SFN: Neuroethics: Hank Greely on the impact of neuroscience on society

First up for me this morning: Hank Greely's talk entitled The Neuroscience Revolution and Society. For those of you not familiar with Hank Greely, he is a law professor at Stanford University who is (to quote his faculty website), a "leading expert on the legal, ethical, and social issues surrounding health law and the biosciences" who specializes in  the"implications of new biomedical technologies, especially those related to neuroscience, genetics, and stem cell research." I have heard Greely speak 2 times previously, discussing the implications of neuroscience (in particular fMRI technology) for society and the law. Last month, Greely chaired a discussion panel on neuroscience evidence in the courtroom - my blog coverage of the event can be read at the link.

He will talk about the ethical challenges that neuroscience raises, and what we, as scientists can do about it. Greely takes us back to 1969, what he calls the peaking of the first modern neuroscience ethics panic, during which the public came together in concern over many neuroscience themes, including neuroscience’s ability to control minds. He notes that concern over mind control led to many regulations being put in to place, based purely on speculative science. Greely fast forwards to today, where he sees the same trend towards public concern, whereas now the panic is caused by science that is actually available, as opposed to the more speculative nature of the science that was causing concern in 1969.

Greely discusses the problem with public policy being established based upon science that isn’t very good – for example eugenics programs based on our knowledge of genetics. He notes that in the case of genetics, fair and responsible public polities are well established, and the maturity of this process is about 10 years ahead of neuroscience.

What are the issues raised by neuroscience? Greely notes we are in a golden age of neuroscience, we are learning a phenomenon amount about neuroscience, and we care a great deal, both at the individual and the social level, about neuroscience given the close association between our brains and our minds. As we learn more about the brain, we will learn more about human thought and motivations. The ethical issues being raised fall into several categories. The first one of these is research ethics – as we learn more about the neuroscience, we will begin to consider questions regarding the ethics of doing research. For instance, what are the ethics regarding incidental information gathered during experiments – for instance tumors discovered during fMRI studies. Alternatively, ethical issues generated by storing brain images of participants in a database – can those images be used to advance information in ways the participants disagree with?

Greely turns to the question of how neuroscience will change our society, including changing education, medical care, and the law. Greely will talk about 6 different ways that neuroscience will impact the society – prediction, mind-reading, responsibility, consciousness, treatment and enhancement.

Prediction: neuroscience is helping us predict better things about people’s behavior. Sometimes, this involves predicting future disease states – neuroimaging or genetic predictions of who will develop Alzheimer’s. Now, this seems like a good thing, but what are the implications. If our ability to predict Alzheimer’s was coupled with a treatment, this would be fantastic. But as in the case of many genetic predictions, we often are able to predict despite being unable to prevent the occurrence of the disease. Greely notes that we are protected under federal law from discrimination based on genetic predispositions, but not predictions based upon brain scans. Predictive information is not just information - it has consequences, both good and bad. Greely poses the question of who will be responsible for producing the predictions (doctors, companies), and who will be able to have access to the information, beyond the patient. He wonders what we would do with information that predicted with 100% accuracy which 8/1000 children will develop schizophrenia, or make accurate predictions on future criminal/violent behavior. He states that if we can ask the question (what do we do with the information), someone will want to answer it.

Mind-Reading: Greely repeats a line I have heard from him before, that humans are all mind-readers. It is important for us to figure out what those around us are thinking, generally using facial cues, body language, etc… He comment that we all try to do it, but we just aren’t very good at it, and the world would look a lot different if we were better at it. And with neuroscience, we are getting better at it. There are many examples of imaging research where scientists look at activity and make suppositions about what the subjects are subjectively thinking. Now, much of that research involves figuring out whether, for example, a person is thinking of a place or a face – this is not of immediate applicability in the courtroom. But what is applicable is research that is attempting to figure out what people believe or think: e.g. lie detection, figuring out whether people are actually feeling chronic pain, whether people are biased. He introduces the current two commercial companies that offer lie detection, and the two recent court cases that asked whether they would allow fMRI-based lie detection as evidence (they both said no). Greely notes that there is currently no regulation of this field but people are still applying the technology.

Responsibility: Greely discusses recent court cases where the defendants use neuroscience brain scans to claim insanity. A more common argument in these court cases is that its not the defendants fault, it is the fault of their brain and how it works. What will juries do when told that a defendant is a psychopath, and their brain makes them a murder?

Consciousness: Greely brings up the recent paper where two groups showed that of a group of 54 patients diagnosed as being in a vegetative or minimally-conscious state, fMRI scans showed that in 5 patients, being told to plan a motor task resulted in activity in the motor planning area. In addition, 4 patients showed activity in brain regions responsible for navigation when told to imagine walking through their homes. Finally, they took one patient, who had been diagnosed in a vegetative state for 5 years, and showed that he was able to answer personal questions by selectively activating either the motor planning or navigation area. What will we do with that information? Greely comments that doctors at Stanford have already started having families of patients diagnosed as being in a vegetative state ask that the patient be put into an fMRI scanner.

Treatment: Greely wonders what happens when we learn how to “cure” things that are not diseases, such as “deviant sexual behaviors”? What happens when a neuroscience attempts to cure addition with brain lesions, as happened recently in China, where doctors made electrolytic lesions of the nucleus accumbens of soldiers addicted to opium. They reported that after the lesion, soldiers did not crave opium, but Greely notes that the peer-reviewed paper did not report what else the soldiers did not crave. Another example are laws requiring that people convicted of a long list of sexual offenses are required to undergo chemical castration, despite the fact that we don’t have much information regarding the efficacy or safety of the chemicals used for the castration. In addition, even if we know that treatments for addition, psychological diseases, etc… are efficacious and safe, when do we mandate their use?

Enhancement: Many (most) scientists use mind-altering drugs – caffeine and chocolate both alter brain chemistry. But there are greater numbers of students who are now using Ritalin without a prescription to enhance their cognitive abilities. Of course, Ritalin and other drugs like it are not that good at enhancing cognition. But what about memory-enhancing drugs developed to treat diseases such as dementia and Alzheimer’s? What do we do if these drugs work on 20-year olds? What should universities or medical schools do about the availability of these drugs? Greely states emphatically that the single greatest cognitive enhancer is primary education, the ability to read and write. What did we do about it? We made it mandatory. How will be respond to a new host of drugs.

And lastly, Greely turns to the question of how society will respond to neuroscience research regarding the human condition. How will we assimilate information regarding the differences (or lack thereof) between the brains of humans and other animals? What about consciousness – when we can identify it, how will this alter how we treat patients, or fetuses? What about free will – how society react once we can identify the exact mechanisms that lead to our decisions, when we can show that circuits in our brains have made a decision long before we consciously acknowledge that decision. How will religion be affected? Greely imagines that it won’t affect society too much – the general public will continue to believe in free will not matter what evidence neuroscience throws at them.

Having talked about these issues, Greely turns to how neuroscience should start to handle them. The first step is to conduct research to show conclusively whether the techniques mentioned over the past hour are effective and safe. Going further, are questions about how we use these techniques if they are effective and safe? Neuroscientists have perhaps a smaller role, but an important one in making sure the public is aware of the complexities of the science and the techniques. And lastly, the deeper existential questions – and here Greely states that neuroscientists and non-neuroscientists all are on an equal footing, each with something to contribute.

So what can we, as neuroscientists, do? Greely calls us to consider the ethical issues of our own work, and to talk about these ethical issues, whether they come out of our own work or the work of others. He encourages neuroscientists to get involved, to join the Society for Neuroethics, to communicate with the public on these issues, to bring our sophisticated understanding of the strengths, weaknesses and limitations of neuroscience to discussions in the public domain. Greely tells us that he must believe that the more we discuss these ethical issues, the less likely we are to mess up the big decisions. In conclusion, he hopes he made us think about the short and long term implications for neuroscience on society, and that he had convinced us of the critical need for educated neuroscientists go get involved in the introduction of our knowledge into society.

Note: Greely suggests that those interested in asking him questions should email him at hgreely@stanford.edu.

SFN: Hikosaka on Motivational Circuitry

Presidential Special Lecture: Motivational Neuronal Circuits for Value, Salience and Information - Okihide Hikosaka After an introduction from Mickey Goldburg*, Hikosaka takes the stage!

Hikosaka begins his talk with ruminations on the meaning of motivation, stating that motivation is the internal drive to accomplish goals. He presents a conceptual scheme describing two networks: action and motivation that work together to produce goal directed activity. Function of these networks is as follows: action network produces a motor action that produces an outcome, which is then evaluated by the motivation network, which either promotes or inhibits the action network. A key feature of the motivation network is its ability to predict the outcome of the action network. In hard neurophysiological terms, the motivational signal is thought be involve dopamine, but the exact signal, and its information content are not well described.

To examine motivational signals, Hikosaka uses the reward-based saccade task for monkeys, which requires a monkey to make a saccade in return for varying amounts of rewards, depending on the cued direction of the saccade. This biased reward paradigm allows the researchers to evaluate the saccade latency when large versus small rewards are expected. Indeed, saccade latencies are significantly faster when a larger reward is predicted. Using this paradigm, HIkosaka has found reward selective neurons in many areas. One such area is the substania nigra/VTA, which contains a population of dopaminergic neurons that project to multiple areas in the striatum, palidum, and cortical areas. The role of dopaminergic neurons in reward has been reported by multiple groups, but HIkosaka’s group has recorded single dopamine neurons, showing that these neurons are activated by reward, and inhibited by the lack of a reward, predicting the future outcome of the motor activity required by the behavioral task.

But what is driving this activity? Hikosaka notes that evidence for direct functional connectivity onto dopamine neurons has been slim. One exception was research suggesting that the habenula is a major input onto these dopaminergic neurons. The habenula is involved in responses to stress and pain, avoidance learning and error monitoring, all of which have been implicated in the etiology of major depression, schizophrenia, and drug-induced psychosis. These phenomenon are quite distinct from those associated with dopaminergic dysfunction. Recording directly from habenula neurons (in particular lateral habenula), they found neurons that responded to reward prediction errors, but with the opposite sign to responses in dopamine neurons.

What drives the lateral habenula? Many brain areas, but the globus pallidus appears likely to be an input important for encoding reward prediction errors. Recordings from the globus pallidus demonstrated neurons that are inhibited following stimuli predicting reward, and excited by stimuli predicting no reward. Further results suggested that negative reward signals are passed from globus pallidus to lateral habenula. Then, additional expeiments showed that the lateral habenula acts on dopaminergic neurons in the substania nigra/VTA is via rostromeidal tegmental nucleus (see the poster by S. Hong from Hikosaka’s lab later on in this week).

Switching subjects slightly, Hikosaka notes that serotonergic neurons in the dorsal raphe nucleus appear to encode current reward state, where as dopamine neurons encode changes in reward value.

Hikosaka states that motivation is often thought to be driven by reward. But Hikosaka suggests that motivation for research is also a valid type of motivation. To examine this potentially distinct expression of motivation, a new paradigm was created, one that presents the monkey with an information cue or a random cue – the information cue gives the monkey advanced information regarding the size of the reward it will get. They use this paradigm to ask which cue the monkey prefers – to know what reward they will get or not. After a few days of training, the monkeys preferred to know if advance whether they would get a large or small reward. What neural mechanisms underlie this desire/preference for advanced knowledge of reward?

Hikosaka’s group recorded from dopamine neurons, confirming that dopamine neurons encode reward prediction error, but also showing that dopamine neurons are excited by the presentation of the information target, but inhibited by the non-informative target. They also recorded from habenular neurons, and found similar responses. This suggests that the habenula/dopamine circuit contribute to the monkey’s desire for knowledge.

Another type of motivation: Motivation for Salience. A reward may come with risk – what are the neural mechanisms underlying the decision to take a risk for the possibility for reward. To test this, another paradigm was constructed wherein a particular image was shown right before a juice reward, with another image displayed before no reward. Building on this, a new picture was associated with an airpuff to the monkey’s face, and another picture with no airpuff. Similar to the reward condition, the latency to looking at the picture predicting the punishing airpuff was faster than the latency to looking at the picture predicting no punishment. The reward and the punishment have opposite valiances, but are both salient – how does the brain encode both? Research into this question was done by Matsumoto, and was published in 2009 (Bloggers note: this paper – Matsumoto and Hikosaka - is well worth a read), showing that lateral habenula neurons encode motivation value in the negative range. Recording from dopamine neurons in VTA, they found two populations, one of which were encoding value for positive valence, another of which encoded motivational salience, not motivational value. So in summary, they found two populations, one motivational value encoding neurons, and another that encode motivational salience. Matsumoto and Hikosaks worked to localize these two populations. They found that motivational value neurons were localized to ventromedial VTA, which is though to project to ventral striatum. Motivation salience neurons were located primarily in dorsolateral VTA, which may be projecting to dorsal striatum. Again, for a more detailed description of this research, see the published research, Matsumoto and Hikosaka, 2009.

Hikosaka returns to his model of action and motivation network, and brings up the question of how the reward system alters the action network, specifically the connection between the dopamine system and the posterior striatum, which eventually feeds forward onto the superior colliculus, which is involved in saccadic eye movements. Hikosaka highlights a portion of the posterior striatum, the tail of the caudal and posterior putamen- this area is known to receive inputs from visual association areas. They recorded neurons from posterior striatum, finding to their surprise that a majority of neurons responded to visual images with a high degree of object and spatial selectivity. They wondered whether this selectivity was dependent on the experience of the monkeys – could previous reward associations influence the selectivity of posterior striatal neurons? They trained the monkeys on a task that associated a set of specific images with reward, and another set of images with no reward. They then recorded the neuronal activity during presentation of a random selection of these images. After several days of training, they started to see a clear preferential bias in monkey behavior and striatal neuron activity in response to the reward-associated images.

Posterior straitum is known to project to SNr – these neurons also bias, but in the opposite sign (excited by no reward-associated images, not activated by reward-associated images). Neurons in the SNr projected to the superior colliculus, where they are presumably influencing generation of the saccade.

Hikosaka concludes his talk by returning again to his model of action and motivation network, stating that the motivational network can control the action network in multiple ways, via multiple pathways. In summary, Hikosaka states that the heterogeneity of the motivation and action network may “allow the brain to adapt to a complex environment, efficiently and robustly”.

*Winner of the Stanford Neuroblog’s Award for Most Epic Bow Tie

[Updated: additional coverage of the Hikosaka lecture, here.]

Oh posters

First day of SFN. Ok I'm tired already. Went to good talks and some posters. Just wanted to make a quick comment before I collapse in bed. Ive been hearing a lot of complaints from students about the quality of posters at this SFN. Maybe it's not unique to this SFN and it's a problem every year, but it seems more talked about this year. Many people feel that presenters are not explaining their posters clearly enough and their descriptions are unintelligible to all except those working in that specific field. Presenters often ignore the big picture and go straight into their "data dive" which may not make much sense unless you've been working in that field for a while. Isn't the point of SFN to get people from various branches of neuroscience to come and be exposed to different ideas and techniques?

So why is it that most people are so inadequately prepared for presenting their posters? Could be that they don't have the presentation skills to lay out the big picture and put things in context before getting into the data on the poster. Or it could be that they do it on purpose so as to deter people not familiar with their research area from spending too much time at their poster (assuming their principal objective is to get good feedback regarding their experiments from people experienced in their field). Or it could just be that people are simply tired of going through everything for the 95th time and just skip to the bare essentials which are not enough to convey to the audience the information that they're trying to convey and hold their interest at the same time.

I don't know. I'm gonna do an experiment tomorrow to try to figure out. Day 2 here I come!

Suraj

SFN: Wurtz and Brain Circuits for Active Vision

Gruber Lecture: Brain Circuits for Active Vision. Robert Wurtz, PhD, National Eye Institute/National Institutes of Health After an brief introduction to the Gruber International Prize Program by Sarah Hreha, Executive Vice President of the Peter and Patricia Gruber Foundation, Michael Goldberg (and his excellent bow tie) present the 2010 International Research Award for Neuroscience to Laura Colgin and Jason Shepherd. Congratulations to them both.

This is followed by the presentation of the Gruber Prize to Robert Wurtz by Sten Grillner (chair of the Neuroscience selection advisory board for the Gruber Foundation). Wurtz long, auspicious career is described, highlighting his groundbreaking work on the visual system of awake-behaving primates. The official text of the award: “Honored for his pioneering work in the neurophysiology of visual cognition, which has led scientists to a deeper understanding of how the brain is organized to produce behavior.”

And after a few acknowledgements, Robert Wurtz begins his talk.

Wurtz notes the usefulness of having post-docs in the lab… for when a monkey gets loose.

When presented with a visual scene, we have the perception that we see every part of that scene with equal clarity at all times. However, neuroscience has shown that this is emphatically not true, we constantly make saccadic eye movements that focus our high acuity vision to examine different parts of the visual field at any time. These eye movements shift the fovea, and visual attention, displacing the retinal image of the visual scene and producing a blurred sweep of visual information during the saccade movement itself. And yet with all this movement and displacement, our brain computes the visual information to produce the illusion of a unified, clear visual field.

The talk will address four points: 1) an overview of the brain areas involved in active vision, 2) attention (enhancement of vision with saccades), 3) suppression (decreases of the inter-saccade blurring) and 4) the mechanism that generates saccades, which underlies both attention and suppression.

First, Wurtz describes the methodologies used to study active vision in awake monkeys. The basic setup is to record neuronal activity from head-fixed monkey who are fixating on a visual location.

Next, he outlines the basic system underlying the generation of saccadic eye movements. From V1, the pathway extends to the posterior parietal cortex and the frontal cortex, and thereon to the superior colliculus, and to the midbrain and pons for generation of motor output. To highlight the role of the superior colliculus, which is a critical component of the saccade generating circuit. For the purposes of the talk, the SC can be divided into two layers, a superficial, retinorecipient layer, and a deeper layer that encodes information regarding planned saccade movements. These visual-motor neurons display a burst of activity immediately prior to the eye movement.

With this type of activity introduced, Wurtz presents a two-fold experimental strategy: 1) correlation of neuron activity to behavior and 2) perturbation of neuron activity via activation or inactivation of neurons. He notes that in the second part of this strategy, classic techniques have been chemical or electrical means, but that recently they have turned to optogenetic inactivation of neurons located in the deep layers of the superior colliculus (this in collaboration with Ed Boyden’s lab).

Correlating and perturbing neuronal activity leads to classical view of superior colliculus, namely that it is largely involved in motor generation of the saccade. Newer research has suggested that the superior colliculus is also a major source of ascending pathways to inform the cerebral cortex about the saccade. These ascending pathways leave the superior colliculus and go directly to the thalamus before going to cortical areas (for example, SC to MD to FEF; SC to Pulvinar to LIP/MT or SC to Reticular Nucleus to thalamocortical relay neurons (LGN)).  Wurtz will focus on the SC to Pulvinar to LIP/MT pathway.

We now turn to the topic of spatial attention, specifically looking at the phenomenon of change blindness. We are showed a demonstration of change blindness, which demonstrates the power of spatial attention to direct

Wurtz describes two types of attention. The first he calls onset attention, which generates saccades to new objection (also known as bottom up, or involuntary attention) – this is eliminated during the change blindness test. The second type is goal directed attention (aka top-down attention) which remains during the change blindness test. Wurtz will discuss this second form of attention, and the role of the superior colliculus. Results from experiments demonstrated a motor theory of attention which postulates that the mechanisms generating saccades to a target contribute to a shift of attention to that target – this theory was demonstrated particularly well by Tirin Moore’s 2002 experiments in stimulating FEF to shift attention and gaze.

The question for Wurtz examined was if the superior colliculus saccade generation activity contributes to attention modulation in cortex. They used a change blindness task, modulating SC activity to attempt to alter cortical processing of visual information. He first describes the paradigm of motion detection change blindness. Briefly, the subject fixates, is presented with 3 groups of dots that are moving in a direction, with out of those groups switching directions after a blank screen is shown (to induce change blindness). Cueing the participant to which group is likely to switch will shift visual attention, increasing the ability of the participant to detect the change in direction. If the visual cue is replaced by stimulation of the superior colliculus, they see a significant improvement in the ability of monkeys to detect change in the stimulus. So stimulating a neuronal component involved in saccade preparation produces a behavioral effect similar to attention. From this research, Wurtz notes with great satisfaction a cognitive function like spatial attention can be understood at the mechanistic level of neuronal activity.

Wurtz now moves on to the suppression of visual activity that occurs during the saccadic eye movement itself. The classic explanation involves corollary discharges, where information generated in sensorimotor processing is sent as a corollary discharge to other brain areas, where it informs those areas about the movement that is about to be made. Where are the saccade corollary discharges produced? Wurtz suggest it is the superior colliculus – he notes that they have identified two corollary discharge pathways: SC to MD to frontal cortex as well as SC to inferior pulvinar to occipital/parietal cortex. To summarize the research on this first pathway: the SC to FEF path provides a corollary discharge that acts of compensate for the displacement of the image on the retina. The second pathway may contribute to elimination of the blur from saccades (aka saccadic suppression).

Why look at superior colliculus as the origin of corollary discharge for saccadic suppression? Recordings from SC neurons show reduced responses to visual stimuli during movement. Furthermore, saccadic suppression starts before the saccade, and SC neurons demonstrate a decrease in responsiveness to visual stimuli immediately prior to saccadic movement. This resulted in a hypothesis stating that intermediate SC layers receive inhibitory inputs – slice recordings support this as occurring. But how does SC-mediated saccadic suppression get into the cortex? Recordings from MT neurons demonstrate saccadic suppression similar to the suppression seen in SC neurons. But are is this cortical suppression the result of the SC suppression? One problem is that it is not clear what the actual pathway is. Wurtz describes experiments that have been done to locate the pulvinar relate in the circuit between the SC and MT. He notes that they have found some relay neurons in a subregion of the inferior pulvinar that are connected to both SC and MT (this research done by Rebecca Berman and involved recording from pulvinar neurons while stimulating both SC and MT).

So does this circuit carry saccadic suppression? To test this, Berman has been recording MT neurons that show saccadic suppression while inactivating SC – her results show that in the absence of SC activity, there is an increase in MT neuron activity – suggesting that suppression in SC contributes of saccadic suppression in cortex. Wurtz notes that MT responses are a combination of SC and V1 inputs – inactivation of the SC removes one (inhibitory) input, leaving only the excitatory V1 inputs.

[Bloggers commentary: the role of the SC-pulvinar-MT connection in suppression of MT activity should perhaps be taken with a grain of salt. The exact components underlying the suppression of MT are not as clear as Wurtz suggested. The pulvinar is not an inhibitory area, so how it could be directly suppressing MT activity is not clear. One possibility is that inhibitory circuitry within in the SC is responsible but again, the exact players involved have not been identified. And intra-SC inhibition would not support their model of MT activity being the sum of SC and V1 inputs, with knocking out SC resulting in increased activity because of removal of inhibitory drive. Indeed, that model would require pulvinar to be responsible for inhibitory drive onto MT, something that is not supported by any currently described circuitry. If intra-SC inhibition is responsible, then you would expect that inactivation of SC would yield MT activation equal to drive from V1 (aka removal of additional excitatory drive), with no additional enhancement of MT (as might be expected if SC inactivation removed inhibitory drive, which Wurtz suggested is the case). In conclusion, the exact connections and role of the superior colliculus in attention and saccadic suppression have not yet been fully defined, End of commentary.]

To sum up his talk, Wurtz restates his claim that our perception of visual stability can be understood at the level of simple neuronal circuits. In conclusion, he notes that the brain circuits he has discussed all have the same basic structure, with their different functions dependent on what signals are conveyed and where those signals are directed. He notes that this structure suggests that corollary discharges and spatial attention can be viewed as variant of a general scheme. Finally, he point out the progress being made in elucidating the brain circuits that underlie cognitive processes for active vision. Still to be fully described are the mechanisms underlying decision for action, working memory, and rewards/values. He notes that understanding these cognitive functions depends on studying circuits at the highest levels of the cerebral cortex, and that understanding of these functions is necessary for comprehending the many diseases of the brain. He lends his support for research utilizing the monkey brain as an experimental model, stating the monkey brain provides unprecedented opportunities for understanding a wide range of cognitive processes and diseases.

Dyslexia and Pattern Detection in Peripheral Visual Fields

Principles of success and failure in reading instruction via the lens of systems neuroscience. McCandliss, Sackler Inst- Weill Med. Col The basic heft of this talk was to present evidence for enhanced visual abilities in dyslexic individuals. The background for this student is two-fold. First, that the parents of many dyslexic school children has claimed for many years that their children are endowed with enhanced visual abilities of one flavor or another. Researchers have been moderately dismissive of these claims (at least according to the speaker), but recently have attempted to directly test these claims. One study showed Escher figures to individuals and quantified the speed with which the subjects could distinguish between possible and impossible structures. The results showed that dsylexics can identify/analyze Escher figures twice as fast as non-dyslexics.

Jumping off from this finding, the researchers looked at dyslexic astrophysicists. A common task in the field of astrophysics is black hole detection. This task , involves identifying patterns amongst a complex field. The researchers hypothesized that dyslexics would have heightened sensitivity for pattern detection across a wide visual field. This is in part based on previous results showing that dyslexics are less able to detect patterns in the foveal receptive fields. The results were that dyslexic astrophysicists are remarkably superior at detecting black holes, showing a significant increase in signal-to-noise threshold at periphery of visual field.

Next, the researchers expanded to wider population, asking students to detect a letter hidden in a photograph. Dyslexic students showed heightened ability to detect the hidden letter - this suggests to the researchers that dsylexics have a differently constructed visual system. The speaker concludes his talk with the comment that they have no idea where the difference is (retina versus cortex versus any other visual-associated brain region).

A question from the audience: what about neurologists who have to read EEG’s, X-rays, or fMRI. The speaker suspects that dyslexics would also be better at pattern detection in these cases than non-dyslexics.

Another question: Are the differences in eye-scanning during reading of dyslexics accounted for by the lower power of the retina to detect patterns and the concomitant increase in peripheral pattern detection capabilities? Answer: possibly, although they have not done the research.

SFN: Calcium Signaling and Alzheimer's

Presenilins, neuronal calcium signaling, and Alzheimer's disease. Presented by I. BEZPROZVANNY from UT Southwestern Med. Ctr. Dallas. This talk was part of the New Advances in Calcium Signaling in Neuronal Function and Disease Symposium. The initial question proposed by the speaker is how mutations in presenilins (PS-FAD mutations) cause excessive calcium release from the ER. They hypothesize that presenilins function as ER calcium leak channels. Mutations disrupt ER calcium leak function and result in overfilled calcium stores. Loss of function for presenilin ER calcium leak becomes gain of function.

Normally, presenilins act in homeostasis of ER calcium stores. In the KO cells, this homeostasis is disrupted, so that ER calcium stores are overfilled, and when ER calcium stores are released, a much greater concentration of calcium is released.

The initial discovery and analysis of ER calcium leak function of presenilins was based on bilayer recordings of recombinant proteins and on calcium imaging experiments with PS DKO mouse embryonic fibroblasts. One question the investigators had was whether presenilins function as neuronal ER calcium leak channels. The answer is yet – recordings (and imaging) from neurons in their presenilin-KO mouse show a 2-3 fold increases in ER calcium pools as compared to wild type neurons.

So with evidence that presnilins are neuronal ER calcium leak channels, they next wondered how neurons compensate for the lack of presenilins. They found a increase in the Ryan receptor in neurons lacking presenilins – implying that the RyanR is involved in homeostatic compensation. Mice lacking RyanRs display a significant increase in the calcium pool. Combination of the presenilin and RyanR KO shows a 15-20 fold increase in the size of the ER calcium pool – significantly enhanced compared to the 2-3 fold increases in calcium pool size that result in the individual presinilin or RyanR KO conditions.

This suggests a model where both presinilin and RyanR are involved in homeostasis of ER calcium stores. Removing one of these mechanisms shifts the load to the other mechanism. However, removal of both mechanisms results in breakdown of ER calcium pool homeostasis, leading to apoptosis and accumulation of amyloid plaques typical of Alzheimer’s.

The speaker notes that loss of ER calcium leak channel homeostasis is not the only determinant of familiar Alzheimer’s – there are several other identified mutations. So the question is, given these multiple mechanisms, is there a downstream mechanism that they all affect, disruption of which results in Alzheimers. He hypothesizes that the identified mutations that underlie familial Alzheimer’s share a tendency towards network hyperexcitability. He proposes that mutations in presinilin cause disruption of ER calcium levels (via altering levels of AB42/40), disrupting neuronal hyperexcitability, which in turn activated a positive feedback loop that ends up further increasing ER calcium stores via up-regulation of AB42/40. Note: the speaker presented a more complex picture of the protein mechanisms behind this loop, further describing a second loop that he proposes to be initiated by hyperexcitability, but spoke too fast for me to note down the specifics.

So how does this relate to aging neurons (due to the link between Alzheimers and advanced age)? He notes that aging neurons are known to have increased levels of internal calcium, and perhaps this tendency is able to initiate the multiple feedback loops he proposed.

SFN: Normalization Model of Multisensory Integration

Normalization model of multisensory integration: Tomokazu Ohshiro. et al. Many physiological studies have investigated how multisensory neurons respond to inputs from different modalities. These neurons display some particular properties that speak to how they integrate the information from multiple modalities. However, a simple computation framework that accounts of these features have not been established.

The basic model proposed by the speak is a divisive model. The basic setup is as follows: individual layers that are modality specific receive information from specific sensory structures. Multiple single-modality layers, with matching (aligned) receptive fields, then target the same multisensory layer, with the inputs from each modality summed in a weighted fashion. Output from this computation is used to divisively normalize the output of the multisensory layer.

Ohshiro next describes the principle of inverse effectiveness, one of the particular properties of multisensory neurons which have not yet been successfully modeled, but which their divisive model supports. He shows an example from cat superior colliculus: when multisensory neurons are co-presented by visual and auditory stimuli that are at threshold (optimal) intensities, the activation is greater than the sum of the responses to each stimuli alone. However, additional multisensory drive (aka increasing the intensity of the multisensory stimuli to super-threshold, non-optimal stimuli) results in a suppression of the responses, such that they are less than the sum of responses to each stimulus alone. Put another way: bimodal responses are larger than the sum of the responses to each stimuli alone at weaker stimulus intensities, but smaller than that sum at stronger intensities. Ohshiro notes that according to their model, this response suppression becomes more robust as you add more sensory types.

Ohshiro moves on to the spatial principle of multisensory integration: another property he will account for in his computational model. Again he presents an example from the superior colliculus, showing that there is a spatial computation, such that if the different inputs are offset spatially, then the bimodal response gets weaker. This suppression of the bimodal response when multisensory inputs are not spatially aligned is a critical prediction of their normalization model, and confirms that the multisensory integration mechanisms is based on aligned spatial maps of sensory inputs.*

Shown next are recordings from Macaque MSTd neurons that again demonstrate that a bimodal stimulus produces a suppression of response when the stimuli are non-optimal (highly superthreshold), whereas weak bimodal inputs are enhanced relative to the sum of responses to the individual modalities.

In summary, Ohshiro et al propose that a multisensory version of divisive normalization can account for basic empirical principles of multisensory integration. Furthermore, they present both a computational model, and physiological data, demonstrating that divisive normalization can underlie the observation that non-optimal input, which is excitatory on its own, can produce cross modal suppression.

*This should not surprise aficionados of the superior colliculus, which contains aligned visual and auditory visual maps, as well as a multisensory integration circuit (see work by Eric Knusden).

SFN: Super-Resolution Synaptic Imaging minisymposium

This was my first event of the conference, so I hope, dear readers, you will keep in mind that I was still getting my science head screwed back on as I took all this down... The session was chaired by U.V. Nägerl from the University of Bordeaux and T.A. Blanpied of U. Maryland School of Medicine. They introduced the session by outlining the critical importance of understanding the structure and function of synapses and pointing out the technological gap that still exists in our ability to investigate these nanoscopic structures. However, we are embarking on a new era in synaptic imaging with the advent of a number of new techniques that bend or break the traditional diffusion limit to image structures in the range of 10s to 100s of nanometers, making synaptic imaging a reality.

The first speaker was D.A. DiGregorio, who admitted that his lab was still working within the boundaries of the diffusion limit, mainly, he joked, to find out just how bad it is for synaptic imaging. He is focused on the giant calyx of Held compound synapse as a model in order to investigate the relationship between the mutual developmental plasticity of morphology and physiology. Specifically, his lab has produced evidence that the increased precision of firing at this synapse with age may be related to refinement of spatial coupling of vesicles and presynaptic calcium channels. His technique involves a refinement of confocal imaging, using "spot imaging" to enable sub-millisecond temporal resolution rather than the slower method of line-scanning.

I'm afraid I missed some crucial parts of the next talk, but here are a few of the main points I caught: A. Triller discussed the role of syntaxin in the docking and fusion of vesicles. His group have labeled syntaxin with pHGFP, a pH sensitive fluorescent marker which localizes to the cell surface. FRAP imaging shows the molecule to diffuse rapidly within the plasma membrane, and the lab uses this diffusion to model sub-membrane events using quantum dot tracking. One principal observation utilizing this method was that syntaxin molecules pause in their free diffusion temporarily when they pass presynaptic sites.

U.V. Nägerl then spoke about imaging actin dynamics inside spines using STED. He eulogized spines as amazing signaling machines with thousands of proteins, key for brain function in health and disease, numerous, dense, dynamic, and SMALL, then hailed the new methods arising to allow the application of physiology and biochemistry to individual synapses and spines. 2-photon imaging has been extensively used to explore the structural changes accompanying synaptic plasticity, but differentiation of distinct synaptic compartments remained a challenge, as these compartments are smaller than diffraction limited resolution. This limit, however, is being broken by super-resolution imaging down to 10-50 nm. The group utilizes STED microscopy, which involves suppressing the fluorescence evoked by a primary laser beam using a secondary annular (or donut-shaped) illumination laser of a different wavelength. This produces a central spot of fluorescence much smaller than the diffraction limit.

Nägerl has been working to use STED to image spines in live cells, and has produced preliminary observations of nicely symmetrical distributions of spine neck diameters (which confocal tended to skew towards the larger diameters it could resolve). The lab has begun to investigate synaptic actin and tubulin to discover mechanisms of "morpho-functional" plasticity. Using Lifeact, a small peptide which reversibly binds to actin within synapses, the group has visualized actin cables inside spines and dendrites, some linear and some curved, presumably "handshaking" with microtubules in the dendritic shaft. In addition, different shapes of actin are observed in the spine head, whose shape changes with plasticity along a ~100nm range. Some evidence has been uncovered of changes in spine neck diameter with chemically induced LTP, which the lab intends to follow up with more refined methods. The group hopes to develop nanoscale imaging of dynamic signals such as Ca2+, to explore the possibility of nanoscale photomanipulation / uncaging, and to combine STED bulk imaging with PALM single-particle tracking methods.

The final talk I caught from this session was by E. Jorgensen of the University of Utah, who described his groups progress developing conjugate fluorescence and electron microscopy - a feat which has stymied many great scientists for decades. His group studies synaptic transmission at the 500nm diameter NMJ of the nematode worm C. elegans. Hoping to understand the arrangement of synaptic proteins, one might wish to tag specific molecules with fluorophores, but at that scale one would only see an unresolvable blob. The resolution (so to speak) of this problem involves 4 microscopy techniques: correlative fluor-EM, STED, PALM, and 'biplane'. First, correlative fluor-EM requires a delicate balance between the conflicting optimizations required for fluorescence and electron microscopy. Sections must be mounted on coverglass and not the grids required for TEM, and both florescence and EM-scale ultrastructure must be preserved. The single nanometer scale of TEM can be sacrificed for the ~5 nm resolution of back-scatter SEM, which permits the use of flat-mounted structures, but the tension between fluorescence and ultrastructure remains. EM works best with dehydrated tissue infiltrated with oxidizing agents such as osmium at an acidic pH, whereas fluorescence requires hydrated tissue, a neutral pH, and is severely disrupted by oxidization. Remarkably, Jorgensen claims to have found a compromise which satisfies both techniques, involving embedding tissue for EM in methacrylate plastics which tolerate moderate (5%) hydration, use of K2MnO4 (potassium permanganate) instead of osmium, and tight pH control using ethanolamine.

However, correlating EM ultrastructure with regular fluorescence imaging does not resolve the problem of how to image proteins at a subcellular scale (you are still correlating a coarse blob with the fine structure), though it may be very useful for identifying labeled cells and axons. Instead, the group has used STED on 100 nm sections in C. elegans to image the subcellular distributions of histones, mitochondrial protein TOM-20, and liprin. The trouble with the STED system, Jorgensen remarked, are that 1) it can only resolve down to 60 nm, 2) it's expensive, and 3) he doesn't have one. The group also successfully used PALM (comparable to STORM, but using photoconvertable markers rather than organic dyes) with a liprin-Eos conjugate which is photoconvertible from green to red by application of a little UV light. Preliminary results using this technique to explore the localization of Actin-4 in the worm nose have suggested that the molecule is to be found in the membrane of glial sheath cells, but not in the sensory cells, as some had presumed. Still, all this conjugation proved very time consuming, which led to the development of biplane microscopy by the lab, which, as the name implies, improves on the efficiency of PALM by imaging in 2 planes at once. The system is largely computerized - as Jorgensen proclaimed, "If you still have an eyepiece, you probably still have a rotary phone - give 'em up!" This system is now commercially available as the Vutura Avalanche (and is present in the vendor stands at SFN!)

All in all, these super-resolution techniques seem to be opening up a bright new future for imaging the tiny world of the synapse!

SFN: Vocalization Minisymposium

Neural Mechanisms Underlying Vocalization in Multiple Species: A Special Focus on Parkinson’s Disease Unfortunately, I missed most (read: all) of this minisymposium due to research-relevant poster sessions. However, I did stop in for the closing remarks, hoping to pick up some interesting tidbits.

Speakers touched on the need to look at vocalizations in animal models in both normal and diseased states. The speaker calls for better integration between the multiple disease models mentioning the possibility of using vocal changes as an early predictor to disease onset, particularly in Parkinson’s, but also in diseases such as Huntington’s, ALS, autism spectrum disorders.

A brief question and answer period:

One researcher suggests bringing back the cat as a research model. The panel agrees that there are many fine animal models, but declines to comment directly on the cat as a model system.

Another question regards the difference between production of ultrasound and “normal” vocalizations. According to a panel member, ultrasonic mouse vocalizations shift their fundamental frequencies when you alter the media through which they propagate – this is not the case for audible vocalizations from the mouse. To the panel member, this suggests distinct vocal production mechanisms for audible and ultrasonic vocalizations.

Where any readers out there present for more of the session? The comments section is open to any notes you may have from the session.

SFN Poster Session: For Lovers of the Superior Colliculus

Most of my first afternoon at SFN was spent in the poster session, specifically hunting for posters regarding functionality in the superior colliculus, and its non-mammalian homolog the optic tectum. Since I work in this brain region, most of my attention has been focused on findings applicable to my own research. Without going too in depth into my own research and why I spend half an hour pondering the release of nicotine into the superficial layers of the pigeon optic tectum (thanks to Macarena Faures' poster), some brief thoughts on the posters: For aficionados of the region, there are several groups who have successfully expressed channelrhodopsin (or halorhodopsin) variants in axons of retinal ganglion cells, using this technique to selectively activate (or inactivate) visual activity into the superior colliculus. Most of the posters show the success of the expression, it seems that we will have to wait until next year for the results of any experiments made possible by these technological advances. One exception is a group that uses a channelrhodopsin variant expressed in a sub-population of retinal ganglion cells to show that connectivity between RGCs and the circuitry of the superior colliculus is in place before maturation of the retinal opsin system. It’s possible that these results are not surprising, given previous research showing that wiring of RGC axons in the superior colliculus is dependant on spontaneous RGC waves. (Someone more familiar with the temporal placement of retinal waves during development should feel free to correct me here).

To turn back to the Faures poster, out of the Marin group - their discussion brings up the possibility that the neurotransmitter identity of a particular brain region, Ipc, has been incorrectly identified. The Ipc is the avian homolog of the mammalian parabigeminal nucleus, and has been classically thought to be cholinergic, due mostly to the presence of ChAT immunoreactivity. However, recent research is apparently calling into question the assumption that the Ipc released acetylcholine - at least according to a researcher in the Marin group. I'm going to withhold my judgement (although I am deeply skeptical) and wait for the proof positive combination of recordings and histochemistry. But that the question is being posed in the first place is fascinating to me - if their concerns are valid, it will highlight the difficulty of exactly characterizing any brain area based on expression of particular proteins.

On a less scientific note: of general amusement has been watching as my PI strode through the poster session, ending up huddled with about 4 other PI's, hotly debating the function of the superior colliculus.