Journal of Neuroscience BehavioralSystemsCognitive

Trial-to-Trial Variability of Single Cells in Motor Cortices Is Dynamically Modified during Visuomotor Adaptation

Mandelblat-Cerf, Y., Paz, R., Vaadia, E. — Wed, 02 Dec 2009 10:02:09 PST

Neurons in all brain areas exhibit variability in their spiking activity. Although part of this variability can be considered as noise that is detrimental to information processing, recent findings indicate that variability can also be beneficial. In particular, it was suggested that variability in the motor system allows for exploration of possible motor states and therefore can facilitate learning and adaptation to new environments. Here, we provide evidence to support this idea by analyzing the variability of neurons in the primary motor cortex (M1) and in the supplementary motor area (SMA-proper) of monkeys adapting to new rotational visuomotor tasks. We found that trial-to-trial variability increased during learning and exhibited four main characteristics: (1) modulation occurred preferentially during a delay period when the target of movement was already known, but before movement onset; (2) variability returned to its initial levels toward the end of learning; (3) the increase in variability was more apparent in cells with preferred movement directions close to those experienced during learning; and (4) the increase in variability emerged at early phases of learning in the SMA, whereas in M1 behavior reached plateau levels of performance. These results are highly consistent with previous findings that showed similar trends in variability across a population of neurons. Together, the results strengthen the idea that single-cell variability can be much more than mere noise and may be an integral part of the underlying mechanism of sensorimotor learning.

Damage to Association Fiber Tracts Impairs Recognition of the Facial Expression of Emotion

Philippi, C. L., Mehta, S., Grabowski, T., Adolphs, R., Rudrauf, D. — Wed, 02 Dec 2009 10:02:09 PST

An array of cortical and subcortical structures have been implicated in the recognition of emotion from facial expressions. It remains unknown how these regions communicate as parts of a system to achieve recognition, but white matter tracts are likely critical to this process. We hypothesized that (1) damage to white matter tracts would be associated with recognition impairment and (2) the degree of disconnection of association fiber tracts [inferior longitudinal fasciculus (ILF) and/or inferior fronto-occipital fasciculus (IFOF)] connecting the visual cortex with emotion-related regions would negatively correlate with recognition performance. One hundred three patients with focal, stable brain lesions mapped onto a reference brain were tested on their recognition of six basic emotional facial expressions. Association fiber tracts from a probabilistic atlas were coregistered to the reference brain. Parameters estimating disconnection were entered in a general linear model to predict emotion recognition impairments, accounting for lesion size and cortical damage. Damage associated with the right IFOF significantly predicted an overall facial emotion recognition impairment and specific impairments for sadness, anger, and fear. One subject had a pure white matter lesion in the location of the right IFOF and ILF. He presented specific, unequivocal emotion recognition impairments. Additional analysis suggested that impairment in fear recognition can result from damage to the IFOF and not the amygdala. Our findings demonstrate the key role of white matter association tracts in the recognition of the facial expression of emotion and identify specific tracts that may be most critical.

Dopaminergic Drugs Modulate Learning Rates and Perseveration in Parkinson's Patients in a Dynamic Foraging Task

Wed, 02 Dec 2009 10:02:09 PST

Making appropriate choices often requires the ability to learn the value of available options from experience. Parkinson's disease is characterized by a loss of dopamine neurons in the substantia nigra, neurons hypothesized to play a role in reinforcement learning. Although previous studies have shown that Parkinson's patients are impaired in tasks involving learning from feedback, they have not directly tested the widely held hypothesis that dopamine neuron activity specifically encodes the reward prediction error signal used in reinforcement learning models. To test a key prediction of this hypothesis, we fit choice behavior from a dynamic foraging task with reinforcement learning models and show that treatment with dopaminergic drugs alters choice behavior in a manner consistent with the theory. More specifically, we found that dopaminergic drugs selectively modulate learning from positive outcomes. We observed no effect of dopaminergic drugs on learning from negative outcomes. We also found a novel dopamine-dependent effect on decision making that is not accounted for by reinforcement learning models: perseveration in choice, independent of reward history, increases with Parkinson's disease and decreases with dopamine therapy.

Response-Dependent Contributions of Human Primary Motor Cortex and Angular Gyrus to Manual and Perceptual Sequence Learning

Rosenthal, C. R., Roche-Kelly, E. E., Husain, M., Kennard, C. — Wed, 02 Dec 2009 10:02:09 PST

Motor sequence learning on the serial reaction time task involves the integration of response-, stimulus-, and effector-based information. Human primary motor cortex (M1) and the inferior parietal lobule (IPL) have been identified with supporting the learning of effector-dependent and -independent information, respectively. Current neurocognitive data are, however, exclusively based on learning complex sequence information via perceptual-motor responses. Here, we investigated the effects of continuous theta-burst transcranial magnetic stimulation (cTBS)-induced disruption of M1 and the angular gyrus (AG) of the IPL on learning a probabilistic sequence via sequential perceptual-motor responses (experiment 1) or covert orienting of visuospatial attention (experiment 2). Functional effects on manual sequence learning were evident during 75% of training trials in the cTBS M1 condition, whereas cTBS over the AG resulted in interference confined to a midpoint during the training phase. Posttraining direct (declarative) tests of sequence knowledge revealed that cTBS over M1 modulated the availability of newly acquired sequence knowledge, whereby sequence knowledge was implicit in the cTBS M1 condition but was available to conscious awareness in the cTBS AG and control conditions. In contrast, perceptual sequence learning was abolished in the perceptual cTBS AG condition, whereas learning was intact and available to conscious awareness in the cTBS M1 and control conditions. These results show that the right AG had a critical role in perceptual sequence learning, whereas M1 had a causal role in developing experience-dependent functional attributes relevant to conscious knowledge on manual but not perceptual sequence learning.

Visual Motion Perception Deficits Due to Cerebellar Lesions Are Paralleled by Specific Changes in Cerebro-Cortical Activity

Handel, B., Thier, P., Haarmeier, T. — Wed, 02 Dec 2009 10:02:09 PST

Recent anatomical studies have revealed strong cerebellar projections into parietal and prefrontal cortex. These findings suggest that the cerebellum might not only play a functional role in motor control but also cognitive domains, an idea also supported by neuropsychological testing of patients with cerebellar lesions that has revealed specific deficits. The goal of the present study was to test whether or not cognitive impairments after cerebellar damage are resulting from changes in cerebro-cortical signal processing. The detection of global visual motion embedded in noise, a faculty compromised after cerebellar lesions, was chosen as a model system. Using magnetoencephalography, cortical responses were recorded in a group of patients with cerebellar lesions (n = 8) and controls (n = 13) who observed visual motion of varied coherence, i.e., motion strength, presented in the peripheral visual field during controlled stationary fixation. Corroborating earlier results, the patients showed a significant impairment in global motion discrimination despite normal fixation behavior. This deficit was paralleled by qualitative differences in responses recorded from parieto-temporal cortex, including a reduced responsiveness to coherent visual motion and a striking loss of bilateral representations of motion coherence. Moreover, the perceptual thresholds correlated with the cortical representation of motion strength on single subject basis. These results demonstrate that visual motion processing in cerebral cortex critically depends on an intact cerebellum and establish a correlation between cortical activity and impaired visual perception resulting from cerebellar damage.

Influence and Limitations of Popout in the Selection of Salient Visual Stimuli by Area V4 Neurons

Burrows, B. E., Moore, T. — Wed, 02 Dec 2009 10:02:09 PST

The neural mechanism of bottom-up attention and its relationship to top-down attention are poorly understood. Visual stimuli that differ from others in their component features are salient and tend to draw attention in a bottom-up manner. "Popout" stimuli differ uniformly from surrounding items and are more easily detected than stimuli composed of a conjunction of surrounding features. We compared the responses of single area V4 neurons to popout and conjunction stimuli appearing within the classical receptive field (CRF) and found that their responses are modulated by popout. This selectivity was more robust when larger numbers of surrounding items and multiple features were included in the display, and it was absent when only a few items were presented immediately outside the CRF. In addition, the popout modulation of V4 activity was eliminated when top-down attention was directed to locations outside of the CRFs during saccade preparation, indicating that the salience of popout stimuli is not sufficient to drive selection by V4 neurons. These results demonstrate that neurons in feature-selective cortex are influenced by bottom-up attention, but that this influence is limited by top-down attention.

Enhanced Excitatory Input to Melanin Concentrating Hormone Neurons during Developmental Period of High Food Intake Is Mediated by GABA

Li, Y., van den Pol, A. N. — Wed, 02 Dec 2009 10:02:09 PST

In contrast to the local axons of GABA neurons of the cortex and hippocampus, lateral hypothalamic neurons containing melanin concentrating hormone (MCH) and GABA send long axons throughout the brain and play key roles in energy homeostasis and mental status. In adults, MCH neurons maintain a hyperpolarized membrane potential and most of the synaptic input is inhibitory. In contrast, we found that developing MCH neurons received substantially more excitatory synaptic input. Based on gramicidin-perforated patch recordings in hypothalamic slices from MCH-green fluorescent protein transgenic mice, we found that GABA was the primary excitatory synaptic transmitter in embryonic and neonatal ages up to postnatal day 10. Surprisingly, glutamate assumed only a minor excitatory role, if any. GABA plays a complex role in developing MCH neurons, with its actions conditionally dependent on a number of factors. GABA depolarization could lead to an increase in spikes either independently or in summation with other depolarizing stimuli, or alternately, depending on the relative timing of other depolarizing events, could lead to shunting inhibition. The developmental shift from depolarizing to hyperpolarizing occurred later in the dendrites than in the cell body. Early GABA depolarization was based on a Cl^–-dependent inward current. An interesting secondary depolarization in mature neurons that followed an initial hyperpolarization was based on a bicarbonate mechanism. Thus during the early developmental period when food consumption is high, MCH neurons are more depolarized than in the adult, and an increased level of excitatory synaptic input to these orexigenic cells is mediated by GABA.

Central, But Not Basolateral, Amygdala Is Critical for Control of Feeding by Aversive Learned Cues

Petrovich, G. D., Ross, C. A., Mody, P., Holland, P. C., Gallagher, M. — Wed, 02 Dec 2009 10:02:09 PST

Environmental factors contribute to the motivation to eat and can override homeostatic signals to stimulate eating in sated states, or inhibit eating in states of hunger. In particular, stress, fear, and anxiety have been linked to suppression of eating and anorexia nervosa. Here, we use a rodent model of an aversive cue-induced cessation of feeding. In this setting, food-deprived rats suppress eating when presented with a tone [conditioned stimulus (CS)] that was previously paired with footshocks [unconditioned stimulus (US)]. To begin to delineate the underlying neural circuitry we examined the two regions of the amygdala with well known roles in associative learning—the central nucleus (CEA) and the basolateral area (BLA; includes the basolateral, basomedial, and lateral nuclei). We produced selective, bilateral, neurotoxic lesions of the CEA or BLA, and then trained these rats together with sham-lesioned controls in a behavioral protocol that allowed a test for food consumption in the presence of an aversive CS. Both sham- and BLA-lesioned rats showed inhibition of eating when presented with the CS. In contrast, bilateral, neurotoxic lesions of the CEA abolished this effect. These results demonstrate that the CEA, but not BLA, is critical for control of feeding by an aversive CS. Previously we demonstrated that enhancement of eating by an appetitive CS is dependent on the integrity of BLA, but not CEA. Those findings together with the current results show a double dissociation between amygdalar subsystems that control food consumption by appetitive and aversive learned cues.

Subthreshold Activation of the Superior Colliculus Drives Saccade Motor Learning

Soetedjo, R., Fuchs, A. F., Kojima, Y. — Wed, 02 Dec 2009 10:02:09 PST

How the brain learns and maintains accurate precision movements is currently unknown. At times throughout life, rapid gaze shifts (saccades) become inaccurate, but the brain makes gradual adjustments so they again stop on target. Previously, we showed that complex spikes (CSs) in Purkinje cells of the oculomotor cerebellum report the direction and amplitude by which saccades are in error. Anatomical studies indicate that this error signal could originate in the superior colliculus (SC). Here, we deliver subthreshold electrical stimulation of the SC after the saccade lands to signal an apparent error. The size of saccades in the same direction as the simulated error gradually increase; those in the opposite direction decrease. The electrically adapted saccades endure after stimulation is discontinued, exhibit an adaptation field, can undergo changes in direction, and depend on error timing. These electrically induced adaptations were virtually identical with those produced by the visually induced adaptations that we report here for comparable visual errors in the same monkeys. Therefore, our experiments reveal that an additional role for the SC in the generation of saccades is to provide a vector error signal that drives dysmetric saccades to adapt. Moreover, the characteristics of the electrically induced adaptation reflect those of error-related CS activity in the oculomotor cerebellum, suggesting that CS activity serves as the learning signal. We speculate that CS activity may serve as the error signal that drives other kinds of motor learning as well.

One-Year Brain Atrophy Evident in Healthy Aging

Wed, 02 Dec 2009 10:02:09 PST

An accurate description of changes in the brain in healthy aging is needed to understand the basis of age-related changes in cognitive function. Cross-sectional magnetic resonance imaging (MRI) studies suggest thinning of the cerebral cortex, volumetric reductions of most subcortical structures, and ventricular expansion. However, there is a paucity of detailed longitudinal studies to support the cross-sectional findings. In the present study, 142 healthy elderly participants (60–91 years of age) were followed with repeated MRI, and were compared with 122 patients with mild to moderate Alzheimer's disease (AD). Volume changes were measured across the entire cortex and in 48 regions of interest. Cortical reductions in the healthy elderly were extensive after only 1 year, especially evident in temporal and prefrontal cortices, where annual decline was ~0.5%. All subcortical and ventricular regions except caudate nucleus and the fourth ventricle changed significantly over 1 year. Some of the atrophy occurred in areas vulnerable to AD, while other changes were observed in areas less characteristic of the disease in early stages. This suggests that the changes are not primarily driven by degenerative processes associated with AD, although it is likely that preclinical changes associated with AD are superposed on changes due to normal aging in some subjects, especially in the temporal lobes. Finally, atrophy was found to accelerate with increasing age, and this was especially prominent in areas vulnerable to AD. Thus, it is possible that the accelerating atrophy with increasing age is due to preclinical AD.

Spatially Global Representations in Human Primary Visual Cortex during Working Memory Maintenance

Ester, E. F., Serences, J. T., Awh, E. — Wed, 02 Dec 2009 10:02:09 PST

Recent studies suggest that visual features are stored in working memory (WM) via sensory recruitment or sustained stimulus-specific patterns of activity in cortical regions that encode memoranda. One important question concerns the spatial extent of sensory recruitment. One possibility is that sensory recruitment is restricted to neurons that are retinotopically mapped to the positions occupied by the remembered items. Alternatively, specific feature values could be represented via a spatially global recruitment of neurons that encode the remembered feature, regardless of the retinotopic position of the remembered stimulus. Here, we evaluated these alternatives by requiring subjects to remember the orientation of a grating presented in the left or right visual field. Functional magnetic resonance imaging and multivoxel pattern analysis were then used to examine feature-specific activations in early visual regions during memory maintenance. Activation patterns that discriminated the remembered feature were found in regions of contralateral visual cortex that corresponded to the retinotopic position of the remembered item, as well as in ipsilateral regions that were not retinotopically mapped to the position of the stored stimulus. These results suggest that visual details are held in WM through a spatially global recruitment of early sensory cortex. This spatially global recruitment may enhance memory precision by facilitating robust population coding of the stored information.

Role of Striatum in Updating Values of Chosen Actions

Kim, H., Sul, J. H., Huh, N., Lee, D., Jung, M. W. — Wed, 25 Nov 2009 10:03:10 PST

The striatum is thought to play a crucial role in value-based decision making. Although a large body of evidence suggests its involvement in action selection as well as action evaluation, underlying neural processes for these functions of the striatum are largely unknown. To obtain insights on this matter, we simultaneously recorded neuronal activity in the dorsal and ventral striatum of rats performing a dynamic two-armed bandit task, and examined temporal profiles of neural signals related to animal's choice, its outcome, and action value. Whereas significant neural signals for action value were found in both structures before animal's choice of action, signals related to the upcoming choice were relatively weak and began to emerge only in the dorsal striatum ~200 ms before the behavioral manifestation of the animal's choice. In contrast, once the animal revealed its choice, signals related to choice and its value increased steeply and persisted until the outcome of animal's choice was revealed, so that some neurons in both structures concurrently conveyed signals related to animal's choice, its outcome, and the value of chosen action. Thus, all the components necessary for updating values of chosen actions were available in the striatum. These results suggest that the striatum not only represents values associated with potential choices before animal's choice of action, but might also update the value of chosen action once its outcome is revealed. In contrast, action selection might take place elsewhere or in the dorsal striatum only immediately before its behavioral manifestation.

Tripartite Purinergic Modulation of Central Respiratory Networks during Perinatal Development: The Influence of ATP, Ectonucleotidases, and ATP Metabolites

Wed, 25 Nov 2009 10:03:10 PST

ATP released during hypoxia from the ventrolateral medulla activates purinergic receptors (P2Rs) to attenuate the secondary hypoxic depression of breathing by a mechanism that likely involves a P2Y₁R-mediated excitation of preBötzinger complex (preBötC) inspiratory rhythm-generating networks. In this study, we used rhythmically active in vitro preparations from embryonic and postnatal rats and ATP microinjection into the rostral ventral respiratory group (rVRG)/preBötC to reveal that these networks are sensitive to ATP when rhythm emerges at embryonic day 17 (E17). The peak frequency elicited by ATP at E19 and postnatally was the same (~45 bursts/min), but relative sensitivity was threefold greater at E19, reflecting a lower baseline frequency (5.6 ± 0.9 vs 19.0 ± 1.3 bursts/min). Combining microinjection techniques with ATP biosensors revealed that ATP concentration in the rVRG/preBötC falls rapidly as a result of active processes and closely correlates with inspiratory frequency. A phosphate assay established that preBötC-containing tissue punches degrade ATP at rates that increase perinatally. Thus, the agonist profile [ATP/ADP/adenosine (ADO)] produced after ATP release in the rVRG/preBötC will change perinatally. Electrophysiology further established that the ATP metabolite ADP is excitatory and that, in fetal but not postnatal animals, ADO at A₁ receptors exerts a tonic depressive action on rhythm, whereas A₁ antagonists extend the excitatory action of ATP on inspiratory rhythm. These data demonstrate that ATP is a potent excitatory modulator of the rVRG/preBötC inspiratory network from the time it becomes active and that ATP actions are determined by a dynamic interaction between the actions of ATP at P2 receptors, ectonucleotidases that degrade ATP, and ATP metabolites on P2Y and P1 receptors.

Sensitivity of Newborn Auditory Cortex to the Temporal Structure of Sounds

Wed, 25 Nov 2009 10:03:10 PST

Understanding the rapidly developing building blocks of speech perception in infancy requires a close look at the auditory prerequisites for speech sound processing. Pioneering studies have demonstrated that hemispheric specializations for language processing are already present in early infancy. However, whether these computational asymmetries can be considered a function of linguistic attributes or a consequence of basic temporal signal properties is under debate. Several studies in adults link hemispheric specialization for certain aspects of speech perception to an asymmetry in cortical tuning and reveal that the auditory cortices are differentially sensitive to spectrotemporal features of speech. Applying concurrent electrophysiological (EEG) and hemodynamic (near-infrared spectroscopy) recording to newborn infants listening to temporally structured nonspeech signals, we provide evidence that newborns process nonlinguistic acoustic stimuli that share critical temporal features with language in a differential manner. The newborn brain preferentially processes temporal modulations especially relevant for phoneme perception. In line with multi-time-resolution conceptions, modulations on the time scale of phonemes elicit strong bilateral cortical responses. Our data furthermore suggest that responses to slow acoustic modulations are lateralized to the right hemisphere. That is, the newborn auditory cortex is sensitive to the temporal structure of the auditory input and shows an emerging tendency for functional asymmetry. Hence, our findings support the hypothesis that development of speech perception is linked to basic capacities in auditory processing. From birth, the brain is tuned to critical temporal properties of linguistic signals to facilitate one of the major needs of humans: to communicate.

Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity

Wed, 25 Nov 2009 10:03:10 PST

While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D₂/D₃ receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [¹⁸F]fallypride to measure striatal dopamine D₂/D₃ receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D₂/D₃ receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D₂/D₃ receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D₂/D₃ receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D₂/D₃ receptor availability may mediate impulsive temperament and thereby influence addiction.

Three Stages and Four Neural Systems in Time Estimation

Morillon, B., Kell, C. A., Giraud, A.-L. — Wed, 25 Nov 2009 10:03:10 PST

Gibbon's scalar expectancy theory assumes three processing stages in time estimation: a collating level in which event durations are automatically tracked, a counting level that reads out the time-tracking system, and a comparing level in which event durations are matched to abstract temporal references. Pöppel's theory, however, postulates a dual system for perception of durations below and above 2 s. By testing the neurophysiological plausibility of Gibbon's proposal using functional magnetic resonance imaging, we validate a three-staged model of time estimation and further show that the collating process is duplicated. Although the motor system automatically tracks durations below 2 s, mesial brain regions of the so-called "default mode network" keep track of longer events. Our results further support unique counting and comparing systems, involving prefrontal and parietal cortices in collators' readout, and the temporal cortex in contextual time estimation. These findings provide a coherent neuroanatomical framework for two theories of time perception.

Functional Variation of the Dopamine D2 Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans

Wed, 25 Nov 2009 10:03:10 PST

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D₂ receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D₂ receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D₂ short, mainly presynaptic, and D₂ long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D₂ signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

Behavioral and Neural Evidence of Incentive Bias for Immediate Rewards Relative to Preference-Matched Delayed Rewards

Luo, S., Ainslie, G., Giragosian, L., Monterosso, J. R. — Wed, 25 Nov 2009 10:03:10 PST

Several theories of self-control [including intertemporal bargaining (Ainslie, 1992) and self-signaling (Bodner and Prelec, 2001)] imply that intertemporal decisions can be more farsighted than would be predicted by the incentive associated with rewards outside a decision context. We examined this hypothesis using behavior and functional neuroimaging. First, subjects expressed preferences between amounts of money delayed by 4 months and smaller amounts available that day. This allowed us to establish "indifference pairs" individualized to each participant: immediate and delayed amounts that were equally preferred. Participants subsequently performed a reaction time functional magnetic resonance imaging task (Knutson et al., 2001a) that provided them with distinct opportunities to win each of the rewards that comprised the indifference pairs. Anatomical region of interest analysis as well as whole-brain analysis indicated greater response recruited by the immediate rewards (relative to the preference-matched delayed rewards) in regions previously implicated as sensitive to incentive value using the same task (including bilateral putamen, bilateral anterior insula, and midbrain). Reaction time to the target was also faster during the immediate relative to delayed reward trials (p < 0.01), and individual differences in reaction time between immediate versus delayed reward trials correlated with variance in magnetic resonance signal in those clusters that responded preferentially to immediate rewards (r = 0.33, p < 0.05). These findings indicate a discrepancy in incentive associated with the immediate versus the preference-matched delayed rewards. This discrepancy may mark the contribution of self-control processes that are recruited during decision-making but that are absent when rewards are individually anticipated.

PACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling

Wed, 25 Nov 2009 10:03:10 PST

The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al. (2006) demonstrated that targeted knock out of the signaling form of the leptin receptor (lepr-B) in steroidogenic factor 1 (SF-1) cells of the hypothalamic ventromedial nucleus (VMN) produces obesity of a similar magnitude to the pro-opiomelanocortin (POMC)-driven lepr-B deleted mouse, via a functionally distinct mechanism. These findings reveal that SF-1 cells of the VMN could be equally as important as POMC cells in mediating leptin's anti-obesity effects. However, the identification of molecular and cellular correlates of this relationship remains tantalizingly unknown. Here, we have shown that mRNA expression of the VMN-expressed neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is regulated according to energy status and that it exerts catabolic effects when administered centrally to mice. Furthermore, we have shown that SF-1 and PACAP mRNAs are colocalized in the VMN, and that leptin signaling via lepr-B is required for normal PACAP expression in these cells. Finally, blocking endogenous central PACAP signaling with the antagonist PACAP_6-38 markedly attenuates leptin-induced hypophagia and hyperthermia in vivo. Thus, it appears that PACAP is an important mediator of central leptin effects on energy balance.

Defective Respiratory Rhythmogenesis and Loss of Central Chemosensitivity in Phox2b Mutants Targeting Retrotrapezoid Nucleus Neurons

Wed, 25 Nov 2009 10:03:10 PST

The retrotrapezoid nucleus (RTN) is a group of neurons in the rostral medulla, defined here as Phox2b-, Vglut2-, neurokinin1 receptor-, and Atoh1-expressing cells in the parafacial region, which have been proposed to function both as generators of respiratory rhythm and as central respiratory chemoreceptors. The present study was undertaken to assess these two putative functions using genetic tools. We generated two conditional Phox2b mutations, which target different subsets of Phox2b-expressing cells, but have in common a massive depletion of RTN neurons. In both conditional mutants as well as in the previously described Phox2b^27Ala mutants, in which the RTN is also compromised, the respiratory-like rhythmic activity normally seen in the parafacial region of fetal brainstem preparations was completely abrogated. Rhythmic motor bursts were recorded from the phrenic nerve roots in the mutants, but their frequency was markedly reduced. Both the rhythmic activity in the RTN region and the phrenic nerve discharges responded to a low pH challenge in control, but not in the mutant embryos. Together, our results provide genetic evidence for the essential role of the Phox2b-expressing RTN neurons both in establishing a normal respiratory rhythm before birth and in providing chemosensory drive.

The Timing of Emotional Discrimination in Human Amygdala and Ventral Visual Cortex

Sabatinelli, D., Lang, P. J., Bradley, M. M., Costa, V. D., Keil, A. — Wed, 25 Nov 2009 10:03:10 PST

Models of visual emotional perception suggest a reentrant organization of the ventral visual system with the amygdala. Using focused functional magnetic resonance imaging in humans with a sampling rate of 100 ms, here we determine the relative timing of emotional discrimination in amygdala and ventral visual cortical structures during emotional perception. Results show that amygdala and inferotemporal visual cortex differentiate emotional from nonemotional scenes ~1 s before extrastriate occipital cortex, whereas primary occipital cortex shows consistent activity across all scenes. This pattern of discrimination is consistent with a reentrant organization of emotional perception in visual processing, in which transaction between rostral ventral visual cortex and amygdala originates the identification of emotional relevance.

The Dorsomedial Striatum Reflects Response Bias during Learning

Kimchi, E. Y., Laubach, M. — Wed, 25 Nov 2009 10:03:10 PST

Previous studies have established that neurons in the dorsomedial striatum track the behavioral significance of external stimuli, are sensitive to contingencies between actions and outcomes, and show rapid flexibility in representing task-related information. Here, we describe how neural activity in the dorsomedial striatum changes during the initial acquisition of a Go/NoGo task and during an initial reversal of stimulus-response contingencies. Rats made nosepoke responses over delay periods and then received one of two acoustic stimuli. Liquid rewards were delivered after one stimulus (S+) if the rats made a Go response (entering a reward port on the opposite wall of the chamber). If a Go response was made to other stimulus (S–), rats experienced a timeout. On 10% of trials, no stimulus was presented. These trials were used to assess response bias, the animals' tendency to collect reward independent of the stimulus. Response bias increased during the reversal, corresponding to the animals' uncertainty about the stimulus-response contingencies. Most task-modulated neurons fired during the response at the end of the delay period. The fraction of response-modulated neurons was correlated with response bias and neural activity was sensitive to the behavioral response made on the previous trial. During initial task acquisition and initial reversal learning, there was a remarkable change in the percentages of neurons that fired in relation to the task events, especially during withdrawal from the nosepoke aperture. These results suggest that changes in task-related activity in the dorsomedial striatum during learning are driven by the animal's bias to collect rewards.

Functional But Not Structural Networks of the Human Laryngeal Motor Cortex Show Left Hemispheric Lateralization during Syllable But Not Breathing Production

Simonyan, K., Ostuni, J., Ludlow, C. L., Horwitz, B. — Wed, 25 Nov 2009 10:03:10 PST

The laryngeal motor cortex (LMC) is indispensible for the vocal motor control of speech and song production. Patients with bilateral lesions in this region are unable to speak and sing, although their nonverbal vocalizations, such as laughter and cry, are preserved. Despite the importance of the LMC in the control of voluntary voice production in humans, the literature describing its connections remains sparse. We used diffusion tensor probabilistic tractography and functional magnetic resonance imaging-based functional connectivity analysis to identify LMC networks controlling two tasks necessary for speech production: voluntary voice as repetition of two different syllables and voluntary breathing as controlled inspiration and expiration. Peaks of activation during all tasks were found in the bilateral ventral primary motor cortex in close proximity to each other. Functional networks of the LMC during voice production but not during controlled breathing showed significant left-hemispheric lateralization (p < 0.0005). However, structural networks of the LMC associated with both voluntary voice production and controlled breathing had bilateral hemispheric organization. Our findings indicate the presence of a common bilateral structural network of the LMC, upon which different functional networks are built to control various voluntary laryngeal tasks. Bilateral organization of functional LMC networks during controlled breathing supports its indispensible role in all types of laryngeal behaviors. Significant left-hemispheric lateralization of functional networks during simple but highly learned voice production suggests the readiness of the LMC network for production of a complex voluntary behavior, such as human speech.

Brain Mechanisms Supporting Discrimination of Sensory Features of Pain: A New Model

Oshiro, Y., Quevedo, A. S., McHaffie, J. G., Kraft, R. A., Coghill, R. C. — Wed, 25 Nov 2009 10:03:10 PST

Pain can be very intense or only mild, and can be well localized or diffuse. To date, little is known as to how such distinct sensory aspects of noxious stimuli are processed by the human brain. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that discrimination of pain intensity, a nonspatial aspect of pain, activates a ventrally directed pathway extending bilaterally from the insular cortex to the prefrontal cortex. This activation is distinct from the dorsally directed activation of the posterior parietal cortex and right dorsolateral prefrontal cortex that occurs during spatial discrimination of pain. Both intensity and spatial discrimination tasks activate highly similar aspects of the anterior cingulate cortex, suggesting that this structure contributes to common elements of the discrimination task such as the monitoring of sensory comparisons and response selection. Together, these results provide the foundation for a new model of pain in which bidirectional dorsal and ventral streams preferentially amplify and process distinct sensory features of noxious stimuli according to top-down task demands.

Superior Parietal Cortex Is Critical for the Manipulation of Information in Working Memory

Koenigs, M., Barbey, A. K., Postle, B. R., Grafman, J. — Wed, 25 Nov 2009 10:03:10 PST

In recent years, theoretical perspectives on posterior parietal function have evolved beyond the traditional visuospatial processing models to include more diverse cognitive operations, such as long-term and working memory. However, definitive neuropsychological evidence supporting the superior parietal lobule's purported role in working memory has been lacking. Here, we studied human brain lesion patients to determine whether the superior parietal lobule is indeed necessary for working memory. We assessed a wide range of memory functions in three participant groups: superior parietal lesions (n = 19), lesions not involving superior parietal cortex (n = 146), and no brain lesions (n = 55). Superior parietal damage was reliably associated with deficits on tests involving the manipulation and rearrangement of information in working memory, but not on working memory tests requiring only rehearsal and retrieval processes, nor on tests of long-term memory. These results indicate that superior parietal cortex is critically important for the manipulation of information in working memory.

Robust Coding of Ego-Motion in Descending Neurons of the Fly

Wertz, A., Gaub, B., Plett, J., Haag, J., Borst, A. — Wed, 25 Nov 2009 10:03:10 PST

In many species, motion-sensitive neurons responding to optic flow at higher processing stages are well characterized; however, less is known how this representation of ego-motion is further transformed into an appropriate motor response. Here, we analyzed in the blowfly Calliphora vicina the visuomotor transformation from motion-sensitive neurons in the lobula plate [V2 and vertical system (VS) cells] onto premotor descending neurons [descending neurons of the ocellar and vertical system (DNOVS) cells] feeding into the motor circuit of the fly thoracic ganglion. We found that each of these cells is tuned to rotation of the fly around a particular body axis. Comparing the responses of presynaptic and postsynaptic cells revealed that DNOVS cells have approximately the same tuning widths as V2 and VS cells. However, DNOVS signals cells are less corrupted by fluctuations arising from the spatial structure of the visual input than their presynaptic elements. This leads to a more robust representation of ego-motion at the level of descending neurons. Thus, when moving from lobula plate cells to descending neurons, the selectivity for a particular optic flow remains unaltered, but the robustness of the representation increases.

Inhibition of Adult Rat Retinal Ganglion Cells by D1-Type Dopamine Receptor Activation

Wed, 25 Nov 2009 10:03:10 PST

The spike output of neural pathways can be regulated by modulating output neuron excitability and/or their synaptic inputs. Dopaminergic interneurons synapse onto cells that route signals to mammalian retinal ganglion cells, but it is unknown whether dopamine can activate receptors in these ganglion cells and, if it does, how this affects their excitability. Here, we show D_1a receptor-like immunoreactivity in ganglion cells identified in adult rats by retrogradely transported dextran, and that dopamine, D₁-type receptor agonists, and cAMP analogs inhibit spiking in ganglion cells dissociated from adult rats. These ligands curtailed repetitive spiking during constant current injections and reduced the number and rate of rise of spikes elicited by fluctuating current injections without significantly altering the timing of the remaining spikes. Consistent with mediation by D₁-type receptors, SCH-23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] reversed the effects of dopamine on spikes. Contrary to a recent report, spike inhibition by dopamine was not precluded by blocking I_h. Consistent with the reduced rate of spike rise, dopamine reduced voltage-gated Na⁺ current (I_Na) amplitude, and tetrodotoxin, at doses that reduced I_Na as moderately as dopamine, also inhibited spiking. These results provide the first direct evidence that D₁-type dopamine receptor activation can alter mammalian retinal ganglion cell excitability and demonstrate that dopamine can modulate spikes in these cells by a mechanism different from the presynaptic and postsynaptic means proposed by previous studies. To our knowledge, our results also provide the first evidence that dopamine receptor activation can reduce excitability without altering the temporal precision of spike firing.

Timing in the Absence of Supraspinal Input II: Regularly Spaced Stimulation Induces a Lasting Alteration in Spinal Function That Depends on the NMDA Receptor, BDNF Release, and Protein Synthesis

Baumbauer, K. M., Huie, J. R., Hughes, A. J., Grau, J. W. — Wed, 18 Nov 2009 10:02:12 PST

The detection of temporal regularity allows organisms to predict the occurrence of future events. When events occur in an irregular manner, uncertainty is increased, and negative outcomes can ensue (e.g., stress). The present study shows that spinal neurons can discriminate between variable- and fixed-spaced stimulation and that the detection of regularity requires training and engages a form of NMDA receptor-mediated plasticity. The impact of stimulus exposure was assessed using a spinally mediated instrumental response, wherein spinally transected rats are given legshock whenever one hindlimb is extended. Over time, they learn to maintain the leg in a flexed position that minimizes net shock exposure. Prior exposure to 180–900 tailshocks given in a variable (unpredictable) manner inhibited this learning. A learning deficit was not observed when 900 tailshocks were applied using a fixed (predictable) spacing. Fixed-spaced stimulation did not have a divergent effect when fewer (180) shocks were presented, implying that the abstraction of temporal regularity required repeated exposure (training). Moreover, fixed-spaced stimulation both prevented and reversed the learning deficit. The protective effect of fixed-spaced shock lasted 48 h, and was prevented by pretreatment with the NMDA receptor antagonist MK-801. Administration of the protein synthesis inhibitor cycloheximide after training blocked the long-term effect. Inhibiting BDNF function, using TrkB-IgG, also eliminated the beneficial effect of fixed-spaced stimulation. The results suggest that spinal systems can detect regularity and that this type of stimulation promotes adaptive plasticity, which may foster recovery after spinal injury.

Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models

Wed, 18 Nov 2009 10:02:12 PST

To determine the respective role played by orexin/hypocretin and histamine (HA) neurons in maintaining wakefulness (W), we characterized the behavioral and sleep–wake phenotypes of orexin (Ox) knock-out (–/–) mice and compared them with those of histidine-decarboxylase (HDC, HA-synthesizing enzyme)–/– mice. While both mouse strains displayed sleep fragmentation and increased paradoxical sleep (PS), they presented a number of marked differences: (1) the PS increase in HDC^–/– mice was seen during lightness, whereas that in Ox^–/– mice occurred during darkness; (2) contrary to HDC^–/–, Ox^–/– mice had no W deficiency around lights-off, nor an abnormal EEG and responded to a new environment with increased W; (3) only Ox^–/–, but not HDC^–/– mice, displayed narcolepsy and deficient W when faced with motor challenge. Thus, when placed on a wheel, wild-type (WT), but not littermate Ox^–/– mice, voluntarily spent their time in turning it and as a result, remained highly awake; this was accompanied by dense c-fos expression in many areas of their brains, including Ox neurons in the dorsolateral hypothalamus. The W and motor deficiency of Ox^–/– mice was due to the absence of Ox because intraventricular dosing of orexin-A restored their W amount and motor performance whereas SB-334867 (Ox1-receptor antagonist, i.p.) impaired W and locomotion of WT mice during the test. These data indicate that Ox, but not HA, promotes W through enhanced locomotion and suggest that HA and Ox neurons exert a distinct, but complementary and synergistic control of W: the neuropeptide being more involved in its behavioral aspects, whereas the amine is mainly responsible for its qualitative cognitive aspects and cortical EEG activation.

Default Mode of Brain Activity Demonstrated by Positron Emission Tomography Imaging in Awake Monkeys: Higher Rest-Related than Working Memory-Related Activity in Medial Cortical Areas

Kojima, T., Onoe, H., Hikosaka, K., Tsutsui, K.-i., Tsukada, H., Watanabe, M. — Wed, 18 Nov 2009 10:02:12 PST

Human neuroimaging studies have demonstrated the presence of a "default system" in the brain, which shows a "default mode of brain activity," i.e., greater activity during the resting state than during an attention-demanding cognitive task. The default system mainly involves the medial prefrontal and medial parietal areas, including the anterior and posterior cingulate cortex. It has been proposed that this default activity is concerned with internal thought processes. Recently, it has been indicated that chimpanzees show high metabolic levels in these medial brain areas during rest. Correlated low-frequency spontaneous activity as measured by functional magnetic resonance imaging was observed between the medial parietal and medial prefrontal areas in the anesthetized monkey. However, there have been few attempts to demonstrate a default system that shows task-induced deactivation in nonhuman primates. We conducted a positron emission tomography study with [¹⁵O]H₂O to demonstrate a default mode of brain activity in the awake monkey sitting on a primate chair. Macaque monkeys showed higher level of regional blood flow in these medial brain areas as well as lateral and orbital prefrontal areas during rest compared with that under a working memory task, suggesting the existence of internal thought processes in the monkey. However, during rest in the monkey, the highest level of blood flow relative to that in other brain regions was observed not in the default system but in the dorsal striatum, suggesting that regions with the highest cerebral blood flow during rest may differ depending on the resting condition and/or species.

Investigating the Functional Heterogeneity of the Default Mode Network Using Coordinate-Based Meta-Analytic Modeling

Laird, A. R., Eickhoff, S. B., Li, K., Robin, D. A., Glahn, D. C., Fox, P. T. — Wed, 18 Nov 2009 10:02:12 PST

The default mode network (DMN) comprises a set of regions that exhibit ongoing, intrinsic activity in the resting state and task-related decreases in activity across a range of paradigms. However, DMN regions have also been reported as task-related increases, either independently or coactivated with other regions in the network. Cognitive subtractions and the use of low-level baseline conditions have generally masked the functional nature of these regions. Using a combination of activation likelihood estimation, which assesses statistically significant convergence of neuroimaging results, and tools distributed with the BrainMap database, we identified core regions in the DMN and examined their functional heterogeneity. Meta-analytic coactivation maps of task-related increases were independently generated for each region, which included both within-DMN and non-DMN connections. Their functional properties were assessed using behavioral domain metadata in BrainMap. These results were integrated to determine a DMN connectivity model that represents the patterns of interactions observed in task-related increases in activity across diverse tasks. Subnetwork components of this model were identified, and behavioral domain analysis of these cliques yielded discrete functional properties, demonstrating that components of the DMN are differentially specialized. Affective and perceptual cliques of the DMN were identified, as well as the cliques associated with a reduced preference for motor processing. In summary, we used advanced coordinate-based meta-analysis techniques to explicate behavior and connectivity in the default mode network; future work will involve applying this analysis strategy to other modes of brain function, such as executive function or sensorimotor systems.

Caudate Nucleus Is Critically Involved in Trace Eyeblink Conditioning

Flores, L. C., Disterhoft, J. F. — Wed, 18 Nov 2009 10:02:12 PST

The basal ganglia are a collection of brain regions involved with motor planning and initiation. The major site of cortical and thalamic input into the basal ganglia network is the striatum, which includes a differentiated caudate nucleus (CN) and the putamen in rabbits. Trace eyeblink conditioning (EBC) is a forebrain-dependent associative learning task in which a stimulus-free time interval separates the presentation of a behaviorally neutral conditioned stimulus (CS) and a behaviorally salient unconditioned stimulus. We investigated whether the CN is essential for acquisition of trace EBC and whether learning-related changes in neuronal activity occur in the caudate nucleus during trace EBC. Bilateral lesions of the CN in rabbits prevent acquisition of trace EBC. In separate cohorts of rabbits, single-unit recordings showed that medium spiny neurons from regions shown to be critical by lesions display strong responses to the CS, especially in the initial days of training before acquisition. Cholinergic interneurons, or tonically active neurons, become responsive to the CS and show dramatic firing rate changes during the trace interval after learning criterion has been met. These data demonstrate that the CN is required for and involved in trace EBC.

Disruption of the Head Direction Cell Signal after Occlusion of the Semicircular Canals in the Freely Moving Chinchilla

Wed, 18 Nov 2009 10:02:12 PST

Head direction (HD) cells in the rat anterodorsal thalamic nucleus (ADN) fire relative to the animal's directional heading. Lesions of the entire vestibular labyrinth have been shown to severely alter VIIIth nerve input and disrupt these HD signals. To assess the specific contributions of the semicircular canals without altering tonic VIIIth nerve input, ADN cells were recorded from chinchillas after bilateral semicircular canal occlusion. Although ADN HD cells (and also hippocampal place cells and theta cells) were identified in intact chinchillas, no direction-specific activity was seen after canal occlusions. Instead, "bursty" cells were observed that exhibited burst-firing patterns similar to normal HD cells but with firing unrelated to the animal's actual head direction. Importantly, when pairs of bursty cells were recorded, the temporal order of their firing was dependent on the animal's turning direction, as is the case for pairs of normal HD cells. These results suggest that bursty cells are actually disrupted HD cells. The present findings further suggest that the HD cell network is still able to generate spiking activity after canal occlusions, but the semicircular canal input is critical for updating the network activity in register with changes in the animal's HD.

Correlations of Neuronal and Microvascular Densities in Murine Cortex Revealed by Direct Counting and Colocalization of Nuclei and Vessels

Wed, 18 Nov 2009 10:02:12 PST

It is well known that the density of neurons varies within the adult brain. In neocortex, this includes variations in neuronal density between different lamina as well as between different regions. Yet the concomitant variation of the microvessels is largely uncharted. Here, we present automated histological, imaging, and analysis tools to simultaneously map the locations of all neuronal and non-neuronal nuclei and the centerlines and diameters of all blood vessels within thick slabs of neocortex from mice. Based on total inventory measurements of different cortical regions (~10⁷ cells vectorized across brains), these methods revealed: (1) In three dimensions, the mean distance of the center of neuronal somata to the closest microvessel was 15 µm. (2) Volume samples within lamina of a given region show that the density of microvessels does not match the strong laminar variation in neuronal density. This holds for both agranular and granular cortex. (3) Volume samples in successive radii from the midline to the ventral-lateral edge, where each volume summed the number of cells and microvessels from the pia to the white matter, show a significant correlation between neuronal and microvessel densities. These data show that while neuronal and vascular densities do not track each other on the 100 µm scale of cortical lamina, they do track each other on the 1–10 mm scale of the cortical mantle. The absence of a disproportionate density of blood vessels in granular lamina is argued to be consistent with the initial locus of functional brain imaging signals.

Reliable Recall of Spontaneous Activity Patterns in Cortical Networks

Marre, O., Yger, P., Davison, A. P., Fregnac, Y. — Wed, 18 Nov 2009 10:02:12 PST

Irregular ongoing activity in cortical networks is often modeled as arising from recurrent connectivity. Yet it remains unclear to what extent its presence corrupts sensory signal transmission and network computational capabilities. In a recurrent cortical-like network, we have determined the activity patterns that are better transmitted and self-sustained by the network. We show that reproducible spiking and subthreshold dynamics can be triggered if the statistics of the imposed external drive are consistent with patterns previously seen in the ongoing activity. A subset of neurons in the network, constrained to replay temporal pattern segments extracted from the recorded ongoing activity of the same network, reliably drives the remaining, free-running neurons to call the rest of the pattern. Comparison with surrogate Poisson patterns indicates that the efficiency of the recall and completion process depends on the similarity between the statistical properties of the input with previous ongoing activity The reliability of evoked dynamics in recurrent networks is thus dependent on the stimulus used, and we propose that the similarity between spontaneous and evoked activity in sensory cortical areas could be a signature of efficient transmission and propagation across cortical networks.

A Comparative Magnetic Resonance Imaging Study of the Anatomy, Variability, and Asymmetry of Broca's Area in the Human and Chimpanzee Brain

Keller, S. S., Roberts, N., Hopkins, W. — Wed, 18 Nov 2009 10:02:12 PST

The frontal operculum—classically considered to be Broca's area—has special significance and interest in clinical, cognitive, and comparative neuroscience given its role in spoken language and the long-held assumption that structural asymmetry of this region of cortex may be related to functional lateralization of human language. We performed a detailed morphological and morphometric analysis of this area of the brain in humans and chimpanzees using identical image acquisition parameters, image analysis techniques, and consistent anatomical boundaries in both species. We report great inter-individual variability of the sulcal contours defining the operculum in both species, particularly discontinuity of the inferior frontal sulcus in humans and bifurcation of the inferior precentral sulcus in chimpanzees. There was no evidence of population-based asymmetry of the frontal opercular gray matter in humans or chimpanzees. The diagonal sulcus was only identified in humans, and its presence was significantly (F = 12.782, p < 0.001) associated with total volume of the ipsilateral operculum. The findings presented here suggest that there is no population-based interhemispheric macroscopic asymmetry of Broca's area in humans or Broca's area homolog in chimpanzees. However, given that previous studies have reported asymmetry in the cytoarchitectonic fields considered to represent Broca's area—which is important given that cytoarchitectonic boundaries are more closely related to the regional functional properties of cortex relative to sulcal landmarks—it may be that the gross morphology of the frontal operculum is not a reliable indicator of Broca's area per se.

How Humans Integrate the Prospects of Pain and Reward during Choice

Talmi, D., Dayan, P., Kiebel, S. J., Frith, C. D., Dolan, R. J. — Wed, 18 Nov 2009 10:02:12 PST

The maxim "no pain, no gain" summarizes scenarios in which an action leading to reward also entails a cost. Although we know a substantial amount about how the brain represents pain and reward separately, we know little about how they are integrated during goal-directed behavior. Two theoretical models might account for the integration of reward and pain. An additive model specifies that the disutility of costs is summed linearly with the utility of benefits, whereas an interactive model suggests that cost and benefit utilities interact so that the sensitivity to benefits is attenuated as costs become increasingly aversive. Using a novel task that required integration of physical pain and monetary reward, we examined the mechanism underlying cost–benefit integration in humans. We provide evidence in support of an interactive model in behavioral choice. Using functional neuroimaging, we identify a neural signature for this interaction such that, when the consequences of actions embody a mixture of reward and pain, there is an attenuation of a predictive reward signal in both ventral anterior cingulate cortex and ventral striatum. We conclude that these regions subserve integration of action costs and benefits in humans, a finding that suggests a cross-species similarity in neural substrates that implement this function and illuminates mechanisms that underlie altered decision making under aversive conditions.

Regaining Motor Control in Musician's Dystonia by Restoring Sensorimotor Organization

Rosenkranz, K., Butler, K., Williamon, A., Rothwell, J. C. — Wed, 18 Nov 2009 10:02:12 PST

Professional musicians are an excellent model of long-term motor learning effects on structure and function of the sensorimotor system. However, intensive motor skill training has been associated with task-specific deficiency in hand motor control, which has a higher prevalence among musicians (musician's dystonia) than in the general population. Using a transcranial magnetic stimulation paradigm, we previously found an expanded spatial integration of proprioceptive input into the hand motor cortex [sensorimotor organization (SMO)] in healthy musicians. In musician's dystonia, however, this expansion was even larger. Whereas motor skills of musicians are likely to be supported by a spatially expanded SMO, we hypothesized that in musician's dystonia this might have developed too far and now disrupts rather than assists task-specific motor control. If so, motor control should be regained by reversing the excessive reorganization in musician's dystonia. Here, we test this hypothesis and show that a 15 min intervention with proprioceptive input (proprioceptive training) restored SMO in pianists with musician's dystonia to the pattern seen in healthy pianists. Crucially, task-specific motor control improved significantly and objectively as measured with a MIDI (musical instrument digital interface) piano, and the amount of behavioral improvement was significantly correlated to the degree of sensorimotor reorganization. In healthy pianists and nonmusicians, the SMO and motor performance remained essentially unchanged. These findings suggest that the differentiation of SMO in the hand motor cortex and the degree of motor control of intensively practiced tasks are significantly linked and finely balanced. Proprioceptive training restored this balance in musician's dystonia to the behaviorally beneficial level of healthy musicians.

Disruption of the Ether-a-go-go K+ Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Wed, 18 Nov 2009 10:02:13 PST

The K⁺ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K⁺ channel genes are expressed in the CNS. The therapeutic potential of K⁺ channel blockers for cognitive enhancement has been discussed, but the contribution each K⁺ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K⁺ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K⁺ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K⁺ channel that contributes preferentially and bidirectionally to cognitive function.

Adding Insult to Injury: Cochlear Nerve Degeneration after "Temporary" Noise-Induced Hearing Loss

Kujawa, S. G., Liberman, M. C. — Wed, 11 Nov 2009 10:02:14 PST

Overexposure to intense sound can cause temporary or permanent hearing loss. Postexposure recovery of threshold sensitivity has been assumed to indicate reversal of damage to delicate mechano-sensory and neural structures of the inner ear and no persistent or delayed consequences for auditory function. Here, we show, using cochlear functional assays and confocal imaging of the inner ear in mouse, that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of afferent nerve terminals and delayed degeneration of the cochlear nerve. Results suggest that noise-induced damage to the ear has progressive consequences that are considerably more widespread than are revealed by conventional threshold testing. This primary neurodegeneration should add to difficulties hearing in noisy environments, and could contribute to tinnitus, hyperacusis, and other perceptual anomalies commonly associated with inner ear damage.

Musical Experience Limits the Degradative Effects of Background Noise on the Neural Processing of Sound

Parbery-Clark, A., Skoe, E., Kraus, N. — Wed, 11 Nov 2009 10:02:14 PST

Musicians have lifelong experience parsing melodies from background harmonies, which can be considered a process analogous to speech perception in noise. To investigate the effect of musical experience on the neural representation of speech-in-noise, we compared subcortical neurophysiological responses to speech in quiet and noise in a group of highly trained musicians and nonmusician controls. Musicians were found to have a more robust subcortical representation of the acoustic stimulus in the presence of noise. Specifically, musicians demonstrated faster neural timing, enhanced representation of speech harmonics, and less degraded response morphology in noise. Neural measures were associated with better behavioral performance on the Hearing in Noise Test (HINT) for which musicians outperformed the nonmusician controls. These findings suggest that musical experience limits the negative effects of competing background noise, thereby providing the first biological evidence for musicians' perceptual advantage for speech-in-noise.

The Synaptic Representation of Sound Source Location in Auditory Cortex

Chadderton, P., Agapiou, J. P., McAlpine, D., Margrie, T. W. — Wed, 11 Nov 2009 10:02:14 PST

A key function of the auditory system is to provide reliable information about the location of sound sources. Here, we describe how sound location is represented by synaptic input arriving onto pyramidal cells within auditory cortex by combining free-field acoustic stimulation in the frontal azimuthal plane with in vivo whole-cell recordings. We found that subthreshold activity was panoramic in that EPSPs could be evoked from all locations in all cells. Regardless of the sound location that evoked the largest EPSP, we observed a slowing in the EPSP slope along the contralateral–ipsilateral plane that was reflected in a temporal sequence of peak EPSP times. Contralateral sounds evoked EPSPs with earlier peak times and consequently generated action potential firing with shorter latencies than ipsilateral sounds. Thus, whereas spiking probability reflected the region of space evoking the largest EPSP, across the population, synaptic inputs enforced a gradient of spike latency and precision along the horizontal axis. Therefore, within auditory cortex and regardless of preferred location, the time window of synaptic integration reflects sound source location and ensures that spatial acoustic information is represented by relative timings of pyramidal cell output.

Local and Large-Range Inhibition in Feature Detection

Bolzon, D. M., Nordstrom, K., O'Carroll, D. C. — Wed, 11 Nov 2009 10:02:14 PST

Lateral inhibition is perhaps the most ubiquitous of neuronal mechanisms, having been demonstrated in early stages of processing in many different sensory pathways of both mammals and invertebrates. Recent work challenges the long-standing view that assumes that similar mechanisms operate to tune neuronal responses to higher order properties. Scant evidence for lateral inhibition exists beyond the level of the most peripheral stages of visual processing, leading to suggestions that many features of the tuning of higher order visual neurons can be accounted for by the receptive field and other intrinsic coding properties of visual neurons. Using insect target neurons as a model, we present unequivocal evidence that feature tuning is shaped not by intrinsic properties but by potent spatial lateral inhibition operating well beyond the first stages of visual processing. In addition, we present evidence for a second form of higher-order spatial inhibition—a long-range interocular transfer of information that we argue serves a role in establishing interocular rivalry and thus potentially a neural substrate for directing attention to single targets in the presence of distracters. In so doing, we demonstrate not just one, but two levels of spatial inhibition acting beyond the level of peripheral processing.

Neural Activity in the Middle Temporal Area and Lateral Intraparietal Area during Endogenously Cued Shifts of Attention

Herrington, T. M., Assad, J. A. — Wed, 11 Nov 2009 10:02:14 PST

We measured the behavioral time course of endogenously cued attentional shifts while recording from neurons in the middle temporal area (MT) and lateral intraparietal area (LIP) of two macaque monkeys. The monkeys were required to detect a subtle speed change of one of two continuously moving stimuli. The likely location of the speed change was cued throughout each trial but could switch at an unpredictable time. Attention was evident as an improvement in detection ability and reaction time at the cued location, and the focus of attention shifted over a 400 ms period in response to a switch of the cued stimulus. Attention modulated the ongoing neural response in both MT and LIP, and the sign of this modulation also rapidly shifted after a cue switch. Our data provide a framework for understanding the link between the neural and behavioral effects of attention. The responses of single neurons to the test stimulus in MT and LIP were correlated with stimulus detection and reaction time and, at the population level, a spike-rate threshold model was able to account for the effect of attention on detection rate and reaction time. In this view, the time course of the attentional shift can be understood as an interaction between the emerging attentional modulation and the neural response to the test stimulus in LIP. We also present evidence that the threshold model is not wholly explained by sensory (feedforward) information but may also be influenced by cognitive (feedback) processes at the time of stimulus detection.

The Spinothalamic System Targets Motor and Sensory Areas in the Cerebral Cortex of Monkeys

Dum, R. P., Levinthal, D. J., Strick, P. L. — Wed, 11 Nov 2009 10:02:14 PST

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.

Cerebral and Cerebrospinal Processes Underlying Counterirritation Analgesia

Piche, M., Arsenault, M., Rainville, P. — Wed, 11 Nov 2009 10:02:14 PST

Pain is a complex experience involving extensive interactions between brain and spinal cord processes. Various interventions that modulate pain, such as the application of a competing noxious stimulus (counterirritation), are thought to involve cerebrospinal regulation through diffuse noxious inhibitory controls (DNICs). However, no study has yet examined the relation between brain and spinal cord activity during counterirritation analgesia in humans. This fMRI study investigates brain responses to phasic painful electrical stimulation administered to the sural nerve to evoke a spinal nociceptive response (RIII reflex) before, during and after counterirritation induced by the immersion of the left contralateral foot in cold water. Responses are compared with a control condition without counterirritation. As expected, counterirritation produced robust pain inhibition with residual analgesia persisting during the recovery period. In contrast, RIII reflex amplitude was significantly decreased by counterirritation only in a subset of subjects. Modulatory effects of counterirritation on pain perception and spinal nociception were paralleled by decreased shock-evoked activity in pain-related areas. Individual changes in shock-evoked brain activity were specifically related to analgesia in primary somatosensory cortex (SI), anterior cingulate cortex and amygdala, and to RIII modulation in supplementary motor area and orbitofrontal cortex (OFC). Moreover, sustained activation induced by the counterirritation stimulus in the OFC predicted shock-pain decrease while sustained activity in SI and the periaqueductal gray matter predicted RIII modulation. These results provide evidence for the implication of at least two partly separable neural mechanisms underlying the effects of counterirritation on pain and spinal nociception in humans.

Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

Wed, 11 Nov 2009 10:02:15 PST

Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing training depend on functional interactions between the BLA and the medial prefrontal cortex (mPFC), a brain region involved in higher-order cognitive and affective processing. The glucocorticoid receptor (GR) agonist 11β,17β-dihydroxy-6,21-dimethyl-17-pregna-4,6-trien-20yn-3-one (RU 28362) administered unilaterally into the left mPFC of male Sprague Dawley rats immediately after inhibitory avoidance training enhanced 48 h retention performance. An ipsilateral, but not contralateral, lesion of the BLA blocked the memory enhancement. In a second experiment, RU 28362 infused into the mPFC after inhibitory avoidance training increased BLA levels of phosphorylated extracellular signal-regulated kinase 1/2 (pErk1/2). Blockade of this pErk1/2 activity in the BLA with the mitogen-activated protein kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] prevented the memory enhancement, suggesting that GR agonist administration into the mPFC enhances memory consolidation via modulation of BLA activity. Conversely, GR agonist infusions administered into the BLA posttraining increased pErk1/2 levels in the mPFC in regulating memory consolidation. Moreover, as assessed with a two-phase inhibitory avoidance procedure designed to separate modulatory influences on memory of context and footshock, posttraining GR agonist infusions into either the BLA or mPFC enhanced memory of the contextual as well as aversive information acquired during inhibitory avoidance training. These findings indicate that glucocorticoid effects on memory consolidation depend on bidirectional interactions between the BLA and mPFC.

Evidence for Hierarchical Processing in Cat Auditory Cortex: Nonreciprocal Influence of Primary Auditory Cortex on the Posterior Auditory Field

Carrasco, A., Lomber, S. G. — Wed, 11 Nov 2009 10:02:15 PST

The auditory cortex of the cat is composed of 13 distinct fields that have been defined on the basis of anatomy, physiology, and behavior. Although an anatomically based hierarchical processing scheme has been proposed in auditory cortex, few functional studies have examined how these areas influence one another. The purpose of the present study was to examine the bidirectional processing contributions between primary auditory cortex (A1) and the nonprimary posterior auditory field (PAF). Multiunit acute recording techniques in eight mature cats were used to measure neuronal responses to tonal stimuli in A1 or PAF while synaptic activity from PAF or A1 was suppressed with reversible cooling deactivation techniques. Specifically, in four animals, electrophysiological recordings in A1 were conducted before, during, and after deactivation of PAF. Similarly, in the other four animals, PAF activity was measured before, during, and after deactivation of A1. The characteristic frequency, bandwidth, and neuronal threshold were calculated at each receptive field collected and the response strength and response latency measures were calculated from cumulative peristimulus time histograms. Two major changes in PAF response properties were observed during A1 deactivation: a decrease in response strength and a reduction in receptive field bandwidths. In comparison, we did not identify any significant changes in A1 neuronal responses during deactivation of PAF neurons. These findings support proposed models of hierarchal processing in cat auditory cortex.

Representation of Cross-Frequency Spatial Phase Relationships in Human Visual Cortex

Henriksson, L., Hyvarinen, A., Vanni, S. — Wed, 11 Nov 2009 10:02:15 PST

An image patch can be locally decomposed into sinusoidal waves of different orientations, spatial frequencies, amplitudes, and phases. The local phase information is essential for perception, because important visual features like edges emerge at locations of maximal local phase coherence. Detection of phase coherence requires integration of spatial frequency information across multiple spatial scales. Models of early visual processing suggest that the visual system should implement phase-sensitive pooling of spatial frequency information in the identification of broadband edges. We used functional magnetic resonance imaging (fMRI) adaptation to look for phase-sensitive neural responses in the human visual cortex. We found sensitivity to the phase difference between spatial frequency components in all studied visual areas, including the primary visual cortex (V1). Control experiments demonstrated that these results were not explained by differences in contrast or position. Next, we compared fMRI responses for broadband compound grating stimuli with congruent and random phase structures. All studied visual areas showed stronger responses for the stimuli with congruent phase structure. In addition, selectivity to phase congruency increased from V1 to higher-level visual areas along both the ventral and dorsal streams. We conclude that human V1 already shows phase-sensitive pooling of spatial frequencies, but only higher-level visual areas might be capable of pooling spatial frequency information across spatial scales typical for broadband natural images.

Local Changes in the Excitability of the Cerebellar Cortex Produce Spatially Restricted Changes in Complex Spike Synchrony

Marshall, S. P., Lang, E. J. — Wed, 11 Nov 2009 10:02:15 PST

Complex spike (CS) synchrony patterns are modulated by the release of GABA within the inferior olive (IO). The GABAergic projection to most of the IO arises from the cerebellar nuclei, which are themselves subject to strong inhibitory control by Purkinje cells in the overlying cortex. Moreover, the connections between the IO and cerebellum are precisely aligned, raising the possibility that each cortical region controls its own CS synchrony distribution. This possibility was tested using multielectrode recordings of CSs and simple spikes (SSs) in crus 2a of anesthetized rats. Picrotoxin or muscimol was applied to the cerebellar cortex at the borders of the recording array. These drugs induced significant changes in CS synchrony and in CS and SS firing rates and changes in post-CS pauses and modulation of SS activity. The level of CS synchrony was correlated with SS firing rate in control, and application of picrotoxin increased both. In contrast, muscimol decreased CS synchrony. Furthermore, when picrotoxin was applied only at the lateral edge of the array, changes in CS synchrony occurred sequentially across the recording array, with cells located in the lateral half of the array having earlier and larger changes in CS synchrony than cells in the medial half. The results indicate that a double-inhibitory feedback circuit from Purkinje cells to the IO provides a mechanism by which SS activity may regulate CS synchrony. Thus, CS synchrony may be a physiologically controlled parameter of cerebellar activity, with the cerebellum and IO comprising a series of self-updating circuits.

Brain Control of Movement Execution Onset Using Local Field Potentials in Posterior Parietal Cortex

Hwang, E. J., Andersen, R. A. — Wed, 11 Nov 2009 10:02:15 PST

The precise control of movement execution onset is essential for safe and autonomous cortical motor prosthetics. A recent study from the parietal reach region (PRR) suggested that the local field potentials (LFPs) in this area might be useful for decoding execution time information because of the striking difference in the LFP spectrum between the plan and execution states (Scherberger et al., 2005). More specifically, the LFP power in the 0–10 Hz band sharply rises while the power in the 20–40 Hz band falls as the state transitions from plan to execution. However, a change of visual stimulus immediately preceded reach onset, raising the possibility that the observed spectral change reflected the visual event instead of the reach onset. Here, we tested this possibility and found that the LFP spectrum change was still time locked to the movement onset in the absence of a visual event in self-paced reaches. Furthermore, we successfully trained the macaque subjects to use the LFP spectrum change as a "go" signal in a closed-loop brain-control task in which the animals only modulated the LFP and did not execute a reach. The execution onset was signaled by the change in the LFP spectrum while the target position of the cursor was controlled by the spike firing rates recorded from the same site. The results corroborate that the LFP spectrum change in PRR is a robust indicator for the movement onset and can be used for control of execution onset in a cortical prosthesis.