Cervical dystonia: a neural integrator disorder

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1 doi: /brain/aww141 BRAIN 2016: 139; UPDATE Cervical dystonia: a neural integrator disorder Aasef G. Shaikh, 1,2 David S. Zee, 3 J. Douglas Crawford 4 and Hyder A. Jinnah 5 Ocular motor neural integrators ensure that eyes are held steady in straight-ahead and eccentric positions of gaze. Abnormal function of the ocular motor neural integrator leads to centripetal drifts of the eyes with consequent gaze-evoked nystagmus. In 2002 a neural integrator, analogous to that in the ocular motor system, was proposed for the control of head movements. Recently, a counterpart of gaze-evoked eye nystagmus was identified for head movements; in which the head could not be held steady in eccentric positions on the trunk. These findings lead to a novel pathophysiological explanation in cervical dystonia, which proposed that the abnormalities of head movements stem from a malfunctioning head neural integrator, either intrinsically or as a result of impaired cerebellar, basal ganglia, or peripheral feedback. Here we briefly recapitulate the history of the neural integrator for eye movements, then further develop the idea of a neural integrator for head movements, and finally discuss its putative role in cervical dystonia. We hypothesize that changing the activity in an impaired head neural integrator, by modulating feedback, could treat dystonia. 1 Department of Neurology, Case Western Reserve University, Cleveland, OH, USA 2 Daroff-DelOsso Ocular Motility Laboratory, Neurology Service, Louis Stoke VA Medical Center, Cleveland, OH, USA 3 Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA 4 Centre for Vision Research and Departments of Psychology, Biology, and Kinesiology and Health Sciences, York University, Toronto, ON, Canada 5 Department of Neurology, Emory University, Atlanta, GA, USA Correspondence to: Aasef G. Shaikh, M.D., Ph.D., Department of Neurology, Euclid Avenue, Cleveland, OH 44110, USA aasefshaikh@gmail.com Keywords: integrator; cerebellum; midbrain; tremor; nystagmus Abbreviation: INC = interstitial nucleus of Cajal Neural integrators: evolution of the concept The human brain requires a series of complex neural processes to accomplish routine tasks. For example, looking at an object and reaching for it first uses the visual system to locate and compute the spatial coordinates of the object of interest (Sparks, 1989; Andersen et al., 1993; Crawford et al., 2011). The eyes and head then turn towards the object and gaze is stabilized in its new position to capture more detailed visual information (Guitton et al., 2003). The arm then reaches for the object and, once stabilized in its new orientation, forms a platform from which the fingers can grasp the object (Gosselin-Kessiby et al., 2008; Monaco et al., 2015). Each of these steps is accompanied by a brief transmission of information encoded in a short-lasting pulse of neural discharge. To use such ongoing bits of information to maintain each step, the brain must convert the transient pulses of neural discharge into sustained neural activity, both at the higher levels of cognition, e.g. working memory (Goldman-Rakic, 1996; Curtis and Lee, 2010), and at lower levels for the control and maintenance of posture. Received March 11, Revised April 24, Accepted May 1, Advance Access publication June 20, 2016 ß The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Neural integrator in cervical dystonia BRAIN 2016: 139; David Hearley, in the early 18th century, proposed the process of converting the pulse of neural discharge into persistent neuronal activity and formation of a short-term memory. Alexander Bain, later in the 1800s, further elaborated the process of short-term memory. Subsequent investigators posited that the conversion of the pulse of neural discharge to steady-state firing requires sustained synaptic activity generated by reverberation in a neuronal network (Lorente De No, 1938; Hebb, 1949). In the 1970s David Robinson further developed the concept of mathematical integration for the ocular motor system, based on the fundamental observation that vestibular inputs encode velocity whereas the ocular motor effector, plant, is a position actuator (Robinson, 1974). This idea was supported by studies showing that pharmacological inactivation of circuits in the medulla, responsible for neural integration in subhuman primates, led to horizontal drift of the eyes from a target location (Cannon and Robinson, 1987; Godaux et al., 1993; Arnold et al., 1999). Other experiments showed analogous integrators for the vertical and torsional components of eye orientation in the midbrain interstitial nucleus of Cajal (INC), where torsion is defined as rotation around the line of gaze at its primary position (King et al., 1981; Fukushima, 1987; Crawford et al., 1991). Together, these integrators appear to control eye orientation about axes or planes similar to those defined by the semicircular canals and the eye muscles themselves (Crawford et al., 2003). alternating drifts and corrective movements define gazeevoked nystagmus (Robinson, 1974; Zee et al., 1976, 1980, 1981). Gaze-evoked nystagmus: the quintessential example of a dysfunctional ocular motor neural integrator Figure 1A C depicts an example of typical gaze-evoked nystagmus. The eyes are relatively stable in the straightahead position (Fig. 1B). The eyes drift to the left after they are turned 30 to the right (Fig. 1A), and are followed by corrective saccades, or quick phases, in the opposite direction (Fig. 1A). Rightward drifts and leftward quick phases follow after the eyes are turned 30 to the left (Fig. 1C). The drift velocity, or slow-phase velocity, changes systematically with the eye-in-orbit position, lessening as the eye-in-orbit position approaches straight-ahead (Fig. 1D). The direction of the drift reverses when the eyein-orbit position passes beyond the straight-ahead to the contralateral side (Fig. 1D). All these features of drifts of the eyes can be attributed to suboptimal neural integration, and are distinct from the constant-velocity drift associated with pure vestibular dysfunction (Robinson, 1974; Zee et al., 1980, 1981; Leigh and Zee, 2015). Feedback dependence of the neural integrator Theoretical constructs for neural integration were supported by studies suggesting that continual feedback between the neurons was fundamental to ensure the efficacy of the neural integrator (Cannon and Robinson, 1985; Arnold and Robinson, 1991; Aksay et al., 2001, 2007; Miri et al., 2011). To ensure perfect neural integration, the synaptic strengths of all network neurons had to be optimally tuned. Most biological systems, however, cannot maintain optimal tuning indefinitely, making neural integrators inherently imperfect. They can become leaky, leading to velocity-decreasing drifts toward a null position, or unstable, leading to velocity-increasing drifts away from the null position. Imperfect integrators can be restored to more faithful activity by appropriate feedback. The cerebellum is one of the key sources of feedback to the neural integrator (Carpenter, 1972; Robinson, 1974; Zee et al., 1976, 1980, 1981; Baier and Dieterich, 2011). A deficit in cerebellar feedback can lead to imperfect neural integration associated with characteristic centripetal drifts in the eyes from eccentric targets. The drifts are followed by corrective saccades in the opposite direction that rapidly realign the eyes towards the target of interest. These Discovery of head neural integrator: an important milestone in motor physiology Until recently the neural integrator concept was largely confined to the ocular motor system. In 2002 Klier and colleagues injected muscimol in the midbrain of subhuman primates to inactivate the INC and surrounding structures such as the rostral interstitial medial longitudinal fasciculus and nucleus of Darkschewitsch (Klier et al., 2002). Based on previous experiments showing that the INC houses part of the ocular motor integrator, and its projections to the spinal cord via the interstitiospinal tract (Fukushima et al., 1981), they expected additional deficits in head movements. As predicted, monkeys developed position-dependent deficits in holding the head still, especially in the vertical and torsional dimensions (Klier et al., 2002; Farshadmanesh et al., 2007). Attempts to voluntarily straighten the head caused repeated drifting of the head towards a resting position (Fig. 2A). This motor behaviour was analogous to gaze-evoked nystagmus of the eyes (Fig. 1). Indeed, when eye and head movements were recorded simultaneously, their drifts were highly correlated

3 2592 BRAIN 2016: 139; A. G. Shaikh et al. Figure 1 Gaze-evoked nystagmus of the eyes. (A C) Example of gaze-evoked nystagmus measured during a 5-s epoch as the subject with a cerebellar lesion attempted to fixate gaze to the right (A), straight-ahead (B), or to the left (C). The nystagmus is characterized by slow phases and rapid corrective quick phases. In a slow phase the eyes drift toward the null (B). Slow-phase velocity systematically changes with eye-in-orbit orientation (D). Each circle in D depicts one cycle of gaze-evoked nystagmus with the slowphase velocity on the y-axis while the corresponding eye-in-orbit position is on the x-axis. Positive signs depict the rightward direction, while negative is leftward. (Farshadmanesh et al., 2007). Eventually, the corrective movements abated and the head settled into a laterally tilted position (Fig. 1A). Finally, unilateral stimulation of the INC produced head rotations that often held their final position (until corrected), as expected by the neural integrator theory (Fig. 2B). In other words, unilateral stimulation and inactivation simply produced head tilts in opposite directions, although the underlying patterns of muscular activation were much more complicated (Farshadmanesh et al., 2008, 2012). Based on these findings it was proposed that the INC could function as a neural integrator for both eye and head movements (Klier et al., 2002; Farshadmanesh et al., 2007). They further proposed that the postural symptoms of cervical dystonia in humans, for example, the fixed neck posturing in torsion dystonia, could be explained by severely imbalanced activity within such an integrator, either from intrinsic dysfunction (as in Fig. 2A) or from an imbalance of inputs (as simulated by stimulation in Fig. 2B), or a combination of these two. For example, the head only drifted in the early stages of INC inactivation because the system was still trying to correct head torsion (Fig. 2A). The eventual settling of head position toward the torsional null position could thus be explained either as an additional deficit in surrounding phasic inputs like the rostral interstitial medial longitudinal fasciculus (obliterating the corrective movements) or as the system accepting a new set-point for torsion at the null position. Other experiments further suggested that the INC controls head orientation about the planes sensed by the four vertical semicircular canals, again analogous to its role in eye position control (Klier et al., 2002, 2007). The head neural integrator in the INC receives inputs from the ventral-caudal and rostral mesencephalic reticular formation. Injections of muscimol into the nucleus subcuneiformis located ventro-caudally in the mesencephalic reticular formation, lateral to the oculomotor nucleus, and caudal to the posterior commissure, as well as into the peri-inc mesencephalic reticular formation, produces head tilts but with less accompanying ocular drift (Waitzman et al., 2000a, b). There must then also be a horizontal head integrator. Head rotations produced by stimulation in the area near the horizontal eye movement generator suggest that the head movement integrator might be located in the pons or medulla (like the eye integrator), but this head integrator has not yet been directly identified (Gandhi and Sparks, 2007). Feedback dependence of the head neural integrator The neural integrator for head movements is also inherently leaky and feedback-dependent. Recent studies hypothesized that the head neural integrator relies on feedback using visual information, neck proprioception, and input from the cerebellum (Chan-Palay, 1977; Noda et al., 1990; Fukushima and Fukushima, 1992). Suboptimal calibration of any of these feedback pathways results in impaired function of the head neural integrator. Healthy subjects with optimal visual and proprioceptive feedback can hold their head steady in eccentric positions (Supplementary Fig. 1A and B). If visual feedback is removed the head drifts from eccentric head positions towards a central null, where drifts are minimal (Supplementary Fig. 1C and D). This observation implies the neural integrator depends at least in part on visual feedback. The velocity of centripetal drift increases when the position of the head shifts farther away from the null (Supplementary Fig. 1D), as predicted by the neural integrator hypothesis. Head movements are more complex than eye movements in the sense that they are controlled by numerous neck muscles; any given neck muscle can be activated during movements in more than one plane, and movements can be around more than one joint. Hence it is advantageous to use multiple independent sources of proprioceptive feedback to advise the brain about the state of the position of the head (Shaikh et al., 2013). When the proprioceptive signal is distorted by vibrating paraspinal neck muscles, centripetal drift of the head increases during eccentric head holding (Supplementary Fig. 1E). The relationship between drift velocity and head on trunk position had a steeper slope suggesting a synergistic relationship between visual and proprioceptive influences to improve the fidelity of the head neural integrator (Supplementary Fig. 1F). In another experiment, in which normal visual feedback was allowed but

4 Neural integrator in cervical dystonia BRAIN 2016: 139; Figure 2 Inactivation and stimulation of INC in macaques cause head postures and oscillations resembling cervical dystonia. (A) Unilateral inactivation of INC results in head postures resembling cervical dystonia. Left INC inactivation results in right laterocollis and left torticollis, while left INC inactivation causes left laterocollis and right torticollis. The effects are schematized with caricatures. The effects of inactivation are progressive, and resolve spontaneously within 24 h. Traces depict the time course of changes in torsional head position after left INC inactivation with muscimol. Black trace is head position while grey is corresponding gaze (eye-in-space). Head (and eye) positions are plotted on the y-axis while the x-axis depicts corresponding time. After 40 min of injections the head remains steadily distorted in 40 torsional position (laterocollis). (B) Electrical stimulation of INC in the form of 50 ma, and 200 Hz cathodal pulse trains of using tungsten microelectrodes results in head position changes, but directions are opposite of what are found with inactivation. Left INC stimulation causes right torticollis and left laterocollis, and retrocollis. Right INC stimulation causes left torticollis, right laterocollis, and retrocollis. proprioception was distorted by vibration, drifts in head position still emerged and were followed by rapid corrective head movements (Supplementary Fig. 1G and H) (Shaikh et al., 2013). These slow drifts and rapid corrections that appear when feedback is altered resemble the jerky oscillations of dystonic tremor in subjects with cervical dystonia, a neurological disorder characterized by involuntary twisting and turning of the head in any of the three dimensions of head rotation. Indeed, in the original description of the head neural integrator Klier and colleagues (2002) proposed that the abnormal head movements shown by monkeys after inactivation of the INC resemble the abnormal torsional head movements in subjects with cervical dystonia (laterocollis). Based on this idea, one would expect to also see chronic horizontal tilts if one could continuously activate one side, and thus one direction, of the (as yet to be localized) horizontal head integrator. Dysfunction of neural integrators: a new twist in the physiology of dystonia The proposal by Klier and colleagues (2002) was at odds with prevailing views of cervical dystonia, which focused on defects in the basal ganglia (Dauer et al., 1998) or sometimes the cerebellum (Neychev et al., 2011) or proprioceptive defects (Tempel and Perlmutter, 1990; Bove et al., 2004). As a result, their idea was neglected until more recent studies resurrected the concept by characterizing the abnormalities of head movement in subjects with cervical dystonia, in relation to the neural integrator model (Shaikh et al., 2013). Figure 3A L depicts head positions for a subject with cervical dystonia, where the favoured head position (null) was 20 to the left of the centre position on the trunk (Fig. 3G I). Drifts of head position were minimal when the subject s head was voluntarily held at the null. Coarse and jerky head movements were seen as the head turned 20 to the right (40 from the null) (Fig. 3A C), or straightahead (20 from the null, Fig. 3D F). Typical of cervical dystonia, the jerky movements were present in all three rotational planes including the horizontal plane (torticollis), vertical plane (antero/retrocollis), and torsional plane (laterocollis). In such instances, the slow drift in head position was directed towards the null. The rapid movements towards the desired head position corrected for the drifts toward the null. Furthermore, in all three planes the drift velocity systematically changed with head position. Figure 3 M and N summarizes the drift trajectories in all three dimensions, shown in the horizontal vertical, and

5 2594 BRAIN 2016: 139; A. G. Shaikh et al. horizontal torsional planes. Qualitatively the drifts are directed towards the null, minimal drifts are present at the null, and there is a further increase in drifts in the opposite direction as the head passes to the opposite side of the null. These features of the drifts are quantitatively shown in Fig. 3O Q. Such jerky, irregular, multidimensional head movements, composed of drifts and corrections in cervical dystonia, are often called dystonic tremor, a term that has generated considerable debate (Quinn et al., 2011; Elble, 2013). It is interesting to note that the movements of dystonic tremor are analogous to the gaze-evoked nystagmus of the eyes. Such a resemblance suggested an alternative label for the dystonic tremor, and that is head nystagmus. Though nystagmus is a term more commonly used in reference to various types of eye oscillations, it can also be applied more generally to any movement that has repetitive cycles of a slow drift followed by a rapid corrective movement in the opposite direction (i.e. a jerk nystagmus). Interestingly, the term head nystagmus was used more than three quarters of a century ago by Hyndman (1939) in his in descriptions of the jerky oscillations in cervical dystonia. Regardless of the best terminology for these head movements, the results show that they can be interpreted as deficits in a head neural integrator (Shaikh et al., 2013). Two types of head oscillations in cervical dystonia: more support for dysfunctional neural integration In addition to the coarse, jerky, oscillatory movements, which we have likened to gaze-evoked nystagmus of the eyes, some subjects with cervical dystonia also had smaller amplitude, sinusoidal, and more regular oscillations. These oscillations, resembling essential tremor, were superimposed on the coarse jerky movements (Fig. 3A and D). It was subsequently shown that these sinusoidal head oscillations had characteristics similar to the pendular eye oscillations that are thought to originate from instability in the ocular motor neural integrator (Das et al., 2000; Shaikh et al., 2015b). Three characteristic features of these sinusoidal head oscillations supported their origin in an abnormal neural integrator. First, the amplitude of oscillation depended upon the head-on-trunk orientation; second there was no influence of head position on the frequency of oscillations; and finally there was a reset in phase of the oscillation after rapid head movements. Thus, these quantitative studies of head movements in cervical dystonia provided strong support for a mixed disorder, combining at least two subtypes of oscillatory head movements, and both could be related to abnormal function of a head neural integrator (Shaikh et al., 2013, 2015b). Concept of a neural integrator to address well-known controversies in dystonia Proposals suggesting a relationship of the head neural integrators in the INC or its surrounding area to cervical dystonia do not imply that pathology in cervical dystonia must be intrinsic to these regions. Major inputs to this area are from the cerebellum (Fig. 4), a region already implicated in cervical dystonia (Pelisson et al., 1998, 2003; Pizoli et al., 2002; Neychev et al., 2008, 2011; Prudente et al., 2013, 2014; Raike et al., 2013). There is an old literature suggesting that cerebellar lesions and more recent experiments using transcranial magnetic stimulation of the cerebellum, show improvements in dystonia and muscle tone (Heimburger, 1967, 1968; Zervas et al., 1967; Hitchcock, 1973, 1977; Siegfried and Verdie, 1977; Zervas, 1977; Sukoff and Ragatz, 1980; Koch et al., 2014; Sokal et al., 2015; Teixeira et al., 2015). Furthermore, close by, the nucleus of Darkschewitsch, an area that is considered a part of peri-rubral complex and also involved with head neural integration, receives projections from the basal ganglia (Onodera and Hicks, 1998, 2009). Tractography has revealed right left asymmetry in white matter projections between the pallidum and the region of the red nucleus in subjects with cervical dystonia (Blood et al., 2012). Subjects with cervical dystonia also have asymmetric local field potentials in the pallidum, suggesting an asymmetry in pallidal outflow (Lee and Kiss, 2014; Moll et al., 2014). The same midbrain regions that we associate with a head neural integrator also indirectly receive afferent information from neck proprioceptors (Fig. 4) (Fukushima et al., 1981; Bakker et al., 1984; Ishii, 1989). Malfunction in proprioceptive, pallidal or cerebellar projections to the head position integrator could affect its function, leading to clinical abnormalities resembling cervical dystonia. This notion emphasizes that dystonia is a clinical syndrome but with heterogeneity in the underlying biological causes. The conceptual framework emphasizing a central role of the neural integrator in cervical dystonia is consistent with contemporary hypotheses for cervical dystonia that underscore the role of altered cerebellar output and inadequate proprioceptive feedback (Pizoli et al., 2002; Neychev et al., 2008, 2011; Shaikh et al., 2008; 2013, 2015b; Prudente et al., 2013, 2014; Raike et al., 2013). The concept also is compatible with more traditional opinions that stress the role of the basal ganglia in dystonia (Fukushima et al., 1981; Berardelli et al., 1998; Vitek et al., 1999; Vitek, 2002; Calderon et al., 2011). Furthermore, this novel view of the pathophysiology of cervical dystonia suggests

6 Neural integrator in cervical dystonia BRAIN 2016: 139; Figure 3 Kinematic properties of head movements in cervical dystonia. (A L) Examples of head movements in subject with cervical dystonia in a 4-s epoch. Horizontal, vertical, and torsional head movements were recorded as the subject attempted to keep the head to the right (A C, respectively), straight-ahead (D F, respectively), or to the left (G L). Head movements to 30 head positions and during the straightahead position depict slow drifts (large open arrows) and rapid corrections (small closed arrows). There are sinusoidal head oscillations superimposed upon the slow drifts (most prominent during the rightward and straight positions). The slow-phase velocity in all three planes of rotation systematically changes with head-on-trunk orientation (M Q). Direction and size of torsional and horizontal (M) and vertical and horizontal drifts (N) are compared. The line depicts the drift trajectory, while the circular symbol depicts the end of the drift. Torsional (M) and vertical (N) are plotted on the y-axis while the x-axis is horizontal position. Oblique lines suggest presence of drifts in horizontal, vertical, and torsional plane. (O Q) Depicts quantitative comparison of the drift velocity and horizontal head on trunk orientation. Horizontal (O), vertical (P), and torsional (Q) drift velocity are plotted on the y-axis, while corresponding head on trunk orientation is plotted on the x-axis. Each circle depicts one drift. Positive signs depict rightward direction, while negative is the leftward.

7 2596 BRAIN 2016: 139; A. G. Shaikh et al. Figure 4 Neural integrator and its feedback system involving the cerebellum, basal ganglia, vision, and neck proprioception. Proposed feedback system projecting to the head neural integrator. Each system is shown in different colours. The basal ganglia (globus pallidus interna) projects to the neural integrator, but it received neck proprioceptive feedback via the subthalamic nucleus. The neck proprioceptors project to the neural integrator via the cerebellum providing an estimation of the headon-trunk orientation (Shaikh et al., 2004). Visual inputs project to the neural integrator, allowing estimation of the head on trunk orientation. Solid arrows depict definitive excitatory input, unfilled arrows a definitive inhibitory signal, while the arrows with striped patterns depict additional but as yet not confirmed inputs. SC/ FEF = superior colliculus/frontal eye field. an answer to an important question: How do defects affecting different anatomical structures cause similar clinical presentations? The neural integrator concept for cervical dystonia: what does it mean to the clinician? These new concepts for the pathogenesis of cervical dystonia, based on the idea of an impaired neural integrator that receives multiple sources of feedback, are not mere academic exercises in anatomical localization or physiology. They have direct implications for treatment. Specifically, the new concept points to potentially novel stimulation targets for deep brain stimulation. Traditionally, deep brain stimulation for cervical dystonia targets the internal segment of the globus pallidus or the subthalamic nucleus, but outcomes are not predictable (Vidailhet et al., 2005; Kiss et al., 2007). The neural integrator concept suggests that stimulation of the INC or its cerebellar inputs may be a future strategy to treat cervical dystonia. The concept of involvement of the midbrain in the control of 3D head orientation is not new. In the early 1950s Hassler and Hess applied monopolar electrical stimulation near the INC to evoke head movements in normal humans (Hassler and Hess, 1954). Two decades later, during electrical stimulation of the INC, medio-superior red nucleus, and parts of medical longitudinal fasciculus posterior and inferior to the intercommisural line and lateral to the midplane, Sano noted vertical head movements accompanied by marked contraction and electromyographic discharges of posterior neck muscles bilaterally, such as the splenius capitis and trapezius in subjects with cervical dystonia (Sano et al., 1970). Ablation of these regions reduced retrocollis (Sano et al., 1970). Stimulation of an area superior, anterior and lateral to INC resulted in contraction of both sternocleidomastoids accompanied by anteroflexion of the neck (Sano et al., 1970). Periaquaductal stimulation using a weaker electrical charge extinguished electromyographic discharges in bilateral posterior neck muscles followed by improvement in neck muscle tone (Sano et al., 1970). Hassler later targeted the efferent projections of the INC, the ventro-oralis internus thalami, for the surgical treatment of torticollis (Hassler and Dieckmann, 1970) and the prestitial nucleus for retrocollis (Hassler et al., 1981). These procedures were largely abandoned as a treatment for cervical dystonia because results were sometimes unpredictable. This unpredictability is not surprising, because of the lack of a guiding conceptual model regarding how manipulations of these regions might alter head positions. However, in light of the neural integrator hypothesis, we can begin to understand the subtleties of these effects, such as the initial drift of head position after the inactivation of INC (Fig. 2A), and the holding of final head orientation after unilateral stimulation of this nucleus (Fig. 2B). Moreover, these new hypotheses incorporating a neural integrator in the pathogenesis of cervical dystonia, encourage us to revisit these target areas with more refined techniques that might offer therapeutic benefit to subjects with cervical dystonia. Contemporary concepts emphasize the role of feedback in the pathogenesis of dystonias and also link to the most popular treatment of cervical dystonia, botulinum toxin injections. Such therapy not only affects the neuromuscular junction, but it also modulates the afferent output of the cholinergic extra and intrafusal fibres (Filippi et al., 1993; Rosales et al., 1996, 2006). In support of this idea about pathogenesis are the effects of botulinum toxin on the spinal and supra-spinal reflex pathways (Rosales et al., 1996). Additional evidence comes from reduced central excitability with trans-cranial magnetic stimulation in humans after injection of botulinum toxin type A injection into the extensor digitorum brevis muscle (Kim et al., 2006). It is also possible that the effects of botulinum toxin are combined with the secondary effects of muscle weakening on spindle activity and proprioception. Clinical observations also support the idea that botulinum toxin affects the muscle spindle as there is a lack of a simple relationship between the required dose of the toxin and the observed clinical benefit. It is often noted that the abnormal neck

8 Neural integrator in cervical dystonia BRAIN 2016: 139; posture remains despite muscle relaxation by the toxin. Such observations support the idea that inappropriate peripheral input to the head neural integrator leads to the shifts of the null position that characterize cervical dystonia (Klier et al., 2002; Farshadmanesh et al., 2007; Shaikh et al., 2013, 2015a). In summary, we present a novel conceptual framework for the pathogenesis of cervical dystonia that emphasizes the role of abnormal feedback to the midbrain head neural integrator. The idea that proprioception, the cerebellum, and basal ganglia are key sources of feedback to the head neural integrator is compatible with contemporary perspectives on cerebellar or proprioceptive abnormalities as contributors to dystonia, as well as conventionally suggested impairments in the function of basal ganglia. 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