Abstract
The mechanisms by which the human brain controls eye movements are reasonably well understood, but those for the head less so. Here, we show that the mechanisms for keeping the head aimed at a stationary target follow strategies similar to those for holding the eyes steady on stationary targets. Specifically, we applied the neural integrator hypothesis that originally was developed for holding the eyes still in eccentric gaze positions to describe how the head is held still when turned toward an eccentric target. We found that normal humans make head movements consistent with the neural integrator hypothesis, except that additional sensory feedback is needed, from proprioceptors in the neck, to keep the head on target. We also show that the complicated patterns of head movements in patients with cervical dystonia can be predicted by deficits in a neural integrator for head motor control. These results support ideas originally developed from animal studies that suggest fundamental similarities between oculomotor and cephalomotor control, as well as a conceptual framework for cervical dystonia that departs considerably from current clinical views.
Introduction
Vision is the most important sense by which we relate ourselves to our external environment. For optimal vision, the brain has mechanisms that allow us to fix the eyes on a stationary target, to smoothly track moving targets, and to make saccades that rapidly redirect the eyes toward new objects. Many of the neural circuits controlling these eye movements are well understood (Leigh and Zee, 2006).
For horizontal saccades, circuits in the pons generate phasic, velocity commands that overcome orbital viscous forces to move the eyes rapidly to a new position (Luschei and Fuchs, 1972). The velocity commands are mathematically integrated by neurons in the rostral medulla into a tonic position command to counteract elastic restoring forces so that the eyes remain on target (Robinson, 1968, 1981; Cannon and Robinson, 1987; Cheron and Godaux, 1987). Separate neural integrator circuits in the midbrain control vertical saccades (King et al., 1981; Fukushima, 1987; Crawford et al., 1991). However, all of these integrators are inherently “leaky,” resulting in centripetal drift of the eyes back to a null position near the midline. A feedback system through the cerebellum improves gaze-holding (Robinson, 1974; Zee et al., 1980, 1981), and cerebellar lesions cause gaze-evoked nystagmus, which is characterized by repetitive cycles of drifts away from the target, followed by rapid corrections back toward the target. The ocular motor neural integrator principle helps to understand how the eyes are directed to a target and kept there, and to understand abnormalities such as gaze-evoked nystagmus.
The control of gaze not only involves movements of the eyes, but also movements of the head. These movements typically occur together to change the line of sight, although eye and head movements can be dissociated (Collins and Barnes, 1999). The central mechanisms controlling head movements are less well understood than those of the eyes, but studies in animals have implied that the brain has evolved mechanisms for head control that are similar to those of the eyes (Freedman and Sparks, 1997a, b; Ceylan et al., 2000; Corneil et al., 2002; Klier et al., 2002; Peterson, 2004; Liao et al., 2005; Farshadmanesh et al., 2007; Gandhi and Sparks, 2007; Klier et al., 2007; Gandhi et al., 2008). More specifically, neural circuits in the interstitial nucleus of Cajal and the nearby nucleus of Darkschewitsch appear to serve as a neural integrator responsible for keeping the head steady when it is turned toward an eccentric target (Hassler and Hess, 1954; Malouin and Bédard, 1982; Klier et al., 2002, 2007; Farshadmanesh et al., 2007). Dysfunction of these circuits may underlie abnormal head movements in certain human diseases.
Here, we address two fundamental questions about the control of head movements in humans. The first is whether the neural integrator hypothesis can predict behaviors of healthy human subjects when they turn their head toward eccentric targets and attempt to hold it steadily on target. The second is whether dysfunction of a head neural integrator can explain abnormal head movements in patients with cervical dystonia (CD, also known as torticollis), a poorly understood disorder characterized by difficulties with controlling and maintaining head positions (Dauer et al., 1998; Singer and Velickovic, 2008).
Materials and Methods
SUBJECTS.
The study was approved by The Johns Hopkins University Institutional Review Board. All subjects gave informed consent. The healthy control group included 11 subjects (4 women and 7 men), while the CD group had 14 subjects (13 women and 1 man). No effort was made to recruit CD patients with a specific pattern of head movements, to avoid the risk that a particular subtype might limit generalization of the results. All subjects had normal visual acuity with corrective lenses. On clinical examination, eye movements were normal, including saccades and steady eccentric gaze holding. All CD patients were being treated with botulinum toxin. Measurements were performed at treatment nadirs, within 1 week before the next scheduled treatment. None were taking other oral medications for tremor or dystonia at the time of testing. We excluded patients with CD who had a known or presumed cause, patients with broader involvement suggestive of segmental or generalized dystonia, and patients with other motor signs suggestive of a more widespread neurodegenerative disorder.
HEAD MOVEMENT RECORDINGS.
Head positions were recorded in a darkened room using the magnetic field search coil technique with a dual (three-dimensional) search coil (Skalar Medical) mounted on a bite bar. Subjects sat within a stationary frame that held the external magnetic field coils. Each subject bit tightly on a bar that was custom molded from dental impression material. A headband with a laser pointer was mounted on the forehead. To establish a baseline reference position for the head, another laser was mounted on the wall in front of the subject and the head was centered in the magnetic field by aligning a vertical and horizontal beam from the wall-mounted laser on the subject's nasion. The intersection of two orthogonally directed laser beams was aligned with the center of the coil frame. Head movements were recorded in the horizontal, vertical, and torsional planes. Horizontal head movements were defined as those around an earth vertical axis passing through the center of the coil frame (i.e., turning the chin to the right or left, also called torticollis). Vertical head movements were those around an earth horizontal axis, passing through the center of the coil frame (i.e., flexion and extension of the head, also called anterocollis or retrocollis). Torsional head movements were those around an earth horizontal axis passing through the center of the coil frame and parallel to the naso-occipital axis of the head (i.e., tilting the head toward the shoulder, also called laterocollis). Although head movements naturally are best expressed in Fick coordinates (Klier et al., 2007), we focused here on rotation of the head to horizontal eccentricities.
EYE MOVEMENT RECORDINGS.
Two-dimensional eye movements from one eye also were recorded with the magnetic search coil technique (Chronos Vision). Search coil annuli were calibrated and then placed on the eye after local anesthesia with oxybuprocaine 0.4%. Calibrations and recordings were conducted in complete darkness except for specific visual targets as previously described (Bergamin et al., 2001). The search coil signals measuring eye and head movements were hardware filtered with a single pole RC filter with bandwidth of 0–90 Hz, and then sampled at 1000 Hz with 12-bit resolution. Data were processed in Matlab (MathWorks).
EXPERIMENTAL DESIGN.
Each subject was evaluated under four different conditions. In the first condition (LED plus laser) subjects were placed in a dark room to minimize visual feedback. An array of LEDs was positioned ∼3 m in front of the subject, with targets appearing at the center, or to the right or left at 10°, 20°, and 30°. The subjects were instructed to aim the head toward a central LED that was illuminated, then rapidly move the head when the center target was turned off and a newly illuminated target appeared to the right or left. The laser beam projector mounted on the forehead provided visual feedback, permitting subjects to correct head positions by superimposing the head-fixed laser beam on the target LED. The laser eliminated the possibility that eye movements could compensate for imprecise head position (Guitton et al., 1986).
In the second condition (LED without laser), subjects were asked to turn their heads rapidly in the horizontal plane toward the LED target in a dark room with the head-fixed laser turned off. This condition was designed to remove visual feedback regarding the accuracy of head position with respect to the target. In the absence of visual feedback, the accuracy of head position must rely on neck muscle proprioception, vestibulo-collic reflex, and cervico-collic reflexes (Peterson et al., 1985). However, in humans the vestibulo-collic reflex is ineffective when the head is fixed on a target or moving very slowly (Guitton et al., 1986; Keshner and Peterson, 1995). Thus, in the absence of visual feedback, when the subject was asked to aim the head toward an eccentrically placed target, head stabilization primarily relies on proprioceptive signals from neck muscles.
In the third condition (LED plus vibration without laser), the subjects were also asked to aim their heads at a continuously illuminated LED target in a dark room without the laser, but vibration with a sinusoidal waveform at 50 Hz frequency and 0.5° amplitude was applied at the same time over the dorsal processes of the cervical spine to distort proprioceptive signals from neck muscles (Burke et al., 1976; Kaji et al., 1995).
In the fourth condition (LED plus laser and vibration), the subjects were asked to turn their heads toward the LED target in a dark room, with the head-fixed laser to provide visual feedback regarding the accuracy of head position, but also with vibration to distort proprioceptive signals from neck muscles.
RELATIONSHIP BETWEEN EYE-IN-ORBIT POSITION AND HEAD MOVEMENTS.
An important goal of these experiments was to assess the influence of perturbations in the visual and proprioceptive inputs on head holding. However, the position of the eye in the orbit may influence head movements. Therefore, eye and head positions were simultaneously measured in seven healthy subjects. For each experimental condition, a shift in the LED target first caused an eye saccade, followed by a head saccade. When the head-fixed laser was turned off, when the head drifted away from the target, the eyes remained on the LED target. The eye movement fixation response could be either a visual-following or vestibulo-ocular reflex. When the head-fixed laser was turned on, regardless of horizontal head orientation, the position of the eye in the orbit when looking at a continuously illuminated LED target with a laser attached to the head remained stable. The position of the eye in the orbit was measured during epochs of various head orientations in all subjects. The average position of the eye in the orbit, during all recording epochs in all subjects, indicating the variability in eye positions around the target, was 0.9 ± 1.0° (mean ± SD) without neck vibration. When neck vibration was added the average position of the eye in the orbit increased to 1.5 ± 1.0° (mean ± SD). Such small variations in eye position would likely be too small to generate meaningful feedback about the position of the eyes in the orbit that in turn could be used to control head position (Gauthier et al., 1990a, b). CD patients with tonic head deviation at baseline had compensatory offsets in eye positions while viewing the center target. Similar to prior studies, CD patients had no difficulties generating accurate saccades or maintaining stable ocular fixation during eccentric positions (Stell et al., 1990). As a result, all remaining normal subjects and CD patients were evaluated without simultaneous eye movement measurements and focused instead on head movements.
DATA ANALYSIS.
The angular position of the search coil with respect to the magnetic fields was digitized at 1000 Hz and the data were processed to compute head positions in three dimensions using Matlab (MathWorks). Head positions were computed from smoothed three-dimensional rotation vectors. Most patients with CD had relatively high-frequency sinusoidal head oscillations that were superimposed on drifts in head position. For the analysis of movements involving drift of the head away from the LED target, the raw signal was filtered first to remove the high-frequency sinusoidal oscillations and to identify epochs of head drifts, using a Matlab algorithm that implements the Savitzky–Golay filter. In most cases in which the sinusoidal oscillations superimposed upon the drifts were minimal, the filter frame length was kept at 21. In occasional cases where the drift had a robust superimposed sinusoidal modulation, the frame length was increased to 101. The same frame length was used to analyze data at all eccentricities in a given patient. The value of the polynomial order of the filter was kept at three. Head saccades and quick phase velocities, however, were always analyzed unfiltered. The analysis scheme is summarized in Figure 1.
Figure 1.Schematic for data analysis. A depicts typical raw head position data from a CD patient. The head position waveform had high amplitude jerky head oscillations and superimposed small sinusoidal oscillations. The first step was to interactively select a region of interest (green box in A). To analyze the large jerky oscillatory head movements, we identified drift of the head position in the region of interest between two red dots (B). The signal was then subject to a Savitzsky–Golay filter, and the time constant of drift in filtered head position was computed (C). To analyze the smaller sinusoidal oscillatory movements, the region of interest between two red dots (D) within the region of interest in the green box (A) was interactively selected and detrended (E). Time points of intersection of zero-line and the signal moving from negative to positive were determined. The difference of these time points was considered as period of oscillation, and the oscillation frequency was determined as the inverse of the time period. H, Initial head position; Hi, Initial head velocity; Tc, decay time constant; OHM, oscillatory head movements.
The beginnings and endings of head drifts were interactively identified on the horizontal head position trace. In some instances, a brief rapid head movement in the opposite direction followed the initial rapid shifts of the head to the new position. In such instances, the beginning of the drift was measured from the end of this rapid backward movement. In most instances, when such rapid movements were absent, the beginning of the drift was identified immediately after the end of the rapid head movement. The epochs of head positions encompassing the drifts were further differentiated to compute drift velocity and divided into three equal segments. The median velocity of the first segment was used as initial head velocity. The same analysis technique was used to compute the velocity of rebound drifts that occurred after return to the straight-ahead position. The ratio of initial head position and initial head velocity was used to determine the decay time constant (Fig. 1C). Since measurements of the time constant require relatively long epochs of sustained head drifts, they were restricted to the second and third experimental conditions (LED only and LED plus neck vibration) in healthy subjects and to LED only in patients with CD. The time constant was measured individually for the drift after every head movement in each subject.
SMALL OSCILLATORY HEAD MOVEMENTS.
Nonfiltered head position data were used for the analysis of small sinusoidal head oscillations when they were present. Epochs of head position was first detrended to remove drifts in head positions and then normalized with mean head position. This permitted data to be realigned along the abscissa such that the peaks of the cycles remained positive and the troughs negative. Cycle-by-cycle analysis was performed on detrended head positions. The x-coordinates of the intersection of the data trace with the abscissa (moving from the negative value to the positive value) were determined. The x-coordinate of the first data point that crossed the abscissa marked the beginning and the subsequent data point marked the end of the cycle. With this definition of a cycle, we then computed its width. The inverse of the cycle width yielded the cycle frequency and the difference between the peak and trough yielded the cycle amplitude. This method is schematized in Figure 1, D and E.
Results
Voluntary head movements in healthy subjects
In the first test condition, all 11 healthy subjects were able to make rapid head movements (head saccades) and aim the head-fixed laser in a darkened room toward illuminated LED targets at the center, or to the right or left at 10°, 20°, and 30°. They also were able to maintain stable head positions toward the target at all orientations tested (Fig. 2A–C). The amplitudes and velocities of head movements when holding the head steady at all tested orientations were very small (Fig. 2B,C, Table 1). The relationships of horizontal head velocities and amplitude to degree of head eccentricity were characterized by linear fit, where smaller values of head velocity slopes reflect smaller drifts with change in position. The mean slope of this line was −0.0001 ± 0.0001 for amplitude and 0.0003 ± 0.001 s−1 for velocity. Head velocities along the vertical and torsional axes were also measured during eccentric horizontal head holding. Similar linear fit revealed velocity slopes of 0.002 ± 0.006 s−1 and 0.0003 ± 0.002 s−1 along the torsional and vertical axes, respectively (Table 2).
https://www.jneurosci.org/content/33/27/11281.full
Comparison of horizontal head drifts under different conditions in healthy individuals
Comparison of slopes of linear relationship of vertical and torsional drift velocities and horizontal head eccentricities under different conditions in healthy individuals
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