Evidence for a causal inverse model in an avian cortico-basal ganglia circuit

Learning by imitation is fundamental to both communication and social behavior and requires the conversion of complex, nonlinear sensory codes for perception into similarly complex motor codes for generating action. To understand the neural substrates underlying this conversion, we study sensorimotor transformations in songbird cortical output neurons of a basal-ganglia pathway involved in song learning. Despite the complexity of sensory and motor codes, we find a simple, temporally specific, causal correspondence between them. Sensory neural responses to song playback mirror motor-related activity recorded during singing, with a temporal offset of roughly 40 ms, in agreement with short feedback loop delays estimated using electrical and auditory stimulation. Such matching of mirroring offsets and loop delays is consistent with a recent Hebbian theory of motor learning and suggests that cortico-basal ganglia pathways could support motor control via causal inverse models that can invert the rich correspondence between motor exploration and sensory feedback.The brain has evolved diverse strategies for combining sensory and motor signals, a prerequisite for many complex behaviors including hunting, communication, and observational learning of motor skills. For example, to accurately sense the external world while simultaneously moving within it, the nervous system must be able to detect changes in its sensory inputs that are not a predictable consequence of self-motion. Indeed, many sensory neurons respond with high sensitivity to unpredictable stimuli during motor behavior despite self-caused sensory feedback (1–5). Such remarkable sensitivity can be achieved by circuit mechanisms that counteract sensory feedback associated with self-generated motor output (6). Such mechanisms are also known as corollary discharges (7) or forward models of the motor system (8), which are synaptic mappings from motor neurons onto sensory neurons that can either predict or suppress sensory feedback from self-generated motor output.In contrast to our understanding of how the brain cancels predictable, motor-induced sensory feedback, much less is known about neural mechanisms for computing motor codes that produce desired sensory targets. However, the ability to learn to produce desired behaviors by observing others is considered to be a key advantage of sociality and a main driver for the evolution of culture (9, 10). Learning by imitation occurs spontaneously when humans learn to speak, parrots imitate surrounding sounds (11), or songbirds learn to imitate a tutor’s song (12). However, insights into the neural implementation of sensory-guided motor learning remain sparse, largely because we lack empirical information about the principles underlying the flow of neural activity through synaptic mappings from sensory to motor areas. Such mappings are known as inverse models and flow in the opposite direction of forward models that direct motor activity to sensory areas.To learn about principles of sensorimotor integration in the zebra finch, a vocal learner, we focus our attention on cortical premotor nuclei necessary for song production and song learning. The premotor area HVC is involved in generating the stereotyped song motifs of adult birds (13), whereas the lateral magnocellular nucleus of the anterior nidopallium (LMAN) forms the output of a basal-ganglia pathway involved in generating subtle song variability (14–17). HVC neurons produce highly stereotyped firing patterns during singing (18, 19), whereas LMAN neurons produce highly variable patterns (15, 20, 21).To gain insights into LMAN’s role in motor control, we consider recent theoretical work that establishes a conceptual link between inverse models and vocal-auditory mirror neurons (22–24). We consider three (nonexhaustive) possibilities about the flow of sensory information into motor areas. First, auditory afferents with some feature sensitivity could map onto motor neurons involved in generating those same features (Fig. 1A). This mapping forms a causal inverse, in which a sensory target input generates a motor activity pattern required to cause, or generate that same sensory target. Second, auditory afferents with some feature sensitivity could map onto motor neurons that typically fire after the ones involved in generating those features (Fig. 1B). This mapping forms a predictive inverse, in which a sensory input at some point in a stereotyped acoustic sequence elicits a predictive motor activity pattern required to generate the next acoustic signal in that sequence. Third, the auditory-to-motor connections could be randomly wired (Fig. 1C), in which case there would be no regularity in the relationship between sensory and motor responses.Open in a separate windowFig. 1.Three hypothetical sensorimotor mappings and associated mirroring offsets. Sensory-to-motor mappings could implement a causal inverse of the motor plan (A), a predictive inverse (B), or be random (C). Under a causal inverse, generated by variable sequences of song features (ABC-CBA), a spike burst in a motor neuron (neuron 2) triggers the production (black arrow) of a song feature (feature B) after latency , and the neuron receives sensory feedback (thick green arrow) from that same feature after an additional latency . In such a neuron, we expect to see a cross-covariance (CC) peak (red arrow) between singing-related and playback-evoked spike bursts (black vertical bars) at a time lag (the so-called mirroring offset, red horizontal bar) given by the delay of the sensorimotor loop . Under a predictive inverse (B), generated by stereotyped sequences of song features (ABC-ABC), the motor neuron 2 again triggers song feature B, but at the same time receives reliable feedback from the previous song feature A (thick green arrow). Thus, we expect to see a CC peak at a time lag much smaller than the sensorimotor loop delay . Finally, under a random sensory-to-motor mapping (C), we expected no CC between the motor- and sensory-evoked firing.Rather than directly characterize the auditory-to-motor mapping (a daunting task), we probe this mapping indirectly by studying the neural responses it causes in experiments in which we compare auditory responses elicited by playback of the bird’s own song (BOS) to motor responses recorded during production of these songs. Indeed, the three possibilities in Fig. 1 make specific, testable predictions at the level of single neurons. Consider for example a motor neuron downstream of a causal inverse model (i.e., neuron 2 in Fig. 1A). This motor neuron generates song feature B after a motor latency . Now, when the bird is not singing, this motor neuron also has a sensory selectivity for song feature B (because it is downstream of a causal inverse model). Therefore, during song playback, this same motor neuron will fire after playback of song feature B with an auditory latency . Thus, if one temporally aligns both the playback-evoked spike train and the singing-related spike train with the onset of song, the playback train will lag, or mirror the singing related train by a mirroring offset equal to the sensorimotor loop delay . In more subtle scenarios in which the motor neuron has selectivity for multiple acoustic features, or is subject to greater degrees of noise, this temporal alignment between the motor and sensory responses of the neuron can still be detected through the position of a peak in the cross-covariance function (CC function) between the playback and singing related spike trains both time-aligned to song (Fig. 1A, Lower), even when the offset may not be visually apparent by simply looking at spike trains (see SI Methods and Fig. S1 for a theory of the CC function in the case of multiple latency auditory responses).Conversely, consider a motor neuron downstream of a predictive inverse model (i.e., neuron 2 in Fig. 1B). Just as before, the neuron generates song feature B with a latency . However, because it is downstream of a predictive inverse model, when the bird is not singing, this neuron now has a sensory selectivity for the previous song feature, A. This selectivity occurs because a predictive inverse model takes a sensory stimulus, in this case song feature A, and generates a motor command for the next feature, in this case song feature B. Thus, when aligned to song, the playback spike occurs after syllable A while the singing related spike occurs before song feature B. The result is that the mirroring offset will be much smaller than the total sensorimotor loop delay , and the peak in the CC function will be much closer to zero time lag. Finally, in the random scenario in Fig. 1C, we expect no pronounced peak in the CC function.In theory, whether to expect a causal or predictive inverse depends on the sequence stereotypy of produced song features (23, 24). What are those features? A song feature could be a song syllable, in which case the sequence of features is stereotyped because adult zebra finches sing stereotyped syllable sequences ABC-ABC (Fig. 1B). Stereotyped song sequences are generated mainly by stereotyped firing patterns in HVC, and according to previous theory (23, 24), we expect a predictive inverse and its associated signature of small mirroring offsets, to arise in HVC.Alternatively, a song feature could be a brief pitch increase or decrease, in which case the features and their variable sequences (ABC, DBA; Fig. 1A) are mainly generated by variable LMAN firing patterns. Accordingly, we expect to find a causal inverse upstream of LMAN (23, 24). Indeed, in HVC neurons the mirroring offset between motor-related spiking and song-playback evoked spiking is less than 10 ms (25), much less than the roughly 40-ms loop delay of HVC estimated using electrical stimulation of HVC and using auditory stimulation of the ear (26–31). By contrast, mirroring offsets in LMAN have not been quantified yet, leaving it open as to whether they provide evidence for causal inverses.     

Impact of glucagon-like peptide-1 on myocardial glucose metabolism revisited

The gut hormone glucagon-like peptide-1 (GLP-1) is an insulinotropic incretin with significant cardiovascular impact. Two classes of medication, GLP-1 analogues and DPP-4 inhibitors, have been developed that circumvent the rapid degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4), both enhance the incretin effect and were developed for the treatment of type 2 diabetes. Several mechanisms suggesting that DPP-4 inhibitors, GLP-1, and analogues could have a protective effect on the cardiovascular risk profile have been forwarded; e.g., reductions of blood glucose, body weight, blood pressure, improvement in left ventricular ejection fraction, myocardial perfusion, atherosclerosis development, and endothelial function. Despite this, the reasons for a decreased risk of developing cardiovascular disease and reduced post-ischaemia damage are still poorly understood. The potentially beneficial effect of GLP-1 stimulation may rely on, among others, improved myocardial glucose metabolism. This review focuses on the dogma that GLP-1 receptor stimulation may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency, by increasing myocardial glucose uptake. The published literature was systematically reviewed and the applied models evaluated since the outcomes of varying studies differ substantially. Reports on the effect of GLP-1R stimulation on myocardial metabolism are conflicting and should be evaluated carefully. There is limited and conflicting information on the impact of these agents in real life patients and while clinical outcome studies investigating the cardiovascular effects of GLP-1 based therapies have been initiated, the first two studies, both on DPP-4 inhibitors, designed specifically to evaluate cardiac safety reported largely neutral outcomes.     

Biochemical markers of bone metabolism reflect osteoclastic and osteoblastic activity in multiple myeloma

In order to evaluate the use of recently developed assays of bone metabolism in multiple myeloma we performed a histomorphometric study of bone biopsies in 16 myeloma patients. Furthermore, we measured the levels of interleukin-6 (IL-6), soluble IL-6 receptor (IL-6sR), IL-1beta, tumour necrosis factor (TNF) alpha, TNFbeta, and transforming growth factor (TGF) beta in marrow plasma aspirated from the biopsy area. MARKERS OF BONE RESORPTION: The N-terminal telopeptide of collagen I (Ntx) in urine showed a strong positive correlation with the dynamic histomorphometric indices of bone resorption (r=0.68-0.72). Slightly weaker correlations were observed between the dynamic indices of bone resorption and the C-terminal telopeptide of collagen I (ICTP) in serum (r= 0.57-0.62) and deoxypyridinoline (Dpyr) in urine (r= 0.54), whereas urinary pyridinoline (Pyr) did not correlate with the histomorphometric findings. MARKERS OF BONE FORMATION: Serum C-terminal propeptide of procollagen I (PICP) and serum bone-specific alkaline phosphatase (bAP) showed significant correlations with the dynamic parameters of bone formation (r=0.57-0.58), whereas serum osteocalcin and serum total AP did not. CYTOKINES: Highly significant correlations were observed between marrow IL-6 and rates of bone resorption and activation frequency (r=0.76-0.82) and with serum ICTP (r=0.63). Minor, but also significant correlations were observed between the resorptive indices and IL-6sR and IL-1beta. The data indicate that measurements of the biochemical markers of bone metabolism may be useful in monitoring myeloma bone disease, and might thus be of use for dose titration of bisphosphonate therapy.     

Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study

OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA. METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study. RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%). CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.     

Intrathecal morphine is superior to intravenous PCA in patients undergoing minimally invasive cardiac surgery

Aim of our study was to evaluate the beneficial effect of low dose intrathecal morphine on postoperative analgesia, over the use of intravenous patient controlled anesthesia (PCA), in patients undergoing fast track anesthesia during minimally invasive cardiac surgical procedures. A randomized controlled trial was undertaken after approval from local ethical committee. Written informed consent was obtained from 61 patients receiving mitral or tricuspid or both surgical valve repair in minimal invasive technique. Patients were assigned randomly to 2 groups. Group 1 received general anesthesia and intravenous patient controlled analgesia (PCA) pump with Piritramide (GA group). Group 2 received a single shot of intrathecal morphine (1.5 μg/kg body weight) prior to the administration of general anesthesia (ITM group). Site of puncture was confined to lumbar (L1-2 or L2-3) intrathecal space. The amount of intravenous piritramide used in post anesthesia care unit (PACU) and the first postoperative day was defined as primary end point. Secondary end points included: time for tracheal extubation, pain and sedation scores in PACU upto third postoperative day. For statistical analysis Mann-Whitney-U Test and Fishers exact test (SPSS) were used. We found that the demand for intravenous opioids in PACU was significantly reduced in ITM group (P <0.001). Pain scores were significantly decreased in ITM group until second postoperative day (P <0.01). There was no time delay for tracheal extubation in ITM group, and sedation scores did not differ in either group. We conclude that low dose single shot intrathecal morphine provides adequate postoperative analgesia, reduces the intravenous opioid consumption during the early postoperative period and does not defer early extubation.     

Feather Pecking in Domestic Fowl is Genetically Related to Locomotor Activity Levels: Implications for a Hyperactivity Disorder Model of Feather Pecking

Feather pecking is a major welfare problem in egg production. Genetic lines differing in the level of feather pecking have been developed by genetic selection. In two experiments correlated responses in locomotor activity were investigated. Firstly, general locomotor activity was estimated using electronic transponders. A total of 325 pullets from three lines: an unselected control line (CON), a line selected for low levels of feather pecking (LFP) and a line selected for high levels of feather pecking (HFP) during 6 generations, were reared in mixed line groups and activity was recorded from 13 to 17 weeks of age using antennas placed in the litter. Locomotor activity was significantly higher in the HFP and significantly lower in the LFP compared to the CON line (lsmeans 0.72 vs. 0.62 vs. 0.57 records per hen per h for HFP, CON and LFP respectively). In a second experiment locomotion was recorded in 40 chickens from the LFP and the HFP line at 5 weeks of age during day time from 09.00 to 16.00 h using a very precise computer facilitated tracking system. Distance travelled was found to be significantly higher in the high feather pecking line compared to the low feather pecking line (lsmeans 122 vs. 99 m per hour in HFP and LFP respectively). These results are discussed in relation to the ontogeny of feather pecking and a hyperactivity disorder model of feather pecking is suggested. Edited by Stephen Maxson.     

Hormone replacement therapy prevents osteoclastic hyperactivity: A histomorphometric study in early postmenopausal women.

In a randomized, double blind, clinical prospective trial comprising 35 women treated with either hormone replacement therapy (HRT) (cyclic estradiol/norethisterone acetate) or placebo we performed histomorphometric studies on paired bone biopsies obtained before and after 2 years of treatment. Untreated women developed a progressively more negative balance at individual bone multicellular units (BMUs) (i.e., wall thickness-erosion depth) (2.2 +/- 1.7 microm vs. -5.7 +/- 1.4 microm; p < 0.01), while women on HRT displayed preservation of bone balance (2.4 +/- 2.4 microm vs. 2.5 +/- 2.5 microm; NS). No significant differences in wall thickness between the two groups were demonstrable, but the untreated women developed a pronounced increase in erosion depth over 2 years (46.9 +/- 1.8 microm vs. 52.0 +/- 1.9 microm; p < 0.05), while the HRT group revealed no change (47.8 +/- 2.7 microm vs. 44.6 +/- 1.7 microm; NS). Furthermore, the placebo group displayed an increased osteoclastic erosion depth (17.8 +/- 1.6 microm vs. 25.0 +/- 1.7 microm; p < 0.001), compared with unchanged values in the HRT group (20.0 +/- 1.6 microm vs. 16.9 +/- 1.4 microm/day; NS). While the placebo group revealed a slight increase in volume referent resorption rate (35 +/- 8% vs. 38 +/- 8%; NS) the HRT group revealed a pronounced decrease (46 +/- 8% vs. 28 +/- 5%; p < 0.05). No significant changes in marrow star volume (an index of trabecular perforations) were demonstrable in either group. Our results demonstrate that bone remodeling in early postmenopausal women is characterized by progressive osteoclastic hyperactivity, which is reduced by cyclic HRT. This reduction of resorptive activity at the BMU level after HRT seems to precede the reduction in activation frequency demonstrated in previous studies on older postmenopausal women.