Monday, 15 July 2013

Deep brain stimulation: Treating or tampering with our brains?

A history of trial and error

Tampering with the brain is inevitably fraught with risks. Everything seemed fine when Henry Molaison awoke from the operation to treat his epilepsy. But all wasn’t well: his ability to form new memories was severely impaired. In the words of Benedict Carey: “For the next 55 years, each time he met a friend, each time he ate a meal, each time he walked in the woods, it was as if for the first time”.

When it comes to mental health, there is a history of trial and error with the development and use of brain treatments. The surgical lobotomy (pre-frontal leucotomy) which was widely practiced in the 1950s is one such example, where the aim was to modify the brain to change moods, thinking, and behaviour. Most people will agree, that despite early optimistic reports on its use, it was a crude and disastrous failure that left many people “debilitated by serious brain damage” (Nuffield report p. 3).

Over the years many mental health drugs have been marketed under the pretext that they might correct imbalances in brain function or structure. They do, however, create all manner of unwanted ill-effects and carry serious risks too. What’s more, there is a view that they create rather than correct chemical imbalances in the brain[1]. To those with an entrepreneurial spirit - this apparent failure to consistently, successfully and safely modify the brain to address psychiatric concerns - may seem like a beckoning gap in the market place.

Novel neurotechnologies such as Deep brain stimulation

New procedures (“novel neurotechnologies” as they are often called) are currently being developed to try and adjust how the brain functions. These are already attracting considerable interest and investment. One such novel neurotechnology is Deep brain stimulation (DBS), in which electrodes are implanted deep within the brain and are then connected to a battery that is implanted in the chest. Then an electric current (modulated by a remote control device) is delivered to a specific location within the brain. It is sometimes compared to a heart pacemaker. Well, that’s the theory. [...]

Neurosurgeons have seen degrees of success in treating neurological disorders (such as Parkinson’s disease) with DBS and are now keen to move further into what they describe as “neuropsychiatric disorders”. The cautious will wonder if history is to some extent repeating itself. And DBS does come at a price. In 2010 a commissioning group in the UK “estimated the average cost of DBS was £33,000 per patient (including surgery, hospital stay and follow-up).” (Source p. 66)

There are various neurotechnologies being developed and some are already in use for psychiatric-type concerns.  In the UK, Transcranial magnetic stimulation has NICE approval for use with severe depression, Vagus nerve stimulation also has approval for severe depression (and some forms of epilepsy), and Deep brain stimulation is an experimental treatment for severe depression and for what is popularly called OCD. It seems reasonable to ask if these developments are a matter for celebration or a cause for concern. We need to take a closer look.

As Dr. Andres Lozano is one of the key pioneers of Deep brain stimulation I will use one of his brief promotional talks as a point of focus and consider DBS in a little more detail. You can see a TED talk by him here.

Dr. Lozano presents as a skilled, caring and devoted neurosurgeon; I respect that, and am sure that there are many people who have a new quality of life resulting from his work. My concern is less about what he has been doing but more about where he and others seem to be heading.

I welcome the transformations and reduced suffering that some people with neurological disorders clearly experience from DBS. And yet, after watching this video (and similar videos by other people) I felt in some way as though I had been listening to a sales talk. It was slick, polished, and seemed just too good to be true. Perhaps it is all of these.

Examples of miracle-like cures are impressive, but I missed some slides with references to clear and independently assessed evidence-based data: data that may well be available. I would rather be wowed by the data than by images of apparent success. And I’m not wowed by brain scans – let’s not forget the dead salmon spoof! But this video does not tell me of success rates, risks, side-effects or failures. This is of course just one short video and too short to consider important ethical issues and possible conflicts of interest.

Ethical concerns - Balancing business and patient interests

The recently published report (Novel neurotechnologies: intervening in the brain, 2013) by the Nuffield Council on Bioethics draws attention to some relevant ethical issues.

With developments such as DBS there can be “close financial links between the companies and clinicians and surgeons” (Nuffield Sec 3.66) which could create conflicts of interest. In addition, clinicians (including neurosurgeons) may be involved in each stage of the process, including invention, the development of devices, and ensuring there is a marketable product. In fact, “they often act as enthusiastic promoters for these devices (Sec 3.66).” It is also true that clinicians can hold intellectual property rights such as patents, and design rights (Sec 3.49). And in the US it is “possible to patent a procedure (Sec 3.49)” too.  

Dr. Lozano is Director and a co-founder of Functional Neuromodulation Ltd – a company that has raised a total of $13.4 million in funding commitments and also lists Medtronic (a key producer of DBS equipment) as a parner/investor. In fact, Dr. Lozano is a consultant for Medtronic. The other co-founder and CEO of Functional Neuromodulation is Dan O’Connell, who has close links with the pharmaceutical industry. O’Connell is also co-founder and managing general partner of NeuroVentures “dedicated to investing in companies focused on the discovery, development and marketing of new drugs, medical devices … to treat Central Nervous System disorders”. As we can see, this is a global business and to date “more than 100,000 people worldwide have received Medtronic DBS therapy”.

Dr. Lozano has “reported a potential conflict of interest, which is that he holds intellectual property in the field of deep brain stimulation (DBS)”. Although the TED talk does not mention the fact that he holds these patent rights, this is made clear at the Functional Neuromodulation website: “He is an inventor on numerous patents as an individual and jointly with leading neuromodulation innovators”. And patents are money makers: US patent records for 2010 show that royalties expected to be paid to neurosurgeons range from $7,000 to $8.261 million. (Nuffield Sec 3.69)

As I said earlier, I felt I had been listening to a sales pitch with the video by Dr. Lozano. It seems I was, to some extent at least, correct in this impression. And one wonders how often TED talks are part of a carefully orchestrated marketing campaign – one assumes it is free advertising.

It’s not that there is anything intrinsically wrong with profiting from businesses that provide health treatments. But pleasing investors and keeping patients’ interests to the fore can be a difficult balance.  It is reasonable to want to know that novel neurotechnologies will not put company and investor profits before the health of those being treated. This is in no way intended as insulting to those developing these technologies: it’s simply a healthy caution.

Bold and simplistic claims make me uneasy

It’s also the bold and simplistic claims that make me cautious. The text accompanying the TED video we have referred to informs us that “Deep brain stimulation is becoming very precise. This technique allows surgeons to place electrodes in almost any area of the brain, and turn them up or down - like a radio dial or thermostat - to correct dysfunction”. The problem is, Dr.Lozano tells us in the video, “rogue neurons misfiring and causing trouble or underactive and not working as they should.”

Other promoters of DBS also speak about the brain in mechanistic and simplistic ways. "The brain works on a circuit board," says Dr. Helen Mayberg, who has been working on DBS as a treatment for depression in conjunction with Dr. Lozano. There are, according to Dr. Thomas Schlaepfer, multiple networks in the brain which can become “misconnected” in mental illness. He asserts that DBS “retrains these dysfunctional networks”. Thus, what is commonly called ‘OCD’ is, in the words of Dr. Brian Snyder, a "disorder of neurocircuitry" or what Dr. Wayne Goodman describes as a kind of "reverberating circuit”(Source).

Neuropsychiatrist Martijn Figee speaks of “resynchronization of a whole brain circuit”. In a study co-authored by Dr. Figee there is the suggestion that DBS is able to “restore disease-related brain networks to a healthy state”. Neuroscientist Rodolfo Llinas claims that there is “an abnormal brain rhythm” behind a “range of neurologic and psychiatric conditions” and DBS is successfully modifying the rhythm of the brain. And if these claims aren’t bold enough, Dr. Lozano adds “We’re upgrading the hardware of the brain”.

Mindful of the fact that the human brain is wonderfully complex, I find these technical explanations (often analogous to computer technology) over-simplified and unconvincing.  Can complex social and emotional experiences really be reduced to “circuit disorders” and be corrected by “tuning synaptic activity”? Can what are conventionally labelled as depression, OCD, mood disorders, addictions, eating disorders, and ‘schizophrenia’ really be reduced to “networks disturbances” within the brain, as is being claimed? I wonder. But I am no scientist. I am, however, left wondering to what extent these “discoveries” are tantalising mirages along the route towards understanding (or miss-understanding).

Consider sadness or depression.  Dr. Lozano tells us that “Area 25 is the sadness area of the brain” and that “this area lights up” when we think about a sad memory. “Depressed people have hyperactivity in this area of the brain… the thermostat is set at 100 degrees”, he tells us. We are then told that electrodes “turn down the sadness”. Yet again I am left wondering. Is it safe from a whole person perspective - bearing in mind that memories are formed through experiences and social interactions - to mechanistically try to over-ride natural processes in this way?

The audience warmly applauded Dr. Lozano when they saw ‘miraculous’ results in response to DBS for people with neurological disorders. But I wonder how many in the audience stopped to think when he transitioned from neurological disorders like Parkinson’s disease to speaking about so-called psychiatric problems, such as depression, OCD and the like. Did they uncritically assume that these were similarly and primarily neurological conditions? Did they also assume that the same miraculous effects could (or will soon) be seen from the use of DBS with mental health concerns? As far as I can see, the studies for DBS with depression and ‘OCD’ don’t appear compelling. And as with drug trials, there is also the possibility of selective selection that can bias results (p. 394). Here I briefly summarise and/or comment on a few studies.

Depression study and DBS

The Schlaepfer et al study  2013 (part-funded by device makers Medtronic, Inc.) is only a pilot study and not a double-blind randomised controlled trial. It is only a small study: “Seven patients were observed for 12 weeks. Four patients were tracked longer (up to 33 weeks).” It would be difficult to claim that the DBS was effective as “The majority of patients were treated with antidepressants and psychotherapy during the study, and only one patient stopped medications, which was associated with a relapse in depression.” From the study design there is no way of knowing if any apparent benefits were a placebo effect. The study concludes: “DBS for Parkinson’s disease is associated with an unexpectedly sizeable sham response. DBS is certainly a major invasive intervention, which at least in principle could be associated with sham effects even in treatment-resistant psychiatric disorders.”

OCD studies and DBS

The Figee et al study 2013 on the use of DBS with ‘OCD’ is a small study of 16 patients but does have a comparison group of 13 healthy controls (all of whom had electrodes implanted in the nucleus accumbens area of the brain). One of the authors, who co-performed neurosurgery and edited the manuscript, is an independent consultant for Medtronic Inc. The study reports symptom reduction.

The Mallet et al study 2008 for DBS with ‘OCD’ was double-blind. It reported that “There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events.” That study concluded: “These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events.”

This does of course raise concerns over the risk-benefit ratio of the treatment. And that is something that does not come across in the Lozano video – RISKS. In fact, he says that neurosurgeons can “reach just about anywhere in the brain quite safely now”. Misleading?

Risks

DBS is an experimental treatment, and the benefits and risks will vary to some extent depending on where the DBS electrodes are placed within the brain. But whatever the specific target, DBS is an invasive treatment, as is any brain surgery.

The TED video we have focused on showed dramatic effects from DBS with Parkinson’s disease. Although there isn't a hint of risks or disappointments, studies paint a more complex picture. A closer look at study results shows a range of known adverse effects, affecting movement and/or speech (e.g. verbal fluency) and sometimes leading to manic symptoms, hypersexuality, weight gain, apathy, depression, anxiety, hallucinations, attempted and/or completed suicide, and deterioration in the symptoms of dementia.  

The mere fact of having brain surgery comes with risks. The Baylor College of Medicine patient information website addresses some of the risks associated with DBS surgery: “There are potential risks associated with any brain surgery, including infection, intracerebral bleeding, leaks of the fluid surrounding the brain (cerebrospinal fluid), strokes, headaches, seizures, weakness, sensory changes, technical problems, wound healing problems, disfiguring scars… Additionally, there may be potential risks associated with receiving anesthesia.”

So, where does this take us?

Simple analogies that try to explain complex problems carry popular appeal. Psychiatry has run with the idea of chemical imbalances for some years - though we now recognise that attributing mental and emotional concerns to high or low neurotransmitter levels in the brain is a gross oversimplification. Is one myth (chemical imbalances) now being replaced by another (neuro-circuit disorders)? If tales of “misconnected neuronal networks”, “rogue neurons misfiring and causing trouble” and “abnormal brain rhythms” that can be adjusted “up” or “down” are really the root of these problems and not a substitute spin, we need clear evidence that this is so. 

At a time when pharmaceutical companies have withdrawn interest and investment from developing new psychiatric drugs, a novel neuro-metaphor may be just what some in psychiatry ‘need’ to attract Pharma attention once again.

And how does DBS work? It seems to me that there is a dearth of evidence and we are left guessing: “Little is known about the underlying neural mechanism of deep brain stimulation” (source). And, as I understand it, brain damage can lead to a feeling of euphoria. When treating depression, could any perceived benefit (aside from placebo effect) be iatrogenic brain damage?

Adverse effects from psychiatric drugs can sometimes go unrecognised as side-effects. This occurs when the side-effects are so similar to the problems being treated, e.g. anxiety, depression, panic, agitation, and suicidality. The fact that “DBS can also be associated with complex unintended effects on mood, cognition and behaviour (Nuffield p. xviii)” poses similar ethical concerns when used to treat mental health concerns.

I am fearful that hope and investment in these treatments will run way beyond a genuine understanding of the human brain. Bearing in mind the “checkered history of psychiatric neurosurgery”, Dr. Insel and Dr. Wayne Goodman have said that the scientific and medical communities “owe the public a promise that clinical applications of DBS in neuropsychiatry will not overstep the bounds of empirical evidence.” Will they and others (including neurosurgeons and any others with a vested interest in these neuro-technologies) actually make (and keep to) that promise?

As you will realise, I remain unconvinced by bold technical explanations (often analogous to computer technology) that try to explain human emotions and behaviour in simplistic terms without due regard for the cultural, social, political, ethnic (injustice and discrimination) and/or economic (including social inequality) factors and circumstances of a person’s life.

I admire Dr. Lozano’s enthusiasm: “We can place electrodes anywhere in the brain. It’s like exploring space. There is so much that’s unknown and so much to discover. That’s where the excitement is (source).” But it’s where he and others are heading that worries me. I see no evidence that what they refer to as neuro-psychiatric problems are simply or primarily brain disorders. And tampering with the brain is inevitably fraught with risks. Risks worth taking?

“The appeal to brain science as an explain-all has at its heart a myth…”
- Prof Raymond Tallis

Mick Bramham is an Existential Psychotherapist based in Dorset, UK.
He has a particular interest in ethical issues and also how our lives are shaped by the society, circumstances and culture in which we live.
He trained at Regent's College London, and is a member of the Society for Existential analysis. 
Although he has serious concerns about the inappropriate and excessive use of mental health medications, he supports the freedom to choose (to take or not to take these drugs) and the right to be fairly informed of their limits and the risks. He offers support for people who are considering reducing or coming off psychiatric drugs.
He has a long-standing interest in non-clinical (and non-coercive) responses to mental and emotional distress.
You can read more about his work and find his contact details here. Follow Mick on Twitter @MickBramham




[1] Moncrieff, J. (2008) The Myth of the Chemical Cure. UK: Palgrave MacMillan

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