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The default brain network and ADD

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So in the previous post I published some New Scientist articles about the ‘default network’ in the brain. This network kicks into action as soon as we stop focusing our attention on a task.

The default network is where we think. Imagine living like this:

People who suffer damage to their medial prefrontal cortex become listless and uncommunicative. One woman who recovered from a stroke in that area recalled inhabiting an empty mind, devoid of the wandering, stream-of-consciousness thoughts that most of us take for granted.

No default network, no thoughts.

The default network is aberrant in schizophrenia, and schizophrenic subjects appear to have problems accessing their default network properly.

In the healthy subjects, the default mode network resonated slowly and regularly as observed by blood flow. In the patients with schizophrenia, the activity in the brain increased and was significantly more irregular, although they performed equally well on the task. Brain’s ‘Default Mode’ Awry In Schizophrenia

Schizophrenia is interesting because it is treated with dopamine antagonists. No direct correlation can be found between schizophrenia and high dopamine levels, though high dopamine is known to cause delusions. However, some scientists believe schizophrenia may be an autoimmune condition in which autoantibodies trigger dopamine receptors in the brain. The fact is, dopamine antagonists control and treat delusions and hallucinations.

In Alzheimer’s, not only is there a loss of dopamine D2 receptors in the brain, but the default network areas specifically accumulate plaques. Alzheimer’s patients appear to turn on their default network when asked to concentrate on a task, while normal subjects turn off their default network.

In terms of neurotransmitters, at the direct opposite end of the spectrum from schizophrenia is attention deficit (hyperactivity) disorder. AD(H)D is considered a condition characterised by low dopamine levels. Low dopamine levels lead to a lack of attention – to daydreaming.

Whilst attention deficit is typically thought to be something that affects children, adults experience it too – though perhaps not so obviously, possibly because the default network is something that matures into a complex and cohesive network during one’s lifetime.

In recent years, the brain’s “default network,” a set of regions characterized by decreased neural activity during goal-oriented tasks, has generated a significant amount of interest, as well as controversy. Much of the discussion has focused on the relationship of these regions to a “default mode” of brain function. In early studies, investigators suggested that, the brain’s default mode supports “self-referential” or “introspective” mental activity. Subsequently, regions of the default network have been more specifically related to the “internal narrative,” the “autobiographical self,” “stimulus independent thought,” “mentalizing,” and most recently “self-projection.” However, the extant literature on the function of the default network is limited to adults, i.e., after the system has reached maturity. We hypothesized that further insight into the network’s functioning could be achieved by characterizing its development. In the current study, we used resting-state functional connectivity MRI (rs-fcMRI) to characterize the development of the brain’s default network. We found that the default regions are only sparsely functionally connected at early school age (7–9 years old); over development, these regions integrate into a cohesive, interconnected network. The maturing architecture of the brain’s default network

What is really fascinating about the default network to me, is that the more I read about it, the more it seems to be how my brain functions.

I’ve been so busy studying autism, perhaps I should have been paying more attention(!) to attention deficit disorder. I have always had ADD. It is the cause of many of my problems, but also the cause of a lot of my talents.

Since being a child I have been chided for being in a permanent daydream. My imagination is constantly in action. I frequently take on the look of the gormless because I disappear off onto my own planet, open-mouthed, as I speculate about some possible future, or some possible theory about the universe. I burn the dinner, I leave tasks half-finished for other tasks, I don’t pay attention to where I am going, I get lost in the supermarket and make six laps because I am too busy pondering the universe, and at any given second I can break off half way through a sentence or a line of code to go google whatever question pops into my head.

I have evolved a lot of coping mechanisms for these traits: I have an OCD level of strictness about making sure I have locked the door, I have thought about the items I need to buy, I have checked my keys are in my bag, I have looked both ways before crossing the road, and I have set the kitchen timer. I often have to make a conscious effort to switch off the wireless internet connection so I can get on with my writing. The OCD is not real: it is simply my conscious way of dealing with my short attention span.

Whilst most of the world may regard this as a disorder, I prefer to regard it as a difference.

When I am not on the failsafe diet (which is never), my attention deficit disorder is very serious indeed, to the point where it could be dangerous for me to drive a car (my driving instructor always chided me for not paying enough attention). Sometimes it has been so bad that I have felt I cannot be gainfully employed due to the time I waste doing everything except working. My brain buzzes, throws disjointed thoughts at me, and repeats itself again and again.

When I am on the failsafe diet, however, I think quite clearly. I can focus when I need to, but I still go off on massive reveries and have epiphanies about things. So what? What’s wrong with spending your time thinking? I’m sure Sir Isaac Newton wouldn’t have discovered all those laws of physics if he hadn’t spent so much time daydreaming.

My big theory about the default network is that it is suppressed by dopamine, and activated when dopamine is low. I’ve found a couple of studies that back up this theory, here and here. Indeed, this blog describes how the use of stimulants like ritalin deactivate the default network.

The default network is where my consciousness lives. I’ve tried meditation before and I find it tremendously difficult to switch off my stream of consciousness. I have no patience for meditation or yoga. Switching off is something that I can perhaps do when I am watching television or reading very intensely, where I just have words going in that I process without thinking about them, though it only lasts a few seconds before the stream of consciousness reasserts itself again.

I find it incredibly uncomfortable to try to switch off that stream of consciousness, like holding one’s breath. It seems to me that being asked to concentrate can make me irritable and tired.

Music is something I have a real problem with. I rarely listen to music. When in the right mood, I like listening to music, but it tends to take over my brain. If it is too loud (i.e. speaking volume), it actually interferes with my stream of consciousness. I find this very, very uncomfortable. If I’m forced to sit in a car and listen to music that is loud enough to interfere with my thoughts, it’s like torture, and I can get really irritable. It’s like I’m being forced to concentrate against my will.

So ADD is not so much a case of “I can’t concentrate,” it’s a case of my dopamine being low and as a result my default network is constantly reasserting itself over the rest of my mind. This is not an unpleasant experience, in fact, I prefer things that way.

The things that the default network is good at doing are the same things that I am good at doing, for example:

Planning: whether a route, or a future event. I always plan things. I am uncomfortable if I don’t plan things. It seems to me that when I get irritated by something, it is almost always because a plan has gone awry and my brain has to re-plan at short notice. I am very good at envisaging future scenarios, even totally unexpected ones. If a conversation is happening where future possibilities are being discussed, I can guarantee to have thought up each of the future possibilities long before someone else suggests them. When I listen to politics on the radio, I am frequently annoyed by the lack of foresight politicians have for the consequences of their policies. I’m an “I told you so,” kind of person. I like to think this trait makes me a good scientist, because when I observe a phenomenon, I can imagine many possible causes and therefore have many theories to suggest and test.

Remembering: particularly autobiographical memories. This elephant never forgets. I often recall scenarios to other people, only to find they have forgotten them. My memory is very reliable, and it’s very rare that I have forgotten something that someone else remembers. I am also a terrifying fact machine, as long as I can relate the facts to myself in some way.

Imagining: I write fantasy and science fiction. I share my big imagination with one grandparent in my family who used to tell us stories when we were kids. This grandparent also has ADHD and can’t sit still.

Moral decision making: I am a very principled, moral person with a complex set of standards that I adhere to. I don’t blindly follow rules however, I think about the consequences of actions and consider the greater good.

Self-awareness: things simply don’t get by me unnoticed the way they seem to get by other people. I always used to wonder why people didn’t understand obvious things about themselves. Now I guess I do know. They aren’t using their default networks as much as I am.

The default network also explains the things I am not very good at, for example – it answers that question I have been asking myself for years – why am I so slow at everything? How come it takes me twice as long to do any task as it takes someone else? How come on those silly facebook quizzes, I always take twice as many minutes to complete them as everyone else?

Though I have a big imagination, I’ve struggled to actually get on and do the process of writing for years and years. I have to go to some unusual extremes in order to write. I can’t concentrate during the day, if there is background noise, if there is anyone else around. I basically have to closet myself in a dark room in the dead of night in order to put down all my ideas on paper.

I see now that my default network is getting in the way, it’s reasserting itself all the time and slowing me down when I have to focus. It’s almost like a kind of epilepsy, I’m just switching off for a few seconds here and there all the time, my mind wandering without me even being aware of it.

Do other people experience conciousness differently to me? When they are concentrating on a task, do they simply stop thinking? I can’t imagine what that feels like.

There is one major anomaly though. According to this (free) review of the studies done on the default network so far, the default network is activated during theory of the mind tasks. Considering how commonly autism and attention deficit disorder occur together in the same individual, this is very odd.

Regarding the function of the default network in autism, the review implies mixed results so far, with some studies suggesting increased brain volume in default network areas, whilst others suggesting absence of activity during passive tasks when the mind would usually wander. This suggests the autistics in question were concentrating very hard on the task they were given! Still other information in the review points out to a complex interaction with the amygdala, which is known to contribute to social cognition, and interacts with the default network.

An intriguing possibility suggested by the authors of the study [...] is that the failure to modulate the default network in ASD is driven by differential cognitive mentation during rest, specifically a lack of self-referential processing [...] Another recent study using analysis of intrinsic functional correlations showed that the default network correlations were weaker in ASD (Cherkassky et al. 2006). Of note, the individuals with ASD showed differences in a fronto-parietal network that has been recently hypothesized to control interactions between the default network and brain systems linked to external attention (Vincent et al. 2007b). These data in ASD suggest an interesting possibility: the default network may be largely intact in ASD but under utilized perhaps because of a dysfunction in control systems that regulate its use. The Brain’s Default Network

Now I’m the first to point out I’m not a typical aspie. Many other aspies seem a lot whackier than me (higher dopamine?), and as far as the theory of the mind goes, I do pretty good (but then, I’m female). I’ve never fitted the Baron-Cohen “extreme male brain” theory. I’m rubbish at maths, but great at logic, pattern-spotting and programming.

However, I’m not alone in being anomalous. Fifty to sixty percent of autistics also qualify for a diagnosis of ADD/ADHD,  see this reference. Yet autism can also occur together with schizophrenia, as can schizophrenia and ADHD occur together.

So what’s going on here?

Written by alienrobotgirl

22 December, 2008 at 6:38 pm

Posted in Neurotransmitters

The default brain network

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More amazing revelations from the New Scientist magazine.

The default network in action

The default network in action

IN 1953 a physician named Louis Sokoloff laid a 20-year-old college student onto a gurney, attached electrodes to his scalp and inserted a syringe into his jugular vein.

For 60 minutes the volunteer lay there and solved arithmetic problems. All the while, Sokoloff monitored his brainwaves and checked the levels of oxygen and carbon dioxide in his blood.

Sokoloff, a researcher at the University of Pennsylvania in Philadelphia, was trying to find out how much energy the brain consumes during vigorous thought. He expected his volunteer’s brain to guzzle more oxygen as it crunched the problems, but what he saw surprised him: his subject’s brain consumed no more oxygen while doing arithmetic than it did while he was resting with his eyes closed.

People have long envisaged the brain as being like a computer on standby, lying dormant until called upon to do a task, such as solving a Sudoku, reading a newspaper, or looking for a face in a crowd. Sokoloff’s experiment provided the first glimpse of a different truth: that the brain enjoys a rich private life. This amazing organ, which accounts for only 2 per cent of our body mass but devours 20 per cent of the calories we eat, fritters away much of that energy doing, as far as we can tell, absolutely nothing.

“There is a huge amount of activity in the [resting] brain that has been largely unaccounted for,” says Marcus Raichle, a neuroscientist at Washington University in St Louis. “The brain is a very expensive organ, but nobody had asked deeply what this cost is all about.”

Raichle and a handful of others are finally tackling this fundamental question – what exactly is the idling brain up to, anyway? Their work has led to the discovery of a major system within the brain, an organ within an organ, that hid for decades right before our eyes. Some call it the neural dynamo of daydreaming. Others assign it a more mysterious role, possibly selecting memories and knitting them seamlessly into a personal narrative. Whatever it does, it fires up whenever the brain is otherwise unoccupied and burns white hot, guzzling more oxygen, gram for gram, than your beating heart.

“It’s a very important thing,” says Giulio Tononi, a neuroscientist at the University of Wisconsin-Madison. “It’s not very frequent that a new functional system is identified in the brain, in fact it hasn’t happened for I don’t know how many years. It’s like finding a new continent.”

The discovery was slow in coming. Sokoloff’s experiment 55 years ago drew little attention. It wasn’t until the 1980s that it started to dawn on researchers that the brain may be doing important things while apparently stuck in neutral.

Eavesdropping on the mind

In those days a novel brain scanning technique called PET was all the rage. By injecting radioactive glucose and measuring where it accumulated, researchers were able to eavesdrop on the brain’s inner workings. In a typical experiment they would scan a volunteer lying down with their eyes closed and again while doing a mentally demanding task, then subtract one scan from the other to find the brain areas that lit up.

Raichle was using PET to find brain areas associated with words when he noticed something odd: some brain areas seemed to go at full tilt during rest, but quietened down as soon as the person started an exercise. Most people shrugged off these oddities as random noise. But in 1997 Raichle’s colleague Gordon Shulman found otherwise.

Shulman sifted through a stack of brain scans from 134 people. Regardless of the task, whether it involved reading or watching shapes on a screen, the same constellation of brain areas always dimmed as soon as the subject started concentrating. “I was surprised by the level of consistency,” says Shulman. Suddenly it looked a lot less like random noise. “There was this neural network that had not previously been described.”

Raichle and Shulman published a paper in 2001 suggesting that they had stumbled onto a previously unrecognised “default mode” – a sort of internal game of solitaire which the brain turns to when unoccupied and sets aside when called on to do something else. This brain activity occurred largely in a cluster of regions arching through the midline of the brain, from front to back, which Raichle and Shulman dubbed the default network (Proceedings of the National Academy of Sciences, vol 98, p 676).

The brain areas in the network were known and previously studied by researchers. What they hadn’t known before was that they chattered non-stop to one another when the person was unoccupied but quietened down as soon as a task requiring focused attention came along. Measurements of metabolic activity showed that some parts of this network devoured 30 per cent more calories, gram for gram, than nearly any other area of the brain.

All of this poses the question – what exactly is the brain up to when we are not doing anything? When Raichle and Shulman outlined the default network, they saw clues to its purpose based on what was already known about the brain areas concerned.

One of the core components is the medial prefrontal cortex (see diagram), which is known to evaluate things from a highly self-centred perspective of whether they’re likely to be good, bad, or indifferent. Parts of this region also light up when people are asked to study lists of adjectives and choose ones that apply to themselves but not to, say, Britney Spears. People who suffer damage to their medial prefrontal cortex become listless and uncommunicative. One woman who recovered from a stroke in that area recalled inhabiting an empty mind, devoid of the wandering, stream-of-consciousness thoughts that most of us take for granted.

Parts of the default network also have strong connections to the hippocampus, which records and recalls autobiographical memories such as yesterday’s breakfast or your first day of kindergarten.

To Raichle and his colleague Debra Gusnard, this all pointed to one thing: daydreaming. Through the hippocampus, the default network could tap into memories – the raw material of daydreams. The medial prefrontal cortex could then evaluate those memories from an introspective viewpoint. Raichle and Gusnard speculated that the default network might provide the brain with an “inner rehearsal” for considering future actions and choices.

Randy Buckner, a former colleague of Raichle’s now at Harvard, agrees. To him the evidence paints a picture of a brain system involved in the quintessential acts of daydreaming: mulling over past experiences and speculating about the future (New Scientist, 24 March 2007, p 36). “We’re very good at imagining possible worlds and thinking about them,” says Bucker. “This may be the brain network that helps us to do that.”

There is now direct evidence to support this idea. Last year, Malia Mason of Dartmouth College in Hanover, New Hampshire, reported that the activity of the default network correlates with daydreaming. Using the brain imaging technique fMRI, Mason found that people reported daydreaming when their default network was active, but not when it dimmed down. Volunteers with more active default networks reported more wandering thoughts overall (Science, vol 315, p 393).

Daydreaming may sound like a mental luxury, but its purpose is deadly serious: Buckner and his Harvard colleague Daniel Gilbert see it as the ultimate tool for incorporating lessons learned in the past into our plans for the future. So important is this exercise, it seems, that the brain engages in it whenever possible, breaking off only when it has to divert its limited supply of blood, oxygen and glucose to a more urgent task.

“Daydreaming may sound like a mental luxury but its purpose is deadly serious”

But people are starting to suspect that the default network does more than just daydream. It started in 2003 when Michael Greicius of Stanford University in California studied the default network in a new way. He got his subjects to lie quietly in an fMRI scanner and simply watched their brains in action. This led him to find what are called resting state fluctuations in the default network – slow waves of neural activity that ripple through in a coordinated fashion, linking its constellation of brain areas into a coherent unit. The waves lasted 10 to 20 seconds from crest to crest, up to 100 times slower than typical EEG brain waves recorded by electrodes on the scalp.

Until then scientists had studied the default network in the old-fashioned way, subtracting resting scans from task scans to measure changes in brain activity. But Greicius’s work showed that you could eavesdrop on the network by simply scanning people as they lay around doing nothing. This allowed scientists to study the network in people who weren’t even conscious, revealing something unexpected.

Raichle reported last year that the network’s resting waves continued in heavily anaesthetised monkeys as though they were awake (Nature, vol 447, p 83). More recently, Greicius reported a similar phenomenon in sedated humans, and other researchers have found the default network active and synchronised in early sleep (Human Brain Mapping, vol 29, p 839 and p 671).

It threw a monkey wrench into the assumption that the default network is all about daydreaming. “I was surprised,” admits Greicius. “I’ve had to revamp my understanding of what we’re looking at.”

Given that the default network is active in early sleep it’s tempting to link it with real dreaming, but Raichle suspects its nocturnal activity has another purpose – sorting and preserving memories. Each day we soak up a mountain of short-term memories but only a few are actually worth adding to the personal narrative that guides our lives.

Raichle now believes that the default network is involved, selectively storing and updating memories based on their importance from a personal perspective – whether they’re good, threatening, emotionally painful, and so on. To prevent a backlog of unstored memories building up, the network returns to its duties whenever it can.

In support of this idea, Raichle points out that the default network constantly chatters with the hippocampus. It also devours huge amounts of glucose, way out of proportion to the amount of oxygen it uses. Raichle believes that rather than burning this extra glucose for energy it uses it as a raw material for making the amino acids and neurotransmitters it needs to build and maintain synapses, the very stuff of memory. “It’s in those connections where most of the cost of running the brain is,” says Raichle.

With such a central role, it shouldn’t be surprising that the default network is implicated in some familiar brain diseases. In 2004, Buckner saw a presentation by William Klunk of the University of Pittsburgh School of Medicine. Klunk presented 3D maps showing harmful protein clumps in the brains of people with Alzheimer’s. Until then people had only looked at these clumps in one brain location at a time, by dissecting the brains of deceased patients. So when Klunk projected his whole-brain map on the screen, it was the first time many people had seen the complete picture. “It was quite surprising,” says Buckner. “It looked just like the default network.”

Raichle, Greicius and Buckner have since found that the default network’s pattern of activity is disrupted in patients with Alzheimer’s disease. They have also begun to monitor default network activity in people with mild memory problems to see if they can learn to predict who will go on to develop Alzheimer’s. Half of people with memory problems go on to develop the disease, but which half? “Can we use what we’ve learned to provide insight into who’s at risk for Alzheimer’s?” says Buckner.

The default network also turns out to be disrupted in other maladies including depression, attention-deficit hyperactivity disorder (ADHD), autism and schizophrenia. It also plays a mysterious role in victims of brain injury or stroke who hover in the grey netherworld between consciousness and brain death known as a minimally conscious or vegetative state. Steven Laureys, a neurologist at the University of Liège in Belgium, has used fMRI to look at patterns of activity in the default networks of people in this state. “You can really see how this network breaks down as coma deepens,” he says. He is now looking for a link between default network activity and whether patients will regain consciousness after, say, 12 months. “We’re hoping to show that it will have prognostic value,” he says.

All of this has been a long time coming since Sokoloff’s surprising observation 55 years ago. Watching the brain at rest, rather than constantly prodding it to do tricks, is now revealing the rich inner world of our private moments. So the next time you’re mooching around doing nothing much, take a moment to remind yourself that your brain is still beavering away – if you can tear yourself away from your daydreams, that is.

Sidebar: The meditating mind

WHEN Zen Buddhists meditate, they may be deliberately switching off their default network, a recently discovered system within the brain that has been strongly linked with daydreaming (see main story).The goal of Zen meditation is to clear the mind of wandering, stream-of-consciousness thoughts by focusing attention on posture and breathing. Giuseppe Pagnoni, a neuroscientist at the University of Modena and Reggio Emilia in Italy, wondered whether this meant they had learned to suppress the activity of their default network.He recruited a group of volunteers trained in Zen meditation and put them in an fMRI scanner. He presented them with random strings of letters and asked them to determine whether each was an English-language word or just gibberish. Each time a subject saw a real word, their default network would light up for a few seconds – evidence of meandering thoughts triggered by the word, such as apple… apple pie… cinnamon. Zen meditators performed just as well as non-meditators on word recognition, but they were much quicker to rein in their daydreaming engines afterwards, doing so within about 10 seconds, versus 15 for non-meditators (PLoS ONE, vol 3, p e3083). The Secret Life of the Brain

Not only is the default network the place where we daydream, it’s also becoming a way to define our consciousness:

Daydreaming your way out of a coma? Unlikely as it sounds, keeping track of a wandering mind may one day help doctors to discover whether a brain-damaged individual is still “in there”.

When a healthy person is daydreaming, their brain is not occupied with specific tasks and the “default network”, a series of specific, connected regions in the brain’s cortex, kicks in. The network’s purpose is still hotly debated but recent evidence suggests it keeps the brain primed and ready to take on new tasks. Problems activating the default network have been linked to cognitive diseases like Alzheimer’s and schizophrenia.

Now Steven Laureys and colleagues at the University of Liège in Belgium have used brain scans to measure the activity of the default network in 13 brain-damaged people whose levels of consciousness were different.

Their study, presented at this week’s meeting of the European Neurology Society in Nice, France, found that activity varied in proportion to the amount of brain damage. Minimally conscious patients had a 10 per cent reduction compared with healthy individuals, while activity was reduced by 35 per cent in coma patients and those in a persistent vegetative state (PVS). There was no activity at all in the default network of a brain-dead patient.

Laureys concludes that such a scan could act as a “consciousness meter”. “This could turn into an utterly useful way to diagnose residual consciousness in brain-damaged patients,” he says. Such a test could dramatically affect the fate of brain-damaged patients, by helping to determine whether to treat them with drugs or therapies, and in some cases, whether to keep them alive at all, says Laureys.

Usually, consciousness is measured by running a battery of behavioural tests. But these may miss some people who are minimally conscious. Two years ago, researchers at the University of Cambridge, together with Laureys’s group, investigated an alternative. They found that the correct brain areas lit up in someone they thought was in a PVS when she was asked to imagine playing tennis. This indicated that she must in fact be conscious (New Scientist, 7 July 2007, p 40).

However, the test is difficult to carry out and negative results are hard to interpret as the patient may simply not be able to think about a particular task. Measuring activity in the resting brain is quicker – and doesn’t depend on the patient responding. “We just scan someone for 10 minutes and get an easily quantifiable read-out,” says Laureys.

John Whyte at the Moss Rehabilitation Research Institute in Philadelphia, Pennsylvania, who is testing drugs that may help restore consciousness, says that although larger studies are needed to determine how reliably the default network indicates consciousness, assessing awareness in the resting brain is crucial to treating unresponsive, brain-damaged patients: “To find the right treatments, we need to be able to classify patients better, and resting assessments like this one should help with that.”

Joseph Giacino at the JFK Medical Center in Edison, New Jersey, agrees: “If this can help us to sort patients by how well connected their brains are, we might be able to use it one day to better predict who will wake up and who won’t.” ‘Consciousness meter’ may predict coma recoveries

The default network is where we imagine the future and the past.

[...] Much of that work has been documented by Gilbert in his book Stumbling on Happiness. “Every time you say, ‘I think I’ll go have lunch’, you’ve just thought about the future,” he says. That is just one small example of a general tendency to project ourselves forwards in time. According to Gilbert, psychologists studying stream of consciousness have found that the average person reports spending about 12 per cent of their waking hours thinking about the future.

It is easy to see the benefits of spending so much time in reverie. Running through future scenarios helps us achieve outcomes we want – and avoid ones we do not, perhaps as a direct result of learning from memories of past mistakes. We can maximise the enjoyment of future events by looking forward to them, while envisioning negative events helps us minimise their impact: volunteers’ hearts beat faster and they sweat more over lesser, but unpredictable, electric shocks than over larger, predictable ones.

In fact, there is evidence that mental time travel is such an important part of our inner lives that our brain will engage in it whenever it gets the chance. For more than 50 years, neuroscientists have known that even when your brain is apparently at rest, there is something important going on inside it. This comes from experiments showing that as the brain shifts gear from a passive, undirected state to an active, directed one – such as solving a puzzle – overall blood flow and oxygen uptake stay the same. So the “default” brain is up to something – but what?

A number of recent studies have tried to answer this, by scanning subjects who are doing nothing in particular. These studies always find the same surprising pattern of brain activity: the brain’s default state shows remarkable overlap with the mental time-travel network discovered in recent brain scans, according to Randy Buckner, another Harvard psychologist (Trends in Cognitive Sciences, vol 11, p 49). It seems that unless called upon to do something specific, your brain is busy recalling the past or projecting into the future. So next time you catch yourself staring into space instead of getting on with your work, or drifting into reverie as you try to read a book, don’t beat yourself up about it. Your daydreams will pay off in the long run. Future recall: your mind can slip through time

I’m very excited about the default network. I’ll post some comments about why in a separate blog.

Written by alienrobotgirl

21 December, 2008 at 11:47 pm

Posted in Neurotransmitters

GABA and ADHD

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I think I am on the right track.

In the last post I speculated that ADHD and ADD were related in some way to GABA deficiency. I believe attention deficit disorder may be characterised by low glutamate levels with low dopamine levels, and attention deficit hyperactivity disorder may be characterised by high glutamate levels with low dopamine levels. I believe all types are characterised by low GABA levels, the same root cause that produces bipolar disorder and some types of autism in other individuals.

So here’s some research to back me up.

Dec. 4, 2003 — Children with attention deficit hyperactivity disorder (ADHD) may actually have different levels of certain chemicals in the brain than other children, a new study shows.

Using new imaging techniques, researchers found that children with the hyperactive form of ADHD had 2 1-2 times more of a brain chemical known as glutamate, which acts like a stimulant in the brain. In addition, the brains of children with this subtype of ADHD also had lower than normal levels of GABA, a chemical that has inhibitory properties in the brain.

Both of these chemicals are neurotransmitters that carry signals to and from nerve cells in the brain. Researchers say these differences may explain the behavior of children with poor impulse control.

“Glutamate is an excitatory amino acid that leads to easier stimulation and excited neuronal pathways,” says researcher Helen Courvoisie, MD, assistant professor of child and adolescent psychiatry at Johns Hopkins Medical Institutions in Baltimore. “GABA is an inhibitory neurotransmitter and inhibits those pathways in the brain.”

In addition to revealing differences in brain chemistry, the study also showed that these gaps correlated to the children’s scores on tests of language, memory, sensory, and learning skills. Brain Scans Reveal ADHD Differences

The study was small and limited, and is a few years old now. I do not know whether it has been followed up with any further studies.

Dr. Courvoisie spoke today at an American Medical Association media briefing on advances in neurology in New York.

“Children with adhd have problems that are associated with the part of the brain called the frontal lobes,” said Dr. courvoisie. “The frontal lobes are like the ‘boss of the brain,’ responsible for what we call executive functioning telling the brain and body what to do.” This area regulates impulse control, attention, movement and elaborating on thoughts.

[...]

“There are three types of adhd: attention-deficit, hyperactive and combined type,” explained Dr. courvoisie. “We focused on the hyperactive type to try to get the clearest picture of what was going awry with their executive function.”

“There is a partial malfunctioning of this ‘boss of the brain’ in adhd,” said Dr. courvoisie. “I describe it as having a poor manager, like the pointy-headed boss in the Dilbert cartoons he doesn’t know what he’s doing, he can”t run a good company and everyone becomes frustrated.”

adhd is characterized by difficulty concentrating and paying attention, and a high degree of restless and impulsive behavior. Although the problems may be less pronounced in adulthood, it is often a lifelong condition.

[...]

“The great increase in the diagnosis of adhd has created some controversy,” said Dr. courvoisie. “It is important to understand and identify the underlying neurology of adhd so that children with adhd can be appropriately treated. There are real deficients these are not just fidgety kids.” Imaging children with ADHD

Here is a link to the pubmed abstract, and another to the free full text of the study online. Something interesting of note is that glutamine as well as glutamate were elevated in both frontal areas of the brain in these children, while increased N-acetyl aspartate and choline were found in the right frontal area of the group.

Eggs contain high amounts of choline. I wonder if this is why some people react badly to eggs? My ADHD sister was sensitive to eggs when she was a child. I am ADD without the hyperactivity, unless I really push up my glutamate levels with B12/folate. I am not sensitive to eggs. The other difference between us is that she is left handed and I am right handed. Could brain laterality affect outcome?

Unfortunately the pubmed abstract does not contain the word ‘GABA’ which makes it difficult to find in searches. Courvisie has also done a similar study on children with bipolar disorder (full text here) and found that glutamate and glutamine were both elevated in the frontal lobes and basal ganglia. They also had elevated lipid levels in the frontal lobes but not the temporal lobes, while while N-acetyl aspartate and choline levels were normal.

If the main problem in ADHD is glutamate/gaba imbalance, one would expect to find that ADHD children are helped by epilepsy medications that enhance GABA signalling, like sodium valproate. So, whilst perusing pubmed, I also found the following mini-study:

We treated three boys with attention deficit/hyperactivity disorder (ADHD) associated with giant somatosensory evoked potentials (SEP). All responded well to extended-release valproate (EVA), a gamma-aminobutyric acid (GABA) enhancer. Improvement particularly involved hyperactivity and impulsivity. When methylphenidate previously was administered to two patients, symptoms worsened. EVA therefore may be preferable for ADHD with giant SEP. Favorable response of ADHD with giant SEP to extended-release valproate

It looks like a ketogenic diet all round then!

Written by alienrobotgirl

10 November, 2008 at 12:59 pm

Posted in Neurotransmitters

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GABA, and DIY for bipolar disorder

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This post started out as a letter to a close relative who is on the verge of being diagnosed with cyclothymia, a mild form of bipolar disorder. The relative has been left out in the cold waiting for a referral to a psychiatrist. This person reminds me too much of myself five years ago, and I have been very worried.

Rather than reference this post with various science articles, I’m simply going to get it out there for now.

The most forward-thinking theory of bipolar disorder is that it is caused by a deficiency of GABA. GABA is a ‘calming’ and ‘regulating’ neurotransmitter. If you imagine GABA as the conductor of an orchestra, if you don’t have enough, all of the other neurotransmitters can get out of hand and start playing their own tunes, and they can swing in whatever direction they want. I believe that the most important thing you can do to control bipolar disorder is to raise your GABA levels.

One important neurotransmitter that is affected by GABA is glutamate. Glutamate is an ‘intelligence’ and ‘wakeful’ neurotransmitter. It’s almost like a volume knob. The more glutamate you have, the faster your brain goes and the louder all the neurotransmitters get. Too much glutamate can actually kill your brain cells. Manic highs are thought to be characterised by high levels of glutamate, characterised by racing thoughts and insomnia, while depressive lows are thought to be caused by low levels of glutamate. When we talk about depression in bipolar disorder, we are not necessarily talking about ‘sadness’, we are talking about a much wider range of symptoms that include grogginess and an increased need for sleep. Low glutamate levels are thought to be associated with some of the symptoms of fibromyalgia. People with unchecked bipolar disorder often describe having to sleep for several extra hours a day, sometimes not being able to get out of bed at all, and feeling hungover and being unable to wake up properly in the morning – very similar to fibromyalgia symptoms.

This isn’t the complete story of what is going on in the brain because bipolar disorder also affects dopamine levels – the ‘attention span’ and ‘pleasure/reward’ neurotransmitter. If you are unable to concentrate and are distracted easily (ADHD), and are unable to get any enjoyment out of the things you are doing, it is a sign that your dopamine levels are too low. Dopamine tends to rise when you are manic and fall when you are depressive.

High dopamine levels are an independent risk factor for bipolar disorder. This is because when dopamine levels become very high, thought becomes delusional and people experience hallucinations – very high dopamine and glutamate levels are thought to characterise schizophrenia. People who have naturally high dopamine levels are more likely to be at risk of delusional/manic episodes as their dopamine is more likely to go too high. A version of a gene called COMT, which causes high dopamine and low adrenaline levels, is associated with bipolar disorder.

However, if you have ADHD, you are to some extent protected from becoming delusional, as your dopamine levels are naturally low. I believe that people with ADHD can experience bipolar disorder quite differently to those who have naturally high dopamine. I believe that they can still have manic highs (insomnia, thoughts racing) caused by high glutamate in which they do not become delusional/hallucinatory, they just get carried away without crossing over into the ‘nuts’ category, as their low dopamine levels protect them from delusions. I believe attention deficit disorder may be characterised by low glutamate levels with low dopamine levels, and attention deficit hyperactivity disorder may be characterised by high glutamate levels with low dopamine levels.

There is a version of mania called ‘irritable mania’. Dopamine can convert quite easily to noradrenaline and adrenaline, which can trigger anger and aggression responses. I believe if you have the version of the COMT gene which causes low dopamine levels and high adrenaline levels, you will more likely experience irritable mania rather than regular delusional mania, in other words, rather than hallucinating or losing your ability to think logically, you will instead get really irritable and angry and lash out at the world. This kind of behaviour is frequently misunderstood as depression.

I believe there are people out there who have ADHD, whose low dopamine levels are protecting them from full-blown bipolar manic episodes. They therefore remain undiagnosed, even though they have the ‘seed’ of bipolar disorder within them, in that their GABA levels are too low and they are experiencing glutamate highs and lows. They will likely be diagnosed with unipolar depression or aggression disorders rather than bipolar disorder or cyclothymia, as they are less likely to recognise that something is wrong during their manic episodes – they simply feel too happy (or too angry), but don’t become delusional. As a result they are treated with drugs – SSRIs – that are totally wrong for their condition, or their aggressive behaviour gets them into trouble with the law, and rather than being diagnosed with a biochemical problem, they are regarded as criminals.

Though serotonin is thought of as the ‘happiness’ neurotransmitter, there’s a lot of evidence that dopamine is more important to happiness in bipolar than serotonin. Low serotonin levels tend to cause OCD and may be involved in aggression. SSRIs can trigger manic episodes in people with bipolar disorder, however. This may actually be because they cross react somewhat with dopamine receptors. Serotonin has multiple different purposes in the brain, and seems to be more of a regulator than a happy/sad neurotransmitter. We have recently observed in the media, the revelation that SSRI’s don’t actually help depression in most people. McManamy makes a very good argument as to why it is dopamine, not serotonin, that we need to worry about in bipolar disorder. Perhaps we need to re-examine our fixation with serotonin.

Raising GABA levels

Ultimately, the way to fix bipolar disorder is to raise GABA levels.

Firstly, a ketogenic diet or low carbohydrate diet can do this. This creates ketones, and the ketones increase several calming neurotransmitters in the brain, particularly GABA levels. This is why a ketogenic diet can help people with epilepsy, which is also caused by too much glutamate/too little GABA.

You can induce some of the effects of a ketogenic diet without having to be on one by taking vinegar. Believe it or not, the main ketone produced on a low carb diet is acetic acid, i.e. vinegar. A tablespoon or two of vinegar before every meal actually produces similar effects to low carbing, and will raise your GABA levels. Unfortunately vinegar is digested and destroyed very quickly, so the effect doesn’t last very long.

Valproate (valproic acid) works on bipolar disorder because it is very, very similar in structure to vinegar and ketones. It’s rather more potent because it takes the body longer to break it down than ketones or vinegar.

Alcohol is similar in structure to acetic acid and has a similar action on the body in that it raises GABA levels. It usually contains lots of impurities that can also make things worse, however, and its effect is very short-lived, and the alcohol withdrawal can actually make you feel worse. If you drink, you need to be very careful about how much you drink, what you drink, and you need to drink regularly, for example, one measure every evening, and be very self-controlled. I would stick to whisky, vodka or gin as they don’t contain the harmful impurities that are problematic for failsafers. Wine and beer contain amines, glutamates, salicylates and SLAs.

A natural alternative to valproate that you can buy in the shops, is the herb valerian, which contains valeric acid. All herbs come with some risk and side effects, but valerian is known to increase GABA in the same way as vinegar and valproate, again, having a very similar structure. A popular over the counter remedy you can get from most pharmacies is ‘Kalms’, and this contains valerian. Take the Kalms Stress version, and avoid the Kalms Sleep version, unless you want to, uh, fall asleep and get a hangover. If you take valerian, you must not under any circumstances get pregnant, as it is similar in structure to valproate, which can cause deformaties and some types of autism in foetuses.

You can actually obtain GABA itself online, though you have to order it from America because it’s illegal to sell in the UK. I have tried taking GABA, though not recently. I found it gave me very vivid dreams.

Another alternative is glutamine, an amino acid that opposes glutamate. The brain makes GABA from glutamate, glucose, and glutamine. You don’t always want to oppose glutamate, but I find it very helpful if I am grumpy or sugar-craving after meals. Theanine is another amino acid with a similar effect. It is found in tea, which is why tea makes you feel calm (however, tea also contains salicylates which will have longer lasting adverse effects).

A secondary regulatory neurotransmitter that interacts with GABA and that might help is taurine.

Two other herbal remedies that raise GABA by rather complicated drug-like actions are kava kava, and scullcap/skullcap.

There is a strong possibility that herbal remedies will make you feel hungover. I would test them all one at a time and see how they make you feel. Don’t take ten things at once!

Calcium is also thought to raise GABA levels through ion channel signalling mechanisms, though it will also raise glutamate levels and dopamine levels. Magnesium opposes the effects of calcium on glutamate. I tend to take calcium when I want to stay awake, use my brain, and extend my attention span, and magnesium when I need to sleep. Do not underestimate the usefulness of calcium! It can make a big difference to your mental state.

Allegedly, if you have the patience for it, relaxation techniques like yoga and meditation can also raise GABA levels. This is probably why perennially moody stars like Madonna and Gwyneth Paltrow witter on about yoga so much. I find that going and sitting somewhere dark and quiet and reciting a mantra/some lyrics/some poetry in my head can help calm me down sometimes.

Lowering glutamate levels

Mania and hypomania aren’t just characterised by happiness, they are also characterised by irritation and anger. As I mentioned, this is because high dopamine levels can convert easily to the closely related neurotransmitter, adrenaline. When you are feeling angry and stressed, this is as much a sign of mania as happiness is. Mania symptoms also include having a racing brain, feeling as though your thoughts are very intelligent and well-crafted, having insomnia, having nightmares and poor sleep, waking too early feeling fantastic, and buzzing about the place feeling really hyperactive.

Vitamin K actually protects against high glutamate levels and helps the body to use up excess glutamate by converting it into the bone-building/clotting protein GLA. I find it very useful for calming me down, helping me sleep, and stopping me from feeling angry. The type of vitamin K you need is a version called K2. I use a Vitamin Research Products brand, which is ideal as you can open the capsule and portion out smaller doses. You can buy it online in the UK from nutricentre. It might make you quite sleepy if you overdo it, but it is very valuable to have around as it works quite quickly. Don’t take it for an extended period though (i.e. every day for a week), as you may give yourself a cold or unbalance your mood in other ways by inducing vitamin A and vitamin D deficiency, which are used up by the same bone-building processes.

Theoretically, B6 should help you to lower glutamate by converting it into GABA. Unfortunately I find it gives me brain fog – perhaps because it lowers glutamate too much.

Raising glutamate levels

You should only ever try to raise glutamate levels when you have brain fog, hangover symptoms, and you can’t wake up in the mornings, otherwise there will be trouble!

I find the best thing is a dose of B12. I use a Metabolics brand ‘adenosylcobalamin’ product, also available from nutricentre. It will make you feel much better, but you should never take a whole capsule as it can trigger mania, anger, and insomnia. I also get strange trapped nerve sensations in my shoulders and neck if I take too much. I take the tiniest sprinkle I can, and even that can make my heart pound sometimes.

Some people find that folic acid is also useful. It depends on your genes. I would only take very small doses (50-100mcg, a quarter to half a tablet) to trial it, as it triggers hypomania and dependence in me very easily. I find I tend to need increasing doses each day to stay free of brain fog and then have an awful comedown if I stop taking it. It might be useful in a very, very small dose.

It is easy to overdo these supplements, so remember that you can calm down high glutamate levels with vitamin K. You might end up falling asleep at your desk though! It’s always best to err on the side of caution with these supplements.

Raising dopamine levels

This would be useful if you are having concentration problems or feel like you don’t care about doing anything. Calcium supplements are supposed to increase dopamine levels. I do find that a glass of goat’s milk helps me to concentrate on my writing.

Avoiding neurotransmitters in foods

There came a point in my late 20’s when a low carbohydrate diet just wasn’t having a strong enough effect on me anymore, and I started going downhill again until I found the failsafe diet. It IS very important to avoid neurotransmitters in foods, be they amines or glutamates. Salicylates mess with dopamine levels, trigger a type of glutamate receptor called an NMDA receptor that is thought to be involved in depression, and inhibit GABA production by blocking calcium ion channels. Salicylates tend to cause brief happy-high feelings just after you eat them, then cause depression, ADHD and brainfog the next day. While ever your GABA levels are too low, neurotransmitters in foods will just send you whatever which way they can, so you will always be up/down/angry/confused.

The worst offending foods are chocolate, cheese, pork, tomato, citrus fruits, grapes, other tropical fruits, broccoli and dark leafy greens. You must avoid all the listed additives, especially colourings and flavourings and (obviously) MSG and flavour enhancers because they will give you ADHD and contribute to depression. Check the food labels of everything before you buy it, including vitamins. They are sneaky and get everywhere. Better still, don’t buy food that’s in packages, it’s always got some crap in it.

It’s also rather important to avoid caffeine. Caffeine is a weak substitute for dopamine and adrenaline. It affects me in the same way as folic acid, and I need increasing amounts to stay free of brain fog and feel like I can wake up in the mornings. The adrenaline it creates will contribute to you feeling angry and stressed.

Ultimately, if you have bipolar disorder, the drugs you will be prescribed are lithium, valproate, or lamotrigine. They do help. Sometimes there is no natural solution. If you do not have the self control to manage your problems with the methods I describe above, you NEED to be on prescription drugs for your own safety.

Written by alienrobotgirl

29 October, 2008 at 8:47 pm

Posted in Neurotransmitters

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Why Britney is manic?

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If anyone reading this blog is remotely interested in the car-crash life of Britney Spears, here’s a little insight for you:

Britney admitted to to the doctors that she was on ADD medication Adderall, aka cocaine in a pill, and was taking up to ten laxatives a day. Perez Hilton

Adderall is an ADHD medication. Technically it’s speed in a pill, not cocaine. Here’s what it does:

Amphetamines, both as dextroamphetamine and levoamphetamine (or a racemic mixture of the two enantiomers), are believed to exert its [sic] effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine and serotonin.

[...]

Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase A and B (MAO-A and MAO-B) in high doses. MAO-A is responsible for the break down of serotonin, dopamine, norepinephrine and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to amphetamine itself and is thought to be involved in feelings of lust, confidence, obsession and sexuality. Adderall

A side effect of adderall is weight loss, probably why Britney has been taking it, as she has struggled with her weight since her first pregnancy.

Adderall increases dopamine: great if you have a DRD4 polymorphism that leaves you with low dopamine levels. Not so great if you are bipolar as a result of high dopamine levels.

What does the FDA say about amphetamines and bipolar disorder?

The FDA also warned that stimulant therapy can exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorders.

Amphetamines should be used with caution in attention-deficit/hyperactive disorder patients with comorbid bipolar disorder because of the potential risk for induction of a mixed/manic episode. Pretreatment screening should therefore also include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Also, psychotic/manic symptoms (eg, hallucinations, delusional thinking, and mania) have been reported at normal amphetamine doses in children and adolescents without prior history of these conditions. Data from a pooled analysis of multiple short-term studies have revealed an incidence rate for these events of 0.4% in methylphenidate- or amphetamine-treated patients compared with 0% for those receiving placebo. A potential causal role for the stimulant should be considered in patients who develop symptoms of psychosis or mania; discontinuation of therapy may be indicated. Medscape Today

Whoever prescribed Britney amphetamines deserves to be struck off. I feel very sorry for her right now.

Edit: more on Britney. Risperdal and Seroquel are both prescribed to people with bipolar disorder and schizophrenia, and they have some really unpleasant side effects – like diabetes. Both currently have class action lawsuits underway against them. Risperdal is a dopamine blocker. Who the heck prescribes Risperdal and Adderall in the same patient?

Written by alienrobotgirl

31 January, 2008 at 8:19 pm

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Melatonin and seizures

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‘m very excited about being able to get hold of some melatonin. As such here are some interesting articles on the subject.

In this study, published in the journal Neurology, the levels of melatonin in the saliva of 11 people with epilepsy and 6 people without epilepsy were studied.

Two major differences were discovered between the two groups. The melatonin levels of people with epilepsy were low – about half of the level of those without epilepsy. In addition, melatonin levels in people with epilepsy peaked at around 11pm, three hours earlier than the peak of those without the condition.

However, following a seizure, melatonin levels tripled, to more than 60 per cent higher than the levels of those without epilepsy.

The findings suggest that the taking of melatonin supplements could help control seizure activity as well as help regulate sleep in people with epilepsy. Low Melatonin Associated with Uncontrolled Seizures

This is an interesting article: Patients with Epilepsy Increasingly Embrace Alternative and Complementary Medicines. A shame Dr Pearl of the Epilepsy Foundation takes such a conservative viewpoint. Lumping “vitamins and herbs” under a generalised “unproven” category is misleading and smacks of laziness in research. There are some extremely useful and clearly proven orthomolecular remedies for epilepsy. For example GABA, taurine and DMG/TMG. Valeric acid, an acid found in valerian, is known to act on GABA levels and is virtually identical to valproic acid (sodium valproate). The kavalactones in kava kava also have clear antiseizure effects based on the evidence available in PubMed. One of the weirdest things about the above article is that it fails to report a large number of studies that are very easy to look up.

Melatonin supplementation may be helpful in treating epilepsy; 5–10 mg of melatonin taken at bedtime reduced the frequency of seizures and improved sleep in a group of children with epilepsy in a small, preliminary trial.22 However, in a group of children suffering from neurological disorders, 1–5 mg of melatonin per night led to an increase in the rate of seizures.23 Children with a seizure disorder called “myoclonus” were reported to have been cured by supplementing with 3–5 mg of melatonin per day in a preliminary trial.24 Until more is known, children with neurological conditions should take melatonin only under medical supervision. Melatonin HealthNotes

Melatonin is only suitable for some types of seizures, as I’ve discussed before, and knowing which type is which is currently more of an art than a science. Successful treatment of non-epileptic myoclonus in children with melatonin [pdf], however, is encouraging because the mechanisms of non-epileptic and epileptic myoclonus are said to be similar if not identical.

A certain kind of cherry (Montmorency cherries) contain melatonin. At 13.5 nanograms per gram, that means 0.0135 micrograms per gram of cherries. The minimum effective dose of melatonin is 300 micrograms. Which means you’ll have to get through 22222.22 grams of cherries. Walnuts contain 2.5 to 4.5 nanograms per gram. Feverfew, St. John’s Wort, and Chinese scullcap or skullcap, and cannabis also contain melatonin. Other foods (anecdotally) said to be high in melatonin include bananas, ginger, tomatoes, corn, cucumber, beetroots and rice (I wonder if that explains why I get whacky dreams when I eat most forms of rice?).

MAO inhibitors may also increase melatonin due to increased levels of serotonin, at the risk of increased levels of all amines. This throws a new light on thiamin, thought to be a natural MAOI. Taking melatonin in the morning wakes one up. Taking melatonin in the evening sends one to sleep. Could it be that our problems with thiamin were caused because it was being taken in the morning? I’ve read some information that thiamin is good for epilepsy: perhaps if it was being taken at night?

Milk is another option. Milk naturally contains melatonin, which is part of the reason it helps us to sleep. Melatonin levels in milk are determined by many factors such as breed, and largely by when the cow is milked: traditional milking just before dawn leads to higher melatonin levels in the milk. Apparently “Night Time Milk” is available from some Sainsburys, Tescos and Waitrose stores.

For those suffering food chemical intolerances who have disturbed sleep patterns or become anxious without milk, melatonin could well be a trigger. Milk is best drunk an hour or two before bedtime.

Written by alienrobotgirl

10 May, 2006 at 11:46 am

Posted in Neurotransmitters

GABA transaminase

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Remember our friend valproic acid, the anti-seizure medication that is very similar in structure to acetone and acetic acid, the ketones that are raised on the ketogenic diet?

Modern medicine has been puzzled for a long time about how valproic acid works, but it turns out it works by blocking GABA transaminase, the enzyme that converts GABA into other substances. Vigabatrin is another anti-seizure drug that blocks GABA transaminase. It is a GABA analog that doesn’t bind to GABA receptors, only to GABA transaminase, thereby lowering free GABA transaminase activity.

An alternative name for valproic acid is 2-propylpentanoic acid or dipropylacetic acid. Also, aminooxyacetic acid and ethanolamine-O-sulfate are both reversible GABA transaminase inhibitors. Aminooxyacetic acid is just acetic acid with a nitrogen atom attached. I’m certain sooner or later that it will be discovered that acetic acid and acetone are GABA transaminase inhibitors.

This isn’t the only way the ketogenic diet works though. The brain works hard to keep blood sugar levels in the brain high, but the body’s levels of blood sugar are lowered. This, with the aide of an amino acid called alanine, helps to dispose of excess glutamic acid that has built up, the excitory neurotransmitter that stands in opposition to GABA.

The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy.

Dahlin M, Elfving A, Ungerstedt U, Amark P.

Department of Pediatrics, Astrid Lindgren Children’s Hospital, Karolinska Hospital, SE-171 76 Stockholm, Sweden. maria.dahlin@karolinska.se

The ketogenic diet (KD) is an established treatment for medically refractory pediatric epilepsy. Its anticonvulsant mechanism is still unclear. We examined the influence of the KD on the CSF levels of excitatory and inhibitory amino acids in 26 children (mean age 6.1 years) with refractory epilepsy. Seventeen amino acids were determined before and at a mean of 4 months after the start of the KD. Seizures were quantified. Highly significant changes were found in eight amino acids: increases in GABA, taurine, serine, and glycine and decreases in asparagine, alanine, tyrosine and phenylalanine. However, aspartate, glutamate, arginine, threonine, citrulline, leucine, isoleucine and valine/methionine remained unchanged. A significant correlation with seizure response was found for threonine (P=0.016). The GABA levels were higher in responders (>50% seizure reduction) than in nonresponders during the diet (P=0.041). In the very good responders (>90% seizure reduction), the GABA levels were significantly higher at baseline as well as during the diet. Age differences were found with significantly larger decreases in glutamate and increases in GABA in connection with the diet in younger children. Our results indicate that the KD significantly alters the levels of several CSF amino acids that may be involved in its mechanism of action and the increase in GABA is of particular interest. PubMed

This is what happens to one’s neurotransmitters on the ketogenic diet:

UP:

  • GABA
  • taurine
  • serine
  • glycine

DOWN:

  • asparagine
  • alanine
  • tyrosine
  • phenylalanine

SAME:

  • aspartate
  • glutamate
  • arginine
  • threonine
  • citrulline
  • leucine
  • isoleucine
  • valine/methionine

The great thing is that it really works. I had forgotten just how good it feels to be in ketosis (I even have ketostix that are showing moderate ketones, so I’m actually wasting some calories). You just feel calm, calm, calm. The problem is sticking to it. One small deviation (like a pear, for example), can bring on a seizure in someone with severe epilepsy.

Written by alienrobotgirl

9 May, 2006 at 12:19 pm

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Nocturnal seizures revisited

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I wrote a brief article about coping strategies for nocturnal seizures not too long ago. There is a lot of contradictory information about the role of melatonin in seizures. I guess it serves me right for taking advice from an epilepsy charity website.

Some seizures are made less likely by melatonin. Other seizures are made more likely. The situation is confused. In some situations, melatonin appears to inhibit GABA. In others, it seems to enhance its action. Why? I am interested in finding out whether Juvenile Myoclonic Epilepsy (JME) is helped or hindered by melatonin production. If you have a seizure at night, is it automatically a “nocturnal seizure”? No, not necessarily. A nocturnal seizure would take place during sleep. JME is a condition where seizures are more likely just as you are falling asleep, but seizures are less likely during sleep. So might melatonin actually help? This is an interesting article about melatonin (free, but you have to register).

What we can say about JME is that it appears to be worsened by serotonin intoxication. Serotonin is a precursor for melatonin. Is it an antagonist? An agonist? Unrelated? Who knows?

Written by alienrobotgirl

7 May, 2006 at 3:16 pm

Posted in Neurotransmitters

Nocturnal seizure coping strategies

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I’ve read five abstracts now on pubmed that all say melatonin (the sleep hormone) depresses GABA receptor function and is probably responsible for some forms of nocturnal seizures. It also seems to inhibit dopamine, which also leads to increased likelihood of seizures. Dopamine is the ‘happy’ or ‘reward’ neurotransmitter.

The simplest way to decrease melatonin is to leave a light on at night. Epilepsy charities say “It has been suggested in the past that sleeping with the light on and with a ticking clock or radio in the room may also decrease the tendency toward seizing. This is at least worth a trial.”

However melatonin attenuates seizures in some people, particularly in those with myoclonus, so decreasing melatonin can also make seizures more likely. The key seems to be to figure out what kind of seizures you are having and whether they are melatonin responsive.

I quote from Wikipedia: “When a subject is deprived of sleep and is trying to fight sleep, hypnic jerks can occur more often. This normally happens after the subject has successfully deprived themselves of sleep for longer than 24 hours.” Myoclonus seems to have a complicated relationship with melatonin.

Mozart helps prevent seizures. It seems particular characteristics of Mozart and Bach decrease seizure activity by training the temporal/spacial part of the brain that misbehaves during seizures. Interestingly, music also increases dopamine levels. The music is quite a ‘happy’ piece.

Seizure potential can also be attenuated by weak magnetic fields. There are quite a few studies that suggest that sudden geomagnetic fluctuations can cause seizures – one study found that around 10-12% of seizures in lab rats could be blamed on geomag fluctuations. Presumably a weak magnetic field near your head will mask the impact of any sudden changes and prevent this.

Written by alienrobotgirl

10 April, 2006 at 5:30 pm

Posted in Neurotransmitters

Antiseizure approaches

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I’ve been compiling a list of ‘natural’ anticonvulsants.

  • Active vitamin B6 (P5P/PLP/Pyridoxal 5 Phosphate/Pyridoxal Phosphate) is a cofactor in the synthesis of GABA from glutamate.
  • Ketones including acetone, acetoacetate, beta-hydroxybutyrate and dibenzylamine all demonstrate anticonvulsant activity and are the basis of the ketogenic diet (those last two are intruiging considering their nature, but benzodiazepines are anticonvulsants too).
  • DMG, aka dimethyl glycine.
  • Alcohol, which is broken down in the body into acetaldehyde and then to acetic acid has anticonvulsant effects when it is drunk, but can increase risk of convulsions during withdrawal.
  • Ferula gummosa Boiss is an Iranian herb containing acetone.
  • The herb valerian, containing valeric acid, similar in structure to valproic acid, an anticonvulsant, also similar in structure to acetic acid.
  • Also, certain B vitamins, taurine, glycine, alanine, calcium, vitamin D, vitamin E, magnesium, manganese, selenium, zinc, coleus forskohlii, hyssop, black cohosh, blue cohosh, lobelia, saiko-Keishi-To.

According to the stuff I’ve seen in pubmed, the longer the chronic administration of acetone continues, the less likely it is that seizures will occur. This confirms the claims of parents who put their kids on the ketogenic diet and eventually see recovery that allows a return to a normal diet.

I don’t think there is any difference between taking herbs and taking pharmaceuticals, so you may as well take pharamaceuticals. Though inhibitory nutrients and a ketogenic diet do have the potential to bypass some of the unpleasant side effects that epilepsy drugs can have.

Written by alienrobotgirl

7 April, 2006 at 10:27 am

Posted in Neurotransmitters

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