BY NIKOS K. LOGOTHETIS, FRIDAY, NOVEMBER 28, 2014

The research aim of the physiology department at the Max Planck Institute for Biological Cybernetics (MPIBC) is to understand the connectivity and operational principles of the neural networks underlying our cognitive capacities. We see the brain as an exquisite example of a so-called dynamic “complex system”, in which the behavior of the whole cannot be predicted from its components.  Complex systems – typically characterized by decentralized control and self-organization – are ubiquitous in nature, ranging from non-adaptive weather and climate patterns to highly adaptive ones such as economies, genomes, and nervous systems. Simultaneous measurement of activity on different spatio-temporal scales is highly useful if we wish to understand the behavior of such systems. Over the last two decades our institute has worked to develop and refine an internationally highly acclaimed methodology that permits just that: concurrent intracranial recording of local neural activity and functional Magnetic Resonance Imaging (fMRI) of the entire brain of animals.

The application of this method has made significant contributions, amongst other things, to a better understanding of functional magnetic resonance imaging (MRI) itself^1,2. Non-invasive imaging methods such as fMRI or positron emission tomography (PET) can only measure surrogates of neural function, e.g. local metabolic changes in tissues. For this reason it is vital that we comprehend the neural processes underlying such metabolic changes in order to be able to correctly interpret the functional scans used to assess the condition of patients with various neurological or psychiatric diseases.

Our laboratory is primarily interested in basic neuroscientific research, performed without any a priori thoughts of immediate practical ends. We hope to discover the very basic neural principles underlying capacities such as perception, recognition, learning and memory. Understanding such principles is the only way to successfully cope with devastating disorders and reduce the invasive character of many clinical procedures applied for their diagnosis and treatment. Specifically, multimodal measurements permit the mapping of cooperative activity patterns of a large number of brain regions that may be correlated with local physiological events in different brain regions. For instance, recently we published the first description of multiple-structure activity (MSA) related to certain hippocampal events which are thought to underlie the process of memory consolidation in humans and animals³. Yet, beyond the fundamental value of such system-state descriptions for the study of memory, fathoming the relationship of MSA to the activity of small local neural populations may itself allow the non-invasive identification of clinically relevant neural episodes. Currently, these can often only be circumstantially investigated in patients during the pre-operative intracranial recordings serving to localize pathological activity, e.g. site of epileptic seizures.

Our research is carried out in nonhuman primates (NHP) and rodents. The biophysical properties of single neurons and microcircuits of small neuronal populations can be studied in any animal, and such studies significantly increase our knowledge of microprocesses. But to understand our brain systems and eventually to gain insights into human behavior and its disorders there is no substitute for research in nonhuman primates with the same basic macro-connectivity patterns and cortical organization as humans. At the same time, it cannot be denied that that same structural and functional similarity of brains between humans and the NHPs poses some difficult ethical problems, because this very similarity increases the likelihood that primates experience pain and suffering in ways that are similar to humans. The aims and methodologies of basic NHP-research are therefore strictly regulated in a manner ensuring minimal discomfort and innovative science at the same time. In fact, current regulations permit animal research only when no alternatives are available.

Nevertheless, even absolute compliance with the letter and the spirit of such regulations cannot possibly guarantee risk-free procedures, a fact that is explicitly discussed and acknowledged in any experimental protocol anywhere in the world, and certainly in those approved by the licensing authorities (i.e. Regierungspräsidium) in Germany. It is precisely these acknowledged risks that make it necessary that invasive experimentation be carried out in animals rather than in humans.

Obviously, invasive experiments involving penetration of the brain with stimulation or recording electrodes have the potential to cause brain damage and infection. For instance, numerous risk-benefit assessments have published on so-called Deep Brain Stimulation (DBS), an invasive method used to treat drug-resistant devastating diseases, such as Parkinson's disease (PD), obesity, obsessions, and various forms of depression. About 1.5 million Americans have Parkinson's disease, and Germany has the largest number of prevalent cases of PD of any country in Europe, with 150 cases per 100,000 inhabitants and 1,800 cases per 100,000 persons over the age of 65 years⁴. The lives of tens of thousands of Parkinson’s patients have been transformed by DBS, a therapy method, I might add, which was developed in monkeys. Implantation of DBS leads is carried out at the highest imaginable quality level. Nonetheless, lead-induced transient hematomas and potentially permanent deficits can occur in 3.3% and 0.5-1% of the cases, respectively. These percentages increase significantly when microelectrode recordings are used to verify anatomical targeting⁵, with infections generally occurring in 5% to 8% of patients⁶.

Just as in humans, brain injury can occur from recording electrodes in animals, and this was recently exploited to misrepresent and discredit our experimental procedures and to stir up public sentiment against out lab and raise doubts about the well-being of our animals. In specific, a caregiver supported by the British Union for the Abolition of Vivisection (BUAV) and the German animal protection organization SOKO infiltrated our primate facilities and “investigated” our procedures and the condition of our animals. The caregiver filmed an animal called “Stella” during a rare emergency situation and presented it in a Stern TV broadcast, exploiting the natural emotional reaction of an uninformed public. This perfidious campaign presented a rare incident as typical, reported partial facts or facts out of context to arrive at the desired conclusions, made false claims and even created artifacts.

Damage to the brain’s vasculature during electrode penetration can lead to hemiparesis, and in cases where there is also infection, increased intracranial blood pressure or the antibiotic treatment may induce emesis. I personally have seen animals with hemiparesis a total of 4 to 5 times in more than 30 years of actively working with primates, and Stella’s case was unique. Although we never take such complications lightly, the fact remains that they may occur even though electrode placement in our laboratory, just like in the hospital setting, follows the precise localization of target structures on the basis of anatomical and angiographic MRI. Animal-protection regulations suggest first attempting to treat an injured monkey before the responsible veterinarian decides to euthanatize the animal. It was during such a prescribed treatment period that the caregiver, Mr. Andrzej Pazgan (alias Pawel), made the broadcasted movie.

The footage also showed a bleeding animal ripping its wound and implant. Following surgery, we always make sure that sufficient analgesia is administered to the animals. When the animal is returned to its cage, medical assistants and caregivers have always carefully followed a standardized recovery protocol under veterinarian supervision. We regularly observe examination of the implant by the monkey, expressed by gentle touching and picking, but none of us had ever seen a monkey ripping at the implant as a consequence of suffering from pain. If this were the case, the observer is instructed to call the veterinarian immediately. After this movie was published, none of the responsible persons in the institute could trace back any alert about this incident from the undercover-caregiver, who was in charge – and in charge of reporting it. In part, the bleeding might be a result of this clawing, but most of the “bleeding” visible in the Stern TV broadcast  shows ichor, not hemorrhage, which is a normal physiological reaction after a surgery. In human surgeries this is managed by the use of bandages or drainages, which cannot be used in monkeys. To prevent hematoma or the accumulation of fluid under the skin, the sutures are spaced farther apart in order to allow the fluid to drain off. Additionally, the head of the monkey is covered with residual Betadine and tissue glue which was used during surgery, which makes it appear even more critical. Until recently, the post-surgery observation prescribed in our standardized recovery protocol could not be continued during the night hours. Thus, the veterinarian always made sure that analgesic treatment was sufficient to last overnight. Although we rarely faced problems before, additional staff has since been approved by the Max Planck Society (MPS) to enable us to establish an overnight “intensive care station” regime.

Lastly, in their effort to “disclose” the animal suffering in our institute, BUAV/SOKO presented a couple of animals with unusual stereotypical movement patterns, such as animals continuously turning in circles. Such behavior patterns are often observed in animals living in small single-animal cages. Our monkeys are held in a natural group setting with an enriched, stimulating environment. Small cages are only used for short times, i.e. if there is  some need to separate an animal from the group, e.g. for medical treatment Such stereotypical movements have not been witnessed in our facilities for over 16 years. They can, however, be induced by any person standing too close to the cages, in particular when the animal is in a small cage and becomes nervous. In the filmed case, such stereotypical movements were almost certainly induced intentionally by the caregiver.

In the 125-document sent out by BUAV/SOKO after their infiltration and secret filming, the organizations allege that inappropriate anesthesia is used, despite the full and open description of anesthesia protocols in our publications and on the MPIBC website. They claim specifically that that we use ketamine anesthesia for major surgical procedures such as craniotomies, headpost and eye-coil implantation. This is quite simply not true. Our surgical facilities are equipped with standard (human) clinical anesthesia machines, and the balanced-anesthesia protocols used in our laboratory were introduced by anesthesiologists who also trained our personnel. In fact, we even took the time to study and publish the state of the animals during anesthesia, determined by closely monitoring several physiological parameters, including stress hormones⁷.

BUAV/SOKO also claims that we use “severe water deprivation”. This is not the case and never was. Firstly, out of 42 monkeys only 8 are used for behavioral experiments, and none of these experiments ever required severe water deprivation. The organization ignores the clear distinction between distressing, extreme thirst and an absence of satiation that will make a juice reward pleasant. Our monkeys are not kept in a state of severe or even unpleasant thirst, but in the experimental context we do not provide liquids to the point that the monkey will refuse to drink. It appears, however, that the organization decided ahead of time that it wanted to show that we treat our monkeys poorly, for the examples used as evidence are completely irrelevant to this issue. When reporting that deprivation was used to train the animals to enter the primate chairs commonly used in behavioral experiments, the organizations often refer to protocols and monkeys that were used exclusively in anesthetized preparation and requiring no liquid reward or chair training at all. None of our experimental protocols and training procedures have ever used negative reinforcement such as aversive saline, and claims to the contrary are simply false.

Unhappily, the BUAV/SOKO report – already circulated in the European Commission and other governmental and regulatory agencies in Germany – utterly violates the constitutional right to privacy of correspondence by publishing internal email communications between collaborators and the veterinarians, which are then systematically presented out of context.

Among the false allegations is also the bizarre claim that animal research in MPIBC is shrouded in secrecy. Ironically, our institute is probably the only primate research facility worldwide that has continuously tried to operate under conditions of maximum transparency. Firstly, we have urged the authorities to visit our facilities any time they wish, without any prior warning, in order to objectively check the state of the animals. In fact, I have personally offered the key of our facilities to the Regierungspräsidium, but they were reluctant to accept it, seeing it as potential violation of regulations. We have repeatedly invited all of the other directors at the Tübingen Max Planck campus, the ministers of Baden-Wurttemberg, the mayor of the city, and even the German TV Channel Two (ZDF) to film our facilities and our surgical procedures. Sadly, the result of several hours of filming and photography by the ZDF were filtered and reduced to the point of unrecognizability and presented out of context to support foregone conclusions. Our website provides full details on our research, our procedures, and our extensive efforts to ensure the well-being of our animals, which ultimately guarantees the integrity of our results. Unfortunately, where full disclosure has been made, as on this website, the veracity of our voluntarily provided information was called into question. Although our own laboratory was targeted, such strategies ultimately threaten all animal research and indeed all basic research.

Following the infiltration, the quality of our facilities and procedures was again publicly evaluated by an external investigator employed by MPS. His report stresses that any medical intervention, whether in humans or animals, always carries risks such as post-operative hemorrhage or suture insufficiency. His report recommends modifications to the Institute’s animal care regime but does not, despite the BUAV’s allegations to the contrary, see fundamental systematic problems. Despite the efforts of BUAV/SOKO to make it appear otherwise, the MPIBC is considered by the international scientific community to be one of the best institutes worldwide in terms of animal welfare, standards of care, and transparency.

Donations to organizations such as BUAV or SOKO might sooth the conscience of animal lovers, but are the activities of antivivisectionists appropriate and reasonable in today’s world? The Beijing municipal government attempted to establish “strict regulations” in an animal welfare law. The draft was withdrawn 2 days later, because a huge number of Chinese reacted strongly, stating that while monkeys in certain laboratories are provided with food, drink, toys and even music, more than one tenth of the population must live on less than $1 a day⁸, the World Bank’s definition of abject poverty. Thousands of needless deaths occurred from famine in East Africa last year because the international community failed to heed early warnings, say two leading British aid organizations (Hunger). Children are the most visible victims of malnutrition. Dirty water kills 5,000 children a day, and nearly two million children a year die for want of clean water and proper sanitation while the world's poor often pay more for their water than people in Britain or the US (Water-Need).

BUAV/SOKO indicated that “the institute has identified a need for improvements”. For the sake of accuracy, it was the Max Planck Society and not the “institute” that identified this need, and the “improvements” referred to the approval of additional personnel resources for the institute. It was never suggested that our procedures and protocols were at fault or that our caregivers were not acting in an absolutely professional manner. We gratefully acknowledge the additional financial support from the MPS, but we also note that the exigencies of budgets will always exist, just as they do in a human hospital; and so will the needs of improvement of welfare of humans. The latter issue appears to be of less importance to the animal-protection organizations.

It is my opinion that the activities of animal extremists have now reached the point where all science-promoting organizations, as well as the government itself in each country, must take a strong stand in defense of research. A failure to do so could jeopardize basic research worldwide. Claims that basic science is useless or that such research has never contributed anything to medical progress would not be worth answering if they were not so easily believed by an uncritical public and were not such an easy way to attract donations. Animal experiments are irreplaceable if we want a healthy society, and animal experiments do have risks and certain discomfort, both of which must be objectively weighed against the benefits of research. What society can ignore human suffering to promote the welfare of mice? If the ultimate benefit of patients is not considered a greater good, then we should indeed stop science and research.
 

References

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