Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Long-range cortical dynamics: a perspective from the mouse sensorimotor whisker system.

In the mammalian neocortex, the capacity to dynamically route and coordinate the exchange of information between areas is a critical feature of cognitive function, enabling processes such as higher-level sensory processing and sensorimotor integration. Despite the importance attributed to long-range connections between cortical areas, their exact operations and role in cortical function remain an open question. In recent years, progress has been made in understanding long-range cortical circuits through work focused on the mouse sensorimotor whisker system. In this review, we examine recent studies dissecting long-range circuits involved in whisker sensorimotor processing as an entry point for understanding the rules that govern long-range cortical circuit function.

Skeletal muscle index based on CT at the 12th thoracic spine level can predict osteoporosis and fracture risk: a propensity score-matched cohort study.

Background: Multiple studies have shown that skeletal muscle index (SMI) measured on abdominal computed tomography (CT) is strongly associated with bone mineral density (BMD) and fracture risk as estimated by the fracture risk assessment tool (FRAX). Although some studies have reported that SMI at the level of the 12th thoracic vertebra (T12) measured on chest CT images can be used to diagnose sarcopenia, it is regrettable that no studies have investigated the relationship between SMI at T12 level and BMD or fracture risk. Therefore, we further investigated the relationship between SMI at T12 level and FRAX-estimated BMD and fracture risk in this study. Methods: A total of 349 subjects were included in this study. After 1∶1 propensity score matching (PSM) on height, weight, hypertension, diabetes, hyperlipidemia, hyperuricemia, body mass index (BMI), age, and gender, 162 subjects were finally included. The SMI, BMD, and FRAX score of the 162 participants were obtained. The correlation between SMI and BMD, as well as SMI and FRAX, was assessed using Spearman rank correlation. Additionally, the effectiveness of each index in predicting osteoporosis was evaluated through the receiver operating characteristic (ROC) curve analysis. Results: The BMD of the lumbar spine (L1-4) demonstrated a strong correlation with SMI (r = 0.416, p < 0.001), while the BMD of the femoral neck (FN) also exhibited a correlation with SMI (r = 0.307, p < 0.001). SMI was significantly correlated with FRAX, both without and with BMD at the FN, for major osteoporotic fractures (r = -0.416, p < 0.001, and r = -0.431, p < 0.001, respectively) and hip fractures (r = -0.357, p < 0.001, and r = -0.311, p < 0.001, respectively). Moreover, the SMI of the non-osteoporosis group was significantly higher than that of the osteoporosis group (p < 0.001). SMI effectively predicts osteoporosis, with an area under the curve of 0.834 (95% confidence interval 0.771-0.897, p < 0.001). Conclusion: SMI based on CT images of the 12th thoracic vertebrae can effectively diagnose osteoporosis and predict fracture risk. Therefore, SMI can make secondary use of chest CT to screen people who are prone to osteoporosis and fracture, and carry out timely medical intervention.

Gaze direction affects linear self-motion heading discrimination in humans.

We investigated the effect of eye-in-head and head-on-trunk direction on heading discrimination. Participants were passively translated in darkness along linear trajectories in the horizontal plane deviating 2° or 5° to the right or left of straight-ahead as defined by the subject's trunk. Participants had to report whether the experienced translation was to the right or left of the trunk straight-ahead. In a first set of experiments, the head was centered on the trunk and fixation lights directed the eyes 16° either left or right. Although eye position was not correlated with the direction of translation, rightward reports were more frequent when looking right than when looking left, a shift of the point of subjective equivalence in the direction opposite to eye direction (two of the 38 participants showed the opposite effect). In a second experiment, subjects had to judge the same trunk-referenced trajectories with head-on-trunk deviated 16° left. Comparison with the performance in the head-centered paradigms showed an effect of the head in the same direction as the effect of eye eccentricity. These results can be qualitatively described by biases reflecting statistical regularities present in human behaviors such as the alignment of gaze and path. Given the known effects of gaze on auditory localization and perception of straight-ahead, we also expect contributions from a general influence of gaze on the head-to-trunk reference frame transformations needed to bring motion-related information from the head-centered otoliths into a trunk-referenced representation.

Cortical gamma-band resonance preferentially transmits coherent input.

Synchronization has been implicated in neuronal communication, but causal evidence remains indirect. We use optogenetics to generate depolarizing currents in pyramidal neurons of the cat visual cortex, emulating excitatory synaptic inputs under precise temporal control, while measuring spike output. The cortex transforms constant excitation into strong gamma-band synchronization, revealing the well-known cortical resonance. Increasing excitation with ramps increases the strength and frequency of synchronization. Slow, symmetric excitation profiles reveal hysteresis of power and frequency. White-noise input sequences enable causal analysis of network transmission, establishing that the cortical gamma-band resonance preferentially transmits coherent input components. Models composed of recurrently coupled excitatory and inhibitory units uncover a crucial role of feedback inhibition and suggest that hysteresis can arise through spike-frequency adaptation. The presented approach provides a powerful means to investigate the resonance properties of local circuits and probe how these properties transform input and shape transmission.

Experience-dependent resonance in amygdalo-cortical circuits supports fear memory retrieval following extinction.

Learned fear and safety are associated with distinct oscillatory states in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). To determine if and how these network states support the retrieval of competing memories, we mimicked endogenous oscillatory activity through optogenetic stimulation of parvalbumin-expressing interneurons in mice during retrieval of contextual fear and extinction memories. We found that exogenously induced 4 Hz and 8 Hz oscillatory activity in the BLA exerts bi-directional control over conditioned freezing behavior in an experience- and context-specific manner, and that these oscillations have an experience-dependent ability to recruit distinct functional neuronal ensembles. At the network level we demonstrate, via simultaneous manipulation of BLA and mPFC, that experience-dependent 4 Hz resonance across BLA-mPFC circuitry supports post-extinction fear memory retrieval. Our findings reveal that post-extinction fear memory retrieval is supported by local and interregional experience-dependent resonance, and suggest novel approaches for interrogation and therapeutic manipulation of acquired fear circuitry.

Context-Dependent Sensory Processing across Primary and Secondary Somatosensory Cortex.

To interpret the environment, our brain must evaluate external stimuli against internal representations from past experiences. How primary (S1) and secondary (S2) somatosensory cortices process stimuli depending on recent experiences is unclear. Using simultaneous multi-area population imaging of projection neurons and focal optogenetic inactivation, we studied mice performing a whisker-based working memory task. We find that activity reflecting a current stimulus, the recollection of a previous stimulus (cued recall), and the stimulus category are distributed across S1 and S2. Despite this overlapping representation, S2 is important for processing cued recall responses and transmitting these responses to S1. S2 network properties differ from S1, wherein S2 persistently encodes cued recall and the stimulus category under passive conditions. Although both areas encode the stimulus category, only information in S1 is important for task performance through pathways that do not necessarily include S2. These findings reveal both distributed and segregated roles for S1 and S2 in context-dependent sensory processing.

In Vivo Magnetic Recording of Neuronal Activity.

Neuronal activity generates ionic flows and thereby both magnetic fields and electric potential differences, i.e., voltages. Voltage measurements are widely used but suffer from isolating and smearing properties of tissue between source and sensor, are blind to ionic flow direction, and reflect the difference between two electrodes, complicating interpretation. Magnetic field measurements could overcome these limitations but have been essentially limited to magnetoencephalography (MEG), using centimeter-sized, helium-cooled extracranial sensors. Here, we report on in vivo magnetic recordings of neuronal activity from visual cortex of cats with magnetrodes, specially developed needle-shaped probes carrying micron-sized, non-cooled magnetic sensors based on spin electronics. Event-related magnetic fields inside the neuropil were on the order of several nanoteslas, informing MEG source models and efforts for magnetic field measurements through MRI. Though the signal-to-noise ratio is still inferior to electrophysiology, this proof of concept demonstrates the potential to exploit the fundamental advantages of magnetophysiology.

Gamma-Rhythmic Gain Modulation.

Cognition requires the dynamic modulation of effective connectivity, i.e., the modulation of the postsynaptic neuronal response to a given input. If postsynaptic neurons are rhythmically active, this might entail rhythmic gain modulation, such that inputs synchronized to phases of high gain benefit from enhanced effective connectivity. We show that visually induced gamma-band activity in awake macaque area V4 rhythmically modulates responses to unpredictable stimulus events. This modulation exceeded a simple additive superposition of a constant response onto ongoing gamma-rhythmic firing, demonstrating the modulation of multiplicative gain. Gamma phases leading to strongest neuronal responses also led to shortest behavioral reaction times, suggesting functional relevance of the effect. Furthermore, we find that constant optogenetic stimulation of anesthetized cat area 21a produces gamma-band activity entailing a similar gain modulation. As the gamma rhythm in area 21a did not spread backward to area 17, this suggests that postsynaptic gamma is sufficient for gain modulation.

Dissociable modulation of overt visual attention in valence and arousal revealed by topology of scan path.

Emotional stimuli have evolutionary significance for the survival of organisms; therefore, they are attention-grabbing and are processed preferentially. The neural underpinnings of two principle emotional dimensions in affective space, valence (degree of pleasantness) and arousal (intensity of evoked emotion), have been shown to be dissociable in the olfactory, gustatory and memory systems. However, the separable roles of valence and arousal in scene perception are poorly understood. In this study, we asked how these two emotional dimensions modulate overt visual attention. Twenty-two healthy volunteers freely viewed images from the International Affective Picture System (IAPS) that were graded for affective levels of valence and arousal (high, medium, and low). Subjects' heads were immobilized and eye movements were recorded by camera to track overt shifts of visual attention. Algebraic graph-based approaches were introduced to model scan paths as weighted undirected path graphs, generating global topology metrics that characterize the algebraic connectivity of scan paths. Our data suggest that human subjects show different scanning patterns to stimuli with different affective ratings. Valence salient stimuli (with neutral arousal) elicited faster and larger shifts of attention, while arousal salient stimuli (with neutral valence) elicited local scanning, dense attention allocation and deep processing. Furthermore, our model revealed that the modulatory effect of valence was linearly related to the valence level, whereas the relation between the modulatory effect and the level of arousal was nonlinear. Hence, visual attention seems to be modulated by mechanisms that are separate for valence and arousal.

[Internal fixation with AO distal humerus plates for the treatment of distal humeral fractures in elderly osteoporotic patients].

OBJECTIVE: To study the clinical effects of AO distal humerus plate (DHP) for the treatment of distal humeral fractures in elderly osteoporotic patients. METHODS: From September 2008 to January 2010, 18 elderly osteoporotic patients with distal humeral fractures were treated with open reduction and internal fixation with DHP. There were 3 males and 15 females, ranging in age from 62 to 83 years (averaged, 71.4 years). According to AO classification, 1 patient was Type A2, 3 patients were Type A3; 2 patients were Type B1, 2 patients were Type B2; 3 patients were Type C1, 4 patients were Type C2, 3 patients were Type C3. The surgical approaches were either bilateral or via olecranon process of ulna. Early mobilization was initiated after surgery. Functional results were evaluated according to the Mayo elbow performance score (MEPS). RESULTS: The average duration of follow-up was 14.6 months (ranged from 11 to 24 months). All the patients had a complete healing of their fractures. There was no infection, hardware failure or loss of reduction after the operations. The average Mayo elbow performance score (MEPS) was (92.2 +/- 9.6) (65 to 100 points), among which the score of pain was (42.5 +/- 5.8) (30 to 45 points), the score of motion range was (19.2 +/- 1.9) (15 to 20 points), the score of stability was (9.2 +/- 1.9) (5 to 10 points), and the score of function was (21.4 +/- 2.9) (15 to 25 points). According to MEPS, 11 patients got excellent results, 5 good and 2 fair. CONCLUSION: Treatment of distal humeral fractures in elderly osteoporotic patients with AO distal humeral plates can obtain immediate stabilization which facilitates early mobilization of the elbow.

[Effective analysis of percutaneous reduction and Kirschner pin fixation for the treatment of intraarticular fractures of the calcaneus in children].

OBJECTIVE: To introduce and evaluate the clinical effects of percutaneous reduction and Kirschner pin fixation for the treatment of intraarticular fractures of the calcaneus in children. METHODS: From March 2001 to February 2009,12 patients with intraarticular calcaneal fractures were treated by percutaneous reduction and Kirschner pin fixation (13 feet). There were 8 males and 4 females,ranging in age from 3 to 14,with an average of 8.7 years. According to Essex-Lopresti classification, among 5 feet were tongue fractures and 8 feet were compressed fractures. According to Sanders classification, 9 feet were type II and 4 feet were type III. The Biihler angle and Gissane angle of the calcaneus were obtained before and after operation. All patients were evaluated according to Maryland Foot Score. RESULTS: All the patients were followed up for 16-71 months (means 35.9 months),and all the incisions were healed without complications and infection. The preoperative X-ray film showed that Böhler angle was (19.7+/-5.3) degrees, Gissane angle was (137.3+/-7.5) degrees. The postoperative X-ray film demonstrated that Böhler angle was (32.6+/-3.7) degrees, Gissane angle was (125.4+/-2.9) degrees. There was a significant difference between preoperative and postoperative (P<0.01). The average Maryland score was 96.3+/-2.4 (range, 92 to 100 points). CONCLUSION: Percutaneous reduction and Kirschner pin fixation is an effective minimally invasive way to treat intraarticular fractures of the calcaneus in children, it has many advantages such as minimal invasion, reliable fixation and satisfactory effects.