedical engineering, and using Magnotta’s expertise in developing MRI (magnetic resonance imaging)-based brain imaging techniques, the researchers developed and tested a new, non-invasive method to detect and monitor pH changes in living brains.
According to Wemmie, the new imaging technique provides the best evidence so far that pH changes do occur with normal function in the intact human brain. The findings were published May 7 in the Proceedings of the National Academy of Sciences (PNAS) Early Edition.
Specifically, the study showed the MRI-based method was able to detect global changes in brain pH in mice. Breathing carbon dioxide, which lowers pH (makes the brain more acidic), increased the signal, while bicarbonate injections, which increases brain pH, decreased the MRI signal. The relationship between the signal and the pH was linear over the range that was tested.
Importantly, the method also seems able to detect localized brain activity. When human volunteers viewed a flashing checkerboard — a classic experiment that activates a particular brain region involved in vision — the MRI method detected a drop in pH in that region. The team also confirmed the pH drop using other methods.
“Our study tells us, first, we have a technique that we believe can measure pH changes in the brain, and second, this MRI-based technique suggests that pH changes do occur with brain function,” Magnotta says.
“The results support our original idea that brain activity can change local pH in human brains during normal activity, meaning that pH change in conjunction with the pH-sensitive receptors could be part of a signaling system that affects brain activity and cognitive function,” Wemmie adds
A new way to view brain activity
Importantly, this technique may also provide a new way to image the brain
Currently, functional MRI (fMRI) measures brain activity by detecting a signal that’s due to oxygen levels in the blood flowing to active brain regions. The UI team showed that their method responds to pH changes but is not influenced by changes in blood oxygenation. Conversely, fMRI does not respond to changes in pH.
“What we show is our method of detecting brain activity probably depends on pH changes and, more than that, it is distinct from the signal that fMRI measures,” says Wemmie. “This gives us another tool to study brain activity.”
pH and brain function
Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.
“Brain activity is likely different in people with brain disorders, such as bipolar or depression and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day; could this signal be abnormal or perturbed in human psychiatric disease? And if so, it might be a target for manipulation and treatment?”
“In the last several years there have been data suggesting that neurobiological changes are happening — [there are] very brain-specific mechanisms at work here,” says Bucci, an associate professor in the Department of Psychological and Brain Sciences.
From his studies, Bucci and his collaborators have revealed important new findings:
- The effects of exercise are different on memory as well as on the brain, depending on whether the exerciser is an adolescent or an adult.
- A gene has been identified which seems to mediate the degree to which exercise has a beneficial effect. This has implications for the potential use of exercise as an intervention for mental illness.
Bucci began his pursuit of the link between exercise and memory with attention deficit hyperactivity disorder (ADHD), one of the most common childhood psychological disorders. Bucci is concerned that the treatment of choice seems to be medication.
“The notion of pumping children full of psycho-stimulants at an early age is troublesome,” Bucci cautions. “We frankly don’t know the long-term effects of administering drugs at an early age — drugs that affect the brain — so looking for alternative therapies is clearly important.”
Anecdotal evidence from colleagues at the University of Vermont started Bucci down the track of ADHD. Based on observations of ADHD children in Vermont summer camps, athletes or team sports players were found to respond better to behavioral interventions than more sedentary children. While systematic empirical data is lacking, this association of exercise with a reduction of characteristic ADHD behaviors was persuasive enough for Bucci.
Coupled with his interest in learning and memory and their underlying brain functions, Bucci and teams of graduate and undergraduate students embarked upon a project of scientific inquiry, investigating the potential connection between exercise and brain function. They published papers documenting their results, with the most recent now available in the online version of the journal Neuroscience.
Bucci is quick to point out that “the teams of both graduate and undergraduates are responsible for all this work, certainly not just me.” Michael Hopkins, a graduate student at the time, is first author on the papers.
Early on, laboratory rats that exhibit ADHD-like behavior demonstrated that exercise was able to reduce the extent of these behaviors. The researchers also found that exercise was more beneficial for female rats than males, similar to how it differentially affects male and female children with ADHD.
Moving forward, they investigated a mechanism through which exercise seems to improve learning and memory. This is “brain derived neurotrophic factor” (BDNF) and it is involved in growth of the developing brain. The degree of BDNF expression in exercising rats correlated positively with improved memory, and exercising as an adolescent had longer lasting effects compared to the same duration of exercise, but done as an adult.
“The implication is that exercising during development, as your brain is growing, is changing the brain in concert with normal developmental changes, resulting in your having more permanent wiring of the brain in support of things like learning and memory,” says Bucci. “It seems important to [exercise] early in life.”
Bucci’s latest paper was a move to take the studies of exercise and memory in rats and apply them to humans. The subjects in this new study were Dartmouth undergraduates and individuals recruited from the Hanover community.
Bucci says that, “the really interesting finding was that, depending on the person’s genotype for that trophic factor [BDNF], they either did or did not reap the benefits of exercise on learning and memory. This could mean that you may be able to predict which ADHD child, if we genotype them and look at their DNA, would respond to exercise as a treatment and which ones wouldn’t.”
Bucci concludes that the notion that exercise is good for health including mental health is not a huge surprise. “The interesting question in terms of mental health and cognitive function is how exercise affects mental function and the brain.” This is the question Bucci, his colleagues, and students continue to pursue.
Catechol-O-methyltransferase is involved in the inactivation of the catecholamine neurotransmitters (dopamine,epinephrine, and norepinephrine). The enzyme introduces a methyl group to the catecholamine, which is donated by S-adenosyl methionine (SAM). Any compound having a catechol structure, like catecholestrogens and catechol-containing flavonoids, are substrates of COMT.
Levodopa, a precursor of catecholamines, is an important substrate of COMT. COMT inhibitors, like entacapone, save levodopa from COMT and prolong the action of levodopa. Entacapone is a widely-used adjunct drug of levodopa therapy. When given with an inhibitor of dopa decarboxylase (carbidopa or benserazide), levodopa is optimally saved. This “triple therapy” is becoming a standard in the treatment of Parkinson’s disease.
Specific reactions catalyzed by COMT include:
- Dopamine → 3-Methoxytyramine
- DOPAC → HVA (homovanillic acid)
- Norepinephrine → Normetanephrine
- Epinephrine → Metanephrine
- Dihydroxyphenylethylene glycol (DOPEG) → Methoxyhydroxyphenylglycol (MOPEG)
- 3,4-Dihydroxymandelic acid (DOMA) → Vanillylmandelic acid (VMA)
In the brain, COMT-dependent dopamine degradation is of particular importance in brain regions with low expression of the presynaptic dopamine transporter (DAT), such as the prefrontal cortex.[5][6] This process is supposed to take place in postsynaptic neurons, as, in general, COMT is located intracellularly in the CNS.[7][8]
COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally.[9] Despite its importance in neurons, COMT is actually primarily expressed in the liver.[10]
