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... Given a fiber diameter of 5.7 to 10 μm and conduction velocities of 25 to 55 m/s, computational modeling supports hyperdirect activation leading to eCR at latencies of 3 to 5 ms (Gunalan and McIntyre, 2020). Additionally, medium-latency responses were not observed with pallidal and thalamic stimulation (Bhanpuri et al., 2014;Devergnas and Wichmann, 2011;Limousin et al., 1998;Miocinovic et al., 2018;Ni et al., 2018;Tisch et al., 2008), with one notable exception (Walker et al., 2012b). The absence of medium-latency eCR for pallidal stimulation indicates that they are likely to represent HDP activation (Miocinovic et al., 2018), which would also be consistent with the broad cortical distribution of medium-latency eCR (Canteras et al., 1988;Miocinovic et al., 2018;Nambu et al., 1997). ...
... With respect to medium-latency eCRs, highest amplitudes are elicited by clinically-used 130 Hz DBS stimulation (Miocinovic et al., 2018). This conforms well to GPi stimulation results in adult and adolescent dystonia patients where the amplitude of eCR around 20 ms correlates with the clinically most effective contact inside the GPi (Bhanpuri et al., 2014;Tisch et al., 2008). Finally, turning to longer latency eCRs, a large amplitude at about 20 ms following STN-DBS in PD patients is predictive for postoperative motor side effects (Romeo et al., 2019). ...
Article
The subthalamic nucleus (STN) receives input from various cortical areas via hyperdirect pathway (HDP) which bypasses the basal-ganglia loop. Recently, the HDP has gained increasing interest, because of its relevance for STN deep brain stimulation (DBS). To understand the HDP's role cortical responses evoked by STN-DBS have been investigated. These responses have short (<2 ms), medium (2–15 ms), and long (20–70 ms) latencies. Medium-latency responses are supposed to represent antidromic cortical activations via HDP. Together with long-latency responses the medium responses can potentially be used as biomarker of DBS efficacy as well as side effects. We here propose that the activation sequence of the cortical evoked responses can be conceptualized as high frequency oscillations (HFO) for signal analysis. HFO might therefore serve as marker for antidromic activation. Using existing knowledge on HFO recordings, this approach allows data analyses and physiological modeling to advance the pathophysiological understanding of cortical DBS-evoked high-frequency activity.
... The mechanisms by which DBS improves motor control are not yet understood, but it is becoming evident that stimulation of the GPi leads to widespread brain net- work changes: in idiopathic/genetic isolated dystonia DBS reduces cortical plasticity ( Tisch et al., 2007) and attenuates pathological low frequency oscillations between the basal ganglia and sensori- motor cortex ( Barow et al., 2014). Modulation of sensorimotor cor- tex by DBS has also been demonstrated with Deep Brain Stimulator Evoked Potentials (DBSEPs) ( Bhanpuri et al., 2014), likely to be mediated via pallido-thalamo-cortical projections (Tisch et al., 2008). The importance of these projections is implied from the finding that the highest amplitude DBSEPs are evoked from those electrode contacts found clinically to produce the most benefit ( Tisch et al., 2008;Bhanpuri et al., 2014), providing further evi- dence that modulation of the sensory network is relevant both to the mechanisms underlying dystonia and to the therapeutic effects of DBS. ...
... Modulation of sensorimotor cor- tex by DBS has also been demonstrated with Deep Brain Stimulator Evoked Potentials (DBSEPs) ( Bhanpuri et al., 2014), likely to be mediated via pallido-thalamo-cortical projections (Tisch et al., 2008). The importance of these projections is implied from the finding that the highest amplitude DBSEPs are evoked from those electrode contacts found clinically to produce the most benefit ( Tisch et al., 2008;Bhanpuri et al., 2014), providing further evi- dence that modulation of the sensory network is relevant both to the mechanisms underlying dystonia and to the therapeutic effects of DBS. Our findings indicate that in some children with dystonia secondary to perinatal brain injury, there is abnormal development of the sensorimotor network as measured with SEPs. ...
Article
Objectives Deep Brain Stimulation (DBS) of the Globus Pallidus Internus produces dramatic benefits in primary dystonia. Improvements in patients with secondary dystonia are smaller and vary markedly between individuals. Predictive markers are lacking. This study tests the hypothesis that Somatosensory Evoked Potentials (SEPs) and Central Motor Conduction Times (CMCT) may predict outcome from DBS in childhood dystonia. Methods Data were obtained from 180 consecutive children with dystonia undergoing multidisciplinary assessment for DBS (mean age 10 years; range 2.5–19). CMCT to each limb was obtained using Transcranial Magnetic Stimulation and the F-wave method. Median and posterior tibial nerve SEPs were recorded over contralateral and midline centro-parietal scalp. Technically unsatisfactory data were excluded. Structural abnormalities were assessed with cranial MRI. Outcome from DBS at 1 year was assessed as percentage improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m). Results Satisfactory CMCT data were obtained from 146 children, of whom 28 (19%) had an abnormal CMCT to at least one limb. Satisfactory cortical SEP data were obtained from 100 children, of whom 47 had at least one abnormal cortical potential. Abnormal CMCTs and SEPs were both observed more frequently in secondary than primary/primary plus dystonia (CMCT abnormal in 22% secondary versus 9% primary patients; SEP abnormal in 53% secondary vs 24% primary patients). Of children proceeding to DBS, improvement in BFMDRS-m was greater in those with normal (n = 78) than abnormal CMCT (n = 11) (Mann Whitney test p = 0.002) and was also greater in those with normal (n = 35) versus abnormal SEPs (n = 16) (Mann Whitney test p = 0.001). On sub-group analysis, the relationships between CMCT/SEPs and BFMDRS-m scores were independent of aetiology (primary versus secondary) and MRI findings (normal versus abnormal). Discussion/Conclusion CMCTs and SEPs provide objective evidence of motor and sensory pathway dysfunction in children with dystonia and relate to DBS outcome. These markers may therefore contribute to patient selection and counselling of families about potential benefit from neuromodulation. Significance We identify neurophysiological markers that can guide the selection of patients for DBS.
... Improvements surpassing MCIDs established among individuals with primary dystonia 68 Twelve non-randomized studies (n=117) reported on adverse events, with overall rates ranging from 0% to 40%. [49][50][51][52][53][54][57][58][59]61,63,64 The most common events included infections requiring hardware removal (7À40%) 51,53,57,61,64 and stimulation-induced dysarthria (17À30%). 49,52,64 DBS may result in an increased risk of adverse events, compared with not receiving DBS in individuals with CP and dystonia (GRADE very low certainty). ...
... While oral medications are used for individuals with CP and dystonia, evidence for their effectiveness and safety is Study Test for overall effect Vidailhet et al. 50 Air et al. 51 Marks et al. 53 Gimeno et al. 54 Lumsden et al. 56 Marks et al. 57 Olaya et al. 58 Gimeno et al. 60 Keen et al. 61 Kim et al. 62,a Romito et al. 64 Koy et al. 65 Kim et al. 49 50 Air et al. 51 Marks et al. 53 Gimeno et al. 54 Lumsden et al. 56 Marks et al. 57 Olaya et al. 58 Bhanpuri et al. 59 Gimeno et al. 60 Keen et al. 61 Kim et al. 62,a Romito et al. 64 Koy et al. 65 Kim et al. 49 Test for overall effect Vidailhet et al. 50 Air et al. 51 Marks et al. 53 Gimeno et al. 54 Gimeno et al. 55 Lumsden et al. 56 Marks et al. 57 Kim et al. 62,a Romito et al. 64 Kim et al. 49 Vidailhet et al. ...
Article
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Aim: To update a systematic review of evidence published up to December 2015 for pharmacological/neurosurgical interventions among individuals with cerebral palsy (CP) and dystonia. Method: Searches were updated (January 2016 to May 2020) for oral baclofen, trihexyphenidyl, benzodiazepines, clonidine, gabapentin, levodopa, botulinum neurotoxin (BoNT), intrathecal baclofen (ITB), and deep brain stimulation (DBS), and from database inception for medical cannabis. Eligible studies included at least five individuals with CP and dystonia and reported on dystonia, goal achievement, motor function, pain/comfort, ease of caregiving, quality of life (QoL), or adverse events. Evidence certainty was evaluated using GRADE. Results: Nineteen new studies met inclusion criteria (two trihexyphenidyl, one clonidine, two BoNT, nine ITB, six DBS), giving a total of 46 studies (four randomized, 42 non-randomized) comprising 915 participants when combined with those from the original systematic review. Very low certainty evidence supported improved dystonia (clonidine, ITB, DBS) and goal achievement (clonidine, BoNT, ITB, DBS). Low to very low certainty evidence supported improved motor function (DBS), pain/comfort (clonidine, BoNT, ITB, DBS), ease of caregiving (clonidine, BoNT, ITB), and QoL (ITB, DBS). Trihexyphenidyl, clonidine, BoNT, ITB, and DBS may increase adverse events. No studies were identified for benzodiazepines, gabapentin, oral baclofen, and medical cannabis. Interpretation: Evidence evaluating the use of pharmacological and neurosurgical management options for individuals with CP and dystonia is limited to between low and very low certainty.
... Evoked potentials (EP) from the DBS pulses within the GPi have been recorded on the cortex and contribute to our understanding of the mechanism of action of GPi DBS. The studies have demonstrated a peak in the central regions, likely to be the primary motor cortex, around 20-30 ms (Tisch et al. 2008;Bhanpuri et al. 2014;Ni et al. 2018). This peak is larger when the most effective contact is being stimulated and in good responders (Tisch et al. 2008;Bhanpuri et al. 2014). ...
... The studies have demonstrated a peak in the central regions, likely to be the primary motor cortex, around 20-30 ms (Tisch et al. 2008;Bhanpuri et al. 2014;Ni et al. 2018). This peak is larger when the most effective contact is being stimulated and in good responders (Tisch et al. 2008;Bhanpuri et al. 2014). The fact that this peak was absent in a patient who had a previous thalamotomy, combined with the latency, suggest the involvement of the pallido-thalamocortical pathway (Tisch et al. 2008). ...
Article
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Dystonia is a movement disorder characterised by involuntary muscle contractions resulting in abnormal movements, postures and tremor. The pathophysiology of dystonia is not fully understood but loss of neuronal inhibition, excessive sensorimotor plasticity and defective sensory processing are thought to contribute to network dysfunction underlying the disorder. Neurophysiology studies have been important in furthering our understanding of dystonia and have provided insights into the mechanism of effective dystonia treatment with pallidal deep brain stimulation. In this article we review neurophysiology studies in dystonia and its treatment with Deep Brain Stimulation, including Transcranial magnetic stimulation studies, studies of reflexes and sensory processing, and oscillatory activity recordings including local field potentials, micro-recordings, EEG and evoked potentials.
... The best improvements are seen in patients with PKAN [62,64,65] and LND, although the number of published cases for the latter is small. In contrast, little to no improvement or even disease progression is expected in patients with GA1 [3,62] and kernicterus associated dystonia [63,66]. The considerable heterogeneity of DBS response in secondary dystonia is likely due (in part) to differences in underlying, disease specific pathophysiology [38] which will be further discussed in the upcoming sections. ...
... The longest reported follow-up is 7 years [72]. In most cases, bilateral GPi is targeted, although a few patients have received combined GPi-STN stimulation [63,66]. One study suggested that significant improvements in speech may occur post-operatively [68]. ...
Article
Introduction: Dystonia, one of the most common childhood movement disorders, is often medically refractory and can lead to profound impacts on the child and their caretakers' quality of life. Limited efficacy of pharmacological treatments has fueled enthusiasm for innovative neurosurgical approaches, notably deep brain stimulation (DBS) as a treatment for refractory dystonia. Areas covered: DBS is increasingly applied to successfully treat childhood dystonia. While generally safe and effective, results vary widely depending on underlying dystonia etiology. The current work synthesizes and highlights advances in research pertaining to the use of DBS for childhood dystonia. The efficacy of DBS for children and youth with dystonia is discussed, with analysis divided among etiological subtypes. The role of DBS as a lifesaving treatment for status dystonicus is also reviewed. Expert Commentary: When carefully selected, certain children and youth with dystonia experience significant symptomatic improvement after DBS. Beyond dystonic symptoms, DBS can improve quality of life and reduce caretaker burden.
... The mechanisms by which DBS improves motor control are not yet understood, but it is becoming evident that stimulation of the GPi leads to widespread brain network changes: in idiopathic/genetic isolated dystonia DBS reduces cortical plasticity (Tisch et al., 2007) and attenuates pathological low frequency oscillations between the basal ganglia and sensorimotor cortex (Barow et al., 2014). Modulation of sensorimotor cortex by DBS has also been demonstrated with Deep Brain Stimulator Evoked Potentials (DBSEPs) (Bhanpuri et al., 2014), likely to be mediated via pallido-thalamo-cortical projections (Tisch et al., 2008). The importance of these projections is implied from the finding that the highest amplitude DBSEPs are evoked from those electrode contacts found clinically to produce the most benefit (Tisch et al., 2008;Bhanpuri et al., 2014), providing further evidence that modulation of the sensory network is relevant both to the mechanisms underlying dystonia and to the therapeutic effects of DBS. ...
... Modulation of sensorimotor cortex by DBS has also been demonstrated with Deep Brain Stimulator Evoked Potentials (DBSEPs) (Bhanpuri et al., 2014), likely to be mediated via pallido-thalamo-cortical projections (Tisch et al., 2008). The importance of these projections is implied from the finding that the highest amplitude DBSEPs are evoked from those electrode contacts found clinically to produce the most benefit (Tisch et al., 2008;Bhanpuri et al., 2014), providing further evidence that modulation of the sensory network is relevant both to the mechanisms underlying dystonia and to the therapeutic effects of DBS. Our findings indicate that in some children with dystonia secondary to perinatal brain injury, there is abnormal development of the sensorimotor network as measured with SEPs. ...
... The mechanisms by which DBS improves motor control are not yet understood, but it is becoming evident that stimulation of the GPi leads to widespread brain network changes: in idiopathic/genetic isolated dystonia DBS reduces cortical plasticity (Tisch et al., 2007) and attenuates pathological low frequency oscillations between the basal ganglia and sensorimotor cortex (Barow et al., 2014). Modulation of sensorimotor cortex by DBS has also been demonstrated with Deep Brain Stimulator Evoked Potentials (DBSEPs) (Bhanpuri et al., 2014), likely to be mediated via pallido-thalamo-cortical projections (Tisch et al., 2008). The importance of these projections is implied from the finding that the highest amplitude DBSEPs are evoked from those electrode contacts found clinically to produce the most benefit (Tisch et al., 2008;Bhanpuri et al., 2014), providing further evidence that modulation of the sensory network is relevant both to the mechanisms underlying dystonia and to the therapeutic effects of DBS. ...
... Modulation of sensorimotor cortex by DBS has also been demonstrated with Deep Brain Stimulator Evoked Potentials (DBSEPs) (Bhanpuri et al., 2014), likely to be mediated via pallido-thalamo-cortical projections (Tisch et al., 2008). The importance of these projections is implied from the finding that the highest amplitude DBSEPs are evoked from those electrode contacts found clinically to produce the most benefit (Tisch et al., 2008;Bhanpuri et al., 2014), providing further evidence that modulation of the sensory network is relevant both to the mechanisms underlying dystonia and to the therapeutic effects of DBS. Our findings indicate that in some children with dystonia secondary to perinatal brain injury, there is abnormal development of the sensorimotor network as measured with SEPs. ...
Article
Objectives: To report Somatosensory Evoked Potentials (SEPs) and Central Motor Conduction Times (CMCT) in children with dystonia and to test the hypothesis that these parameters predict outcome from Deep Brain Stimulation (DBS). Methods: 180 children with dystonia underwent assessment for Globus pallidus internus (GPi) DBS, mean age 10 years (range 2.5-19). CMCT to each limb was calculated using Transcranial Magnetic Stimulation. Median and posterior tibial nerve SEPs were recorded over contralateral and midline centro-parietal scalp. Structural abnormalities were assessed with cranial MRI. One-year outcome from DBS was assessed as percentage improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m). Results: Abnormal CMCTs and SEPs were found in 19% and 47% of children respectively and were observed more frequently in secondary than primary dystonia. Of children proceeding to DBS, better outcome was seen in those with normal (n = 78/89) versus abnormal CMCT (n = 11/89) (p = 0.002) and those with normal (n = 35/51) versus abnormal SEPs (n = 16/51) (p = 0.001). These relationships were independent of dystonia aetiology and cranial MRI findings. Conclusions: CMCTs and SEPs provide objective evidence of motor and sensory pathway dysfunction in children with dystonia and relate to DBS outcome. Significance: CMCTs and SEPs can contribute to patient selection and counselling of families about potential benefit from neuromodulation for dystonia.
... Doing so distills concepts into testable hypotheses on which neural pathways are directly tied to symptom relief and/or disease state. This pivots the modeling strategy from predicting behavioral outcomes, which are idiosyncratic and temporally dynamic, to predicting direct physiological responses that are mechanistically well-defined [37,108,109]. ...
Article
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Background Subthalamic deep brain stimulation (DBS) is an effective surgical treatment for Parkinson’s disease and continues to advance technologically with an enormous parameter space. As such, in-silico DBS modeling systems have become common tools for research and development, but their underlying methods have yet to be standardized and validated. Objective Evaluate the accuracy of patient-specific estimates of neural pathway activations in the subthalamic region against intracranial, cortical evoked potential (EP) recordings. Methods Pathway activations were modeled in eleven patients using the latest advances in connectomic modeling of subthalamic DBS, focusing on the hyperdirect pathway (HDP) and corticospinal/bulbar tract (CSBT) for their relevance in human research studies. Correlations between pathway activations and respective EP amplitudes were quantified. Results Good model performance required accurate lead localization and image fusions, as well as appropriate selection of fiber diameter in the biophysical model. While optimal model parameters varied across patients, good performance could be achieved using a global set of parameters that explained 60% and 73% of electrophysiologic activations of CSBT and HDP, respectively. Moreover, restricted models fit to only EP amplitudes of eight standard (monopolar and bipolar) electrode configurations were able to extrapolate variation in EP amplitudes across other directional electrode configurations and stimulation parameters, with no significant reduction in model performance across the cohort. Conclusions Our findings demonstrate that connectomic models of DBS with sufficient anatomical and electrical details can predict recruitment dynamics of white matter. These results will help to define connectomic modeling standards for preoperative surgical targeting and postoperative patient programming applications.
... For these reasons, botulinum toxin, targeting the final endpoint -the muscle movement-is commonly used as a treatment (Jankovic, 2006;Sanger et al., 2007;Bragg and Sharma, 2014). Deep-brain stimulation, an invasive procedure, is also used to partially restore normal brain dynamics (Tarsy, 2007;Johnson et al., 2008;Air et al., 2011;Bhanpuri et al., 2014). ...
Article
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A large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas including basal ganglia, thalamus, cerebellum, and sensory and motor cortices. Most research in dystonia has focused on basal ganglia, while much pharmacological treatment is provided directly at muscles to prevent contraction. Motor cortex is another potential target for therapy that exhibits pathological dynamics in dystonia, including heightened activity and altered beta oscillations. We developed a multiscale model of primary motor cortex, ranging from molecular, up to cellular, and network levels, containing 1715 compartmental model neurons with multiple ion channels and intracellular molecular dynamics. We wired the model based on electrophysiological data obtained from mouse motor cortex circuit mapping experiments. We used the model to reproduce patterns of heightened activity seen in dystonia by applying independent random variations in parameters to identify pathological parameter sets. These models demonstrated degeneracy, meaning that there were many ways of obtaining the pathological syndrome. There was no single parameter alteration which would consistently distinguish pathological from physiological dynamics. At higher dimensions in parameter space, we were able to use support vector machines to distinguish the two patterns in different regions of space and thereby trace multitarget routes from dystonic to physiological dynamics. These results suggest the use of in silico models for discovery of multitarget drug cocktails.
... Contrary to VIM and STN stimulation, there seems to be no antidromic activation due to GP stimulation. When investigating the clinical relevance of the corticallyevoked responses in children due to GPi stimulation, ( Bhanpuri et al., 2014 ) found that the clinically chosen contact led to higher evoked potentials in the ipsilateral sensorimotor areas. This finding might help clinicians choose the best contact, because the clinical benefits in dystonia often only occur after 6 months of chronic stimulation, which makes finding the optimal stimulator settings difficult. ...
Article
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Deep brain stimulation (DBS) is an effective treatment method for a range of neurological and psychiatric disorders. It involves implantation of stimulating electrodes in a precisely guided fashion into subcortical structures and, at a later stage, chronic stimulation of these structures with an implantable pulse generator. While the DBS surgery makes it possible to both record brain activity and stimulate parts of the brain that are difficult to reach with non-invasive techniques, electroencephalography (EEG) and magnetoencephalography (MEG) provide complementary information from other brain areas, which can be used to characterize brain networks targeted through DBS. This requires, however, the careful consideration of different types of artifacts in the data acquisition and the subsequent analyses. Here, we review both the technical issues associated with EEG/MEG recordings in DBS patients and the experimental findings to date. One major line of research is simultaneous recording of local field potentials (LFPs) from DBS targets and EEG/MEG. These studies revealed a set of cortico-subcortical coherent networks functioning at distinguishable physiological frequencies. Specific network responses were linked to clinical state, task or stimulation parameters. Another experimental approach is mapping of DBS-targeted networks in chronically implanted patients by recording EEG/MEG responses during stimulation. One can track responses evoked by single stimulation pulses or bursts as well as brain state shifts caused by DBS. These studies have the potential to provide biomarkers for network responses that can be adapted to guide stereotactic implantation or optimization of stimulation parameters. This is especially important for diseases where the clinical effect of DBS is delayed or develops slowly over time. The same biomarkers could also potentially be utilized for the online control of DBS network effects in the new generation of closed-loop stimulators that are currently entering clinical use. Through future studies, the use of network biomarkers may facilitate the integration of circuit physiology into clinical decision making.
... Through the experiment, the timing of early IVIG therapy's usage causes the viremia stage to be less in time with the association of better prognosis and may be crucial to survival. Moreover, IVIG used in animal models and clinical trials on infants is maybe protective against acute viral myocarditis [50,51] Pleconaril, a viral inhibitor, acts through the viral RNA's uncoating by binding to the major hydrophobic capsid protein. ...
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Enterovirus D68 (EV-D68) is a single-stranded positive-sense RNA virus, and it is one of the family Picornaviridae. Except for EV-D68, the family Picornaviridae has been illustrated in literature. EV-D68 was first discovered and isolated in California, USA, in 1962. EV-D68 has resulted in respiratory disorders’ outbreaks among children worldwide, and it has been detected in cases of various neurological diseases such as acute flaccid myelitis (AFM). A recent study documented a higher number of EV-D68 cases associated with AFM in Europe in 2016 compared to the 2014 outbreak. EV-D68 is mainly diagnosed by quantitative PCR, and there is an affirmative strategy for EV-D68 detection by using pan-EV PCR on the untranslated region and/or the VP1 or VP2, followed by sequencing of the PCR products. Serological tests are limited due to cross-reactivity of the antigens between the different serotypes. Many antiviral drugs for EV-D68 have been evaluated, and showed promising results. In our review, we discuss the current knowledge about EV-D68 and its role in the development of AFM.
... We chose to model the time domain evoked response because this feature has been demonstrated as a potential feedback control signal for adjusting DBS parameters for tremor reduction (29). DBS evoked response in scalp EEG has also been shown to be a good discriminator between primary and secondary dystonia (66). Evoked compound nerve action potentials have been used to design an autonomous neural control for vagus nerve stimulation for treating epileptic and depressed patients (67). ...
Article
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Objective: Deep brain stimulation (DBS) is a valuable tool for ameliorating drug resistant pathologies such as movement disorders and epilepsy. DBS is also being considered for complex neuro-psychiatric disorders, which are characterized by high variability in symptoms and slow responses that hinder DBS setting optimization. The objective of this work was to develop an in-silico platform to examine the effects of electrical stimulation in regions neighboring a stimulated brain region. Approach: We used the Jansen-Rit neural mass model of single and coupled nodes to simulate the response to a train of electrical current pulses at different frequencies (10-160 Hz) of the local field potential recorded in the amygdala and cortical structures in human subjects and a non-human primate. Results: We found that using a single node model, the evoked responses could be accurately modeled following a narrow range of stimulation frequencies. Including a second coupled node increased the range of stimulation frequencies whose evoked responses could be efficiently modeled. Furthermore, in a chronic recording from a non-human primate, features of the in vivo evoked response remained consistent for several weeks, suggesting that model re-parameterization for chronic stimulation protocols would be infrequent. Significance: Using a model of neural population activity, we reproduced the evoked response to cortical and subcortical stimulation in human and non-human primate. This modeling framework provides an environment to explore, safely and rapidly, a wide range of stimulation settings not possible in human brain stimulation studies. The model can be trained on a limited dataset of stimulation responses to develop an optimal stimulation strategy for an individual patient.&#13.
Article
Deep Brain Stimulation (DBS) has become a mainstay of dystonia management in adulthood. Typically targeting electrode placement in the GPi, sustained improvement in dystonic symptoms are anticipated in adults with isolated genetic dystonias. Dystonia in childhood is more commonly a symptomatic condition, with dystonia frequently expressed on the background of a structurally abnormal brain. Outcomes following DBS in this setting are much more variable, the reasons for which have yet to be elucidated. Much of the focus on improving outcomes following DBS in dystonia management has been on the importance of patient selection, with, until recently, little discussion of the choice of target. In this review, we advance the argument that patient selection for DBS in childhood cannot be made separate from the choice of target nuclei. The anatomy of common DBS targets are considered, and factors influencing their choice for electrode insertion are discussed. We propose an ‘ABC” for DBS in childhood dystonia is proposed: Appropriate Child selected; Best nuclei chosen for electrode insertion; Correct position within that nucleus.
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Vibratory feedback can be a useful tool for rehabilitation. We examined its use in children with dystonia to understand how it affects muscle activity in a population that does not respond well to standard rehabilitation. We predicted scaled vibration (ie, vibration that was directly or inversely proportional to muscle activity) would increase use of the vibrated muscle because of task-relevant sensory information, whereas nonscaled vibration would not change muscle use. The study was conducted on 11 subjects with dystonia and 14 controls. Each subject underwent 4 different types of vibration on the more dystonic biceps muscle (or nondominant arm in controls) in a 1-dimensional, bimanual myocontrol task. Our results showed that only scaled vibratory feedback could bias muscle use without changing overall performance in children with dystonia. We believe there may be a role in rehabilitation for scaled vibratory feedback to retrain abnormal muscle patterns.
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Introduction Increasing clinical use of Intrathecal baclofen (ITB) in Australian tertiary paediatric hospitals, along with the need for standardised assessment and reporting of adverse events, saw the formation of the Australian Paediatric ITB Research Group (APIRG). APIRG developed a National ITB Audit tool designed to capture clinical outcomes and adverse events data for all Australian children and adolescents receiving ITB therapy. Methods and analysis The Australian ITB Audit is a 10 year, longitudinal, prospective, clinical audit collecting all adverse events and assessment data across body functions and structure, participation and activity level domains of the ICF. Data will be collected at baseline, 6 and 12 months with ongoing capture of all adverse event data. This is the first Australian study that aims to capture clinical and adverse event data from a complete population of children with neurological impairment receiving a specific intervention between 2011 and 2021. This multi-centre study will inform ITB clinical practice in children and adolescents, direct patient selection, record and aid decision making regarding adverse events and investigate the impact of ITB therapy on family and patient quality of life. Ethics and dissemination This project was approved by the individual Human Research Ethics committees at the six Australian tertiary hospitals involved in the study. Results will be published in various peer reviewed journals and presented at national and international conferences. Trial registration number ACTRN 12610000323022; Pre-results.
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A monosynaptic projection from the cortex to the subthalamic nucleus is thought to have an important role in basal ganglia function and in the mechanism of therapeutic subthalamic deep-brain stimulation, but in humans the evidence for its existence is limited. We sought physiological confirmation of the cortico-subthalamic hyperdirect pathway using invasive recording techniques in patients with Parkinson’s disease (9 men, 1 woman). We measured sensorimotor cortical evoked potentials using a temporary subdural strip electrode in response to low-frequency deep-brain stimulation in patients undergoing awake subthalamic or pallidal lead implantations. Evoked potentials were grouped into very short latency (<2 ms), short latency (2–10 ms), and long latency (10 –100 ms) from the onset of the stimulus pulse. Subthalamic and pallidal stimulation resulted in very short-latency evoked potentials at 1.5 ms in the primary motor cortex accompanied by EMG-evoked potentials consistent with corticospinal tract activation. Subthalamic, but not pallidal stimulation, resulted in three short-latency evoked potentials at 2.8, 5.8, and 7.7 ms in a widespread cortical distribution, consistent with antidromic activation of the hyperdirect pathway. Long-latency potentials were evoked by both targets, with subthalamic responses lagging pallidal responses by 10 –20 ms, consistent with orthodromic activation of the thalamocortical pathway. The amplitude of the first short-latency evoked potential was predictive of the chronic therapeutic stimulation contact.
Article
Objective: Internal globus pallidus (GPi) deep brain stimulation (DBS) relieves symptoms in dystonia patients. However, the physiological effects produced by GPi DBS are not fully understood. In particular, how a single-pulse GPi DBS changes cortical circuits has never been investigated. We studied the modulation of motor cortical excitability and plasticity with single-pulse GPi DBS in dystonia patients with bilateral implantation of GPi DBS. Methods: The cortical evoked potentials from DBS were recorded with electroencephalography. Transcranial magnetic stimulation with a conditioning-test paired-pulse paradigm was used to investigate the effect of GPi DBS on the primary motor cortex. How GPi DBS might modulate the motor cortical plasticity was tested using a paired associative stimulation paradigm with repetitive pairs of GPi DBS and motor cortical stimulation at specific time intervals. Results: GPi stimulation produced two peaks of cortical evoked potentials with latencies of ∼10 and ∼25 ms in the motor cortical area. Cortical facilitation was observed at ∼10 ms after single-pulse GPi DBS and cortical inhibition was observed at ∼25 ms interval. Repetitive pairs of GPi stimulation with cortical stimulation at these two time intervals produced long term potentiation-like effects in the motor cortex. Interpretation: Single-pulse DBS modulates cortical excitability and plasticity at specific time intervals. These effects may be related to the mechanism of action of DBS. Combination of DBS with cortical stimulation at appropriate timing has therapeutic potential and could be explored in the future as a method to enhance the effects of neuromodulation for neurological and psychiatric diseases. This article is protected by copyright. All rights reserved.
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Parkinson's disease is associated with altered neural activity in the motor cortex. High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) suppresses parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal was to determine the neural origin of cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA lesioned parkinsonian rats. Second, we used a biophysically-based model of the thalamocortical network to deconstruct the neural origin of the cEP. The in vivo cEP included short (R1), intermediate (R2) and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. R1 was generated by antidromic activation of layer 5 pyramidal neurons, while recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced R2. R3 was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cEP by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms.
Article
Objectives To characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming. Materials and Methods Serial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement. Results In the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45–0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands. Conclusions Our findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming.
Chapter
Cervical spine problems in children with cerebral palsy are uncommon. Some children with severe movement disorder and those with extensor posturing, however, may develop occipital cervical instability. Atlantoaxial instability can also occur in patients with torsional dystonia. Cervical extensor contractures occur in those children with severe extensor posturing. Symptoms of cervical problems are usually pain or occasionally related to spinal cord compression. Spinal cord compression symptoms cause either increase spasticity in the legs or sudden loss of spasticity and decreased movement in the lower extremities. Mid-cervical spinal stenosis and degenerative arthritis occur in adults with movement disorders especially those with athetosis. Lower cervical spine problems occur primarily as a residual of high kyphosis. The treatment for this drop off kyphosis requires surgical correction if it is symptomatic. Other spinal problems that occur after posterior spinal fusion are relatively uncommon although on rare occasions children will develop pseudarthrosis which become symptomatic and require repair. When the spinal instrumentation is not strong enough or solidly connected, deformities may occur around the instrumentation. Treatments of these complex problems are discussed in this chapter.
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Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode, but has negligible effects on population-level firing rate, or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multi-electrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates (M. fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12 - 30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were 3 times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS. Copyright © 2014, Journal of Neurophysiology.
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Increased motor cortex excitability is a common finding in dystonia, and transcranial direct current stimulation can reduce motor cortex excitability. In an earlier study, we found that cathodal direct-current stimulation decreased motor overflow for some children with dystonia. To investigate this observation further, we performed a sham-controlled, double-blind, crossover study of 14 children with dystonia. We found a significant reduction in overflow following real stimulation, when participants performed the experimental task with the hand contralateral to the cathode. While these results suggest that cathodal stimulation may help some children to reduce involuntary overflow, the size of the effect is small. Further research will need to investigate ways to increase the magnitude of the effect of cathodal transcranial direct current stimulation.
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Studies suggest that dystonia is associated with increased motor cortex excitability. Cathodal transcranial direct current stimulation can temporarily reduce motor cortex excitability. To test whether stimulation of the motor cortex can reduce dystonic symptoms in children, we measured tracking performance and muscle overflow using an electromyogram tracking task before and after stimulation. Of 10 participants, 3 showed a significant reduction in overflow, and a fourth showed a significant reduction in tracking error. Overflow decreased more when the hand contralateral to the cathode performed the task than when the hand ipsilateral to the cathode performed the task. Averaged over all participants, the results did not reach statistical significance. These results suggest that cathodal stimulation may allow a subset of children to control muscles or reduce involuntary overflow activity. Further testing is needed to confirm these results in a blinded trial and identify the subset of children who are likely to respond.
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Neuronal activity within and across the cortex and basal ganglia is pathologically synchronized, particularly at approximately 20 Hz in patients with Parkinson's disease. Defining how activities in spatially distributed brain regions overtly synchronize in narrow frequency bands is critical for understanding disease processes like Parkinson's disease. To address this, we studied cortical responses to electrical stimulation of the subthalamic nucleus (STN) at various frequencies between 5 and 30 Hz in two cohorts of eight patients with Parkinson's disease from two different surgical centres. We found that evoked activity consisted of a series of diminishing waves with a peak latency of 21 ms for the first wave in the series. The cortical evoked potentials (cEPs) averaged in each group were well fitted by a damped oscillator function (r > or = 0.9, P < 0.00001). Fits suggested that the natural frequency of the subthalamo-cortical circuit was around 20 Hz. When the system was forced at this frequency by stimulation of the STN at 20 Hz, the undamped amplitude of the modelled cortical response increased relative to that with 5 Hz stimulation in both groups (P < or = 0.005), consistent with resonance. Restoration of dopaminergic input by treatment with levodopa increased the damping of oscillatory activity (as measured by the modelled damping factor) in both patient groups (P < or = 0.001). The increased damping would tend to limit resonance, as confirmed in simulations. Our results show that the basal ganglia-cortical network involving the STN has a tendency to resonate at approximately 20 Hz in Parkinsonian patients. This resonance phenomenon may underlie the propagation and amplification of activities synchronized around this frequency. Crucially, dopamine acts to increase damping and thereby limit resonance in this basal ganglia-cortical network.
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Co-contraction and overflow of EMG activity of inappropriate muscles are typical features of all dystonic movements whether voluntary or involuntary. Voluntary movements are slow and more variable than normal, and there is particular difficulty switching between component movements of a complex task. Reduced spinal cord and brainstem inhibition is common to many reflex studies (long-latency reflexes, cranial reflexes and reciprocal inhibition). These reflex abnormalities may contribute to the difficulties in voluntary movements but cannot be causal as they can occur outside the clinically involved territory. Clinical and neurophysiological studies have emphasized the possible role of sensory feedback in the generation of dystonic movements. Abnormalities of cortical and basal ganglia function have been described in functional imaging and neurophysiological studies of patients with dystonia and in animal models of primary dystonia. Studies of cortical function have shown reduced preparatory activity in the EEG before the onset of voluntary movements, whilst magnetic brain stimulation has revealed changes in motor cortical excitability. Functional imaging of the brain in primary dystonia has suggested reduced pallidal inhibition of the thalamus with consequent overactivity of medial and prefrontal cortical areas and underactivity of the primary motor cortex during movements. These findings are supported by preliminary neuronal recordings from the globus pallidus and the thalamus at the time of stereotaxic surgery in patients with dystonia. All this evidence suggests that primary dystonia results from a functional disturbance of the basal ganglia, particularly in the striatal control of the globus pallidus (and substantia nigra pars reticulata). This causes altered thalamic control of cortical motor planning and executive areas, and abnormal regulation of brainstem and spinal cord inhibitory interneuronal mechanisms.
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We present a new computational model for the development of task-specific focal dystonia. The purpose of the model is to explain how altered sensory representations can lead to abnormal motor behavior. Dystonia is described as the result of excessive gain through a sensorimotor loop. The gain is determined in part by the sensory cortical area devoted to each motor function, and behaviors that lead to abnormal increases in sensory cortical area are predicted to lead to dystonia. Properties of dystonia including muscular co-contraction, overflow movements, and task specificity are predicted by properties of a linear approximation to the loop transformation. We provide simulations of several different mechanisms that can cause the gain to exceed 1 and the motor activity to become sustained and uncontrolled. The model predicts that normal plasticity mechanisms may contribute to worsening of symptoms over time.
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Dystonia is a relatively common neurological syndrome characterized by twisting movements or sustained abnormal postures. Although the basal ganglia have been implicated in the expression of dystonia, recent evidence suggests that abnormal cerebellar function is also involved. In these studies, a novel mouse model was developed to study the role of the cerebellum in dystonia. Microinjection of low doses of kainic acid into the cerebellar vermis of mice elicited reliable and reproducible dystonic postures of the trunk and limbs. The severity of the dystonia increased linearly with kainate dose. Kainate-induced dystonia was blocked by the glutamatergic antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide and reproduced by domoic acid microinjection, suggesting that the induction of dystonia is dependent on glutamatergic activation in this model. The abnormal movements were not associated with kainate-induced seizures, because EEG recordings showed no epileptiform activity during the dystonic events. Neuronal activation, as assessed by in situ hybridization for c-fos, revealed c-fos mRNA expression in the cerebellum, locus ceruleus, and red nucleus. In contrast, regions associated with epileptic seizures, such as the hippocampus, did not exhibit increased c-fos expression after cerebellar kainate injection. Furthermore, in transgenic mice lacking Purkinje cells, significantly less dystonia was induced after kainic acid injection, implicating Purkinje cells and the cerebellar cortex in this model of dystonia. Together, these data suggest that abnormal cerebellar signaling produces dystonia and that the cerebellum should be considered along with the basal ganglia in the pathophysiology of this movement disorder.
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In our hypothesis of focal dystonia, attended repetitive behaviors generate aberrant sensory representations. Those aberrant representations interfere with motor control. Abnormal motor control strengthens sensory abnormalities. The positive feedback loop reinforces the dystonic condition. Previous studies of primates with focal hand dystonia have demonstrated multi-digit or hairy-glabrous responses at single sites in area 3b, receptive fields that average ten times larger than normal, and high receptive field overlap as a function of horizontal distance. In this study, we strengthen and elaborate these findings. One animal was implanted with an array of microelectrodes that spanned the border between the face and digits. After the animal developed hand dystonia, responses in the initial hand representation increasingly responded to low threshold stimulation of the face in a columnar substitution. The hand-face border that is normally sharp became patchy and smeared over 1 mm of cortex within 6 weeks. Two more trained animals developed a focal hand dystonia variable in severity across the hand. Receptive field size, presence of multi-digit or hairy-glabrous receptive fields, and columnar overlap covaried with the animal's ability to use specific digits. A fourth animal performed the same behaviors without developing dystonia. Many of its physiological measures were similar to the dystonic animals, but receptive field overlap functions were minimally abnormal, and no sites shared response properties that are normally segregated such as hairy-glabrous combined fields, or multi-digit fields. Thalamic mapping demonstrated proportionate levels of abnormality in thalamic representations as were found in cortical representations.
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Here we test the hypothesis that there are distinct temporal patterns of synchronized neuronal activity in the pallidum that characterize untreated and treated parkinsonism and dystonia. To this end we recorded local field potentials (LFPs) from the caudal and rostral contact pairs of macroelectrodes implanted into the pallidum of patients for the treatment of Parkinson's disease (12 cases recorded on and off medication, 17 macroelectrodes) and dystonia (10 cases, 19 macroelectrodes). Percentage LFP power in the 11-30 Hz band was decreased and that in the 4-10 Hz band increased across both contact pairs in treated Parkinson's disease compared with untreated Parkinson's disease. Dystonic patients had even less 11-30 Hz power and greater 4-10 Hz power compared with untreated or treated Parkinson's disease patients. The change in the 4-10 Hz band in patients with dystonia was particularly manifest in the more rostral contact pair, presumed to be within or bridging the globus pallidus externus. We conclude that untreated and treated Parkinson's disease and dystonia are characterized by different spatiotemporal patterns of activity in the human pallidum.
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Primary generalized dystonia (PGD) is a medically refractory disease of the brain causing twisting or spasmodic movements and abnormal postures. In more than 30% of cases it is associated with the autosomal DYT1 mutation. Continuous electrical stimulation of the globus pallidus internus (GPi) has been used successfully in the treatment of PGD. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of PGD in children and adults with and without the DYT1 mutation. Thirty-one patients with PGD were selected for surgery. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators that were inserted subcutaneously. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) before and after implantation. The efficacy of stimulation improved with time. After 2 years, compared with preoperative values, the mean (+/- standard deviation) clinical and functional BFMDRS scores had improved by 79 +/- 19% and 65 +/- 33%, respectively. At the 2-year follow-up examination the improvement was comparable in patients with and without the DYT1 mutation in both the functional (p = 0.12) and clinical (p = 0.33) scores. Children displayed greater improvements in the clinical score than adult patients (p = 0.04) at 2 years of follow up. In contrast, there was no significant difference in functional scores between children and adults (p = 0.95). Electrical stimulation of the GPi is an effective, reversible, and adaptable treatment for PGD and should be considered for conditions refractory to pharmaceutical therapies.
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Writer's cramp, or focal hand dystonia, is characterized by involuntary coactivation of antagonist or unnecessary muscles while writing or performing other tasks. Although the mechanism underlying this muscle overactivation is unknown, recent studies of changes in cerebral blood flow during writing have demonstrated a reduction in the activation of the primary motor cortex (MC) and hyperactivity of parts of the frontal non-primary motor areas. Therefore, any measures that decrease the activities of non-primary motor areas such as the premotor cortex (PMC) and the supplementary motor area (SMA) might improve dystonic symptoms. To explore this possibility, we studied nine patients with writer's cramp and seven age-matched control subjects, using subthreshold low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS), which exerts an inhibitory action on the cortex. Previous studies have demonstrated shortened cortical silent periods in dystonia, suggesting deficient cortical inhibition in the MC. We compared the silent periods and computer-assisted ratings of handwriting before and after rTMS applied to the MC, SMA or PMC. We also used the sham coil for control runs. Stimulation of the PMC but not the MC significantly improved the rating of handwriting (mean tracking error from the target, P = 0.004; pen pressure, P = 0.01) and prolonged the silent period (P = 0.02) in the patient group. rTMS over the other sites or using a sham coil in the patient group or trials in the control group revealed no physiological or clinical changes. This increased susceptibility of the PMC in dystonia suggests that the lack of inhibition in the MC is secondary to the hyperactivity of PMC neurons. Inhibition of the PMC using rTMS could provide a therapeutic measure of writer's cramp.
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Deep brain stimulation (DBS) is widely used as a safe and effective medical treatment for certain neurological disorders. It continues to evolve with improving techniques in functional neurosurgery and biomedical device engineering. This paper provides an overview of the enabling science and technology that have allowed DBS to successfully treat certain neurological disorders. It also points toward some of the engineering advances that will enable DBS to yield a more predictable outcome for current indications and to be systematically developed as a treatment for new indications.
Article
Background Deep brain stimulation has become a routine therapy for movement disorders, but it is relatively invasive and costly. Although stimulation intensity relates to battery longevity, less is known about how diagnosis and stimulation target contribute to this clinical outcome. Here we evaluate battery longevity in movement disorders patients who were treated at a tertiary referral center. Objective To compare single channel pulse generator longevity in patients with movement disorders. Methods With Institutional Review Board approval, we evaluated 470 consecutive Soletra implants for routine care. Battery longevity was estimated with Kaplan-Meier analyses, and group comparisons were performed with the log rank mean test. The frequency of clinic encounters for ongoing care was evaluatedacross diagnoses with analysis of variance (ANOVA). Results The mean pulse generator longevity was 44.9±1.4 months. Pallidal DBS for dystonia was associated with shorter battery longevity than subthalamic and thalamic DBS for Parkinson's disease and essential tremor (28.1±2.1 versus 47.1±1.8 and 47.8±2.6 months, respectively, mean ± standard error, p<0.001), and dystonia patients required more frequent clinic visits for routine care (F=6.0, p=0.003). Pallidal DBS for Parkinson's disease and thalamic DBS for cerebellar outflow tremor were associated with shorter battery longevity, as well (35.3±4.6 and 26.4±4.3 months, respectively). Conclusions Pallidal DBS for dystonia was associated with shorter battery longevity and more frequent stimulator adjustments versus DBS for Parkinson’s disease and essential tremor. Characteristics of the stimulation target and disease pathophysiology both likely contribute to battery longevity in patients with movement disorders.
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In a recent issue of Experimental Neurology, Prudente et al. (2013) investigated the neuropathology of cervical dystonia in six patients. Their most important finding was a patchy loss of cerebellar Purkinje cells in the cerebellum. In this article we discuss their findings in the context of a review including primary and secondary cervical dystonia An update is given of the current knowledge on structural and functional brain abnormalities in idiopathic cervical dystonia with a special focus on the cerebellum.
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Despite the best available medical treatments, many patients continue to be disabled by neurologic and psychiatric disorders, resulting in a large unmet need. Advances in imaging and neurophysiology over the last two decades have led to a reinterpretation of some neurologic and psychiatric conditions as primarily disorders of circuit function, or "circuitopathies." These developments have been accompanied by advances in neurosurgical techniques with the increasingly widespread utilization of deep brain stimulation (DBS) to recalibrate dysfunctional circuits. The versatility of DBS as both a probe and modulator of neural circuits is making it a powerful tool to study the human brain, helping provide important details of the pathophysiology of circuit dysfunction. We are currently in a phase of active investigation to determine which circuits and disorders could be treated with DBS. Here we review recent advances in the DBS field and discuss potential future directions in targeted intracranial neuromodulation.
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Surgical therapy for the secondary dystonias is generally perceived to be less effective than for primary disease. However, a number of case reports and small open series have recently appeared describing quite favorable outcomes following surgery for some nonprimary dystonias. We discuss surgical treatment options for this group of diverse conditions, including tardive dystonia, dystonic cerebral palsy, and certain heredodegenerative diseases in which deep brain stimulation and ablative lesions of the posteroventral pallidum have been shown to be effective. Other types of secondary dystonia respond less well to pallidal surgery, particularly when anatomical lesions of the basal ganglia are prominent on preoperative imaging. For these conditions, central baclofen delivery and botulinum toxin denervation may be considered. With optimal medical and surgical care, some patients with secondary dystonia have achieved reductions in disability and pain that approach those documented for primary dystonia. © 2012 Movement Disorder Society.
Article
When considering a patient with dystonia for deep brain stimulation (DBS) surgery several factors need to be considered. Level B evidence has shown that all motor features and associated pain in primary generalized and segmental dystonia are potentially responsive to globus pallidus internus (GPi) DBS. However, improvements in clinical series of ≥90% may reflect methods that need improvement, and larger prospective studies are needed to address these factors. Nevertheless, to date the selection criteria for DBS—specifically in terms of patient features (severity and nature of symptoms, age, time of evolution, or any other demographic or disease aspects)—have not been assessed in a systematic fashion. In general, dystonia patients are not considered for DBS unless medical therapies have been previously and extensively tested. The vast majority of reported patients have had DBS surgery when the disease was provoking important disability, with loss of independence and impaired quality of life. There does not appear to be an upper age limit or a minimum age limit, although there are no published data regarding the outcome of GPi DBS for dystonia in children younger than 7 years of age. There is currently no enough evidence to prove that subjects with primary-generalized dystonia who undergo DBS at an early age and sooner rather than later after disease onset may gain more benefit from DBS than those undergoing DBS after the development of fixed skeletal deformities. There is no enough evidence to refuse or support consideration of DBS in patients with previous ablative procedures. © 2011 Movement Disorder Society
Article
Dystonia has generally been considered a basal ganglia (BG) disorder. Early models hypothesized that dystonia occurred as the result of reduced mean discharge rates in the internal segment of the globus pallidus (GPi). Increasing evidence suggests a more systemwide disruption of the basal ganglia thalamic circuit (BGTC) resulting in altered firing patterns, synchronized oscillations, and widened receptive fields. A model of dystonia incorporating these changes within the BGTC is presented in which we postulate that this pathophysiology arises from disruptions within the striatum. Alterations in the cerebellothalamocortical (CBTC) pathway to the development of dystonia may also play a role. However, the contribution of CBTC abnormalities to dystonia remains unclear and may vary with different etiologies of dystonia. Finally, the relevance of established and emerging theories related to the pathophysiology of dystonia is addressed within the context of improving conventional approaches for deep brain stimulation (DBS) treatment strategies.
Article
The year 2012 marks the 25th anniversary of the birth of modern deep brain stimulation (DBS), which was introduced by Benabid et al in 1987, initially to treat tremor with DBS of the ventral intermediate nucleus of the thalamus. The subsequent extension of DBS to the subthalamic nucleus (STN), demonstrating its efficacy on virtually all symptoms of advanced Parkinson's disease (PD), sparked an era of intense clinical and research activities, eventually transcending PD and movement disorders to encompass mood and mind. Investigations of the role of DBS in a variety of neurological, psychiatric, cognitive, and behavioral conditions is ongoing. Serendipitous discoveries and advances in functional imaging are providing "new" brain targets for an increasing number of pathologies. Toward the end of this quarter of a century of DBS, there have been some indications that the field may be at risk of gliding down a slippery slope, reminiscent of the excesses of the old-era DBS. Although there are many reasons this year to celebrate the achievements of 25 years of modern DBS, there are also reasons to fear the opening of a new Pandora's box.
Article
Subthalamic deep brain stimulation (DBS) is superior to medical therapy for the motor symptoms of advanced Parkinson's disease (PD), and additional evidence suggests that it improves refractory symptoms of essential tremor, primary generalized dystonia, and obsessive-compulsive disorder. Despite this, its therapeutic mechanism is unknown. We hypothesized that subthalamic stimulation activates the cerebral cortex at short latencies after stimulus onset during clinically effective stimulation for PD. In 5 subjects (six hemispheres), EEG measured the response of cortex to subthalamic stimulation across a range of stimulation voltages and frequencies. Novel analytical techniques reversed the anode and cathode electrode contacts and summed the resulting pair of event-related potentials to suppress the stimulation artifact. We found that subthalamic brain stimulation at 20 Hz activates the somatosensory cortex at discrete latencies (mean latencies: 1.0 ± 0.4, 5.7 ± 1.1, and 22.2 ± 1.8 ms, denoted as R1, R2, and R3, respectively). The amplitude of the short latency peak (R1) during clinically effective high-frequency stimulation is nonlinearly dependent on stimulation voltage (P < 0.001; repeated-measures analysis of variance), and its latency is less variable than that of R3 (1.02 versus 19.46 ms; P < 0.001, Levene's test). We conclude that clinically effective subthalamic brain stimulation in humans with PD activates the cerebral cortex at 1 ms after stimulus onset, most likely by antidromic activation. These findings suggest that alteration of the precise timing of action potentials in cortical neurons with axonal projections to the subthalamic region may be an important component of the therapeutic mechanism of subthalamic brain stimulation.
Conference Paper
Writer's cramp, or focal hand dystonia, is characterized by involuntary coactivation of antagonist or unnecessary muscles while writing or performing other tasks. Recent studies of changes in cerebral blood flow during writing have demonstrated a reduction in the activation of the primary motor cortex (MC) and hyperactivity of the parts of frontal nonprimary motor areas. Therefore, any measures that decrease the activities of nonprimary motor areas like the premotor cortex (PMC) or supplementary motor area (SMA) might improve dystonic symptoms. We explore this possibility of acute effect, Nine patients with writer's cramp and seven age-matched control subjects were recruited. After the preliminary experiments, we used subthreshold low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS), which exerts an inhibitory action on the cortex. We compared the silent periods and computer-assisted ratings of handwriting before and after rTMS applied to the MC, SMA, or PMC. Stimulation of the PMC but not the MC significantly improved the rating of handwriting (mean tracking error from the target, P=0.004; pen pressure, P=0.01) and prolonged the silent period (P=0.02) in the patient group. This increased susceptibility of the PMC in dystonia suggests that lack of inhibition in the MC is secondary to the hyperactivity of PMC neurons. Further physiological studies disclosed that the amplitude of frontal N30 component was significantly increased after rTMS over the PMC in control subjects (p=0.014) but not in dystonic patients, and 99mTc-ECD SPECT showed the different activation pattern in between control subjects (Brodmann area 9 and 6 including PMC and prefrontal cortex) and patients (parietal and cerebellar cortices). These findings support the idea that cortical network pattern induced by rTMS is quite different in the two groups. It is not clear whether the activated areas seen in dystonia is due to primary or compensatory mechanism, but our findings sugge- st the PMC plays an important role in the pathophysiology of dystonia. Additionally we showed 0.2 Hz rTMS over the premotor cortex was rather effective than ordinary 1 Hz stimulation over the MC, demonstrating that different frequency and stimulation site is to be explored in each disease depending on its own pathophysiology.
Article
Previous studies in primary dystonia suggested that abnormal oscillations of 5–18 Hz in the bilateral internal globus pallidus (GPi) may be a specific feature of dystonia.1–3 Moreover, voluntary movements were associated with bilateral desynchronization of β (<30 Hz) and contralateral synchronization of γ (∼70 Hz) frequencies in the GPi.2–4 We recorded local field potentials (LFPs) from the GPi and motor thalamus in a patient with severe hemidystonia to test the following hypotheses. First, the 5–18 Hz synchronization is present in the basal ganglia (BG)–thalamic circuit in patients with secondary dystonia. Second, the bilaterally coherent 5–18 Hz activity may be transmitted between the hemispheres through the motor thalamus. Finally, if the 5–18 Hz rhythm is related to dystonia, attempted movements of dystonic muscles would result in less attenuation of this 5–18 Hz oscillation compared to normal movements.
Article
Deep Brain Stimulation is an effective treatment of generalized dystonia. Optimal stimulation parameters vary between patients. This article investigates the influence of electrical brain impedance and delivered current on the brain response to stimulation. Twenty-four patients were bilaterally stimulated in the globus pallidus internus through two implanted four-contact electrodes. The variation of brain impedance and current measurements was correlated with stimulation parameters, time course, and clinical outcome. When a contact was activated, a statistically significant and reversible decrease of brain impedance was found. Impedance and current values and their variations with time significantly differed between patients. The absolute impedance did not significantly correlate with the final outcome. We conclude that the reversible decrease of impedance reflects an adaptive long-term mechanism, which could be due to a plasticity phenomenon, but has no prognostic value. Impedance and current measurements give new complementary information for parameter adjustment and trouble shooting and should therefore be included in all patients' follow-up.
Article
Deep brain stimulation (DBS) is an established technique for the treatment of several movement disorders in adults. However, the technical approach, complications, and results of DBS in children have not been well documented. A database of DBS implantations performed at a single institution, prospectively established in 1998, was reviewed for patients who received DBS prior to the age of 18. Diagnoses, surgical technique, and complications were noted. Outcomes were assessed using standard rating scales of neurological function. Of 815 patients undergoing DBS implantation over a 12-year period, 31 were children (mean age at surgery 13.2 years old, range 4-17 years old). Diagnoses included the following: DYT1 primary dystonia (autosomal dominant, Tor1AΔGAG mutation, 10 cases), non-DYT1 primary dystonia (3 cases), secondary dystonia (11 cases), neurodegeneration with brain iron accumulation (NBIA, 3 cases), levodopa-responsive parkinsonism (2 cases), Lesch-Nyhan disease (1 case), and glutaric aciduria Type 1 (1 case). Six children ages 15-17 years old underwent awake microelectrode-guided surgery. For 25 children operated under general anesthesia, the surgical technique evolved from microelectrode-guided surgery to image-guided surgeries using real-time intraoperative MR imaging or CT for lead location confirmation. Complications included 5 hardware infections, all in children younger than 10 years old. At 1 year after implantation, patients with DYT1 dystonia had a mean improvement in the Burke-Fahn-Marsden Dystonia Rating Scale movement subscore of 75%, while those with secondary dystonia had only small improvements. Outcomes in the 3 children with NBIA were disappointing. Results of DBS in children with primary and secondary dystonias were similar to those in adults, with excellent results for DYT1 dystonia in children without fixed orthopedic deformity and much more modest results in secondary dystonia. In contrast to reported experience in adults with NBIA, these results in children with NBIA were poor. Infection risk was highest in the youngest patients.
Article
The pathophysiology of dystonia has been best studied in patients with focal hand dystonia. A loss of inhibitory function has been demonstrated at spinal, brainstem and cortical levels. Many cortical circuits seem to be involved. One consequence of the loss of inhibition is a failure of surround inhibition, and this appears to directly lead to overflow and unwanted muscle spasms. There are mild sensory abnormalities and deficits in sensorimotor integration; these also might be explained by a loss of inhibition. Increasing inhibition may be therapeutic. A possible hypothesis is that there is a genetic loss of inhibitory interneurons in dystonia and that this deficit is a substrate on which other factors can act to produce dystonia. This article is part of a Special Issue entitled "Advances in dystonia".
Article
Several studies have confirmed that subthalamic and pallidal local field potential activity in the beta frequency band (13-30 Hz) is exaggerated in untreated patients with Parkinson's disease (PD) and is suppressed by dopaminergic treatment. This particular spectral pattern differs from that in patients with dystonia in whom pallidal activity is prominent at low frequencies (<12 Hz). Here we demonstrate that tetrabenazine induced monoamine depletion and dopamine blockade is associated with increased activity in the low beta band (13-20 Hz) in the internal pallidum of patients with dystonia. Beta activity was elevated in six patients treated with tetrabenazine compared to six patients in whom this drug was not used. Our findings suggest that beta activity is enhanced in the chronically dopamine-depleted and blocked state irrespective of the underlying pathology, consistent with the idea that excessive synchrony in the beta band is directly related to dopaminergic hypofunction, rather than some degenerative disease-specific attribute of Parkinson's disease.
Article
Information about the basal ganglia has accumulated at a prodigious pace over the past decade, necessitating major revisions in the authors' concepts of the structural and functional organization of these nuclei. Recent anatomical and physiological findings have further substantiated the concept of segregated basal ganglia-thalamocortical pathways, and reinforced the general principle that basal ganglia influences are transmitted only to restricted portions of the frontal lobe (even though the striatum receives projections from nearly the entire neocortex). Using the 'motor' circuit as a model, the authors have reexamined the available data on other portions of the basal ganglia-thalamocortical pathways and found that the evidence strongly suggests the existence of at least four additional circuits organized in parallel with the 'motor' circuit. In the discussion that follows, they review some of the anatomic and physiologic features of the 'motor circuit,' as well as the data that support the existence of the other proposed parallel circuits, which they have designated the 'oculomotor,' the 'dorsolateral prefrontal,' the 'lateral orbitofrontal,' and the 'anterior cingulate,' respectively. Each of these five basal ganglia-thalamocortical circuits appears to be centered upon a separate part of the frontal lobe. This list of basal ganglia-thalamocortical circuits is not intended to be exhaustive. In fact, if the conclusions suggested in this review are valid, future investigations might be expected to disclose not only further details (or the need for revisions) of these five circuits, but perhaps also the existence of additional parallel circuits whose identification is currently precluded by a paucity of data.
Article
The goal of this study was to determine which neural elements are excited by microstimulation of the central nervous system. A cable model of a neuron including an axon, initial segment, axon hillock, soma, and simplified dendritic tree was used to study excitation with an extracellular point source electrode. The model reproduced a wide range of experimentally documented extracellular excitation patterns. The site of action potential initiation (API) was a function of the electrode position, stimulus duration, and stimulus polarity. The axon or initial segment was always the site of API at threshold. When the electrode was positioned near the cell body, the site of excitation was dependent on the stimulus amplitude. With the electrode in close proximity to the neuron, short-duration cathodic pulses produced lower thresholds with the electrode positioned over the axon than over the cell body, and long-duration stimuli produced opposite relative thresholds. This result was robust to alterations in either the maximum conductances or the intracellular resistivities of the model. The site of maximum depolarization was not always an accurate predictor of the site of API, and the temporal evolution of the changes in membrane potential played a strong role in determining the site of excitation.
Article
The reliability and responsiveness of the Barry-Albright Dystonia (BAD) Scale, a 5-point ordinal severity scale for secondary dystonia, was assessed. For interrater reliability, 13 raters scored 10 videotaped patients; for intrarater reliability, two raters rated the videotape again. For test-retest reliability, patients were rated on two occasions. Four inexperienced raters scored patients, received training, then scored additional patients. To assess responsiveness, we compared patient and physician global ratings of change (better, same, and worse) with BAD Scale score changes for 18 patients on intrathecal baclofen (ITB) trials. We assessed reliability with the intraclass correlation coefficient (ICC). The mean ICC for total BAD Scale scores were as follows: interrater reliability 0.866, intrarater reliability 0.967 and 0.978, test-retest reliability 0.978 (before training) and 0.967 (after training). We found the BAD Scale responsive to change, with most improved scores in patients rated by the patient, family, and neurosurgeon as 'better'. The total scores were reliable for experienced raters. We recommend training for clinicians interested in using the scale.
Article
The traditional view that the basal ganglia are simply involved in the control of movement has been challenged in recent years. Three lines of evidence indicate that the basal ganglia also are involved in nonmotor operations. First, the results of anatomical studies clearly indicate that the basal ganglia participate in multiple circuits or 'loops' with cognitive areas of the cerebral cortex. Second, the activity of neurons within selected portions of the basal ganglia is more related to cognitive or sensory operations than to motor functions. Finally, in some instances basal ganglia lesions cause primarily cognitive or sensory disturbances without gross motor impairments. In this report, we briefly review some of these data and present a new anatomical framework for understanding the basal ganglia contributions to nonmotor function.
Article
In seven selected patients with dystonia musculorum deformans-1 generalised dystonia (DYT1), continuous bilateral stimulation of the globus pallidus internus was associated with substantial improvement of dystonia and functional disability.
Article
To record the potentials evoked at the scalp by stimulation through electrodes targeted at the human subthalamic nucleus (STN) and to determine whether the responsible pathways continue to be excited or become blocked with high frequency stimulation. We recorded the potentials evoked at the scalp in response to single and multiple stimuli delivered through STN contacts in 6 patients with Parkinson's disease. On 9/11 sides tested, single stimuli elicited a negative potential with latency of approximately 3 ms which was largest over the frontal region. Its short chronaxie (50 micros) and refractory period imply that it arose from the activation of low threshold neural elements, possibly myelinated axons. This potential could follow at 100 Hz. This early potential was sometimes followed by later negative potentials at approximately 5 ms (6/11 sides) and approximately 8 ms (8/11 sides). The responsible neural elements had the same short chronaxie. These potentials were augmented by paired stimuli at separations of 2-7 ms and by trains of stimuli at 200 Hz. Trains of stimuli delivered to the STN may excite low threshold neural elements which can transmit impulses at frequencies >100 Hz without blocking and which may produce postsynaptic facilitation at the cortex.
Article
The clinical success of deep brain stimulation (DBS) for treating Parkinson's disease, tremor, or dystonia critically depends on the quality of postoperative neurologic management. Movement disorder specialists becoming involved with this therapy need to acquire new skills to optimally adapt stimulation parameters and medication after implantation of a DBS system. In clinical practice, the infinite number of possible parameter settings in DBS can be reduced to few relevant combinations. In this article, the authors describe a general scheme of selecting stimulation parameters in DBS and provide clinical and neurophysiological arguments for such a standardized algorithm. They also describe noninvasive technical trouble shooting by using programming features of the commercially available neurostimulation devices.
Article
The goal of this project was to develop a quantitative understanding of the volume of axonal tissue directly activated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). The 3-dimensionally inhomogeneous and anisotropic tissue medium surrounding DBS electrodes complicates our understanding of the electric field and tissue response generated by the stimulation. We developed finite element computer models to address the effects of DBS in a homogeneous isotropic medium, and a medium with tissue conductivity properties derived from human diffusion tensor magnetic resonance data. The second difference of the potential distribution generated in the tissue medium was used as a predictor of the volume of tissue supra-threshold for axonal activation. The model predicts that clinically effective stimulation parameters (-3 V; 0.1 ms; 150 Hz) result in activation of large diameter (5.7 microm) myelinated axons over a volume that spreads outside the borders of the STN. The shape of the activation volume was dependent on the strong dorsal-ventral anisotropy of the internal capsule, and the moderate anterior-posterior anisotropy of the region around zona incerta. Small deviations ( approximately 1 mm) in the electrode position within STN can substantially alter the shape of the activation volume as well as its spread to neighboring structures. STN DBS represents an effective treatment for medically refractory movement disorders such as Parkinson's disease. However, stimulation induced side effects such as tetanic muscle contraction, speech disturbance and ocular deviation are not uncommon. Quantitative characterization of the spread of stimulation will aid in the development of techniques to maximize the efficacy of DBS.
Article
High-frequency electrical stimulation through electrodes implanted in the subthalamic nucleus (STN) has been shown to reduce significantly the cardinal symptoms of Parkinson's disease (PD). Despite the success of this treatment, the mechanisms of action of stimulation are poorly understood. To elucidate further the mechanisms of action of deep brain stimulation and its effects on cortical activity, we recorded electroencephalographic potentials from 61 scalp-surface electrodes during low-frequency (5-10 Hz) bipolar stimulation in 11 patients with advanced PD (14 implanted electrodes were tested). In all electrodes tested, stimulation through at least one of the four contacts produced a medium-latency waveform with an average onset of 14 +/- 3 ms and peak at 23 +/- 4 ms. This potential typically increased in magnitude across contacts from ventral to dorsal. Within-subject comparisons of median nerve somatosensory evoked potentials demonstrated that the generator of the medium-latency potential was within the primary sensorimotor cortex or lateral premotor cortex ipsilateral to stimulation. The timing and topography of this potential were consistent with indirect activation of the cortex by excitation of pallido-thalamic axons that traverse the dorsal aspect of the STN. The potential evoked by stimulation through the contact used for optimal clinical effect was highly variable across electrodes and frequently different from the medium-latency potential described above, suggesting that the neuronal elements mediating the medium-latency potential were different from those that mediate the clinical effects.
Article
Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases. To describe the characteristics of an unusual dystonia-plus phenotype associated with cerebellar atrophy. We selected patients with predominant dystonia and cerebellar atrophy among the 861 families referred to us for genetic testing from 1992 to 2003. The main secondary heredodegenerative causes and the major genes responsible for hereditary dystonias and autosomal dominant or recessive ataxias were excluded. We identified 12 patients in 8 families with an unusual dystonia-plus phenotype characterized by dystonia and cerebellar atrophy on brain MRI. The mean age at onset was 27.3 +/- 11.5 years (range: 9 to 42 years) and the mean disease duration 14.7 +/- 7.7 years (range: 4 to 30). At onset, dystonia was focal or multifocal, mainly affecting vocal cords (n = 8) and upper limbs (n = 2). During the disease course spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five. Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. Four families with two affected sibs support the hypothesis of an autosomal recessive disorder. However, X-linked inheritance is possible since only men were affected. We have characterized an unusual familial phenotype associating dystonia and cerebellar atrophy in 12 male patients.
Article
DOI:€10.1212/01.wnl.0000246112.19504.61 Neurology 2006;67;1740-1741 H. A. Jinnah and Ellen J. Hess A new twist on the anatomy of dystonia: The basal ganglia and the cerebellum? This information is current as of November 28, 2006 http://www.neurology.org/cgi/content/full/67/10/1740 located on the World Wide Web at: The online version of this article, along with updated information and services, is
Article
To determine the effect of globus pallidus internus (GPi) deep brain stimulation (DBS) on motor cortex plasticity in patients with primary generalised dystonia. We studied 10 patients with primary generalised dystonia (5 DYT1+, 5 idiopathic, 5 female, mean age 42) following GPi DBS and 10 healthy subjects. Motor cortex plasticity was assessed using transcranial magnetic stimulation (TMS) paired associative stimulation (PAS) of motor cortex and median nerve, a method which has been shown in healthy subjects to produce LTP-like effects. Thresholds and TMS intensity to produce a resting motor evoked potential (MEP) of 1 mV were determined. Resting MEP amplitude and stimulus response curves were recorded before and after PAS. Patients were recorded ON and OFF DBS in separate sessions. The mean TMS intensity to produce a resting MEP of 1 mV was 54% of maximum stimulator output when OFF and 52% ON DBS. Fifteen minutes after PAS the resting MEP amplitude increased in patients OFF DBS and in control subjects whereas it decreased in patients ON DBS. Similarly, after PAS, the mean amplitude of the stimulus response curve increased OFF DBS, but this effect was abolished with DBS ON. Furthermore, patients who had the largest clinical response to chronic DBS also had the largest difference in the effect of PAS with DBS ON vs. OFF. After PAS, patients with primary generalised dystonia showed a similar pattern of increased motor cortex excitability as healthy subjects when GPi DBS was OFF but not with GPi DBS ON. These results suggest that GPi DBS may reduce LTP-like motor cortex plasticity, which could contribute to its mechanism of action in dystonia.
Article
Deep brain stimulation (DBS) of globus pallidus internus (GPi) has emerged as an effective treatment for primary generalized dystonia. However, the physiological mechanisms of improvement are not fully understood. Cortical activity in response to pallidal stimulation was recorded in 6 patients with primary generalized dystonia >6 months after bilateral GPi DBS. Scalp electroencephalogram was recorded using 60 surface electrodes during 10 Hz bipolar pallidal DBS at each electrode contact pair. Anatomical position of the electrode contacts in relation to the GPi, medial medullary lamina and globus pallidus externus (GPe) was determined from the postoperative stereotactic MRI. In all six patients an evoked potential (EP) was observed with average onset latency of 10.9 ms +/- 0.77, peak latency 26.6 ms +/- 1.6, distributed mainly over the ipsilateral hemisphere, maximal centrally. The mean amplitude of this potential was larger with stimulation in posteroventral GPi than in GPe (3.36 microV vs. 0.50 microV, P < 0.0001). The EP was absent in one patient-side, ipsilateral to a previous thalamotomy. Low frequency GPi stimulation produces an EP distributed centrally over the ipsilateral hemisphere. The latency and distribution of the EP are consistent with stimulation of pallidothalamic neurons projecting to the sensorimotor cortex. Because the EP is larger and more consistently present with stimulation of posteroventral GPi than GPe, it may provide a physiological tool to identify contacts within the optimal surgical target.
Neuroanatomy Through Clinical Cases, Second Edition with Sylvius 4
  • H Blumenfeld
Blumenfeld H. Neuroanatomy Through Clinical Cases, Second Edition with Sylvius 4. 2