Clinical features of dystonia: a pathophysiological revisitation Angelo Quartarone, Vincenzo Rizzo and Francesca Morgante

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1 Clinical features of dystonia: a pathophysiological revisitation Angelo Quartarone, Vincenzo Rizzo and Francesca Morgante Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche, Università di Messina, Messina, Italy Correspondence to Dr Angelo Quartarone, Dipartimento di Neuroscienze, Scienze Psichiatriche ed Anestesiologiche, UOC Neuropatologia, Via Consolare Valeria 1, Messina, Italy Tel: ; fax: ; angelo.quartarone@unime.it Current Opinion in Neurology 28, 21: Purpose of review To elucidate the pathophysiology of some clinical features of dystonic patients and to provide some new insight into the mechanisms underlying task-specific dystonia. Recent findings There are three general lines of work at the present time that may indicate the physiological substrate for dystonia. All three are persuasive and it is not clear whether they are related to each other or whether one is more important than the others. According to the first line of research, a loss of inhibition at different levels of the central nervous system might contribute for the excessive movement seen in dystonia. Another field of research suggests that dystonic patients may have faulty processing within the lemniscal pathway with abnormalities in the sensory-motor integration. Finally, another convincing line of evidence is that in some susceptible individuals, during the acquisition of new motor skills, the mechanisms of neuroplasticity are subtly abnormal. In the presence of such predisposition, several environmental factors, such as repetitive training or peripheral nervous system injury, can trigger an abnormal maladaptive plasticity, which can lead to an overt dystonia. Summary These findings may be relevant in the development of new therapeutic strategies in dystonia. Keywords cortical plasticity, dystonia, surround inhibition, task specificity Curr Opin Neurol 21: ß 28 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction Dystonia is defined as a neurological syndrome characterized by an involuntary, sustained, patterned and often repetitive muscle contraction of opposite muscles, causing twisting movements or abnormal posture [1]. It represents the third most common movement disorder in humans [2,3]. Primary adult-onset dystonia is the most common form of dystonia; it is often focal and includes a large number of clinical syndromes such as blepharospasm, oromandibular dystonia, cervical dystonia, laryngeal dystonia, or upper limb dystonia. Usually, dystonic movements tend to worsen when performing a specific action (action dystonia). As the dystonic condition progresses, less specific actions of the affected limb or voluntary movements in other parts of the body can induce dystonic postures (overflow). With further worsening, dystonia is present even at rest and the limb goes into the classic sustained posture. Although they have a limited tendency to generalize, adult-onset focal dystonias may spread over time to adjacent body regions with a higher risk within the first 5 years of disease for patients with blepharospam [4]. Another fascinating and intriguing feature of dystonia is the task specificity. For instance, in simple writer s cramp, the simple act of handwriting induces the classic dystonic posture, whereas the same patient can use the hand normally in other motor tasks [5]. In the present review article, an attempt has been made to elucidate the pathophysiology of some clinical features related to dystonia and provide some new insight into the mechanisms underlying task-specific dystonia. Abnormal muscle cocontraction in dystonia The core feature of dystonia is an abnormal cocontraction of agonists and antagonists muscles worsened by certain task-specific actions and sometimes relieved by some sensory tricks [6]. The abnormal cocontraction is caused by a dysfunction either at the spinal or cortical level or both. Reciprocal inhibition is the central nervous system process in which a muscle is inhibited when its antagonist is activated. It has several components and the second longer phase of reciprocal inhibition, tested at the spinal level, is absent in patients with focal hand dystonia [7]. This decreased reciprocal inhibition is due to reduced presynaptic ß 28 Wolters Kluwer Health Lippincott Williams & Wilkins

2 Pathophysiological hallmark of dystonia Quartarone et al. 485 inhibition of the muscle afferent input onto the inhibitory Ia interneuron innervating the muscle antagonist to the input. This alteration could arise from either a defective descending control or changes in the tonic afferent input to the Ia interneuron from cutaneous and muscle afferents [8]. The inhibitory interactions between antagonist muscles are also abnormal at the sensory-motor cortex level [9]. Intramuscular injection of botulinum toxin in dystonic patients can successfully ameliorate the involuntary muscle activity and improve the reciprocal inhibition by increasing presynaptic inhibition [1]. It has been postulated that the toxin alters the circuits of reciprocal inhibition by modifying the tonic sensory outflow from the injected muscles as the gamma motoneuron synapses onto the muscle spindles will be blocked. The fact that muscle afferents have a role in producing dystonic movements is also supported by the work of Kaji et al. [11] who studied the tonic vibration reflex in writer s cramp. A vibrator applied on the hand induced a dystonic posture and local injection of lidocaine into muscles markedly decreased the dystonic movements. Pathophysiology of overflow phenomena in muscular contraction One peculiar clinical feature of dystonia is the excess of movement. This has been demonstrated with electromyographic (EMG) recordings that have shown abnormally long bursts of EMG activity, cocontraction of antagonist muscles, and an overflow of activity into muscles not involved in the task [12]. Several lines of evidence suggest that a loss of inhibition may contribute to the excessive movement seen in dystonic patients. This alteration of inhibitory circuit has been reported at the spinal level (reciprocal inhibition), brainstem, and at the cortical level [13]. Transcranial magnetic stimulation (TMS) allows the study of inhibitory interneurons at the cortical level by looking at different phenomena, including short intracortical inhibition, long intracortical inhibition, and the silent period. The details of these techniques are given elsewhere [14]. Several studies have reported alterations of many types of cortical inhibition in patients with dystonia [15 19]. However, these alterations are rather nonspecific in that they have also been observed in various other neurological conditions and even in psychogenic dystonia [19]. How can a deficit of inhibitory intracortical circuits translate into the typical dystonic unfocused muscular activation? It is likely that when a specific voluntary movement is generated, the brain has to suppress other possible movements [2]. In this way, the motor cortex could produce a more accurate movement, just as surround inhibition in sensory systems allows a fine perception. Evidence that bicuculline injected into the primate motor cortex produces cocontraction of various muscles strongly suggests that surrounding inhibition is mediated through gamma aminobutyric acid A (GABAA) inhibitory intracortical mechanisms [21]. Several observations have demonstrated the presence of reduced levels of GABA in both the basal ganglia and the sensory motor cortex in dystonic patients [22]. There is now good evidence for surround inhibition in human movement. Sohn and Hallett [23] have shown that with the movement of one finger there is widespread inhibition of muscles, not involved in the task, in the contralateral limb. Patients with focal hand dystonia showed a clear alteration of this surround inhibition compared with normal individuals as studied with TMS [24] (Fig. 1). These results are clinically relevant and can explain the difficulty of dystonic patients to focus voluntary motor command. As an extension of these data, we have recently demonstrated an alteration of surround inhibition even when dystonic patients imagine a voluntary movement [25]. Briefly, we applied focal TMS over the primary motor area and recorded motor evoked potentials (MEPs) from the contralateral hand and arm muscles while participants imagined a tonic abduction of the index finger contralateral to the stimulated hemisphere. In healthy individuals, the MEP amplitude in the relaxed first dorsal interosseus (FDI) muscle showed a muscle-specific increase during motor imagery with no change in the other hand and forearm muscles. On the contrary, in patients with focal hand dystonia, the MEP amplitude also increased in surrounding muscles not involved in the imagined movement. The abnormalities we observed during imagination can explain why dystonic movements can be worsened by the attempt to perform a voluntary action. For instance, in patients with writer s cramp, the typical dystonic posture develops just from holding a pen, even before writing. In some patients, the mere intention of writing can occasionally trigger dystonic spasms [26]. Sensory symptoms and sensory abnormalities in dystonia Although dystonia is generally considered as a motor disorder, it is often preceded by sensory symptoms [27]. Indeed, discomfort, pain, and abnormal kinaesthetic

3 486 Movement disorders Figure 1 Study of surround inhibition in healthy individuals and in patients affected by focal hand dystonia (a) (b) (c) (d) Changes in motor-evoked potential (MEP) amplitude of tested muscles in self-triggered transcranial magnetic stimulation (TMS) at each interval (3, 15, 4, 8, 2, 5, and milliseconds) from electromyography (EMG) onset of flexor digitorum superficialis (FDSs) to TMS, compared with the resting state. (a) MEP amplitudes of abductor digiti minimi (ADM) are significantly suppressed in healthy individuals but are enhanced in patients during voluntary flexion of the index finger. (b d) MEP amplitudes of first dorsal interosseus (FDI), extensor indicis proprius, and FDS were significantly enhanced both in patients and healthy individuals during and immediately after voluntary flexion of the index finger. () significant difference between patients and healthy individuals (P <.5). () patients; () normal individuals. sensations are frequently reported weeks or months before dystonic symptoms appear. Moreover, patients with blepharospasm often complain of ocular symptoms such as irritation or dry eye [28]. Patients sometimes interpret their dystonic movements as an attempt to decrease the discomfort caused by these abnormal sensations [29]. Although there are no gross abnormalities of elemental sensation in dystonia, psychophysical studies have demonstrated an impairment of somatosensory temporal and spatial discrimination in dystonia [3 33]. The deficit of temporal discrimination is likely to be a primary alteration of dystonia as it is impaired in unaffected body parts such as the hand, in patients with blepharospasm [34] and in the unaffected carriers of the DYT1 mutation [35 ]. What is the cause of these subtle sensory abnormalities? Several neurophysiological evidences suggest that patients with dystonia have faulty processing within the lemniscal pathway with abnormalities in the sensorymotor integration [29,36]. In particular, Abbruzzese et al. [37] demonstrated that motor cortical excitability (as tested with TMS) is significantly reduced to 2 ms after conditioning stimulation of the contralateral median nerve in normal individuals but not in patients with focal hand dystonia (Fig. 2). Finally, functional neuroimaging studies suggest that finger representation within the primary motor cortex is distorted with abnormal finger representation with enlarged and overlapping tactile receptive fields [38 4]. In addition, Meunier et al. [41] have shown that in unilateral task-specific dystonia, disorganization of somatic representation is not only limited to the dystonic

4 Pathophysiological hallmark of dystonia Quartarone et al. 487 Figure 2 Effect of conditioning stimulation of the median nerve on the test motor-evoked potential amplitude in normal controls, in patients with cervical dystonia, and in patients with hand dystonia Conditioned 2 Conditioned 15 5 APB FCR Conditioned 15 Conditioned 15 5 FDI 5 ECR Each point corresponds to the mean (þ standard error) size of the conditioned MEP, expressed as a percentage of the mean size of the unconditioned MEP. The C-T intervals are reported in the abscissa. The test MEPs in the APB and FDI muscles are inhibited by conditioning the stimulation of the median nerve at the wrist in normal controls and cervical dystonia patients, whereas they are facilitated in the hand dystonia patients. No significant modification was observed for the test MEPs in the FCR and ECR muscles. APB, abductor pollicis brevis; C-T, conditioning-test; ECR, extensor carpi radialis; FCR, flexor carpi radialis; FDI, first dorsal interosseus; HC, patients with hand dystonia; MEP, motor-evoked potential; NC, normal controls; ST, patients with cervical dystonia. ( & ) NC; ( & ) HC; ( ~ ) ST. hand but also to the nondystonic hand, suggesting that these sensory abnormalities could be an endophenotypic trait of dystonias. The correct execution of a voluntary movement depends crucially also on the peripheral sensory feedback. Hence a faulty sensory assistance to ongoing motor programs might result in motor abnormalities such as a simultaneous contraction of agonist and antagonist muscles (cocontraction) or inappropriate contraction of distant surrounding muscles (overflow) [29]. Task specificity: the case of occupational dystonias In some focal dystonias, symptoms become only apparent if patients perform a specific motor task [26] and are absent when the same part of the body is used in a different task. The occurrence of dystonia in these high-skilled movements suggests a breakdown within motor memories [42]. This task specificity may be observed in other types of focal dystonia such as pianist s cramp, typist s cramp, and other cramps, which are known as occupational dystonias. In some patients, dystonic symptoms can be associated with periods of intensive training of a particular movement. This is very common in musician s dystonia, in which the patients spend many hours per day with their attention focused on instrumental practice. In an animal model of dystonia, Byl et al. [43] demonstrated that primates who were trained to make a particular highly specific hand movement (while receiving a synchronous vibration on the whole hand) can develop a clinical condition which is very similar to focal hand dystonia. What is interesting to note is that the finger map within the somatosensory cortex was distorted with larger receptive fields and overlapping representations of the individual digits. Musician s dystonia can be considered a form of traininginduced dystonia comparable to that described in the primate models. It can be postulated that, if motor training is pushed to an extreme, it can produce a maladaptive sensory-motor reorganization, which interferes with the task performance rather than improving it.

5 488 Movement disorders However, this model of dystonia only shows that some types of repetitive activity can lead to an abnormal reorganization of the sensory-motor cortex and dystonia but does not give any clues as to why only in humans, some develop dystonia after excessive training whereas others are completely healthy. Thus, it may be that focal dystonias in humans, caused by excess practice or injury, only occur in individuals with preexisting abnormalities of neural plasticity that are probably under genetic influence. There are several evidences suggesting that normal mechanisms of neural plasticity that are recruited after injury or during practice may be subtly abnormal in dystonic patients [44 47]. A number of noninvasive neurophysiological methods have recently been developed to study plasticity at a system regional level in the human brain looking at longterm potentiation (LTP) and long-term depression (LTD) phenomena. In an experimental protocol named paired associative stimulation (PAS), low-frequency median nerve stimulation is paired with TMS over the primary motor cortex. The direction of excitability changes induced by PAS critically depends on the interstimulus interval (ISI) between the peripheral and cortical stimulus [48]. Depending on the ISI between median nerve stimulation and TMS, PAS can facilitate or inhibit the excitability of corticospinal output neurons as indexed by changes in MEP amplitude. In addition, PAS after-effects have a topographical specificity in that they are limited to muscles innervated by the median nerve. Patients with focal hand dystonia show two main abnormalities: first, the amount of MEP facilitation and inhibition is larger than normal; and second, the spatial specificity is lost so that the after-effects also occur in muscles that are innervated by the ulnar nerve [44,45] (Fig. 3). This excessive motor cortex plasticity is not restricted to the circuits clinically affected by dystonia but generalizes across the entire sensorimotor system, possibly representing an endophenotypic trait of the disease [47]. Considering that the circuits tested by PAS are the same engaged by motor learning [49,5] we could assume that dystonic patients may have subtle learning abnormalities within the motor cortex. This is in keeping with the work of Ghilardi et al. [51]who demonstrated that DYT1 gene carriers exhibit a defect in the learning of sequential movements. Another well established artificial protocol to induce plasticity in human motor cortex is the theta burst stimulation (TBS) [52]. In this paradigm, TMS pulses are applied in high-frequency bursts of three pulses at 5 Hz, repeated five times per second. These are theta burst paradigms, so called because the theta rhythm in electroencephalogram has a frequency of 5 Hz. Bursts that are applied intermittently (2 s on, 8 s off, repeated 2 times to give 6 TMS pulses in total) cause facilitation Figure 3 Abnormal plasticity of sensori-motor circuits in focal hand dystonia (a) (b) Baseline APB muscle 25 ms FDI muscle (a) During interventional stimulation, 9 pairs of stimuli, consisting of electrical stimuli delivered to the right median nerve followed by TMS over the left hemisphere at the optimal site for activating the APB muscle, were applied at an interstimulus interval of 25 ms and interpair interval of 2 s (.5 Hz). (b) Effect of associative stimulation on the size of MEPs of the right APB and FDI muscle in 1 healthy controls and 1 patients with writer s cramp. The bar chart illustrates the mean percentage of MEP increase with respect to baseline after associative stimulation. Each error bar equals SEM. Associative stimulation led to an increase in in patients and controls. However, in dystonic patients, the facilitatory effect was significantly stronger and less focused, spreading also in ulnar innervated muscles. APB, abductor pollicis brevis; FDI, first dorsal interosseus; MEP, motor-evoked potential. healthy individuals; focal hand dystonia. whereas continuous theta bursts for 4 s (a total of 6 pulses) lead to suppression. Edwards et al. [53] reported that long-lasting effects after TBS were enhanced in patients with primary dystonia either due to the DYT1 gene or non genetic. Nonaffected DYT1 gene carriers also differed from controls but in the opposite direction, with no effect of such an intervention. In other words, the lack of TBS after-effects in nonaffected DYT1 gene carriers may protect them from developing dystonia. What drives the abnormal responsiveness of the sensorymotor cortex in focal dystonia to these artificial paradigms inducing plasticity? To maintain the overall synaptic excitation at a stable level, synaptic plasticity needs to be constrained by homeostatic regulatory mechanisms [54,55]. According to the homeostatic rule, a prolonged increase in the ongoing activity would lower the LTD threshold and raise the LTP threshold; conversely, the lower the

6 Pathophysiological hallmark of dystonia Quartarone et al. 489 activity of the postsynaptic neurones, the more effective are processes that lead to LTP. We have tested homeostatic plasticity in the human motor cortex of patients affected by focal hand dystonia by employing a protocol recently described in humans [56]. Indeed, patients with focal hand dystonia have a difficulty to depotentiate the motor cortex after an artificial protocol inducing LTP [57]. How can abnormalities of cortical plasticity translate to the usual symptoms experienced by dystonic patients? We can speculate that, during the formation of motor engrams, a fine-tuning of plasticity levels through homeostatic mechanisms could reduce behavioral interference between subsequent motor tasks, thus avoiding the consolidation of movement combinations that are not wanted. When this process goes wrong, it leads to the consolidation of abnormal motor engrams containing redundant muscular activation, which can culminate in an overt dystonia. Conclusion In conclusion, it could be hypothesized that in susceptible individuals during the acquisition of new motor skills, the mechanisms of neuroplasticity are subtly abnormal (genetic influence). Work trying to identify abnormal genes controlling plasticity in patients with focal dystonia is ongoing, but this is very difficult given the low penetrance. On top of that, several environmental factors such as repetitive training or peripheral nervous system injury in the presence of this genetic background can trigger an abnormal maladaptive plasticity, which can lead to an overt dystonia. PAS abnormalities may be an important link in demonstrating how environmental influences can trigger dystonia. What is the relevance of these new concepts on the development of new therapeutic approaches? Several rehabilitative treatments employing sensory and motor training have been proposed on the basis that this may help patients to activate their muscles more selectively [58]. All these approaches produce some improvement in the short term, and the challenge is to make them last longer. It is likely that if the primary disorder is one of homeostatic regulation of neural plasticity, this will predispose individuals to relapse to dystonia, particularly if the system is overloaded again by excessive training. The implication is that retraining should be monitored carefully to see whether or not it is beginning to induce excessive plastic changes in the motor system, which can induce the reoccurrence of dystonic movements. 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