Impaired sequence learning in carriers of the DYT1 dystonia mutation

Abstract

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age-matched controls. Regional differences in brain function during task performance were assessed with simultaneous H 2 15 O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning. Neurol 2003;54:102-109 Primary torsion dystonia is a hyperkinetic movement disorder associated with several genetic variants. Ann1 One genetic variant is the GAG deletion in the DYT1 gene at 9q34. This mutation commonly causes early limb onset primary torsion dystonia and is inherited as an autosomal dominant condition with incomplete (30 -40%) clinical penetrance.2 Using 18 F-fluorodeoxyglucose and positron emission tomography (PET), we had identified previously abnormalities in resting glucose utilization in the putamen/globus pallidus, supplementary motor area (SMA), and cerebellum of DYT1 mutation carriers, including clinically nonpenetrant subjects in whom signs and symptoms of dystonia are lacking. 3,4 Given the presence of metabolic abnormalities in key elements of motor control pathways, we sought to determine whether clinically unaffected mutation carriers also display abnormalities in the trajectory control of reaching movements and in learning motor sequences. To this end, we utilized a series of tasks with similar and welldefined kinematics to assess performance during motor execution and learning. 5,6 Simultaneous PET recordings were acquired during task performance to determine whether specific abnormalities in brain activation responses were present within corticostriatopallidothalamocortical loops and related pathways. Subjects and Methods SubjectsWe studied 12 right-handed nonmanifesting carriers of the DYT1 mutation (four men and eight women; aged 50.3 Ϯ 14.4 years, mean Ϯ standard deviation [SD]). These subjects were recruited through the Dystonia Clinical Research Center at Beth Israel Hosp...

Implicit and explicit aspects of sequence learning in pre-symptomatic Huntington's disease

“…General features of the motor tasks have been detailed previously [16,17]. Briefly, subjects moved a cursor on a digitizing tablet with their right hand out and back from a central starting point to one of eight radially arrayed targets at 1.6 cm distance.…”

“…We use tasks where subjects are explicitly asked to learn and anticipate the order of appearance of eight targets. We have previously shown that, with these tasks, normal subjects typically learn the order of simple repeating sequences in ninety seconds or less, either when learning occurs while reaching for targets or when, in a less demanding situation, the sequence order is first learned visually, without moving [16][17][18]. Learning of the sequence order is reflected by decreases of onset time, as subjects move out of reaction-time mode and anticipate target appearance, and measured with discrete variables, such as the number of correct anticipatory movements.…”

“…This implicit learning occurs in tasks where target anticipation is possible and is seen as a shift from a time-saving (as in reaction time tasks) to an energy-saving (as in timed-response tasks) strategy. In summary, in our sequence learning tasks, the order of the elements is mostly learned explicitly and can be quantified with the number of correct anticipatory movements, while the ability to modulate movement time and thus, to change motor strategy is learned without awareness, implicitly, and can be measured with movement time changes [16][17][18].…”

Neuroimaging and therapeutics in movement disorders

“…38 Whereas this characteristic pattern was initially identified in affected PTD patients, 106 its presence was subsequently confirmed in genotyped subjects, even without clinical manifestations. 38,39,107 Further studies revealed subtle behavioral impairments in nonmanifesting DYT1 carriers, 108 as well as abnormalities in brain activation responses during movement and nonmotor learning. It is therefore possible that TDRP expression can represent an endophenotype for dystonia, which may be useful in gene identification in at risk populations (FIG.…”

TorsinA and the Pathophysiology of DYT1 Dystonia

“…Theoretically, this cerebellar abnormality could be primary or secondary to dysfunction of the basal ganglia. However, in DYT1 carriers, functional imaging suggests the primary dysfunction of the basal ganglia leads to compensatory maladaptive neural output from the cerebellum (Ghilardi et al, 2003;Carbon et al, 2008b).…”