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Electrophysiological and behavioral studies in primary dystonia suggest abnormalities during movement preparation, but this crucial phase preceding movement onset has not yet been studied specifically with functional magnetic resonance imaging (fMRI). To identify abnormalities in brain activation during movement preparation, we used event-related fMRI to analyze behaviorally unimpaired sequential finger movements in 18 patients with task-specific focal hand dystonia (FHD) and 18 healthy subjects. Patients and controls executed self-initiated or externally cued prelearnt four-digit sequential movements using either right or left hands. In FHD patients, motor performance of the sequential finger task was not associated with task-related dystonic posturing and their activation levels during motor execution were highly comparable with controls. On the other hand reduced activation was observed during movement preparation in the FHD patients in left premotor cortex / precentral gyrus for all conditions, and for self-initiation additionally in supplementary motor area, left mid-insula and anterior putamen, independent of effector side. Findings argue for abnormalities of early stages of motor control in FHD, manifesting during movement preparation. Since deficits map to regions involved in the coding of motor programs, we propose that task-specific dystonia is characterized by abnormalities during recruitment of motor programs: these do not manifest at the behavioral level during simple automated movements, however, errors in motor programs of complex movements established by extensive practice (a core feature of FHD), trigger the inappropriate movement patterns observed in task-specific dystonia.

The basal ganglia-thalamo-cortical circuits are viewed as segregated parallel feed back loops crucially involved in motor control, cognition, and emotional processing. Their role in planning novel, as compared to overlearned movement patterns is as yet not well defined. We tested for the involvement of the associative striatum (caudate/anterior putamen) in the generation of novel movement patterns, which is a critical cognitive requirement for non-routine motor behavior. Using event related functional MRI in 14 right-handed male subjects, we analyzed brain activity in the planning phase of four digit finger sequences. Subjects either executed a single overlearned four digit sequence (RECALL), or self-determined four digit sequences of varying order (GENERATE). In both conditions, RECALL and GENERATE, planning was associated with activation in mesial/lateral premotor cortices, motor cingulate cortex, superior parietal cortex, basal ganglia, insula, thalamus, and midbrain nuclei. When contrasting the planning phase of GENERATE with the planning phase of RECALL, there was significantly higher activation within this distributed network. At the level of the basal ganglia, the planning phase of GENERATE was associated with differentially higher activation located specifically within the associative striatum bilaterally. On the other hand, the execution phase during both conditions was associated with a shift of activity towards the posterior part of the putamen. Our data show the specific involvement of the associative striatum during the planning of non-routine movement patterns and illustrate the propagation of activity from rostral to dorsal basal ganglia sites during different stages of motor processing.

The mesial premotor cortex is crucial for planning sequential procedures and movement initiation. With event-related (ER) functional magnetic resonance imaging (fMRI) it has been possible to separate mesial premotor activation before, during, and after self-initiated movements and, thereby, to distinguish advance planning from execution. The mesial premotor cortex is part of distributed cortico-basal ganglia-thalamo-cortical networks but, to date, the subcortical contributions to self-initiated movements are far less well understood. Using ER fMRI at 3T in 12 right-handed male volunteers, we studied the subcortical activation preceding an automated four-digit finger sequence that was either self-initiated or triggered externally by a visual cue. Beyond typical cortical activation increases in fronto-parietal regions, both initiation modes induced consistent subcortical activation in basal ganglia, midbrain (substantia nigra), and ipsilateral cerebellum. The planning phase of the internally initiated condition, when contrasted with the externally triggered condition, was associated with enhanced activity in frontal regions (mesial premotor cortex/rostral cingulate zone, dorsolateral prefrontal cortex), parietal regions (precuneus, inferior parietal cortex, encroaching onto V5/MT), insula, contralateral anterior putamen and midbrain (bilateral red nucleus/subthalamic nucleus). These data demonstrate the impact of initiation mode on planning-related activity in the ventral basal ganglia and interconnected midbrain nuclei, thereby stressing the crucial role of distributed cortico-basal ganglia-thalamo-cortical networks for self-initiated automated motor repertoires. Involvement of the substantia nigra during planning, as shown here, indicates dopaminergic gating of motor sequences.

Audiovisual perception and imitation are essential for musical learning and skill acquisition. We compared professional pianists to musically naive controls with fMRI while observing piano playing finger-hand movements and serial finger-thumb opposition movements both with and without synchronous piano sound. Pianists showed stronger activations within a fronto-parieto-temporal network while observing piano playing compared to controls and contrasted to perception of serial finger-thumb opposition movements. Observation of silent piano playing additionally recruited auditory areas in pianists. Perception of piano sounds coupled with serial finger-thumb opposition movements evoked increased activation within the sensorimotor network. This indicates specialization of multimodal auditory-sensorimotor systems within a fronto-parieto-temporal network by professional musical training. Musical ''language,'' which is acquired by observation and imitation, seems to be tightly coupled to this network in accord with an observation-execution system linking visual and auditory perception to motor performance.

The inability to imitate gestures is an essential feature of apraxia. However, discrepancies exist between clinical studies in apraxic patients and neuroimaging findings on imitation. We therefore aimed to investigate: (1) which areas are recruited during imitation under conditions similar to clinical tests for apraxic deficits; (2) whether there are common lateralized areas subserving imitation irrespective of the acting limb side; and also (3) whether there are differences between hand and finger gestures. We used fMRI in 12 healthy, right handed subjects to investigate the imitation of four types of variable gestures that were presented by video clips (16 different finger and 16 different hand gestures with either the right or the left arm). The respective control conditions consisted of stereotyped gestures (only two gestures presented in pseudorandom order). Subtraction analysis of each type of gesture imitation (variable>stereotyped) revealed a bilateral activation pattern including the inferior parietal cortex Brodmann Area (BA 40), the superior parietal cortex, the inferior frontal cortex (opercular region), the prefrontal motor cortex, the lateral occipito-temporal junction, and the cerebellum. These results were supported by statistical conjunction of all four subtraction analyses and by the common analysis of all four types of gesture imitation. The direct comparison of the right and left hemispheric activation revealed a lateralization to the left only of the inferior parietal cortex. Comparisons between different types of gesture imitation yielded no significant results. In conclusion, gesture imitation recruits bilateral fronto-parietal regions, with significant lateralization of only one area, namely the left inferior parietal cortex. These in vivo data indicate left inferior parietal dominance for gesture imitation in right handers, confirming lesion-based theories of apraxia.

Motor imagery is a state of mental rehearsal of single movements or movement patterns and has been shown to recruit motor networks overlapping with those activated during movement execution. We wished to examine whether the brain areas subserving control of sequential processes could be delineated by pure mental imagery, their activation levels reflecting the processing demands of a sequential task. We studied six right-handed volunteers (39.0 +/- 14 years) with H(2)(15)O positron emission tomography (PET) while they continuously mentally pursued with their right hand one of five sequences differing in complexity (i.e., increases in sequence length, single-finger repetitions, and reversals). Conditions were repeated twice, alternating with two rest scans. Each imagined single motor element was paced at a frequency of 1 Hz. Significant activation increases (P < 0.05, corrected) associated with imagination of right finger movement sequences (conditions I to V combined)--compared to the rest condition--were observed in left sensorimotor cortex (M1/S1) and the adjacent inferior parietal cortex. Further activation increases (P < 0.001, uncorrected) occurred in bilateral dorsal premotor (PMd) cortex, left caudal supplementary motor area, bilateral ventral premotor cortex, right M1, left superior parietal cortex, left putamen, and right cerebellum. Activation decreases occurred in bilateral prefrontal and right temporo-occipital cortex. Activation increases that correlated with sequence complexity were observed only in specific areas of the activated network, notably in left PMd, right superior parietal cortex, and right cerebellar vermis (P < 0.05, corrected). In conclusion, our study, by varying the sequence structure of imagined finger movements, identified task-related activity changes in parietopremotor-cerebellar structures, reflecting their role in mediating sequence control.

The aim of this study was to use time-resolved functional magnetic resonance imaging (fMRI) to investigate temporal differences in the activation of the supplementary motor area (SMA) and the primary motor cortex (M1). We report data from eight human volunteers who underwent fMRI examinations in a 1.5T Philips Gyroscan ACS-NT MRI scanner. While wearing a contact glove, subjects executed a complex automated sequence of finger movements either spontaneously or in response to external auditory cues. Based on the result of a functional scout scan, a single slice that included the M1 and the SMA was selected for image acquisition (echo planar imaging, repetition time 100 ms, echo time 50 ms, 64 x 64 matrix, 1,000 images). Data were analyzed with a shifting cross-correlation approach using the STIMULATE program and in-house programs written in Interactive Data Language (IDL(TM)). Time-course data were generated for regions of interest in the M1 as well as in the rostral and caudal SMA. Mean time between onset of the finger movement sequence and half-maximum of the signal change in M1 was 3.6 s for the externally cued execution (SD 0.5) and 3.5 s for the spontaneous execution (SD 0.6). Activation in the rostral section of the SMA occurred 0.7 s earlier than it did in the M1 during the externally cued execution and 2.0 s earlier during the spontaneous execution, a difference significant at the P < 0.01 level. Our results indicate that rostral SMA activation precedes M1 activation by varying time intervals in the sub-second range that are determined by the mode of movement initialization. By applying a paradigm that exerts a differential influence on temporal activation, we could ensure that the observed timing differences were not the result of differences in hemodynamic response function.

Event-related functional MRI (fMRI) was used to study blood oxygen level dependent cortical signal changes associated with volitional limb movements off and on levodopa in Parkinson's disease. Eight patients with early stage akinetic Parkinson's disease and eight healthy volunteers underwent three functional imaging runs (high speed echo planar imaging with 600 scans/run) while performing paced single joystick movements in a freely chosen direction every 7-15 s. The non-magnetic joystick was linked to a monitoring system for on-line registration of performance parameters along with timing of the pacing tones and fMRI-scan acquisition parameters. This allowed correlation of movement onset, i.e. event-onset, to scanning time. We repeated the scanning procedure in the Parkinson's disease patients when akinesia improved 30 min after oral levodopa. Compared with the control group, patients both off and on levodopa showed movement-related impaired activation in the rostral supplementary motor area and increased activation in primary motor cortex (M1) and the lateral premotor cortex bilaterally. Levodopa led to a relative normalization of the impaired activation in the mesial premotor cortex and decreased signal levels in M1, lateral premotor and superior parietal cortex. We conclude that levodopa improves impaired motor initiation in the supplementary motor area and decreases hyperfunction of lateral premotor and M1 associated with Parkinson's disease during simple volitional movements.

We used the Tower of London task (TOL) and H(2)(15)O-PET to map the network of brain structures involved in planning. Six healthy right-handed subjects had 12 measurements of relative regional cerebral blood flow (rrCBF) during six conditions, each performed twice. There was one rest condition, and five sets of TOL problems at different complexity levels, performed on a touch-sensitive computer monitor with the right arm. Complexity was defined as the number of moves required to solve each problem. Activation was analysed in two ways: a category analysis comparing levels of rrCBF during rest and task was done to identify all structures involved in performance of the TOL; and a correlation analysis was carried out to delineate a subset of structures where the levels of rrCBF correlated with task complexity. Activated brain areas in which rrCBF increases did not correlate with complexity could be grouped into: (i) regions belonging to the dorsal stream of visual input processing, namely visual cortical areas 17, 18 and 19, and posterior parietal cortical areas 7 and 40; and (ii) regions involved in the execution and sequencing of arm movements (right cerebellum, left primary motor cortex and supplementary motor area). Brain regions where levels of rrCBF correlated with task complexity included lateral premotor cortex (area 6), rostral anterior cingulate cortex (areas 32 and 24), dorsolateral prefrontal cortex (areas 9 and 46) bilaterally, and right dorsal caudate nucleus. We propose that dorsolateral prefrontal, lateral premotor, anterior cingulate and caudate areas form a network for the planning of movement that interacts with brain areas primarily involved in visual processing and movement execution.

Repeated PET cerebral blood flow measurements using H2(15)O were performed in 13 patients with confirmed Huntington's disease and nine age-matched controls. The activation paradigm consisted of an externally triggered finger opposition task (1.5 Hz) with the dominant hand, the control condition being the auditory input. In the patients with Huntington's disease, impaired activity of the striatum and its frontal motor projection areas (rostral supplementary motor area, anterior cingulate and premotor cortex) could be demonstrated along with enhanced activity mainly in parietal areas during movement. The results suggest that the pathology of Huntington's disease causes impairment of the output part of the basal ganglia-thalamo-cortical motor circuit and may induce a compensatory recruitment of additional accessory motor pathways involving the parietal cortex.

Regional cerebral blood flow was measured with H2(15)O PET in seven patients with choreic Huntington's disease and seven age-matched control subjects. Subjects were scanned at rest and when performing paced joystick movements, in freely chosen directions, with the dominant arm. During movement, the patients showed impaired activation of contralateral primary motor, medial premotor, bilateral parietal and bilateral prefrontal areas along with increased activation of bilateral insular areas. The underactivity of frontal areas in Huntington's disease is similar to the pattern of impaired activation in Parkinson's disease and is likely to result from degeneration of basal ganglia to frontal projections. Primary motor underactivity may explain the bradykinesia that these patients exhibit and, if inhibitory neurons are involved, also their chorea.

Patients with Parkinson's disease have great difficulty in performing sequential and bimanual movements. We used H2(15)O PET to study the regional cerebral blood flow associated with performance of sequential finger movements made unimanually and bimanually in a group of Parkinson's disease patients and a group of control volunteers. In controls, sequential finger movements led to activation of the contralateral motor cortex and inferior parietal cortex (Brodmann area 40), the lateral premotor cortex and bilateral supplementary motor area. No prefrontal activation was seen. Sequential finger movements in the Parkinson's disease group were associated with a similar pattern of activation but there was relative impairment of activation in the mesial frontal and prefrontal areas. A novel finding was the presence of relative overactivity in the lateral premotor and inferolateral parietal regions. We conclude that in Parkinson's disease there is a switch from the use of striato-mesial frontal to parietal-lateral premotor circuits in order to facilitate performance of complex finger movements.

Abstract: The existence of forward internal models is a fundamental principle in theories of predictive motor control. There are indications that internal models are represented in the cerebellum. So far, no conclusive data exist on automated procedures involving predictive motor behavior. In particular, it is unknown whether single or multiple task-specific internal models handle the broad range of behavioral situations in which they occur. Using H2 15O PET in eight subjects, we examined predictive motor control in an automated grip force–load force coupling task at three differing load force levels. In the experimental condition, subjects pulled a grasped object against an isometric resistance while simultaneously producing anticipatory grip forces. There were three control conditions (pull force isolated; grip force isolated; motor rest). A 2 × 2 factorial design was chosen to reveal the interaction effect of grip force–pull force coupling. The factors were pull force (with/without) and grip force (with/without). Grip and load forces were well matched between experimental and control conditions. Conjunction inference and interaction analyses identified force coupling related activity in the ipsilateral posterior cerebellum that was independent of force levels. Interaction effects were also identified in the anterior cingulate and frontal association regions, the right caudate nucleus, and the left lingual gyrus. These data demonstrate the existence of modular representations for predictive force coupling, with the ipsilateral cerebellum playing a major role. Moreover, the data implicate that the representations for predictive force control are applicable to a range of different environmental affordances. [Copyright &y& Elsevier]