Measurement of upper limb kinematics and joint angle patterns during deep brain stimulation for parkinson's disease.

Therapeutic benefits of subthalamic nucleus (STN) deep brain stimulation (DBS) for motor symptoms of Parkinson's disease (PD) are well-documented. However, the mechanisms underlying motor improvement with DBS remain poorly understood. We tested the hypothesis that STN-DBS-related improvements in voluntary arm movement kinematics are mediated by changes in the velocity and temporal sequencing of proximal joint angles. We evaluated a 56 year old male and 66 year old female with idiopathic Parkinson's disease chronically implanted with bilateral STN-DBS. Patients performed a button press task while off medication in the DBS-on and DBS-off conditions. Movements of the upper limb were recorded using a 3D motion analysis system, and detailed kinematic measures were obtained for the arm and forearm. As expected, reaction and movement times were improved in the DBS-on compared to DBS-off condition. The two subjects differed with regards to the magnitude of their changes in peak linear velocity and peak angular velocities (shoulder flexion extension, shoulder abduction adduction and elbow flexion extension). Surprisingly, both PD patients increased the frequency with which they used a preferred sequence of shoulder and elbow joint activations when in the DBS-on condition. This preferred pattern was adopted with twice the frequency than in the DBS-off condition, and with increased frequency relative to a control group of 9 age-matched controls. These results suggest that STN-DBS may improve movement execution at the cost of flexibility in movement execution strategy.

Head movements produced during linear translations in unexpected directions.

Passive translation of the body in space elicits a complex combination of directionally-specific torques that are exerted on the neck. The inertial torques that are produced by linear translation are counteracted by linear vestibular and proprioceptive reflexes that maintain head stability. A novel experimental apparatus was used in this study to translate human subjects in a random and unpredictable direction in order to quantify the head's 3-D movement with respect to the direction of translation. Head movements were found to be produced in systematic patterns as a function of stimulus direction. Roll and yaw head movements were produced in proportion to the magnitude of the lateral component of the translation. Pitch head movements were proportionate to the magnitude of the fore-aft component of the translation. One surprising observation was that head movements produced during lateral translations were, on average, 17% smaller than those produced during fore-aft translations. This suggests that linear vestibular reflexes that stabilize the head may be directionally-specific and more active during lateral whole body translations.

Reweighting sensory signals to maintain head stability: adaptive properties of the cervicocollic reflex.

A major goal of this study was to characterize the cervicocollic reflexes (CCRs) in awake squirrel monkeys and compare it to observations in cat. This was carried out by stabilizing the head in space while rotating the lower body. The magnitude and phase of the torque produced between the head and the restraint system was used as an indicator of the CCR. Many properties of the squirrel monkey's CCR were found to be similar to those of the cat. The torque decreased as a function of frequency and amplitude. In addition, the static level of torque increased with head eccentricity. One difference was that the torque was 90x smaller in squirrel monkeys. Biomechanical differences, such as differences in head inertia, could account for these differences. The second goal was to determine if the CCR was sensitive to increases in the head's inertia. To test this, we increased the head's inertia by a factor of 36 and allowed the reflexes to adapt by rotating the whole body while the head was free to move. The CCR was rapidly assessed by periodically stabilizing the head in space during whole-body rotations. The magnitude of the torque increased by nearly 60%, suggesting that the CCR may adapt when changes in the head's inertia are imposed. Changes in the torque were also consistent with changes in head-movement kinematics during whole-body rotation. This suggests that the collic reflexes may dynamically adapt to maintain the performance and kinematics of reflexive head movement.

Head movements produced during whole body rotations and their sensitivity to changes in head inertia in squirrel monkeys.

The head's inertia produces forces on the neck when the body moves. One collective function of the vestibulocollic and cervicocollic reflexes (VCR and CCR) is thought to be to stabilize the head with respect to the trunk during whole body movements. Little is known as to whether their head-movement kinematics produced by squirrel monkeys during whole body rotations are similar to those of cats and humans. Prior experiments with cats and human subjects have shown that yaw head-movement kinematics are unaffected by changes in the head's inertia when the whole body is rotated. These observations have led to the hypothesis that the combined actions of the VCR and CCR accommodate for changes in the head's inertia. To test this hypothesis in squirrel monkeys, it was imperative to first characterize the behavior of head movements produced during whole body rotation and then investigate their sensitivity to changes in the head's inertia. Our behavioral studies show that squirrel monkeys produce only small head movements with respect to the trunk during whole body rotations over a wide range of stimulus frequencies and velocities (0.5-4.0 Hz; 0-100 degrees /s). Similar head movements were produced when only small additional changes in the head's inertia occurred. Electromyographic recordings from the splenius muscle revealed that an active process was utilized such that increases in muscle activation occurred when the inertia of the head was increased. These results are consistent with prior cat and human studies, suggesting that squirrel monkeys have a similar horizontal VCR and CCR.

Vestibular-evoked reflexive head movements and their dependence on the body's orientation in space.

When the body is passively moved in space the mass of the head imposes force on the cervical spinal column. Reflexive activation of the neck musculature during whole body motion is hypothesized to function to counteract the inertial forces of the head. However, even when the body is stationary in space gravitational acceleration imposes force on segments of the body. Counteracting this force is complicated because it changes as the body's orientation changes with respect to gravity. In this study, we have focused on a subset of vestibulo-collic reflexes that act to stabilize the head when the whole body is rotated. The kinematics of reflexive head movements produced in response to whole body rotation were recorded from Squirrel Monkeys. The orientation of the body was sequentially manipulated to determine how gravity influences the kinematics of the reflexive head movements. Only small changes in reflexive head movement gain were observed at low stimulus frequencies. In contrast, larger changes in gain were observed at higher stimulus frequencies. These results suggest the vestibular system compensates for the body's orientation in space while regulating the postural stability of the head with respect to the trunk during low frequency perturbations of the body.

Current concepts of vestibular nucleus function: transformation of vestibular signals in the vestibular nuclei.

The vestibular nerve sends signals to the brain that code the movement and position of the head in space. These signals are used for a variety of functions, including the control of reflex and voluntary movements and the construction of a sense of self-motion. In order to carry out these functions, sensory vestibular signals need to be transformed in a variety of ways. Transformations are thought to occur at an early stage of sensory processing in the brain, and in many cases are apparent in the responses of neurons in the vestibular nuclei that receive direct inputs from the vestibular nerve. Several specific examples of sensory transformation in the vestibular nuclei are presented, and current hypotheses about the mechanisms that are used to produce the transformations are discussed.

The neurophysiological substrate for the cervico-ocular reflex in the squirrel monkey.

Passive rotation of the trunk with respect to the head evoked cervico-ocular reflex (COR) eye movements in squirrel monkeys. The amplitude of the reflex varied both within and between animals, but the eye movements were always in the same direction as trunk rotation. In the dark, the COR typically had a gain of 0.3-0.4. When animals fixated earth-stationary targets during low-frequency passive neck rotation or actively tracked moving visual targets with head movements, the COR was suppressed. The COR and vestibulo-ocular reflex (VOR) summed during passive head-on-trunk rotation producing compensatory eye movements whose gain was greater than 1.0. The firing behavior of VOR-related vestibular neurons and cerebellar flocculus Purkinje cells was studied during the COR. Passive neck rotation produced changes in firing rate related to neck position and/or neck velocity in both position-vestibular-pause neurons and eye-head-vestibular neurons, although the latter neurons were much more sensitive to the COR than the former. The neck rotation signals were reduced or reversed in direction when the COR was suppressed. Flocculus Purkinje cells were relatively insensitive to COR eye movements. However, when the COR was suppressed, their firing rate was modulated by neck rotation. These neck rotation signals summed with ocular pursuit signals when the head was used to pursue targets. We suggest that the neural substrate that produces the COR includes central VOR pathways, and that the flocculus plays an important role in suppressing the reflex when it would cause relative movement of a visual target on the retina.

Neck proprioceptive inputs to primate vestibular nucleus neurons.

The contribution of neck proprioceptive signals to signal processing in the vestibular nucleus was studied by recording responses of secondary horizontal canal-related neurons to neck rotation in the squirrel monkey. Responses evoked by passive neck rotation while the head was held stationary in space were compared with responses evoked by passive whole body rotation and by forced rotation of the head on the trunk. Most neurons (76%; 45/59) were sensitive to neck rotation. The nature and strength of neck proprioceptive inputs varied and usually combined linearly with vestibular inputs. In most cases (94%), the direction of the neck proprioceptive input was "antagonistic" or "reciprocal" with respect to vestibular sensitivity and, consequently, reduced the vestibular response during head-on-trunk rotation. Different types of vestibular neurons received different types of proprioceptive input. Neurons whose firing behavior was related to eye position (position-vestibular-pause neurons and position-vestibular neurons) were often sensitive to the position of the head with respect to the trunk. The sensitivity to head position was usually in the same direction as the neuron's eye position sensitivity. Non-eye-movement related neurons and eye-head-velocity neurons exhibited the strongest sensitivity to passive neck rotation and had signals that were best related to neck velocity. The results suggest that neck proprioceptive inputs play an important role in shaping the output of the primate vestibular nucleus and its contribution to posture, gaze and perception.

Sensory processing in the vestibular nuclei during active head movements.

Many secondary vestibular neurons are sensitive to head on trunk rotation during reflex-induced and voluntary head movements. During passive whole body rotation the interaction of head on trunk signals related to the vestibulo-collic reflex with vestibular signals increases the rotational gain of many secondary vestibular neurons, including many that project to the spinal cord. In some units, the sensitivity to head on trunk and vestibular input is matched and the resulting interaction produces an output that is related to the trunk velocity in space. In other units the head on trunk inputs are stronger and the resulting interaction produces an output that is larger during the reflex. During voluntary head movements, inputs related to head on trunk movement combine destructively with vestibular signals, and often cancel the sensory reafferent consequences of self-generated movements. Cancellation of sensory vestibular signals was observed in all of the antidromically identified secondary vestibulospinal units, even though many of these units were not significantly affected by reflexive head on trunk movements. The results imply that the inputs to vestibular neurons related to head on trunk rotation during reflexive and voluntary movements arise from different sources. We suggest that the relative strength of reflexive head on trunk input to different vestibular neurons might reflect the different functional roles they have in controlling the posture of the neck and body.

Firing behavior of vestibular neurons during active and passive head movements: vestibulo-spinal and other non-eye-movement related neurons.

The firing behavior of 51 non-eye movement related central vestibular neurons that were sensitive to passive head rotation in the plane of the horizontal semicircular canal was studied in three squirrel monkeys whose heads were free to move in the horizontal plane. Unit sensitivity to active head movements during spontaneous gaze saccades was compared with sensitivity to passive head rotation. Most units (29/35 tested) were activated at monosynaptic latencies following electrical stimulation of the ipsilateral vestibular nerve. Nine were vestibulo-spinal units that were antidromically activated following electrical stimulation of the ventromedial funiculi of the spinal cord at C1. All of the units were less sensitive to active head movements than to passive whole body rotation. In the majority of cells (37/51, 73%), including all nine identified vestibulo-spinal units, the vestibular signals related to active head movements were canceled. The remaining units (n = 14, 27%) were sensitive to active head movements, but their responses were attenuated by 20-75%. Most units were nearly as sensitive to passive head-on-trunk rotation as they were to whole body rotation; this suggests that vestibular signals related to active head movements were cancelled primarily by subtraction of a head movement efference copy signal. The sensitivity of most units to passive whole body rotation was unchanged during gaze saccades. A fundamental feature of sensory processing is the ability to distinguish between self-generated and externally induced sensory events. Our observations suggest that the distinction is made at an early stage of processing in the vestibular system.

Integration of vestibular and head movement signals in the vestibular nuclei during whole-body rotation.

Single-unit recordings were obtained from 107 horizontal semicircular canal-related central vestibular neurons in three alert squirrel monkeys during passive sinusoidal whole-body rotation (WBR) while the head was free to move in the yaw plane (2.3 Hz, 20 degrees /s). Most of the units were identified as secondary vestibular neurons by electrical stimulation of the ipsilateral vestibular nerve (61/80 tested). Both non-eye-movement (n = 52) and eye-movement-related (n = 55) units were studied. Unit responses recorded when the head was free to move were compared with responses recorded when the head was restrained from moving. WBR in the absence of a visual target evoked a compensatory vestibulocollic reflex (VCR) that effectively reduced the head velocity in space by an average of 33 +/- 14%. In 73 units, the compensatory head movements were sufficiently large to permit the effect of the VCR on vestibular signal processing to be assessed quantitatively. The VCR affected the rotational responses of different vestibular neurons in different ways. Approximately one-half of the units (34/73, 47%) had responses that decreased as head velocity decreased. However, the responses of many other units (24/73) showed little change. These cells had signals that were better correlated with trunk velocity than with head velocity. The remaining units had responses that were significantly larger (15/73, 21%) when the VCR produced a decrease in head velocity. Eye-movement-related units tended to have rotational responses that were correlated with head velocity. On the other hand, non-eye-movement units tended to have rotational responses that were better correlated with trunk velocity. We conclude that sensory vestibular signals are transformed from head-in-space coordinates to trunk-in-space coordinates on many secondary vestibular neurons in the vestibular nuclei by the addition of inputs related to head rotation on the trunk. This coordinate transformation is presumably important for controlling postural reflexes and constructing a central percept of body orientation and movement in space.

Intrinsic oscillations and discharge regularity of units in the dorsal cochlear nucleus (DCN) of the barbiturate anesthetized gerbil.

Spike discharge patterns showing intrinsic oscillations (IOs) have been reported in units in the dorsal cochlear nucleus (DCN) of the decerebrate cat. These oscillations are related to the regularity of a unit's discharge rate and may be important for pitch perception. A DCN unit's regularity can be affected by several factors including: synaptic architecture, cell membrane properties, and the auditory nerve discharge rate. Responses to multiple presentations of short-duration tone bursts (200 ms duration, 1 s trial) at the unit's best frequency (BF) at 20 dB re threshold were recorded from 297 units in the DCN of the barbiturate-anesthetized gerbil. Comparisons of unit regularity properties and IO properties are shown. The relative power spectrum (Fourier transform of the autocorrelogram normalized by the average rate) was used to quantify IO properties. Most units (84%) exhibited IOs in their sustained discharge rate. With the exception of Onset units and most bursting units, the mean inter-spike interval was correlated with the IO frequency and the coefficient of variation was correlated with the IO magnitude. These results suggest that stimulus-encoding mechanisms utilizing IOs may depend on the temporal evolution of the units' regularity properties.

Response map properties of units in the dorsal cochlear nucleus of barbiturate-anesthetized gerbil (Meriones unguiculatus).

The response map scheme introduced by Evans and Nelson (1973) and modified by others, including Davis et al. (1996) for use with gerbils, has been used primarily for classifying units recorded in the cochlear nucleus of unanesthetized decerebrate preparations. Units lacking spontaneous activity (SpAc) have been classified as either type I/III or type II units based on the relative strength of their responses to broad-band noise compared to their responses to best-frequency (BF) tones. The relative noise index (rho), a ratio of these responses after SpAc is subtracted out, provides a convenient measure of this relative strength. In this paper, responses of 320 units recorded in the dorsal cochlear nucleus (DCN) of barbiturate-anesthetized gerbils to short-duration BF tones and broad-band noise were recorded. Since 87.5% of these units lacked SpAc, their response maps resembled those of type II and type I/III units. Units were characterized by rho and the normalized slope (m) of a best line fit to the BF rate versus level plot starting from the sound level corresponding to the first inflection point of the rate curve (typically its maximum value or the start of its sloping saturation). The distributions of rho and m values do not form distinct clusters as they do for units in the decerebrate preparation. Thus, the criteria developed for classifying DCN units in the decerebrate preparation do not appear appropriate for units in the barbiturate-anesthetized preparation. Deposits of horseradish peroxidase were used to locate 52 units. Most of the low SpAc units, 56% with poor noise responses (5/9) and nearly 70% with strong noise responses (25/36), and nearly all of the high SpAc units (6/7), were located either within or below the fusiform cell layer.

A statistically based method to generate response maps objectively.

One scheme to classify the physiological response properties of single units in the cochlear nucleus is based on the average discharge rate of the unit and is reflected in the distribution of excitatory and inhibitory regions in a frequency-level map (response map) that spans the unit's receptive area (e.g., Evans and Nelson, 1973; Young and Brownell, 1976; Young and Voigt, 1982; Shofner and Young, 1985, Spirou and Young, 1991). Typically, discharge rate versus level curves are acquired at many frequencies and the investigator determines that a unit is excited or inhibited at a given level if the driven rate is above or below a spontaneous rate estimate by a specified criterion (for example, 20%). The investigator then encloses regions of excitation and inhibition where responses over adjacent frequencies and levels are consistent. In the present report, we describe an objective 3-step computer-based method to generate response maps: raw driven and spontaneous rate estimates are smoothed with a low-pass spatial filter; a unit is said to be excited or inhibited at a given level if the filtered driven rate is above or below the mean filtered spontaneous rate for that frequency by a specified criterion (percentage or statistical); and resultant response maps are median spatial filtered to eliminate spurious regions. The results shown here demonstrate that use of a statistical criterion provides a more reliable detection of excitation and inhibition than a 20% criterion, particularly when the variance of the rate estimates is high. Further, the statistically based method permits unit classification based on response map data that are more rapidly acquired with shorter duration stimuli (32 vs. 200 ms). Although this method is applied to units recorded in the dorsal cochlear nucleus, the technique may be applicable to studies of receptive fields and their plasticity in other systems.

A simple device for the computer quantification of depth measurements in thick light microscope sections.

The use of computerized techniques to characterize quantitatively the anatomy of individual neurons has been increasing. One difficulty has been the quantification of the z-axis or depth measurements within thick light microscopic sections. In the present report we describe a simple device which employs an incremental optical encoder to transduce the movements of the focusing knob of the microscope so that depth information can be recorded directly by a computer. A resolution of 0.13 micron over a range of approximately 8.5 cm is achieved. The mechanical interface to the microscope is simple and applicable to a wide variety of microscopes. Interfacing circuits which allow the optical encoder to be used with an IBM-PC compatible computer are presented and described. The accuracy of the depth measurements is limited only by the mechanical tolerances of the focusing mechanism and by the optics of the microscope.