Genetic basis for vulnerability to drug addiction.

Yacubian et al.(link to full text) demonstrate that human genetic variations that alter dopamine neurotransmission involved in reward pathways correlate with change in sensitivity to rewards and also with activity in the ventral striatum reward system. The data suggest a potential genetic basis for drug vulnerability. Here is their abstract:

Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene–gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.

Fantastic Dances...

Three of them, by Shostakovitch, which I recorded on my Steinway B at Twin Valley, Middleton Wisconsin.

Brain imaging that reflects moral responsibility.

In the common law tradition, criminal conviction depends on both actus reus (a harmful consequence and mens rea (the intent to harm). Young et al. (PDF here) set up an experimental test using different small stories to demonstrate that a subject's belief that he/she has caused intentional harm causes a larger increase in the activation of a region of the right temporal parietal junction (RTPJ in the figure.) than attempted harm, unknowing harm, and neutral effect.) The study suggests that moral judgments depend on the cognitive processes mediated by the RTPJ, previously associated with belief attribution, and, to a lesser extent, the PC, LTPJ, and MPFC, which compose a network of brain regions implicated in theory of mind.

The discussion of the paper is well worth reading. Here is one clip:

The current results also reveal an asymmetry between moral judgments of incompetent criminals (whose false beliefs prevent intended harm from occurring) and unlucky innocents (whose false beliefs lead them to cause unintended harms. Judgments of incompetent criminals were harsh, made on the basis of beliefs alone, and associated with enhanced recruitment of circuitry involved in belief attribution. By contrast, unlucky innocents were not entirely exculpated for causing harm on the basis of their false beliefs. Instead of showing an increased response in brain regions associated with belief attribution, whole-brain analyses revealed recruitment of brain regions associated with cognitive conflict: right inferior parietal cortex, PC, bilateral middle frontal gyrus, and bilateral anterior cingulate sulcus. All of these regions have been implicated in cognitive conflict associated with moral dilemmas, specifically where subjects endorse emotionally salient harmful acts to prevent greater harm. Here subjects had to override judgments against harm in favor of utilitarian considerations (e.g., the greatest good for the greatest number). Analogously, in the context of unknowing harm, subjects may partially override judgments against harm to exculpate agents on the basis of their false beliefs. Moral judgment may therefore represent the product of two distinct and at times competing processes, one responsible for representing harmful outcomes and another for representing beliefs and intentions.

Potential drug for chronic pain?

A new era in pain research may be coming. A particular class of sodium nerve channels (resistant to tetrodotoxin) are central in generating pain signals. Extensive screening for drugs that block this channel have yielded A-803467, a furan-amide. Jarvis et al. show that this drug attenuates neuropathic and inflammatory pain in a rat model. Chronic pain affects about 1.5 million people worldwide, and is currently treated with sodium channel blockers originally developed as anticonvulsants or antiarrhythmics. While beneficial for some patients, their clinical usefulness has been limited.

A magnet for your sleep?

Massimini et al. show that the deep sleep important in brain restoration and memory consolidation (associated with EEG slow-wave activity of 0.5–4.5 Hz) can be triggered and deepened by appropriate transcranial magnetic stimulation at less than 1 Hz. (PDF here.) How long will it be before we are being offered electromagnetic "sleep caps" to improve our memory and brain restoration during sleep?
Here is their abstract:

During much of sleep, cortical neurons undergo near-synchronous slow oscillation cycles in membrane potential, which give rise to the largest spontaneous waves observed in the normal electroencephalogram (EEG). Slow oscillations underlie characteristic features of the sleep EEG, such as slow waves and spindles. Here we show that, in sleeping subjects, slow waves and spindles can be triggered noninvasively and reliably by transcranial magnetic stimulation (TMS). With appropriate stimulation parameters, each TMS pulse at less than 1 Hz evokes an individual, high-amplitude slow wave that originates under the coil and spreads over the cortex. TMS triggering of slow waves reveals intrinsic bistability in thalamocortical networks during non-rapid eye movement sleep. Moreover, evoked slow waves lead to a deepening of sleep and to an increase in EEG slow-wave activity (0.5–4.5 Hz), which is thought to play a role in brain restoration and memory consolidation.

Videos on How the Mind Works.

Check out this link for interesting talks by Dennett, Gilbert, Schwartz, Savage-Rumbaugh, and others.

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.