Neuroscience

Researchers at the National Institutes of Health and University of California-San Francisco have found that stimulating a key part of the brain reduces compulsive cocaine-seeking and suggests the possibility of changing addictive behavior generally. NIH Director Francis Collins, MD, PhD, discussed the study, and the significance of the findings in a blog post earlier this month:

The researchers studied rats that were chronically addicted to cocaine. Their need for the drug was so strong that they would ignore electric shocks in order to get a hit. But when those same rats received the laser light pulses, the light activated the [prelimbic area of the prefrontal cortex], causing electrical activity in that brain region to surge. Remarkably, the rat’s fear of the foot shock reappeared, and assisted in deterring cocaine seeking. On the other hand, when the team used a different optogenetics technique to reduce activity in this same brain region, rats that were previously deterred by the foot shocks became chronic cocaine junkies.

Clearly this same approach wouldn’t be used in humans. But it does suggest that boosting activity in the prefrontal cortex using methods like transcranial magnetic stimulation (TMS), which is already used to treat depression, might help.

This image shows optogenetic stimulation using laser pulses illuminating the prelimbic cortex. The channelrhodopsins used to create the photo were provided to researchers by Stanford bioengineer Karl Deisseroth, MD, PhD.

Previously: Better than the real thing: How drugs hot wire our brains’ reward circuitry, The brain’s control tower for pleasure and Addiction: All in the mind?
Photo by Billy Chen and Antonello Bonci

The traumatic events at yesterday’s Boston Marathon have many of us bracing ourselves for what might be coming next. And, as explained in a Healthland piece, this feeling of being on high alert is a result of how our brain processes traumatic experiences.

As writer Maia Szalavitz explains, “when the brain is under severe threat, it immediately changes the way it processes information, and starts to prioritize rapid responses.” While this behavior is important to our survival, it can be be harmful to our health if it persists after the threat has passed. So what can we do to help each other heal from the tragedy and reduce the risk of those most affected from developing post-traumatic stress disorder (PTSD)? Szalavitz writes:

Fortunately, our brains are designed to modulate fear responses and at least 80% of people exposed to a severe traumatic event will not develop PTSD. Studies show that the more support, altruism and connection people share, the lower the risk for the disorder and the easier the recovery. Because such interactions aren’t always easy in the immediate aftermath of a harrowing experience, Hollander is investigating whether medications based on oxytocin— a hormone linked with love and parent/child bonding— might help to ease this connection.

If fear short circuits the brain’s normally logical and reasoned thinking, social support may be important in rerouting those networks back to their normal state. Which is why the selflessness and altruism we see in the wake of terror attacks is often the key to helping us to process and overcome the shock of living through them.

Szalavitz’s message of using compassion to combat fear was echoed in this TED blog post, which encourages people to “look for the helpers” as we process what happened yesterday, and in Mashable’s list of touching acts of kindness at the marathon.

Previously: Can social media improve the mental health of disaster survivors?, Grieving on Facebook: A personal story and 9/11: Grieving in the age of social media
Photo by Alex E. Proimos

Your brain and my brain are shaped slightly differently. But, it’s a good bet, in almost the identical spot within each of them sits a clump of perhaps 1 to 2 million nerve cells that gets much more excited at the sight of numerals (“5,” for example) than when we see their spelled-out equivalents (“five”), lookalike letters (“5″ versus “S”) or scrambled symbols composed of rearranged components of the numerals themselves.

Josef Parvizi, MD, PhD, director of Stanford’s Human Intracranial Cognitive Electrophysiology Program, and his colleagues identified this numeral-recognition module by recording electrical activity directly from the brain surfaces of epileptic volunteers. Their study describing these experiments was just published in The Journal of Neuroscience.

As I explained in my release about the work:

[A]s a first step toward possible surgery to relieve unremitting seizures that weren’t responding to therapeutic drugs, [the patients had] had a small section of their skulls removed and electrodes applied directly to the brain’s surface. The procedure, which doesn’t destroy any brain tissue or disrupt the brain’s function, had been undertaken so that the patients could be monitored for several days to help attending neurologists find the exact location of their seizures’ origination points. While these patients are bedridden in the hospital for as much as a week of such monitoring, they are fully conscious, in no pain and, frankly, a bit bored.

Seven patients, in whom electrodes happened to be positioned near the area Parvizi’s team wanted to explore, gave the researchers permission to perform about an hour’s worth of tests. In the first, they watched a laptop screen on which appeared a rapid-fire random series of letters or numerals, scrambled versions of them, or foreign number symbols with which the experimental subjects were unfamiliar. In a second test, the experimental subjects viewed, again in thoroughly mixed-up sequence, numerals along with words for them as well as words that sounded the same (1″, “one”, “won”, “2″, “two”, “too”, etc.).

A region within a part of the brain called the inferior temporal gyrus showed activity in response to all kinds of squiggly lines, angles and curves. But within that area a small spot measuring about one-fifth of an inch across lit up preferentially in response to numerals compared with all the other stimuli.

The fact that this spot is embedded in a larger brain area generally responsive to lines, angles, and curves testifies to the human brain’s “plasticity:” its ability to tailor its form and function according to the dictates of experience.

“Humans aren’t born with the ability to recognize numbers,” says Parvizi. He thinks evolution may have generated, in the brains of our tree-dwelling primate ancestors, a brain region particularly adept at computing lines, angles and curves, facilitating snap decisions required for swinging quickly from one branch to the next.

Apparently, one particular spot within that larger tree-branch-interesection recognition area is easily diverted to the numeral-recognition activity constantly rewarded by parents and teachers during the numeracy boot camp called childhood.

Nobody can say those little monkeys don’t learn anything in kindergarten.

Previously: Metamorphosis: At the push of a button, a familiar face becomes a strange one and Why memory and math don’t mix: They require opposing states of the same brain circuitry
Photo by qthomasbower

Earlier this week, fellow Scope contributor Bruce Goldman reported on a paradigm-shifting process developed by Stanford psychiatrist and bioengineer Karl Deisseroth, MD, PhD, and colleagues. Using the process, called CLARITY, scientists were able to turn a mouse brain into an “optically transparent, histochemically permeable replica of itself.”

National Institutes of Health Director Francis Collins, MD, PhD, commented on the breakthrough in a recent blog post, saying:

CLARITY is powerful. It will enable researchers to study neurological diseases and disorders, focusing on diseased or damaged structures without losing a global perspective. That’s something we’ve never before been able to do in three dimensions.

This haunting image depicts a three-dimensional rendering of clarified brain imaged from the ventral half. To fully experience the new method’s awe-inspiring capabilities, watch this fly-through video.

Previously: Scientific community (and Twitter) buzzing over Stanford’s see-through brain, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact and Peering deeply – and quite literally – into
Photo by Deisseroth lab

Earlier this month, the White House announced that William Newsome, PhD, a professor of neurobiology at Stanford, was one of two scientists selected to lead the BRAIN Initiative, a $100 million research effort aimed at developing new technologies and methods for understanding the human brain. Now comes news that Newsome has been appointed to direct Stanford’s new interdisciplinary neuroscience institute.

A story published today in the Stanford Report offers a closer look at how the institute “will catalyze new interdisciplinary collaborations at the boundaries of neuroscience and a broad array of disciplines.” Bjorn Carey writes:

A committee of faculty leaders has been planning the institute’s make-up for more than a year, and has identified six major research themes that will form the backbone of the effort:

• The “Language” of the Brain: Cracking the Neural Code
• Enhancing the Brain: Brain-Machine Interfaces and Neuromodulation
• Understanding Human Thought: Decisions, Memory and Emotion
• The Brain in Disease: Neurological and Psychiatric Disorders
• The Changing Brain: Development, Learning and Aging
• Neuroscience for Society: Education, Law and Business

One of Newsome’s first efforts will be to meet with faculty from various departments that have a stake in current neuroscience research at Stanford, as well as with faculty and departments who are new to the field, to discuss how they might get involved.

“I think most people will be able to look at these six initiatives and see where they fit in, but we’ll need interdisciplinary leadership to determine where the best research opportunities lie,” he said. Which of these areas of study take flight will depend somewhat on the scientific opportunities that emerge, and where faculty and students band together to work cooperatively on an important research goal.

Previously: Experts weigh in on the new BRAIN Initiative and A federal push to further brain research

Ever wonder – say, while sitting quietly in a concert hall or screaming your lungs out in a crowded ampitheater – whether the musical experience you’re having is anything like that of the person three seats up or three sheets to the wind on your right?

A partial answer is in: Our brains process music in pretty much the same way, providing it’s got the requisite combination of components (rhythm, melody, harmony, etc.), according to Stanford neuroscientist Vinod Menon, PhD. In a just-published study, Menon’s group monitored several healthy peoples’ brains while these subjects listened to the same piece of music. As the music played on, activity in a broadly distributed network of neuroanatomically connected brain areas waxed and waned very similarly for each listener. This synchrony among individual responses was absent when participants listened to “pseudomusic” stripped of  either rhythmic or tonal characteristics.

The inter-subject synchronization extended to the brain’s movement-planning zone. Evolution, it seems, has designed us this way. As I wrote in my release about the study:

[O]ur brains respond naturally to musical stimulation by foreshadowing movements that typically accompany music listening: clapping, dancing, marching, singing or head-bobbing. The apparently similar activation patterns among normal individuals make it more likely our movements will be socially coordinated.

It’s easy to imagine the survival value of coordinated movement in response to auditory cues. Hunting, gathering, warmaking – all benefit from choreography. That would objectively explain how people who run, shout and pump their fists in synch might win the evolutionary race.

But about the subjective aspect of this synchronization, I’m not so sure.

Look. It’s important that our brains respond similarly to identical stimuli. But what about our minds? In the house of mirrors that is our consciousness, how can we know whether music sounds the same, or color looks the same, to different people?

This takes me back to long ago when, as a philosophy major at the University of Wisconsin, I flunked a course in epistemology. That’s the philosophy of what we know and how we know it, and what we think we know that, actually, we don’t. Turns out I didn’t know much.

One day, the professor – a tweedy, pipe-puffing Princeton man who paced the room in an elbow-patch-bedecked jacket - shouted to the motley assortment of assembled esistentialist ectomorphs: “I PROPOSE. THAT. WHEN I SAY: ‘BLUE!’ ALL OF YOU. SEE. EXACTLY. THE SAME. COLOR!!!”

He paused. “Refute. That. Hypothesis,” he snarled, taking a toke from his pugnacious pipe.

I didn’t raise my hand. It raised itself. He called on me. “I see the same color slightly differently with each eye,” I said, illustrating my claim with alternating winks of my left and right eye. Seemed like a slam-dunk to this Milwaukee boy. (It also happened to be true.)

He glared at me, cross-examined me fiendishly for five long minutes and, striding to the blackboard (I did tell you this was long ago), multiplied the number of minutes we had dueled by the dwindled number of my classmates and thundered: “You’ve wasted 45 student-minutes of class time!”

It was right about then that I started thinking maybe I should switch to science.

So, what is “music,” really? Well, we don’t really know. But whatever it is, it makes us wanna shout, kick our heels up and shout, throw our hands up and shout, throw our heads back and shout.

Previously: New research tracks “math anxiety” in the brain, Why memory and math don’t mix: They require opposing states of the same circuitry and Can playing familiar music boost cognitive response among patients with brain damage?
Photo by gilmorec

Yesterday’s announcement about Stanford scientists developing a process that renders tissue, specifically a mouse brain, transparent spurred a significant amount of excitement among both the scientific community and general public. We’ve captured the reactions in tweets, blog posts, videos and quotes from new articles on our Storify page.

Among the video content is an interview with Karl Deisseroth, MD, PhD, explaining the work, a fly-through of a complete mouse brain using fluorescent imaging, and commentary from Michelle Freund, PhD, a project officer in the National Institute of Mental Health Division of Neuroscience and Basic Behavioral Science, discussing the significance of the work. Mixed in with the videos are remarks from experts about how the breakthrough will advance the field of neuroscience and other research applications and candid comments from Twitter users. We hope the collection provides a broader perspective on the research and its potential to revolutionize cell biology.

Previously: Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact and Peering deeply – and quite literally – into the intact brain: A video fly-through

I’m ashamed to admit that the study of statistics was regarded (at least by me) as a necessary evil when I was in graduate school. I vaguely remember one course that attempted to teach a lecture hall of sleepy, stressed-out students how to calculate p values, the differences between retrospective, prospective and case-control studies, and the nuances between sensitivity and specificity. And don’t even get me started on odds ratios. Can you tell I’m still a bit fuzzy? In fact, I keep a reference guide at my desk for help (which I have to consult embarrassingly often).

Statistics might be dull, but there’s no denying its importance in scientific research – and the fallout when scientists fail to appreciate its power. Now, Stanford researcher John Ioannidis, MD, DSci, (of the “Why most published research findings are false” fame) has joined forces with Marcus Munafo, PhD, and others at the University of Bristol to publish a new study in in Nature Reviews Neuroscience (subscription required) delineating the statistical flaws in many published neuroscience studies. Essentially, the researchers found that, although many scientists realize that an under-powered study (for example, one with too few study subjects to adequately capture the phenomena being investigated) is less likely to find statistically significant results, they don’t necessary realize the converse: that any statistically significant finding from such a study is less likely to represent a true effect.

Stellar science blogger Ed Yong explains the sobering implications in an excellent post today:

Statistical power refers to the odds that a study will find an effect—say, whether antipsychotic drugs affect schizophrenia symptoms, or whether impulsivity is linked to addiction—assuming those effects exist. Most scientists regard a power of 80 percent as adequate—that gives you a 4 in 5 chance of finding an effect if there’s one to be found. But the studies that Munafo’s team examined tended to be so small that they had an average (median) power of just 21 percent. At that level, if you ran the same experiment five times, you’d only find an effect on one of those. The other four tries would be wasted.

But if studies are generally underpowered, there are more worrying connotations beyond missed opportunities. It means that when scientists do claim to have found effects—that is, if experiments seem to “work”—the results are less likely to be real. And it means that if the results are actually real, they’re probably bigger than they should be. As the team writes, this so-called “winner’s curse” means that “a ‘lucky’ scientist who makes the discovery in a small study is cursed by finding an inflated effect.”

I encourage you to read all of Ed’s post, which includes multiple comments from Ioannidis, Munafo and other researchers uninvolved in the study. It’s a fascinating analysis of why many studies are designed as they are, and it discusses some of the obstacles that must be overcome to improve their fidelity. And don’t overlook the comment stream, which is currently hosting a rich discussion among scientists in the field.

Previously: NIH funding mechanism “totally broken” says Stanford researcher, Research shows small studies may overestimate the effects of many medical interventions and Animal studies: necessary but often flawed, says Stanford’s Ioannidis
Photo by futureshape

Earlier today I wrote about a breakthrough method called CLARITY, pioneered by Stanford psychiatrist/bioengineer Karl Deisseroth, MD, PhD, for rendering intact tissue samples transparent. Above is a video clip showing off the new method’s capabilities. First you’ll witness a “fly-through” of a complete mouse brain using fluorescent imaging. The immediately following clip – it’s spectacular! – provides a three-dimensional view of a mouse hippocampus (the brain’s brain’s memory hub), with projecting neurons depicted in green, connecting interneurons in red, and layers of support cells, or glia, in blue.

Note that in both cases, there was no need to slice the tissue into ultra-thin sections, analyze them chemically and/or optically and then laboriously “sew” them back together via computer algorithms in order to reconstruct a 3-D virtual image of the biological sample. All that was required, after performing the necessary hocus-pocus, was to ”send in the stain” (i.e., use histochemical means to paint different cell types different colors) and move the sample or camera lens or shift the latter’s focal length. Nice trick. With big implications for biomedical research.

Previously: Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact, Visualizing the brain as a Universe of synapses and A federal push to further brain research

Stanford psychiatrist and bioengineer Karl Deisseroth, MD, PhD, spent much of this century’s first decade developing a revolutionary method for studying the brain: optogenetics. In 2010, Nature Methods  heralded optogenetics as its “method of the year.”

It looks as though lightning has struck the Deisseroth lab again.

Suppose, just for a moment, that you’re conducting espionage on a heavily guarded multi-story building strongly suspected to be an advanced nuclear-weapons facility. The building quickly proves utterly inaccesible. Fortunately, you manage (through methods too covert to be revealed here) to procure a floor plan. Nice going. Now, you know a lot about the floors themselves and a bit of cross-sectional detail on the bases of whatever’s sitting on them. Better than nothing.

Now, imagine - in fantasyland, anything goes – that you can don goggles enabling you to peer right through the building’s outer walls and directly observe its three-dimensional structure, including its concealed laboratories and the instruments and manufacturing machinery inside of them. Payday!

An analogous technique developed by Deisseroth promises to revolutionize cell biology. Exploring connections among, and contents within, the billions of cells in a chunk of tissue often involves slicing the chunk into ultra-thin sections, exposing each slice’s top and bottom surfaces for microscopy or histochemical and electrical manipulation. Sophisticated computation can stitch the slices back together (virtually), roughly reconstructing the sample’s three-dimensional structure. (That’s the floor plan I mentioned earlier.)

Unfortunately, all this sawing disrupts key connections within the tissue and distorts its constitutent cells’ geography. Plus, while those sections are thin, they’re not infinitely thin. Light and chemicals can penetrate only so far. Volumes of valuable information about their innards remains concealed.

Deisseroth’s paradigm-shifting method, called CLARITY, renders tissue transparent while leaving it structurally intact, yet accessible to large “detective” molecules scientist use to gain information about cells’ surface features and genetic contents. In a study just published in Nature, a group led by Deisseroth (who discusses his work in the video above) converted an entire adult mouse brain into an optically transparent, histochemically permeable replica of itself. The position and structure of proteins embedded in the membranes of cells and their intracellular organelles remained intact.

Okay, step back with me for a minute. Essentially, all cells are liquid-filled bubbles of oil. (Nerve cells are better visualized as long, branching, liquid-filled tubes whose walls are made of fat.) These oil/fat (in science-speak, “lipid“) bubbles and walls (“membranes”) both house and compartmentalize their contents, so operations inside them can be carried out in relative isolation. Dotting membranes’ surfaces are all kinds of proteins performing innumerable activities key to the health of the cells they enclose and the tissues those cells compose.

Evolution designed lipid membranes to be mostly impermeable to large molecules, and they happen to be opaque (or else we’d all be transparent). In a feat of chemical engineering, Deisseroth’s team replaced the lipids with, for all purposes, clear plastic. With their work, you could literally read a newspaper through the mouse’s brain. Formerly membrane-bound proteins remained anchored in the membranes’ doppelgangers, retaining their structures (a big deal, as a protein’s structure determines its function). The tissue was also nanoporous: It permitted bulky “reporter”molecules such as stain-carrying antibodies and strips of DNA to flow deep into the transformed tissue sample and out again.

Obviously you wouldn’t want to try this on yourself, although Plastic Man certainly seems to have worked out the kinks.

Previously: Researchers induce social deficits associated with autism, schizophrenia in mice, Anti-anxiety circuit found in unlikely brain region and Nature Methods names optogenetics its “Method of the Year
Photo in featured entry box by kainet