Transient increased thalamic-sensory connectivity and decreased whole-brain dynamism in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

BACKGROUND: The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. METHODS: Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. RESULTS: In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. CONCLUSIONS: This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

Neuropsychological performance changes following subthalamic versus pallidal deep brain stimulation in Parkinson's disease: a systematic review and metaanalysis.

BACKGROUND: Studies comparing subthalamus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) for the management of Parkinson's disease in terms of neuropsychological performance are scarce and heterogeneous. Therefore, we performed a systematic review and metaanalysis to compare neuropsychological outcomes following STN DBS versus GPi DBS. METHODS: A computer literature search of PubMed, the Web of Science, and Cochrane Central was conducted. Records were screened for eligible studies, and data were extracted and synthesized using Review Manager (v. 5.3 for Windows). RESULTS: Seven studies were included in the qualitative synthesis. Of them, four randomized controlled trials (n=345 patients) were pooled in the metaanalysis models. The standardized mean difference (SMD) of change in the Stroop color-naming test favored the GPi DBS group (SMD=-0.31, p=0.009). However, other neuropsychological outcomes did not favor either of the two groups (Stroop word-reading: SMD=-0.21, p=0.08; the Wechsler Adult Intelligence Scale (WAIS) digits forward: SMD=0.08, p=0.47; Trail Making Test Part A: SMD=-0.05, p=0.65; WAIS-R digit symbol: SMD=-0.16, p=0.29; Trail Making Test Part B: SMD=-0.14, p=0.23; Stroop color-word interference: SMD=-0.16, p=0.18; phonemic verbal fluency: bilateral DBS SMD=-0.04, p=0.73, and unilateral DBS SMD=-0.05, p=0.83; semantic verbal fluency: bilateral DBS SMD=-0.09, p=0.37, and unilateral DBS SMD=-0.29, p=0.22; Boston Naming Test: SMD=-0.11, p=0.33; Beck Depression Inventory: bilateral DBS SMD=0.15, p=0.31, and unilateral DBS SMD=0.36, p=0.11). CONCLUSIONS: There was no statistically significant difference in most of the neuropsychological outcomes. The present evidence does not favor any of the targets in terms of neuropsychological performance.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache.

BACKGROUND: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. OBJECTIVES: We present our long-term results of analysis of the target and its structural connectivity. METHODS: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). RESULTS: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. CONCLUSIONS: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

Optimizing Prelemniscal Radiations as a Target for Motor Symptoms in Parkinson's Disease Treatment.

OBJECTIVE: To better define prelemniscal radiations (Raprl) as a target for the control of tremor and rigidity in Parkinson's disease (PD). METHODS: A total of 36 deep brain stimulation (DBS) electrodes were stereotactically implanted in Raprl contralateral to the extremities to be treated. Effects on symptoms were evaluated using UPDRS-III before and after DBS, and significance was determined using the Wilcoxon test. The location of DBS contacts in cases with optimum versus suboptimum results was evaluated using Student's t test and percentage improvement correlated through a bivariable Pearson test. The power and percentage of spike components for microelectrode recordings were statistically compared between the target point and structures located above and below. RESULTS: Raprl-DBS improved tremor and rigidity (p < 0.01). The potency of microelectrode recordings indicated that the target was formed by fibers. There was no correlation between demographic characteristics and clinical outcome, and there were no significant differences in stereotactic placement between cases with optimum and suboptimum results. Tremor and rigidity were selectively improved in cases with suboptimum results. CONCLUSION: Raprl-DBS is an effective treatment for the motor symptoms of PD. Selective improvement of symptoms suggests that the target has different fiber components related to either tremor or rigidity, and variations in improvement between cases may derive from individual variations of the location of these fibers.

Expanded functional coupling of subcortical nuclei with the motor resting-state network in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) impairs signal transmission along cortico-cortical and cortico-subcortical connections, affecting functional integration within the motor network. Functional magnetic resonance imaging (fMRI) during motor tasks has revealed altered functional connectivity in MS, but it is unclear how much motor disability contributed to these abnormal functional interaction patterns. OBJECTIVE: To avoid any influence of impaired task performance, we examined disease-related changes in functional motor connectivity in MS at rest. METHODS: A total of 42 patients with MS and 30 matched controls underwent a 20-minute resting-state fMRI session at 3 Tesla. Independent component analysis was applied to the fMRI data to identify disease-related changes in motor resting-state connectivity. RESULTS: Patients with MS showed a spatial expansion of motor resting-state connectivity in deep subcortical nuclei but not at the cortical level. The anterior and middle parts of the putamen, adjacent globus pallidus, anterior and posterior thalamus and the subthalamic region showed stronger functional connectivity with the motor network in the MS group compared with controls. CONCLUSION: MS is characterised by more widespread motor connectivity in the basal ganglia while cortical motor resting-state connectivity is preserved. The expansion of subcortical motor resting-state connectivity in MS indicates less efficient funnelling of neural processing in the executive motor cortico-basal ganglia-thalamo-cortical loops.

The impact of low-frequency stimulation of subthalamic region on self-generated isometric contraction in patients with Parkinson's disease.

Growing evidence suggests that spontaneous oscillatory low-frequency synchronization in the subthalamic nuclei (STN) may modulate motor performance in patients with Parkinson's disease (PD). To explore this in more detail, 15 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both STN were stimulated bilaterally at 5, 10, 20, 50 and 130 Hz and the effects of the DBS on self-initiated isometric elbow flexion (FLEX) and finger pinch (PINCH) were compared to performance without DBS. Baseline performance was very much impaired. Peak force was significantly greater during 130 and 10 Hz stimulation when compared to no stimulation in both tasks. Cumulative sums of the changes in mean rising force and peak force in the two tasks upon stimulation at 10 and 20 Hz demonstrated that patients improved their performance on stimulation, except for those with the best performance off stimulation who deteriorated with stimulation at 20 Hz. Thus, no effect was detected with 20 Hz stimulation at the group level. The current study highlights the need to consider the baseline performance of a subject in a given task when determining the effects of low-frequency STN stimulation in PD patients. It also demonstrates that stimulation at 10 Hz can improve motor function in subjects with poor baseline function.

Possible mechanisms involved in subthalamotomy-induced dyskinesia in patients with Parkinson's disease.

BACKGROUND/AIMS: Operation-induced dyskinesia (OID) occurs in approximately 10% of patients submitted to subthalamotomy. The goal of the authors was to determine the possible causes of this feared complication. METHODS: The 54 patients who underwent unilateral subthalamotomy were divided into two groups: the OID group (OIDG), composed of 6 patients who developed dyskinesia following the operation, and the control group (CG), consisting of 48 patients who did not present this complication. The two groups were compared regarding age; sex; presence of levodopa-induced dyskinesia (LID) and/or stimulation-induced dyskinesia (SID); side of the operation; territories of the subthalamic nucleus (STN) involved by the lesion, and degree of lesion extension towards the zona incerta (ZI). RESULTS: The lesion involved the dorsolateral territory of the STN and was almost completely restricted to this nucleus in all patients of the OIDG, while it spread to the ZI in all but 1 patient of the CG. SID was significantly (p < 0.05) more frequent in the OIDG. There was also a strong trend favoring LID (p = 0.055). CONCLUSIONS: Damage to the dorsolateral territory of the STN and sparing of the ZI seem to be essential for the development of OID. SID and, to a lesser extent, LID are apparently significant risk factors for the development of this complication.

Long term follow-up of deep brain stimulation of the caudal zona incerta for essential tremor.

PURPOSE: The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS. METHODS: 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3-5 years after surgery (mean 48.5±10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated. RESULTS: A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time. CONCLUSION: cZi DBS is a safe and effective treatment for the long term suppression of ET.

Swallowing function in Parkinson's patients following Zona Incerta deep brain stimulation.

OBJECTIVE: The purpose of the present study was to examine whether there was a negative effect of caudal Zona Incerta deep brain stimulation (cZI DBS) on pharyngeal swallowing function in Parkinson's patients (PD). There are no former reports including swallowing and cZI DBS. METHODS: Eight patients (aged 49-71 years; median 62) were evaluated pre- and post-operatively, at 6 and 12 months after DBS surgery. Evaluation tools were fiberoptic endoscopic evaluation of swallowing examinations and patients' self-assessments of their swallowing function including a visual analog scale and quality-of-life-related questions. The swallowing protocol included Rosenbek's Penetration-Aspiration Scale, Secretion Severity Scale and parameters for preswallow spillage, pharyngeal residue, and pharyngeal clearance. RESULTS: There was no clear-cut effect of neurostimulation post-operatively at 6 and 12 months on any of the swallowing parameters except for the preswallow spillage that was slightly worsened in the stimulation on condition 12 months post-operatively. The answers to the self assessment questions did not vary significantly. CONCLUSIONS: The effect of the stimulation on the swallowing function varied among individuals, but the overall outcome was that cZI DBS did not seem to have a negative influence on swallowing function in the eight patients studied.

Bilateral caudal zona incerta nucleus stimulation for essential tremor: outcome and quality of life.

BACKGROUND: Over the past few years, bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) has been performed by the authors in patients with essential tremor (ET). Outcomes including quality of life data in 15 patients with a follow-up period of up to 84 months (mean 31.7 ± 28.6 months) are presented. METHODS: 15 consecutive ET patients underwent MRI guided bilateral cZI deep brain stimulation implantation. Patients were assessed by applying the Fahn-Tolosa-Marin Tremor Rating Scale and the Short Form Health Survey-36 (SF-36) to assess quality of life. RESULTS: The total tremor score improved by 73.8% (p<0.0001). The part A score (items 1-9) improved by 86.6% (p<0.0001). Postural tremor improved by 88.2% (p<0.0001) and action tremor by 82.2% (p<0.0001). The part B score, which evaluates the functional activities of the upper limbs, improved by 60.1% (p<0.0001). Part C score, which evaluates the activities of daily living, improved by 80.0% (p<0.0001). The SF-36 physical component score improved by 23.7% (p<0.0001) and the mental component score by 22.4% (p<0.0001). There was one wound infection and three patients developed stimulation related transient dysarthria. None developed any disequilibrium or tolerance to stimulation. CONCLUSION: Bilateral cZI stimulation is safe and effective in suppressing the postural and action component of ET. It is associated with a low incidence of stimulation related complications and patients do not develop tolerance to stimulation with maintained clinical benefit over a follow-up period of up to 7 years.

Deep brain stimulation of the subthalamic nucleus versus the zona incerta in the treatment of essential tremor.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for essential tremor (ET). Currently the ventrolateral thalamus is the target of choice, but the posterior subthalamic area (PSA), including the caudal zona incerta (cZi), has demonstrated promising results, and the subthalamic nucleus (STN) has been suggested as a third alternative. The objective of the current study was to evaluate the effect of STN DBS in ET and to compare this to cZi DBS. METHODS: Four patients with ET were implanted with two ipsilateral electrodes, one in the STN and one in the cZi. All contacts were evaluated concerning the acute effect on tremor, and the effect of chronic DBS in either target was analyzed. RESULTS: STN and cZi both proved to be potent targets for DBS in ET. DBS in the cZi was more efficient, since the same degree of tremor reduction could here be achieved at lower energy consumption. Three patients became tremor-free in the treated hand with either STN or cZi DBS, while the fourth had a minor residual tremor after stimulation in either target. CONCLUSION: In this limited material, STN DBS was demonstrated to be an efficient treatment for ET, even though cZi DBS was more efficient. The STN may be an alternative target in the treatment of ET, pending further investigations to decide on the relative merits of the different targets.

Outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with Parkinson's disease.

INTRODUCTION: Axial symptoms including postural instability, falls and failure of gait initiation are some of the most disabling motor symptoms of Parkinson's disease (PD). We performed bilateral deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) in combination with the caudal zona incerta (cZi) in order to determine their efficacy in alleviating these symptoms. METHODS: Seven patients with predominant axial symptoms in both the 'on' and 'off' medication states underwent bilateral cZi and PPN DBS. Motor outcomes were assessed using the motor component of the Unified Parkinson's Disease Rating Scale (UPDRS 3) and a composite axial subscore was derived from items 27, 28, 29 and 30 (arising from chair, posture, gait and postural stability). Quality of life was measured using the PDQ39. Comparisons were made between scores obtained at baseline and those at a mean follow-up of 12 months. RESULTS: In both the off and on medication states, a statistically significant improvement in the UPDRS part 3 score was achieved by stimulation of the PPN, cZi and both in combination. In the off medication state, our composite axial subscore of the UPDRS part 3 improved with stimulation of the PPN, cZi and both in combination. The composite axial subscore, in the 'on' medication state, however, only showed a statistically significant improvement when a combination of cZi and PPN stimulation was used. CONCLUSIONS: This study provides evidence that a combination of PPN and cZi stimulation can achieve a significant improvement in the hitherto untreatable 'on' medication axial symptoms of PD.

Revisiting Forel Field Surgery.

BACKGROUND: Lesioning the Forel field or the subthalamic region is considered a possible treatment for tremoric patients with Parkinson disease, essential tremor, and other diseases. This surgical treatment was performed in the 1960s to 1970s and was an alternative to thalamotomy. Recently, there has been increasing interest in the reappraisal of stimulating and/or lesioning these targets, partly as a result of innovations in imaging and noninvasive ablative technologies, such as magnetic resonance-guided focused ultrasonography. OBJECTIVE: We wanted to perform a thorough review of the subthalamic region, both from an anatomic and a surgical standpoint, to offer a comprehensive and updated analysis of the techniques and results reported for patients with tremor treated with different techniques. METHODS: We performed a systematic review of the literature, gathering articles that included patients who underwent ablative or stimulation surgical techniques, targeting the pallidothalamic pathways (pallidothalamic tractotomy), cerebellothalamic pathway (cerebellothalamic tractotomy), or subthalamic area. RESULTS: Pallidothalamic tractotomy consists of a reduced area that includes pallidofugal pathways. It may be considered an interesting target, given the benefit/risk ratio and the clinical effect, which, compared with pallidotomy, involves a lower risk of injury or involvement of vital structures such as the internal capsule or optic tract. Cerebellothalamic tractotomy and/or posterior subthalamic area are other alternative targets to thalamic stimulation or ablative surgery. CONCLUSIONS: Based on the significant breakthrough that magnetic resonance-guided focused ultrasonography has meant in the neurosurgical world, some classic targets such as the pallidothalamic tract, Forel field, and posterior subthalamic area may be reconsidered as surgical alternatives for patients with movement disorders.

Somnolence Preceded the Development of a Subthalamic Lesion in Neuromyelitis Optica Spectrum Disorder.

A 67-year-old woman with neuromyelitis optica spectrum disorder (NMOSD) developed severe somnolence. Ten days after admission, fluid-attenuated inversion-recovery magnetic resonance imaging (MRI) revealed hyperintense areas around the bilateral hypothalamus, which were not present on MRI at admission. The orexin level, which is decreased in idiopathic narcolepsy, was slightly decreased in her cerebrospinal fluid. Immunosuppressive treatment and methylphenidate markedly improved her somnolence. This case shows that NMOSD in the acute phase can cause somnolence in a patient without apparent lesions in the hypothalamus.

Entacapone potentiates the long-duration response but does not normalize levodopa-induced molecular changes.

Coadministration of entacapone with levodopa attenuates motor complications in experimental models of Parkinson's disease. The mechanisms underlying entacapone effects are unknown. We investigated the effect of entacapone, on: long-duration response (LDR) to levodopa, levodopa-induced postsynaptic pharmacodynamic mechanisms and molecular changes in hemiparkinsonian rats. 6-Hydroxydopamine-unilaterally lesioned rats were treated with levodopa (25 mg/kg)+vehicle; levodopa+entacapone (30 mg/kg) or saline, twice daily for 22 days. The LDR and the apomorphine-induced rotations were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin and dopamine D-3 receptor mRNAs, subthalamic cytochrome oxidase mRNA and nigral glutamic acid decarboxylase mRNA. Entacapone potentiated the LDR but did not modify either the apomorphine-induced rotational behavior or the molecular changes. Our results suggest that the effects of entacapone on levodopa-induced motor response are not mediated by postsynaptic mechanisms and that administration of entacapone is not able to normalize the molecular alterations induced by levodopa in the basal ganglia.

Bilateral stimulation of the caudal zona incerta nucleus for tremor control.

INTRODUCTION: The ventrolateral (VL) nucleus of the thalamus is the commonly chosen target for deep brain stimulation (DBS) to alleviate tremor. However, it has a poor efficacy in alleviating proximal tremor and patients may develop tolerance to the action component of tremor. We performed bilateral stimulation of the caudal or motor part of the zona incerta nucleus (cZI) to determine its safety and efficacy in alleviating tremor. METHODS: 5 patients with parkinsonian tremor and 13 with a range of tremors (Holmes (HT), cerebellar (CT), essential (ET), multiple sclerosis (MS) and dystonic tremor (DT)) affecting both the proximal and distal body parts underwent MRI guided, bilateral cZI DBS. Tremor was assessed by the Fahn-Tolosa-Marin (FTM) tremor scale at baseline and at a mean follow-up of 12 months. RESULTS: Resting PD tremor improved by 94.8% and postural tremor by 88.2%. The total tremor score improved by 75.9% in 6 patients with ET. HT improved by 70.2%, proximal CT by 60.4% and proximal MS tremor by 57.2% in the total tremor rating score. In the single patient with DT, there was improvement in both the dystonia and the tremor. Patients required low voltages of high-frequency stimulation and did not develop tolerance to it. Stimulation-related side effects were transient. CONCLUSION: This prospective study shows that the cZI may be an alternative target for the treatment of tremor with DBS. In contrast to bilateral DBS of the VL nucleus, it improves all components of tremor affecting both the distal and proximal limbs as well as the axial musculature.

Induction of parkinsonian resting tremor by stimulation of the caudal zona incerta nucleus: a clinical study.

INTRODUCTION: We hypothesise that parkinsonian tremor arises when the caudal zona incerta (cZI) and subthalamic nucleus (STN) are deprived of dopamine and become increasingly responsive to motor cortical alpha and beta frequency oscillations. These oscillations are synchronised and amplified through the basal ganglia thalamocortical loop and entrained into the cerebello-thalamocortical loop via the cZI. On receiving potent gamma-aminobutyric acid (GABA)-ergic alpha and beta frequency oscillations in cZI afferents, ventrolateral (VL) thalamocortical neurons become hyperpolarised and rebound burst fire, generating 4-6 Hz tremor oscillations. We test this hypothesis by stimulating the cZI at alpha and beta frequencies using deep brain stimulation (DBS) in non-tremulous parkinsonian patients to see whether a 4-6 Hz tremor can be induced. METHOD: This study included 11 patients with non-tremulous Parkinson's disease (PD), who had DBS leads implanted in a range of targets, including the cZI, STN, VL nucleus, globus pallidus internus (GPi), centromedian and parafascicular nucleus (CM/Pf), and the pedunculopontine nucleus (PPN). All patients underwent stimulation of active contacts within their respective targets at a standard pulse width, with frequencies ranging from 5 to 80 Hz up to a maximum tolerated voltage. The frequency of the tremor induced in the hands was recorded by accelerometry. RESULT: Resting tremor in the 4-6 Hz range could be readily induced following stimulation of the cZI and the VL nucleus between 5 and 40 Hz. Tremor was also seen following STN stimulation; however, this was only at high stimulation voltages (>5 volts). No tremor could be induced following CM/Pf, PPN or GPi stimulation. CONCLUSION: We discuss the implications of these findings and argue that resting tremor in PD is generated in the cortico-ZI-VL-thalamocortical loop rather than in the cortico-basal-ganglia-thalamocortical loop.

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

Less is more - Pulse width dependent therapeutic window in deep brain stimulation for essential tremor.

BACKGROUND: Shorter pulse widths than conventional pulse width settings may lead to reduction of side effects and therefore be a valuable therapeutic option for deep brain stimulation (DBS) in patients with essential tremor (ET). OBJECTIVE: To compare the DBS effect of shorter pulse width at 40 µs (DBS-40 µs) to conventional pulse width at 60 µs (DBS-60 µs) on the therapeutic window in ET patients. METHODS: For this prospective, randomized, double-blind, crossover study 9 ET patients with chronic DBS of the ventral intermediate nucleus (VIM)/posterior subthalamic area (PSA) were recruited. Therapeutic window was calculated by determining efficacy and side effect thresholds for DBS-40 µs and DBS-60 µs. Tremor Rating Scales and Kinesia tremor analyses were used to compare clinical efficacy between the considered settings and deactivated DBS (DBS-OFF). Volume of neural activation (VNA) was calculated for both efficacy and side effect thresholds at each pulse width. RESULTS: DBS-40 µs showed a significantly larger therapeutic window than DBS-60 µs mainly due to higher side-effect thresholds. Both conditions significantly improved tremor compared to DBS-OFF, while efficacy was comparable between DBS-40 µs and DBS-60 µs. Moreover, VNA at efficacy threshold was smaller and less energy was required for tremor suppression with DBS-40 µs compared to DBS-60 µs. CONCLUSIONS: VIM/PSA-DBS with short pulse width represents a promising programming option for DBS in ET as it reduces side effects while maintaining efficient tremor suppression. Furthermore, our data support the notion of pulse width dependent selective modulation of distinct fiber tracts leading to widening of the therapeutic window.