The Brain's High School Spot

It's been known for a long time that electrical stimulation of the brain's temporal lobe can sometimes evoke vivid memories.

The famous neurosurgeon Wilder Penfield first noticed this effect as part of his pioneering stimulation experiments, but he believed that it was both uncommon and haphazard with any given stimulation able to evoke any memory, more or less at random.

A new paper, however, says different. Philadelphia's Joshua Jacobs et al report that they found a spot in the left temporal lobe of a male patient, stimulation of which evoked memories of the man's time at high school. The guy was in his 30s at the time, so these are quite distant memories.

When it first happened, he is reported to have said:

Iʼm, like, remembering stuff from, like, high school…. Why is this suddenly popping in my head?

Repeated stimulation of the same electrode - but not nearby electrodes - caused other high school memories to emerge.

Even more interestingly, when the same stimulating electrode was used to record activity during memory retrieval, the "high school spot" was found to be significantly less active when high school was being remembered, compared to when various other kinds of memories were being accessed.

This graph shows that all kinds of memories evoked high-frequency activity in the high-school zone, but high-school memories did so less:

No other electrode location caused the same effects (or indeed, any detectable memory effects), although as you can see on the image at the top, the electrode coverage was not huge.

A little background: the guy had these electrodes in place because he suffered from epilepsy, resistant to medication, which was believed to originate in the temporal lobe. Temporal lobe epilepsy can cause memory phenomena rather like this, but this patient had never experienced that, and the electrically-evoked memories were experienced as entirely novel.

It's a nice case report and it raises many questions. Why is the high-school spot less active during memory retrieval? That seems the wrong way around (I did a double-take to make sure I was reading it properly).

And what would happen if you somehow disabled (or overactivated) this area, and asked him to remember a particular school memory? Would he draw a blank, or would he remember it but without the "high-school-ness"? What would that feel like?

Either way, this case suggests that memories are stored in the brain "by topic", in the sense that "similar" memories are associated with nearby areas of the brain. At least sometimes. But then, why didn't nearby electrodes evoke other memories? If there's a high-school spot, why not a kindergarten spot, a my-first-job spot?

Maybe those spots lay in areas with no electrode coverage... but the fact that many temporal electrodes didn't bring back any memories suggests that there's lots of cortex which isn't part of a "spot". Perhaps those areas are "spare", waiting to be used up? Clearly, he wasn't born with a high school spot. It must have emerged during high school. But in that case there had to be a "blank" area first.


Jacobs J, Lega B, and Anderson C (2011). Explaining How Brain Stimulation Can Evoke Memories. Journal of cognitive neuroscience PMID: 22098266

Do We Need Placebos?

A news feature in Nature asks whether placebo controls are always a good idea: Why Fake It?

The piece looks at experimental neurosurgical treatments for Parkinson's, such as "Spheramine". This consists of cultured human cells, which are implanted directly into the brain of the sufferer. The idea is that the cells will grow and help produce dopamine, which is deficient in Parkinson's.

Peggy Willocks, a 44 year old teacher, took part in a trial of the surgery in 2000. She says it helped stave off the symptoms for years, but the development of Spheramine was axed in 2008 after a controlled trial found it didn't work any better than a placebo.

The placebo was "sham surgery" i.e. putting the patient through a full surgical procedure, and making holes in their skull, but without doing anything to their brain.

It's cheap and easy to do a placebo controlled trial of a drug - all you need is a sugar pill. But with neurosurgery, it's clearly a lot more involved. A placebo has to be believable. Convincing sham surgery is expensive, time-consuming, and it has real risks, albeit small ones.

Is it ethical to put patients through that?

That, I think, can only be decided on a trial-by-trial basis. It depends on the likely benefits of the treatment, and whether the trial is scientifically sound. Obviously, it'd be wrong to do sham surgery as part of a flawed trial that won't tell us anything useful.

The Nature article, however, goes further than this, and suggests that placebo controlled trials may be unsuitable for testing these kinds of treatments, failing to detect a real benefit in some patients:

There are hints from some of the failed phase II trials that patients followed up beyond study endpoints might tell a more positive story. Some say, therefore, that sham controls are sinking the prospects of valuable drugs.

Anders Björklund, a neuroscientist at Lund University in Sweden who is collaborating with [Roger Barker of Cambridge], says that sham surgery can lead researchers to throw out a strategy prematurely if the trial fails because of technical or methodological glitches rather than a true lack of efficacy.

A patient advocate agrees:

According to Perry Cohen, who leads a network of patient activists called the Parkinson Pipeline Project, that’s exactly what is happening. He had always questioned the need for sham surgery, he says, but after the string of phase II failures, “We started saying, ‘Hey, this is a problem. These trials failed, but we know they are working for some people.’”

...Cohen [says] that patients have different priorities and that researchers must take these into account. Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives — which can sink a therapy before it has been optimized.

I'm not sure about this. If I had Parkinson's, I would certainly hate to miss out on the genuine cure because a trial had failed to recognize that it worked. But equally, I would not be happy to be given a rubbish treatment that would have failed a placebo controlled trial, but never got one, because of arguments like this.

Placebo controlled trials can fail to detect benefits if they are too short, too small, methodologically flawed, or whatever. Certainly, a trial can be placebo controlled, and still crap. But the answer is surely to do better trials, not no trials.

It may well be that we shouldn't rush to do placebo controlled trials until later in the development process, when the technique has been properly refined. But the history of medicine is littered with treatments that "we know work for some people" - that didn't.

Katsnelson, A. (2011). Experimental therapies for Parkinson's disease: Why fake it? Nature, 476 (7359), 142-144 DOI: 10.1038/476142a

A Stroke Of Good Fortune Cures OCD?

A 45 year old female teacher had a history of severe obsessive-compulsive disorder, along with other problems including ADHD. Her daughter, and many other people in her family, had suffered the same problems and in a few cases had Tourette's Syndrome.But all that changed - when she suffered a stroke. This is according to a brief case report from Drs. Diamond and Ondo of Texas:

[she] had a long history of constant intrusive and obsessive thoughts that interrupted her daily activities and sleep. She had constant unfounded fears that something bad would happen to her family and had persistent violent thoughts of using knives to harm family members. She would check the door locks up to 15 times a day. In addition to her OCD symptoms, she had ... inattention, poor concentration, and difficulty sitting still.

She had never been treated for the OCD, despite how it interfered with her life, because she feared losing her job as a teacher if she sought psychiatric help. But then...

Nine months before approaching us, she developed the acute onset of paresthesia [weird sensations] and weakness in the left upper extremity and face, associated with slurred speech. Initially, she was unable to lift her arm against gravity.

These are classic signs of a stroke, but it was a very mild one, because the symptoms only lasted a few minutes and were pretty much gone even before she arrived at the emergency room. She made a full recovery. More than a full recovery in fact:

Within weeks of her stroke, she realized that her obsessive and intrusive thoughts, fears, rituals, and impulsive behavior had completely resolved. In addition, there was some improvement in her temperament. There was no improvement in attention or concentration. Owing to her improvement in neuropsychiatric symptoms, she strongly felt that her stroke was beneficial. These benefits have persisted for 24 months.

Most medical case reports concern patients who died, or got really sick, in a particularly interesting fashion, but this one has a happy ending. Strokes can be devastating, of course, although people also make full recoveries - it all depends on the severity of the stroke, and whether they get prompt treatment.

There have been a few other cases of brain damage which brought unexpectedly beneficial effects. In Vietnam veterans, for example, people with damage to the vmPFC due to combat trauma seemed to be protected from depression.

Whether the stroke really cured her, or whether it was some kind of psychological "placebo" effect, we'll never know. It's hard to see why a stroke would have a placebo effect, but on the other hand, an MRI scan revealed that the stroke occured in an area of the brain - the right frontoparietal cortex - which is fairly low down on the list of "OCD-ish" areas.

The authors make some vague comments about "modulation of the cortical–subcortical circuits" but this is really the neuroscientific equivalent of saying "We guess it did something", because the entire brain is made of cortical-subcortical circuits, given that the cortex is at the top and everything else is, by definition, the sub-cortex. It's quite possible. But we really can't tell.

Diamond A, & Ondo WG (2011). Resolution of Severe Obsessive-Compulsive Disorder After a Small Unilateral Nondominant Frontoparietal Infarct. The International journal of neuroscience PMID: 21426244

Shotgun Psychiatry

There's a paradox at the heart of modern psychiatry, according to an important new paper by Dr Charles E. Dean, Psychopharmacology: A house divided.

It's a long and slightly rambling article, but Dean's central point is pretty simple. The medical/biological model of psychiatry assumes that there are such things as psychiatric diseases. Something biological goes wrong, presumably in the brain, and this causes certain symptoms. Different pathologies cause different symptoms - in other words, there is specificity in the relationship between brain dysfunction and mental illness.

Psychiatric diagnosis rests on this assumption. If and only if we can use a given patient's symptoms to infer what kind of underlying illness they have (schizophrenia, bipolar disorder, depression), diagnosis makes sense. This is why we have DSM-IV which consists of a long list of disorders, and the symptoms they cause. Soon we'll have DSM-V.

The medical model has been criticized and defended at great length, but Dean doesn't do either. He simply notes that modern psychiatry has in practice mostly abandoned the medical model, and the irony is, it's done this because of medicines.

If there are distinct psychiatric disorders, there ought to be drugs that treat them specifically. So if depression is a brain disease, say, and schizophrenia is another, there ought to be drugs that only work on depression, and have no effect on schizophrenia (or even make it worse.) And vice versa.

But, increasingly, psychiatric drugs are being prescribed for multiple different disorders. Antidepressants are used in depression, but also all kinds of anxiety disorders (panic, social anxiety, general anxiety), obsessive-compulsive disorder, PTSD, and more. Antipsychotics are also used in mania and hypomania, in kids with behaviour problems, and increasingly in depression, leading some to complain that the term "antipsychotics" is misleading. And so on.

So, Dean argues, in clinical practice, psychiatrists don't respect the medical model - yet that model is their theoretical justification for using psychiatric drugs in the first place.

He looks in detail at one particularly curious case: the use of atypical antipsychotics in depression. Atypicals, like quetiapine (Seroquel) and olanzapine (Zyprexa), were originally developed to treat schizophrenia and other psychotic states. They are reasonably effective, though most of them are no more so than older "typical" antipsychotics.

Recently, atypicals have become very popular for other indications, most of all mood disorders: mania and depression. Their use in mania is perhaps not so surprising, because severe mania has much in common with psychosis. Their use in depression, however, throws up many paradoxes (above and beyond how one drug could treat both mania and its exact opposite, depression.)

Antipsychotics block dopamine D2 receptors. Psychosis is generally considered to be a disorder of "too much dopamine", so that makes sense. The dopamine hypothesis of psychosis and antipsychotic action is 50 years old, and still the best explanation going.

But depression is widely considered to involve too little dopamine, and there is lots of evidence that almost all antidepressants (indirectly) increase dopamine release. Wouldn't that mean that antidepressants could cause psychosis (they don't?). And why, Dean asks, would atypicals, that block dopamine, help treat depression?

Maybe it's because they also act on other systems? On top of being D2 antagonists, atypicals are also serotonin 5HT2A/C receptor blockers. Long-term use of antidepressants reduces 5HT2 levels, and some antidepressants are also 5HT2 antagonists, so this fits. However, it creates a paradox for the many people who believe that 5HT2 antagonism is important for the antipsychotic effect of atypicals as well - if that were true, antidepressants should be antipsychotics as well (they're not.) And so on.

There may be perfectly sensible answers. Maybe atypicals treat depression by some mechanism that we don't understand yet, a mechanism which is not inconsistent with their also treating psychosis. The point is that there are many such questions standing in need of answers, yet psychopharmacologists almost never address them. Dean concludes:

it seems increasingly obvious that clinicians are actually operating from a dimensional paradigm, and not from the classic paradigm based on specificity of disease or drug... the disjunction between those paradigms and our approach to treatment needs to be recognized and investigated... Bench scientists need to be more familiar with current clinical studies, and stop using outmoded clinical research as a basis for drawing conclusions about the relevance of neurochemical processes to drug efficacy. Bench and clinical scientists need to fully address the question of whether the molecular/cellular/anatomical findings, even if interesting and novel, have anything to do with clinical outcome.

Dean CE (2010). Psychopharmacology: A house divided. Progress in neuro-psychopharmacology & biological psychiatry PMID: 20828593

Zapping Memory Better in Alzheimer's

Last month I wrote about how electrical stimulation of the hippocampus causes temporary amnesia - Zapping Memories Away.

Now Toronto neurologists Laxton et al have tried to use deep brain stimulation (DBS) to improve memory in people with Alzheimer's disease. Progressive loss of memory is the best-known symptom of this disorder, and while some drugs are available, they provide partial relief at best.

This study stems from a chance discovery by the same Toronto group. In 2008, they reported that stimulation of the hypothalamus caused vivid memory recollections a 50 year old man. In that case, the effect was entirely unintended and unexpected. The patient was being given DBS to try to curb his appetite (he weighed 420 pounds.) The hypothalamus is involved in regulating appetite, not memory - but the fornix, a nerve bundle that passes through that area, is. It's the main pathway connecting the hippocampus to the rest of the brain, and the hippocampus is vital for memory.

In this new study, Laxton et al implanted electrodes to stimulate the fornix in 6 patients with mild (early-stage) Alzheimer's. What happened? The results, unfortunately, were quite messy. On average, the patients symptoms got worse over the course of the year. Alzheimer's is a progressive degenerative disease, so this is what you'd expect to happen without treatment. The authors say that the decline was a bit slower than you'd expect in these kinds of patients, but to be honest, it's impossible to tell because there was no control group.

However, two patients did show memory improvements, and these were the same two who reported vivid recollections when the electrodes were first implanted (similar to the original obese guy):

Two of the 6 patients reported stimulation induced experiential phenomena. Patient 2 reported having the sensation of being in her garden, tending to the plants on a sunny day... Patient 4 reported having the memory of being fishing on a boat on a wavy blue colored lake with his sons and catching a large green and white fish. On later questioning in both patients, these events were autobiographical, had actually occurred in the past, and were accurately reported according to the patient’s spouse.

Also, the stimulation caused brain activation, generally switching "on" the areas that are turned "off" in Alzheimer's, and this lasted for a year (the length of the study so far). And there were no major side-effects. That's all good.

Overall, these results are extremely interesting, but we don't know how well the treatment really works, and we won't know until someone does a randomized controlled trial with a longer follow-up period; something which is, unfortunately, true of a lot of the latest DBS studies.

Link: The Neurocritic on the original 2008 paper.

Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, & Lozano AM (2010). A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Annals of neurology PMID: 20687206

Inception for Dummies

If you haven't watched Inception yet, don't read this post. It's great and I don't want to spoil it for you. So stop. You didn't though, did you, you're still reading this right now. Well, I warned you.

Inception as everyone knows is about people who can hack into other people's dreams to access their subconcious. The plot concerns their attempts to achieve, well, inception - putting an idea into someone's mind, which makes what they usually do, stealing secret ideas, seem easy by comparison.

The problem is that it's easy to plant an idea, but the victim always knows that it's an external imposition - they don't really believe it. Leonardo DiCaprio comes up with the plan of going into the victim's subconcious's subconcious, and planting an emotional idea about his father, in order to lead him to conclude, on his own, that he should break up his father's business empire. I'm not sure what Freud would have thought of this plan.

Could you actually do this? Well. Hacking into people's dreams is high fantasy: we have absolutely no idea how you'd do that, and in the movie the only explanation we get is that it involves fancy machines and unspecified drugs. It's safe to say no-one will be gatecrashing your dream party any time soon.

But here's one way to achieve the same kind of effect, inspired by two recent papers: this one that I wrote about in my last post, finding that electrical stimulation of the hippocampus produces temporary amnesia, and this one covered at Neurophilosophy, finding that stimulating a mouse's lateral amygdala at the same time as playing it a noise makes it fear that noise.

Simple fear conditioning happens in the amygdala, not the hippocampus (although conditioned fear to some partiuclarly complex stimuli, like places, does.) So assuming you were a neurosurgeon with a desire to do some inception and no ethical scruples whatsoever, here's what you might decide to do.

Knock your victim out with a sedative. Keep them unconscious while you implant electrodes in their hippocampus and their amygdala. Wake them up, but make sure that you constantly stimulate their hippocampus to disrupt it, from the moment they awake. This will leave them fully aware, but will mean they'll have no subsequent concious memory of what you do, because such concious declarative memories depend upon the hippocampus.

Now, you condition them to fear something, by showing it to them whilst stimulating their lateral amygdala. (To be honest, you could just give them a slap in the face and it would probably be just as effective - but that would be a bit unrefined. This is a high-tech evil medical procedure, not a common punch-up.) Maybe you could make them scared of the face of a business rival who you don't want them to cut a deal with. Or you could make a terrorist leader abhor the symbols of his own ideology. The possibilities are endless.

Once you're done, sedate them again and return them to their house. Yeah, you'd have to do this all in the course of one night, but no-one said Inception was going to be easy. With any luck, they'll wake up with no concious recollection of anything, but with the emotional conditioning still intact.

The lack of memory is of course crucial: if they remembered what had happened, they'd realize that the conditioning was an external imposition, and wouldn't be swayed by it. And they'd bust you to the cops, obviously. But without that concious knowledge as to the true source of the feelings, they'd have no alternative interpretation of the fear they now feel - they'd take it as their own, and really start to dislike whatever it was you'd made them afraid of, constructing elaborate rationalizations along the way. The dream is real...

Zapping Memories Away

Imagine you're about to have to do something horrible or embarrasing, like say, admitting that you read Neuroskeptic. Wouldn't it be nice to be able to switch off your memory for a while, so you at least didn't have to remember it?

Well, now you can, as long as you have electrodes implanted in your brain. Lacruz et al, based at London's Institute of Psychiatry, report that Single pulse electrical stimulation of the hippocampus is sufficient to impair human episodic memory.

They took 12 people who were undergoing neurosurgery for severe epilepsy, and found that giving a single brief electrical pulse to the hippocampus caused momentary amnesia. Patients were much less likely to remember seeing a word or a picture presented immediately (within 150 milliseconds) after the pulse.

It only worked if you zapped the hippocampus on both the left and the right side simultaneously; if you only disrupt one, memory is unaffected, suggesting that one can compensate for the lack of the other.

It's been known for 60 years that damage to the hippocampus causes amnesia (e.g.), and previous electrode stimulation studies have shown amnesia after a few minutes of repeated shocks, but this is the first study to show that a single pulse can cause ultra-short memory impairment.

Follow up work confirmed that the stimulation only affected memory, rather than the perception of the items. Stimulation immediately before asking people to remember the items had no effect, showing that the hippocampus is only required for encoding, not retrieval.

This is a great study which adds to our knowledge of the memory functions of the hippocampus - although we need to avoid the temptation to see the hippocampus as purely a "memory module", since it's also known to be involved in space perception.

It's also a good example of why epilepsy patients are the unsung heroes of modern neuroscience - because they're basically the only people in whom it's ethical to do this kind of experiments. Surgeons need to stimulate their brains in order to optimize their treatment. It would be unethical to open someone's skull and poke around their grey matter purely for research purposes, but given that it's going to happen anyway for medical reasons, you might as well do a little research too...

Lacruz ME, Valentín A, Seoane JJ, Morris RG, Selway RP, & Alarcón G (2010). Single pulse electrical stimulation of the hippocampus is sufficient to impair human episodic memory. Neuroscience PMID: 20643192

More on Deep Brain Stimulation for OCD

Over the past few years, deep brain stimulation (DBS) has emerged as a promising treatment for severe psychiatric disorders that haven't responded to conventional approaches. A new paper from the University of Florida reports on a trial of DBS in obsessive-compulsive disorder (OCD), and unlike most DBS studies, it was placebo-controlled: Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder.


Six patients were implanted with electrodes in the "ventral capsule/ventral striatum" (VC/VS). This area has previously been used as a DBS target for OCD. The original reason for choosing to implant electrodes in this region was that it's long been known that destroying the anterior limb of the internal capsule (capsulotomy) alleviates OCD symptoms in many cases, especially if the ventral (lower) part is removed.

Did it work? Yes, but not for everyone. Out of the 6 patients who entered the trial, all of whom were extremely ill despite having tried multiple medications and psychotherapy, 4 (66%) eventually responded well. The other 2 unfortunately got little or no benefit over the 12 month trial period.

The study had a double-blind, placebo-controlled phase: the patients weren't told when the DBS electrodes were going to be switched on. As the graphs show, in the 3 patients who were randomly selected to have them switched on early, 2 responded pretty much immediately, while in the 3 patients whose electrodes were left off, none responded until they were turned on 30 days later, although the response at this point was fairly gradual.

One person (S1), who responded very well initially, suddenly relapsed about a year later. Upon investigation, it turned out that the battery powering their electrodes had worn out, although no-one knew this until the OCD symptoms returned, so this can't have been a placebo effect. They recovered after getting a new battery.

Overall there are few surprises here. These results confirm what we already knew about DBS: it works in many people, but not all, with response rates of around 60%; When it works, it works very well; but sometimes the effects take weeks or months to become fully apparent. This could be either because DBS starts some gradual process of change in the brain which takes time to work; or it could be that it often takes a long time to find the right stimulation parameters (voltage, frequency, etc.) which provide a good response, since this has to be done by trial-and-error. Most likely, it's a bit of both.

What I found most interesting was that the VC/VS stimulation didn't just treat people's obsessions and compulsions. It also had a mood-improving effect, and crucially, it sounds as though mood was the first thing to improve, with OCD symptoms following days or weeks later:

Finding the optimal settings for an individual subject proved challenging...unlike other experiences with DBS, there is not a clear positive symptom (e.g., tremor improvement) to gauge settings. In this study... the goal was to select parameters that produced some benefit in mood or anxiety symptoms acutely, with minimal side effects.

and mood was the first thing that got worse when the DBS was accidentally turned off for whatever reason:

Worsening in mood or increased anxiety were typically the first symptoms reported following battery depletion or inadvertent inactivation by metal detectors. Other signs of depression, such as diminished energy or interest, also emerged within days of device interruption... Exacerbation of OCD symptoms generally lagged the emergence of affective or anxiety symptoms.

And in fact, four people experienced temporary hypomania, i.e. abnormally elevated mood, which is usually seen in bipolar disorder, although none of the patients in this study had a history of bipolar. People also commonly reported increased alertness, motivation, and difficulty falling asleep.

This all fits with the fact that VC/VS stimulation has been used as a DBS target for clinical depression, as well as for OCD. Indeed, this suggests that DBS probably works in essentially the same way in both conditions. The drugs that are used to treat OCD are all antidepressants - specifically serotonin-based ones - so this makes sense too.

With luck, research on DBS in animals and humans will finally allow us to understand the neural basis of mood states like depression, and mania - something which, despite decades of research on drugs like antidepressants and mood stabilizers, is still deeply mysterious...

Goodman, W., Foote, K., Greenberg, B., Ricciuti, N., Bauer, R., Ward, H., Shapira, N., Wu, S., Hill, C., & Rasmussen, S. (2010). Deep Brain Stimulation for Intractable Obsessive Compulsive Disorder: Pilot Study Using a Blinded, Staggered-Onset Design Biological Psychiatry, 67 (6), 535-542 DOI: 10.1016/j.biopsych.2009.11.028

"Cortical Stimulation" for Depression

The last decade saw a number of new experimental treatments for depression based around the idea of using electricity to alter brain function - deep brain stimulation (DBS), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).

The mechanics of these technologies differ, but they're all being promoted as options for "treatment-resistant depression" - depression which hasn't responded to more conventional approaches. They're also alike in that their usefulness is uncertain - either because there have been no randomized-controlled trials (DBS), or because the results of randomized trials are mixed at best (TMS,VNS).

Now there's a new kid on the neurostimulatory block: epidural prefrontal cortical stimulation (EpCS). This involves implanting electrodes beneath the skull, but above the meninges, the "skin" surrounding the brain. So it's unlike deep brain stimulation (DBS), in which the electrodes are placed inside the brain itself.

Late last year, Nahas et al reported on EpCS in a paper, Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression. They took 5 severely depressed patients, with either major depression or bipolar disorder, who'd all tried many treatments and experienced no benefit:

The mean age was 44.2 years. Four were women, and three were diagnosed with recurrent major depressive disorder; two others had bipolar affective disorder I, depressed type. All were unemployed, and three were receiving disability. The average length of depressive illness was 25.6 years. The average length of the current depressive episode was 3 years, 7 months ... participants had received an average of 9.8 unsuccessful clinical treatments during the current major depressive episode ... They enrolled in the study taking on average 6 psychotropic drugs.

Electrodes were implanted bilaterally over the "anterior and midlateral frontal cortex". This is as sensible a place to stimulate as any, although we really don't know what these parts of the brain do, or how they relate to depression. Nor do we know what "60 Hz, 2–4 V, 30 min on/ 2.5 hours off from 8 AM to 10 PM." stimulation does to these areas.

2 weeks after surgery the electricity was turned on, and the stimulation was then optimized over 2-3 weeks. Did it work? Out of the 5 patients, one didn't get any better, two felt somewhat better, and two were greatly improved at the end of the study 7 months post-op. And there were no major side effects or cognitive changes; one patient got a bacterial infection, but it was treatable. Hurrah!

But hang on. There was no control group, so the improvement could have been due to the placebo effect or, more likely, the passage of time. The guy with the single best response, Subject 2, was as depressed as ever during the first 4 months, but then improved dramatically by month 7. It may not be a coincidence that this subject was bipolar. Bipolar people who are depressed eventually stop being depressed - that's kind of the point.

Indeed, all of the others who improved did so between 2 weeks and 4 months after the stimulation was started, not straight away. So it's not like flicking a switch and turning off the depression... but on the other hand it's exactly that if you listen to what the patients say during the operation itself.

They reported feeling happier and less anxious as soon as the current was turned on (they weren't told when this was, so this is unlikely to have been a placebo effect). Some said things like

“I feel attentive,” “feel better and I can talk now,” “I can think clearer.” A patient noted during anterior frontal pole stimulation feeling as if a “weight [was] lifting off my shoulder,” “I feel calm”; another stated, “and although I am worried, I feel
dissociated from it. I can think back at my worry.”

Subject 2, the guy who got much better a long time after the operation, was the only patient who didn't enjoy any nice effects during the operation itself, which only adds to my suspicions that he would have got better anyway.

What does all this mean? It's hard to say. The results are very similar to those seen with DBS for depression - patients report suddenly feeling happier as soon as the current is turned on during the operation (the only placebo-controlled aspect of the trials), but afterwards the improvement seems gradual, taking weeks or months.

There's two main ways of interpreting this. The optimistic view is that stimulating the right bits of the brain instantly treats depression, and the apparent "time lag" in improvement after the operation is a product of the fact that when someone's been depressed for so long, as these patients have, it takes time for them to readjust to normal life even once they start feeling much better.

The pessimistic view is that stimulating the brain doesn't treat depression, it just causes a "high" which doesn't last very long, and the subsequent slow, gradual improvement would have happened anyway.

This is why we need randomized controlled trials. Nahas et al note that there has been one randomized controlled trial of EpCS for depression, comparing active EpCS to placebo EpCS with the electrodes switched off. It hasn't been published yet, but a preliminary analysis found no difference between the two conditions - it didn't work. And that trial was more than twice as big as this one (12 patients vs. 5). But, they point out, in that trial only the left side of the brain was stimulated, whereas they stimulated both sides.

Overall, just like DBS, EpCS could be either a great leap forward or a waste of time, money and neurosurgery. Hopefully, by the end of this decade, we'll know. Watch this space.

Links: Dr Shock covered this paper when it came out.

Nahas, Z., Anderson, B., Borckardt, J., Arana, A., George, M., Reeves, S., & Takacs, I. (2010). Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression Biological Psychiatry, 67 (2), 101-109 DOI: 10.1016/j.biopsych.2009.08.021

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 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