Invasive experimental procedures such as deep brain stimulation, cell transplantation, and gene therapy offer the potential to treat a variety of debilitating neurological conditions, but they also raise ethical dilemmas.
Experts in the use of each of these techniques discussed the ethical issues during the William Safire lecture on Neuroethics, held at the FENS Forum on Neuroscience in Barcelona last week.
Helen Mayberg, professor of psychiatry, neurology, and radiology at Emory University School of Medicine, discussed the use of deep brain stimulation (DBS) for the treatment of drug-resistant depression. DBS is a surgical technique that involves implanting electrodes that deliver electrical pulses to, and alter the activity of, specified brain regions. In 2002, the FDA approved its use for treating Parkinson’s disease, and so far the technique has been used to treat around 85,000 people who have the condition. It has also started to be used to treat other conditions, including obsessive-compulsive disorder, depression, addiction, and eating disorders.
Earlier this year, Mayberg and her colleagues published a small trial showing that DBS appears to be both safe and effective for treating drug-resistant depression and bipolar disorder for up to two years. She pointed out, however, that there are already many misconceptions about its therapeutic potential.
“There’s a plethora of small studies that show promising results and this has been picked up by the media,” said Mayberg, also a member of the Dana Alliance for Brain Initiatives. “It’s as if we already know the answer. But this is still at the experimental stage and is only just moving toward full-scale, properly controlled clinical trials.”
She added that researchers still can't tell which patients would be most helped by DBS; as well, the long-term implantation of electrodes carries the risk of infection and permanent brain damage, neither of which has yet been adequately assessed. And assuming that the implants are permanent, who should be responsible for maintaining them and repairing them if they malfunction?
Psychiatrist Damiaan Denys of the University of Amsterdam used specific cases to demonstrate that DBS can sometimes have unexpected—and unwanted—side effects. Denys and his colleagues have used the technique to treat around 75 patients with obsessive-compulsive disorder (OCD), depression, heroin addiction, and eating disorders.
One case was that of an artist in his sixties who had suffered from severe depression for 25 years. He responded very well to DBS, but became far more impulsive as a result, to the extent that his wife asked the surgical team to lower the voltage of the implant, “to make him a little more depressed again.”
“There’s a huge gap between assessing efficacy as a doctor and what the patient feels,” says Denys. “The sudden and dramatic change can cause problems for the family because they do not recognize the person they have known, whose illness they have learned to cope with.”
Another was a 26-year-old woman with severe OCD, who washed her hands for 6–8 hours a day. Denys and his team spent more than a year adjusting the settings on her electrodes, and although the treatment significantly improved her mood, it did not alleviate her OCD symptoms.
“This is an extreme case that was a tough ethical problem for us,” says Denis. “It’s not our duty to induce artificial happiness, so we decided to stop the stimulation. This raised a lot of controversy in the treatment team, the patient’s family, and throughout the country. But eventually, we found good settings that diminished her OCD symptoms without initiating happiness.”
John Rothwell, a professor of human neurophysiology at the Institute of Neurology in London, discussed the use of DBS as a treatment for Parkinson’s disease. He stressed the importance of testing large numbers of patients to determine who will best respond and what the likely side effects will be. He noted that we have just reached this position with Parkinson’s disease. Extensive testing shows that younger patients without significant cognitive or psychiatric symptoms are the ones who respond best to DBS, and that increased depression, apathy, and impulsivity are possible side effects in these patients.
With other conditions, however, there is still a long way to go—to date, about 200 patients with OCD and 180 with depression have been treated using the technique. “To get this amount of information about using DBS to treat other conditions is going to be very difficult,” says Rothwell, “and we’ll end up with patients undergoing treatment with insufficient evidence.”
Rothwell also discussed brain stimulation techniques that are non-invasive—transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS)—as a treatment option for people with depression and to improve rehabilitation for people recovering from stroke.
“Some are now thinking of using these techniques not only to treat diseases but also to enhance cognitive function in healthy people,” says Rothwell, “and the ease of these techniques will make it difficult to control their applications.”
Parkinson’s disease is characterised by the death of midbrain neurons that produce the neurotransmitter dopamine, so other potential treatments for the condition include replacing the dead neurons with transplanted cells, or to enhance dopamine synthesis with gene therapy.
Roger Barker, a professor of clinical neuroscience at the University of Cambridge, discussed the ethical issues raised by these approaches. He referred to one small study, which showed that direct infusion of glial cell line-derived neurotrophic factor (GDNF) into the brain led to improvement in five patients by inducing sprouting of new fibers among the remaining dopaminergic neurons. On the basis of these results, another study involving 10 more patients was conducted, with similar results.
Neither study, however, was double blind or placebo-controlled, the gold standard for clinical trials. All fifteen participants knew that they had received the treatment, as did the researchers involved.
A properly controlled trial was then carried out, involving 34 more patients, some of whom were infused with salt water instead of GDNF. This time, no difference was observed between the two groups of patients.
“The consequence was that GDNF was not given to any more patients,“ says Barker, “and those patients who had benefited from it had it withdrawn. The message was that growth factors are ineffective treatments for Parkinson’s because a double blind, placebo-controlled study it has been found not to work, but the power to detect something with such small studies is, at best, marginal.”
Cell transplantation treatments raise other ethical concerns, because the cells used are often derived from aborted fetuses, and because a properly conducted clinical trial involves a control group that receives sham surgery, in which control patients undergo the same procedures as those who are actually going to receive the treatment.
“All patients go to [operating] theater and have a hole drilled in their skull,” says Barker. This brings many risks, and raises major questions about whether we should be doing sham surgery in trials of this nature.”
“Many would say that cell transplantation and gene therapy for Parkinson’s should be consigned to history, but I would say that what we’ve learnt is that we still have no idea how to do these studies.”