Closed-loop DBS triggered by real-time movement and tremor decoding based on thalamic LFPs for essential tremor.

High frequency Deep Brain Stimulation (DBS) targeting the motor thalamus is an effective therapy for essential tremor (ET). However, since tremor mainly affects periods of voluntary movements and sustained postures in ET, conventional continuous stimulation may deliver unnecessary current to the brain. Here we tried to decode movement states based on local field potentials (LFPs) recorded from motor thalamus and zona incerta in real-time to trigger the switching on and off of DBS in three patients with ET. Patient-specific models were first identified using thalamic LFPs recorded while the patient performed movements that tended to trigger tremor in everyday life. During the real-time test, LFPs were continuously recorded to decode movements and tremor, and the detection triggered stimulation. Results show that voluntary movements can be detected with a mean sensitivity ranging from 76.8% to 88.6% and a false positive rate ranging from 16.0% to 23.1% Postural tremor was detected with similar accuracy. The closed-loop DBS triggered by tremor detection suppressed intention tremor by 90.5% with a false positive rate of 20.3%.Clinical Relevance- This is the first study on closed-loop DBS triggered by real-time movement and tremor decoding based solely on thalamic LFPs. The results suggest that responsive DBS based on movement and tremor detection can be achieved without any requirement for external sensors or additional electrocorticography strips.

Update on the Treatment of Ataxia: Medication and Emerging Therapies.

While rehabilitation therapies always help patients with ataxia, there are currently no FDA-approved treatments for ataxia. Medications are available to treat symptoms that may complicate an ataxic illness, e.g., tremor, myoclonus, dystonia, and rigidity, which are discussed elsewhere in this volume. Spasticity, pain, fatigue, depression, sleep disturbances, cognitive decline, and bowel and bladder dysfunction, if they occur, all have multiple available drugs and therapies for symptomatic use. There is also an extensive literature on off-label uses of various medications to improve imbalance. The pipeline of emerging therapies for symptomatic and possible disease-modifying management of ataxia gives hope that we will soon see the first of many FDA-approved drugs for ataxic illnesses.

Acquired Holmes Tremor in a Human Immunodeficiency Virus Immune Reconstitution Inflammatory Syndrome Patient Treated with Deep Brain Stimulation.

BACKGROUND: The authors present a case of a 66-year-old male who was diagnosed with human immunodeficiency virus, and his medical course of highly active antiretroviral therapy was complicated with the development of immune reconstitution inflammatory syndrome, which led to development of movement disorder consisting of right-sided resting tremor, neck dystonia, and jaw clenching. CASE DESCRIPTION: The patient's symptoms resembled that of rubral tremor, and he underwent placement of a deep brain stimulation electrode into the left ventral intermediate nucleus of the thalamus with significant improvement of symptoms. CONCLUSIONS: This is the first reported case in the literature of a human immunodeficiency virus-positive patient's treatment course complicated with immune reconstitution inflammatory syndrome with neurologic manifestation, which was refractory to medical therapy and thus treated with deep brain stimulation.

[Clinical and cognitive aspects of functional (psychogenic) tremor]. / Klinische und kognitive Neurologie des funktionellen (psychogenen) Tremors.

Functional (psychogenic) tremor is the most common functional movement disorder. Characteristic clinical features, so called red flags, can help to make the clinical distinction of this type from other tremor disorders. The most common features include the variability of frequency and amplitude. Clinical examination should include different types of distraction including motor or cognitive tasks or testing the influence of suggestibility on tremor amplitude, frequency or direction. Patients often report sudden onset and remissions that may last for months or even years. In some cases, the tremor is only present in highly specific situations. Although functional tremor shares characteristics with voluntary actions, patients experience their abnormal movements as involuntary. Recent experimental approaches have revealed an impairment in sense of agency. The diagnosis can be supported by neurophysiological measurements including accelerometry, which achieved a sensitivity of 89.5% and a specificity of 95.9% in a validated test battery, thus providing a useful additional diagnostic tool. Psychotherapeutic treatment is indicated in patients with and without evident psychological symptoms. A specific physiotherapeutic approach for functional tremor is re-trainment.

Holmes tremor: Clinical description, lesion localization, and treatment in a series of 29 cases.

OBJECTIVE: To describe the clinical features, etiology, findings from neuroimaging, and treatment results in a series of 29 patients with Holmes tremor (HT). METHODS: A retrospective study was performed based on review of medical records and videos of patients with HT diagnosis. RESULTS: A total of 16 women and 13 men were included. The mean age at the moment of CNS insult was 33.9 ± 20.1 years (range 8-76 years). The most common causes were vascular (48.3%), ischemic, or hemorrhagic. Traumatic brain injury only represented 17.24%; other causes represented 34.5%. The median latency from lesion to tremor onset was 2 months (range 7 days-228 months). The most common symptoms/signs associated with HT were hemiparesis (62%), ataxia (51.7%), hypoesthesia (27.58%), dystonia (24.1%), cranial nerve involvement (24.1%), and dysarthria (24.1%). Other symptoms/signs were vertical gaze disorders (6.8%), bradykinesia/rigidity (6.8%), myoclonus (3.4%), and seizures (3.4%). Most of the patients had lesions involving more than one area. MRI showed lesions in thalamus or midbrain or cerebellum in 82.7% of the patients. Levodopa treatment was effective in 13 out of 24 treated patients (54.16%) and in 3 patients unilateral thalamotomy provided excellent results. CONCLUSIONS: The most common causes of HT in our series were vascular lesions. The most common lesion topography was mesencephalic, thalamic, or both. Treatment with levodopa and thalamic stereotactic lesional surgery seems to be effective.

Visual snow: A thalamocortical dysrhythmia of the visual pathway?

In this paper we review the visual snow (VS) characteristics of a case cohort of 32 patients. History of symptoms and associated co-morbidities, ophthalmic examination, previous investigations and the results of intuitive colourimetry were collected and reviewed. VS symptoms follow a stereotypical description and are strongly associated with palinopsia, migraine and tinnitus, but also tremor. The condition is a chronic one and often results in misdiagnosis with psychiatric disorders or malingering. Colour filters, particularly in the yellow-blue colour spectrum, subjectively reduced symptoms of VS. There is neurobiological evidence for the syndrome of VS that links it with other disorders of visual and sensory processing such as migraine and tinnitus. Colour filters in the blue-yellow spectrum may alter the koniocellular pathway processing, which has a regulatory effect on background electroencephalographic rhythms, and may add weight to the hypothesis that VS is a thalamocortical dysrhythmia of the visual pathway.

Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting.

OBJECTIVE: We conducted intraoperative measurements of tremor during DBS containing short pauses (⩽50 ms) to determine if there is a minimum pause duration that preserves tremor suppression. METHODS: Nine subjects with ET and thalamic DBS participated during IPG replacement surgery. Patterns of DBS included regular 130 Hz stimulation interrupted by 0, 15, 25 or 50 ms pauses. The same patterns were applied to a model of the thalamic network to quantify effects of pauses on activity of model neurons. RESULTS: All patterns of DBS decreased tremor relative to 'off'. Patterns with pauses generated less tremor reduction than regular high frequency DBS. The model revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but pauses in stimulation allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions. CONCLUSIONS: The temporal pattern of stimulation influences the efficacy of thalamic DBS. Pauses in stimulation resulted in decreased tremor suppression indicating that masking of pathological bursting is a mechanism of thalamic DBS for tremor. SIGNIFICANCE: Pauses in stimulation decreased the efficacy of open-loop DBS for suppression of tremor.

Morphometric and functional MRI changes in essential tremor with and without resting tremor.

The etiopathogenesis of essential tremor (ET) is still debated, since the predominant role of circuit dysfunction or brain degenerative changes has not been clearly established. The relationship with Parkinson's Disease (PD) is also controversial and resting tremor occurs in up to 20 % of ET. We investigated the morphological and functional changes associated with ET and we assessed potential differences related to the presence (ET+R) or absence (ET-R) of resting tremor. 32 ET patients (18 ET+R; 14 ET-R) and 12 healthy controls (HC) underwent 3T-MRI protocol including Spoiled Gradient T1-weighted sequence for Voxel-Based Morphometry (VBM) analysis and functional MRI during continuous writing of "8" with right dominant hand. VBM analysis revealed no gray and white matter atrophy comparing ET patients to HC and ET+R to ET-R patients. HC showed a higher BOLD response with respect to ET patients in cerebellum and other brain areas pertaining to cerebello-thalamo-cortical circuit. Between-group activation maps showed higher activation in precentral gyrus bilaterally, right superior and inferior frontal gyri, left postcentral gyrus, superior and inferior parietal gyri, mid temporal and supramarginal gyri, cerebellum and internal globus pallidus in ET-R compared to ET+R patients. Our findings support that the dysfunction of cerebello-thalamo-cortical network is associated with ET in absence of any morphometric changes. The dysfunction of GPi in ET+R patients, consistently with data reported in PD resting tremor, might suggest a potential role of this structure in this type of tremor.

Generalised involuntary limb twitching after ingestion of Mesobuthus martensii Karsch (Quanxie) powder.

Mesobuthus martensii Karsch, commonly known as the Chinese scorpion or Manchurian scorpion, has been used in traditional Chinese medicine as Quanxie to treat chronic pain, tetanus, tremors, convulsion, and paralysis for more than a thousand years. We report a case of poisoning after ingestion of a teaspoon of Quanxie powder. The patient presented with chest pain, dizziness, diaphoresis, generalised involuntary limb twitching, and hypertonia around 15 minutes post-ingestion. The patient recovered uneventfully after supportive management. Intravenous diazepam appeared to be effective in alleviating limb twitching. Failure to accurately measure the dose and to boil before consumption may have contributed to his clinical toxicities.

Clinical features, MRI brain, and MRS abnormalities of drug-naïve neurologic Wilson's disease.

BACKGROUND: Magnetic resonance imaging (MRI) helps in the diagnosis of neurologic Wilson's disease (WD). The literature regarding MR spectroscopy (MRS) and diffusion-weighted imaging (DWI) in WD is limited. OBJECTIVES: To evaluate the clinical features and neuroimaging findings in drug-naïve neurologic WD and to find correlation between clinical stage and disease duration with different imaging findings. MATERIALS AND METHODS: The study subjects included consecutive and follow-up neurologic WD patients attending movement disorder clinic. The initial clinical and MRI features before commencement of chelation therapy were noted. Of 78 patients, 34 underwent DWI study and MRS was done in 38 patients and in 32 control subjects. RESULTS: Dystonia, dysarthria, tremor, and behavioral abnormality were common presenting features. All patients had MRI abnormality with major affection of basal ganglia. The clinical severity and anatomical extent of MRI abnormalities were positively correlated (P < 0.001; r s = 0.709). Presence of diffusion restriction was inversely related to duration of disease (P < 0.001; r s = 0.760). WD patients had reduced N-acetylaspartate/creatine (Cr) and choline (Cho)/Cr ratio (P < 0.001) as compared with control subjects in MRS study. CONCLUSION: Dystonia, dysarthria and tremor are common neurological features of WD. In this study, MRI abnormalities were positively correlated with disease severity; diffusion restriction was inversely correlated with the duration of the disease process. MRS was also a sensitive tool for diagnosing patient of neurologic WD.

Targeting the red nucleus for cerebellar tremor.

Deep brain stimulation of the thalamus (and especially the ventral intermediate nucleus) does not significantly improve a drug-resistant, disabling cerebellar tremor. The dentato-rubro-olivary tract (Guillain-Mollaret triangle, including the red nucleus) is a subcortical loop that is critically involved in tremor genesis. We report the case of a 48-year-old female patient presenting with generalized cerebellar tremor caused by alcohol-related cerebellar degeneration. Resistance to pharmacological treatment and the severity of the symptoms prompted us to investigate the effects of bilateral deep brain stimulation of the red nucleus. Intra-operative microrecordings of the red nucleus revealed intense, irregular, tonic background activity but no rhythmic components that were synchronous with upper limb tremor. The postural component of the cerebellar tremor disappeared during insertion of the macro-electrodes and for a few minutes after stimulation, with no changes in the intentional (kinetic) component. Stimulation per se did not reduce postural or intentional tremor and was associated with dysautonomic symptoms (the voltage threshold for which was inversed related to the stimulation frequency). Our observations suggest that the red nucleus is (1) an important centre for the genesis of cerebellar tremor and thus (2) a possible target for drug-refractory tremor. Future research must determine how neuromodulation of the red nucleus can best be implemented in patients with cerebellar degeneration.

Pathological tremor prediction using surface electromyogram and acceleration: potential use in 'ON-OFF' demand driven deep brain stimulator design.

OBJECTIVE: We present a proof of concept for a novel method of predicting the onset of pathological tremor using non-invasively measured surface electromyogram (sEMG) and acceleration from tremor-affected extremities of patients with Parkinson's disease (PD) and essential tremor (ET). APPROACH: The tremor prediction algorithm uses a set of spectral (Fourier and wavelet) and nonlinear time series (entropy and recurrence rate) parameters extracted from the non-invasively recorded sEMG and acceleration signals. MAIN RESULTS: The resulting algorithm is shown to successfully predict tremor onset for all 91 trials recorded in 4 PD patients and for all 91 trials recorded in 4 ET patients. The predictor achieves a 100% sensitivity for all trials considered, along with an overall accuracy of 85.7% for all ET trials and 80.2% for all PD trials. By using a Pearson's chi-square test, the prediction results are shown to significantly differ from a random prediction outcome. SIGNIFICANCE: The tremor prediction algorithm can be potentially used for designing the next generation of non-invasive closed-loop predictive ON-OFF controllers for deep brain stimulation (DBS), used for suppressing pathological tremor in such patients. Such a system is based on alternating ON and OFF DBS periods, an incoming tremor being predicted during the time intervals when DBS is OFF, so as to turn DBS back ON. The prediction should be a few seconds before tremor re-appears so that the patient is tremor-free for the entire DBS ON-OFF cycle and the tremor-free DBS OFF interval should be maximized in order to minimize the current injected in the brain and battery usage.

Target identification for stereotactic thalamotomy using diffusion tractography.

BACKGROUND: Stereotactic targets for thalamotomy are usually derived from population-based coordinates. Individual anatomy is used only to scale the coordinates based on the location of some internal guide points. While on conventional MR imaging the thalamic nuclei are indistinguishable, recently it has become possible to identify individual thalamic nuclei using different connectivity profiles, as defined by MR diffusion tractography. METHODOLOGY AND PRINCIPAL FINDINGS: Here we investigated the inter-individual variation of the location of target nuclei for thalamotomy: the putative ventralis oralis posterior (Vop) and the ventral intermedius (Vim) nucleus as defined by probabilistic tractography. We showed that the mean inter-individual distance of the peak Vop location is 7.33 mm and 7.42 mm for Vim. The mean overlap between individual Vop nuclei was 40.2% and it was 31.8% for Vim nuclei. As a proof of concept, we also present a patient who underwent Vop thalamotomy for untreatable tremor caused by traumatic brain injury and another patient who underwent Vim thalamotomy for essential tremor. The probabilistic tractography indicated that the successful tremor control was achieved with lesions in the Vop and Vim respectively. CONCLUSIONS: Our data call attention to the need for a better appreciation of the individual anatomy when planning stereotactic functional neurosurgery.

Tremor revisited: treatment of PD tremor.

Parkinsonian tremor is among the most emblematic medical signs and is one of the cardinal manifestations of Parkinson's disease (PD). Its semiology has been extensively addressed by ancient and contemporary medical literature, but more attention has been dedicated to its medical treatment in the past than nowadays. Among the hundreds of studies performed to determine the value of medical and surgical approaches on motor and non motor signs of PD, only a minority specifically considered effect on tremor as an efficacy outcome. Current available guidelines for PD treatment include attempts to specifically address tremor treatment but stress the low level of evidences available. In these conditions, with its still poorly understood pathophysiological basis and variable clinical expression PD tremor treatment is a clinical challenge. Only surgery (lesion or high frequency stimulation) of discrete deep brain targets consistently provides symptomatic long lasting alleviation. Through revision of contemporary scientific evidence, the purpose of this paper is to offer a systematic pragmatic approach to symptomatic management of tremor as one of the distinctive signs of PD that may generate substantial disability.

Multimodal BCI-mediated FES suppression of pathological tremor.

Tremor constitutes the most common movement disorder; in fact 14.5% of population between 50 to 89 years old suffers from it. Moreover, 65% of patients with upper limb tremor report disability when performing their activities of daily living (ADL). Unfortunately, 25% of patients do not respond to drugs or neurosurgery. In this regard, TREMOR project proposes functional compensation of upper limb tremors with a soft wearable robot that applies biomechanical loads through functional electrical stimulation (FES) of muscles. This wearable robot is driven by a Brain Neural Computer Interface (BNCI). This paper presents a multimodal BCI to assess generation, transmission and execution of both volitional and tremorous movements based on electroencephalography (EEG), electromyography (EMG) and inertial sensors (IMUs). These signals are combined to obtain: 1) the intention to perform a voluntary movement from cortical activity (EEG), 2) tremor onset, and an estimation of tremor frequency from muscle activation (EMG), and 3) instantaneous tremor amplitude and frequency from kinematic measurements (IMUs). Integration of this information will provide control signals to drive the FES-based wearable robot.

Adaptive band-pass filter (ABPF) for tremor extraction from inertial sensor data.

Cancelling pathological tremor in everyday living activities may be possible with functional electrical stimulation (FES). One such feasible FES system with feedback from inertial sensors would rely on tremor estimates in real time. We present an adaptive band-pass filter (ABPF) that estimates tremor from volitional hand movement with zero-phase lag. The proposed algorithm is simple and easy to implement. Performance of the ABPF is compared to one popular well-established method for tremor extraction (weighted-frequency Fourier linear combiner, WFLC) using both synthetic data and data from inertial sensors, recorded in tremor patients during "finger to nose" task execution. The results were comparable, favoring ability of ABPF for faster adaptation, higher accuracy and robustness.

[Psychogenic tremor: a positive diagnosis]. / Temblor psicógeno: un diagnóstico en positivo.

Psychogenic movement disorders are a daily challenge for the neurologist. A mistake in its recognition may have important consequences for the patients. As a result, the diagnosis must be considered very carefully in clinical practice. However, psychogenic movement disorders are not unusual, are mainly tremors, and a wrong diagnosis is common. Psychogenic is an unspecific term that usually masks the real mental disorder, and should be called somatoform disorders, factitious disorders, malingering, depression, anxiety and histrionic personality disorder, although the absence of a psychiatric diagnosis does not preclude a psychogenic cause. The diagnosis may often be difficult and should be made by an expert neurologist. Organic movement disorders must be excluded after a detailed neurological history, examination, and appropriate diagnostic studies. Psychogenic tremor is not only a diagnosis of exclusion, it can be diagnosed positively by its neurological signs, mainly: variability in frequency and amplitude, bilateral and sudden onset, non-progressive with frequent remissions, absence of finger, tongue or face tremor and coactivation of antagonistic muscles. Several tests can be useful in diagnosis, such as: accelerometry, EMG and response to placebo or suggestion. The treatment requires close cooperation between the medical team and patient. The problem must never be minimised and early diagnosis and treatment must be attempted.