Scientific Commentary |
New advances in the pathophysiology of focal dystonias
In this issue of Brain two studies using different techniques report novel findings on the pathophysiology of focal dystonias. The first paper (Dresel et al., 2006
) reports a functional MRI (fMRI) study in patients with cranial dystonia during a whistling task and the second (Fiorio et al., 2006) describes the results of a study on mental body rotation in patients with writer's cramp. Both papers open interesting new questions for further study.
Dystonia is a syndrome characterized by excessive and sustained muscle contractions causing abnormal postures and involuntary movements. It is attributed to basal ganglia abnormalities and to a dysfunction of the cortico-striato-thalamo-cortical circuits. Focal dystonia is more common than generalized dystonia. It affects a single body part: the cranium, the neck or the hand. Cranial dystonia is characterized by involuntary spasms of the orbicularis oculi muscles (blepharospasm) resulting in forced eyelid closure and involuntary movements in the lower part of the face (oromandibular dystonia). Both conditions may manifest in the same patient or one condition alone may be present. Over the past two decades, studies using neurophysiological and neuroimaging techniques have done much to clarify the pathophysiological mechanisms underlying cranial and hand dystonia (Berardelli et al., 1998).
In patients with cranial dystonia, neurophysiological investigations have demonstrated various abnormalities of brainstem function. For example, reflex testing discloses abnormalities in the R2 component of the blink reflex, reflecting enhanced excitability of the brainstem interneuronal pathways. The blink reflex abnormalities have been attributed to an abnormal descending control of blink circuits, secondary to abnormal activity within the basal ganglia thalamo-cortical loops. Studies using the technique of magnetic brain stimulation in patients with cranial dystonia have also disclosed cortical dysfunction (Currà et al., 2000). Finally, studies testing how sensory information is processed have introduced the concept that patients with cranial dystonia also have impaired sensorimotor integration (Abbruzzese and Berardelli, 2003).
In their study of cranial dystonia, Dresel and co-workers report on brain activation patterns obtained with fMRI in patients with blepharospasm and oromandibular dystonia during whistling, a skilled orofacial movement with a high sensorimotor demand. This experimental paradigm tests the oromandibular motor system that affected in patients with cranial dystonia presenting with blepharospasm and oromandibular dystonia. The authors tested this system also in patients with blepharospasm alone, in whom the oromandibular system is clinically spared. In patients with blepharospasm and oromandibular dystonia, fMRI showed deficient activation of the primary motor and ventral premotor cortex within the mouth representation area during whistling, whereas in patients with blepharospasm alone it showed normal cortical activation. Another finding was that in both groups of patients, compared with healthy subjects, fMRI activation patterns during the whistling task showed overactivity in the somatosensory regions and in the caudal supplementary motor area (SMA).
The changes in cortical activation that Dresel et al. report in patients with cranial dystonia partially differ from the abnormalities previously described in generalized and focal dystonia. Previous neuroimaging studies have reported findings compatible with enhanced activation of primary sensorimotor cortex in patients with dystonias, probably reflecting differences in the underlying pathophysiology. For example, abnormalities in sensorimotor integration play a less important role in the pathophysiology of generalized dystonia than in the focal forms (Molloy et al., 2003). In addition, neurophysiological differences have been demonstrated even between the various forms of focal hand dystonia (Rosenkranz et al., 2005).
What causes the impaired activation of motor and premotor cortex as demonstrated with neuroimaging techniques still needs further study. The fMRI technique used by Dresel and co-workers unfortunately cannot specify whether abnormal motor cortical activation reflects changes in the activity of the excitatory or the inhibitory structures in the motor cortex. More information could be gained with neurophysiological methods combined with an imaging technique such as fMRI.
The action of toxins on the central nervous system has provided useful insight into the pathophysiology of dystonia. Dresel and co-workers show that in patients with blepharospasm and oromandibular dystonia, botulinum toxin therapy partly reversed the overactivity in the post-central gyrus and caudal SMA but left the impaired activation of the motor and premotor cortex unchanged. The authors conclude that the impaired motor activation is caused by the primary dysfunction in orofacial dystonia. The effects seen with neuroimaging techniques after botulinum toxin injection are intriguing. In patients with dystonia, some evidence shows that botulinum toxin therapy can alter the excitability of the motor cortex possibly by reducing kinaesthetic input after peripheral motor denervation (Gilio et al., 2001; Kañovsk
et al., 2005). Botulinum toxin can therefore produce clinical effects not only by producing muscle weakness but also by normalizing the abnormal cortical somatosensory activation presented by these patients.
Fiorio and co-workers investigated a mental rotation task in patients with hand dystonia. Mental rotation is a cognitive task in which subjects imagine moving their body parts from the actual posture into that of the stimulus.
Patients with hand dystonia may have dystonic movements at rest or during specific motor tasks, such as writing or playing a musical instrument. In the past decade, numerous neurophysiological studies have investigated the pathophysiology of hand dystonia. Reflex studies have demonstrated a lack of inhibition at the spinal cord level and magnetic stimulation of motor cortex has shown increased excitability and an abnormal plasticity of cortical motor areas (Berardelli et al., 1998). Another common neurophysiological finding in patients with hand dystonia is defective sensorimotor integration, a process whereby sensory information is used for the control and execution of a voluntary movement (Abbruzzese and Berardelli 2003). For example, patients with dystonia have impairment of graphaesthesia, spatio-temporal discrimination and temporal processing of visuotactile and tactile stimuli. Fiorio and co-workers demonstrate that patients with writer's cramp have impairment of mental hand rotation. This task integrates sensory information with motor actions. The authors found that the reaction time in mentally rotating hands was longer in patients with hand dystonia than in normal subjects. Insofar as the mental rotation task investigates a complex form of sensorimotor integration, the abnormally long reaction time adds further information to growing evidence indicating defective sensorimotor information in hand dystonia.
Because the mental hand-rotation task used in this study activates a complex neural network including the basal ganglia, Fiorio et al. conclude that the abnormalities of mental rotation function in hand dystonia arise from basal ganglia dysfunction. Because mental rotation requires the integrity of cortical as well as subcortical structures, precisely how the various brain systems controlling this cognitive task contribute nevertheless remains to be elucidated in these patients. Further studies might investigate how performance of the mental hand-rotation task differs in patients with cranial dystonia and those with other motor disorders, such as Parkinson's disease and Huntington's disease.
These two papers usefully extend our understanding of the pathophysiology of cranial and hand dystonia. In addition to the well-accepted concept that dystonias are characterized by a lack of inhibition at various motor system levels, by an abnormal cortical plasticity and by defective sensorimotor integration, the challenge for the coming years will be to identify the pathophysiological differences between the different types of dystonia, conditions that are still considered clinically similar.
Department of Neurological Sciences and Neuromed Institute, University of Rome ‘La Sapienza’, Rome, Italy E-mail: alfredo.berardelli{at}uniroma1.it
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