Low-frequency stimulation enhances burst activity in cortical cultures during development

The intact brain is continuously targeted by a wealth of stimuli with distinct spatio-temporal patterns which modify, since the very beginning of development, the activity and the connectivity of neuronal networks. In this paper, we used dissociated neuronal cultures coupled to microelectrode arrays (MEAs) to study the response of cortical neuron assemblies to low-frequency stimuli constantly delivered over weeks in vitro. We monitored the spontaneous activity of the cultures before and after the stimulation sessions, as well as their evoked response to the stimulus. During in vitro development, the vast majority of the cultures responded to the stimulation by significantly increasing the bursting activity and a widespread stabilization of electrical activity was observed after the third week of age. A similar trend was present between the spontaneous activity of the networks observed over 30 min after the stimulus and the responses evoked by the stimulus itself, although no significant differences in spontaneous activity were detected between stimulated and non-stimulated cultures belonging to the same preparations. The data indicate that the stimulation had a delayed effect modulating responsiveness capability of the network without directly affecting its intrinsic in vitro development.     

Reprogramming of grip aperture in a double-step virtual grasping paradigm

 The present study investigated the control of manual prehension movements in humans. Subjects grasped luminous virtual discs with the thumb and index finger, and we recorded the instantaneous grip aperture, defined as the 3-D distance between the thumb and index finger. Target size could remain constant (single-step trials) or unexpectedly change shortly after target appearance (double-step trials). In single-step responses, grip aperture varied throughout the movement in a consistent fashion. Double-step responses exhibited distinct corrective modifications, which followed the target change with a latency similar to the normal reaction time. This suggests that visual size information has a fast and continuous access to the processes involved in grip formation. The grip-aperture profiles of single-step responses had a different shape when the target called for an increase than when it called for a decrease in the initial finger distance. The same asymmetry was observed for aperture corrections in double-step trials. These findings indicate that increases and decreases of grip aperture are controlled through separate processes, engaged equally by the appearance and by the size change of a target. Corrections of grip aperture in double-step trials had a higher peak velocity and reached their maximum as well as their final value earlier than the aperture profiles of single-step trials. Nevertheless, the total duration of double-step trials was prolonged. These response characteristics did not fit with either of the three corrective strategies previously proposed for double-step pointing movements, which could indicate that grasping and pointing movements are controlled by different mechanisms. However, more data are needed to substantiate this view. Received: 20 April 1998 / Accepted: 28 October 1998     

The resting brain and our self: self-relatedness modulates resting state neural activity in cortical midline structures

The resting brain shows high neural activity in various regions, the default-mode network, chief among them the cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures' degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus's degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness.     

Motor cortical activity in a memorized delay task

Summary Two rhesus monkeys were trained to move a handle on a two-dimensional (2D) working surface in directions specified by a light at the plane. They first captured with the handle a light on the center of the plane and then moved the handle in the direction indicated by a peripheral light (cue signal). The signal to move (go signal) was given by turning off the center light. The following tasks were used: (a) In the non-delay task the peripheral light was turned on at the same time as the center light went off. (b) In the memorized delay task the peripheral light stayed on for 300 ms and the center light was turned off 450–750 ms later. Finally, (c) in the non-memorized delay task the peripheral light stayed on continuously whereas the center light went off 750–1050 ms after the peripheral light came on. Recordings in the arm area of the motor cortex (N= 171 cells) showed changes in single cell activity in all tasks. In both delay tasks, the neuronal population vector calculated every 20 ms after the onset of the peripheral light pointed in the direction of the upcoming movement, which was instructed by the cue light. Moreover, the strength of the population signal showed an initial peak shortly after the cue onset in both the memorized and non-memorized delay tasks but it maintained a higher level during the memorized delay period, as compared to the non-memorized task. These results indicate that the motor cortex is involved in encoding and holding in memory directional information concerning a visually cued arm movement and that these processes can be visualized using neuronal population vector analysis.     

A comparison of stimulus synchronous activity in the primary motor cortices of athletes and non-athletes

In this study, we measured primary motor cortex (MI) activity during a reaction time task to examine the appearance of MI activity that synchronized with the stimulus presentation (stimulus synchronous MI activity, SSMA). Because brain activity was expected to be enhanced by the repetitive/extensive activation, we hypothesized that the SSMA would be more clearly observable in athletes who were trained to perform reactive movements than in non-athletes. MI activity was measured in ten athletes and ten non-athletes by magnetoencephalography. The tasks were a simple reaction task and a Go/Nogo reaction task in which the subjects were asked to abduct their right index fingers in response to a visual stimulus. The Go/Nogo reaction time task was adopted to confirm the presence of the SSMA, because the MI activity in response to a Nogo stimulus did not overlap with the MI activity that was synchronous with the execution of the movement. The results show that the SSMA was clearly apparent in the athlete group (9/10). In the non-athlete group, however, only three subjects showed the SSMA (3/10). Moreover, the MI activity of the athletes tended to be larger than that of the non-athletes, even though the athletes did not specifically practice these index finger movements during their daily training. We concluded that long-term physical training promotes MI activity and the effects of reactive task repetition were more clearly apparent in the MI activity of the athletes.     

Effects of hand movement path on motor cortical activity in awake,behaving rhesus monkeys

Summary Neuronal activity was studied in the primary (M1), supplementary (M2), dorsal premotor (PMd), and ventral premotor (PMv) cortex of awake, behaving rhesus monkeys. The animals performed forelimb movements to three targets, each approached by three different types of trajectories. With one trajectory type, the monkey moved its hand straight to the target, with another, the path curved in a clockwise direction, and with a third, the path curved in a counter-clockwise direction. We examined whether neuronal activity in these areas exclusively reflects a hand movement's net distance and direction or, alternatively, whether other factors also influence cortical activity. It was found that neuronal activity during all phases of a trial reflects aspects of movement in addition to target location. Among these aspects may be selection of an integrated motor act from memory, perhaps specifying the entirety of a path by which the hand moves to a target.     

Long-term motor practice induces practice-dependent modulation of movement-related cortical potentials (MRCP) preceding a self-paced non-dominant handgrip movement in kendo players

Effects of long-term motor practice on movement-related brain activities were investigated by measuring from the scalp, movement-related cortical potentials (MRCP) associated with self-paced right (dominant) and left (non-dominant) brisk handgrip movements with a 20% maximal voluntary contraction (MVC) in 8 elite kendo players (kendo group) and 8 healthy young adults (control group). The kendo players had engaged in regular practice since childhood. Three components of MRCP were obtained from all subjects. These components relating to the preparation (Bereitschaftspotential: BP and negative slope: NS′) and initiation (motor potential: MP) of the movements were compared between the two groups. The BP onset time for a non-dominant handgrip task was significantly earlier in the control group than in the kendo group. Moreover, BP onset time appeared significantly earlier preceding the non-dominant handgrip task as compared with the dominant one only in the control group. Furthermore, MP amplitudes in the kendo group were significantly larger than in the control group. These findings suggest that long-term motor practice affects brain activities, leading to practice-dependent modulations in the cortical areas involved in the preparation and initiation of self-paced non-dominant handgrip movements in kendo players.     

Vascular endothelial growth factor‐C modulates cortical NMDA receptor activity in cortical lesions of young patients and rat model with focal cortical dysplasia

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor‐C (VEGF‐C) and corresponding receptors VEGFR‐2, VEGFR‐3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF‐C, VEGFR‐2, and VEGFR‐3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF‐C, VEGFR‐2 and VEGFR‐3 was located in the micro‐columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked‐EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor‐ and AMPA receptor‐mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X‐ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF‐C, however, could be antagonized by ki8751, the blocker of VEGFR‐2. These results suggest that VEGF‐C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor–mediated currents.     

The process of learning a tool-use movement in monkeys, with special reference to vision

Monkeys learned to use forceps to pick up food. The learning progressed in two stages. After having understood the task to have to use forceps through guidance, they (1) brought forceps toward food without seeing food until it was reached (1st stage), and (2) made forceps reach accurately to food using vision (2nd stage). We suggest that the learning without vision was a process of incorporating grasped-forceps into the body-scheme, thus enabling reaching with the extension (forceps) to a certain place in space. Using vision at the final stage was to precisely reach and to pick up food with the extension.     

Effects of bromazepam in frontal theta activity on the performance of a sensorimotor integration task: A quantitative electroencephalography study

Our objective is to verify the modulatory effects of bromazepam on EEG theta absolute power when subjects were submitted to a visuomotor task (i.e., car driver task). Sample was composed of 14 students (9 males and 5 females), right handed, with ages varying between 23 and 42 years (mean = 32.5 ± 9.5), absence of mental or physical impairments, no psychoactive or psychotropic substance use and no neuromuscular disorders (screened by a clinical examination). The results showed an interaction between condition and electrodes (p = 0.034) in favor of F8 electrode compared with F7 in both experimental conditions (t-test; p = 0.001). Additionally, main effects were observed for condition (p = 0.001), period (p = 0.001) and electrodes (p = 0.031) in favor of F4 electrode compared with F3. In conclusion, Br 6 mg of bromazepam may interfere in sensorimotor processes in the task performance in an unpredictable scenario allowing that certain visuospatial factors were predominant. Therefore, the results may reflect that bromazepam effects influence the performance of the involved areas because of the acquisition and integration of sensory stimuli processes until the development of a motor behavior based on the same stimuli.     

Programming the duration of a motor sequence: role of the primary and supplementary motor areas in man

Event-related potentials were recorded in a reaction time (RT) paradigm, where the duration of a learned interval (either 0.7 s or 2.5 s) delimited by two brief button-presses was to be accurately controlled. A preparatory signal (PS) either did not give or gave prior information concerning the duration of the following response (neutral condition or primed conditions, respectively). In the latter case, the information was either validated (valid condition) or invalidated (invalid condition) by the response signal (RS). When duration was not known in advance (invalid and neutral conditions), RTs were longer before a response of short than long duration. This difference was not found under the valid condition. During the preparatory period (PP), the amplitude of the contingent negative variation (CNV) was larger when the duration was primed than when it was not. A larger CNV appeared when the PS primed a short rather than a long duration. This effect occurred in the early part of the PP over the supplementary motor area (SMA) and in its latest part over the primary motor area (MI). The RT and the electrophysiological pattern were interpreted as revealing the occurrence of programming operations regarding the temporal dimension of the response. The time course of the CNV over the SMA and MI suggested that these two areas were hierarchically organized. Between the RS and the onset of the response, differences probably related to programming effects were still found over MI: the activities were larger under the valid than under the neutral condition. However, no sign of deprogramming (expected in the invalid condition) was observed: similar amplitudes were found under the neutral and invalid conditions. Deprogramming operations seemed to be postponed during response execution where the invalid condition evoked larger activities than the two other conditions over the SMA. Finally, MI but not the SMA yielded a Bereitschaftpotential before the second press ending the response (i.e., during response execution). These results suggest that the duration of a motor response can be a part of the motor program and that the SMA plays a major role in programming processes but not in response execution, contrary to MI.     

Participation of primary motor cortical neurons in a distributed network during maze solution: representation of spatial parameters and time-course comparison with parietal area 7a

Traditionally, primary motor cortex (M1) has been thought to be involved solely in planning and generating movements. Recent evidence suggests that the arm area of M1 plays a role in other functions, such as the representation of serial order (Pellizzer et al. 1995, Science 269:702–705; Carpenter et al. 1999, Science 283:1752–1757) and spatial processing (Georgopoulos et al. 1989, Science 243:234–236). Previous studies of such cognitive processes have used tasks in which a directed arm movement was required, raising a question as to whether this brain area is involved in cognitive processing per se, or whether such cognitive signals may be gated into the arm area of M1 only when arm movements are required. To study this question, we developed a task that required a spatial analysis of a complex visual stimulus, but required no arm movement as a response. In this task, monkeys were shown an octagonal maze. After an imposed delay of 2 to 2.5 s, they indicated whether a path that emanated from the center of the maze exited at the perimeter (exit maze) or terminated within the maze (no-exit maze) by pressing a pedal with their left or right foot, respectively. We recorded from 785 cells from the arm area of M1 from two monkeys during the delay period of the maze task. We found that cell activity was influenced by both the exit status and the direction of the path, beginning soon after the maze was displayed. This activity was not related to the activation of arm muscles, suggesting that the directional signals observed represented abstract spatial aspects of maze processing. Finally, we compared maze-related activity of M1 neurons with those recorded from posterior parietal area 7a, reported previously (Crowe et al. 2004). Interestingly, cells from each area exhibited similar properties. Both the exit status and path direction were encoded by cells in M1 and 7a, although to different extents. An analysis of the time-course of the neural representation of these factors revealed that area 7a and M1 begin to encode these factors at the same time, suggesting these brain areas are part of a distributed system performing the spatial computations involved in maze solution.     

Simultaneous constraints on pre- and post-synaptic cells couple cortical feature maps in a 2D geometric model of orientation preference.

The most prominent feature of mammalian striate cortex (V1) is the spatial organization of response preferences for the position and orientation of elementary visual stimuli. Models for the formation of cortical maps of orientation and 'retinotopic' position typically rely on a combination of Hebbian or correlation-based synaptic plasticity, and constraints on the distribution of synaptic weights. We consider a simplified model of orientation and retinotopic specificity based on the geometry of the feed-forward synaptic weight distribution from an 'unoriented' layer of cells to a first weakly oriented layer. We model the feed-forward weight distribution as a system of planar Gaussian receptive fields each elongated in the direction matching the preferred orientation of the postsynaptic cell. Under the constraint of presynaptic weight normalization (each cell in the oriented layer receives the same net synaptic weight) and a uniform retinotopic map (displacement of centres of mass of receptive fields in the unoriented layer is strictly proportional to the displacement of the corresponding cells in the oriented layer), we find that imposing a pattern of orientation preference forces the system to violate postsynaptic weight normalization (each cell in the unoriented layer no longer sends forth the same net synaptic weight). We study this deviation from uniformity of the postsynaptic weight, and find that the deviation has a distinct form in the vicinity of the 'pinwheel' singularities of the orientation map. We show that uniform synaptic coverage of the unoriented layer can be restored by introducing a distortion in the retinotopic locations of the receptive fields. We calculate, to first order in the relative elongation of the receptive fields, the retinotopic distortion vector field. Both the pattern of postsynaptic weight non-uniformity and the corrective retinotopic distortion vector field fail to possess the reflection symmetry commonly assumed to relate orientation singularities with topological index +/- pi. Hence, we show that 'right-handed' and 'left-handed' orientation singularities are funda-mentally distinct anatomical structures when full 2D synaptic architecture is taken into account. Finally, we predict specific patterns of retinotopic distortion that should obtain in the vicinity of +/- pi-fold orientation singularities, if uniform pre- and post-synaptic weight constraints are strongly enforced.     

Identification,analysis, and interpretation of a human serum metabolomics causal network in an observational study

Untargeted metabolomics, measurement of large numbers of metabolites irrespective of their chemical or biologic characteristics, has proven useful for identifying novel biomarkers of health and disease. Of particular importance is the analysis of networks of metabolites, as opposed to the level of an individual metabolite. The aim of this study is to achieve causal inference among serum metabolites in an observational setting. A metabolomics causal network is identified using the genome granularity directed acyclic graph (GDAG) algorithm where information across the genome in a deeper level of granularity is extracted to create strong instrumental variables and identify causal relationships among metabolites in an upper level of granularity.Information from 1,034,945 genetic variants distributed across the genome was used to identify a metabolomics causal network among 122 serum metabolites. We introduce individual properties within the network, such as strength of a metabolite. Based on these properties, hypothesized targets for intervention and prediction are identified. Four nodes corresponding to the metabolites leucine, arichidonoyl-glycerophosphocholine, N-acyelyalanine, and glutarylcarnitine had high impact on the entire network by virtue of having multiple arrows pointing out, which propagated long distances. Five modules, largely corresponding to functional metabolite categories (e.g. amino acids), were identified over the network and module boundaries were determined using directionality and causal effect sizes. Two families, each consists of a triangular motif identified in the network had essential roles in the network by virtue of influencing a large number of other nodes. We discuss causal effect measurement while confounders and mediators are identified graphically.