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Tottering mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background.

Tottering (tg) mice inherit a recessive mutation of the calcium channel alpha 1A subunit gene, which encodes the pore-forming protein of P/Q-type voltage-sensitive calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons. The phenotypic consequences of the tottering mutation include ataxia, polyspike discharges, and an intermittent motor dysfunction best described as paroxysmal dystonia. These dystonic episodes induce c-fos mRNA expression in the cerebellar circuitry, including cerebellar granule and Purkinje neurons, deep cerebellar nuclei, and the postsynaptic targets of the deep nuclei. Cellular abnormalities associated with the mutation include hyperarborization of brainstem nucleus locus ceruleus axons and abnormal expression of L-type calcium channels in cerebellar Purkinje cells. Here, the role of these two distinct neural pathways in the expression of tottering mouse intermittent dystonia was assessed. Lesion of locus ceruleus axons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine (DSP-4) did not affect the frequency of tottering mouse dystonic episodes. In contrast, removal of cerebellar Purkinje cells with the Purkinje cell degeneration (pcd) mutation by generation of tg/tg; pcd/pcd double mutant mice completely eliminated tottering mouse dystonia. Further, the c-fos expression pattern of tg/tg; pcd/pcd double mutants following restraint was indistinguishable from that of wild-type mice, suggesting that the pcd lesion eliminated an essential link in this abnormal neural network. These data suggest that the cerebellar cortex, where the mutant gene is abundantly expressed, contributes to the expression of tottering mouse dystonic episodes.

Animals↗

Target selection for saccadic eye movements: prelude activity in the superior colliculus during a direction-discrimination task.

We investigated the role of the superior colliculus (SC) in saccade target selection while macaque monkeys performed a direction-discrimination task. The monkeys selected one of two possible saccade targets based on the direction of motion in a stochastic random-dot display; the difficulty of the task was varied by adjusting the strength of the motion signal in the display. One of the two saccade targets was positioned within the movement field of the SC neuron under study while the other target was positioned well outside the movement field. Approximately 30% of the neurons in the intermediate and deep layers of the SC discharged target-specific preludes of activity that "predicted" target choices well before execution of the saccadic eye movement. Across the population of neurons, the strength of the motion signal in the display influenced the intensity of this "predictive" prelude activity: SC activity signaled the impending saccade more reliably when the motion signal was strong than when it was weak. The dependence of neural activity on motion strength could not be explained by small variations in the metrics of the saccadic eye movements. Predictive activity was particularly strong in a subpopulation of neurons with directional visual responses that we have described previously. For a subset of SC neurons, therefore, prelude activity reflects the difficulty of the direction discrimination in addition to the target of the impending saccade. These results are consistent with the notion that a restricted network of SC neurons plays a role in the process of saccade target selection.

Action Potentials↗

Perirhinal and parahippocampal cortices of the macaque monkey: Intrinsic projections and interconnections.

We investigated the topographic and laminar organization of the intrinsic projections and interconnections of the macaque monkey perirhinal and parahippocampal cortices. Discrete anterograde tracer injections placed at various rostrocaudal and mediolateral levels in these cortices revealed extensive associational connections both within and between the perirhinal and parahippocampal cortices. Areas 35, 36rm, 36rl, 36cm, and 36cl are highly interconnected, whereas area 36d (encompassing the dorsal portion of the medial temporal pole) shares only modest connections with the rest of the perirhinal cortex. Areas TH, TFm, and TFl of the parahippocampal cortex also share an extensive network of associational connections that tend to be heaviest within a given subdivision. Area 36c of the perirhinal cortex is the main interface between the perirhinal and parahippocampal cortices. Its heaviest connections are with area 36r and the anterior aspect of area TF. The laminar organization of all these connections is typical of associational projections. Anterograde tracer experiments revealed that these projections are distributed through both deep and superficial layers, although heavier projections are directed toward the superficial layers. Results of retrograde tracer experiments suggested that the projections from caudal areas (36c or TF) to area 36r are of the feedforward type, whereas the projections from areas 36r and 36c to area TF are of the feedback type. These findings suggest that the perirhinal cortex is at a higher level than the parahippocampal cortex in the hierarchy of associational cortices. We discuss the functional implications of the organization of these extensive networks of intrinsic, associational projections.

Animals↗

The venous return simulator: an effective tool for investigating the effects of external compression on the venous hemodynamics--first results after thigh compression.

BACKGROUND: To present a virtual model, the venous return simulator (VRS), designed to compute venous hemodynamic variations when compression is applied to the leg. METHODS: The VRS defines a numerical network of the lower extremity and computes the dynamic variables (flow rate, venous diameter and internal pressure) for a defined external pressure. The VRS was based on physiological data from the literature and clinical studies on healthy subjects. Clinical correlations were required to confirm its validity; for this purpose, we carried out experiments simulating the conditions of a clinical trial, in which the diameter of superficial and deep veins was measured while increasing pressures (20, 40 and 60 mmHg.) were applied to the thighs of patients enduring deep valvular insufficiency and venous ulcers. The diameters and flow rates calculated using our VRS model were compared with the experimental data obtained at the same thigh compression levels. RESULTS: The numerical results of VRS are in good agreement with the clinical data obtained by Duplex, (R2 = 0.96). In accordance with the in vivo measurement the computed results show that only a pressure greater than 40 mmHg is able to reduce the venous diameter at thigh-level, both in the great saphenous vein and in the femoral vein. CONCLUSION: The venous return simulator computes lower limb hemodynamic parameters under static conditions. The good correlation existing between the VRS and the data obtained in a previous clinical study shows that this numerical approach could provide a useful means of predicting the hemodynamic consequences of compression therapy.

Bandages↗

The great gate: control of sensory information flow to the cerebellum.

An evident feature of the physiology of the inferior olivary nucleus is modulation of the responsiveness of neurons to peripheral stimulation by the behavioral state of the subject animal. The olivary response to self-generated sensory inputs, as well as to input predictable from association with other stimuli, is suppressed. This suppression occurs in part at the level of the inferior olivary nucleus itself. On the other hand, the cells respond readily to sensory inputs that are not anticipated. On a cellular level inferior olivary neurons exhibit two properties that might account for information gating. The first one is the organization of synaptic inputs on olivary spines in glomerular structures, where extrinsic inhibitory and excitatory inputs, confined to the same olivary dendritic spine, can efficiently cancel each other if they arrive within a certain time window. About half of the inhibitory inputs to olivary glomeruli originate in the deep cerebellar nuclei and are regarded as an inhibitory feedback. The second property is subthreshold membrane potential oscillations, a property of the electrotonically coupled olivary network. Extrinsic synaptic inputs to the nucleus modulate the subthreshold oscillations, and consequently, the response properties of olivary neurons. A considerable amount of indirect evidence indicates that the occurrence of oscillations corresponds to states of increased responsiveness of the neurons to peripheral stimulation. The sensory filtering role of the inferior olivary nucleus invites comparison between the cerebellum and cerebellar-like structures. This comparison sheds important light on the function of the cerebellum.

Afferent Pathways↗

Organization of area 3a in macaque monkeys: contributions to the cortical phenotype.

The detailed organization of somatosensory area 3a was examined in macaque monkeys using multiunit electrophysiological recording techniques. By examining topographic relationships, changes in receptive field size, and the type of stimulus that neurons responded to, functional boundaries of area 3a were determined and related to architectonic boundaries. One striking observation was that the location of area 3a varied with respect to the central sulcus. In one-half of the cases area 3a was on the rostral bank and fundus of the central sulcus and in the other half of the cases it was on the caudal bank and fundus of the central sulcus. In terms of topographic organization, we found that area 3a contains a complete representation of deep receptors and musculature of the contralateral body, and that the general organization of body part representations mirrors that of the primary somatosensory area, 3b. These results as well as results from studies of area 3a in ours and other laboratories indicate that area 3a is part of a network involved in proprioception, postural control, and the generation of coordinated movements. Further, comparative analysis of area 3a in a variety of species suggests that its construction is based, to a large extent, on the use of a particular body part rather than on innervation density.

Animals↗

Electrophysiological characterization of interlaminar entorhinal connections: an essential link for re-entrance in the hippocampal-entorhinal system.

The hippocampal formation communicates with the neocortex mainly through the adjacent entorhinal cortex. Neurons projecting to the hippocampal formation are found in the superficial layers of the entorhinal cortex and are largely segregated from the neurons receiving hippocampal output, which are located in deep entorhinal layers. We studied the communication between deep and superficial entorhinal layers in the anaesthetized rat using field potential recordings, current source density analysis and single unit measurements. We found that subiculum stimulation was able to excite entorhinal neurons in deep layers. This response was followed by current sinks in superficial layers. Both responses were subject to frequency dependent facilitation, but not depression. Selective blockade of deep layer responses also abolished subsequent superficial layer responses. This clearly demonstrates a functional deep-to-superficial layer communication in the entorhinal cortex, which can be triggered by hippocampal output. This pathway may provide a means by which processed hippocampal output is integrated or compared with new incoming information in superficial entorhinal layers, and it constitutes an important link in the process of re-entrance of activity in the hippocampal-entorhinal network, which may be important for consolidation of memories or retaining information for short periods.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Development of the human retinal vasculature: cellular relations and VEGF expression.

We have investigated the relationships of the cellular constituents of the retinal vasculature--astrocytes, microglia and pericytes--to the differentiating endothelium in human fetal retina. The vascular endothelium was stained using NADPH-diaphorase histochemistry in 12 human fetal retinae ranging in gestational age from 15-22 weeks. Specimens were double labeled using antibodies against glial fibrillary acid protein, alpha smooth muscle actin, or major histocompatibility complex class II antigens to label astrocytes, contractile cells and microglia, respectively. In addition, specimens of 12, 14, 16 and 20 weeks gestation were hybridized in situ for VEGF expression. In retinal wholemounts the vascularized area comprised four lobes that converged on the optic disc. The vascular network was more dense in the temporal lobes than in the nasal lobes, and different growth patterns were evident. Astrocytes were distributed in two layers--one associated with the optic axons and a deeper layer associated with the developing vessels. In retinae younger than 20 weeks, astrocytes in the deep layer were only loosely associated with the developing vessels and extended as far as 150 microns ahead of the most peripheral vessels. A closer register between retinal vessels and the distribution of astrocytes was evident in the nasal region of retinas older than 20 weeks. In situ hybridization demonstrated expression of VEGF mRNA in the vascular layer, superficial to the ganglion cell layer, at the margins of the vascularized zone. Differences were evident in the density of astrocyte coverage of developing vessels and in the extent of VEGF expression in different regions of the retina: the relationship of these differences to differentiation gradients in the neural retina is discussed. Intensely immunoreactive microglia were observed in the vascular layer, associated with the vascular endothelium as far as the most peripheral loops, but not beyond. Alpha smooth muscle actin-containing cells covered the proximal parts of large arteries, but not corresponding veins; they were absent from arterial side-arm branches, as well as the newly formed and small diameter vessels in the age range studies. The results suggest that microglia, contractile cells and astrocytes have distinct temporo-spatial relationships to the differentiating vascular endothelium in human retinas and that VEGF expression at the vascular front, presumably by astrocytes, is associated with the spread of the retinal vasculature, as described in other species.

Cell Differentiation↗

NASA high performance computing, communications, image processing, and data visualization-potential applications to medicine.

High-speed information processing technologies being developed and applied by the Jet Propulsion Laboratory for NASA and Department of Defense mission needs have potential dual-uses in telemedicine and other medical applications. Fiber optic ground networks connected with microwave satellite links allow NASA to communicate with its astronauts in Earth orbit or on the moon, and with its deep space probes billions of miles away. These networks monitor the health of astronauts and or robotic spacecraft. Similar communications technology will also allow patients to communicate with doctors anywhere on Earth. NASA space missions have science as a major objective. Science sensors have become so sophisticated that they can take more data than our scientists can analyze by hand. High performance computers--workstations, supercomputer and massively parallel computers are being used to transform this data into knowledge. This is done using image processing, data visualization and other techniques to present the data--one's and zero's in forms that a human analyst can readily relate to and understand. Medical sensors have also explored in the in data output--witness CT scans, MRI, and ultrasound. This data must be presented in visual form and computers will allow routine combination of many two dimensional MRI images into three dimensional reconstructions of organs that then can be fully examined by physicians. Emerging technologies such as neural networks that are being "trained" to detect craters on planets or incoming missiles amongst decoys can be used to identify microcalcification in mammograms.

Image Interpretation, Computer-Assisted↗

Amygdala input promotes spread of excitatory neural activity from perirhinal cortex to the entorhinal-hippocampal circuit.

A number of sensory modalities most likely converge in the rat perirhinal cortex. The perirhinal cortex also interconnects with the amygdala, which plays an important role in various motivational and emotional behaviors. The neural pathway from the perirhinal cortex to the entorhinal cortex is considered one of the main paths into the entorhinal-hippocampal network, which has a crucial role in memory processes. To investigate the potential associative function of the perirhinal cortex with respect to sensory and motivational stimuli and the influence of the association on the perirhinal-entorhinal-hippocampal neurocircuit, we prepared rat brain slices including the perirhinal cortex, entorhinal cortex, hippocampal formation, and amygdala. We used an optical imaging technique with a voltage-sensitive dye to analyze 1) the spatial and functional distribution of inputs from the lateral nucleus of the amygdala to the perirhinal cortex; 2) the spread of neural activity in the perirhinal cortex after layers II/III stimulation, which mimics sensory input to the perirhinal cortex; and 3) the effect of associative inputs to the perirhinal cortex from both the lateral amygdaloid nucleus and layers II/III of the perirhinal cortex on the perirhinal-entorhinal-hippocampal neurocircuit. Following stimulation in the superficial layers of the perirhinal cortex, electrical activity only propagated into the entorhinal cortex when sufficient activation occurred in the deep layers of perirhinal area 35. We observed that single stimulation of either the perirhinal cortex or amygdala did not result in sufficient neural activation of the deep layers of areas 35 to provoke activity propagation into the entorhinal cortex. However, the deep layers of area 35 were depolarized much more strongly when the two stimuli were applied simultaneously, resulting in spreading activation in the entorhinal cortex. Our observations suggest that a functional neural basis for the association of higher-order sensory inputs and emotion-related inputs exists in the perirhinal cortex and that transfer of sensory information to the entorhinal-hippocampal circuitry might be affected by the association of that information with incoming information from the amygdala.

Amygdala↗

Automated CEAP Classification of Venous Duplex Reports Using Multimodal Artificial Intelligence.

OBJECTIVE: To develop and internally validate a prototype multimodal artificial intelligence system for automated CEAP (Clinical, Etiological, Anatomical and Pathophysiological) classification of venous duplex ultrasound (VDUS) reports, integrating natural language processing of free-text components with computer vision analysis of hand-drawn anatomical diagrams. METHODS: Single centre retrospective observational study using routinely collected clinical data. One thousand consecutive venous duplex ultrasound reports from Cambridge University Hospitals NHS Foundation Trust, UK (July 2024 - May 2025) were labelled according to the CEAP classification, excluding the Etiological component, which could not be reliably determined from duplex reports alone. Transfer learning was applied using ClinicalBERT for text and MobileNetV3 for diagrammatic data. Clinical classes were predicted from request line text. Text- and image-based pathophysiological models were developed for four anatomical territories (Great Saphenous Vein, Small Saphenous Vein, Deep system, Perforators), combined using late fusion with probability averaging. RESULTS: The clinical CEAP model achieved accuracy of 0.91, macro-F1 of 0.82, and macro-AUC of 0.98. Pathophysiological prediction varied, with text models broadly outperforming image models. Fusion yielded heterogeneous benefits, improving SSV performance but reducing Deep system accuracy. The performance of the final pathophysiological CEAP fusion models varied across anatomical territories: accuracy ranged from 0.70-0.92 and macro-AUC from 0.80-0.92. CONCLUSION: This study demonstrates the feasibility of automated CEAP classification from VDUS reports. Despite class imbalance affecting minority class predictions, the strong discriminatory performance validates this multimodal ML model for extracting clinically meaningful information from real-world data. This approach offers potential, pending external validation, to streamline vascular services through automated triage and guideline-compliant decision making.

Artificial intelligence↗

Deep entry of defibrillating effects into homogeneous cardiac tissue.

A simple, idealized mathematical model of cardiac tissue is used to show that electrical fields applied with the intent of defibrillating the heart can be effective deep within (that is, many space constants into) cardiac tissue, even in cases when the tissue is assumed to have completely homogeneous electrical properties. This conclusion is drawn from the analysis of the two eigenmodes present in the model, which have fundamentally different characteristics. One mode decays very rapidly with space, implying that the associated membrane potential is only present with appreciable amplitude within a few space constants of the tissue surface. The other mode, however, is not directly dependent on the value of the space constant, and allows deep penetration of the membrane potential and, by implication, its associated defibrillating effects. For deep membrane potentials to be generated by this mechanism, the intracellular and extracellular resistivity anisotropy ratios must be unequal, as is typically the case in cardiac tissue. The model also predicts that this mechanism is most effective for a given applied field strength when the electrode size and separation, or spatial features of the externally applied field at the heart surface, are characterized by scalelengths that are commensurate with approximately two times the heart wall thickness.

Action Potentials↗

The effects of age on the neural correlates of episodic encoding.

Young and old adults underwent positron emission tomographic scans while encoding pictures of objects and words using three encoding strategies: deep processing (a semantic living/nonliving judgement), shallow processing (size judgement) and intentional learning. Picture memory exceeded word memory in both young and old groups, and there was an age-related decrement only in word recognition. During the encoding tasks three brain activity patterns were found that differentiated stimulus type and the different encoding strategies. The stimulus-specific pattern was characterized by greater activity in extrastriate and medial temporal cortices during picture encoding, and greater activity in left prefrontal and temporal cortices during encoding of words. The older adults showed this pattern to a significantly lesser degree. A pattern distinguishing deep processing from intentional learning of words and pictures was identified, characterized mainly by differences in prefrontal cortex, and this pattern also was of significantly lesser magnitude in the old group. A final pattern identified areas with increased activity during deep processing and intentional learning of pictures, including left prefrontal and bilateral medial temporal regions. There was no group difference in this pattern. These results indicate age-related dysfunction in several encoding networks, with sparing of one specifically involved in more elaborate encoding of pictures. These age-related changes appear to affect verbal memory more than picture memory.

Adult↗

The organization of projections from the amygdala to visual cortical areas TE and V1 in the macaque monkey.

We examined the organization of amygdaloid projections to visual cortical areas TE and V1 by injecting anterograde tracers into the amygdaloid complex of Macaca fascicularis monkeys. The magnocellular and intermediate divisions of the basal nucleus of the amygdala gave rise to heavy projections to both superficial layers (border of I/II) and deep layers (V/VI) throughout the rostrocaudal extent of area TE. Although most of the injections led to heavier fiber and terminal labeling in the superficial layers of area TE, the most dorsal injections in the basal nucleus produced denser labeled fibers and terminals in the deep layers of area TE. Area V1 received projections primarily from the magnocellular division of the basal nucleus, and these terminated exclusively in the superficial layers. As in area TE, projections from the amygdala to area V1 were distributed throughout its rostrocaudal and transverse extents. Labeled axons demonstrated 11.67 varicosities/100 microm on average in the superficial layers of area TE and 8.74 varicosities/100 microm in the deep layers. In area V1 we observed 8.24 varicosities/100 microm. Using confocal microscopy, we determined that at least 55% of the tracer-labeled varicosities in areas TE and V1 colocalized synaptophysin, a marker of synaptic vesicles, indicating that they are probably synaptic boutons. Electron microscopic examination of a sample of these varicosities confirmed that labeled boutons formed synapses in areas TE and V1. These feedback-like projections from the amygdala have the potential of modulating key areas of the visual processing system.

Afferent Pathways↗

c-kit-dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract.

In vivo injection of a neutralizing, monoclonal antibody (ACK2) to the receptor tyrosine kinase (c-kit) disrupts the normal motility patterns of the mouse small intestine. Immunohistochemical studies showed that cells expressing c-kit-like immunoreactivity (c-kit-LI) decreased in numbers in response to ACK2, but the identity of these cells is unknown. We investigated the identity and development of the cells that express c-kit-LI in the mouse small intestine and colon. Cells in the region of the myenteric plexus and deep muscular plexus of the small intestine and in the subserosa, in the myenteric plexus region, within the circular and longitudinal muscle layers, and along the submucosal surface of the circular muscle in the colon were labeled with ACK2. The distribution of cells that express c-kit-LI was the same as that of interstitial cells (ICs). In whole-mount preparations cells with c-kit-LI were interconnected, forming a network similar to the network formed by cells that stained with methylene blue, which has been used as a marker for ICs in the mouse gastrointestinal tract. Immunocytochemistry verified that ICs were labeled with ACK2. Multiple injections of animals with ACK2 between days 0 and 8 post partum (pp) caused a dramatic reduction in the number of ICs compared to control animals. From an ultrastructural point of view, the proliferation and development appeared to be suppressed in some classes of ICs, while others displayed an altered course of development. Functional studies showed that the decrease in ICs was accompanied by a loss of electrical rhythmicity in the small intestine and reduced neural responses in the small bowel and colon. Morphological experiments showed that c-kit-positive cells are ICs, and physiological evidence reinforced the concept that ICs are involved in generation of rhythmicity and translation of neural inputs in gastrointestinal smooth muscles. Controlling the development of ICs provides a powerful new tool for the investigation of the physiological role of these cells.

Animals↗

Intraoperative microelectrode recording equipment: what features are necessary?

Intraoperative neurophysiologic methods for localizing targets deep in the brain require the use of specialized monitoring and recording equipment, including stimulators, neurophysiologic recording devices, and image manipulation tools. When using microelectrode recording devices there are some specifications that are more important than others, such as signal-to-noise ratios and amplifier impedance. As more companies develop tools to be used in the operating room, the end users have more choices. Some of the more important specifications are discussed and a comparison is made of the five major brands on the market today.

Action Potentials↗

On the transmission of rate code in long feedforward networks with excitatory-inhibitory balance.

The capability of feedforward networks composed of multiple layers of integrate-and-fire neurons to transmit rate code was examined. Synaptic connections were made only from one layer to the next, and excitation was balanced by inhibition. When time is discrete and the synaptic potentials rise instantaneously, we show that, for random uncorrelated input to layer one, the mean rate of activity in deep layers is essentially independent of input firing rate. This implies that the input rate cannot be transmitted reliably in such feedforward networks because neurons in a given layer tend to synchronize partially with each other because of shared inputs. As a result of this synchronization, the average firing rate in deep layers will either decay to zero or reach a stable fixed point, depending on model parameters. When time is treated continuously and the synaptic potentials rise instantaneously, these effects develop slowly, and rate transmission over a limited number of layers is possible. However, the correlations among neurons at the same layer hamper reliable assessment of firing rate by averaging over 100 msec (or less). When the synaptic potentials develop gradually, as is the realistic case, transmission of rate code fails. In a network in which inhibition only balances the mean excitation but is not timed precisely with it, neurons in each layer fire together, and this volley successively propagates from layer to layer. We conclude that the transmission of rate code in feedforward networks is highly unlikely.

Animals↗

Muscular innervation of the proximal duodenum of the guinea pig.

We investigated the muscular structure and innervation of the gastroduodenal junction in the guinea pig. In the gastroduodenal junction, the innermost layer of the circular muscle contained numerous nerve fibers and terminals. Since this nerve network continued onto the deep muscular plexus (DMP) of the duodenum, we surmised that the numerous nerve fibers in the gastroduodenal junction were specialized DMP in the most proximal part of the duodenum. The innermost layer containing many nerve fibers was about 1,000 microm in length and 100 microm in thickness in the proximal duodenum. This layer contained numerous connective tissue fibers composed of collagen and elastic fibers. Five to 30 smooth muscle cells lay in contact with each other and were surrounded by fine connective tissue. The nerve fibers in the proximal duodenum contained nerve terminals immunoreactive for choline acetyltransferase, dynorphin, enkephalin, galanin, gastrin-releasing peptide, nitric oxide synthase, substance P, and vasoactive intestinal polypeptide. Adrenergic fibers which contained tyrosine hydroxylase immunoreactivity were rare in the proximal duodenum. In the innermost layer of the proximal duodenum, there were numerous c-Kit immunopositive cells that were in contact with nerve terminals. This study allowed us to clarify the specific architecture of the most proximal portion of the duodenum. The functional significance of the proximal duodenum in relation to the electrical connection and neural cooperation of the musculature between the antrum and the duodenum is also discussed.

Actins↗