Validity of the Bern Score as a Surrogate Marker of Clinical Severity in Patients with Spontaneous Intracranial Hypotension.

BACKGROUND AND PURPOSE: The Bern score is a quantitative scale characterizing brain MR imaging changes in spontaneous intracranial hypotension. Higher scores are associated with more abnormalities on brain MR imaging, raising the question of whether the score can serve as a measure of disease severity. However, the relationship between clinical symptom severity and the Bern score has not been evaluated. Our purpose was to assess correlations between Bern scores and clinical headache severity in spontaneous intracranial hypotension. MATERIALS AND METHODS: This study was a single-center, retrospective cohort of patients satisfying the International Classification of Headache Disorders-3 criteria for spontaneous intracranial hypotension. Fifty-seven patients who completed a pretreatment headache severity questionnaire (Headache Impact Test-6) and had pretreatment brain MR imaging evidence of spontaneous intracranial hypotension were included. Pearson correlation coefficients (ρ) for the Headache Impact Test-6 and Bern scores were calculated. Receiver operating characteristic curves were used to assess the ability of Bern scores to discriminate among categories of headache severity. RESULTS: We found low correlations between clinical headache severity and Bern scores (ρ = 0.139; 95% CI, -0.127-0.385). Subgroup analyses examining the timing of brain MR imaging, symptom duration, and prior epidural blood patch showed negligible-to-weak correlations in all subgroups. Receiver operating characteristic analysis found that the Bern score poorly discriminated subjects with greater headache severity from those with lower severity. CONCLUSIONS: Pretreatment Bern scores show a low correlation with headache severity in patients with spontaneous intracranial hypotension. This finding suggests that brain imaging findings as reflected by Bern scores may not reliably reflect clinical severity and should not replace clinical metrics for outcome assessment.

Adherence to medications in systemic lupus erythematosus.

BACKGROUND: Lack of adherence is a ubiquitous problem which can be a hindrance in the treatment of chronic conditions like systemic lupus erythematosus (SLE). OBJECTIVES: A random sample of 63 SLE patients attending rheumatology clinics associated with University Medical Centers were surveyed to measure level of adherence to their SLE medications and to identify the risk factors that have been associated previously with nonadherence to these medications. METHODS: Information on traditional SLE outcomes was obtained by face-to-face interviews and medical record review. Various patient proposed strategies were identified to improve adherence to these medications. RESULTS: When considering adherence estimates of > or =80% as representing sufficient adherence for achieving a therapeutic response, adherence to medications was only modestly adherent, likely limiting the effectiveness of the prescribed medication regimens. Based on pharmacy refill information 61% of the patients were sufficiently adherent to prednisone, 49% to hydroxychloroquine, and 57% to other immunosuppressant medications. Significant risk factors of insufficient adherence included being single, low educational level, presence of other comorbidities, limited comprehension of physician explanations and instructions, and having to take the medication more than one daily. Based on subject reports, busy life styles were among the most important barriers to adherence whereas pillboxes were considered most helpful for helping with medication adherence. CONCLUSION: Although lack of sufficient adherence to medications appears to be a multifactorial problem, improved communication between the healthcare provider and the patient, and less complicated medication regimens, may be especially suitable interventions to improve adherence to medications.

Effectively measuring adherence to medications for systemic lupus erythematosus in a clinical setting.

OBJECTIVE: To assess the reliability and concurrent validity of the Medication Adherence Self-report Inventory (MASRI) when used in systemic lupus erythematosus (SLE), to investigate the predictive validity of the MASRI using pharmacy refill information as the criterion standard, and to propose a sensible approach to the screening for nonadherence in a clinical setting. METHODS: Adherence to 2 medications (hydroxychloroquine and prednisone) was measured in 55 patients using the MASRI, pill counts, and physician ratings (MD scale). Adherence based on pharmacy refill information served as a criterion standard with nonadherence defined as adherence rates <80%. To determine test-rest reliability of the MASRI, 20 patients completed the measure twice within a 2-week period. RESULTS: Using pharmacy information, 39% of the patients were nonadherent to prednisone and 51% to hydroxychloroquine. The MASRI had acceptable internal consistency (Cronbach's alpha 0.7) and good reliability. Irrespective of the drug assessed, MASRI ratings were moderately correlated with patient adherence (pharmacy), supporting the concurrent validity of the MASRI. The combination of adherence estimation by MD scale rating at <85% and by MASRI at <90% was 87% sensitive and 86% specific for identifying patients who were nonadherent to prednisone. These cutoff values also appeared suitable for identifying nonadherence to hydroxychloroquine. CONCLUSION: The MASRI is a reliable measure of adherence to medications in SLE. The measure has concurrent and predictive validity. When combined with the MD scale, the MASRI appears to be a useful screening tool for nonadherence in patients with SLE that could be suitable for clinical practice.

Action selection and refinement in subcortical loops through basal ganglia and cerebellum.

Subcortical loops through the basal ganglia and the cerebellum form computationally powerful distributed processing modules (DPMs). This paper relates the computational features of a DPM's loop through the basal ganglia to experimental results for two kinds of natural action selection. First, functional imaging during a serial order recall task was used to study human brain activity during the selection of sequential actions from working memory. Second, microelectrode recordings from monkeys trained in a step-tracking task were used to study the natural selection of corrective submovements. Our DPM-based model assisted in the interpretation of puzzling data from both of these experiments. We come to posit that the many loops through the basal ganglia each regulate the embodiment of pattern formation in a given area of cerebral cortex. This operation serves to instantiate different kinds of action (or thought) mediated by different areas of cerebral cortex. We then use our findings to formulate a model of the aetiology of schizophrenia.

Movement-related discharge in the cerebellar nuclei persists after local injections of GABA(A) antagonists.

Limb movement-related neurons in the cerebellar nuclei (CN) typically produce bursts of discharge in association with movement. Consequently, given the inhibitory nature of the Purkinje cell (PC) projection to CN, it is puzzling that only a minority of movement-related PCs pause; the majority burst. Some of the movement-related CN activity may be the result of excitation from collaterals of mossy and climbing fiber projections to the cerebellar cortex. The only other input to CN is diffuse and neuromodulatory, from locus ceruleus and raphe nuclei. To investigate the role of the excitatory mossy fiber input, single units in CN were recorded in macaque monkeys during the performance of reaching and manipulation tasks, before and after blocking the PC input with local microinjections of GABA(A) antagonists (bicuculline or SR95531). After these injections, the movement-related modulation of CN discharge was greater and began earlier, compared with the modulation in the preinjection group of neurons. These observations indicate that an important excitatory drive is provided by extracerebellar inputs to CN, most likely from collaterals of mossy fibers. PCs may serve primarily to regulate this activity, by either pausing or bursting as necessary.

Features of motor performance that drive adaptation in rapid hand movements.

In order to explore how subjects correct for errors in movement and adapt their motor programs, we studied rapid hand movements. Subjects grasped a grooved knob and made brisk turning movements to various targets, similar to tuning a radio dial. A motor attached to the knob shaft was configured to apply a destabilizing negative viscous perturbation. Following a period of practice with no perturbations, the negative viscosity was engaged, which caused a large change in overall kinematics: the peak velocity increased, the movement amplitude was too large, and discrete corrective submovements were generated to bring the pointer back onto the target. After about an hour and nearly 1000 trials, subjects learned to move accurately in the new dynamic environment, returning their overall kinematics near to previous levels. Measures of performance included the endpoint error of the primary movement (the initial movement segment), the frequency and amplitude of corrective submovements, task success rate, mean squared jerk, and deviation from a "normal" angular velocity temporal profile. Both the amplitude and frequency of corrective submovements decreased progressively during adaptation as the subjects made fewer target overshoot errors. These results are consistent with motor learning schemes in which adaptation of the motor controller is driven by an attempt to reduce the endpoint error of the primary movement. While there have been many theories regarding what is being optimized in motor control, in general, biologically plausible mechanisms for implementing these schemes have not been described. A biologically plausible optimization criterion is the minimization of the occurrence and amplitude of corrective submovements, since the latter have been proposed as realistic climbing fiber training signals for adaptive changes in the cerebellum. We postulate that the other criteria that have been proposed are instead secondary to an increased accuracy of the primary movement and a corresponding decrease in the occurrence and amplitude of corrective submovements.

The role of the cerebellum in modulating voluntary limb movement commands.

We recorded the activity of cerebellar Purkinje cells (PCs), primary motor cortical (M1) neurons, and limb EMG signals while monkeys executed a sequential reaching and button pressing task. PC simple spike discharge generally correlated well with the activity of one or more forelimb muscles. Surprisingly, given the inhibitory projection of PCs, only about one quarter of the correlations were negative. The largest group of neurons burst during movement and were positively correlated with EMG signals, while another significant group burst and were negatively correlated. Among the PCs that paused during movement most were negatively correlated with EMG. The strength of these various correlations was somewhat weaker, on average, than equivalent correlations between M1 neurons and EMG signals. On the other hand, there were no significant differences in the timing of the onset of movement related discharge among these groups of PCs, or between the PCs and M1 neurons. PC discharge was modulated largely in phase, or directly out of phase, with muscle activity. The nearly synchronous activation of PCs and muscles yielded positive correlations, despite the fact that the synaptic effect of the PC discharge is inhibitory. The apparent function of this inhibition is to restrain activity in the limb premotor network, shaping it into a spatiotemporal pattern that is appropriate for controlling the many muscles that participate in this task. The observed timing suggests that the cerebellar cortex learns to modulate PC discharge predictively. Through the cerebellar nucleus, this PC signal is combined with an underlying cerebral cortical signal. In this manner the cerebellum refines the descending command as compared with the relatively crude version generated when the cerebellum is damaged.

The use of overlapping submovements in the control of rapid hand movements.

Rapid targeted movements are subject to special control considerations, since there may be inadequate time available for either visual or somatosensory feedback to be effective. In our experiments, subjects rapidly rotated a knob to align a pointer to one of several targets. We recognized three different types of movement segments: the primary movement, and two types of submovement, which frequently followed. The submovements were initiated either before or after the end of the primary movement. The former, or "overlapping" type of submovement altered the kinematics of the overall movement and was consequently difficult to detect. We used a direct, objective test of movement regularity to detect overlapping submovements, namely, examining the number of jerk and snap zero crossings during the second half of a movement. Any overlapping submovements were parsed from the overall movement by subtracting the velocity profile of the primary movement. The velocity profiles of the extracted submovements had near-symmetric bell shapes, similar to the shapes of both pure primary movements and nonoverlapping submovements. This suggests that the same neural control mechanisms may be responsible for producing all three types of movement segments. Overlapping submovements corrected for errors in the amplitude of the primary movement. Furthermore, they may account for the previously observed, speed-dependent asymmetry of the velocity profile. We used a nonlinear model of the musculoskeletal system to explain most of the kinematic features of these rapid hand movements, including how discrete submovements are superimposed on a primary movement. Finally, we present a plausible scheme for how the central nervous system may generate the commands to control these rapid hand movements.

Cerebellar input to magnocellular neurons in the red nucleus of the mouse: synaptic analysis in horizontal brain slices incorporating cerebello-rubral pathways.

We studied the synaptic input from the nucleus interpositus of the cerebellum to the magnocellular division of the red nucleus (RNm) in the mouse using combined electrophysiological and neuroanatomical methods. Whole-cell patch-clamp recordings were made from brain slices (125-150 microm) cut in a horizontal plane oriented to pass through both red nucleus and nucleus interpositus. Large cells that were visually selected and patched were injected with Lucifer Yellow and identified as RNm neurons. Using anterograde tracing from nucleus interpositus in vitro, we examined the course of interposito-rubral axons which are dispersed in the superior cerebellar peduncle. In vitro monosynaptic responses in RNm were elicited by an electrode array placed contralaterally in this pathway but near the midline. Mixed excitatory post-synaptic potentials (EPSPs)/inhibitory post-synaptic potentials (IPSPs) were observed in 48 RNm neurons. Excitatory components of the evoked potentials were studied after blocking inhibitory components with picrotoxin (100 microM) and strychnine (5 microM). All RNm neurons examined continued to show monosynaptic EPSPs after non-N-methyl-D-aspartate (NMDA) glutamate receptor components were blocked with 10 microM 6,7-dinitroquinoxaline-2,3-dione or 5 microM 2,3-dihydro-6-nitro-7-sulfamoyl-benzo(f)-quinoxaline (NBQX; n=12). The residual potentials were identified as NMDA receptor components since they (i) were blocked by the addition of the NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid (APV), (ii) were voltage-dependent, and (iii) were enhanced by Mg(2+) removal. Inhibitory components of the evoked potentials were studied after blocking excitatory components with NBQX and APV. Under these conditions, all RNm neurons studied continued to show IPSPs. Blockade of GABA(A) receptors reduced but did not eliminate the IPSPs. These were eliminated when GABA(A) receptor blockade was combined with strychnine to eliminate glycine components of the IPSPs. Thus, IPSPs evoked by midline stimulation of the superior cerebellar peduncle, while blocking alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and NMDA receptors, raise the possibility of direct inhibitory inputs to RNm from the cerebellum. In summary we propose that the special properties of the NMDA receptor components are considered important for the generation of RNm motor commands: their slow time course will contribute a steady driving force for sustained discharge and their voltage dependency will facilitate abrupt transitions from a resting state of quiescence to an active state of intense motor command generation.

Context dependency in the globus pallidus internal segment during targeted arm movements.

Extracellular discharges from single neurons in the internal segment of the globus pallidus (GPi) were recorded and analyzed for rate changes associated with visually guided forearm rotations to four different targets. We sought to examine how GPi neurons contribute to movement preparation and execution. Unit discharge from 108 GPi neurons recorded in 35 electrode penetrations was aligned to the time of various behavioral events, including the onset of cued and return movements. In total, 39 of 108 GPi neurons (36%) were task-modulated, demonstrating statistically significant changes in discharge rate at various times between the presentation of visual cues and movement generation. Most often, strong modulation in discharge rate occurred selectively during either the cued (n = 32) or return (n = 2) phases of the task, although a few neurons (n = 5) were well-modulated during both movement phases. Of the 34 neurons that were modulated exclusively during cued or return movements, 50% (n = 17) were modulated similarly in association with movements to any target. The remaining 17 neurons exhibited considerable diversity in their discharge properties associated with movements to each target. Cued phases of behavior were always rewarded if executed correctly, whereas return phases were never rewarded. Overall, these data reveal that many GPi neurons discharged in a context-dependent manner, being modulated during cued, rewarded movements, but not during similar self-paced, unrewarded movements. When considered in the light of other observations, the context-dependence we have observed seems likely to be influenced by the animal's expectation of reward.

Kinematic properties of rapid hand movements in a knob turning task.

In order to understand how the central nervous system controls the kinematics of rapid finger and hand movements, we studied the motions of subjects turning a knob to light-emitting diode targets, similar to tuning a radio dial. On many trials, subjects turned the knob with a single, smooth, and regular motion as revealed by the angular position and velocity trajectories, but on others, subjects produced irregularities in the kinematics. Like many past studies, we interpreted these irregularities as discrete corrective submovements. Unlike other studies, we used a direct, objective algorithm to identify overlapping submovements, detecting appreciable inflections in the acceleration traces by examining zero crossings in their derivatives, jerk and snap. The movements without overlapping submovements on average had a near symmetric, bell-shaped velocity profile that was independent of speed, and which matched the theoretical minimum jerk velocity very closely. We proposed three plausible mechanisms for altering the shape of movement kinematics, and implemented a mass-spring model with nonlinear damping to explore the possibilities. Although there was relatively little variability in the shape and symmetry of movements across trials, there was a fair amount of variability in their amplitude. We show that subjects attempted to eliminate the need for corrective submovements by making more accurate primary movements with practice, but that the variability inherent in rapid movements dictated the need for corrective submovements. Subjects used corrective submovements to improve final endpoint accuracy while reducing endpoint variability, resulting in higher task success rates.

Functional connectivity between cerebellum and primary motor cortex in the awake monkey.

Simultaneous single neuron and local field potential (LFP) recordings were made in arm-related areas of the cerebellar nuclei (CN) and primary motor cortex (M1) of two monkeys during a reaching and button pressing task. Microstimulation of focal sites in CN caused short latency (median = 3.0 ms) increases in discharge in 25% of 210 M1 neurons. Suppressive effects were less common (13%) and observed at longer latencies (median = 9.9 ms). Stimulation in CN also caused reciprocal facilitation and suppression in averages of antagonist muscle electromyograms (EMGs). The latency of these effects was approximately 8-11 ms. In contrast to the selectivity of unit and EMG effects, stimulation-evoked changes in LFP occurred over a broad range of sites. There were no significant short-latency effects detected in cross-correlation histograms between single neurons in CN and M1. However, CN spike-triggered averages of M1 LFPs were observed in a few cases (10% of 126 cases). In one-half of these, there were effects both before and after the CN spikes, which may reflect causal effects from M1 to CN, as well as from CN to M1. Overall, these results demonstrate a spatially specific, short latency, primarily excitatory pathway from CN to M1. The relatively rare effects at the single neuron level may have resulted from the difficulty in achieving optimal alignment between cerebellar and cerebral sites because of the specificity of these connections.

Emergence of symmetric, modular, and reciprocal connections in recurrent networks with Hebbian learning.

While learning and development are well characterized in feedforward networks, these features are more difficult to analyze in recurrent networks due to the increased complexity of dual dynamics - the rapid dynamics arising from activation states and the slow dynamics arising from learning or developmental plasticity. We present analytical and numerical results that consider dual dynamics in a recurrent network undergoing Hebbian learning with either constant weight decay or weight normalization. Starting from initially random connections, the recurrent network develops symmetric or near-symmetric connections through Hebbian learning. Reciprocity and modularity arise naturally through correlations in the activation states. Additionally, weight normalization may be better than constant weight decay for the development of multiple attractor states that allow a diverse representation of the inputs. These results suggest a natural mechanism by which synaptic plasticity in recurrent networks such as cortical and brainstem premotor circuits could enhance neural computation and the generation of motor programs.

Relationship between modulation of the cerebellorubrospinal system in the in vitro turtle brain and changes in motor behavior in rats: effects of novel sigma ligands.

Saturation and competition binding studies showed that the turtle brain contains sigma sites labeled by both [3H]di-o-tolylguanidine (DTG) and [3H](+)-pentazocine. There was a significant correlation between the IC50 values of sigma ligands for [3H]DTG sites in the turtle vs. rat brain, suggesting that the sites are comparable in the two species. In contrast, [3H](+)-pentazocine, which primarily labels sigma1 sites in the rodent brain, labels a heterogeneity of sites in the turtle brain. In extracellular recordings from the in vitro turtle brainstem, some sigma ligands enhanced the burst responses of red nucleus (RN) neurons (DTG, haloperidol, BD1031, BD1052, BD1069) while other sigma ligands decreased the burst responses (BD1047, BD1063). Control compounds (turtle Ringer vehicle control, opiate antagonist naloxone, atypical neuroleptic sulpiride) had no significant effects on the RN burst responses recorded from the in vitro turtle brain. The ED50s of the ligands for altering the burst responses in RN neurons from the turtle brain were correlated with their IC50s for turtle brain sites labeled with [3H]DTG, but not [3H](+)-pentazocine; this pattern is identical to that previously reported in rats, where there is a correlation between the potencies of sigma ligands for producing dystonic postures after microinjection into the rat RN and their binding to rat brain sites labeled with [3H]DTG, but not [3H](+)-pentazocine. When the novel sigma ligands were microinjected into the rat RN, dystonic postures were produced by ligands that increased the burst duration of RN neurons in the turtle brain. Novel sigma ligands that reduced the burst responses in the in vitro turtle brain have previously been reported to have no effects on their own when microinjected into the rat RN, but to block the dystonic postures produced by other sigma ligands. Taken together, the data suggest that the opposite effects of the novel ligands in the turtle electrophysiological studies represent the actions of agonists vs. antagonists, and that the directionality of the effects has predictive value for the expected motor effects of the drugs.

A cerebellar model of timing and prediction in the control of reaching.

A simplified model of the cerebellum was developed to explore its potential for adaptive, predictive control based on delayed feedback information. An abstract representation of a single Purkinje cell with multistable properties was interfaced, using a formalized premotor network, with a simulated single degree-of-freedom limb. The limb actuator was a nonlinear spring-mass system based on the nonlinear velocity dependence of the stretch reflex. By including realistic mossy fiber signals, as well as realistic conduction delays in afferent and efferent pathways, the model allowed the investigation of timing and predictive processes relevant to cerebellar involvement in the control of movement. The model regulates movement by learning to react in an anticipatory fashion to sensory feedback. Learning depends on training information generated from corrective movements and uses a temporally asymmetric form of plasticity for the parallel fiber synapses on Purkinje cells.

Model of cortical-basal ganglionic processing: encoding the serial order of sensory events.

Several lines of evidence suggest that the prefrontal (PF) cortex and basal ganglia are important in cognitive aspects of serial order in behavior. We present a modular neural network model of these areas that encodes the serial order of events into spatial patterns of PF activity. The model is based on the topographically specific circuits linking the PF with the basal ganglia. Each module traces a pathway from the PF, through the basal ganglia and thalamus, and back to the PF. The complete model consists of an array of modules interacting through recurrent corticostriatal projections and collateral inhibition between striatal spiny units. The model's architecture positions spiny units for the classification of cortical contexts and events and provides bistable cortical-thalamic loops for sustaining a representation of these contextual events in working memory activations. The model was tested with a simulated version of a delayed-sequencing task. In single-unit studies, the task begins with the presentation of a sequence of target lights. After a short delay, the monkey must touch the targets in the order in which they were presented. When instantiated with randomly distributed corticostriatal weights, the model produces different patterns of PF activation in response to different target sequences. These patterns represent an unambiguous and spatially distributed encoding of the sequence. Parameter studies of these random networks were used to compare the computational consequences of collateral and feed-forward inhibition within the striatum. In addition, we studied the receptive fields of 20,640 model units and uncovered an interesting set of cue-, rank- and sequence-related responses that qualitatively resemble responses reported in single unit studies of the PF. The majority of units respond to more than one sequence of stimuli. A method for analyzing serial receptive fields is presented and utilized for comparing the model units to single-unit data.

Organization of reaching and grasping movements in the primate cerebellar nuclei as revealed by focal muscimol inactivations.

Two monkeys were trained to point to targets and to retrieve fruit bits from a Kluver board, bottles, and tubes. Once proficient in the tasks, the macaques underwent aseptic surgical implantation of a recording chamber over the cerebellar nuclei on the side of their preferred hand. After recovery from surgery, a series of mapping penetrations were completed to identify task-related areas within the cerebellar nuclei. Muscimol (4- 16 microgram; 1-2 microgram/microliter) was pressure injected at different sites within the forelimb zone, and the resultant deficits were observed as the monkeys performed the behavioral tasks. Quantitative measures of task performance were supplemented by direct observation of live and videotaped performance. The locations of nuclear inactivation sites were reconstructed from marking lesions and tracks visible in histological sections. Injections placed in the cerebellar interpositus nucleus and adjacent regions of dentate caused a variety of deficits in forelimb function. A prominent anteroposterior specialization was apparent within the forelimb zone of this intermediate nuclear region. Injections into the anterior interpositus nucleus and adjacent dentate impaired preshaping of the hand and the manipulation of objects, whereas injections placed more posteriorly in posterior interpositus nucleus and adjacent dentate produced deficits in the aiming of reach and the stability of the arm. During anterior injections, the monkeys failed to adequately extend their fingers in preparation for target contact, as documented for >85% of the reaches in the pointing task of monkey J. Up to 38% of the fruit bits it attempted to retrieve from the Kluver board were dropped. In comparison, during posterior inactivations, 15% were dropped and during control conditions 3% were dropped. The monkeys made significantly greater pointing errors during posterior inactivations (11 times for monkey J and 4 times for monkey C) than during anterior inactivations (8 times for monkey J and 2 times for monkey C). We refer to the region producing hand deficits as the anterior hand zone and the region producing reaching deficits as the posterior reach zone. These results are discussed in relation to the problem of achieving spatiotemporal coordination in the large population of nuclear cells that participate in any given movement. The results do not favor the hypothesis that coordination is achieved through a selection of Purkinje cells along beams of parallel fibers. Instead, it is proposed that distal and proximal musculature is coordinated by the adaptive influences of climbing fiber input to Purkinje cells. We envision a relatively nonspecific recruitment of anterior and posterior nuclear cells due to positive feedback in the limb premotor network, which then is shaped into an appropriate spatiotemporal pattern of discharge through the inhibitory input from Purkinje cells.

Organization of ascending pathways to the forelimb area of the dorsal accessory olive in the cat.

The purpose of these experiments was to define the topography of cuneate and spinal projections to the forelimb representation in the rostral dorsal accessory olive (rDAO). We were interested in determining whether the spinal and cuneate inputs constitute a homogeneous afferent source, and whether there is evidence that they serve different functional roles. We were also interested in determining whether the somatotopy of rDAO is the result of a point-to-point projection from its afferent sources, or whether the projection suggests a reorganization of afferents at the olive. Single unit recording was used to identify specific regions of rDAO, and the topography of inputs to the identified regions was determined by using wheat germ agglutinin-horseradish peroxidase (WGA-HRP) as a tracer. The results from retrograde tracing were confirmed by using WGA-HRP as an anterograde tracer from input sources. The cuneate and spinal neurons providing input to rDAO constitute two distinct neural populations. One consists of cells in the caudal cuneate nucleus and lamina VI of the rostral two cervical segments, the other consists of cells in the rostral cuneate nucleus. The cells in the caudal cuneate nucleus and the rostral cervical segments are large, multipolar neurons that form a single column of rDAO input cells. The column of cells projects to the contralateral rDAO in a topographic fashion with rostral regions of the column projecting to rostral rDAO, which contains cells that respond to somatosensory stimulation of the contralateral shoulder, trunk, and proximal forelimb. Caudal regions of the column project to caudal rDAO, which contains cells that respond to stimulation of the distal forelimb. Despite this topography, there is a large degree of overlap in the terminations from neighboring regions of the input column, indicating that a major reorganization occurs at the rDAO. The projection from the rostral cuneate nucleus arises from small neurons that project bilaterally to rDAO, and the input from the rostral cuneate nucleus lacks a clear topography. We propose that input from the cell column is responsible for the somatosensory sensitivity of rDAO neurons, whereas input from rostral cuneate is most likely modulatory, probably inhibitory, in nature.

Cerebellar guidance of premotor network development and sensorimotor learning.

Single unit and imaging studies have shown that the cerebellum is especially active during the acquisition phase of certain motor and cognitive tasks. These data are consistent with the hypothesis that particular sensorimotor procedures are acquired and stored in the cerebellar cortex and that this knowledge can then be exported to the cerebral cortex and premotor networks for more efficient execution. In this article we present a model to illustrate how the cerebellar cortex might guide the development of cortical-cerebellar network connections and how a similar mechanism operating in the adult could mediate the exportation of sensorimotor knowledge from the cerebellum to the motor cortex. The model consists of a three-layered recurrent network representing the cerebello-thalamocortical-ponto-cerebellar limb premotor network. The cerebellar cortex is not explicitly modeled. Our simulations show that Hebbian learning combined with weight normalization allows the emergence of reciprocal and modular structure in the limb premotor network. Reciprocal connections allow activity to reverberate around specific loops. Modularity organizes the connections into specific channels. Furthermore, we show that cerebellar learning can be exported to motor cortex through these modular and reciprocal premotor circuits. In particular, we simulate developmental alignment of visuomotor relations and their realignment as a consequence of prism exposure. The exportation of sensorimotor knowledge from the cerebellum to the motor cortex may allow faster and more efficient execution of learned motor responses.

Network models of the basal ganglia.

Over the past year, a number of conceptual and mathematical models of the basal ganglia and their interactions with other areas of the brain have appeared in the literature. Even though the models each differ in significant ways, several computational principles, such as convergence, recurrence and competition, appear to have emerged as common themes of information processing in the basal ganglia. Simulation studies of these models have provoked new types of questions at the many levels of inquiry linking biophysics to behavior.