The Partly Asleep Brain

Some animals - such as dolphins and whales - are able to "sleep with half their brain". One side of the brain goes into sleep-mode activity while the other remains awake.


But a remarkable new study has revealed that something similar may happen in humans as well - every night.

The research used a combination of scalp EEG, and electrodes planted inside the brain, to record brain activity from 5 people undergoing surgery to help cure severe epilepsy. The subjects were then allowed to go to sleep for the night, while recording took place.

As expected, after falling asleep, the EEG showed delta wave activity - strong, slow waves of electrical activity (0.5 to 4 Hz) which are typical of deep, dreamless "slow wave sleep".

However, the electrodes inside the brain told a different story. While they recorded delta waves most of the time, they also showed that there were episodes, lasting from a few seconds to up to 2 minutes, in which the motor cortex suddenly went into "waking mode". Delta waves disappeared, and were replaced with fast, unpredictable activity.

This image shows one episode, lasting just 5 seconds. The hotter the color, the more activity in a particular frequency. The higher the band, the higher the frequency. This shows a clear burst of high frequency activity in the motor cortex. The other parts of the brain showed the opposite effect - even stronger slow wave activity - at the same time.

Another area, the dorsolateral prefrontal cortex, also showed this phenomenon occasionally, but it was much less common than in the motor cortex.

There's a few caveats. These patients had severe epilepsy, and they were taking anti-convulsant drugs. This wouldn't obviously create the effects seen here, but we can't rule it out. Still, these results are intriguing.

They challenge the view of slow wave sleep as a "whole brain" phenomenon. We've known for a while that this isn't true of animals, and in people with certain sleep disorders, but this is first demonstration in healthy humans.

It may help to explain the mysterious fact that, although slow wave sleep is often referred to as "dreamless", there are consistent reports that people woken up from this phase of sleep do report dreaming (or at least thinking) about things.

While episodic arousal of the motor cortex probably wouldn't explain this per se, if the same thing happens in the visual cortex or other sensory areas, it might create dreams.

Nobili L, Ferrara M, Moroni F, De Gennaro L, Russo GL, Campus C, Cardinale F, & De Carli F (2011). Dissociated wake-like and sleep-like electro-cortical activity during sleep. NeuroImage PMID: 21718789

The Partly Asleep Brain

Some animals - such as dolphins and whales - are able to "sleep with half their brain". One side of the brain goes into sleep-mode activity while the other remains awake.


But a remarkable new study has revealed that something similar may happen in humans as well - every night.

The research used a combination of scalp EEG, and electrodes planted inside the brain, to record brain activity from 5 people undergoing surgery to help cure severe epilepsy. The subjects were then allowed to go to sleep for the night, while recording took place.

As expected, after falling asleep, the EEG showed delta wave activity - strong, slow waves of electrical activity (0.5 to 4 Hz) which are typical of deep, dreamless "slow wave sleep".

However, the electrodes inside the brain told a different story. While they recorded delta waves most of the time, they also showed that there were episodes, lasting from a few seconds to up to 2 minutes, in which the motor cortex suddenly went into "waking mode". Delta waves disappeared, and were replaced with fast, unpredictable activity.

This image shows one episode, lasting just 5 seconds. The hotter the color, the more activity in a particular frequency. The higher the band, the higher the frequency. This shows a clear burst of high frequency activity in the motor cortex. The other parts of the brain showed the opposite effect - even stronger slow wave activity - at the same time.

Another area, the dorsolateral prefrontal cortex, also showed this phenomenon occasionally, but it was much less common than in the motor cortex.

There's a few caveats. These patients had severe epilepsy, and they were taking anti-convulsant drugs. This wouldn't obviously create the effects seen here, but we can't rule it out. Still, these results are intriguing.

They challenge the view of slow wave sleep as a "whole brain" phenomenon. We've known for a while that this isn't true of animals, and in people with certain sleep disorders, but this is first demonstration in healthy humans.

It may help to explain the mysterious fact that, although slow wave sleep is often referred to as "dreamless", there are consistent reports that people woken up from this phase of sleep do report dreaming (or at least thinking) about things.

While episodic arousal of the motor cortex probably wouldn't explain this per se, if the same thing happens in the visual cortex or other sensory areas, it might create dreams.

Nobili L, Ferrara M, Moroni F, De Gennaro L, Russo GL, Campus C, Cardinale F, & De Carli F (2011). Dissociated wake-like and sleep-like electro-cortical activity during sleep. NeuroImage PMID: 21718789

Gamma Waves: The Brain's Clock, Or Neural Noise?

Gamma waves are very hot at the moment.


Gamma band activity is a term for electrical oscillations recorded from the brain that have a frequency of over 25 Hz. In most brains, a peak frequency of about 40 Hz is seen. This makes gamma waves the fastest brain waves.

If you believe some recent claims, gamma waves are the answer to all the mysteries of life and the universe. They're said to underlie the symptoms of schizophrenia and autism, and they've been invoked to answer deep questions such as the binding problem and maybe conciousness itself. You can even buy a Nintendo game that promises to boost them.

A new paper from Burns et al casts doubt on all of these grand claims. Gamma-based theories of brain function all assume that gamma waves act a bit like a clock, with a consistent rhythm of about 40 Hz. Activity of about 40 Hz is indeed observed in brain recordings but is that just because the brain is randomly generating all kinds of signals, and only the 40 Hz ones "get through"?

To put it another way, imagine that you got a letter in the mail at 9 am every morning. That could be because someone is sending you one letter each day like clockwork. But it could also be that loads of people are sending you letters at random times, and your mailman only has room in his sack to deliver one each morning.

Here's the key data, recorded using electrodes implanted into the brains of two male macaque monkeys:


This shows that the monkey data closely resemble what you'd expect if gamma activity were filtered noise, and are not what you'd see if it were a more meaningful "clock". The "triangle" on the graph shows the number of bursts of a given frequency and duration.
The data also show that the phase of the gamma activity isn't consistent, which it would be if it were clocklike. In fact, the phases change entirely randomly.

So if gamma is just "filtered noise", what's the "filter"? Why 40 Hz, not 80 or 4000? Probably because this is just the maximum frequency at which neurons can fire. It takes a certain finite amount of time for cells to communicate with each other: a silicon chip can get a clock speed of many billions of hertz, but a cell just physically can't.

There's a catch, though. These monkeys were asleep, anaesthetized with the powerful opiate sufentanil. This is a good choice of drug: unlike most other sedatives and anaesthetics, you wouldn't expect an opiate to directly affect gamma oscillations. But still. If you believe that coherent gamma waves are the key to high-level concious experience, as many do, you might not expect to see much of that in the primary visual cortex in asleep animals.

However, this is clearly a very important issue, and it's not the first gamma-skeptic paper. In 2008, Yuval-Greenberg et al reported that many attempts to measure gamma activity using EEG were contaminated by electrical activity from scalp muscles. Rather than coming from the brain, the "gamma" activity reflected nothing more than tiny eye movements. The implications are still being debated.

This paper attacks the gamma hypothesis from a completely different angle, saying that even the "real" gamma in the brain, may be nothing more interesting than filtered noise.

Burns SP, Xing D, & Shapley RM (2011). Is gamma-band activity in the local field potential of v1 cortex a "clock" or filtered noise? The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (26), 9658-64 PMID: 21715631

Gamma Waves: The Brain's Clock, Or Neural Noise?

Gamma waves are very hot at the moment.


Gamma band activity is a term for electrical oscillations recorded from the brain that have a frequency of over 25 Hz. In most brains, a peak frequency of about 40 Hz is seen. This makes gamma waves the fastest brain waves.

If you believe some recent claims, gamma waves are the answer to all the mysteries of life and the universe. They're said to underlie the symptoms of schizophrenia and autism, and they've been invoked to answer deep questions such as the binding problem and maybe conciousness itself. You can even buy a Nintendo game that promises to boost them.

A new paper from Burns et al casts doubt on all of these grand claims. Gamma-based theories of brain function all assume that gamma waves act a bit like a clock, with a consistent rhythm of about 40 Hz. Activity of about 40 Hz is indeed observed in brain recordings but is that just because the brain is randomly generating all kinds of signals, and only the 40 Hz ones "get through"?

To put it another way, imagine that you got a letter in the mail at 9 am every morning. That could be because someone is sending you one letter each day like clockwork. But it could also be that loads of people are sending you letters at random times, and your mailman only has room in his sack to deliver one each morning.

Here's the key data, recorded using electrodes implanted into the brains of two male macaque monkeys:


This shows that the monkey data closely resemble what you'd expect if gamma activity were filtered noise, and are not what you'd see if it were a more meaningful "clock". The "triangle" on the graph shows the number of bursts of a given frequency and duration.
The data also show that the phase of the gamma activity isn't consistent, which it would be if it were clocklike. In fact, the phases change entirely randomly.

So if gamma is just "filtered noise", what's the "filter"? Why 40 Hz, not 80 or 4000? Probably because this is just the maximum frequency at which neurons can fire. It takes a certain finite amount of time for cells to communicate with each other: a silicon chip can get a clock speed of many billions of hertz, but a cell just physically can't.

There's a catch, though. These monkeys were asleep, anaesthetized with the powerful opiate sufentanil. This is a good choice of drug: unlike most other sedatives and anaesthetics, you wouldn't expect an opiate to directly affect gamma oscillations. But still. If you believe that coherent gamma waves are the key to high-level concious experience, as many do, you might not expect to see much of that in the primary visual cortex in asleep animals.

However, this is clearly a very important issue, and it's not the first gamma-skeptic paper. In 2008, Yuval-Greenberg et al reported that many attempts to measure gamma activity using EEG were contaminated by electrical activity from scalp muscles. Rather than coming from the brain, the "gamma" activity reflected nothing more than tiny eye movements. The implications are still being debated.

This paper attacks the gamma hypothesis from a completely different angle, saying that even the "real" gamma in the brain, may be nothing more interesting than filtered noise.

Burns SP, Xing D, & Shapley RM (2011). Is gamma-band activity in the local field potential of v1 cortex a "clock" or filtered noise? The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (26), 9658-64 PMID: 21715631

Consciousness? FFS...

An interesting paper on the neurobiology of conscious awareness: Unconscious High-Level Information Processing.


The authors propose that consciousness may be associated, not with activation in any given area of the brain, but with recurrent information processing between areas, a kind of neural ping-pong.

When presented with sensory information, say the sight of an object, signals travel up through the brain from "primary" sensory areas to "higher" areas associated with more complicated processing. They call this the Fast Feedforward Sweep, or "FFS". Maybe not the best acronym.

Anyway, depending on the nature of the stimulus, this can lead to activation in almost any part of the brain. However, they say that it's not enough to generate consciousness; only if the later areas feedback to the earlier areas, and start a recurrent processing loop, does this happen.

This stands in contrast to the popular view, which seems to fit with common sense, that primary areas are unconscious and that consciousness is directly associated with activity in the higher areas, in particular, the prefrontal cortex (PFC).

The authors refer to fMRI and EEG studies showing that even "high level" processes, such as selective attention to stimuli, and inhibition of an action, can be triggered by subconscious cues, and that this is associated with activation in the prefrontal cortex - unconscious activation.

The details of these studies are fairly arcane but the point is that the prefrontal cortex is generally agreed to be the most developed, "highest level" part of the brain. If anywhere in the brain was going to be the seat of the soul, it's the PFC.


This shouldn't come as a surprise, though. While it's tempting to look for a part of the brain which "does" conscious experience - the "me module" - Daniel Dennet pointed out a while ago that this temptation is motivated by a fundamental confusion.

Likewise, while it seems common sense that conciousness is the "highest mental function" and therefore must be located in the highest brain area, this is a presumption: consciousness is a mystery, and we don't know if it's a high level function or not, or whether that question even makes sense.

Nor should the fact that consciousness isn't an inevitable consequence of high-level cognition come as a shock: in fact, that would be impossible. As Ryle pointed out in The Concept of Mind, this would create an infinite regression. Any conscious experience has to come from somewhere.

Right now I'm concious of choosing certain words rather than others in typing this post, in a conscious attempt to make it read better. But I'm not aware of all of the rules and experiences that guide my choices. I just feel that some words work. This feeling seems to come out of nowhere, or rather, out of the words themselves.

It isn't, of course, it's a product of calculations taking place in my brain, but I've no idea what they are. I wouldn't want to be, either: I'm too busy typing.

van Gaal S, & Lamme VA (2011). Unconscious High-Level Information Processing: Implication for Neurobiological Theories of Consciousness. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry PMID: 21628675

Consciousness? FFS...

An interesting paper on the neurobiology of conscious awareness: Unconscious High-Level Information Processing.


The authors propose that consciousness may be associated, not with activation in any given area of the brain, but with recurrent information processing between areas, a kind of neural ping-pong.

When presented with sensory information, say the sight of an object, signals travel up through the brain from "primary" sensory areas to "higher" areas associated with more complicated processing. They call this the Fast Feedforward Sweep, or "FFS". Maybe not the best acronym.

Anyway, depending on the nature of the stimulus, this can lead to activation in almost any part of the brain. However, they say that it's not enough to generate consciousness; only if the later areas feedback to the earlier areas, and start a recurrent processing loop, does this happen.

This stands in contrast to the popular view, which seems to fit with common sense, that primary areas are unconscious and that consciousness is directly associated with activity in the higher areas, in particular, the prefrontal cortex (PFC).

The authors refer to fMRI and EEG studies showing that even "high level" processes, such as selective attention to stimuli, and inhibition of an action, can be triggered by subconscious cues, and that this is associated with activation in the prefrontal cortex - unconscious activation.

The details of these studies are fairly arcane but the point is that the prefrontal cortex is generally agreed to be the most developed, "highest level" part of the brain. If anywhere in the brain was going to be the seat of the soul, it's the PFC.


This shouldn't come as a surprise, though. While it's tempting to look for a part of the brain which "does" conscious experience - the "me module" - Daniel Dennet pointed out a while ago that this temptation is motivated by a fundamental confusion.

Likewise, while it seems common sense that conciousness is the "highest mental function" and therefore must be located in the highest brain area, this is a presumption: consciousness is a mystery, and we don't know if it's a high level function or not, or whether that question even makes sense.

Nor should the fact that consciousness isn't an inevitable consequence of high-level cognition come as a shock: in fact, that would be impossible. As Ryle pointed out in The Concept of Mind, this would create an infinite regression. Any conscious experience has to come from somewhere.

Right now I'm concious of choosing certain words rather than others in typing this post, in a conscious attempt to make it read better. But I'm not aware of all of the rules and experiences that guide my choices. I just feel that some words work. This feeling seems to come out of nowhere, or rather, out of the words themselves.

It isn't, of course, it's a product of calculations taking place in my brain, but I've no idea what they are. I wouldn't want to be, either: I'm too busy typing.

van Gaal S, & Lamme VA (2011). Unconscious High-Level Information Processing: Implication for Neurobiological Theories of Consciousness. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry PMID: 21628675

Free Will Is In The Brain

Warning: this post may change your brain.


Well, all of my posts change your brain, because everything changes your brain. But this one might make a rather bigger impact than usual.

According to a new paper in Psychological Science, reading a short article which argues that free will is an illusion causes measurable changes in brain function: Inducing Disbelief in Free Will Alters Brain Correlates of Preconscious Motor Preparation.

The authors took 30 people and randomly assigned them to read one of two passages from this book. One of the quotes was a fairly forceful attack on the concept of free will, saying that all of our actions are determined by our genes and environment. The other, placebo extract, was the same length and talked about conciousness but made no reference to free will.

After that, all the volunteers were given EEG while performing the Libet Task. This was invented by the neuroscientist Benjamin Libet, and it's famous as evidence against free will. Basically, the task just involves pushing a button, and you can make an entirely free choice as to when to push it. You then report, with the help of a clock, the moment at which you decided to push it.

What Libet found, using EEG recording, was that there's an electrical change in the brain, a negative voltage called the readiness potential, which starts about 2 seconds before you move. However, most people report "deciding" to move just 200 milliseconds before the actual button click - long after "their brain decided to move", in terms of the readiness potential. Maybe.

Anyway, in the current study they found that reading about determinism reduced the size of the readiness potential, although it still happened:

So ironically, reading an argument against free will reduces the size of a phenomenon which is itself used as an argument against free will... it's enough to make your head spin. The authors say that this fits with earlier work showing that "The early RP...is restricted to movements that are executed with the 'introspective feelings of the willful realization of the intention to move at a particular time'."

This is interesting, but there's a few caveats. The result was nicely significant with a p value of 0.011, but we're not shown the data from individual participants, only the group averages so the effect might be driven by one or two outliers with huge or absent readiness potentials.

Also, it's possible that the effect wasn't about belief in free will as such, but just some kind of distraction. Maybe being confronted with the idea that free will is an illusion just shook the participants up and got them thinking hard, distracting them from the task. To their credit the authors did try to control for this by also measuring EEG responses to simple visual stimuli, finding no effect, but ideally I'd want to see a control consisting of a very controversial, non-free-will article.

In case you were wondering, here's the start of the readiness-potential-reducing passage:

“You,” your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules. Who you are is nothing but a pack of neurons.

Most religions hold that some kind of spirit exists that persists after one’s bodily death and, to some degree, embodies the essence of that human being. Religions may not have all the same beliefs, but they do have a broad agreement that people have souls. Yet the common belief of today has a totally different view. It is inclined to believe that the idea of a soul, distinct from the body and not subject to our known scientific laws, is a myth.

It is quite understandable how this myth arose without today’s scientific knowledge of nature of matter and radiation, and of biological evolution. Such myths, of having a soul, seem only too plausible. For example, four thousand years ago almost everyone believed the earth was flat. Only with modern science has it occurred to us that in fact the earth is round.

From modern science we now know that all living things, from bacteria to ourselves, are closely related at the biochemical level. We now know that many species of plants and animals have evolved over time. We can watch the basic processes of evolution happening today, both in the field and in our test tubes and therefore, there is no need for the religious concept of a soul to explain the behavior of humans and other animals...

It goes on, but I'll stop there... for the sake of your brain.

Rigoni D, Kühn S, Sartori G, & Brass M (2011). Inducing disbelief in free will alters brain correlates of preconscious motor preparation: the brain minds whether we believe in free will or not. Psychological science : a journal of the American Psychological Society / APS, 22 (5), 613-8 PMID: 21515737

Free Will Is In The Brain

Warning: this post may change your brain.


Well, all of my posts change your brain, because everything changes your brain. But this one might make a rather bigger impact than usual.

According to a new paper in Psychological Science, reading a short article which argues that free will is an illusion causes measurable changes in brain function: Inducing Disbelief in Free Will Alters Brain Correlates of Preconscious Motor Preparation.

The authors took 30 people and randomly assigned them to read one of two passages from this book. One of the quotes was a fairly forceful attack on the concept of free will, saying that all of our actions are determined by our genes and environment. The other, placebo extract, was the same length and talked about conciousness but made no reference to free will.

After that, all the volunteers were given EEG while performing the Libet Task. This was invented by the neuroscientist Benjamin Libet, and it's famous as evidence against free will. Basically, the task just involves pushing a button, and you can make an entirely free choice as to when to push it. You then report, with the help of a clock, the moment at which you decided to push it.

What Libet found, using EEG recording, was that there's an electrical change in the brain, a negative voltage called the readiness potential, which starts about 2 seconds before you move. However, most people report "deciding" to move just 200 milliseconds before the actual button click - long after "their brain decided to move", in terms of the readiness potential. Maybe.

Anyway, in the current study they found that reading about determinism reduced the size of the readiness potential, although it still happened:

So ironically, reading an argument against free will reduces the size of a phenomenon which is itself used as an argument against free will... it's enough to make your head spin. The authors say that this fits with earlier work showing that "The early RP...is restricted to movements that are executed with the 'introspective feelings of the willful realization of the intention to move at a particular time'."

This is interesting, but there's a few caveats. The result was nicely significant with a p value of 0.011, but we're not shown the data from individual participants, only the group averages so the effect might be driven by one or two outliers with huge or absent readiness potentials.

Also, it's possible that the effect wasn't about belief in free will as such, but just some kind of distraction. Maybe being confronted with the idea that free will is an illusion just shook the participants up and got them thinking hard, distracting them from the task. To their credit the authors did try to control for this by also measuring EEG responses to simple visual stimuli, finding no effect, but ideally I'd want to see a control consisting of a very controversial, non-free-will article.

In case you were wondering, here's the start of the readiness-potential-reducing passage:

“You,” your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules. Who you are is nothing but a pack of neurons.

Most religions hold that some kind of spirit exists that persists after one’s bodily death and, to some degree, embodies the essence of that human being. Religions may not have all the same beliefs, but they do have a broad agreement that people have souls. Yet the common belief of today has a totally different view. It is inclined to believe that the idea of a soul, distinct from the body and not subject to our known scientific laws, is a myth.

It is quite understandable how this myth arose without today’s scientific knowledge of nature of matter and radiation, and of biological evolution. Such myths, of having a soul, seem only too plausible. For example, four thousand years ago almost everyone believed the earth was flat. Only with modern science has it occurred to us that in fact the earth is round.

From modern science we now know that all living things, from bacteria to ourselves, are closely related at the biochemical level. We now know that many species of plants and animals have evolved over time. We can watch the basic processes of evolution happening today, both in the field and in our test tubes and therefore, there is no need for the religious concept of a soul to explain the behavior of humans and other animals...

It goes on, but I'll stop there... for the sake of your brain.

Rigoni D, Kühn S, Sartori G, & Brass M (2011). Inducing disbelief in free will alters brain correlates of preconscious motor preparation: the brain minds whether we believe in free will or not. Psychological science : a journal of the American Psychological Society / APS, 22 (5), 613-8 PMID: 21515737

Clever New Scheme

CNS Response are a California-based company who offer a high-tech new approach to the personalized treatment of depression: "referenced EEG" (rEEG).

This is not to be confused with qEEG, which I have written about previously. What is rEEG? It involves taking an EEG recording of resting brain activity and sending it - along with a cheque, naturally - to CNS Response, who compare it to their database of over 1,800 psychiatric patients who likewise had EEGs taken before they started on various drugs. They look to see which drugs worked best in people with an EEG profile similar to yours, and give you a fancy report with their recommendations.

That's not completely implausible. It could work. Does it? CNS Response and some academic collaborators have just published a paper saying yes: The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression. How solid is it? Well, it would be wrong to say that there are many problems with this study. But then if you run off a cliff and plummet into a volcano, you've only made one mistake.

Depressed patients were randomized to one of two groups: treatment-as-usual, which generally meant the common antidepressants bupropion, citalopram, or venlafaxine, vs. rEEG-guided personalized drug treatment. The trial was pretty large, with 114 patients randomized, and pretty long, 12 weeks. The patients had failed to respond to at least one antidepressant (mean: 1.5) during the current episode, so they were slightly "treatment-resistant", though not extremely so.

What happened? The rEEG-guided group did better on the QIDS16SR self-report scale, and on most other measures. Not enormously: take a look at the graph, notice that the vertical axis doesn't start at zero. But better.
Great, they did better. But why? The problem with this study is that the rEEG-guided group got a very different set of drugs to the control group. No less than 55% of them got stimulants, either methylphenidate (Ritalin) and dexamphetamine (speed). These drugs make you feel good. That's why they're illegal, that's why people pay good money for them on the street.

It's debatable whether stimulants are clinically useful as antidepressants in the long term, but they've got a good chance of making you feel nice for a few weeks, and make you say you feel better on a rating scale. Plus there's nothing like a pep pill to drive active placebo effects.

The authors say that "Almost all of the studies with depression not associated with medical disorders have reported minimal or no antidepressant effect of stimulants", and refer to some 1980s studies - yet their own trial has just shown that they do work in more than 50% of patients, and the latest Cochrane meta-analysis finds stimulants do work in the short term...

The other big names in the EEG group were MAOis (selegiline or tranylcypromine). These are often effective in treatment-resistant depression. Not necessarily more so than other drugs, but remember that these patients had already failed at least one SSRI(*). Yet the control group were, it seems, almost all given SSRIs - either citalopram, or venlafaxine, which is effectively an SSRI at low doses, e.g. the average dose used here, 141 mg. (It does other stuff, but only at higher doses of 225 mg or 300 mg.)

In summary, there were two groups in this trial and they got entirely different sets of drugs. One group also got rEEG-based treatment personalization. That group did better, but that might have nothing to do with the rEEG: they might have done equally well if they'd just been assigned to stimulants or MAOis etc. by flipping a coin. We cannot tell, from these data, whether rEEG offered any benefits at all.

What's curious is that it would have been very simple to avoid this issue. Just give everyone rEEG, but shuffle the assignments in the control group, so that everyone was guided by someone else's EEG. So you'd give control Patient 2 the drugs that Patient 1 should have got, and vice versa; swap 3 and 4, 5 and 6, etc.

This would be a genuinely controlled test of the personalized rEEG system, because both groups would get the same kinds of drugs. It would have been a lot easier too. For one thing it wouldn't require the additional step of deciding what drugs to give the control group. The authors decided to follow the STAR*D treatment protocol in this study, which is not unreasonable, but that must have been a bit of a hard decision.

Second, it would allow the trial to be double-blind: in this study the investigators knew which group people were in, because it was obvious from the drug choice. Thirdly, it wouldn't have meant they had to exclude people whose rEEG recommended they get the same treatment that they would have got in the control group... and so on.

Hmm. Mysterious. Anyway, we may be hearing more about CNS Response soon, so watch this space.

(*) - Technically, some of them had failed an SSRI and some had failed "2 or more classes of antidepressants", but one of those classes will almost certainly have been an SSRI, because they're the first-line treatment.

DeBattista, C., Kinrys, G., Hoffman, D., Goldstein, C., Zajecka, J., Kocsis, J., Teicher, M., Potkin, S., Preda, A., & Multani, G. (2010). The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression Journal of Psychiatric Research DOI: 10.1016/j.jpsychires.2010.05.009

Clever New Scheme

CNS Response are a California-based company who offer a high-tech new approach to the personalized treatment of depression: "referenced EEG" (rEEG).

This is not to be confused with qEEG, which I have written about previously. What is rEEG? It involves taking an EEG recording of resting brain activity and sending it - along with a cheque, naturally - to CNS Response, who compare it to their database of over 1,800 psychiatric patients who likewise had EEGs taken before they started on various drugs. They look to see which drugs worked best in people with an EEG profile similar to yours, and give you a fancy report with their recommendations.

That's not completely implausible. It could work. Does it? CNS Response and some academic collaborators have just published a paper saying yes: The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression. How solid is it? Well, it would be wrong to say that there are many problems with this study. But then if you run off a cliff and plummet into a volcano, you've only made one mistake.

Depressed patients were randomized to one of two groups: treatment-as-usual, which generally meant the common antidepressants bupropion, citalopram, or venlafaxine, vs. rEEG-guided personalized drug treatment. The trial was pretty large, with 114 patients randomized, and pretty long, 12 weeks. The patients had failed to respond to at least one antidepressant (mean: 1.5) during the current episode, so they were slightly "treatment-resistant", though not extremely so.

What happened? The rEEG-guided group did better on the QIDS16SR self-report scale, and on most other measures. Not enormously: take a look at the graph, notice that the vertical axis doesn't start at zero. But better.
Great, they did better. But why? The problem with this study is that the rEEG-guided group got a very different set of drugs to the control group. No less than 55% of them got stimulants, either methylphenidate (Ritalin) and dexamphetamine (speed). These drugs make you feel good. That's why they're illegal, that's why people pay good money for them on the street.

It's debatable whether stimulants are clinically useful as antidepressants in the long term, but they've got a good chance of making you feel nice for a few weeks, and make you say you feel better on a rating scale. Plus there's nothing like a pep pill to drive active placebo effects.

The authors say that "Almost all of the studies with depression not associated with medical disorders have reported minimal or no antidepressant effect of stimulants", and refer to some 1980s studies - yet their own trial has just shown that they do work in more than 50% of patients, and the latest Cochrane meta-analysis finds stimulants do work in the short term...

The other big names in the EEG group were MAOis (selegiline or tranylcypromine). These are often effective in treatment-resistant depression. Not necessarily more so than other drugs, but remember that these patients had already failed at least one SSRI(*). Yet the control group were, it seems, almost all given SSRIs - either citalopram, or venlafaxine, which is effectively an SSRI at low doses, e.g. the average dose used here, 141 mg. (It does other stuff, but only at higher doses of 225 mg or 300 mg.)

In summary, there were two groups in this trial and they got entirely different sets of drugs. One group also got rEEG-based treatment personalization. That group did better, but that might have nothing to do with the rEEG: they might have done equally well if they'd just been assigned to stimulants or MAOis etc. by flipping a coin. We cannot tell, from these data, whether rEEG offered any benefits at all.

What's curious is that it would have been very simple to avoid this issue. Just give everyone rEEG, but shuffle the assignments in the control group, so that everyone was guided by someone else's EEG. So you'd give control Patient 2 the drugs that Patient 1 should have got, and vice versa; swap 3 and 4, 5 and 6, etc.

This would be a genuinely controlled test of the personalized rEEG system, because both groups would get the same kinds of drugs. It would have been a lot easier too. For one thing it wouldn't require the additional step of deciding what drugs to give the control group. The authors decided to follow the STAR*D treatment protocol in this study, which is not unreasonable, but that must have been a bit of a hard decision.

Second, it would allow the trial to be double-blind: in this study the investigators knew which group people were in, because it was obvious from the drug choice. Thirdly, it wouldn't have meant they had to exclude people whose rEEG recommended they get the same treatment that they would have got in the control group... and so on.

Hmm. Mysterious. Anyway, we may be hearing more about CNS Response soon, so watch this space.

(*) - Technically, some of them had failed an SSRI and some had failed "2 or more classes of antidepressants", but one of those classes will almost certainly have been an SSRI, because they're the first-line treatment.

DeBattista, C., Kinrys, G., Hoffman, D., Goldstein, C., Zajecka, J., Kocsis, J., Teicher, M., Potkin, S., Preda, A., & Multani, G. (2010). The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression Journal of Psychiatric Research DOI: 10.1016/j.jpsychires.2010.05.009

Mmm... Food-Induced Seizures

In a tasty new paper, British neurologists Kate El Bouzidi et al report on the case of a woman who suffered epileptic seizures whenever she saw, smelled, or ate food:

A 44-year-old right-handed woman was walking in the Scottish highlands. Upon unwrapping her lunch, she had a focal seizure with witnessed onset on the right side of the face and secondary generalization... She was airlifted to hospital. Three weeks later, the smell of food triggered another seizure and she was admitted to the neurology unit...

Even hospital fare was able to provoke the attacks:

The next morning, the patient had a simple partial seizure after eating a spoonful of porridge. Thereafter, most meals triggered seizures, as did other food-related stimuli such as being offered a piece of cake, seeing her visitors pass around food at her bedside, and smelling the hospital dinner trolley.

Anti-convulsant drugs failed to control the seizures. An MRI scan revealed an abnormal mass and electrode recordings from the surface of the brain confirmed that the seizure activity was starting nearby. The mass was surgically removed - it turned out to have been a grade IV glioblastoma cancer - which put an end to the seizures, although sadly we're told that the surgery was "subtotal" i.e. they weren't able to remove the tumour entirely.

The authors note that eating-induced seizures have been reported hundreds of times, most commonly in India and Sri Lanka, curiously enough, but this is the first known case in which merely seeing or thinking about food was also a trigger. Why it happens is a mystery: presumably, neural activation in response to the taste or smell of food somehow spills over into the epileptic focus... but the details are sketchy.

In this case, seizures were specifically triggered by food-related stimuli in the context of hunger. The finding of a seizure focus in the left frontal operculum, adjacent to the tumor, is consistent with the hypothesis that activation of this region by appetite triggered seizure activity that then propagated to the surrounding cortex and was manifest clinically as a motor seizure.

El Bouzidi K, Duncan S, Whittle IR, & Butler CR (2010). Lesional reflex epilepsy associated with the thought of food. Neurology, 74 (7), 610-2 PMID: 20157165

Mmm... Food-Induced Seizures

In a tasty new paper, British neurologists Kate El Bouzidi et al report on the case of a woman who suffered epileptic seizures whenever she saw, smelled, or ate food:

A 44-year-old right-handed woman was walking in the Scottish highlands. Upon unwrapping her lunch, she had a focal seizure with witnessed onset on the right side of the face and secondary generalization... She was airlifted to hospital. Three weeks later, the smell of food triggered another seizure and she was admitted to the neurology unit...

Even hospital fare was able to provoke the attacks:

The next morning, the patient had a simple partial seizure after eating a spoonful of porridge. Thereafter, most meals triggered seizures, as did other food-related stimuli such as being offered a piece of cake, seeing her visitors pass around food at her bedside, and smelling the hospital dinner trolley.

Anti-convulsant drugs failed to control the seizures. An MRI scan revealed an abnormal mass and electrode recordings from the surface of the brain confirmed that the seizure activity was starting nearby. The mass was surgically removed - it turned out to have been a grade IV glioblastoma cancer - which put an end to the seizures, although sadly we're told that the surgery was "subtotal" i.e. they weren't able to remove the tumour entirely.

The authors note that eating-induced seizures have been reported hundreds of times, most commonly in India and Sri Lanka, curiously enough, but this is the first known case in which merely seeing or thinking about food was also a trigger. Why it happens is a mystery: presumably, neural activation in response to the taste or smell of food somehow spills over into the epileptic focus... but the details are sketchy.

In this case, seizures were specifically triggered by food-related stimuli in the context of hunger. The finding of a seizure focus in the left frontal operculum, adjacent to the tumor, is consistent with the hypothesis that activation of this region by appetite triggered seizure activity that then propagated to the surrounding cortex and was manifest clinically as a motor seizure.

El Bouzidi K, Duncan S, Whittle IR, & Butler CR (2010). Lesional reflex epilepsy associated with the thought of food. Neurology, 74 (7), 610-2 PMID: 20157165

Predicting Antidepressant Response with EEG

One of the limitations of antidepressants is that they don't always work. Worse, they don't work in an unpredictable way. Some people benefit from some drugs, and others don't, but there's no way of knowing in advance what will happen in any particular case - or of telling which pill is right for which person.

As a result, drug treatment for depression generally involves starting with a cheap medication with relatively mild side-effects, and if that fails, moving onto a series of other drugs until one helps. But since it can take several weeks for any new drug to work, this can be a frustrating process for patients and doctors alike.

Some means of predicting the antidepressant response would thus be very useful. Many have been proposed, but none have entered widespread clinical use. Now, a pair of papers(1,2) from UCLA's Andrew Leuchter et al make the case for prediction using quantitative EEG (QEEG).

EEG, electroencephalography, is a crude but effective way of recording electrical activity in the brain via electrodes attached to the head. "Quantitative" EEG just means using EEG to precisely measure the level of certain kinds of activity in the brain.

Leuchter et al's system is straightforward: it uses six electrodes on the front of the head. The patient simply relaxes with their eyes closed for a few minutes while neural activity is recorded.

This procedure is performed twice, once just before antidepressant treatment begins and then again a week later. The claim is that by examining the changes in the EEG signal after one week of drug treatment, the eventual benefit of the drug can be predicted. It's not an implausible idea, and if it did work, it would be rather helpful. But does it?

Leuchter et al say: yes! The first paper reports that in 73 depressed patients who were given the antidepressant escitalopram 10mg/day, QEEG changes after one week predicted clinical improvement six weeks later. Specifically, people who got substantially better at seven weeks had a higher "Antidepressant Treatment Response Index" (ATR) at one week than people who didn't: 59.0 ± 10.2 vs 49.8 ± 7.8, which is highly significant (p less than 0.001).

In the companion paper, the authors examined patients who started on escitalopram and then either kept taking it or switched to a different antidepressant, bupropion. They found that patients who had a high ATR after a week of escitalopram tended to do well if they stayed on it, while patients who had a low ATR to escitalopram did better when they switched to the other drug.

These are interesting results, and they follow from ten years of previous work (mostly, but not exclusively, from the same group) on the topic. Because the current study didn't include a placebo group, we can't say that the QEEG predicts antidepressant response as such, only that it predicts improvement in depression symptoms. But even this is pretty exciting, if it really works.

In order to verify that it does, other researchers need to replicate this experiment. But they may find this a little difficult. What is the Antidepressant Treatment Response Index use in this study? It's derived from an analysis of the EEG signal, and we're told that you get it from this formula:

Some of the terms here are common parameters that any EEG expert will understand. But "A", "B", and "C" are not. They're constants, which are not given in the paper. They're secret numbers. Without knowing what those numbers are, no-one can calculate the "ATR" even if they have an EEG machine.

Why keep them secret? Well...

"Financial support of this project was provided by Aspect Medical Systems. Aspect participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript."

Aspect is a large medical electronics company who developed the system used here. Presumably, they want to patent it (or already have). We're told that

"To facilitate independent replication of the work reported here, Aspect intends to make available a limited number of investigational systems for academic researchers. Please contact Scott Greenwald, Ph.D... for further information."

All very nice of them, but if they'd told us the three magic numbers, academics could start trying to independently replicate these results tomorrow. As it is, anyone who wants to do so will have to get Aspect's blessing, which, with the best will in the world, means they will not be entirely "independent".

[BPSDB]

Leuchter AF, Cook IA, Gilmer WS, Marangell LB, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, Fava M, Iosifescu D, & Greenwald S (2009). Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry research PMID: 19709754

Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, & Greenwald S (2009). Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study. Psychiatry research PMID: 19712979