By directing ultrasound to a specific area of the brain, scientists at the University of Washington have succeeded in inducing a state very similar to hibernation in rats and mice. This state, called "torpor", involves a reduction in metabolism and body temperature to save energy. According to the authors, who publish their results in the journal Nature Metabolism, if it could be applied to humans it could be used in space travel or in medicine, to increase the chances of survival in life-threatening situations such as heart attacks or strokes.
It is a significant advancement since it is the first to use a non-invasive technology. This will open new exciting fields of research. The experiments are well conceived, testing both in a hibernator (mouse) and a non-hibernator (rat).
It fits well with what we know about the neural control of torpor. A few technical details also open interesting new questions.
The implication is significant since i) the paper shows the use of a non-invasive tech; ii) it offers a way to maintain a torpor-like state for 24h automatically. This last part complements the main findings because it will allow automated control of physiological states.
The main limitation is the technology's very modest effect on rats (although present). So, there is still work to do in that compartment. We may be headed towards a composite system that can merge Ultrasound stimulation with pharmaceuticals to reach for a significant hypometabolism in humans. The limited, although significant, effects on rats also suggest there is still work to do to have suitable human applications. Considering the degree of hypometabolism reached, I believe this technology will be helpful in specific conditions where even modest hypothermia can be already very beneficial, more than for interplanetary travels.
There is a great deal of interest in the topic and research in this area is important. The possibility of human hibernation is obviously fascinating and has wide ranging implications - from clinical applications to space travel. For example, when metabolism is reduced, cells require less oxygen, and therefore in conditions such as stroke or heart failure hibernation can be neuroprotective.
However, this study raises more questions than provides answers, in my opinion. First of all, the contribution of thermal stimulation must be controlled for and addressed. Perhaps stimulated neurons "feel" warmth induced by ultrasound stimulation and this is what induces compensatory hypothermia. Secondly, we know well that there are changes in body temperature in laboratory rodents occurring spontaneously, for example, hypothermia during sleep. I would be very interested to know whether ultrasound stimulation of the preoptic area of the hypothalamus induces altered state of arousal and awareness or may be even sleep? Overall, changes induced by stimulation in this study are rather modest.
The key novelty is the attempt to use mechanical stimulation to induce hypometabolism, but given the caveat of thermal effects, which must be addressed, any conclusions from this study are preliminary. Generally it fits with evidence, but I would say, provocatively, that it is not particularly difficult to induce a state of hypometabolism in laboratory mice by a variety of pharmacological and non-pharmacological means. The question always remains whether we are inducing normal, physiological hibernation or an abnormal state. We need to be careful because it can have very negative consequences for the body and the brain if it is "enforced". I talk about this in my recent TED talk.
While it is highly likely that humans can hibernate, in some way, the underlying neurophysiological and molecular mechanisms can be quite different from other animals. For example, daily torpor can be induced in mice by acute fasting, and this does not happen in humans, as far as we know. Seasonal hibernators initiate preparation to hibernation many weeks before hibernation occurs, and this may happen even without any external inputs. Humans are less seasonal, and therefore mechanisms and meaning of hibernation in humans may be very different. Still, hibernation is a really clever strategy used by so many species to deal with adverse environmental conditions, and could fundamentally be a default state of our physiology, very similar across organisms including humans.
Professor in the Department of Biomedical and Neuromotor Sciences, University of Bologna (Italy) and Research Assistant Professor of Neurological Surgery in the Oregon Health and Science University School of Medicine (USA)
The techniques used are very good and of good quality. Also, the development of a small implantable device for research in mice is novel. However, the study does not provide any novel information either on the neuronal control of torpor or on the control of normal thermogenesis. Several decades of study had already proved the role of the preoptic area of the hypothalamus in the control of body temperature and its role in fever. Pioneering works at the beginning of the last century had already shown that warming the preoptic area of the hypothalamus (POA) produced inhibition of thermogenesis and vasodilation (heat dissipation). This response was mediated by a group of neurons able to respond to warm stimuli directly applied to the POA. It was already known that such warm sensitive neurons were capable of sensing temperature through a specific temperature sensor located on their membrane, TRPM2.
The ultrasound stimulation used in this work is just producing an increase in temperature of this important hypothalamic area, which most luckily results in stimulating the warm neurons through the already known TRPM2 receptor. Then, other than the new technique (ultrasound) to stimulate this area, there is no novel information about the mechanism of torpor that would produce advancement in our scientific knowledge.
Mice are very small animals compared to humans. The preoptic area of the hypothalamus is a very deep region in the human brain and it would be difficult to imagine that an extracranial stimulus could be effective a targeting such a deep region without interfering with brain regions in between. However implantable microdevice, similar to deep brain stimulation electrodes, could probably be implanted directly into the POA, and this (not without side effects) would be probably applicable. Would it be done? Probably not. Pharmacological approaches, that normally would interfere with a much large area of the brain or the entire body, giving rise to several side effects. This is why we need alternative mechanisms to target more specific areas to treat pathology or maybe to induce hibernation.
Whether it is important to find alternatives to the pharmacological approaches, I do not think mechanical stimulation, such as deep brain stimulation, ultrasound, and transcranial magnetic stimulation, would help us in being more specific at targeting specific areas. Furthermore, torpor is a complex mechanism, and hypothermia and hypometabolism is just a component of a larger orchestra, that requires the regulation of many factors to be suitable for life. It would be hard to believe that tricking one single area of the brain would make the job. These mice are recovering from hypothermia, but would they survive a long period (up to 6 months) as a true hibernator does?
In my opinion, the use of refined molecular techniques and genetic implementation would be the future of medicine able to produce targeted molecules that are going to specifically interreact with targeted neurons and functions. However, this would require more investigation, would be less accepted by public opinion, and would be not immediately viable to a large population, as should be subject designed and it would be expensive. This is the reason why mechanical approaches are still in large use and high demand.
- Research article
- Experimental study
- Peer reviewed