THE FIRSTS: The Mirror Neurons (1988)

There are some neurons in the human brain that fire both when the person is doing some behavior and when watching that behavior performed by someone else. These cells are called mirror neurons and were first discovered in 1988 (see NOTE) by a group of researchers form the University of Parma, Italy, led by Giacomo Rizzolatti.

The discovery was done by accident. The researchers were investigating the activity of neurons in the rostral part of the inferior premotor cortex (riPM) of macaque monkeys with electrophysiological recordings. They placed a box in front of the monkey which had various objects in it. When the monkey pressed a switch, the content of the box was illuminated, then a door would open and the monkey reached for an object. Under each object was hidden a small piece of food. Several neurons were discharging when the animal was grasping the object. But the researchers noticed that some of these neurons ALSO fired when the monkey was motionless and watching the researcher grasping the objects!

The authors then did more motions to see when exactly the two neurons were firing, whether it’s related to the food or threatening gestures and so on. And then they recorded from some 182 more neurons while the monkey or the experimenter were performing hand actions with different objects. Importantly, they also did an electromyogram (EMG) and saw that when the neurons that were firing when the monkey was observing actions, the muscles did not move at all.

They found that some neurons responded to both when doing and seeing the actions, whereas some other neurons responded only when doing or only when seeing the actions. The neurons that are active when observing are called mirror neurons now. In 1996 they were identified also in humans with the help of positron emission tomography (PET).

88mirror - Copy
In yellow, the frontal region; in red, the parietal region. Credits: Brain diagram by Korbinian Brodmann under PD license; Tracing by Neuronicus under PD license; Area identification and color coding after Rizzolatti & Fabbri-Destro (2010) © Springer-Verlag 2009.

It is tragicomical that the authors first submitted their findings to the most prestigious scientific journal, Nature, believing that their discovery is worth it, and rightfully so. But, Nature rejected their paper because of its “lack of general interest” (Rizzolatti & Fabbri-Destro, 2010)! Luckily for us, the editor of Experimental Brain Research, Otto Creutzfeld, did not share Nature‘s opinion.

Thousands of experiments followed the tremendous discovery of mirror neurons, even trying to manipulate their activity. Many researchers believe that the activity of the mirror neurons is fundamental for understanding the intentions of others, the development of theory of mind, empathy, the process of socialization, language development and even human self-awareness.

NOTE: Whenever possible, I try to report both the date of the discovery and the date of publication. Sometimes, the two dates can differ quite a bit. In this case, the discovery was done in 1988 and the publishing in 1992.

 References:

  1. di Pellegrino G, Fadiga L, Fogassi L, Gallese V, & Rizzolatti G (October 1992). Understanding motor events: a neurophysiological study. Experimental Brain Research, 91(1):176-180. DOI: 10.1007/BF00230027. ARTICLE  | Research Gate FULLTEXT PDF
  2. Rizzolatti G & Fabbri-Destro M (Epub 18 Sept 2009; January 2010). Mirror neurons: From discovery to autism. Experimental Brain Research, 200(3): 223-237. DOI: 10.1007/s00221-009-2002-3. ARTICLE  | Research Gate FULLTEXT PDF 

By Neuronicus, 15 July 2016

Intracranial recordings in human orbitofrontal cortex

81 ofc - CopyHow is reward processed in the brain has been of great interest to neuroscience because of the relevance of pleasure (or lack of it) to a plethora of disorders, from addiction to depression. Among the cortical areas (that is the surface of the brain), the most involved structure in reward processing is the orbitofrontal cortex (OFC). Most of the knowledge about the human OFC comes from patients with lesions or from imaging studies. Now, for the first time, we have insights about how and when the OFC processes reward from a group of scientists that studied it up close and personal, by recording directly from those neurons in the living, awake, behaving human.

Li et al. (2016) gained access to six patients who had implanted electrodes to monitor their brain activity before they went into surgery for epilepsy. All patients’ epilepsy foci were elsewhere in the brain, so the authors figured the overall function of OFC is relatively intact.

While recording directly form the OFC the patients performed a probabilistic monetary reward task: on a screen, 5 visually different slot machine appeared and each machine had a different probability of winning 20 Euros (0% chances, 25%, 50%, 75% and 100%), fact that has not been told to the patients. The patients were asked to press a button if a particular slot machine is more likely to give money. Then they would use the slot machine and the outcome (win 20 or 0 Euros) would appear on the screen. The patients figured out quickly which slot machine is which, meaning they ‘guessed’ correctly the probability of being rewarded or not after only 1 to 4 trails (generally, learning is defined in behavioral studies as > 80% correct responses). The researchers also timed the patients during every part of the task.

Not surprisingly, the subjects spent more time deciding whether or not the 50% chance of winning slot machine was a winner or not than in all other 4 possibilities. In other words, the more riskier the choice, the slower the time reaction to make that choice.

The design of the task allowed the researchers to observe three 3 phases which were linked with 3 different signals in the OFC:

1) the expected value phase where the subjects saw the slot machine and made their judgement. The corresponding signal showed an increase in the neurons’ firing about 400 ms after the slot machine appeared on the screen in moth medial and lateral OFC.

2) the risk or uncertainty phase, when subjects where waiting for the slot machine to stop its spinners and show whether they won or not (1000-1500 ms). They called the risk phase because both medial and lateral OFC had the higher responses when there was presented the riskiest probability, i.e. 50% chance. Unexpectedly, the OFC did not distinguish between the winning and the non-wining outcomes at this phase.

3) the experienced value or outcome phase when the subjects found out whether they won or not. Only the lateral OFC responded during this phase, that is immediately upon finding if the action was rewarded or not.

For the professional interested in precise anatomy, the article provides a nicely detailed diagram with the locations of the electrodes in Fig. 6.

The paper is also covered for the neuroscientists’ interest (that is, is full of scientific jargon) by Kringelbach in the same Journal, a prominent neuroscientist mostly known for his work in affective neuroscience and OFC. One of the reasons I also covered this paper is that both its full text and Kringelbach’s commentary are behind a paywall, so I am giving you a preview of the paper in case you don’t have access to it.

Reference: Li Y, Vanni-Mercier G, Isnard J, Mauguière F & Dreher J-C (1 Apr 2016, Epub 25 Jan 2016). The neural dynamics of reward value and risk coding in the human orbitofrontal cortex. Brain, 139(4):1295-1309. DOI: http://dx.doi.org/10.1093/brain/awv409. Article

By Neuronicus, 25 March 2016

Making new neurons from glia. Fully functional, too!

NeuroD1 transforms glial cells into neurons. Summary of the first portion of the Guo et al. (2014) paper.
Fig. 1. NeuroD1 transforms glial cells into neurons. Summary of the first portion of the Guo et al. (2014) paper.

Far more numerous than the neurons, the glial cells have many roles in the brain, one of which is protecting an injury site from being infected. In doing so, they fill up the injury space, but they also prohibit other neurons to grow there.

Guo et al. (2015) managed to turn these glial cells into neurons. Functioning neurons, that is, fully integrated within the rest of the brain network! They did it in a mouse model of stab injury and a mouse model of Alzeihmer’s in vivo. Because a mouse is not a man, they also metamorphosized human astrocytes into functioning glutamatergic neurons in a Petri dish, that is in vitro.

It is an elegant paper that crossed all the Ts and dotted all the Is. They went to a lot of double checking in different ways (see Fig. 1) to make sure their fantastic claim is for real (this kind of double, triple, quadruple checking is what gets a paper into the Big Name journals, like Cell). Needles to say, the findings show a tremendous therapeutic potential for people with central nervous system injuries, like paralyses, strokes, Alzheimer’s, Parkinson’s, Huntington, tumor resections, and many many more. Certainly worth a read!

Reference: Guo Z, Zhang L, Wu Z, Chen Y, Wang F, & Chen G (6 Feb 2014, Epub 19 Dec 2013). In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell, 14(2):188-202. doi: 10.1016/j.stem.2013.12.001. Article | FREE FULLTEXT PDF | Cell cover

By Neuronicus, 18 October 2015

I’m not like you, inside and out

Credit: Dawn of the Planet of the Apes
Screenshot from “Dawn of the Planet of the Apes” (Director: Tim Burton, 2001)

One mistake than many neuroscientists make (myself included) is the implicit assumption that the human brain is a rodent brain scaled-up, plus a few more bits. Here is a remainder that “a rat is not a monkey is not a human”, in the famous words of A. D. (Bud) Craig (2009).

Mohan et al. (2015) analyzed a portion of the brain (Brodmann area 21) obtained from 28 individuals that had to undergo neurosurgery and have it removed for various illnesses. Using some good microscopy, fancy statistics, and 3-D modeling, they reconstructed the shape of individual neurons from that region. The main finding is that 88% of human pyramidal neurons were distinctly different than their mouse or macaque counterparts. Also, they managed to record the electrical activity of these neurons in less than 10 minutes after resection. So it appears that this morphological distinctness of ours results in unique electrical properties of human neurons, which may account for the “distinct cognitive capabilities of humans”, as the authors put it.

Approximate location of Brodmann Area 21, corresponding to gyrus temporalis medium. Credit: Brain template to _DJ_; Area tracing to Neuronicus
Approximate location of Brodmann Area 21, corresponding to gyrus temporalis medium. Credit: Brain template to _DJ_; Area tracing to Neuronicus

Citation: Mohan, H., Verhoog, M. B., Doreswamy, K. K., Eyal, G., Aardse, R., Lodder, B. N., Goriounova, N. A., Asamoah, B., B. Brakspear, A. B. C., Groot, C., van der Sluis, S., Testa-Silva, G., Obermayer, J., Boudewijns, Z. S., Narayanan, R. T., Baayen, J. C., Segev, I., Mansvelder, H. D., de Kock, C. P. (28 August 2015; Epub ahead of print). Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex. Cerebral Cortex, 1-15. doi: 10.1093/cercor/bhv188. Article + FREE PDF

Obscure protein restores memory decline

In the not-too-distant-future, your grandma may give you a run for your money on your video games. Photo credit: http://www.funtoosh.com/pictures/
In the not-too-distant-future, your grandma may give you a run for your money on your video games. Photo credit: Funtoosh

Aging comes with all sorts of maladies, but one of the most frustrating is the feeling that you are not as sharp as you used to be. Cognitive decline has been previously linked, at least in part, to a dysregulation in the neuronal calcium homeostasis in the hippocampus, which is a brain region essential for learning and memory. One player that keeps in check the proper balance of calcium use is the protein FKBP1b, and, not surprisingly, its amounts are reduced in aging rats and Alzheimer’s suffering patients.

FKBP1b overexpression in hippocampal neurons reversed spatial memory deficits in aged rats. Fig. 3 (partial) from Gant, J. C., Chen, K. C., Kadish, I., Blalock, E. M., Thibault, O., Porter, N. M., Landfield, P. W. (29 July 2015). Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. The Journal of Neuroscience, 35(30):10878 –10887. doi: 10.1523/JNEUROSCI.1248-15.2015.
FKBP1b overexpression in hippocampal neurons reversed spatial memory deficits in aged rats. Fig. 3 (partial) from Gant et al. (2015): doi: 10.1523/JNEUROSCI.1248-15.2015.

Gant et al. (2015) sought to increase the expression of the FKBP1b protein in the hippocampus, in the hopes that its increase would result in better calcium homeostasis and, as a result, better memory performance in aging rats. They built a virus that carried the gene for making the FKBP1b protein and they injected this directly in the hippocampus. After they waited 5-6 weeks for the gene to be expressed, they tested the rats in the Morris water maze, a test for spatial memory. The old rats that received the injection performed as well as the young rats, and far better than the old rats who didn’t get the injection. Then the researchers made sure that the injection is the one responsible for the results, by checking the levels of the FKBP1b protein in the hippocampus (increased, as per specs), by recording from those neurons (they were awesome), and by imaging the calcium to make sure the balance was restored (ditto).

Reference: Gant, J. C., Chen, K. C., Kadish, I., Blalock, E. M., Thibault, O., Porter, N. M., Landfield, P. W. (29 July 2015). Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus. The Journal of Neuroscience, 35(30):10878 –10887. doi: 10.1523/JNEUROSCI.1248-15.2015. Article + FREE PDF + Journal of Neuroscience cover

Wireless mice, batteries not included (optrodes and electrodes in one wireless contraption)

A neuron is expressing the light-gated cation channel channelrhodopsin-2 (small green shapes), and is being illuminated by a focused beam of blue light (coming from the top). The opsins have opened, depolarizing or electrically activating the cell. The pulse of electricity spreads throughout the inside of the cell (white highlights), triggering the release of neurotransmitters to downstream cells. Credit: Ed Boyden and Massachusetts Institute of Technology McGovern Institute Courtesy: National Science Foundation
A neuron is expressing the light-gated cation channel channelrhodopsin-2 (small green shapes), and is being illuminated by a focused beam of blue light (coming from the top). The opsins have opened, depolarizing or electrically activating the cell. The pulse of electricity spreads throughout the inside of the cell (white highlights), triggering the release of neurotransmitters to downstream cells. Credit: Ed Boyden and Massachusetts Institute of Technology McGovern Institute. Courtesy: National Science Foundation

Optogenetics is the new (and very popular) kid on the block of neurotechniques arsenal. Before optogenetics, in order to manipulate how the neurons behave in a particular brain region, one had to do so electrically or chemically by inserting into that region an electrode or a tube, respectively. The trouble with that is that you never know exactly which neurons you are manipulating, given that any brain regions has many kinds of cells that project to many other regions and they are not nicely arranged in clumps but interspersed in a messy mesh. But with optogenetics, you can select exactly which neurons you want to manipulate. You take a mouse and you genetically engineer it to express in your favorite neurons a particular protein that is sensitive to a certain light wavelength (like a rhodopsin). Then, you shine the light in the mouse’s brain, turning on and off the neurons of your interest. The technique, besides having tremendous success in fundamental research, also shows promise for neuroprosthetics for some diseases, like Parkinson’s.

Despite rapid improvements of the technique due to increasing demand form the neuroscience community, it is still difficult to record from the freely-moving animal, mainly because the animal is attached to the fiber optic that delivers the light pulses. There have been some wireless attempts (some successful), but because the resultant contraption was too big and heavy for the animal, they have reduced options as compared to the wired devices. Gagnon-Turcotte et al. (2015) describe here a way to build a wireless headtsage that can deliver light pulses AND record the electrophysiological activity of the neurons. And, equally important, is cheap and can be build with off-the-shelf components.

Reference: Gagnon-Turcotte, G., Kisomi, A. A., Ameli, R., Camaro, C.-O. D., LeChasseur, Y., Néron, J.-L., , Bareil, P. B., Fortier, P., Bories, C., de Koninck, Y., & Gosselin, B. (9 September 2015). A Wireless Optogenetic Headstage with Multichannel Electrophysiological Recording Capability. Sensors, 15(9): 22776-22797; doi:10.3390/s150922776. Article + FREE PDF

By Neuronicus, 22 September 2015

Update (27 September 2015). The author Gabriel Gagnon-Turcotte wins the Mitacs 2015 prize for exceptional innovation for the development of a wireless system to study the brain