Secondary dystonia is most commonly associated with lesions of the putamen or globus pallidus, so a common assumption prevails that striatal dysfunction is the principal cause of primary dystonia. Dystonia can, however, also result from lesions of the caudate, thalamus and brainstem (and possibly the cerebellum and frontal or parietal cortex). In fact, in primary dystonia, abnormal CNS function has been documented in nearly every region of the CNS that is relevant for motor control and sensorimotor integration, including the spinal cord, brainstem, cerebellum, basal ganglia and cerebral cortex. Physiological abnormalities can even be present in brain regions that do not correspond to the involved body parts (for example, abnormalities in the ipsilateral cortex, or spinal cord reflex abnormalities in patients with cervical dystonia). The fact that lesions of diverse brain structures can cause secondary dystonia, and the finding that physiological abnormalities in multiple areas of the nervous system are associated with primary dystonia, support the idea that dystonia should be thought of as a motor system or motor circuit disorder, rather than as an abnormalcy of a particular motor structure.
The characteristics of dystonic movements have been used to formulate hypotheses about the nature of the neural processing abnormalities that cause dystonia. The fact that dystonia can be highly task specific has led some to suggest that specific motor programs are disrupted, although this concept remains incompletely understood. Dystonia does not typically spread to body parts corresponding to the well-known somatotopic organization of the nervous system; that is, it does not typically spread from leg to arm to face. In fact, it is not uncommon for dystonia to spread from one limb to the contralateral limb, leading to so-called bibrachial (arms) or bicrural (legs) patterns of involvement. These patterns of spread and the task specificity that can characterize dystonic movements hint at an undefined functional organization of the motor system that could be affected by the disease. Others have hypothesized that co-contraction of agonists and antagonists and spread of activation to muscles not normally involved in a task raise the possibility that the basal ganglia are normally involved in the selection of competing movement representations, a notion that is consistent with some aspects of basal ganglia organization.5
The circuit abnormalities underlying dystonia have been explored using widely varying techniques, including clinical electrophysiological methods (for example, transcranial magnetic stimulation [TMS]), PET and DTI. Two issues confound the interpretation of these studies. First, these methods measure different properties of neural circuits and are performed in a variety of clinical settings, making it difficult to compare the various studies and reconcile them into an integrated view of circuit dysfunction. Second, distinguishing the network abnormalities that cause dystonia from compensatory changes or internal representations of persistent movement or posture is a challenging task. A related complication that arises when studying secondary dystonia is that of determining whether the physiological alterations identified are relevant to dystonia or to the associated neurological abnormalities that exist in these patients.
Eidelberg and colleagues have begun to unravel some of these issues in a series of studies on patients with defined genetic forms of primary dystonia.6–9
They took advantage of the fact that the dominantly inherited mutation that causes DYT1 dystonia ( and discussed below) is only ~30% penetrant, allowing the effects of the mutation to be compared in patients with and without dystonic movements. By performing 18
F-fluorodeoxyglucose PET imaging on non-manifesting DYT1
mutation carriers, as well as on patients with clinically manifesting DYT1 dystonia, both while awake and during sleep (when no dystonic movements are evident), the investigators identified two independent regional metabolic covariance patterns, termed ‘movement-related’ and ‘movement-free’. The movement-related pattern was characterized by increased metabolic activity in the midbrain, cerebellum and thala-mus. This pattern of activity decreased with sleep and was not present in non-manifesting DYT1
mutation carriers. By contrast, the movement-free pattern was characterized by elevated metabolic activity in the lentiform nuclei (putamen and globus pallidus), supplementary motor area and cerebellum, and was present in the brains of both manifesting and non-manifesting DYT1
mutation carriers, including during sleep in the affected patients. These findings indicate the existence of an abnormal motor circuit, represented by the movement-free pattern that is tightly linked to the disease mutation, regardless of the penetrance of dystonia. Interestingly, the abnormalities that are common to manifesting and non-manifesting patients could explain reports that non-manifesting carriers show impairments in motor sequence learning10
or the ability to envision rotation of body parts.11
One cause of the DYT1
-linked aberrant metabolic activity could be abnormalities of white matter micro-structure (that is, an abnormal number, density or morphology of white matter axons). Through use of probabilistic tractography, an imaging method based on DTI scans, Eidelberg and colleagues reported abnormalities of the cerebellothalamocortical axon tracts in manifesting and non-manifesting carriers of the DYT1
All individuals with dystonia-linked genotypes exhibited reductions of the cerebellothalamic tract, but only non-manifesting patients had additional reductions of the thalamocortical tract. These findings give rise to an updated view of the abnormal motor circuitry underlying primary dystonia ().
Figure 2 Motor circuit abnormalities associated with DYT1 genotype and clinical symptom manifestation. Left column shows simplified motor circuit diagrams and right column shows cerebellothalamocortical tract reconstructions from fiber tractography data.4 The (more ...)