High speeding mapping of neural circuits with optical techniques.

Before I was seduced by studying how the brain works, I used to be a membrane biophysics, cellular, molecular biologist, and occasionally I come across a bit of work that is so neat and powerful that I want to mention it.

Wang et al. engineer the genetic delivery into neurons of a light sensitive rhodopsin membrane channel protein (ChR2), from an algae. Illumination of ChR2-positive neurons in cortical slices produces rapid photocurrents that can elicit action potentials. The timing, number, and spatial location of these action potentials can be controlled precisely by light, allowing functional mapping of cortical circuits. Here is their abstract:

To permit rapid optical control of brain activity, we have engineered multiple lines of transgenic mice that express the light-activated cation channel Channelrhodopsin-2 (ChR2) in subsets of neurons. Illumination of ChR2-positive neurons in brain slices produced photocurrents that generated action potentials within milliseconds and with precisely timed latencies. The number of light-evoked action potentials could be controlled by varying either the amplitude or duration of illumination. Furthermore, the frequency of light-evoked action potentials could be precisely controlled up to 30 Hz. Photostimulation also could evoke synaptic transmission between neurons, and, by scanning with a small laser light spot, we were able to map the spatial distribution of synaptic circuits connecting neurons within living cerebral cortex. We conclude that ChR2 is a genetically based photostimulation technology that permits analysis of neural circuits with high spatial and temporal resolution in transgenic mammals.

Fluorescence image of dye-filled layer VI pyramidal neuron; circles indicate locations where light-evoked synaptic responses were evoked.

A parietal EEG signal reflects social coordination

Tognoli et al. offer an interesting study (PDF here). They employed a rhythmic task in which pairs of subjects move their fingers at their own preferred frequency and amplitude with and without vision of the other's movements. Previous behavioral studies had shown that unintended spontaneous coupling may occur (transitions from independent to phase-locking behavior) when subjects see each other's hand movements. They were able to identify three distinct EEG rhythms [alpha - (mean frequency of 10.61 Hz); mu - (mean frequency of 9.63 Hz); and a lateralized centro-parietal component that they call phi (spanning the range 9.2–11.5 Hz; Fig. 2B)], one of which (phi, located over right centro-parietal cortex) "neuromarked" the presence or absence of social coordination. Here is their abstract:

Many social interactions rely upon mutual information exchange: one member of a pair changes in response to the other while at the same time producing actions that alter the behavior of the other. However, little is known about how such social processes are integrated in the brain. Here, we used a specially designed dual-electroencephalogram system and the conceptual framework of coordination dynamics to identify neural signatures of effective, real-time coordination between people and its breakdown or absence. High-resolution spectral analysis of electrical brain activity before and during visually mediated social coordination revealed a marked depression in occipital alpha and rolandic mu rhythms during social interaction that was independent of whether behavior was coordinated or not. In contrast, a pair of oscillatory components (phi1 and phi2) located above right centro-parietal cortex distinguished effective from ineffective coordination: increase of phi1 favored independent behavior and increase of phi2 favored coordinated behavior. The topography of the phi complex is consistent with neuroanatomical sources within the human mirror neuron system. A plausible mechanism is that the phi complex reflects the influence of the other on a person's ongoing behavior, with phi1 expressing the inhibition of the human mirror neuron system and phi2 its enhancement.

Identification of spectral components in the brain activity of participants. (A) The dual-EEG of pairs was recorded with two caps each containing 60 channels. The head schematic of the subject on the right shows the 60 electrodes color-coded to reflect their spatial location. Circled areas indicate regions of peak rhythmic activity: mu (electrodes colored brown situated above Rolandic fissure); phi (burgundy above right centro-parietal area); and alpha (blue above the occipital pole). Spectral plots were used to identify mu, phi, and alpha components during visual contact.

A Fantasia

This week's bit of relief...by Joseph Haydn, recorded on my Steinway B at Twin Valley, Middleton Wisconsin.

Neuroimaging of Subliminal Motivation

Pessiglione et al. (PDF here) do an interesting experiment in which they flash a picture of either a penny or a pound coin for 17, 50, 100 msec. followed by a masking picture. Subjects can report seeing the last, but not the first two images, so these first two are assumed to be subliminal. To characterize the effects of the monetary stakes, they recorded not only brain activity but also skin conductance and hand-grip force. Skin conductance response (SCR) is linked to autonomic sympathetic arousal and is interpreted as reflecting an affective evaluation of the monetary stake. Online visual feedback of the force exerted was displayed as a fluid level moving up and down within a thermometer depicted on the screen (see figure). Subjects were instructed that the higher the fluid level rose, the more of the monetary stake they would get to keep. At the end of the trial, subjects were given visual feedback of the amount of money that they had accumulated.

The incentive force task. Successive screens displayed in one trial are shown from left to right, with durations in ms. Coin images, either one pound (£1) or one penny (1p), indicate the monetary value attributed to the top of the thermometer image. The fluid level in the thermometer represents the online force exerted on the hand grip. The last screen indicates cumulative total of the money won so far...

The data show that the 50 msec stimulus of a pound coin image, which is not reported as seen, causes an increase in skin conductance and activity in the ventral pallidum that is almost as large as the increase caused by the 100 msec stimulus, which is seen. Both activities are much lower for the one penny stimulus. (Ventral pallidal neurons encode rewarding properties of environmental stimuli, and are thought to play a role in incentive motivation.)

Caudate, putamen, and accumbens are shown in green; external and internal pallidum are shown in blue, with limbic sectors in violet.

Cortical networks while the brain is at rest...

Pinsk and Kastner, review work (PDF here) of Vincent and colleagues (PDF here) on spontaneous fluctuations of neural activity in monkey brains during anaesthesia.

....studies have shown that the main human cortical networks exhibit correlated spontaneous activity while subjects are at rest. Vincent and colleagues provide the first evidence that such activity is neither restricted to the human brain nor tied to a conscious state. Their findings suggest that fluctuations of spontaneous activity across anatomically interconnected brain regions constitute a fundamental principle of brain organization. Such an interpretation is supported by the fact that organized patterns of brain activity are present in both humans and non-human primates.

As to the functional significance of correlated signal fluctuations, it may be that they maintain the integrity of the networks by reinforcing the synaptic connections between neurons that are essential for network operations in the awake state. Indeed, in stroke patients, the functional connectivity of a brain network has been found to break down when one of its parts is damaged. This loss of connectivity seemed to be correlated with the patients' behavioural impairments. Thus, the new findings may help in understanding both normal and pathological brain function.

Vincent et al. also investigated a possible monkey homologue of a cortical network that thus far has been studied only in humans. This human 'default' network exhibits BOLD activations when subjects are not performing any particular task, and is thought to support uniquely human functions — for example, thinking about ourselves and others, imagining the future, and daydreaming. The authors chose to study a seed region in the posterior cingulate cortex of the monkey brain; this brain region is anatomically similar in both species and is part of the human default network. They identified correlated activity in discrete regions of the frontal, parietal and temporal cortex, which may thus form an analogous default network in the monkey brain.

These findings challenge the view that the default network is uniquely human and is tied to human mental capabilities. But that challenge depends on the assumption that the posterior cingulate cortex is analogous in both species: despite the anatomical similarities, it is not known whether this area serves similar brain functions in the two species. Furthermore, the human default network has been defined in the awake state, whereas this possible monkey homologue was investigated under deep anaesthesia.

Do computer games keep you young?

Ichiko Fuyuno canvasses the opinion of neuroscientists on what brain training ploys can achieve. (PDF here).

A pill to boost or restore memory?

David Sweatt describes recent experiments by Fischer et al. on a compound that enhances memory performance in mice.

a, (click on figure to enlarge it.) Mouse models of age-dependent neurodegeneration exhibit poor learning and memory performance in spatially based learning tasks. However, when Fischer et al. administered HDAC inhibitors for 4 weeks before training, the performance of the mice was restored to essentially normal levels. b, After receiving HDAC inhibitors, the mice could even recall memories that had been formed and then apparently lost through neurodegeneration.

The authors provide a convincing proof-of-principle demonstrating that the inhibition of histone deacetylases can improve memory capabilities in a genetically engineered mouse model of neurodegeneration in the central nervous system (CNS).

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine amino acids in proteins, including proteins in the nucleus called histones. Histones interact with DNA to form a complex known as chromatin and control the accessibility of DNA for gene transcription. Generally, acetylated histones form active chromatin complexes with DNA, which makes the DNA accessible to RNA polymerases, thereby regulating gene transcription. Inhibitors of HDACs block the ability of these enzymes to deacetylate histones, promoting histone acetylation in the nucleus and thus altering gene expression. Because altered transcription is known to be necessary for the formation of long-term memories, HDAC inhibitors have the potential to boost memory formation. This has been demonstrated in normal rats and mice; and the effectiveness of HDAC inhibitors in restoring memory function in mouse models of a human learning disability called Rubinstein–Taybi syndrome has also been documented.

Fischer and colleagues extend these findings through their studies of a genetically manipulated mouse model that they have generated. Such animals show age-dependent neurodegeneration in the hippocampus, a brain region that is essential for long-term spatial-memory formation in rodents. Indeed, using a variety of behavioural assays, the authors previously showed that these mice have pronounced deficits in recalling long-term spatial memories.

In their present work, Fischer et al. demonstrate that HDAC inhibitors restore the capacity for spatial memory. They also show that another known memory-boosting manipulation — environmental enrichment through exposing the animals to a variety of experiences over their lifetime — improves the memory of the genetically engineered mice by increasing the levels of histone acetylation in their hippocampi. Together, these findings provide compelling evidence that increased histone acetylation can overcome the diminution of memory function seen in this mouse model of age-dependent neurodegeneration.

Drink milk and live longer?

An interesting article is summarized in the Research Highlights section of the May 10 issue of Nature Magazine:

In yeast at least, the molecular pathway that extends an organism's life when it is put on a diet can be induced — without calorie restriction — by a vitamin found in milk. So says a team led by Charles Brenner from Dartmouth Medical School in Lebanon, New Hampshire, and Jeffrey Smith from the University of Virginia Health System in Charlottesville. (Cell, Volume 129, Issue 3, Pages 473-484)

The researchers showed that the vitamin, called nicotinamide riboside, raises in yeast the levels of a molecule known as NAD (nicotinamide adenine dinucleotide). This, in turn, activates the anti-ageing protein Sir2. Yeast make use of the vitamin through molecular pathways that have some genes in common with humans, raising the possibility that supplements could be designed to enhance humans' longevity.

Coding gains and losses in the striatum...

Seymour et al. examine differential encoding of losses and gains in the human striatum:

Studies on human monetary prediction and decision making emphasize the role of the striatum in encoding prediction errors for financial reward. However, less is known about how the brain encodes financial loss. Using Pavlovian conditioning of visual cues to outcomes that simultaneously incorporate the chance of financial reward and loss, we show that striatal activation reflects positively signed prediction errors for both. Furthermore, we show functional segregation within the striatum, with more anterior regions showing relative selectivity for rewards and more posterior regions for losses. These findings mirror the anteroposterior valence-specific gradient reported in rodents and endorse the role of the striatum in aversive motivational learning about financial losses, illustrating functional and anatomical consistencies with primary aversive outcomes such as pain.

fMRI - a, Aversive prediction error, right ventral striatum This contrast also revealed a peak in the right anterior insula. b, Reward prediction error, right ventral striatum. Yellow corresponds to c, Sagittal view showing the two peaks, reward (green) and aversive (red).

Integrating different theory of mind models.

Keysers and Gazzola propose a speculative model (Trends in Cognitive Sciences
Volume 11, Issue 5, May 2007, Pages 194-196. PDF here) that attempts to integrate the perspective of two polarized camps:

The simulation camp focuses on so-called shared circuits (SCs) that are involved in one's own actions, sensations and emotions and in perceiving those of others. The theory of mind (ToM) camp emphasizes the role of midline structures in mentalizing about the states of others.

Social cognitions range from the intuitive examples studied by simulationists to the reflective ones used by ToM investigators. Witnessing someone drink a glass of milk with a face contracting in an expression of disgust is an example at the intuitive extreme of this continuum. In such cases, premotor and parietal areas for actions, the insula for emotions and and SII for sensations form SCs that translate the bodily states of others into the neural language of our own states. These SCs seem to implement a pre-reflective, intuitive and empathic level of representation: neural activity in these areas does not require specific instructions that encourage conscious reflections.

Thinking about what gift would please a foreign colleague is an example at the more reflective extreme. In such cases, we must browse consciously through what we know about his country and culture to deduce what he might like. Such explicit knowledge about the inner life of others is the product of reflecting upon the states of others and is linked with activity in midline structures and the temporoparietal junction. False beliefs are prototypical examples of such reflective representations.

They suggest a working hypothesis:

While dealing with states of the self, areas of the SCs represent pre-reflective bodily states. If asked to introspect and report these states, subjects additionally activate (v)mPFC structures. When dealing with states of other individuals, activity in SCs might represent the empathic transformation of the bodily states of others into pre-reflective neural representations of similar states of the self. These simulated pre-reflective representations correlate with empathy and might provide an intuitive understanding of what goes on in others. If asked to reflect on the states of others, the pathways that are normally used to reflect on the bodily representations of the self are now used on simulated bodily states of others, leading to simulated reflective representations. Thus, SCs and midline structures form an integrated system that applies to cases where we perceive the other as similar enough for simulation to be useful. In this view, both SCs and vmPFC reflect simulation, albeit at different levels (pre-reflective versus reflective), rather than radically different processes (SC versus ToM).

Illustration of the model (click to enlarge). The self is shown in red, the other is shown in green and candidate brain areas that are thought to implement representation are shown in blue. During our own experiences, pre-reflective representations can lead, through introspection, to reflective representations (red). While witnessing the states of others, mirroring leads to activations that simulate pre-reflective representations of our own bodily states. A process of social introspection, utilizing the mechanisms of introspection, activates representations that simulate reflective representations of our own bodily states. A more cognitive route leads to more abstract knowledge about the other that escapes from the constraints of our own experiences.

Emotion and Consciousness

Tsuchiyaa and Adolphs offer a review of brain structures central to emotion and consciousness, and how they overlap in several areas. (Trends in Cognitive Sciences, Volume 11, Issue 4, April 2007, Pages 158-167. PDF here). Here I reproduce their useful summary of the time stages in emotional processing.


Microgenesis of emotional processing. Emotional responses span a large temporal range (from 100 ms or less, to minutes). (a) Responses to emotional visual stimuli can occur rapidly in prefrontal cortex [50] or amygdala, in part mediated by subcortical inputs. Emotional response in the amygdala also influences early visual processing and is modulated by volitional self-regulation. (b) At later time slices (100–200 ms), sensory cortices provide more detailed input to emotion-inducing structures like the amygdala. Two components that are important to face processing are shown: the superior temporal cortex (green), important for encoding dynamic information such as facial expression, and the fusiform gyrus (blue), important for encoding static information such as identity. (c) Once the emotional meaning of a stimulus has been evaluated by the brain, emotional responses are triggered in the body via projections from amygdala and medial prefrontal cortex to brainstem nuclei and hypothalamus (not shown), and are in turn represented in structures such as the insula. This figure emphasizes that what we refer to as an ‘emotion state’ throughout this article is in fact a complex set of processes that unfold at various points in time. Color key: black, primary visual cortex; blue, fusiform gyrus; green, superior temporal cortex; purple, insula; faint red, orbitofrontal cortex; solid red, amygdala; yellow, superior colliculus.

Brain abnormalities and responsibility

Mobbs et al offer an excellent article reviewing how alterations of prefrontal or limbic cortex can influence pro- and anti-social behaviors. They discuss issues of responsibility and law.

Prefrontal regions associated with pro-social behavior.







(click to enlarge)
(A) Medial and lateral view of the PFC.
(B) View of the ventral surface of the PFC and temporal poles.
(C) Coronal slice illustrating the amygdalar and insular cortex.
ACC, anterior cingulate cortex; dlPFC, dorsolateral PFC; MFd, medial PFC; oMFC, orbitomedial PFC; TP, temporal pole; vlPFC, ventrolateral PFC; vmPFC, ventromedial PFC.

Regions associated with atypical social behavior:
Using positron emission tomography scanning, neuroscientists have found attenuated resting regional cerebral blood flow in the frontal lobes of violent individuals and convicted criminals. In healthy volunteers, evoked anger and imagined aggressive transgressions are associated with reduced modulation of the orbital and medial PFC. Collectively, these studies suggest that impulsive violent acts stem from diminished recruitment of the PFC's “inhibition” systems....In humans, brain-imaging and lesion studies have suggested a role of the amygdala in theory of mind, aggression, and the ability to register fear and sadness in faces . According to the violence inhibition model, both sad and fearful facial cues act as important inhibitors if we are violent towards others. In support of this model, recent investigations have shown that individuals with a history of aggressive behaviour have poorer recognition of facial expressions, which might be due to amygdala dysfunction.

Religion good for society? It depends....

I've been meaning to point out an interesting essay by Michael Shermer titled "Bowling for God."
A contrast:

"In general, higher rates of belief in and worship of a creator correlate with higher rates of homicide, juvenile and early adult mortality, STD [sexually transmitted disease] infection rates, teen pregnancy, and abortion in the prosperous democracies...Indeed, the U.S. scores the highest in religiosity and the highest (by far) in homicides, STDs, abortions and teen pregnancies."

While:

"By providing community meeting places, linking neighbors together, and fostering altruism, in many (but not all) faiths, religious institutions seem to bolster the ties of belonging to civic life."

Thus:

Religious social capital leads to charitable generosity and group membership but does comparatively worse than secular social capital for such ills as homicides, STDs, abortions and teen pregnancies. Three reasons suggest themselves: first, these problems have other causes entirely; second, secular social capital works better for such problems; third, these problems are related to what I call moral capital, or the connections within an individual between morality and behavior that are best fostered within families, the fundamental social unit in our evolutionary history that arose long before religions and governments. Thus, moral restraints on aggressive and sexual behavior are best reinforced by the family, be it secular or sacred.

Meditation can alter attentional resource allocation

A striking observation from the Wisconsin group on how meditation can improve performace in discriminating closely spaced stimuli. Here is their summary:

Meditation includes the mental training of attention, which involves the selection of goal-relevant information from the array of inputs that bombard our sensory systems. One of the major limitations of the attentional system concerns the ability to process two temporally close, task-relevant stimuli. When the second of two target stimuli is presented within a half second of the first one in a rapid sequence of events, it is often not detected. This so-called “attentional-blink” deficit is thought to result from competition between stimuli for limited attentional resources. We measured the effects of intense meditation on performance and scalp-recorded brain potentials in an attentional-blink task. We found that three months of intensive meditation reduced brain-resource allocation to the first target, enabling practitioners to more often detect the second target with no compromise in their ability to detect the first target. These findings demonstrate that meditative training can improve performance on a novel task that requires the trained attentional abilities.

Personal space in virtual reality

Check out the fascinating video in this link, showing how rules of personal space and eye contact carry over into the Second Life virtual reality game.

Discover Magazine on Mind and Brain

A variety of interesting articles in an online Mind and Brain section of Discover Magazine.

Wisdom and the Amygdala...

The Sunday May 6 New York Times Magazine has an intersting article by Stephen Hall titled "The Older-and-Wiser Hypothesis" describing efforts to define what constitutes wise behavior (PDF here). It describes the "Berlin Paradigm" which in essence defines wisdom as

“an expert knowledge system concerning the fundamental pragmatics of life.” It emphasizes several complementary qualities: expert knowledge of both the “facts” of human nature and the “how” of dealing with decisions and dilemmas; an appreciation of one’s historical, cultural and biological circumstances during the arc of a life span; an understanding of the “relativism” of values and priorities; and an acknowledgment, at the level of both thought and action, of uncertainty.

Central to wisdom is emotion regulation:

...despite the well-documented cognitive declines associated with advancing age, older people seem to have figured out how to manage their emotions in a profoundly important way. Compared with younger people, they experience negative emotions less frequently, exercise better control over their emotions and rely on a complex and nuanced emotional thermostat that allows them to bounce back quickly from adverse moments. Indeed, they typically strive for emotional balance, which in turn seems to affect the ways their brains process information from their environment.

The article quotes Richard Davidson at Wisconsin:

“Those people who are good at regulating negative emotion, inferred by their ability to voluntarily use cognitive strategies to reappraise a stimulus, show reductions in activation in the amygdala,” says Davidson, who added that such regulation probably results from “something that has been at least implicitly trained over the years.” It is difficult (not to say dangerous) to generalize from such a small, focused study, but the implication is that people who learn, or somehow train themselves, to modulate their emotions are better able to manage stress and bounce back from adversity. Although they can register the negative, they have somehow learned not to get bogged down in it. Whether this learning is a form of “wisdom” accumulated over a lifetime of experience, as wisdom researchers see it, or can be acquired through training exercises like meditation, as Davidson’s previous research has shown, the recent message from neuroscience laboratories is that the optimal regulation of emotion can be seen in the brain.

Further clips:

Similarly, several years ago, Carstensen; Mara Mather of the University of California at Santa Cruz; John Gabrieli, a neuroscientist now at the Massachusetts Institute of Technology; and several colleagues performed f.M.R.I. studies of young and old people to see whether the ability to regulate emotions left a trace in the amygdala. The study indicated that the amygdala in young people becomes active when they view both positive and negative images; the amygdala in older people is active only when they view positive images. Put another way, young people tend to cling to the negative information, neurologically speaking, while older people seem better able to shrug it off and focus more on positive images. This neural selectivity, this focus on the positive, is virtually instantaneous, Gabrieli says, and yet probably reflects a kind of emotional knowledge or experience that guides cognitive focus; Carstensen says older people “disattend” negative information. This “disattention” also echoes some very old thoughts on wisdom. In his 1890 book “The Principles of Psychology,” William James observed, “The art of being wise is the art of knowing what to overlook.” In modern neuroscience parlance, Gabrieli says, “you could say that in older people the amygdala is overlooking the negative.”

Much of the research to date has reflected a predominantly Western notion of wisdom, but its definition can be further muddied by cultural vagaries. In one cross-cultural study, researchers found that Americans and Australians essentially equated being wise with being experienced and knowledgeable; being old and discreet were seen as less-than-desirable qualities. People in India and Japan, by contrast, linked wisdom to being discreet, aged and experienced.

Nevertheless, the notion of wisdom is sufficiently universal that it raises other questions: Where does it come from, and how does one acquire it? Surprisingly, a good deal of evidence, both anecdotal and empirical, suggests that the seeds of wisdom are planted earlier in life — certainly earlier than old age, often earlier than middle age and possibly even earlier than young adulthood. And there are strong hints that wisdom is associated with an earlier exposure to adversity or failure. That certainly seems to be the case with emotional regulation and is perfectly consistent with Carstensen’s ideas about shifting time horizons. Karen Parker and her colleagues at Stanford have published several striking animal studies showing that a very early exposure to mild adversity (she calls it a “stress inoculation”) seems to “enhance the development of brain systems that regulate emotional, neuroendocrine and cognitive control” — at least in nonhuman primates. Some researchers are also exploring the genetic basis of resilience.

This week's piano - Suite Bergmanesque

This week's recording, another Debussy piece. The Prelude from Suite Bergmanesque.....

One Clever Raven

Heinrich and Bugnyar have an interesting article in the April 2007 Scientific American titled "Just How Smart Are Ravens?" It reminds me of this video that I have used in my teaching, made by Weir et al., of a Raven who obviously understands a few things about physical forces and causal relations. It takes a straight wire and fashions a hook to lift from a tube a container that contains a piece of meat.

Brain Lessons

Steven Pinker, Oliver Sacks, and others on how learning about their brains changed the way they live. I particularly like the paragraph by Alison Gopnik, author of the critique of the mirror neuron myth that I have posted and co-author of The Scientist in the Crib: Minds, Brains, and How Children Learn.

Consciousness, attention, and brain plasticity all seem to be linked. And attention and plasticity are much more widely distributed in young animals—including human babies—than older ones. For grown-ups, consciousness is like a spotlight; for babies it's like a lantern. I have always loved the childlike moments, however brief, when our minds seem to open to the entire world around us—the experience celebrated by Romantic poets and Zen sages alike. The neuroscience makes me think that these moments aren't just a passing thrill. Cultivating this childlike "lantern consciousness," this broad focus, might help make us almost as good as babies at changing our brains.