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1.  The functional neuroimaging correlates of psychogenic versus organic dystonia 
Brain  2013;136(3):770-781.
The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family-wise small-volume correction). These data show a cortical–subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions.
doi:10.1093/brain/awt008
PMCID: PMC3580272  PMID: 23436503
psychogenic movement disorder; fixed dystonia; DYT1 gene; functional imaging; motor; cerebellum; basal ganglia; dorsolateral prefrontal cortex; attention
2.  Plasticity of cortical inhibition in dystonia is impaired after motor learning and Paired-Associative Stimulation 
Summary
Artificial induction of plasticity by paired associative stimulation (PAS) in healthy subjects (HV) demonstrates Hebbian-like plasticity in selected inhibitory networks as well as excitatory ones. In a group of 17 patients with focal hand dystonia and a group of 19 HV, we evaluated how PAS and the learning of a simple motor task influence the circuits supporting long interval intracortical inhibition (LICI, reflecting activity of GABAB interneurons) and long latency afferent inhibition (LAI, reflecting activity of somatosensory inputs to the motor cortex).
In HV, PAS and motor learning induced LTP-like plasticity of excitatory networks and a lasting decrease of LAI and LICI in the motor representation of the targeted or trained muscle. The better the motor performance, the larger was the decrease of LAI. Although motor performance in the patient group was similar to that of the control group, LAI did not decrease during the motor learning as it did in the control group. In contrast, LICI was normally modulated. In patients the results after PAS did not match those obtained after motor learning: LAI was paradoxically increased and LICI did not exhibit any change.
In the normal situation, decreased excitability in inhibitory circuits after induction of LTP-like plasticity may help to shape the cortical maps according to the new sensorimotor task.
In patients, the abnormal or absent modulation of afferent and intracortical long-interval inhibition might indicate maladaptive plasticity that possibly contributes to the difficulty that they have to learn a new sensorimotor task.“
doi:10.1111/j.1460-9568.2012.08034.x
PMCID: PMC3310890  PMID: 22429246
motor learning; dystonia; transcranial magnetic stimulation; GABA; plasticity
3.  Convergent evidence for abnormal striatal synaptic plasticity in dystonia 
Neurobiology of disease  2009;37(3):558-573.
Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abnormal plasticity in dystonia comes from measures of sensorimotor cortical organization and physiology. However, the basal ganglia also play a critical role in sensorimotor function. Furthermore, the basal ganglia are prominently implicated in traditional models of dystonia, are the primary targets of stereotactic neurosurgical interventions, and provide a neural substrate for sensorimotor learning influenced by neuromodulators. Our working hypothesis is that abnormal plasticity in the basal ganglia is a critical link between the etiology and pathophysiology of dystonia. In this review we set up the background for this hypothesis by integrating a large body of disparate indirect evidence that dystonia may involve abnormalities in synaptic plasticity in the striatum. After reviewing evidence implicating the striatum in dystonia, we focus on the influence of two neuromodulatory systems: dopamine and acetylcholine. For both of these neuromodulators, we first describe the evidence for abnormalities in dystonia and then the means by which it may influence striatal synaptic plasticity. Collectively, the evidence suggests that many different forms of dystonia may involve abnormal plasticity in the striatum. An improved understanding of these altered plastic processes would help inform our understanding of the pathophysiology of dystonia, and, given the role of the striatum in sensorimotor learning, provide a principled basis for designing therapies aimed at the dynamic processes linking etiology to pathophysiology of the disease.
doi:10.1016/j.nbd.2009.12.003
PMCID: PMC2846420  PMID: 20005952
Striatum; synaptic plasticity; long-term potentiation; long-term depression; dopamine; acetylcholine
4.  Thalamic Post-Inhibitory Bursting Occurs in Patients with Organic Dystonia more often than Controls 
Brain research  2013;1541:81-91.
We now test the hypothesis that post-inhibitory bursting in the human pallidal receiving nucleus of the thalamus (ventral oral) mediates inhibitory pallido-thalamic transmission during dystonia. We have compared thalamic single neuron activity in nine patients with organic dystonia to that in a patient with psychogenic dystonia (Psyd) and in healthy waking monkeys.
In organic dystonia, EMG power is commonly concentrated at the lowest frequency of the smoothed autopower spectrum (0.39Hz). Therefore, segments of spike trains with a signal-to-noise ratio ≥ 2 at 0.39 Hz were termed dystonia frequency (DF) segments, which occurred more commonly during dystonia related to movement. Those with a SNR < 2 were termed non-dystonia frequency (nDF) segments, which are associated with spontaneous dystonia. We concentrated on nDF activity since neuronal activity in our controls was measured at rest. Neuronal spike trains were categorized into those with post-inhibitory bursts (G, grouped), with single spikes (NG, non-grouped), or with both single spikes and bursts (I, intermediate). nDF spike trains in ventral oral had more G category firing in dystonia than in controls. The burst rate and the pre-burst silent period in nDF firing of organic dystonia were consistently greater than those of both the monkeys and the patient with Psyd. The distribution of the pre-burst silent period was bimodal with a longer mode of approximately GABAb (gamma amino butyric acid receptor - type b) duration.
These results demonstrate distinct differences of post-inhibitory bursting in organic dystonia versus controls. The presence of inhibitory events consistent with GABAb duration suggests interventions for treatment of dystonia.
doi:10.1016/j.brainres.2013.10.006
PMCID: PMC3889805  PMID: 24125808
dystonia; thalamus; single neuron analysis; low threshold spike bursts; thalamotomy
5.  Task-specific Dystonias 
Task-specific dystonias are primary focal dystonias characterized by excessive muscle contractions producing abnormal postures during selective motor activities that often involve highly skilled, repetitive movements. Historically these peculiar postures were considered psychogenic but have now been classified as forms of dystonia. Writer’s cramp is the most commonly identified task-specific dystonia and has features typical of this group of disorders. Symptoms may begin with lack of dexterity during performance of a specific motor task with increasingly abnormal posturing of the involved body part as motor activity continues. Initially, the dystonia may manifest only during the performance of the inciting task, but as the condition progresses it may also occur during other activities or even at rest. Neurological exam is usually unremarkable except for the dystonia-related abnormalities. Although the precise pathophysiology remains unclear, increasing evidence suggests reduced inhibition at different levels of the sensorimotor system. Symptomatic treatment options include oral medications, botulinum toxin injections, neurosurgical procedures, and adaptive strategies. Prognosis may vary depending upon body part involved and specific type of task affected. Further research may reveal new insights into the etiology, pathophysiology, natural history, and improved treatment of these conditions.
doi:10.1196/annals.1444.012
PMCID: PMC2652841  PMID: 18990127
dystonia; task-specific dystonia; writer’s cramp; musician’s cramp; embouchure dystonia; pathophysiology; primary focal dystonia; functional neuroimaging; review; focal hand dystonia; laryngeal dystonia; golfer’s yips; botulinum toxin
6.  Deep Brain Stimulation effects in Dystonia: Time course of electrophysiological changes in early treatment 
Background
Deep brain stimulation (DBS) to the internal globus pallidus is an effective treatment for primary dystonia. The optimal clinical effect often occurs only weeks to months after starting stimulation. To better understand the underlying electrophysiological changes in this period we assessed longitudinally two pathophysiological markers of dystonia in patients prior to and in the early treatment period (1,3,6 months) after DBS-surgery.
Methods
Transcranial magnetic stimulation was used to track changes in short latency intracortical inhibition (SICI), a measure of excitability of GABAA-ergic corticocortical connections and long-term potentiation-like synaptic plasticity (as a response to paired associative stimulation, PAS). DBS remained ON for the duration of the study.
Results
Prior to surgery, inhibition was reduced and plasticity increased in patients compared to healthy controls. Following surgery and commencement of DBS, SICI increased towards normal levels over the following months with the same monotonic time course as the patients' clinical benefit. In contrast, synaptic plasticity changed rapidly following a non-monotonic time course: it was absent early (1 month) after surgery, and then over the following months increased towards levels observed in healthy individuals.
Conclusion
We postulate that before surgery pre-existing high levels of plasticity form strong memories of dystonic movement patterns. When DBS is turned ON, it disrupts abnormal basal ganglia signals resulting in the absent response to PAS at one month. Clinical benefit is delayed because engrams of abnormal movement persist and take time to normalise. Our observations suggest that plasticity may be a driver of long term therapeutic effects of DBS in dystonia.
doi:10.1002/mds.23731
PMCID: PMC3174341  PMID: 21547950
dystonia; deep brain stimulation; plasticity; longitudinal; human; excitability; mechanism
7.  Physiology of Psychogenic Movement Disorders 
Psychogenic movement disorders (PMDs) are common, but their physiology is largely unknown. In most situations, the movement is involuntary, but in a minority, when the disorder is malingering or factitious, the patient is lying and the movement is voluntary. Physiologically, we cannot tell the difference between voluntary and involuntary. The Bereitschaftspotential (BP) is indicative of certain brain mechanisms for generating movement, and is seen with ordinarily voluntary movements, but by itself does not indicate that a movement is voluntary. There are good clinical neurophysiological methods available to determine whether myoclonus or tremor is a PMD. For example, psychogenic myoclonus generally has a BP, and psychogenic stimulus-sensitive myoclonus has a variable latency with times similar to normal reaction times. Psychogenic tremor will have variable frequency over time, be synchronous in the two arms, and might well be entrained with voluntary rhythmic movements. These facts suggest that PMDs share voluntary mechanisms for movement production. There are no definitive tests to differentiate psychogenic dystonia from organic dystonia, although one has been recently reported. Similar physiological abnormalities are seen in both groups. The question arises as to how a movement can be produced with voluntary mechanisms, but not be considered voluntary.
doi:10.1016/j.jocn.2009.11.021
PMCID: PMC2902582  PMID: 20493708
Clinical neurophysiology; Conversion disorder; Dystonia; Gait; Myoclonus; Parkinsonism; Psychogenic movement disorders; Somatization; Tremor
8.  Psychogenic movement disorders: frequency, clinical profile, and characteristics. 
Of 842 consecutive patients with movement disorders seen over a 71 month period, 28 (3.3%) were diagnosed as having a documented or clinically established psychogenic movement disorder. Tremor was most common (50%) followed by dystonia, myoclonus, and parkinsonism. Clinical descriptions of various types are reviewed. Clinical characteristics common in these patients included distractability (86%), abrupt onset (54%), and selective disabilities (39%). Distractability seems to be most important in tremor and least important in dystonia. Other diagnostic clues included entrainment of tremor to the frequency of repetitive movements of another limb, fatigue of tremor, stimulus sensitivity, and previous history of psychogenic illness. On examination, 71% had other psychogenic features. Over 60% had a clear history of a precipitating event and secondary gain and 50% had a psychiatric diagnosis (usually depression). Twenty five per cent of patients presented with combined psychogenic movement disorder and organic movement disorder; 35% resolved and this subgroup had a shorter duration of disease than those who are unresolved. Psychogenic movement disorder represents an uncommon diagnosis among patients with movement disorders. The ability to make a diagnosis rests on the presence of a multitude of clinical clues and therapeutic action should be taken as early as possible.
PMCID: PMC486078  PMID: 7561921
9.  Adult onset asymmetric upper limb tremor misdiagnosed as Parkinson’s disease: A clinical and electrophysiological study 
Summary
Approximately 10% of subjects thought clinically to have early Parkinson’s disease (PD) have normal dopaminergic functional imaging (SWEDDs – Scans Without Evidence of Dopaminergic Deficit). SWEDDs are a heterogeneous group. Here we aimed to delineate clinical and electrophysiological characteristics of a distinct subgroup of SWEDDs patients from PD and to clarify the underlying pathophysiology of this subgroup as a form of parkinsonism or dystonia. Therefore we compared clinical details of 25 patients referred with a diagnosis of tremor-dominant PD but with normal DaT SPECT scans (SWEDDs) with 12 tremor-dominant PD patients with abnormal DaT SPECT scans. We performed tremor analysis using accelerometry in the following patients with 1) SWEDDs, 2) PD, 3) primary segmental dystonia with dystonic limb tremor and 4) essential tremor (ET). We used transcranial magnetic stimulation with a facilitatory paired associative stimulation (PAS) paradigm to test if sensorimotor plasticity in SWEDDs resembled the pattern seen in PD, dystonia or ET. Although PD and SWEDDs patients shared several clinical features, the lack of true bradykinesia, occurrence of dystonia, and position- and task-specificity of tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs as well as presence of nonmotor symptoms made PD more likely. Basic tremor parameters overlapped between SWEDDs, PD, segmental dystonia and ET. However, a combination of re-emergent tremor and highest tremor amplitude in the resting condition was characteristic of PD tremor, while SWEDDs, dystonia and ET subjects had the highest tremor amplitude during action. Both SWEDDs and segmental dystonia patients exhibited an exaggerated pattern of sensorimotor plasticity in response to the PAS paradigm, with spread of excitation to an adjacent hand muscle. In contrast, PD patients showed no response to PAS, and the response of ET patients was no different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs.
doi:10.1002/mds.23019
PMCID: PMC2996567  PMID: 20131394
SWEDDs; benign tremulous Parkinson’s disease; dystonic tremor; accelerometry; paired associative stimulation
10.  Emerging Concepts in the Physiological Basis of Dystonia 
Work over the past two decades has led to substantial changes in our understanding of dystonia pathophysiology. Three general abnormalities appear to underlie the pathophysiological substrate. The first line is a loss of inhibition. This makes sense considering that it may be responsible for the excess of movement and for the overflow phenomena seen in dystonia. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Third, evidence from animal models of dystonia as well as from patients with primary dystonia has revealed significant alterations of synaptic plasticity characterised by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. We speculate that during motor learning this abnormal plasticity may lead to an abnormal sensorimotor integration leading to consolidation of abnormal motor engrams. If so, then removing this abnormal plasticity might have little immediate effect on dystonic movements because bad motor memories have already been “learned” and are difficult to erase. These considerations might explain the delayed clinical effects of DBS in patients with generalized dystonia. Current lines of research will be discussed from a network perspective.
doi:10.1002/mds.25532
PMCID: PMC4159671  PMID: 23893452
11.  Recognizing Uncommon Presentations of Psychogenic (Functional) Movement Disorders 
Background
Psychogenic or functional movement disorders (PMDs) pose a challenge in clinical diagnosis. There are several clues, including sudden onset, incongruous symptoms, distractibility, suggestibility, entrainment of symptoms, and lack of response to otherwise effective pharmacological therapies, that help identify the most common psychogenic movements such as tremor, dystonia, and myoclonus.
Methods
In this manuscript, we review the frequency, distinct clinical features, functional imaging, and neurophysiological tests that can help in the diagnosis of uncommon presentations of PMDs, such as psychogenic parkinsonism, tics, and chorea; facial, palatal, and ocular movements are also reviewed. In addition, we discuss PMDs at the extremes of age and mass psychogenic illness.
Results
Psychogenic parkinsonism (PP) is observed in less than 10% of the case series about PMDs, with a female–male ratio of roughly 1:1. Lack of amplitude decrement in repetitive movements and of cogwheel rigidity help to differentiate PP from true parkinsonism. Dopamine transporter imaging with photon emission tomography can also help in the diagnostic process. Psychogenic movements resembling tics are reported in about 5% of PMD patients. Lack of transient suppressibility of abnormal movements helps to differentiate them from organic tics. Psychogenic facial movements can present with hemifacial spasm, blepharospasm, and other movements. Some patients with essential palatal tremor have been shown to be psychogenic. Convergence ocular spasm has demonstrated a high specificity for psychogenic movements. PMDs can also present in the context of mass psychogenic illness or at the extremes of age.
Discussion
Clinical features and ancillary studies are helpful in the diagnosis of patients with uncommon presentations of psychogenic movement disorders.
doi:10.7916/D8VM4B13
PMCID: PMC4303603  PMID: 25667816
Psychogenic movement disorders; functional movement disorders; parkinsonism; tics; palatal tremor; chorea
12.  Botulinum Toxin Injections Reduce Associative Plasticity in Patients with Primary Dystonia 
Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long-term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation-evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short-interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity.
doi:10.1002/mds.23681
PMCID: PMC4235250  PMID: 21469207
botulinum toxin; primary dystonia; cervical dystonia; cortical plasticity; paired associative stimulation; transcranial magnetic stimulation; TMS
13.  Psychopathology and Psychogenic Movement Disorders 
Psychogenic movement disorder is defined as abnormal movements unrelated to a medical cause and presumed related to underlying psychological factors. Although psychological factors are of both clinical and pathophysiological relevance, very few studies to date have systematically assessed their role in psychogenic movement disorder. We sought to assess the role of previous life stress using validated quantitative measures in patients with psychogenic movement disorder compared with age- and sex-matched healthy volunteers as well as a convenience sample of patients with focal hand dystonia. Sixty-four patients with psychogenic movement disorder (72% female; mean age, 45.2 years [standard deviation, 15.2 years]), 38 healthy volunteers (74% female; mean age, 49 years [standard deviation, 13.7 years]), and 39 patients with focal hand dystonia (37% female; mean age, 48.7 years [standard deviation, 11.7 years]) were evaluated using a standardized psychological interview as well as validated quantitative scales to assess trauma and previous stressors, depression, anxiety, and personality traits. Patients with psychogenic movement disorder reported higher rates of childhood trauma, specifically greater emotional abuse and physical neglect, greater fear associated with traumatic events, and a greater number of traumatic episodes compared with healthy volunteers and patients with focal hand dystonia controlled for depressive symptoms and sex (Bonferroni corrected P < .005). There were no differences in categorical psychiatric diagnoses or scores on childhood physical or sexual abuse subscales, personality traits, or the dissociative experience scale. Our findings highlight a biopsychosocial approach toward the pathophysiology of psychogenic movement disorder, although the association with psychological issues is much less prominent than expected compared with the nonepileptic seizure population. A careful psychological assessment is indicated to optimize therapeutic modalities.
doi:10.1002/mds.23830
PMCID: PMC4049464  PMID: 21714007
dystonia; movement disorders; psychogenic; psychological measures; trauma
14.  Defective cerebellar control of cortical plasticity in writer’s cramp 
Brain  2013;136(7):2050-2062.
A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer’s cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients’ maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (−40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer’s cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer’s cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer’s cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing.
doi:10.1093/brain/awt147
PMCID: PMC3692031  PMID: 23801734
cerebellum; dystonia; plasticity; transcranial magnetic stimulation; sensorimotor adaptation
15.  Primary Dystonia: Conceptualizing the Disorder Through a Structural Brain Imaging Lens 
Tremor and Other Hyperkinetic Movements  2013;3:tre-03-152-3638-4.
Background
Dystonia is a hyperkinetic movement disorder characterized by involuntary, repetitive twisting movements. The anatomical structures and pathways implicated in its pathogenesis and their relationships to the neurophysiological paradigms of abnormal surround inhibition, maladaptive plasticity, and impaired sensorimotor integration remain unclear.
Objective
We review the use of high-resolution structural brain imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) techniques for evaluating brain changes in primary torsion dystonia and their relationships to the pathophysiology of this disorder.
Methods
A PubMed search was conducted to identify relevant literature.
Results
VBM and DTI studies produced somewhat conflicting results across different forms of primary dystonia and reported increases, decreases, or both in gray matter volume and white matter integrity. However, despite the discrepancies, these studies are consistent in revealing brain abnormalities in dystonia that extend beyond the basal ganglia and involve the sensorimotor cortex and cerebellum.
Discussion
Although limited to date, structural magnetic resonance imaging (MRI) studies combined with functional brain imaging and neurophysiological modalities begin to establish structural-functional relationships at different levels of the abnormal basal ganglia, cortical, and cerebellar networks and provide clues into the pathophysiological mechanisms that underlie primary dystonia. Cross-disciplinary studies are needed for further investigations of the interplay between structural-functional brain abnormalities and environmental and genetic risk factors in dystonia patients.
PMCID: PMC3629863  PMID: 23610744
Primary dystonia; voxel-based morphometry; diffusion tensor imaging; MRI
16.  Restoration of motor inhibition through an abnormal premotor-motor connection in dystonia 
To clarify the rationale for using rTMS of dorsal premotor cortex (PMd) to treat dystonia, we examined how the motor system reacts to an inhibitory form of rTMS applied to the PMd in healthy subjects and in a group of patients with focal hand dystonia and DYT1 gene carriers. Continuous theta burst transcranial magnetic stimulation (cTBS) with 300 and 600 pulses (cTBS300 and cTBS600) was applied to PMd and its after-effects were quantified by measuring the amplitude of MEPs evoked by single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), short interval intracortical inhibition/facilitation (SICI/ICF) within M1, the third phase of spinal reciprocal inhibition (RI) and writing tests. In addition, in DYT1 gene carriers, the effects of cTBS300 over M1 and PMd on MEPs were studied in separate experiments. In healthy subjects cTBS300 and cTBS600 over PMd suppressed MEPs for 30min or more and cTBS600 decreased SICI and RI. In contrast, neither form of cTBS over PMd had any significant effect on MEPs, while cTBS600 increased effectiveness of SICI and RI and improved writing in patients with writer's cramp. NMDYT1 had a normal response to cTBS300 over left PMd. We suggest that the reduced PMd to M1 interaction in dystonic patients is likely to be due to reduced excitability of PMd-M1 connections. The possible therapeutic effects of premotor rTMS may therefore involve indirect effects of PMd on SICI and RI, which this study has shown can be normalised by cTBS.
doi:10.1002/mds.22814
PMCID: PMC3000921  PMID: 20309999
Premotor; rTMS; dystonia; theta burst; TBS
17.  Disordered plasticity in the primary somatosensory cortex in focal hand dystonia 
Brain  2009;132(3):749-755.
Interventional paired associative stimulation (PAS) can induce plasticity in the cortex, and this plasticity was previously shown to be disordered in the primary motor cortex in focal hand dystonia (FHD). This study aimed to test whether associative plasticity is abnormal in the primary somatosensory cortex (S1) in FHD and whether PAS modulates excitatory or inhibitory interneurons within the cortex. Ten FHD patients and 10 healthy volunteers were studied. We investigated the changes in single- and double-pulse somatosensory-evoked potentials before and after PAS, which consisted of peripheral electrical nerve stimulation and subsequent transcranial magnetic stimulation over S1. Four sessions of somatosensory-evoked potentials recordings were performed: before PAS, and immediately, 15 and 30 min after PAS. We compared the time course of the somatosensory-evoked potentials between the FHD and healthy groups. In the single-pulse condition, the P27 amplitudes were significantly higher in FHD immediately after PAS than before PAS, while no changes were observed in healthy subjects. In the double-pulse condition, significant differences in the suppression ratio of P27 were found immediately after and 15 min after PAS, while there were no significant differences in healthy subjects. The P27 suppression tended to normalize toward the level of the healthy volunteer group. In FHD, PAS transiently induced an abnormal increase in excitability in S1. In addition, intracortical inhibition in S1 was found to increase as well. This abnormal plasticity of the intracortical neurons in S1 may contribute to the pathophysiology of dystonia.
doi:10.1093/brain/awn348
PMCID: PMC2724923  PMID: 19151081
associative plasticity; paired associative stimulation; focal hand dystonia; somatosensory-evoked potential
18.  Levodopa Responsiveness in Adult-onset Lower Limb Dystonia is Associated with the Development of Parkinson’s Disease 
Tremor and Other Hyperkinetic Movements  2013;3:tre-03-150-3598-2.
Background
Adult-onset primary lower limb dystonia (AOPLLD) has been reported as an early sign of Parkinson’s disease (PD) or Parkinson-plus syndrome in case series. No prior systematic analysis has assessed clinical clues predicting later development of PD or Parkinson-plus syndrome.
Methods
We identified patients with AOPLLD from medical records. We excluded patients who had not been diagnosed by a neurologist, and who had a pre-existing diagnosis of PD, psychogenic, or secondary dystonia. Records were subdivided into those who later developed PD or Parkinson-plus disorders and those who did not. The following clinical characteristics were compared between the two groups: dystonia onset age, type of dystonia, levodopa response, anticholinergic response, and family history of Parkinsonism or tremor.
Results
Twenty-two AOPLLD patients were identified: 77% female; the median dystonia onset age was 53 years. Eight (37%) developed Parkinson’s disease; 2 (9%) developed corticobasal syndrome. Twelve patients (54%) did not develop Parkinsonism after a median follow-up period of 1.5 years. There was a significant difference in leg dystonia levodopa response between the two groups (p = 0.02).
Conclusion
In patients with AOPLLD, leg dystonia with levodopa response is associated with the future development of PD.
PMCID: PMC3629864  PMID: 23610745
Dystonia; Parkinson’s disease; leg dystonia; levodopa
19.  Correlation of Clinical Neuromusculoskeletal and Central Somatosensory Performance: Variability in Controls and Patients With Severe and Mild Focal Hand Dystonia 
Neural Plasticity  2002;9(3):177-203.
Focal hand dystonia (FHd) is a recalcitrant, disabling movement disorder, characterized by involuntary co-contractions of agonists and antagonists, that can develop in patients who overuse or misuse their hands. The aim of this study was to document clinical neuromusculoskeletal performance and somatosensory responses (magnetoencephalography) in healthy controls and in FHd subjects with mild versus severe hand dystonia. The performance of healthy subjects (n = 17) was significantly better than that of FHd subjects (n = 17) on all clinical parameters. Those with mild dystonia (n = 10) demonstrated better musculoskeletal skills, task-specific motor performance, and sensory discrimination, but the performance of sensory and fine motor tasks was slower than that of patients with severe dystonia. In terms of somatosensory evoked field responses (SEFs), FHd subjects demonstrated a significant difference in the location of the hand representation on the x and y axes, lower amplitude of SEFs integrated across latency, and a higher ratio of mean SEF amplitude to latency than the controls. Bilaterally,. those with FHd (mild and severe) lacked progressive sequencing of the digits from inferior to superior. On the affected digits, subjects with severe dystonia had a significantly higher ratio of SEF amplitude to latency and a significantly smaller mean volume of the cortical hand representation than those with mild dystonia. Severity of dystonia positively correlated with the ratio of SEF mean amplitude to latency (0.9029 affected, 0.8477 unaffected; p<0.01). The results of the present study strengthen the evidence that patients with FHd demonstrate signs of somatosensory degradation of the hand that correlates with clinical sensorimotor dysfunction, with characteristics of the dedifferentiation varying by the severity of hand dystonia. If these findings represent aberrant learning, then effective rehabilitation must incorporate the principles of neuroplasticity. Training must be individualized to each patient to rebalance the sensorimotor feedback loop and to restore normal fine motor control.
doi:10.1155/NP.2002.177
PMCID: PMC2565401  PMID: 12757370
20.  Motor cortical hyperexcitability in idiopathic scoliosis: could focal dystonia be a subclinical etiological factor? 
European Spine Journal  2009;19(2):223-230.
The aetiology of idiopathic scoliosis (IS) remains unknown; however, there is a growing body of evidence suggesting that the spine deformity could be the expression of a subclinical nervous system disorder. A defective sensory input or an anomalous sensorimotor integration may lead to an abnormal postural tone and therefore the development of a spine deformity. Inhibition of the motor cortico-cortical excitability is abnormal in dystonia. Therefore, the study of cortico-cortical inhibition may shed some insight into the dystonia hypothesis regarding the pathophysiology of IS. Paired pulse transcranial magnetic stimulation was used to study cortico-cortical inhibition and facilitation in nine adolescents with IS, five teenagers with congenital scoliosis (CS) and eight healthy age-matched controls. The effect of a previous conditioning stimulus (80% intensity of resting motor threshold) on the amplitude of the motor-evoked potential induced by the test stimulus (120% of resting motor threshold) was examined at various interstimulus intervals (ISIs) in both abductor pollicis brevis muscles. The results of healthy adolescents and those with CS showed a marked inhibitory effect of the conditioning stimulus on the response to the test stimulus at interstimulus intervals shorter than 6 ms. These findings do not differ from those reported for normal adults. However, children with IS revealed an abnormally reduced cortico-cortical inhibition at the short ISIs. Cortico-cortical inhibition was practically normal on the side of the scoliotic convexity while it was significantly reduced on the side of the scoliotic concavity. In conclusion, these findings support the hypothesis that a dystonic dysfunction underlies in IS. Asymmetrical cortical hyperexcitability may play an important role in the pathogenesis of IS and represents an objective neurophysiological finding that could be used clinically.
doi:10.1007/s00586-009-1243-y
PMCID: PMC2899814  PMID: 20033462
Adolescent idiopathic scoliosis; Dystonia; Cortico-cortical inhibition; Cortical hyperexcitability; Transcranial magnetic stimulation
21.  Convergent mechanisms in etiologically-diverse dystonias 
Expert opinion on therapeutic targets  2011;15(12):1387-1403.
Introduction
Dystonia is a neurological disorder associated with twisting motions and abnormal postures, which compromise normal movements and can be both painful and debilitating. It can affect a single body part (focal), several contiguous regions (segmental), or the entire body (generalized), and can arise as a result of numerous causes, both genetic and acquired. Despite the diversity of causes and manifestations, shared clinical features suggest that common mechanisms of pathogenesis may underlie many dystonias.
Areas Covered
This review identifies shared themes in etiologically-diverse dystonias on several biological levels. At the cellular level, abnormalities in the dopaminergic system, mitochondrial function, and calcium regulation are discussed. At the anatomical level, the roles of the basal ganglia and the cerebellum in dystonia are described. Global central nervous system dysfunction, with regard to aberrant neuronal plasticity, inhibition, and sensorimotor integration is also discussed. Using clinical data and data from animal models, this article seeks to highlight shared pathways that may be critical in understanding mechanisms and identifying novel therapeutic strategies in dystonia.
Expert Opinion
Identifying shared features of pathogenesis can provide insight into the biological processes that underlie etiologically-diverse dystonias, and can suggest novel targets for therapeutic intervention that may be effective in a broad group of affected individuals.
doi:10.1517/14728222.2011.641533
PMCID: PMC3514401  PMID: 22136648
dystonia; dopamine; mitochondria; calcium; basal ganglia; cerebellum; plasticity
22.  Electrophysiologic Evaluation of Psychogenic Movement Disorders 
Journal of Movement Disorders  2011;4(1):21-32.
Psychogenic movement disorders (PMD) are a group of disorders which are in the border zone between neurology and psychiatry. All necessary laboratory investigations should be done to rule out an underlying organic disorder. While clinical acumen of a trained movement disorder specialist may be sufficient to diagnose most PMD, there are clinical situations where electrophysiological tests are required either to rule out an organic movement disorder or even diagnose a PMD. Current electrophysiological test are most useful for tremor, followed by jerks and least for spasms or dystonia. Commonly used electrophysiologic tests include multichannel surface electromyography (EMG), accelerometry, electroencephalography time locked with EMG, premovement potential (Bereitschaftspotential), and somatosensory evoked potentials. Psychogenic tremor is a low frequency tremor with variable frequency and duration of EMG bursts, entrainable, has a high coherence with voluntary movements, and presence of coactivation sign. Patients with psychogenic jerks have well organized triphasic pattern of activation of agonist and antagonist muscles. The jerks are associated with EMG bursts of long duration (usually > 70 ms), long and variable latencies in stimulus induced jerks, absence of craniocaudal pattern of muscle recruitment in apparent startle response, and often a Breitschaftspotential (premovement potential) precedes the jerk. Electrophysiological characterization of psychogenic dystonia is difficult and the tests are usually performed to rule out organic dystonia with characteristic findings. Finally, caution should be exerted in interpreting the electrophysiological tests as both false positive and false negative diagnosis of PMD may still occur.
doi:10.14802/jmd.11004
PMCID: PMC4027703  PMID: 24868388
Psychogenic movement disorders; Electrophysiological tests
23.  Altered Cortical Swallowing Processing in Patients with Functional Dysphagia: A Preliminary Study 
PLoS ONE  2014;9(2):e89665.
Objective
Current neuroimaging research on functional disturbances provides growing evidence for objective neuronal correlates of allegedly psychogenic symptoms, thereby shifting the disease concept from a psychological towards a neurobiological model. Functional dysphagia is such a rare condition, whose pathogenetic mechanism is largely unknown. In the absence of any organic reason for a patient's persistent swallowing complaints, sensorimotor processing abnormalities involving central neural pathways constitute a potential etiology.
Methods
In this pilot study we measured cortical swallow-related activation in 5 patients diagnosed with functional dysphagia and a matched group of healthy subjects applying magnetoencephalography. Source localization of cortical activation was done with synthetic aperture magnetometry. To test for significant differences in cortical swallowing processing between groups, a non-parametric permutation test was afterwards performed on individual source localization maps.
Results
Swallowing task performance was comparable between groups. In relation to control subjects, in whom activation was symmetrically distributed in rostro-medial parts of the sensorimotor cortices of both hemispheres, patients showed prominent activation of the right insula, dorsolateral prefrontal cortex and lateral premotor, motor as well as inferolateral parietal cortex. Furthermore, activation was markedly reduced in the left medial primary sensory cortex as well as right medial sensorimotor cortex and adjacent supplementary motor area (p<0.01).
Conclusions
Functional dysphagia - a condition with assumed normal brain function - seems to be associated with distinctive changes of the swallow-related cortical activation pattern. Alterations may reflect exaggerated activation of a widely distributed vigilance, self-monitoring and salience rating network that interferes with down-stream deglutition sensorimotor control.
doi:10.1371/journal.pone.0089665
PMCID: PMC3929717  PMID: 24586948
24.  Thalamic Neuronal and EMG Activity in Psychogenic Dystonia compared with Organic Dystonia 
This study is a retrospective analysis of thalamic neuronal and electromyogram activities between subjects with organic dystonia and a subject with psychogenic dystonia, in whom a thalamotomy was carried out before a diagnosis psychogenic dystonia was made.
The electromyogram signal to noise ratio in the lowest frequency band (<0.76Hz, dystonia frequency – DF) in the electromyogram was not significantly different by diagnosis or muscle (Table 1). The coherence at dystonia frequency for wrist flexors X biceps electromyograms was significantly higher in organic dystonia, while the phase was not apparently different from zero for either diagnosis.
In a thalamic pallidal relay nucleus (ventral oral posterior), neuronal firing rates were not apparently different between psychogenic and organic dystonia. The neuronal signal to noise ratio in ventral oral posterior was significantly higher in organic dystonia than in psychogenic dystonia, while both were greater than in controls with chronic pain. Spike X electromyogram coherence was not apparently different between psychogenic and organic dystonia. The proportion of thalamic cells responding to joint movements was higher in the cerebellar relay nucleus (ventral intermediate) of psychogenic dystonia than organic dystonia.
These results suggest that some features, such as firing rates and thalamic reorganization, are similar in psychogenic and organic dystonia. Other features differ, such as the coherence between the electromyograms from different muscles, and the thalamic neuronal signal to noise ratio, which may reflect pathophysiological factors in organic dystonia.
doi:10.1002/mds.23565
PMCID: PMC3690304  PMID: 21500279
Psychogenic Dystonia; Organic Dystonia; Human thalamus; Neuronal activity; Plasticity; Dystonia related activity
25.  Primary dystonia: molecules and mechanisms 
Nature reviews. Neurology  2009;5(11):598-609.
Primary dystonia is characterized by abnormal, involuntary twisting and turning movements that reflect impaired motor system function. The dystonic brain seems normal, in that it contains no overt lesions or evidence of neurodegeneration, but functional brain imaging has uncovered abnormalities involving the cortex, striatum and cerebellum, and diffusion tensor imaging suggests the presence of microstructural defects in white matter tracts of the cerebellothalamocortical circuit. Clinical electrophysiological studies show that the dystonic CNS exhibits hyperactive plasticity—perhaps related to deficient inhibitory neurotransmission—in a range of brain structures, as well as the spinal cord. Dystonia is, therefore, best conceptualized as a motor circuit disorder, rather than an abnormalcy of a particular brain structure. None of the aforementioned abnormalities can be strictly causal, as they are not limited to regions of the CNS subserving clinically affected body parts, and are found in seemingly healthy patients with dystonia-related mutations. The study of dystonia-related genes will, hopefully, help researchers to unravel the chain of events from molecular to cellular to system abnormalities. DYT1 mutations, for example, cause abnormalities within the endoplasmic reticulum–nuclear envelope endomembrane system. Other dystonia-related gene products traffic through the endoplasmic reticulum, suggesting a potential cell biological theme underlying primary dystonia.
doi:10.1038/nrneurol.2009.160
PMCID: PMC2856083  PMID: 19826400

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