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Introduction: Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Twelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [11C]-PHNO. Severity of ICD was assessed with the QUIP-RS. Results: We found that lower ventral striatum D3 receptor availability measured with [11C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03). Conclusion: These findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.

ObjectiveThe mechanisms contributing to the pathogenesis of tremor and/or dysmetria in multiple sclerosis (MS) are poorly understood. Abnormal oscillations within the olivo-cerebello-thalamo-cortical networks are believed to play an important part in tremor aetiology, but could also contribute to intention dysmetria due to disruptions in motor timing. Conversely, delayed central motor conduction times are a common feature of ataxias, but could also contribute to the expression of dysmetria in MS. This study examined the roles of central conduction delays in the manifestation of tremor and/or dysmetria in MS.MethodsTwenty-three individuals with MS participated: 8 with no movement disorder, 6 with tremor, 4 with pure dysmetria and 5 with both tremor and dysmetria. Median nerve somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) over the motor cortex and cervical spine, stretch reflexes were used assess sensory and motor conduction times.ResultsCentral, but not peripheral, sensory conductions time were significantly delayed in participants with dysmetria, regardless of the presence of tremor. Similarly, the TMS evoked muscles responses and the long-latency component of stretch reflexes were significantly delayed in those with dysmetria, but not pure tremor.ConclusionDysmetria in MS is associated with delays in central conduction of sensory or motor pathways, or both, likely leading to disruption of muscle activation timing and terminal oscillations that contribute to dysmetria.SignificanceThe presence of dysmetria in MS is associated with decreased conduction velocities in central sensory and/or motor pathways likely reflects greater demyelination of these axons compared to those with no movement disorder or pure tremor.

Despite that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favored intervention for patients with medically intractable dystonia, the pathophysiological mechanisms of dystonia are largely unclear. In eight patients with primary dystonia who were treated with bilateral chronic pallidal stimulation, we correlated symptom-related electromyogram (EMG) activity of the most affected muscles with the local field potentials (LFPs) recorded from the globus pallidus electrodes. In 5 dystonic patients with mobile involuntary movements, rhythmic EMG bursts in the contralateral muscles were coherent with the oscillations in the pallidal LFPs at the burst frequency. In contrast, no significant coherence was seen between EMG and LFPs either for the sustained activity separated out from the compound EMGs in those 5 cases, or in the EMGs in 3 other cases without mobile involuntary movements and rhythmic EMG bursts. In comparison with the resting condition, in both active and passive movements, significant modulation in the GPi LFPs was seen in the range of 8-16 Hz. The finding of significant coherence between GPi oscillations and rhythmic EMG bursts but not sustained tonic EMG activity suggests that the synchronized pallidal activity may be directly related to the rhythmic involuntary movements. In contrast, the sustained hypertonic muscle activity may be represented by less synchronized activity in the pallidum. Thus, the pallidum may play different roles in generating different components of the dystonic symptom complex.

With the rapid increase in provision of deep brain stimulation for Parkinson's disease, the efficacy of pallidotomy in symptom alleviation appears to be increasingly ignored. We demonstrate that lesional surgery is effective with benefit over a significant period of time with very significant societal cost savings. Such studies are essential for future planning of services so that maximum numbers of patients can benefit from surgery, both lesional and neuromodulation, as deemed appropriate.

Objective To differentiate physiological from harmonic components in coherence analysis of the tremor-related neural and muscular signals by comparing power, cross-power and coherence spectra. Methods Influences of waveform, burst-width and additional noise on generating harmonic peaks in the power, cross-power and coherence spectra were studied using simulated signals. The local field potentials (LFPs) of the subthalamic nucleus (STN) and the EMGs of the contralateral forearm muscles in PD patients with rest tremor were analysed. Results (1) Waveform had significant effect on generating harmonics; (2) noise significantly decreased the coherence values in a frequency-dependent fashion; and (3) cross-spectrum showed high resistance to harmonics. Among six examples of paired LFP–EMG signals, significant coherence appeared at the tremor frequency only, both the tremor and double tremor frequencies and the double-tremor frequency only. Conclusions In coherence analysis of neural and muscular signals, distortion in waveform generates significant harmonic peaks in the coherence spectra and the coherence values of both physiological and harmonic components are modulated by extra noise or non-tremor related activity. Significance The physiological or harmonic nature of a coherence peak at the double tremor frequency may be differentiated when the coherence spectra are compared with the power and in particular the cross-power spectra.

The effect of stereotactic lesional surgery for the treatment of tremor in multiple sclerosis was examined in a prospective case-controlled study. Surgery was not undertaken in 33 patients (72% of 46 cases referred for stereotactic surgery), two of whom died within 4 months of referral. Twenty-four multiple sclerosis patients were included in the study; 13 underwent surgery and were matched against 11 controls on the basis of age, sex, expanded disability system scores (EDSS) and disease duration. Assessments were carried out at baseline/preoperatively, and then 3 and 12 months later; these included accelerometric and clinical ratings of tremor, spirography, handwriting, a finger-tapping test, nine-hole peg test, tremor-related disability, general neurological examination, Barthel Activities of Daily Living (ADL) Index of general disability, EDSS, a 0-4 ataxia scale, Mini-Mental State (MMS) examination, speech and swallowing assessments and grip strength. Postoperative MRI scans demonstrated that tremor could be attenuated by lesions centred on the thalamus in seven cases, on the zona incerta in five cases and in the subthalamic nucleus in one case. Two patients developed hemiparesis and in two cases epilepsy recurred. Two surgical patients and one control patient died between the 3 and 6 months assessments. Both groups had a significant deterioration in EDSS but not Barthel ADL Index scores at 1 year, but the difference between the groups was not significant. Similarly, no differences between the groups' rates of deterioration of speech or swallowing or MMS were found. Significant improvements in contralateral upper limb postural (P2) and kinetic tremors, spiral scores and head tremor were detected at 3 and 12 months after surgery (but not handwriting or nine-hole peg test performance). Tremor-related disability and finger-tapping speed were also significantly better 12 months after surgery, the latter having significantly worsened for the control group. A 3 Hz 'filter' for postural (P2) upper limb tremor was detected by accelerometry/spectral analysis above which tremor was always abolished and at or below which some residual tremor invariably remained. Criteria for selecting multiple sclerosis patients for this form of surgery are discussed.

The assessment of the extent of involvement of the distal and proximal joints in a complex arm tremor is important clinically, as tremor generated around the distal and proximal arm joints can be differentially alleviated by surgical intervention to the thalamic and subthalamic targets, respectively. We observed that the tremor present in spiral drawings shows a diagonal directional preference. We hypothesized that the directional preference of tremor within spiral drawings could be related to the involvement of different arm joints. In this study, we tested this hypothesis by: (1) studying simulated tremulous drawings performed by healthy subjects with the joints selectively restrained; (2) recording surface EMGs from the forearm extensor and deltoid muscles during drawing; and (3) mathematical modelling the kinematics of the arm in 2D drawings. Our data showed that a "main diagonal" axis of orientation of the tremor along the orientation of the forearm indicates a predominantly proximal tremor driven by the shoulder, and a "cross diagonal" axis of orientation of tremor (i.e. perpendicular to the forearm) indicates that the tremor is predominantly distal and driven by the elbow or wrist. We conclude that the spiral drawing task can be used as an objective and quantitative method for differentiating the involvement of the proximal and distal arm joints in complex arm tremors.

Lesioning or chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius results in abolition of tremor in the contralateral limbs in Parkinson's disease (PD) and also in essential tremor. Recently, chronic DBS of the subthalamic nucleus has also proved to be very effective in reducing contralateral limb tremor in PD. These targets have been less effective in controlling the complex limb tremor often seen in multiple sclerosis (MS). Consequently, other targets have been sought in cases of MS with tremor. We describe a patient with MS with disabling proximal and distal involuntary arm movements in whom we were able to obtain sustained control of contralateral arm tremor and achieve functional improvement of the affected arm by chronic DBS of the region of the zona incerta. We also highlight the important role played by local field potentials recorded from the brain, with simultaneous recording of corresponding EMGs, in target localisation. © 2002 Harcourt Publishers Ltd.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

Tremor in multiple sclerosis is considered to be a persistent and progressive sign. We describe five patients with multiple sclerosis in whom upper limb tremor severity gradually decreased over a period of several years after deep brain stimulation. In every case this attenuation of tremor was accompanied by increasing pyramidal weakness in the relevant upper limb. In two patients this attenuation of tremor remained after stimulation was permanently switched off. In one other patient, where upper limb strength remained normal, tremor severity gradually worsened in spite of continuing stimulation. There was a highly significant difference (p = 0.0007) between the changes in intention tremor severities when the arms with increasing pyramidal weakness (n = 9) were compared to those in which normal strength was retained throughout follow-up period (n = 3); intention tremor decreased in the former and increased in the latter by means of -3.66 and +4.0 points of a 0-10 tremor scale respectively. There was also a significant correlation (0.699; p = 0.0359) between decreasing upper limb strength and decreasing intention tremor severity for the upper limbs of patients that had undergone contralateral DBS.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

OBJECTIVE: The underlying pathophysiology of tremor in Parkinson disease (PD) is unclear; however, it is known that tremor does not appear to be as responsive to dopaminergic medication as bradykinesia or rigidity. It is suggested that serotonergic dysfunction could have a role in tremor development.METHODS: Using (11)C-DASB PET, a marker of serotonin transporter binding, and clinical observations, we have investigated function of serotonergic terminals in 12 patients with tremor-predominant and 12 with akinetic-rigid PD. Findings were compared with those of 12 healthy controls.RESULTS: Reductions of (11)C-DASB in caudate, putamen, and raphe nuclei significantly correlated with tremor severity on posture and action, but not with resting tremor. The tremor-predominant group also showed reductions of (11)C-DASB in other regions involved in motor circuitry, including the thalamus and Brodmann areas 4 and 10.CONCLUSIONS: Our findings support a role for serotonergic dysfunction in motor circuitries in the generation of postural tremor in PD.

In 15 patients with primary dystonia (six cervical and nine generalized dystonias) who were treated with bilateral chronic pallidal stimulation, we investigated the sensorimotor modulation of the oscillatory local field potentials (LFPs) recorded from the pallidal electrodes. We correlated these with the surface electromyograms in the affected muscles. The effects of involuntary, passive and voluntary movement and muscle-tendon vibration on frequency ranges of 0-3 Hz, theta (3-8 Hz), alpha (8-12 Hz), low (12-20 Hz) and high beta (20-30 Hz), and low (30-60 Hz) and high gamma (60-90 Hz) power were recorded and compared between cervical and generalized dystonia groups. Significant decreases in LFP synchronization at 8-20 Hz occurred during the sensory modulation produced by voluntary or passive movement or vibration. Voluntary movement also caused increased gamma band activity (30-90 Hz). Dystonic involuntary muscle spasms were specifically associated with increased theta, alpha and low beta (3-18 Hz). Furthermore, the increase in the frequency range of 3-20 Hz correlated with the strength of the muscle spasms and preceded them by ∼320 ms. Differences in modulation of pallidal oscillation between cervical and generalized dystonias were also revealed. This study yields new insights into the pathophysiological mechanisms of primary dystonias and their treatment using pallidal deep brain stimulation. © The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

We report a 61-year-old hypertensive man who underwent deep brain stimulation of the periventricular/periaqueductal grey area for the relief of chronic neuropathic pain affecting his oral cavity and soft palate. During intraoperative stimulation, we were able to modulate his blood pressure up or down, depending on electrode location. This is the first evidence that hypertension could be effectively treated with electrical stimulation of the midbrain.

For almost one hundred years, the exact role of human brain structures controlling the cardiorespiratory response to exercise ('central command') has been sought. Animal experiments and functional imaging studies have provided clues, but the underlying electrophysiological activity of proposed relevant neural sites in humans has never been measured. In this study, local field potentials were directly recorded in a number of 'deep' brain nuclei during an exercise task designed to dissociate the exercise from peripheral feedback mechanisms. Several patient groups had electrodes implanted sterotaxically for the treatment of movement disorder or chronic pain. Fast Fourier transform analysis was applied to the neurograms to identify the power of fundamental spectral frequencies. Anticipation of exercise resulted in increases in heart rate, blood pressure and ventilation. The greatest neural changes were found in the periaqueductal grey area (PAG) where anticipation of exercise was accompanied by an increase of 43% in the power of the 12-25 Hz frequency band (P = 0.007). Exercise increased the activity by 87% compared to rest (P = 0.006). Changes were also seen in the 60-90 Hz band when anticipation or exercise increased power by 32% (P = 0.006) and 109% (P < 0.001), respectively. In the subthalamic nucleus there was a reduction in the power of the beta frequency during both anticipation (7.6 +/- 0.68% P = 0.001) and exercise (17.3 +/- 0.96% P < 0.001), whereas an increase was seen with exercise only at higher frequencies (93 +/- 1.8% P = 0.007). No significant changes were seen in the globus pallidus during anticipation of exercise. We provide direct electrophysiological evidence highlighting the PAG as an important subcortical area in the neural circuitry of the cardiorespiratory response to exercise, since stimulation of this structure is known to alter blood pressure in awake humans.

It is the practice in many centres to externalise deep brain electrodes in functional neurosurgery to confirm efficacy of therapy prior to full implantation of the pacemaker. It has been a concern that such practice might lead to an increased rate of infection. We report a retrospective study of the rates of infection in two major centres where all electrodes are externalised in one centre and directly implanted in the other. We have not found an increased rate of infection as a result of externalisation and feel, particularly in pain patients, that doing so can lead to significant cost savings by avoiding ineffective implantations.

Deep brain stimulation (DBS) therapy is a continually expanding field of functional neurosurgery for the treatment of movement disorders and neuropathic pain. However, occurrence of adverse events related to implanted hardware cannot be ignored, particularly in patients with dystonic conditions. We report on two such patients who required emergency hospital admission and pulse generator re-implantation following sudden and unexpected cessation of DBS effectiveness resulting from battery failure.

It has been demonstrated that selective unilateral surgical ablation of posteroventral globus pallidus interna relieves the movement disorders associated with advanced Parkinson's disease, without necessarily incurring the executive cognitive sequelae that have been observed following gross pathological lesions to this brain region. This finding is consistent with established theory that underlying neuronal circuitry is functionally segregated into parallel cortico-striatal-pallidal-thalamo-cortical 'loops'. We have studied a series of 12 patients with advanced Parkinson's disease at baseline, and then following bilateral pallidotomy, with a battery of neuropsychological tests including the Cambridge Neuro psychological Test Automated Battery. We identified a selective and universal loss of individual patients' ability to shift attention to novel dimensions in a test of abstract rule-learning following surgery, which was not reliably associated with any other change in cognition, personality, mood or medication. This finding is rare in its specificity and has implications for theoretical models of the functional architecture and pathophysiology of the globus pallidus, and the clinical practice of pallidotomy.

The small size and surrounding neuronal structures and fibre tracts make the STN a difficult stereotactic target. In this article we present the technique used by us to target the STN. Our combined experience from two centres comprises 18 lesions and 27 stimulator implants in the STN. Our criteria for patient selection and the use of MRI, frame-on CT and volumetric image fusion are presented. The role of a movement disorder specialist neurologist in the operating theatre, local field potential recording, impedance monitoring, macrostimulation, post-operative CT/MRI and test stimulation are detailed.

To identify those multiple sclerosis (MS) patients with disabling tremor who will benefit most from thalamotomy, measurements of frequency spectra of involuntary movements during visually guided wrist tracking were carried out in 11 consecutive patients with MS before and after ventrolateral thalamotomy. Thalamotomy was significantly more effective if patients had disruptive action tremor which appeared as a single peak in the frequency spectra. Such patients showed an average reduction of nearly 80% in tremor magnitude after thalamotomy. In comparison, surgery produced an average reduction of only 30% in 3 other patients who had action tremor but showed multiple peaks in the frequency spectra. Frequency analysis of involuntary movements identifies those MS patients with disabling tremor who benefited most from thalamotomy.

Deep brain stimulation (DBS) is an increasingly used clinical treatment for various neurological disorders, particularly movement disorders such as Parkinson's disease. However, the mechanism by which these high frequency electrical pulses act on neuronal activity is unclear. Once the stimulating electrode is placed in situ, an electrode–brain interface (EBI) is created. To compensate for the lack of studies on the effects of this generic depth EBI on therapeutic DBS, we constructed a three-dimensional computational model of the EBI using the finite element method, in which the structural details and biophysical properties of the EBI are preserved. Our investigations focus on the peri-electrode space as a significant element of the EBI, and its physiological and pathological modulation, in particular by brain pulsation and giant cell formation. We also consider the difference between the current fields induced by different configurations of the quadripolar electrode contacts. These results quantitatively demonstrated that the peri-electrode space is a significant element of the EBI and its biophysical properties are modulated by brain pulsation and giant cell formation, as well as by the choice of electrode contact configuration. This study leads to a fuller understanding of the EBI and its effects on the crossing electric currents, and will ultimately lead to optimisation of the therapeutic effects of DBS.