Circuit Neuroscience

Recently, research into psychiatric disease has made great strides, but continued progress may require unpopular and ethically murky research. Joshua Gordon, the new director of the National Institutes of Mental Health writes in this month’s Nature Neuroscience:

“At this unique and exciting time for psychiatry, novel therapies for individuals with mental illnesses seem just around the corner. In particular, recent technological advancements in the study of neural circuits provide reasons to be optimistic that the field is headed in the right direction. Nonetheless, maximizing the chances of translating these advancements into real improvements in patient care requires a carefully considered road map.” – Joshua Gordon, “On Being a Circuit Psychiatrist”

Gordon, a professor at Columbia University, studies ‘circuit neuroscience’—a new term given to the subfield of neuroscience that uses new technologies to monitor and manipulate very specific subgroups of neurons within the brain and measure their behavioral effects.

To give you an idea of circuit neuroscience, here’s a short talk Gordon gave about his research in 2011, describing how the coupling between two brain regions, the hippocampus and medial prefrontal cortex, may be disrupted in anxiety disorders and schizophrenia:

In the time since Gordon gave that talk, his lab has extended these findings from mere correlations to causative mechanisms of disease, in a new study, which shows that, amazingly, inhibiting the connection between the ventral hippocampus and medial prefrontal cortex decreases anxiety-like behavior in mice.

This kind of finding is really exciting. While my anxiety might be more abstract and existential than a mouse’s (for example, no mouse is worrying about the 2016 presidential election), the basic brain systems for fear are thought to have been conserved throughout evolutionary history, so there is good reason to think that these findings are relevant to helping humans who suffer from anxiety disorders.

Alright. So we can decrease anxiety in mice, so why don’t we do the exact same thing in humans? Can we specifically inhibit that connection between the ventral hippocampus and medial prefrontal cortex in humans using the same technology we used for mice?

An example of the kind of combinatorial targeting optogenetics allows. From neurowiki.

In the mouse study, Gordon inhibited the specific pathway using optogenetics, a technique that uses genetics to target cells with a certain biological profile in a certain area of the brain, and make those cells express a special protein that, when you shine line on them. Then they insert fiber-optic cables into a specific part of the brain. When they turn the light on they only affect the cells in the area where they’re shining the light which matched the biological profile of interest. So in this case they used genetic techniques to make cells in the ventral hippocampus express the light-sensitive protein, and then shined light into the medial prefrontal cortex to specifically inhibit communication from the ventral hippocampus to the medial prefrontal cortex.

Unfortunately, while theoretically this same approach should work in humans, we can’t implement it using the exact same technology and techniques we’ve developed with mice. For example, most of the technology we’ve used to genetically target groups of neurons in mice, only work in mice that have been given mutations that allow those cells to be genetically targeted. (Incidentally a big part of why this type of research is done in mice in the first place.) Additionally, the equivalent circuits and brain areas in humans are much bigger and methods for delivering the light-sensitive optogenetic proteins or light itself don’t always scale. Modifying these approaches to work in humans is going to take some troubleshooting in bigger animals. And here is where Gordon in his opinion piece has buried the lead:

“For some questions, like how to transduce and illuminate large brain regions, any large animal model might suffice. Indeed, attempts to use gene transfer models for the treatment of chronic pain have used large animal models to induce widespread central nervous system expression of pharmacogenetic effectors¹³. But for other questions, such as how to direct gene expression to specific prefrontal cortical regions, only primate models will suffice¹⁴. Given the current societal pressures against nonhuman primate research, strong ethical as well as scientific foundations will be required in order to facilitate this important work.” –“On Being a Circuit Psychiatrist”

The Primate Paradox – Ethics of experimenting on Non-human Primates and the ethics of experimenting on humans

Gordon clearly has protecting the need for primates model organism on his mind–and with good reason. In late 2011, the United States Institute of Medicine declared that “most current use of chimpanzees for biomedical research is unnecessary,” and the NIH began to dramatically cut funding of research and retire laboratory animals. In 2015, a new rule by the the U.S. Fish and Wildlife Service (FWS), ended a loophole allowing invasive research on chimps despite their endangered species status and effectively banned biomedical research on chimps in the U.S.

Then this September, twenty-one eminent scientists and naturalists, including David Attenburough and Jane Goodall (both of whom I greatly respect), signed an open letter they sent to The Independent newspaper calling for the end of neuroscience research on all primates that involves deprivation from fluids and movement restraint, citing a recently published article by Bailey and Taylor in the journal Alternatives to Laboratory Animals. In that article, Bailey and Taylor take a more extreme stance, arguing not just against fluid-deprivation and movement restraint but primate research in general. They argue that recordings from primates have been made obsolete and are no longer worth the harm they cause because of advances in techniques that allow us to record from humans: either non-invasively through techniques like fMRI or through invasive recordings performed alongside neurosurgeries on patients being treated for diseases. Neither of these techniques though can be used to answer the question Gordon poses of studying how to direct gene expression to specific prefrontal cortical regions.

It’s extremely important to think about the ethics of primate research. Translational research on primates has a fundamental ethical paradox: it is the similarity between primates’ brains and our own that makes an intervention that was effective on a primate likely to also be effective in humans, but that same similarity brings them closer to our moral sphere. It means we need to be more careful when we consider whether these experiments are ethical given the pain or suffering they might cause (despite anesthesia and pain medications being given to animals). But we must also consider the burden of uncured brain diseases and what will happen if we don’t perform this experiments on animals; is it more ethical to perform these same experiments on people—people so afflicted by disease that they are willing to try experimental brain surgery?

One of my uncles suffered from Parkinson’s, a disease that makes movements slow, rigid, and difficult to initiate, and is often accompanied by a tremor in the hands and distortion of speech. As a retiree and avid golfer, the tremor and movement problems seemed especially cruel. At first his symptoms could be treated with medication, but after the meds stopped working, as they do in all cases of Parkinson’s, my uncle elected to undergo a radical treatment, one of the first and most circuit neuroscience treatments in medical history.

Doctors performed neurosurgery on my uncle, cutting open his skull, and implanting a device, known as a deep brain stimulator, into a precise location of the brain, the subthalamic nucleus, After the surgery, when they turned the stimulator on his symptoms were greatly improved, and he went from a man who was incapacitated to a man who could again play golf.

Deep brain stimulation, and all neurosurgery for that matter, has a long history of research on primates, going all the way back to experiments done on primates by Horsely and Clarke in 1908, which developed the devices for accurately targeting regions within in the brain, and paved the way for neurosurgery. STN deep brain stimulation in particular was researched on a Parkinson’s model in macaque monkeys, as Bailey and Taylor acknowledge in their review of the ethics of Nonhuman Primate Research that argued primate research is no longer necessary:

“Advocates of NHP [Non Human Primates] research claim that macaque experiments (subsequent to the development of the so-called ‘MPTP macaque model’ of PD in 1983) have been indispensable to its development, and specifically to the development of DBS of the subthalamic nucleus (STN). Indeed, this argument, in addition to the others described in this review, is repeatedly used as a ‘flagship’ to showcase NHP neuroscience as a means of convincing the public, as well as regulators and legislators, that NHP neuroscience is vital to progress in neurological medicine (e.g. 17, 41, 88–92). However, in common with BOLD fMRI above, this is of historic interest only, and has little or nothing to add to the critical consideration of the current and future value of NHP neuroscience.”

Bailey and Taylor then further argue that non-human primate research may have been unnecessary for researching Deep Brain Stimulation of the STN. They cite the history experimental work on humans that preceded the creation of the MPTP macaque model of Parkinson’s as evidence that the macaque research was unnecessary. They concede that the deliberate targeting of the STN (as opposed to surrounding regions) emerged from the macaque research, but say the technique was refined through human surgeries, and that they think that these discoveries would have eventually been made through human research.

However, I feel they miss some key points both scientific and ethical. For example, they argue post-mortem anatomical studies following electrode implantations can be done in humans and may even give better data than experiments performed on non-human primates. While this is true, human patients like my uncle, often live for years after these surgeries are performed, so researching only humans would slow down the pace of such experiments by orders of magnitude. And with millions of patients suffering around the world, the speed of these discoveries is imperative. Additionally, Bailey and Taylor, insist that the same discoveries would have eventually been made by experimenting on humans, but seem to ignore the ethical problem of imposing unnecessary risks of those experiments on humans.

Sources: Annual Report Animal Usage by Fiscal Year, United States Department of Agriculture, Animal and Plant Inspection Service, July 2011. From goo.gl/OSD6KR.

I understand why people oppose research on non-human primates and why we need to consider these ethical questions. Frankly, I’m not sure I could perform the experiments myself because I wouldn’t want to be there right in front of a primate in pain. At the same time, I know that many of the people who work with non-human primates are doctors working to cure diseases they have to see patients, human primates, suffering from every day. I also know many researchers who studied neuroscience or went into research to work on diseases that affected their friends or family. Hearing about my uncle’s experience influenced the lab I joined in graduate school.

At the same time, I also know, not from personal experience but from the history of the field that some callow scientists have disregarded the life of animals in laboratories, and we need systems put in place to prevent those kinds of acts. Does research that involves deprivation from fluids and movement restraint (that David Attenburough and Jane Goodall signed the letter protesting) fall into that category? I’m not sure.

I think we can experiment on primates without causing them unnecessary pain. However experiments will likely cause the moderate pain that humans experience in surgery, and will likely require the euthanasia of animals. Like euthanizing a pet, I don’t think animal euthanasia is inherently immoral or unethical. I think the only pain from death is felt by friends and family, and therefore painlessly euthanizing an animal in and of itself is a neutral act (but I understand some may not agree with this viewpoint).

With those caveats in mind, I think we end up with a two level ethical problem. On the first level we have to decide how you value human versus animal lives, especially these animals whose consciousness might be very similar to our own, and also how much we value the importance of consent. From a utilitarian perspective, if we then end up with a gray area where we value a consenting-humans life over a non-consenting ape, but not absolutely, than we get to the second level. We must perform a cost-benefit analysis to compare the harm we inflect on chimps to the benefit that humans will derive. But assessing the benefit is a scientific argument, and will depend on scientific and medical intuition and is ultimately unknowable. And experts like with those most knowledge about the likelihood of benefits, are scientists and doctors, who may have their own biases. (For example, those who have do invasive research on apes want to continue funding their labs, self-selected into doing this research, and would suffer huge amounts of guilt and cognitive dissonance if they concluded invasive primate research was unethical.)

Some may disagree with these ideas, saying we have no right to experiment on animals, even if, from a utilitarian perspective, the ends may justify the means and the tens of millions of humans suffering from psychiatric diseases right now stand to benefit (not to mention future generations).

Animal rights activists might argue this is a speciesist argument: we must protect the individual voiceless primates that would be experimented on from the tyranny of the human majority, and that doing these experiments on animals would be just as immoral as doing them on humans (though by that logic that makes most of us cannibals, and by that logic stopping factory farming should be animal activists greatest priority since, unlike research, there are no benefits other than hedonistic ones to eating meat).

Conclusions

The laboratory I work in at Tokyo University uses mice. Every year, the labs in our institution gather for a “doubutsu jikken kuyo,” a memorial service to honor the animals sacrificed in scientific research.

Picture of a Doubutsu Jikken Kuyo held at Nippon Pharmaceutical University in 2009.

Two days ago I attended this year’s memorial. I thought about the nonhuman primates who unwittingly, and unwillingly sacrificed their lives. I thought about my Uncle, who died this year and whose memorial service I could not attend, and how he benefited from circuit neuroscience therapy. And, I thought about how this is just the beginning of circuit neuroscience, and how this science will incrementally move forward—but only, if we allow it.

Like most ethical questions, there are no clear answers here. However, if you oppose research on primates, I ask you to consider the millions of people suffering from psychiatric diseases and neurodegenerative diseases that stand to benefit from potential therapies, and the risks they will have to take in searching for cures, if we don’t perform experiments on primates.

To repeat the quote from the start of this essay:

“At this unique and exciting time for psychiatry, novel therapies for individuals with mental illnesses seem just around the corner. In particular, recent technological advancements in the study of neural circuits provide reasons to be optimistic that the field is headed in the right direction. Nonetheless, maximizing the chances of translating these advancements into real improvements in patient care requires a carefully considered road map.” – Joshua Gordon, “On Being a Circuit Psychiatrist”

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If this has gotten you thinking about ethical issues, I recommend Harvard professor Michael Sandel’s free online course and book:

Justice: What’s the Right Thing to Do?