Article

Increased sensorimotor network activity in DYT1 dystonia: a functional imaging study.

Centre for Neurosciences, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, USA.
Brain (Impact Factor: 10.23). 03/2010; 133(Pt 3):690-700. DOI: 10.1093/brain/awq017
Source: PubMed

ABSTRACT Neurophysiological studies have provided evidence of primary motor cortex hyperexcitability in primary dystonia, but several functional imaging studies suggest otherwise. To address this issue, we measured sensorimotor activation at both the regional and network levels in carriers of the DYT1 dystonia mutation and in control subjects. We used (15)Oxygen-labelled water and positron emission tomography to scan nine manifesting DYT1 carriers, 10 non-manifesting DYT1 carriers and 12 age-matched controls while they performed a kinematically controlled motor task; they were also scanned in a non-motor audio-visual control condition. Within- and between-group contrasts were analysed with statistical parametric mapping. For network analysis, we first identified a normal motor-related activation pattern in a set of 39 motor and audio-visual scans acquired in an independent cohort of 18 healthy volunteer subjects. The expression of this pattern was prospectively quantified in the motor and control scans acquired in each of the gene carriers and controls. Network values for the three groups were compared with ANOVA and post hoc contrasts. Voxel-wise comparison of DYT1 carriers and controls revealed abnormally increased motor activation responses in the former group (P < 0.05, corrected; statistical parametric mapping), localized to the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and the inferior parietal cortex. Network analysis of the normative derivation cohort revealed a significant normal motor-related activation pattern topography (P < 0.0001) characterized by covarying neural activity in the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and cerebellum. In the study cohort, normal motor-related activation pattern expression measured during movement was abnormally elevated in the manifesting gene carriers (P < 0.001) but not in their non-manifesting counterparts. In contrast, in the non-motor control condition, abnormal increases in network activity were present in both groups of gene carriers (P < 0.001). In this condition, normal motor-related activation pattern expression in non-manifesting carriers was greater than in controls, but lower than in affected carriers. In the latter group, measures of normal motor-related activation pattern expression in the audio-visual condition correlated with independent dystonia clinical ratings (r = 0.70, P = 0.04). These findings confirm that overexcitability of the sensorimotor system is a robust feature of dystonia. The presence of elevated normal motor-related activation pattern expression in the non-motor condition suggests that abnormal integration of audio-visual input with sensorimotor network activity is an important trait feature of this disorder. Lastly, quantification of normal motor-related activation pattern expression in individual cases may have utility as an objective descriptor of therapeutic response in trials of new treatments for dystonia and related disorders.

Download full-text

Full-text

Available from: Maren Carbon, Jun 26, 2015
0 Followers
 · 
109 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sequential behaviour is widespread not only in humans but also in animals, ranging in different degrees of complexity from locomotion to birdsong or music performance. The capacity to learn new motor sequences relies on the integrity of basal ganglia-cortical loops. In Parkinson’s disease the execution of habitual action sequences as well as the acquisition of novel sequences is impaired partly due to a deficiency in being able to generate internal cues to trigger movement sequences. In addition, patients suffering from Parkinson’s disease have difficulty initiating or terminating a self-paced sequence of actions. Direct recordings from the basal ganglia in these patients show an increased level of beta (14–30 Hz) band oscillatory activity associated with impairment in movement initiation. In this framework, the current study aims to evaluate in patients with Parkinson’s disease the neuronal activity in the subthalamic nucleus related to the encoding of sequence boundaries during the explicit learning of sensorimotor sequences. We recorded local field potential activity from the subthalamic nucleus of 12 patients who underwent deep brain stimulation for the treatment of advanced Parkinson’s disease, while the patients in their usual medicated state practiced sequences of finger movements on a digital piano with corresponding auditory feedback. Our results demonstrate that variability in performance during an early phase of sequence acquisition correlates across patients with changes in the pattern of subthalamic beta-band oscillations; specifically, an anticipatory suppression of beta-band activity at sequence boundaries is linked to better performance. By contrast, a more compromised performance is related to attenuation of beta-band activity before within-sequence elements. Moreover, multivariate pattern classification analysis reveals that differential information about boundaries and within-sequence elements can be decoded at least 100 ms before the keystroke from the amplitude of oscillations of subthalamic nucleus activity across different frequency bands, not just from the beta-band. Additional analysis was performed to assess the strength of how much the putative signal encoding class of ordinal position (boundaries, within-sequence elements) is reflected in each frequency band. This analysis demonstrates that suppression of power in the beta-band contains the most class-related information, whereas enhancement of gamma band (31–100 Hz) activity is the second main contributor to the encoding. Our findings support the hypothesis that subthalamic nucleus-mediated gating of salient boundary elements during sequence encoding may be a prerequisite for the adequate acquisition of action sequences and the transition to habitual behaviour.
    Brain 07/2014; DOI:10.1093/brain/awu191 · 10.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dystonia has historically been considered a disorder of the basal ganglia. This notion comes from the observation that most lesions responsible for secondary dystonia involve the basal ganglia and from the clinical analogy between primary and secondary dystonia. However, recent evidence coming from neuroimaging, neurophysiological and behavioral studies suggested that the Cerebellum may be involved in the pathophysiology of dystonia. Structural and functional magnetic resonance imaging studies documented a widespread pattern of dysfunction in primary dystonia, thus leading us to reconsider it as a neurodevelopmental motor circuit disorder, characterized by an abnormal functioning of a network of cortical and subcortical areas including the Cerebellum. The most compelling neurophysiological evidence supporting the role of the Cerebellum in the pathophysiology of dystonia comes from studies of the eyeblink conditioning paradigm and of the cerebello-cortical interaction. Preliminary data from patients with primary cervical and focal hand adult-onset dystonia show that performance on the eyeblink conditioning paradigm, which is specifically dependent upon the olivo-cerebellar pathway, is abnormal. Cerebello-cortical interaction can be tested with transcranial magnetic stimulation by investigating how a conditioning stimulus over the Cerebellum influences a subsequent stimulus over the controlateral motor cortex. A reduced cerebellar modulation of motor cortex excitability has been reported in dystonia. At the behavioral level, the dystonia cerebellar function has been explored in a broader range of behaviors. Data present in the literature suggest that the Cerebellum may be involved in the impairment of different abilities in dystonic patients ranging from movement control to sensory perception and motor learning. Overall, this body of evidence suggests that in dystonia the Cerebellum has an abnormal activity; however whether this activity is compensatory, secondary to pathology elsewhere within the sensori-motor network, or plays a primary role in the pathophysiology of dystonia is still open to question.
    12/2012; 2(4):231–235. DOI:10.1016/j.baga.2012.05.003
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(35):11991-2004. DOI:10.1523/JNEUROSCI.0041-12.2012 · 6.75 Impact Factor