Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity.

Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C(POMC) mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP(3) (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C(POMC) mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C(POMC) mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance.

Speech target modulates speaking induced suppression in auditory cortex.

BACKGROUND: Previous magnetoencephalography (MEG) studies have demonstrated speaking-induced suppression (SIS) in the auditory cortex during vocalization tasks wherein the M100 response to a subject's own speaking is reduced compared to the response when they hear playback of their speech. RESULTS: The present MEG study investigated the effects of utterance rapidity and complexity on SIS: The greatest difference between speak and listen M100 amplitudes (i.e., most SIS) was found in the simple speech task. As the utterances became more rapid and complex, SIS was significantly reduced (p = 0.0003). CONCLUSION: These findings are highly consistent with our model of how auditory feedback is processed during speaking, where incoming feedback is compared with an efference-copy derived prediction of expected feedback. Thus, the results provide further insights about how speech motor output is controlled, as well as the computational role of auditory cortex in transforming auditory feedback.

Background MR gradient noise and non-auditory BOLD activations: a data-driven perspective.

The effect of echoplanar imaging (EPI) acoustic background noise on blood oxygenation level dependent (BOLD) activations was investigated. Two EPI pulse sequences were compared: (i) conventional EPI with a pulsating sound component of typically 8-10 Hz, which is a potent physiological stimulus, and (ii) the more recently developed continuous-sound EPI, which is perceived as less distractive despite equivalent peak sound pressure levels. Sixteen healthy subjects performed an established demanding visual n-back working memory task. Using an exploratory data analysis technique (tensorial probabilistic independent component analysis; tensor-PICA), we studied the inter-session/within-subject response variability introduced by continuous-sound versus conventional EPI acoustic background noise in addition to temporal and spatial signal characteristics. The analysis revealed a task-related component associated with the established higher-level working memory and motor feedback response network, which exhibited a significant 19% increase in its average effect size for the continuous-sound as opposed to conventional EPI. Stimulus-related lower-level activations, such as primary visual areas, were not modified. EPI acoustic background noise influences much more than the auditory system per se. This analysis provides additional evidence for an enhancement of task-related, extra-auditory BOLD activations by continuous-sound EPI due to less distractive acoustic background gradient noise.

Layer and broiler chicks exhibit similar hypothalamic expression of orexigenic neuropeptides but distinct expression of genes related to energy homeostasis and obesity.

Layer and broiler chickens demonstrate striking differences in body weight and body composition. However, the mechanism underlying such difference is elusive. Hypothalamus-pituitary-adrenal (HPA) axis regulates energy homeostasis and body size in mammals, but information in birds is scarce. Here we test the hypothesis that such breed difference is more associated with hypothalamic expression of genes related to HPA axis, rather than orexigenic neuropeptides. Broiler chicks exhibit significantly higher body weight and food intake at day (D) 7 posthatching, but the food intake relative to body weight gain was actually lower. No breed differences were observed for hypothalamic expression of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), orexin (ORX), leptin receptor (LEPR), acetyl-CoA carboxylase (ACC) or fatty acid synthase (FAS). However, broiler chicks expressed significantly higher glucocorticoid receptor (GR) mRNA (P<0.05) and protein (P<0.01) in hypothalamus compared to layer chicks, which is associated with lower corticotropin-releasing hormone (CRH) mRNA (P<0.05) yet higher accumulation of CRH peptide in hypothalamus, suggesting an augmented GR-mediated negative feedback regulation of CRH transcription and release in broiler chicks. Furthermore, fat mass and obesity associated (FTO) gene was also more highly expressed in hypothalamus of broiler chicks (P<0.05). These results suggest that the genes related to energy homeostasis and obesity, such as GR, CRH and FTO, rather than orexigenic neuropeptides, are impacted by the genetic selection practices and play a role in breed-specific body weight setpoint regulation in the chicken.

Sound-induced flash illusion is resistant to feedback training.

A single flash accompanied by two auditory beeps tends to be perceived as two flashes (Shams et al. Nature 408:788, 2000, Cogn Brain Res 14:147-152, 2002). This phenomenon is known as 'sound-induced flash illusion.' Previous neuroimaging studies have shown that this illusion is correlated with modulation of activity in early visual cortical areas (Arden et al. Vision Res 43(23):2469-2478, 2003; Bhattacharya et al. NeuroReport 13:1727-1730, 2002; Shams et al. NeuroReport 12(17):3849-3852, 2001, Neurosci Lett 378(2):76-81, 2005; Watkins et al. Neuroimage 31:1247-1256, 2006, Neuroimage 37:572-578, 2007; Mishra et al. J Neurosci 27(15):4120-4131, 2007). We examined how robust the illusion is by testing whether the frequency of the illusion can be reduced by providing feedback. We found that the sound-induced flash illusion was resistant to feedback training, except when the amount of monetary reward was made dependent on accuracy in performance. However, even in the latter case the participants reported that they still perceived illusory two flashes even though they correctly reported single flash. Moreover, the feedback training effect seemed to disappear once the participants were no longer provided with feedback suggesting a short-lived refinement of discrimination between illusory and physical double flashes rather than vanishing of the illusory percept. These findings indicate that the effect of sound on the perceptual representation of visual stimuli is strong and robust to feedback training, and provide further evidence against decision factors accounting for the sound-induced flash illusion.

Combined feedforward and feedback control of a redundant, nonlinear, dynamic musculoskeletal system.

A functional electrical stimulation controller is presented that uses a combination of feedforward and feedback for arm control in high-level injury. The feedforward controller generates the muscle activations nominally required for desired movements, and the feedback controller corrects for errors caused by muscle fatigue and external disturbances. The feedforward controller is an artificial neural network (ANN) which approximates the inverse dynamics of the arm. The feedback loop includes a PID controller in series with a second ANN representing the nonlinear properties and biomechanical interactions of muscles and joints. The controller was designed and tested using a two-joint musculoskeletal model of the arm that includes four mono-articular and two bi-articular muscles. Its performance during goal-oriented movements of varying amplitudes and durations showed a tracking error of less than 4 degrees in ideal conditions, and less than 10 degrees even in the case of considerable fatigue and external disturbances.

Corticothalamic feedback dynamics for neural correlates of auditory selective attention.

Auditory evoked cortical potentials (AECPs) have been consolidated as a diagnostic tool in audiology. Further applications of this technique are in experimental neuropsychology, neuroscience, and psychiatry, e.g., for the attention deficit disorder, schizophrenia, or for studying the tinnitus decompensation. In particular, numerous psychophysiological studies have emphasized their dynamic characteristics in relation to exogenous and endogenous attention. However, the effect of corticothalamic feedback dynamics to neural correlates of focal and nonfocal attention and its large-scale effect reflected in AECPs is far from being understood. To address this issue, we model neural correlates of auditory selective attention reflected in AECPs by using corticothalamic feedback dynamics. In our framework, we make use of a well-known multiscale model of evoked potentials, for which we define for the first time a neurofunctional map of relevant corticothalamic loops to the hearing path. Such loops are in turn are coupled to our proposed probabilistic scheme of auditory selective attention. It is concluded that our model represents a promising approach to gain a deeper understanding of the neurodynamics of auditory attention and might be used as an efficient forward model to support hypotheses that are obtained in experimental paradigms involving AECPs.

Motor imagery and action observation: modulation of sensorimotor brain rhythms during mental control of a brain-computer interface.

OBJECTIVE: This study investigates the impact of a continuously presented visual feedback in the form of a grasping hand on the modulation of sensorimotor EEG rhythms during online control of a brain-computer interface (BCI). METHODS: Two groups of participants were trained to use left or right hand motor imagery to control a specific output signal on a computer monitor: the experimental group controlled a moving hand performing an object-related grasp ('realistic feedback'), whereas the control group controlled a moving bar ('abstract feedback'). Continuous feedback was realized by using the outcome of a real-time classifier which was based on EEG signals recorded from left and right central sites. RESULTS: The classification results show no difference between the two feedback groups. For both groups, ERD/ERS analysis revealed a significant larger ERD during feedback presentation compared to an initial motor imagery screening session without feedback. Increased ERD during online BCI control was particularly found for the lower alpha (8-10 Hz) and for the beta bands (16-20, 20-24 Hz). CONCLUSIONS: The present study demonstrates that visual BCI feedback clearly modulates sensorimotor EEG rhythms. When the feedback provides equivalent information on both the continuous and final outcomes of mental actions, the presentation form (abstract versus realistic) does not influence the performance in a BCI, at least in initial training sessions. SIGNIFICANCE: The present results are of practical interest for classifier development and BCI use in the field of motor restoration.

Differential effects of startle on reaction time for finger and arm movements.

Recent studies using a reaction time (RT) task have reported that a preprogrammed response could be triggered directly by a startling acoustic stimulus (115-124 dB) presented along with the usual "go" signal. It has been suggested that details of the upcoming response could be stored subcortically and are accessible by the startle volley, directly eliciting the correct movement. However, certain muscles (e.g., intrinsic hand) are heavily dependent on cortico-motoneuronal connections and thus would not be directly subject to the subcortical startle volley in a similar way to muscles whose innervations include extensive reticular connections. In this study, 14 participants performed 75 trials in each of two tasks within a RT paradigm: an arm extension task and an index finger abduction task. In 12 trials within each task, the regular go stimulus (82 dB) was replaced with a 115-dB startling stimulus. Results showed that, in the arm task, the presence of a startle reaction led to significantly shorter latency arm movements compared with the effect of the increased stimulus intensity alone. In contrast, for the finger task, no additional decrease in RT caused by startle was observed. Taken together, these results suggest that only movements that involve muscles more strongly innervated by subcortical pathways are susceptible to response advancement by startle.

Topography of attention in the primary visual cortex.

Previous research suggests that feedback circuits mediate the effect of attention to the primary visual cortex (V1). This inference is mainly based on temporal information of the responses, where late modulation is associated with feedback signals. However, temporal data alone are inconclusive because the anatomical hierarchy between cortical areas differs significantly from the temporal sequence of activation. In the current work, we relied on recent physiological and computational models of V1 network architecture, which have shown that the thalamic feedforward, local horizontal and feedback contribution are reflected in the spatial spread of responses. We used multifocal functional localizer and quantitative analysis in functional magnetic resonance imaging to determine the spatial scales of attention and sensory responses. Representations of 60 visual field regions in V1 were functionally localized and four of these regions were targets in a subsequent attention experiment, where human volunteers fixated centrally and performed a visual discrimination task at the attended location. Attention enhanced the peak amplitudes significantly more in the lower than in the upper visual field. This enhancement by attention spread with a 2.4 times larger radius (approximately 10 mm, assuming an average magnification factor) compared with the unattended response. The corresponding target region of interest was on average 20% stronger than that caused by the afferent sensory stimulation alone. This modulation could not be attributed to eye movements. Given the contemporary view of primate V1 connections, the activation spread along the cortex provides further evidence that the signal enhancement by spatial attention is dependent on feedback circuits.

Determination of the human brainstem respiratory control network and its cortical connections in vivo using functional and structural imaging.

This study combined functional and structural magnetic resonance imaging techniques, optimized for the human brainstem, to investigate activity in brainstem respiratory control centres in a group of 12 healthy human volunteers. We stimulated respiration with carbon dioxide (CO(2)), and utilized novel methodology to separate its vascular from its neuronal effects upon the blood oxygen level dependent (BOLD) signal. In the brainstem we observed activity in the dorsal rostral pons (representing the Kölliker-Fuse/parabrachial (KF/PB) nuclei and locus coeruleus), the inferior ventral pons and the dorsal and lateral medulla. These areas of activation correspond to respiratory nuclei identified in recent rodent studies. Our results also reveal functional participation of the anteroventral (AV), ventral posterolateral (VPL) ventrolateral thalamic nuclei, and the posterior putamen in the response to CO(2) stimulation, suggesting that these centres may play a role in gating respiratory information to the cortex. As the functional imaging plane was limited to the brainstem and adjacent subcortical areas, we employed diffusion tractography to further investigate cortical connectivity of the thalamic activations. This revealed distinct connectivity profiles of these thalamic activations suggesting subdivision of the thalamus with regards to respiratory control. From these results we speculate that the thalamus plays an important role in integrating respiratory signals to and from the brainstem respiratory centres.

Motor-induced suppression of the auditory cortex.

Sensory responses to stimuli that are triggered by a self-initiated motor act are suppressed when compared with the response to the same stimuli triggered externally, a phenomenon referred to as motor-induced suppression (MIS) of sensory cortical feedback. Studies in the somatosensory system suggest that such suppression might be sensitive to delays between the motor act and the stimulus onset, and a recent study in the auditory system suggests that such MIS develops rapidly. In three MEG experiments, we characterize the properties of MIS by examining the M100 response from the auditory cortex to a simple tone triggered by a button press. In Experiment 1, we found that MIS develops for zero delays but does not generalize to nonzero delays. In Experiment 2, we found that MIS developed for 100-msec delays within 300 trials and occurs in excess of auditory habituation. In Experiment 3, we found that unlike MIS for zero delays, MIS for nonzero delays does not exhibit sensitivity to sensory, delay, or motor-command changes. These results are discussed in relation to suppression to self-produced speech and a general model of sensory motor processing and control.

Reflexive and volitional voice fundamental frequency responses to an anticipated feedback pitch error.

The pitch-shift reflex is a corrective voice fundamental frequency (F0) response triggered by a sudden shift or "error" in auditory feedback pitch. We investigated how anticipating a voice pitch error affects the pitch-shift reflex and volitional voice F0 responses. Adults sustained the vowel/u/at a comfortable pitch and pressed a button to deliver a 100 cent, 100 ms auditory feedback pitch shift immediately or after a random delay. Pitch shift direction was either constant (up) or randomized (up or down). Onset anticipation often resulted in an anticipatory voice F0 change, but stimulus direction predictability did not affect the responses. When pitch error onset and direction were both anticipated, some participants produced an ideomotor voice F0 change that partially imitated the error, but they produced no apparent pitch-shift reflex. Results imply that when voice pitch errors are anticipated, volitional voice F0 responses may reduce or enhance voice F0 stability.

Mind the bend: cerebral activations associated with mental imagery of walking along a curved path.

The use of functional magnetic resonance imaging (fMRI) to examine mental imagery of locomotion has become an attractive way to investigate supraspinal gait control in humans. Whereas cerebral activation patterns associated with walking along a straight line have already been investigated, data on activations associated with the initiation of turns and the maintenance of a curved path are sparse. Electrophysiological findings in animals show that electrical stimulation of the striatum induces a contraversive turn of eyes, head, and body. In the present study, fMRI was used to investigate brain activity in 12 healthy volunteers during mental imagery of walking along a curved path, walking straight ahead, and upright stance. The major findings were as follows: (1) A shift of activation to the hemisphere contralateral to the turn was found in the putamen, and-for initiation of the turn-in the caudate nucleus. These findings confirm the important role of the striatum in the initiation of movement and the execution of contraversive body turns. (2) Parahippocampal and fusiform gyri, known to be involved in visually guided navigation, showed more activity when walking along a curved path than when walking straight ahead. (3) Deactivations were found in the superior and medial temporal gyri, areas belonging to the multisensory and vestibular cortical network. This reduced activity may reflect the suppression of vestibular signal processing in favour of-potentially conflicting-visual input. (4) Mental imagery of walking along a curved path induced ipsiversive eye movements in most subjects, as did actually walking along a curve. These data complement earlier findings on the role of anticipatory eye movements during initiation of turns and suggest that there is a very close neurophysiologic relation between locomotion and its mental imagery.

Motor preparation in an anticipation-timing task.

Previous findings from experiments involving anticipation-timing tasks have indicated that a point in time may exist after which a participant is committed to producing a pre-programmed movement. For example, if a "stop" signal is given too long after a "go" signal but prior to movement initiation, the response is often still produced. It has been suggested that a startling stimulus may act to elicit a pre-programmed response in reaction time (RT) tasks without involvement of the cerebral cortex (Valls-Solé et al. 1999). The present experiment employed a startling stimulus to investigate the temporal course of motor preparation during a stop-signal anticipation-timing task. Participants timed a key release coincident with the sweep of a clock hand reaching a target. On some trials, the clock hand stopped prior to reaching the target (meaning participants were to refrain from responding), which was accompanied by either a startling acoustic stimulus (124 dB) or control stimulus (82 dB). Results from startle trials indicate that while some advance preparation of motor circuits was evident, subcortical pre-programming and storage of the motor command in circuits common to the voluntary and startle response pathways was not completed well in advance of response production.

Reverberation challenges the temporal representation of the pitch of complex sounds.

Accurate neural coding of the pitch of complex sounds is an essential part of auditory scene analysis; differences in pitch help segregate concurrent sounds, while similarities in pitch can help group sounds from a common source. In quiet, nonreverberant backgrounds, pitch can be derived from timing information in broadband high-frequency auditory channels and/or from frequency and timing information carried in narrowband low-frequency auditory channels. Recording from single neurons in the cochlear nucleus of anesthetized guinea pigs, we show that the neural representation of pitch based on timing information is severely degraded in the presence of reverberation. This degradation increases with both increasing reverberation strength and channel bandwidth. In a parallel human psychophysical pitch-discrimination task, reverberation impaired the ability to distinguish a high-pass harmonic sound from noise. Together, these findings explain the origin of perceptual difficulties experienced by both normal-hearing and hearing-impaired listeners in reverberant spaces.

Embodied models of delayed neural responses: spatiotemporal categorization and predictive motor control in brain based devices.

In order to respond appropriately to environmental stimuli, organisms must integrate over time spatiotemporal signals that reflect object motion and self-movement. One possible mechanism to achieve this spatiotemporal transformation is to delay or lag neural responses. This paper reviews our recent modeling work testing the sufficiency of delayed responses in the nervous system in two different behavioral tasks: (1) Categorizing spatiotemporal tactile cues with thalamic "lag" cells and downstream coincidence detectors, and (2) Predictive motor control was achieved by the cerebellum through a delayed eligibility trace rule at cerebellar synapses. Since the timing of these neural signals must closely match real-world dynamics, we tested these ideas using the brain based device (BBD) approach in which a simulated nervous system is embodied in a robotic device. In both tasks, biologically inspired neural simulations with delayed neural responses were critical for successful behavior by the device.

Feedback from horizontal cells to rod photoreceptors in vertebrate retina.

Retinal horizontal cells (HCs) provide negative feedback to cones, but, largely because annular illumination fails to evoke a depolarizing response in rods, it is widely believed that there is no feedback from HCs to rods. However, feedback from HCs to cones involves small changes in the calcium current (I(Ca)) that do not always generate detectable depolarizing responses. We therefore recorded I(Ca) directly from rods to test whether they were modulated by feedback from HCs. To circumvent problems presented by overlapping receptive fields of HCs and rods, we manipulated the membrane potential of voltage-clamped HCs while simultaneously recording from rods in a salamander retinal slice preparation. Like HC feedback in cones, hyperpolarizing HCs from -14 to -54, -84, and -104 mV increased the amplitude of I(Ca) recorded from synaptically connected rods and caused hyperpolarizing shifts in I(Ca) voltage dependence. These effects were blocked by supplementing the bicarbonate-buffered saline solution with HEPES. In rods lacking light-responsive outer segments, hyperpolarizing neighboring HCs with light caused a negative activation shift and increased the amplitude of I(Ca). These changes in I(Ca) were blocked by HEPES and by inhibiting HC light responses with a glutamate antagonist, indicating that they were caused by HC feedback. These results show that rods, like cones, receive negative feedback from HCs that regulates the amplitude and voltage dependence of I(Ca). HC-to-rod feedback counters light-evoked decreases in synaptic output and thus shapes the transmission of rod responses to downstream visual neurons.

Functional evidence for internal feedback in the songbird brain nucleus HVC.

The song control system of songbirds consists mainly of the 'motor pathway' and 'anterior forebrain pathway'. The medial magnocellular nucleus of anterior nidopallium (mMAN) projects to the song control nucleus HVC, which is the point of divergence of the two pathways. We made simultaneous multiunit electrophysiological recordings from the mMAN and HVC in anesthetized Bengalese finches. We confirmed that the mMAN neurons showed song-selective auditory responses, and found temporal correlations between song-related activities of the mMAN and HVC neurons. The temporal relationship between the neural activation of the HVC and mMAN suggests that these nuclei are parts of a closed loop, which could provide internal feedback to the HVC for sequential syllable control.

Granger causality: cortico-thalamic interdependencies during absence seizures in WAG/Rij rats.

Linear Granger causality was used to identify the coupling strength and directionality of information transport between frontal cortex and thalamus during spontaneous absence seizures in a genetic model, the WAG/Rij rats. Electroencephalograms were recorded at the cortical surface and from the specific thalamus. Granger coupling strength was measured before, during and after the occurrence of spike-wave discharges (SWD). Before the onset of SWD, coupling strength was low, but associations from thalamus-to-cortex were stronger than vice versa. The onset of SWD was associated with a rapid and significant increase of coupling strength in both directions. There were no changes in Granger causalities before the onset of SWD. The strength of thalamus-to-cortex coupling remained constantly high during the seizures. The strength of cortex-to-thalamus coupling gradually diminished shortly after the onset of SWD and returned to the pre-SWD level when SWD stopped. In contrast, the strength of thalamus-to-cortex coupling remained elevated even after cessation of SWD. The strong and sustained influence of thalamus-to-cortex may facilitate propagation and maintenance of seizure activity, while rapid reduction of cortex-to-thalamus coupling strength may prompt the cessation of SWD. However, the linear estimation of Granger coupling strength does not seem to be sufficient for predicting episodes with absence epilepsy.