Book: Deep Brain Stimulation

Jamie Talan's Deep Brain Stimulation: A New Treatment Shows Promise In The Most Difficult Cases is the first book to offer a popular look at DBS, one of the more exciting emerging treatments in neurology and psychiatry.

Deep Brain Stimulation is not a textbook and the depth of scientific detail is kept pretty low, but the breadth of the material is good. Talan reviews the many kinds of disorders for which DBS has been trialled, from the early 1990s when it was used in Parkinson's disease up to the past five years where it's been tried for everything from epilepsy, depression and Tourette's Syndrome up to lifting patients out of persistent vegetative states (maybe).

Unfortunately, Talan doesn't discuss the controversial history of the first era of human brain stimulation, including the morally murky work of Robert G. Heath at Tulane University in the 1960s. She mentions Tulane once in passing but more detail would have been welcome, if only because it's a rather spicy tale.

The book's most engaging passages are the stories of individual patients. There's the man with Parkinson's who experienced amazing benefits from DBS, and who was so keen to keep them that he didn't tell doctors about the infection which developed a few weeks after surgery, in case they took the electrode out. After literally keeping the infected site under his hat for a few days, it progressed to a brain abscess, and he nearly died. Happily, he not only survived but was able to get the electrodes reimplanted.

Then there's the most moving case, that of the woman suffering from severe OCD and depression, who was given experimental DBS for the former condition. She died by suicide several months later, but said in her suicide note that the DBS had worked - her OCD symptoms were gone. Her depression was as bad as ever, though, and this is what led her to suicide. She wanted people to know that deep brain stimulation helped her, and didn't want her death to go down in the records as a mark against it.

The precursor to DBS was ablative neurosurgery - destroying particular parts of the brain in order to relieve symptoms. Talan describes its use in movement disorders such as Parkinson's, but she glosses over the history of "psychosurgery", the use of surgery to treat mental illness. People using DBS in psychiatry often prefer not to talk about psychosurgery - it's not exactly good PR. But clearly it is relevant. For all its faults, psychosurgery did seem to help some patients, which is why it's still used today in rare cases, although DBS may soon replace it.

DBS for depression and OCD usually target the same prefrontal white matter pathways that psychosurgery severed, so scientifically, psychosurgery has lessons for DBS. The ethical issues overlap too. Although DBS is reversible, unlike brain lesioning, it carries the same risks of serious complications like infection or brain bleeding. And there's the same question of whether seriously mentally ill people can give informed consent.

The book's strongest chaper is the last, which covers the ethical and practical difficulties of DBS. The danger is that enthusiastic doctors with no experience of the procedure, encouraged by the tales from other hospitals, might start doing it inappropriately. There's also a risk that patients or their families might volunteer for DBS prematurely or have impossibly high expectations. The initial results have been very promising, but there have been no large placebo-controlled trials so far (except in some movement disorders). And even with the best surgeons, in most disorders the response rate seems to hover around the 50-60% mark. Talan warns that DBS risks being a victim of its own hype. That's an important message.

Book: Deep Brain Stimulation

Jamie Talan's Deep Brain Stimulation: A New Treatment Shows Promise In The Most Difficult Cases is the first book to offer a popular look at DBS, one of the more exciting emerging treatments in neurology and psychiatry.

Deep Brain Stimulation is not a textbook and the depth of scientific detail is kept pretty low, but the breadth of the material is good. Talan reviews the many kinds of disorders for which DBS has been trialled, from the early 1990s when it was used in Parkinson's disease up to the past five years where it's been tried for everything from epilepsy, depression and Tourette's Syndrome up to lifting patients out of persistent vegetative states (maybe).

Unfortunately, Talan doesn't discuss the controversial history of the first era of human brain stimulation, including the morally murky work of Robert G. Heath at Tulane University in the 1960s. She mentions Tulane once in passing but more detail would have been welcome, if only because it's a rather spicy tale.

The book's most engaging passages are the stories of individual patients. There's the man with Parkinson's who experienced amazing benefits from DBS, and who was so keen to keep them that he didn't tell doctors about the infection which developed a few weeks after surgery, in case they took the electrode out. After literally keeping the infected site under his hat for a few days, it progressed to a brain abscess, and he nearly died. Happily, he not only survived but was able to get the electrodes reimplanted.

Then there's the most moving case, that of the woman suffering from severe OCD and depression, who was given experimental DBS for the former condition. She died by suicide several months later, but said in her suicide note that the DBS had worked - her OCD symptoms were gone. Her depression was as bad as ever, though, and this is what led her to suicide. She wanted people to know that deep brain stimulation helped her, and didn't want her death to go down in the records as a mark against it.

The precursor to DBS was ablative neurosurgery - destroying particular parts of the brain in order to relieve symptoms. Talan describes its use in movement disorders such as Parkinson's, but she glosses over the history of "psychosurgery", the use of surgery to treat mental illness. People using DBS in psychiatry often prefer not to talk about psychosurgery - it's not exactly good PR. But clearly it is relevant. For all its faults, psychosurgery did seem to help some patients, which is why it's still used today in rare cases, although DBS may soon replace it.

DBS for depression and OCD usually target the same prefrontal white matter pathways that psychosurgery severed, so scientifically, psychosurgery has lessons for DBS. The ethical issues overlap too. Although DBS is reversible, unlike brain lesioning, it carries the same risks of serious complications like infection or brain bleeding. And there's the same question of whether seriously mentally ill people can give informed consent.

The book's strongest chaper is the last, which covers the ethical and practical difficulties of DBS. The danger is that enthusiastic doctors with no experience of the procedure, encouraged by the tales from other hospitals, might start doing it inappropriately. There's also a risk that patients or their families might volunteer for DBS prematurely or have impossibly high expectations. The initial results have been very promising, but there have been no large placebo-controlled trials so far (except in some movement disorders). And even with the best surgeons, in most disorders the response rate seems to hover around the 50-60% mark. Talan warns that DBS risks being a victim of its own hype. That's an important message.

Deep Brain Stimulation for Depressed Rats

Deep-brain stimulation (DBS) is probably the most exciting emerging treatment in psychiatry. DBS is the use of high-frequency electrical current to alter the function of specific areas of the brain. Originally developed for Parkinson's disease, over the past five years DBS has been used experimentally in severe clinical depression, OCD, Tourette's syndrome, alcoholism, and more.

Reports of the effects have frequently been remarkable, but there have been few scientifically rigorous studies, and the number of psychiatric patients treated to date is just dozens. So the true usefulness of the technique is unclear. How DBS works is also a mystery. Even the most basic questions - such as whether high-frequency stimulation switches the brain "on" or "off" - are still being debated.

Recent data from rodents sheds some important light on the issue: Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. The authors took rats, and implanted DBS electrodes in the infralimbic cortex. This area is part of the vmPFC. It's believed to be the rat equivalent of the human region BA25, the subgenual cingulate cortex, which is the most common target for DBS in depression. The current settings (100 microA, 130 Hz, 90 microsec) were chosen to be similar to the ones used in humans.

In a standard rat model of depression, the forced-swim test, infralimbic DBS exerted antidepressant-like effects. DBS was equally as effective as imipramine, a potent antidepressant, in terms of reducing "depression-like" behaviours, namely immobility.

This is not all that surprising. Almost everything which treats depression in humans also reduces immobility in this test (along with few things which don't treat it). Much more interesting is what did and did not block the effects of DBS in these rats.

First off, DBS worked even when the rat's infralimbic cortex had been destroyed by the toxin ibotenic acid. This strongly suggests that DBS does not work simply by activating the infralimbic cortex, even though this is where the electrodes were implanted.

Crucially, infralimbic lesions did not have an antidepressant effect per se, which also rules out the theory that DBS works by inactivating this region. (Infralimbic lesions produced by other methods did have a mild antidepressant effect, but it was smaller than the effect of DBS. This may still be important, however.)

What did block the effects of DBS was the depletion of serotonin (5HT). Serotonin is known to its friends as the brain's "happy chemical", although it's a bit more complicated than that. Most antidepressants target serotonin. And rats whose serotonin systems had been lesioned got no benefit from DBS in this study.

So this suggests that DBS might work by affecting serotonin, and indeed, DBS turned out to greatly increase serotonin release, even in a distant part of the brain (the hippocampus). Interestingly this lasted for nearly two hours after the electrodes were switched off.

Depletion of another neurotransmitter, noradrenaline, did not alter the effects of DBS.

Overall, it seems that infralimbic DBS works by increasing serotonin release, but that this is not because it activates or inactivates the infralimbic cortex itself. Rather, nearby structures must be involved. The most likely explanation is that DBS affects nearby white-matter tracts carrying signals between other areas of the brain; the infralimbic cortex might just happen to be "by the roadside". Many researchers believe that this is how DBS works in humans, but this is the first hard evidence for this.

Of course, evidence from rats is never all that hard when it comes to human mental illness. We need to know whether the same thing is true in people. As luck would have it, you can temporarily reduce human serotonin levels with a technique called acute tryptophan depletion This reverses the effects of antidepressants in many people. If this rat data is right, it should also temporarily reverse the benefits of DBS. Someone should do this experiment as soon as possible - I'd like to do it myself, but I'm British, and all the DBS research happens in America. Bah, humbug, old bean.

There's a couple of others things to note here. In other behavioural tests, infralimbic DBS also had antidepressant-like effects: it seemed to reduce anxiety, and it made rats more resistant to the stress of having electrical shocks (although only slightly.) Finally, DBS in another region, the striatum, had no antidepressant effect at all. That's a bit odd because DBS of the striatum does seem to treat depression in humans - but the part of the striatum targeted here, the caudate-putamen, is quite separate to the one targeted in human depression, the nucleus accumbens.

Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2009). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats Biological Psychiatry DOI: 10.1016/j.biopsych.2009.08.025

Deep Brain Stimulation for Depressed Rats

Deep-brain stimulation (DBS) is probably the most exciting emerging treatment in psychiatry. DBS is the use of high-frequency electrical current to alter the function of specific areas of the brain. Originally developed for Parkinson's disease, over the past five years DBS has been used experimentally in severe clinical depression, OCD, Tourette's syndrome, alcoholism, and more.

Reports of the effects have frequently been remarkable, but there have been few scientifically rigorous studies, and the number of psychiatric patients treated to date is just dozens. So the true usefulness of the technique is unclear. How DBS works is also a mystery. Even the most basic questions - such as whether high-frequency stimulation switches the brain "on" or "off" - are still being debated.

Recent data from rodents sheds some important light on the issue: Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats. The authors took rats, and implanted DBS electrodes in the infralimbic cortex. This area is part of the vmPFC. It's believed to be the rat equivalent of the human region BA25, the subgenual cingulate cortex, which is the most common target for DBS in depression. The current settings (100 microA, 130 Hz, 90 microsec) were chosen to be similar to the ones used in humans.

In a standard rat model of depression, the forced-swim test, infralimbic DBS exerted antidepressant-like effects. DBS was equally as effective as imipramine, a potent antidepressant, in terms of reducing "depression-like" behaviours, namely immobility.

This is not all that surprising. Almost everything which treats depression in humans also reduces immobility in this test (along with few things which don't treat it). Much more interesting is what did and did not block the effects of DBS in these rats.

First off, DBS worked even when the rat's infralimbic cortex had been destroyed by the toxin ibotenic acid. This strongly suggests that DBS does not work simply by activating the infralimbic cortex, even though this is where the electrodes were implanted.

Crucially, infralimbic lesions did not have an antidepressant effect per se, which also rules out the theory that DBS works by inactivating this region. (Infralimbic lesions produced by other methods did have a mild antidepressant effect, but it was smaller than the effect of DBS. This may still be important, however.)

What did block the effects of DBS was the depletion of serotonin (5HT). Serotonin is known to its friends as the brain's "happy chemical", although it's a bit more complicated than that. Most antidepressants target serotonin. And rats whose serotonin systems had been lesioned got no benefit from DBS in this study.

So this suggests that DBS might work by affecting serotonin, and indeed, DBS turned out to greatly increase serotonin release, even in a distant part of the brain (the hippocampus). Interestingly this lasted for nearly two hours after the electrodes were switched off.

Depletion of another neurotransmitter, noradrenaline, did not alter the effects of DBS.

Overall, it seems that infralimbic DBS works by increasing serotonin release, but that this is not because it activates or inactivates the infralimbic cortex itself. Rather, nearby structures must be involved. The most likely explanation is that DBS affects nearby white-matter tracts carrying signals between other areas of the brain; the infralimbic cortex might just happen to be "by the roadside". Many researchers believe that this is how DBS works in humans, but this is the first hard evidence for this.

Of course, evidence from rats is never all that hard when it comes to human mental illness. We need to know whether the same thing is true in people. As luck would have it, you can temporarily reduce human serotonin levels with a technique called acute tryptophan depletion This reverses the effects of antidepressants in many people. If this rat data is right, it should also temporarily reverse the benefits of DBS. Someone should do this experiment as soon as possible - I'd like to do it myself, but I'm British, and all the DBS research happens in America. Bah, humbug, old bean.

There's a couple of others things to note here. In other behavioural tests, infralimbic DBS also had antidepressant-like effects: it seemed to reduce anxiety, and it made rats more resistant to the stress of having electrical shocks (although only slightly.) Finally, DBS in another region, the striatum, had no antidepressant effect at all. That's a bit odd because DBS of the striatum does seem to treat depression in humans - but the part of the striatum targeted here, the caudate-putamen, is quite separate to the one targeted in human depression, the nucleus accumbens.

Hamani, C., Diwan, M., Macedo, C., Brandão, M., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A., Fletcher, P., & Nobrega, J. (2009). Antidepressant-Like Effects of Medial Prefrontal Cortex Deep Brain Stimulation in Rats Biological Psychiatry DOI: 10.1016/j.biopsych.2009.08.025

Deep Brain Stimulation Cures Urge To Break Glass

Deep Brain Stimulation (DBS) is in. There's been much buzz about its use in severe depression, and it has a long if less glamorous record of success in Parkinson's disease. Now that it's achieved momentum as a treatment in psychiatry, DBS is being tried in a range of conditions including chronic pain, obsessive-compulsive disorder and Tourette's Syndrome. Is the hype justified? Yes - but the scientific and ethical issues are more complex, and more interesting, than you might think.

Biological Psychiatry have just published this report of DBS in a man who suffered from severe, untreatable Tourette's syndrome, as well as OCD. The work was performed by a German group, Neuner et. al. (who also have a review paper just out), and they followed the patient up for three years after implanting high-frequency stimulation electrodes in an area of the brain called the nucleus accumbens. It's fascinating reading, if only for the insight into the lives of the patients who receive this treatment.

The patient suffered from the effects of auto-aggressive behavior such as self-mutilation of the lips, forehead, and fingers, coupled with the urge to break glass. He was no longer able to travel by car because he had broken the windshield of his vehicle from the inside on several occasions.

It makes even more fascinating viewing, because the researchers helpfully provide video clips of the patient before and after the procedure. Neuropsychiatric research meets YouTube - truly, we've entered the 21st century. Anyway, the DBS seemed to work wonders:

... An impressive development was the cessation of the self-mutilation episodes and the urge to destroy glass. No medication was being used ... Also worthy of note is the fact that the patient stopped smoking during the 6 months after surgery. In the follow-up period, he has successfully refrained from smoking. He reports that he has no desire to smoke and that it takes him no effort to refrain from doing so.

Impressive indeed. DBS is, beyond a doubt, an exciting technology from both a theoretical and a clinical perspective. Yet it's worth considering some things that tend to get overlooked.

Firstly, although DBS has a reputation as a high-tech, science-driven, precisely-targeted treatment, it's surprisingly hit-and-miss. This report involved stimulation of the nucleus accumbens, an area best known to neuroscientists as being involved in responses to recreational drugs. (It's tempting to infer that this must have something to do with why the patient quit smoking.) I'm sure there are good reasons to think that DBS in the nucleus accumbens would help with Tourette's - but there are equally good reasons to target several other locations. As the authors write:

For DBS in Tourette's patients, the globus pallidus internus (posteroventrolateral part, anteromedial part), the thalamus (centromedian nucleus, substantia periventricularis, and nucleus ventro-oralis internus) and the nucleus accumbens/anterior limb of the internal capsule have all been used as target points.

For those whose neuroanatomy is a little rusty, that's a fairly eclectic assortment of different brain regions. Likewise, in depression, the best-known DBS target is the subgenual cingulate cortex, but successful cases have been reported with stimulation in two entirely different areas, and at least two more have been proposed as potential targets (Paper.) Indeed, even once a location for DBS has been chosen, it's often necessary to try stimulating at several points in order to find the best target. The point is that there is no "Depression center" or "Tourette's center" in the brain which science has mapped out and which surgery can now fix.

Second, by conventional standards, this was an awful study: it only had one patient, no controls, and no blinding. Of course, applying usual scientific standards to this kind of research is all but impossible, for ethical reasons. These are people, not lab rats. And it does seem unlikely that the dramatic and sustained response in this case could be purely the placebo effect, especially given that the patient had tried several medications previously.

So what the authors did was certainly reasonable under the circumstances - but still, this article, published in a leading journal, is basically an anecdote. If it had been about a Reiki master waving his hands at the patient, instead of a neurosurgeon sticking electrodes into him, it wouldn't even make it into the Journal of Alternative and Complementary Medicine. This is par for the course in this field; there have been controlled trials of DBS, but they are few and very small. Is this a problem? It would be silly to pretend that it wasn't - there is no substitute for good science. There's not much we can do about it, though.

Finally, Deep Brain Stimulation is a misleading term - the brain doesn't really get stimulated at all. The electrical pulses used in most DBS are at such a high frequency (145 Hz in this case) that they "overload" nearby neurons and essentially switch them off. (At least that's the leading theory.) In effect, turning on a DBS electrode is like cutting a hole in the brain. Of course, the difference is that you can switch off the electrode and put it back to normal. But this aside, DBS is little more sophisticated than the notorious "psychosurgery" pioneered by Walter Freeman performed back in the 1930s and that have since become so unpopular. I see nothing wrong with that - if it works, it works, and psychosurgery worked for many people, which is why it's still used in Britain today. It's interesting, though, that whereas psychosurgery is seen as the height of psychiatry barbarity, DBS is lauded as medical science at its most sophisticated.

For all that, DBS is the most interesting thing in neuroscience at the moment. Almost all research on the human brain is correlational - we look for areas of the brain which activate on fMRI scans when people are doing something. DBS offers one of the very few ways of investigating what happens when you manipulate different parts of the human brain. For a scientist, it's a dream come true. But of course, the only real reason to do DBS is for the patients. DBS promises to help people who are suffering terribly. If it does, that's reason enough to be interested in it.

See also: Someone with Parkinson's disease writes of his experiences with DBS on his blog.


I NEUNER, K PODOLL, D LENARTZ, V STURM, F SCHNEIDER (2008). Deep Brain Stimulation in the Nucleus Accumbens for Intractable Tourette's Syndrome: Follow-Up Report of 36 Months Biological Psychiatry DOI: 10.1016/j.biopsych.2008.09.030

Deep Brain Stimulation Cures Urge To Break Glass

Deep Brain Stimulation (DBS) is in. There's been much buzz about its use in severe depression, and it has a long if less glamorous record of success in Parkinson's disease. Now that it's achieved momentum as a treatment in psychiatry, DBS is being tried in a range of conditions including chronic pain, obsessive-compulsive disorder and Tourette's Syndrome. Is the hype justified? Yes - but the scientific and ethical issues are more complex, and more interesting, than you might think.

Biological Psychiatry have just published this report of DBS in a man who suffered from severe, untreatable Tourette's syndrome, as well as OCD. The work was performed by a German group, Neuner et. al. (who also have a review paper just out), and they followed the patient up for three years after implanting high-frequency stimulation electrodes in an area of the brain called the nucleus accumbens. It's fascinating reading, if only for the insight into the lives of the patients who receive this treatment.

The patient suffered from the effects of auto-aggressive behavior such as self-mutilation of the lips, forehead, and fingers, coupled with the urge to break glass. He was no longer able to travel by car because he had broken the windshield of his vehicle from the inside on several occasions.

It makes even more fascinating viewing, because the researchers helpfully provide video clips of the patient before and after the procedure. Neuropsychiatric research meets YouTube - truly, we've entered the 21st century. Anyway, the DBS seemed to work wonders:

... An impressive development was the cessation of the self-mutilation episodes and the urge to destroy glass. No medication was being used ... Also worthy of note is the fact that the patient stopped smoking during the 6 months after surgery. In the follow-up period, he has successfully refrained from smoking. He reports that he has no desire to smoke and that it takes him no effort to refrain from doing so.

Impressive indeed. DBS is, beyond a doubt, an exciting technology from both a theoretical and a clinical perspective. Yet it's worth considering some things that tend to get overlooked.

Firstly, although DBS has a reputation as a high-tech, science-driven, precisely-targeted treatment, it's surprisingly hit-and-miss. This report involved stimulation of the nucleus accumbens, an area best known to neuroscientists as being involved in responses to recreational drugs. (It's tempting to infer that this must have something to do with why the patient quit smoking.) I'm sure there are good reasons to think that DBS in the nucleus accumbens would help with Tourette's - but there are equally good reasons to target several other locations. As the authors write:

For DBS in Tourette's patients, the globus pallidus internus (posteroventrolateral part, anteromedial part), the thalamus (centromedian nucleus, substantia periventricularis, and nucleus ventro-oralis internus) and the nucleus accumbens/anterior limb of the internal capsule have all been used as target points.

For those whose neuroanatomy is a little rusty, that's a fairly eclectic assortment of different brain regions. Likewise, in depression, the best-known DBS target is the subgenual cingulate cortex, but successful cases have been reported with stimulation in two entirely different areas, and at least two more have been proposed as potential targets (Paper.) Indeed, even once a location for DBS has been chosen, it's often necessary to try stimulating at several points in order to find the best target. The point is that there is no "Depression center" or "Tourette's center" in the brain which science has mapped out and which surgery can now fix.

Second, by conventional standards, this was an awful study: it only had one patient, no controls, and no blinding. Of course, applying usual scientific standards to this kind of research is all but impossible, for ethical reasons. These are people, not lab rats. And it does seem unlikely that the dramatic and sustained response in this case could be purely the placebo effect, especially given that the patient had tried several medications previously.

So what the authors did was certainly reasonable under the circumstances - but still, this article, published in a leading journal, is basically an anecdote. If it had been about a Reiki master waving his hands at the patient, instead of a neurosurgeon sticking electrodes into him, it wouldn't even make it into the Journal of Alternative and Complementary Medicine. This is par for the course in this field; there have been controlled trials of DBS, but they are few and very small. Is this a problem? It would be silly to pretend that it wasn't - there is no substitute for good science. There's not much we can do about it, though.

Finally, Deep Brain Stimulation is a misleading term - the brain doesn't really get stimulated at all. The electrical pulses used in most DBS are at such a high frequency (145 Hz in this case) that they "overload" nearby neurons and essentially switch them off. (At least that's the leading theory.) In effect, turning on a DBS electrode is like cutting a hole in the brain. Of course, the difference is that you can switch off the electrode and put it back to normal. But this aside, DBS is little more sophisticated than the notorious "psychosurgery" pioneered by Walter Freeman performed back in the 1930s and that have since become so unpopular. I see nothing wrong with that - if it works, it works, and psychosurgery worked for many people, which is why it's still used in Britain today. It's interesting, though, that whereas psychosurgery is seen as the height of psychiatry barbarity, DBS is lauded as medical science at its most sophisticated.

For all that, DBS is the most interesting thing in neuroscience at the moment. Almost all research on the human brain is correlational - we look for areas of the brain which activate on fMRI scans when people are doing something. DBS offers one of the very few ways of investigating what happens when you manipulate different parts of the human brain. For a scientist, it's a dream come true. But of course, the only real reason to do DBS is for the patients. DBS promises to help people who are suffering terribly. If it does, that's reason enough to be interested in it.

See also: Someone with Parkinson's disease writes of his experiences with DBS on his blog.


I NEUNER, K PODOLL, D LENARTZ, V STURM, F SCHNEIDER (2008). Deep Brain Stimulation in the Nucleus Accumbens for Intractable Tourette's Syndrome: Follow-Up Report of 36 Months Biological Psychiatry DOI: 10.1016/j.biopsych.2008.09.030