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The top 11 (or 23) unanswered questions in neuroscience

This post has been in my draft for a while, and recently it came up as a question over at Quora, so I finally got around to finishing it.

What are the really big questions right now in neuroscience?

This is a fun game that a lot of neuroscientists like to play (usually over a few drinks). Generally our responses fall under one of two categories (of which I'd argue all others are just more detailed sub-questions). They are:

  • Consciousness WTF!?
  • How can atoms and molecules combine to a behaving animal?

When I was first starting my PhD there was a series of book chapter PDFs that were getting passed around from a book co-authored and edited by David Eagleman and Patricia Churchland that was supposedly going to be published in 2006 titled, Ten Unsolved Questions of Neuroscience.

As far as I can tell, that book never saw print, though you can find the draft chapters online in that link above. The authors of the chapters in that non-book are an excellent selection of outstanding neuroscientists from 2006.

In 2007, Eagleman basically turned what I assume was the book outline into a short essay in Discover titled "10 unsolved mysteries of the brain".

The list from his Discover piece differs slightly from the 10 chapters of the book:

  • How is information coded in neural activity?
  • How are memories stored and retrieved?
  • What does the baseline activity in the brain represent?
  • How do brains simulate the future?
  • What are emotions?
  • What is intelligence?
  • How is time represented in the brain?
  • Why do brains sleep and dream?
  • How do the specialized systems of the brain integrate with one another?
  • What is consciousness?

The following question was not in the Discover piece, but is in the book draft:

  • How do brains balance plasticity against retention?

It's this last one that I find the most fascinating. So much so, that the (PDF) opening line of my PhD thesis is:

How do we maintain a stable percept of the world in the face of the powerful drive of neuroplasticity in both health and disease?

(If you've read any of my research, this should be no surprise.)

Now, it seems that the woo woo crowds (and bad science journalists) have a tendency to pull out the word neuroplasticity about as readily as they will the word quantum when "explaining" certain nebulous phenomena. This is so common that "neuroplasticity" is becoming a dirty word.

Yet, as Micah Allen pointed out last night:

I find it funny in the space of 10 years we've gone from excited about neuroplasticity to totally cynical. I'm an anti-cynic.less than a minute ago via TweetDeck Favorite Retweet Reply

Hype sucks, but let's not go back to the days when neurologists refused to treat patients because "the brain isn't plastic."less than a minute ago via TweetDeck Favorite Retweet Reply

I find it interesting that Eagleman chose to replace the question about neuroplasticity with the question about consciousness for the Discover piece.

You know you're in bad shape when consciousness seems to be the more reasonable alternative.

Jordan Grafman has a fun, short article published in Brain and Cognition in 2000 titled, Picking Two Scientific Roses for the Next Century. In that, he highlights neuroplasticity as a major research endeavor, but he breaks it down more scientifically:

"Neuroplasticity has at least four distinctive expressions:
  • (1) Flexibility of local cortical (representational) maps to expand and contract and to store new items;
  • (2) Homologous region adaptation—-for example, when brain damage affects the left parietal lobe, can the right parietal lobe reorganize itself to allow the representation of forms of information previously stored in the left parietal lobe?
  • (3) Sensory substitution where one cortical area previously committed to processing information in one sensory domain (e.g., vision) adapts to input from a different sensory domain (e.g., touch);
  • (4) Compensatory reorganization where the remaining components of a configured cognitive process perform well enough so that the person can achieve the desired performance outcome (even if it is now accomplished somewhat differently than before)."

A ton of exciting research has been done on these questions since that writing.

In addition to the Eagleman list, there's a more specifically detailed list from a book edited by J. Leo van Hemmen and Terry Sejnowski called (PDF) 23 Problems in Systems Neuroscience which was published in 2006 by Oxford University Press.

While there is certainly overlap with the Eagleman questions, the van Hemmen/Sejnowski list includes more biologically-specific, "lower-level" questions, as opposed to Eagleman's "higher-level" conceptual questions:

  • Shall We Even Understand the Fly's Brain?
  • Can We Understand the Action of Brains in Natural Environments?
  • Hemisphere Dominance of Brain Function--Which Functions Are Lateralized and Why?
  • What Is the Function of the Thalamus?
  • What Is a Neuronal Map, How Does It Arise, and What Is It Good For?
  • What Is Fed Back?
  • How Can the Brain Be So Fast?
  • What Is the Neural Code?
  • Are Single Cortical Neurons Soloists or Are They Obedient Members of a Huge Orchestra?
  • What Is the Other 85 Percent of V1 Doing?
  • Which Computation Runs in Visual Cortical Columns?
  • Are Neurons Adapted for Specific Computations?
  • How Is Time Represented in the Brain?
  • How General Are Neural Codes in Sensory Systems?
  • How Does the Hearing System Perform Auditory Scene Analysis?
  • How Does Our Visual System Achieve Shift and Size Invariance?
  • What Is Reflected in Sensory Neocortical Activity: External Stimuli or What the Cortex Does with Them?
  • Do Perception and Action Result from Different Brain Circuits?
  • What Are the Projective Fields of Cortical Neurons?
  • How Are the Features of Objects Integrated into Perceptual Wholes That Are Selected by Attention?
  • Where Are the Switches on This Thing?
  • Synesthesia: What Does It Tell Us about the Emergence of Qualia, Metaphor, Abstract Thought, and Language?
  • What Are the Neuronal Correlates of Consciousness?

This is a great list because the problems are (generally) better defined and seem more tractable. But it's less fun for the same reason!

There are dozens of paper citations I'd love to add here to complement that list, but that would take forever. So if you're more interested in any specific topic, shoot me a message in the comments and I'll try and point you to some of my favorite references.

Grafman, J. (2000). Picking Two Scientific Roses for the Next Century Brain and Cognition, 42 (1), 10-12 DOI: 10.1006/brcg.1999.1147
Voytek B, Davis M, Yago E, Barceló F, Vogel EK, & Knight RT (2010). Dynamic neuroplasticity after human prefrontal cortex damage. Neuron, 68 (3), 401-8 PMID: 21040843
Sadato N, Pascual-Leone A, Grafman J, Ibañez V, Deiber MP, Dold G, & Hallett M (1996). Activation of the primary visual cortex by Braille reading in blind subjects. Nature, 380 (6574), 526-8 PMID: 8606771


  1. In the vein of some of these big questions (e.g. what is the neural code, what is consciousness) it's generally assumed that the firing of action potentials is required for conscious thought, information processing/retrieval etc. Every once in a while I wonder whether subthreshold types of activity (oscillations, synaptic events etc) could be responsible, at least in part, for these processes. Is conscious experience merely action potentials or might it be the sum total of all the neural activity occurring in one's brain? DEEP STUFF!

  2. Anonymous10:15

    Thanks for the great post. Being involved with base-line brain activity, specifically spontaneous BOLD fluctuations, I am interested to know which papers and references you have found interesting in this domain.

  3. I liken consciousness to this:

    "There was once a mammal. It needed a lot of little bits of operating systems in order to let all components of its body function properly. Over time they became so numerous that it needed a system to coordinate the other bits . That system became so complex that it was capable to reprogram itself in order to be able to assimilate the ever increasing flow of information. It called itself: conscience.
    Objectively impossible to determine if it exists, since conscience itself determines what are the criteria defining conscience.

    That conscience, in an attempt to preprogram future acts of the body, starts tell a tale to itself.
    A continuous flowchart enabling it by correlating previous events and by means of extrapolation to arrive at a predefined future action.

    The conscience calls that tale: reality. Again objectively impossible to determine if it exists, the conscience stipulates what is reality."

    The questions posed in the OP are fun to consider. Bit imo they rely on the false assumption that consciousness is something extra special.

    To me it's just an unnecessary artifact of a overgrown brain and in survival terms a negative factor.

    With just 100.000 years or so under our belt and practically on the brink of selfdestruction one can legitimately wonder what's so superior about us as compared to for example a jellyfish with 500.000.000 years on us and still going strong regardless our best efforts.

    It's fine and dandy to sit back and admire ourselves but hubris is imo to much of an understatement.

    When all is said and done we are just procreating monkeys that exist because they do.

  4. I guess along with atoms and molecules some form of energy (maybe electrical, magnetic or in combination) has to be combined to result into a behaving animal. Thanks for this intoxicating post! Each question is like a dose of some potent psychoactive drug.

  5. Jason: I'm so with you! After many long conversations with a philosopher friend of mine, I've begun throwing in the question: "what does a neuron *do*?" in some of my talks. It's funny to corner other neuroscientists with this question because, when you get right down to it, the only real answer is biochemical. Lots of other things are attributed to neurons ("processing", "computing", "transmitting", etc.) but are *so completely different* conceptually that a neuron can't be doing all of those things.

  6. Anonymous: *THE* classic is, of course, "Searching for a baseline: functional imaging and the resting human brain" by Gusnard DA, Raichle ME, 2001.

    "Neurophysiological investigation of the basis of the fMRI signal" by Logothetis et al., 2001
    "What we can do and what we cannot do with fMRI" also by Logothetis in 2008
    "Coupling between neuronal firing, field potentials, and FMRI in human auditory cortex" by Mukamel in 2005
    "Identifying natural images from human brain activity" by Kay et al. in 2008
    "Global and local fMRI signals driven by neurons defined optogenetically by type and wiring" by Lee et al., 2010

  7. petrossa: procreating self-humoring monkeys with the ability to ask--and begin to answer--some of these questions. Some may approach them with hubris, others with awe, and others with dispassion. The approach is unimportant.

  8. Healing: of course! These questions are part of what make the job so fun. :)