Pallidal lead placement in dystonia: leads of non-responders are contained within an anatomical range defined by responders.

BACKGROUND: Deep brain stimulation (DBS) within the pallidum represents an effective and well-established treatment for isolated dystonia. However, clinical outcome after surgery may be variable with limited response in 10-25% of patients. The effect of lead location on clinical improvement is still under debate. OBJECTIVE: To identify stimulated brain regions associated with the most beneficial clinical outcome in dystonia patients. METHODS: 18 patients with cervical and generalized dystonia with chronic DBS of the internal pallidum were investigated. Patients were grouped according to their clinical improvement into responders, intermediate responders and non-responders. Magnetic resonance and computed tomography images were co-registered, and the volume of tissue activated (VTA) with respect to the pallidum of individual patients was analysed. RESULTS: VTAs in responders (n = 11), intermediate responders (n = 3) and non-responders (n = 4) intersected with the posterior internal (GPi) and external (GPe) pallidum and the subpallidal area. VTA heat maps showed an almost complete overlap of VTAs of responders, intermediate and non-responders. VTA coverage of the GPi was not higher in responders. In contrast, VTAs of intermediate and non-responders covered the GPi to a significantly larger extent in the left hemisphere (p < 0.01). CONCLUSIONS: DBS of ventral parts of the posterior GPi, GPe and the adjacent subpallidal area containing pallidothalamic output projections resulted in favourable clinical effects. Of note, non-responders were also stimulated within the same area. This suggests that factors other than mere lead location (e.g., clinical phenotype, genetic background) have determined clinical outcome in the present cohort.

Phase-Dependent Suppression of Beta Oscillations in Parkinson's Disease Patients.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

Towards unambiguous reporting of complications related to deep brain stimulation surgery: A retrospective single-center analysis and systematic review of the literature.

BACKGROUND AND OBJECTIVE: To determine rates of adverse events (AEs) related to deep brain stimulation (DBS) surgery or implanted devices from a large series from a single institution. Sound comparisons with the literature require the definition of unambiguous categories, since there is no consensus on the reporting of such AEs. PATIENTS AND METHODS: 123 consecutive patients (median age 63 yrs; female 45.5%) treated with DBS in the subthalamic nucleus (78 patients), ventrolateral thalamus (24), internal pallidum (20), and centre médian-parafascicular nucleus (1) were analyzed retrospectively. Both mean and median follow-up time was 4.7 years (578 patient-years). AEs were assessed according to three unambiguous categories: (i) hemorrhages including other intracranial complications because these might lead to neurological deficits or death, (ii) infections and similar AEs necessitating the explantation of hardware components as this results in the interruption of DBS therapy, and (iii) lead revisions for various reasons since this involves an additional intracranial procedure. For a systematic review of the literature AE rates were calculated based on primary data presented in 103 publications. Heterogeneity between studies was assessed with the I2 statistic and analyzed further by a random effects meta-regression. Publication bias was analyzed with funnel plots. RESULTS: Surgery- or hardware-related AEs (23) affected 18 of 123 patients (14.6%) and resolved without permanent sequelae in all instances. In 2 patients (1.6%), small hemorrhages in the striatum were associated with transient neurological deficits. In 4 patients (3.3%; 0.7% per patient-year) impulse generators were removed due to infection. In 2 patients electrodes were revised (1.6%; 0.3% per patient-year). There was no lead migration or surgical revision because of lead misplacement. Age was not statistically significant different (p>0.05) between patients affected by AEs or not. AE rates did not decline over time and similar incidences were found among all patients (423) implanted with DBS systems at our institution until December 2016. A systematic literature review revealed that exact AE rates could not be determined from many studies, which could not be attributed to study designs. Average rates for intracranial complications were 3.8% among studies (per-study analysis) and 3.4% for pooled analysis of patients from different studies (per-patient analysis). Annual hardware removal rates were 3.6 and 2.4% for per-study and per-patient analysis, respectively, and lead revision rates were 4.1 and 2.6%, respectively. There was significant heterogeneity between studies (I2 ranged between 77% and 91% for the three categories; p< 0.0001). For hardware removal heterogeneity (I2 = 87.4%) was reduced by taking study size (p< 0.0001) and publication year (p< 0.01) into account, although a significant degree of heterogeneity remained (I2 = 80.0%; p< 0.0001). Based on comparisons with health care-related databases there appears to be publication bias with lower rates for hardware-related AEs in published patient cohorts. CONCLUSIONS: The proposed categories are suited for an unequivocal assessment of AEs even in a retrospective manner and useful for benchmarking. AE rates in the present cohorts from our institution compare favorable with the literature.

Spatio-temporal dynamics of cortical drive to human subthalamic nucleus neurons in Parkinson's disease.

Pathological synchronisation of beta frequency (12-35Hz) oscillations between the subthalamic nucleus (STN) and cerebral cortex is thought to contribute to motor impairment in Parkinson's disease (PD). For this cortico-subthalamic oscillatory drive to be mechanistically important, it must influence the firing of STN neurons and, consequently, their downstream targets. Here, we examined the dynamics of synchronisation between STN LFPs and units with multiple cortical areas, measured using frontal ECoG, midline EEG and lateral EEG, during rest and movement. STN neurons lagged cortical signals recorded over midline (over premotor cortices) and frontal (over prefrontal cortices) with stable time delays, consistent with strong corticosubthalamic drive, and many neurons maintained these dynamics during movement. In contrast, most STN neurons desynchronised from lateral EEG signals (over primary motor cortices) during movement and those that did not had altered phase relations to the cortical signals. The strength of synchronisation between STN units and midline EEG in the high beta range (25-35Hz) correlated positively with the severity of akinetic-rigid motor symptoms across patients. Together, these results suggest that sustained synchronisation of STN neurons to premotor-cortical beta oscillations play an important role in disrupting the normal coding of movement in PD.

The Pioneering and Unknown Stereotactic Approach of Roeder and Orthner from Göttingen. Part II: Long-Term Outcome and Postmortem Analysis of Bilateral Pallidotomy in the Pre-Levodopa Era.

Before the advent of levodopa, pallidotomy was initially the most effective treatment for Parkinson disease, but it was soon superseded by thalamotomy. It is widely unknown that, similar to Leksell, 2 neurologists from Göttingen, Orthner and Roeder, perpetuated pallidotomy against the mainstream of their time. Postmortem studies demonstrated that true posterior and ventral pallidoansotomy sparing the overwhelming mass of the pallidum was accomplished. This was due to a unique and individually tailored stereotactic technique even allowing bilateral staged pallidotomies. In 1962, the long-term effects (3-year follow-up on average) of the first 18 out of 36 patients with staged bilateral pallidotomies were reported in great detail. Meticulous descriptions of each case indicate long-term improvements in parkinsonian rigidity and associated pain, as well as posture, gait, and akinesia (e.g., improved repetitive movements and arm swinging). Alleviation of tremor was found to require larger lesions than needed for suppression of rigidity. No improvement in speech, drooling, or seborrhea was observed. By 1962, the team had operated 13 patients with postencephalitic oculogyric crises with remarkable results (mean follow-up: 5 years). They also described alleviation of nonparkinsonian hyperkinetic disorders (e.g., hemiballism and chorea) with pallidotomy. The reported rates for surgical mortality and other complications had been remarkably low, even if compared to those reported after the revival of pallidotomy by Laitinen in the post-levodopa era. This applies also to bilateral pallidotomy performed with a positive risk-benefit ratio that has remained unparalleled to date. The intricate history of pallidotomy for movement disorders is incomplete without an appreciation of the achievements of the Göttingen group.

Adverse events in deep brain stimulation: A retrospective long-term analysis of neurological, psychiatric and other occurrences.

BACKGROUND AND OBJECTIVE: The extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression. PATIENTS AND METHODS: We retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinson's disease (82), dystonia (18), tremor of different etiology (21), Huntington's disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy. RESULTS: Over a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs. CONCLUSIONS: DBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Targeting of the Subthalamic Nucleus for Deep Brain Stimulation: A Survey Among Parkinson Disease Specialists.

BACKGROUND: Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target. METHODS: To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN. RESULTS: The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule. CONCLUSIONS: This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients.

The Pioneering and Unknown Stereotactic Approach of Roeder and Orthner from Göttingen. Part I. Surgical Technique for Tailoring Individualized Stereotactic Lesions.

During the 1950s through the 1970s, Hans Orthner and Fritz Roeder, two German neurologists from Göttingen, developed a sophisticated technique to perform functional stereotactic surgery with outstanding accuracy. They introduced direct air ventriculography performed in the same surgical session as the ablative stereotactic procedure. For individualized surgical targeting, Orthner prepared a stereotactic atlas (>60 brains) with an ingenious brain-slicing device, the Göttinger macrotome. Brains were grouped based on similarity of six different head and ventricle measurements. A brain cluster representing the best match for a patient was selected for stereotactic targeting. Stereotactic lesions were tailored in an individual manner and shaped by stringing together multiple small coagulations following intraoperative test stimulation. This was achieved from a single probe trajectory by using well-engineered string electrodes with calibrated curving and involved laborious calculations. Only high-frequency thermocoagulation was regarded as appropriate for lesioning. With this meticulous technique, the most advanced stereotactic procedures were performed, including bilateral pallidotomy that ultimately could be restricted to the ansa lenticularis and ventromedial hypothalamotomy, the most delicate stereotactic operation performed to date. Outside Göttingen, this technique has only been used by Prof. Dieter Müller in Hamburg, Germany. This elaborate stereotactic approach is widely unknown and deserves to be discussed in a historical context.

Activity parameters of subthalamic nucleus neurons selectively predict motor symptom severity in Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥ 10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinson's Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

The influence of tamoxifen on the secretion of transforming growth factor-beta2 (TGF-beta2) in glioblastomas: in vitro and in vivo findings.

BACKGROUND: Only a minority of patients with malignant gliomas respond to continuous high-dose tamoxifen (TAM) treatment. Therefore a method to predict the efficiency of TAM-treatment would be desirable. Analogous to previous studies in breast cancer patients, we investigated whether the dynamics of TGF-beta2 plasma levels allow the prediction of response to TAM-treatment in glioblastoma patients as well. MATERIALS AND METHODS: TGF-beta2 plasma levels of glioblastoma patients treated with 200 mg TAM/day on a continuous basis and of control patients not treated with TAM were measured by using an ELISA. In addition, the effect of TAM and 4-OH-TAM on the secretion of TGF-beta2 by established glioma cell lines as well as the effect of TGF-beta2 itself on cell proliferation were investigated in vitro. RESULTS: The effect of TAM on TGF-beta2 plasma levels did not correlate with the clinical response to TAM-therapy in glioblastoma patients. The in vitro experiments showed that TAM and 4-OH-TAM stimulate established glioma cell lines to increase their secretion of TGF-beta2. Externally added TGF-beta2 (nM) had no effect on cell proliferation of the same cell lines. CONCLUSION: In contrast to breast cancer patients, the clinical response to TAM in glioblastoma patients is not reflected by changes of TGF-beta2 plasma levels. It has to be assumed that, despite an increase of TGF-beta2 production by glioblastoma cells in response to TAM in vitro, such elevated production in vivo does not reach the plasma due to either the lower tumor burden in glioblastoma disease compared to breast cancer patients or due to some local sequestration process.