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The subthalamic nucleus (STN) is involved in motor and cognitive performance through its key role in the basal ganglia-thalamocortical circuits, but how these different modalities (motor and cognition) are controlled (similar vs. dissimilar) has not yet been elucidated. In the present study, the effects of bilateral STN deep brain stimulation (DBS) on motor and cognitive performance were investigated in a rat model of Parkinson disease (PD). After being trained in a choice reaction time (CRT) task, rats received bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width), and varying amplitudes of 1, 3, 30, and 150 microA during the CRT task. Finally, rats were sacrificed and the brains processed for staining to determine the dopaminergic lesion (TH immunohistochemistry) and localization of the electrode tip (HE histochemistry). Bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc) and increased motor time (MT), proportion of premature responding (PR), and reaction time (RT). Bilateral STN stimulation with an amplitude of 3 microA normalized 6-OHDA-induced deficits in PR and RT. Simulation with an amplitude of 30 microA reversed the lesion-induced deficits in MT and RT. Our data show for the first time that bilateral STN stimulation differentially affected the 6-OHDA-induced motor and cognitive deficits. This means that basal ganglia-thalamocortical motor and associative circuits responsible for specific motor and cognitive performance, which are processed through the STN, have unique physiological properties that can acutely and separately be modulated by specific electrical stimuli.

The aim of the present study was to determine the effects of monopolar and bipolar high frequency stimulation (HFS) on histological damage and current flow using a commonly applied stimulus amplitude (300 microA). Bipolar HFS resulted in a large amount of histological damage whereas with monopolar HFS no damage was observed except for the electrode trajectory. Oscilloscopic readings confirmed that this was due to the application of twice as much current to the target with bipolar HFS. Our results demonstrate that there are differences in tissue damage dependent of polarity. In order to create a better comparison to the clinical condition, we suggest that the present rodent models for studying the effect of chronic HFS require further adjustment. This can be achieved by decreasing the present current densities to a level comparable to the human situation.

Penile erection is a complex neurovascular event. The neuronal system involved is often divided into a spinal (generator) and supraspinal (controller) network. Little is known about the supraspinal control. The recent finding of changes in penile erection following deep brain stimulation of the thalamus in two patients has raised the question as to what extent the thalamus is involved in erectile function. The thalamus has generally been regarded as a group of relay nuclei that served as a 'gate' for sexual information from the spinal cord towards higher centres. Recent evidence, however, suggests a more integrated regulatory function. Our review of the literature from 1960 until 2003 revealed 13 reports describing original data (preclinical and clinical). Various thalamic regions, varying from the midline thalamus to the posterior thalamus, have been reported to be activated during erection. The majority of the reports, however, showed that mainly the mediodorsal (MD) nucleus and the centromedian-parafascicular nucleus (Cm-Pf complex) are involved in penile erection. MD is the second largest nuclear aggregation located within the medial part of the thalamus. Anatomically, the MD is closely related to the Cm-Pf complex. The Cm-Pf complex is one of the most important relay stations in which the anterolateral spinothalamic pathway is further processed. This pathway is thought to transmit peripheral sexual sensations. On the whole, the present data on the role of the thalamus in erection are far from complete and future experiments are required to delineate its involvement.

Objective. To report our experience on hardware-related infections following deep brain stimulation (DBS). Methods. The present article presents the retrospective clinical notes review of gained in a two-centre, single-surgeon study experience of 108 consecutive DBS cases between 1996 and 2002. In all patients the minimum follow-up was six months. One hundred and eight patients received an intracerebral electrode implantation and 106 underwent internalization. Results. In total 178 electrodes were implanted with a mean follow-up of 42.6 months and a cumulative follow-up of 367.7 patient-years. Four patients (3.8%) developed an infection related to the DBS-hardware and all were initially treated with antibiotics. Two patients eventually required additional surgical treatment. Conclusion. Infections due to DBS-hardware can result in considerable levels of morbidity. In certain cases antibiotic therapy may be adequate. In others, surgical intervention to externalise the electrodes may be necessary. In our experience, there was never a need to remove the electrodes.

Functional magnetic resonance imaging (fMRI) studies showed that the brain at rest exhibits spontaneous BOLD (Blood Oxygenation Level Dependent) fluctuations over time that correlate between functionally connected brain areas ( Biswal et al., 1995 ). However, the lower temporal resolution of fMRI precludes the study of neuronal coding and temporal information flow with an appropriate level of temporal acuity in these networks. EEG is better suited for the study of the temporal dynamics in such networks because of its millisecond resolution; however, due to its limited spatial resolution, contributions from subcortical structures are likely not well represented. Not surprisingly though, results from fMRI resting state studies clearly indicate that subcortical structures are important key players in these networks. In order to gain better insights into the interactions of cortical–subcortical circuits at rest, we performed recordings from multiple scalp electrodes simultaneously with chronically implanted deep brain stimulation electrodes in subcortical targets of human subjects. Computed partial directed coherence based on Granger causality ( Plomp et al., 2014 ) was performed to identify the major drivers of the network and the sites that were subject to them. Here we report on obsessive–compulsive disorder patients who were bilaterally implanted in the nucleus accumbens as well as Tourette syndrome patients with bilateral thalamic implants. In all patients, local circumscribed networks surrounding specific subcortical electrodes were identified as major drivers of the larger pathological network. Recordings which were performed with 256-channel scalp EEG electrodes were subject to source localization methods and connectivity analysis was performed in the source space ( Coito et al., 2015 ). Our cortical–subcortical simultaneous recordings provide the platform for a deeper understanding of the temporal dynamics of whole-brain networks in humans, which includes the intimate contribution of deep structures and opens new ways of identifying neurophysiological markers of these psychiatric diseases.

Question First reports on the application of deep brain stimulation of the Nucleus basalis of Meynert reported feasibility and safety of the intervention in patients with Alzheimer’s disease. However, clinical effects vary and the mechanisms of actions are still not well understood. Methods We studied preoperative T1-weighted MR images of ten patients with Alzheimer’s disease and correlated the clinical outcome with volumetric differences in a vertex-based analysis, controlling for age, sex and the total intracranial volume. Clinical assessments, 12 months after the intervention, included the Alzheimer’s Disease Assessment Scale with its subitems for cognition and memory as well as the mini mental status examination. Results A fronto-parietal pattern including significant clusters covering the inferior and superior parietal gyrus, the precuneus, the superior and middle frontal gyrus were found to be correlated with a beneficial outcome. Conclusion Our results support the assumption, that patients with less advanced morphological changes may benefit more from deep brain stimulation of the Nucleus basalis of Meynert. Furthermore, we conclude that positive effects are mediated by a preserved fronto-parietal interplay.

✓✓ Based on the results of thalamotomies described by Hassler in 1970, the authors performed bilateral thalamic highfrequency stimulation (HFS) in three patients with intractable Tourette syndrome (TS). In this report they describe the long-term effects. Three male patients (42, 28, and 45 years of age) had manifested motor and vocal tics since early childhood. The diagnosis of TS was made according to the criteria of the Tourette Syndrome Classification Study Group. Any drug or alternative treatment had been either ineffective or only temporarily effective in all three patients. There was no serious comorbidity. The target for stimulation was chosen at the level of the centromedian nucleus, substantia periventricularis, and nucleus ventrooralis internus. After 2 weeks of test stimulation, the pulse generators were implanted. After a follow-up period of 5 years in the patient in Case 1, 1 year in the patient in Case 2, and 8 months in the patient in Case 3, all major motor and vocal tics had disappeared and no serious complications had occurred. When stimulation was applied at the voltage necessary to achieve an optimal result on the tics, a slight sedative effect was noted in all three patients. In the patients in Cases 1 and 3 there were stimulation-induced changes in sexual behavior. Chronic thalamic HFS may be an effective and safe treatment for medically intractable TS in adult patients. Unwanted stimulation-induced side effects may occur.

Tourette syndrome (TS) is a neuropsychiatric disorder with onset in early childhood. It is characterized by tics and often accompanied by disturbances in behavior, such as obsessive-compulsive disorder (OCD). In most cases, the disorder is self-limited or can be treated by medication or behavioral therapy. In a small percentage, however, symptoms are intractable to any conservative treatment. Since 1955, various attempts have been made to treat these patients through neurosurgical procedures. The target sites have been diverse and include the frontal lobe (prefrontal lobotomy and bimedial frontal leucotomy), the limbic system (limbic leucotomy and anterior cingulotomy), the thalamus, and the cerebellum. Combined approaches have also been tried such as anterior cingulotomies plus infrathalamic lesions. The results have often been unsatisfactory or major side effects have occurred, such as hemiplegia or dystonia. Our review of the literature from 1960 until 2003 revealed 21 reports and 3 descriptions in textbooks covering about 65 patients in total who had undergone ablative procedures for intractable TS, the first being reported in 1962. In 1999, deep brain stimulation (DBS) was introduced as a new approach for intractable TS. To date, 3 patients have been reported who underwent bilateral thalamic stimulation, with promising results on tics and obsessive-compulsive symptoms.

✓ The aim of this study was to investigate the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in patients with a subtype of multiple system atrophy (MSA) in which levodopa-unresponsive MSA parkinsonism (MSA-P) is predominant. After a local anesthetic was administered, electrodes were stereotactically implanted bilaterally into the STN in four patients with MSA-P and predominantly akinetorigid symptoms. Unified Parkinson's Disease Rating Scale (UPDRS) scores were evaluated preoperatively, at 1 month, and at long-term follow up. At 1 month the median decrease in the UPDRS III motor score was 22 on the 56-point scale (decreases of 16, 13, 29, and 15 points compared with baseline for Cases 1, 2, 3, and 4, respectively). This was mainly due to an improvement in rigidity and akinesia. The median decrease in the UPDRS II score was 11 on the 52-point scale (respective decreases of 5, 7, 13, and 9 points). At 2 years (mean follow up 27 months) there was a median decrease in the UPDRS III score of 12 (respective decreases of 18, 13, 21, and 9 points), and in the UPDRS II score of 5 (with respective decreases of 2, 2, 17, and 2), both compared with the stimulation off state. At long-term follow up there was an increase in the individual Schwab and England scores of 10 to 15% in the stimulation on compared with the stimulation off condition. There was a beneficial effect of STN HFS in these four patients on both a short-term and a long-term basis. A larger prospective study is justified.

The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structures are the NAcc and the ventral anterior and ventro-lateral nuclei (VA/VL) of the thalamus, for OCD and TS, respectively. The feedback related negativity (FRN) is an event-related potential associated with feedback processing reflecting posterior medial frontal cortex (pMFC) activity. Here we report on three cases where we recorded scalp EEG and local field potentials (LFP) from externalized electrodes located in the NAcc or thalamus (VA/VL) while patients engaged in a modified time estimation task, known to engage feedback processing and elicit the FRN. Additionally, scalp EEG were recorded from 29 healthy participants (HP) engaged in the same task. The signal in all structures (pMFC, NAcc, and thalamus) was differently modulated by positive and negative feedback. LFP activity in the NAcc showed a biphasic time course after positive feedback during the FRN time interval. Negative feedback elicited a much weaker and later response. In the thalamus a monophasic modulation was recorded during the FRN time interval. Again, this modulation was more pronounced after positive performance feedback compared to negative feedback. In channels outside the target area no modulation was observed. The surface-FRN was reliably elicited on a group level in HP and showed no significant difference following negative feedback between patients and HP. German Clinical Trial Register: Neurocognitive specification of dysfunctions within basal ganglia-cortex loops and their therapeutic modulation by deep brain stimulation in patients with obsessive compulsive disorder and Tourette syndrome, http://www.drks.de/DRKS00005316.

Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation.

Addiction remains one of the most serious public health problems worldwide. The successful use of deep brain stimulation (DBS) for treating movement disorders has prompted researchers to consider whether DBS might be a promising treatment modality for addiction as well. Indeed, there is emerging evidence from preliminary case reports of patients suffering from alcohol and heroin addiction, respectively, that indicates abstinence after DBS within the nucleus accumbens (NAc). These findings are further supported by translational studies showing modulation of addictive behavior patterns in animals by stimulating the NAc and other structures related to the brain’s intrinsic reward system. Explanations for the positive effect of DBS on abstinence are modulative mechanisms on the dysfunctional reward system. Moreover, we intend to expand this by giving a more general view that also includes alternative neurostimulatory techniques different from classical DBS, such as transcranial magnet stimulation (TMS) and transcranial direct current stimulation (tDCS) for evaluating their possible virtues in treating different issues of addiction.

Background For patients with psychiatric illnesses remaining refractory to ‘standard’ therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered ‘established’ in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient's capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-up evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.

Background: Since the introduction of subthalamic nucleus deep brain stimulation (STN DBS), many clinical studies have shown that this therapy is safe and effective in the short and medium term. Only little is known about long-term results. Objectives: To provide an analysis of motor and cognitive outcome 10 years after STN DBS. Methods: In this observational cohort study, we report on the motor and cognitive outcome in a cohort of 26 Parkinson's disease patients who were prospectively followed up for 10 years after STN DBS surgery. Results: In the early post-operative phase, improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) III (10.6, p < 0.01) and IV (2.5, p < 0.01) was seen as well as a 32% reduction in levodopa equivalent dose (p < 0.01). After 5 years, a worsening of the motor performance was observed. The worsening of motor performance was mainly due to a deterioration in bradykinesia (12.4 ± 4.6, p < 0.05) and axial symptoms (6.9 ± 2.8, p < 0.01). Memory function seemed to improve in the short term, but there was a significant decline between 1 and 5 years after surgery (p < 0.01). Mood remained relatively stable during follow-up, and one third of the patients showed impulsive behaviour after surgery. Conclusions: The motor performance of patients showed deterioration over time, due to an increase in bradykinesia and axial symptoms.

Inflammation plays a key role in the development of sensitization after peripheral nerve damage. We recently demonstrated that tumor necrosis factor-α receptor (TNFR) levels in the spinal cord correlate with pain sensation in herniated disc patients in a rat chronic constriction injury (CCI) model. By using the sciatic nerve CCI model, we studied the effect of anti-TNF-α treatment on recovery from hypersensitivity and TNFR expression in the dorsal root ganglion (DRG) and dorsal horn (DH). Experimental groups consisted of sham-operated and CCI-operated rats that received two s.c. injections (one immediately after surgery, the other 5 days later), both containing saline, etanercept (3 mg/kg body weight), or infliximab (10 mg/kg body weight). Mechanical allodynia (with von Frey filaments) and thermal hyperalgesia (Hargreaves test) were assessed preoperatively and weekly during the first 4 postoperative weeks. DRG and DH samples were collected 2 and 4 weeks after surgery and analyzed for TNFR1 and TNFR2 protein levels by Western blotting and analyzed for mRNA levels by quantitative real-time polymerase chain reaction. Anti-TNF-α treatment resulted in a significant alleviation of pain. TNFR levels were increased five- to sixfold in CCI rats compared with sham controls. Both treatments significantly diminished these increased levels. Treated animals that showed a ≥50% alleviation of pain exhibited a significantly reduced TNF R1/R2 mRNA ratio compared with treated animals that recovered less well. These results demonstrate that attenuation of TNFR expression is associated with recovery from nerve injury and suggest that this may be one of the working mechanisms of anti-TNF therapies.

Intervening with serotonergic neurotransmission can have profound effects on mobility. For instance, the peripheral administration of the 5-HT 2A/C agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), changes the locomotor activity substantially. Locomotor activity is classically linked to the basal ganglia, in which the subthalamic nucleus (STN) plays a pivotal role. In this study, we tested the hypothesis that deep brain stimulation (DBS) of the STN modulates DOI-induced hypomobility. Rats were implanted with stimulating electrodes at the level of the STN and were tested in an open field (OF) task in various conditions (stimulation on/off, in combination with DOI treatment). We found that DOI administration (i.p.) reduced the behavioural activity of the animals and that STN HFS reversed these effects. This study provides the first evidence that the therapeutic effect of STN HFS may also be mediated by a 5-HT-dependent mechanism.

We thank Dr. Fiorentino and colleagues for their interest in our article comparing dosimetric treatment plan quality in intracranial stereotactic radiosurgery (SRS) [12]. The purpose of our study was to test whether robotic radiosurgery can create at least equivalent treatment plans when compared to classical SRS with a linear accelerator (linac-SRS). Linac-SRS with conical collimators or a micro-multileaf collimator is widely used and a well-established clinical standard for the treatment of small intracranial target volumes [7, 10]. Treatment plan comparisons allow, if they are carried out properly, reliable statements to be made about the clinical utility of a new irradiation method or new radiation device [9]. Since plan comparisons can generally be carried out using a matched pair analysis, the required number of cases investigated can be kept low. Usually about 10 cases (range 1–15) are used in the literature [1, 3, 5, 6, 8, 9]. Vice versa, methodological requirements for meaningful plan

Objectives: To investigate the effects of low- and high-frequency deep brain stimulation (DBS) on the nucleus accumbens (ACC) and the adjacent internal capsule in 3 patients with obsessive-compulsive disorder (OCD) using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) under intraoperative conditions. Methods: After placement of the electrode in the right ACC, the patients underwent an MR scan inside the operating room. BOLD imaging was performed and interpreted using a boxcar paradigm with alternating high-frequency stimulation of the ACC and the internal capsule versus rest. Correlation maps were calculated employing SPM99. Results: During high-frequency stimulation of the right ACC, focal activation could be found in the right striatum, the right frontal lobe and the right hippocampus, whereas low-frequency stimulation was correlated to right insular activation. Interpretation: Intraoperative BOLD-fMRI is feasible during DBS surgery of OCD patients. Our results support the existence of an ipsilateral hemispheric circuit involving the frontal lobe, anterior cingulate, parahippocampal gyrus and striatum. Intraoperative fMRI may be used to acquire additional information regarding the pathophysiology of OCD that can be used to improve the results of DBS in OCD.

Deep brain stimulation (DBS) is an established, in selected cases therapeutically effective, non-lesional treatment method delivering current rectangular pulses into dysfunctional brain structures via chronically implanted stimulation electrodes. DBS is a recognized method applied in movement disorders and is increasingly evaluated as a possible therapeutic option for psychiatric diseases such as refractory obsessive-compulsive disorders, Gilles de la Tourette syndrome, major depression and substance-related addiction. Latest research indicates that DBS may be a method for improving cognitive functions in Alzheimer’s dementia (AD). Translational data in healthy and AD animals appear to support this notion. Nevertheless, many aspects remain unclear, particularly with regard to the optimal target structure. The objective of this review is to present a systematic overview regarding published research on DBS and cognitive functioning in animal and human studies as well as to provide a systematic overview of the feasibility and efficacy of the treatment. We describe three studies investigating the effects of DBS in patients with dementia, using either the fornix or the nucleus basalis of Meynert as a target. In total, we identified 25 animal studies with 10 brain structures being targeted: fornix, nucleus basalis of Meynert, anterior caudate nucleus, dorsal striatum, anterior thalamic nucleus, midline thalamic nuclei, central thalamic nuclei, lateral hypothalamus, hippocampus (entorhinal cortex, perforant path) and amygdala. Considering the wide and diverse spectrum of targets, we add to this review a supposition about possible underlying mechanisms of operation and recommendations for further research.

Background Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS. Methods In this prospective open-label trial, eight patients (three female, five male) 19–56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset. Results Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome. Conclusions Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics, often associated with behavioral disorders, with typical onset in early childhood. In most patients, the symptoms decrease spontaneously when adulthood is reached, or can be treated with behavioral therapy or medication. Only a small proportion of patients are candidates for surgical treatment. In 1999, thalamic deep brain stimulation (DBS) was introduced for intractable Tourette syndrome. Since then, a diversity of targets have been used, located mainly at the level of the medial part of the thalamus, in the globus pallidus internus (anteromedial limbic and posteroventrolateral motor part), the globus pallidus externus, and the internal capsule/nucleus accumbens. The pathophysiology of Tourette syndrome is still a matter of considerable debate. Current knowledge of cortical-basal ganglia-thalamocortical circuits provides explanations for the beneficial effects of DBS on tics. Inclusion and exclusion criteria have been formulated to identify good candidates for DBS. Because of the small number of patients, there is a strong need for multicenter double-blind trials with standard protocols.

Introduction Thalamic deep brain stimulation is effective in reducing tics in patients with severe Tourette syndrome at the short-term. Here, we report on the long-term outcome. Methods Seven patients with refractory Tourette syndrome were referred to the Maastricht University Medical Centre and underwent bilateral thalamic deep brain stimulation between 2001 and 2008. The target was the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus cross point of the thalamus. During the visits to the outpatient clinic, effects on tics, side-effects and stimulations parameters were evaluated. The follow-up duration varied between 12 to 78 months. Results Patient 1 showed an improvement on tics of 81.6% after 60 months, but due to higher voltage stimulation after some years needed to suppress the tics, side-effects became more severe and the target was changed to the anterior part of the internal pallidum. Patient 2 showed a tic improvement of 50% after 36 months, but due to increasing side-effects, he switched the stimulator permanently off. In patient 3 the stimulator is still active and showed satisfying results with an improvement on tics of 88.9% after 78 months. Patient 4 experienced a tic improvement of 34% after 16 months. However, side-effects became more severe, and when the whole system had to be removed due to a persisting hardware infection after six years, the target was changed to the anterior part of the internal pallidum. Patient 5 showed a minor tic improvement of 27.5% after 12 months. He was unsatisfied and went to abroad for stimulation of the external globus pallidus. Patient 6 developed cerebral atrophy due to a neurodegenerative disease and experienced several non-stimulation related side-effects. His tic improvement was 34% on the YGTSS after 26 months and he decided to turn the stimulator off. The positive effect on tics in patient 7 decreased over time until an improvement of only 9% at 60 months of follow-up. The target was changed to the anterior part of the internal pallidum. Conclusion Thalamic deep brain stimulation in patients with severe Tourette syndrome is effective in reducing tics, at least at the short-term. At the long-term only in one patient the stimulator is still active, in three patients the target was changed to the anterior part of the internal pallidum due to side-effects and three were unsatisfied and turned off their stimulator. There seems to be an increasing disbalance of effects versus side effects leading to either switching off the stimulator or re-surgery changing the target. These clinical cases reflect the strong heterogeneity of the disease, with serious comorbity, interfering with effects and side-effects of deep brain stimulation.

Question This pilot study aimed to assess the therapeutic potential of chronically implanted directional DBS leads in patients with Parkinson’s disease. The therapeutic effect of deep brain stimulation (DBS) in the subthalamic nucleus is frequently limited by side-effects resulting from unintended stimulation of neighboring areas. Recently available chronically implantable DBS leads capable of directional steering might overcome this problem. Methods Randomized, double-blinded, standardized monopolar reviews were conducted in consecutive patients, about one week after implantation of a novel DBS system capable of directional stimulation. Clinical effects and side-effect thresholds were compared between unidirectional and circular DBS. After a two-day double-blind crossover phase, patients were asked to opt for either circular or unidirectional DBS. Results Unidirectional DBS offered increased side-effect thresholds compared to circular DBS depending on stimulation direction. Highest side-effect thresholds were achieved with posteromedial or anterior stimulation in most cases. Conclusions This pilot study provides preliminary evidence for advantages of directional DBS systems. Large cohorts with long-term follow-up are needed to confirm these results.

Introduction Patients with severe Tourette syndrome are potential candidates for deep brain stimulation (DBS). We have shown that bilateral thalamic as well as pallidal stimulation can be effective in reducing the severity of motor and vocal tics. However, one of the challenges is the anesthetic approach in this type of surgery. During surgery there is an ’awake’ and an ’asleep’ phase. In the ’awake’ phase, anesthesia has three goals. First, to reduce the intraoperative tics to avoid the dislocation of the stereotactic frame. Second, adequate level of consciousness to allow intraoperative testing of stimulation effects. Third, avoid interference with the single-unit electrophysiological recordings. To date there is no consensus on how to reach these goals. In this study, we report our own experience in the past 15 years. In the ‘asleep’ phase there is the internalization of the extension leads and pulsgenerator. Methods From 1999 to 2015 surgery was performed in 15 patients (12 males and 3 females) with severe Tourette syndrome. Eight patients were operated in the thalamic target (cross point of the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus) and 7 in the pallidal target (the anteromedial part of the internal globus pallidus). During the procedure different short-acting anesthetic regimens were used. In the ’awake’ phase we used a combination of propofol and remifentanil, remifentanil and clonidine, and remifentanil as a single anesthetic. In the asleep phase all patients were intubated and received a combination of propofol and remifentanil. Results With our awake-asleep anesthetic protocols, none of the patients experienced dislocation of the stereotactic frame during surgery. In the awake phase, all patients were cooperative and neuropsychological testing was possible. Moreover, stimulation related side effects could be screened. We obtained adequate single-unit recordings from the thalamic and pallidal neurons. Conclusion Tailored anesthetic techniques with low-dose sedation make it possible to achieve adequate tic reduction in the ‘awake’ phase, allowing intraoperative clinical testing, and obtain good neurophysiological recordings.

Objective Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2–3% and often bears a high level of suffering and a great impact on psychosocial functioning and quality of life. International guidelines agree on cognitive behavioural therapy and pharmacological interventions as first line treatments. Only 70% of patients with OCD respond to these treatments, a substantial proportion of patients remain severely affected, for these patients deep brain stimulation of the nucleus accumbens (NAcc-DBS) might be a useful neuromodulative therapy approach. Methods Twenty treatment-resistant OCD patients treated with NAcc-DBS from the Psychiatric DBS Centre Cologne. After implantation of DBS electrodes in the NAcc patients entered an open label phase, stimulation parameters were adjusted to achieve best clinical outcome and the primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale score. Symptom severity was assessed after 6 and 12 months along with neuropsychological and personality scales. Results After six months four of 18 were responders, and five were partial-responders. After one year six out of 12 were responders and two were partial-responders. Conclusion NAcc-DBS is an effective treatment method for otherwise treatment-resistant OCD patients. Nevertheless there are a lot of open questions regarding mechanisms of action as well as response predictors. These questions need to be addressed in future studies to further improve DBS treatment.

Chronic motor cortex stimulation (MCS) is currently being investigated as a treatment method for Parkinson's disease (PD). Unfortunately, the underlying mechanisms of this treatment are unclear and there are many uncertainties regarding the most effective stimulation parameters and electrode configuration. In this paper, we present a MCS model with a 3D representation of several axonal populations. The model predicts that the activation of either the basket cell or pyramidal tract (PT) type axons is involved in the clinical effect of MCS. We propose stimulation protocols selectively targeting one of these two axon types. To selectively target the basket cell axons, our simulations suggest using either cathodal or bipolar stimulation with the electrode strip placed perpendicular rather than parallel to the gyrus. Furthermore, selectivity can be increased by using multiple cathodes. PT type axons can be selectively targeted with anodal stimulation using electrodes with large contact sizes. Placing the electrode epidurally is advisable over subdural placement. These selective protocols, when practically implemented, can be used to further test which axon type should be activated for clinically effective MCS and can subsequently be applied to optimize treatment. In conclusion, this paper increases insight into the neuronal population involved in the clinical effect of MCS on PD and proposes strategies to improve this therapy.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in Parkinson’s disease (PD) patients. However, in a substantial number of patients the beneficial effects of STN DBS are overshadowed by psychiatric side effects. We hypothesize that stimulation of the STN motor area will provide the optimal effect on the motor symptoms without inducing these side effects, and expect that motor cortex stimulation (MCS) evokes a spatially specific response within the STN, which identifies the STN motor area. We previously showed that MCS evokes responses in the unit activity specifically within certain areas of the STN. Unit activity is generally considered a measure of the output activity. To gain more insight into the neuronal input into the STN, we describe the results of cortically evoked subthalamic local field potentials (LFPs). We show that the cortically evoked LFPs follow a certain temporal and spatial pattern. The significant peaks of the evoked LFPs coincide with the timing of some of the inhibitions and excitations present in the unit responses. The spatial resolution of responses measured in the LFP to MCS is not high enough to identify the STN motor region. However, we believe that optimizing targeting techniques and the development of novel DBS electrodes will improve STN DBS therapy for PD patients.

Deep brain stimulation (DBS) has been firmly established as a therapy for movement disorders. Recently, evidence from case reports and small case series also suggests DBS to be effective in psychiatric disorders including addiction. Here we review the rationale of DBS in addiction and the selection of possible targets. We then consider evidence from animal models as well as human case studies. We conclude that DBS in particular of the nucleus accumbens (NAcc) represents a promising treatment option in addiction which deserves further investigation.

Contains fulltext : 109610.pdf (Publisher’s version ) (Open Access) Deep brain stimulation (DBS) for Parkinson's disease often alleviates the motor symptoms, but causes cognitive and emotional side effects in a substantial number of cases. Identification of the motor part of the subthalamic nucleus (STN) as part of the presurgical workup could minimize these adverse effects. In this study, we assessed the STN's connectivity to motor, associative, and limbic brain areas, based on structural and functional connectivity analysis of volunteer data. For the structural connectivity, we used streamline counts derived from HARDI fiber tracking. The resulting tracks supported the existence of the so-called "hyperdirect" pathway in humans. Furthermore, we determined the connectivity of each STN voxel with the motor cortical areas. Functional connectivity was calculated based on functional MRI, as the correlation of the signal within a given brain voxel with the signal in the STN. Also, the signal per STN voxel was explained in terms of the correlation with motor or limbic brain seed ROI areas. Both right and left STN ROIs appeared to be structurally and functionally connected to brain areas that are part of the motor, associative, and limbic circuit. Furthermore, this study enabled us to assess the level of segregation of the STN motor part, which is relevant for the planning of STN DBS procedures.

Previous experimental models have shown that proinflammatory cytokines modulate peripheral and central nociception. However, the direct correlation between inflammation and pain in patients remains unclear. Our aim is to correlate the levels of inflammation in the spine with pre- and postoperative pain scores after discectomy. Paravertebral muscle, annulus fibrosus (AF) and nucleus pulposus (NP) biopsies were intraoperatively collected from ten lumbar disc hernia (LDH) patients suffering from chronic sciatic pain and, as painless controls, five scoliosis patients. IL-1 beta and IL-6 expressions in these biopsies were assessed by qPCR and western blot. The amount of pain, indicated on a 0-10 point visual analogue scale (VAS), was assessed 1 day before surgery and 6 weeks and 1 year after surgery. For analysis purposes, LDH patients were grouped into painful (VAS a parts per thousand yen 3.5) and non-painful (VAS

The subthalamic nucleus (STN) is a major player in the input and output of the basal ganglia motor circuitry. The neuronal regular firing pattern of the STN changes into a pathological bursting mode in both advanced Parkinson's disease (PD) and in PD animals models with severe dopamine depletion. One of the current hypothesis, based on clinical and experimental evidence, is that this typical burst activity is responsible for some of the principal motor symptoms. In the current study we tested whether mild DA depletion, mimicking early stages of PD, induced deficits in motor behaviour and changes in STN neuronal activity. The present study demonstrated that rats with a mild lesion (20–40% loss of DA neurons) and a slowed motor response, but without gross motor abnormalities already have an increased number of bursty STN neurons under urethane anaesthesia. These findings indicate that the early increase in STN burst activity is a compensatory mechanism to maintain the dopamine homeostasis in the basal ganglia.

In 1999 deep brain stimulation was introduced as a new therapeutic option for patients with intractable Tourette syndrome. Tourette syndrome is a neurodegenerative disorder characterized by tics and associated behavioural disorders, with typical onset in early childhood. In most patients, the symptoms decrease spontaneously when adulthood is reached, or can be treated with behavioural therapy or medication. Only a small proportion of patients are candidates for surgical treatment. About 70–80 Tourette syndrome patients having received deep brain stimulation have been described in the literature. A diversity of targets have been used, mainly located at the level of the medial part of the thalamus, in the globus pallidus interna (anteromedial limbic and posteroventrolateral motor part), the globus pallidus externa, and the internal capsule/nucleus accumbens. Because of the small number of patients, there is a strong need for multicentre, double-blind trials with standard protocols.

Deep brain stimulation (DBS) has been firmly established as a therapy for movement disorders. Recently, evidence from case reports and small case series also suggests DBS to be effective in psychiatric disorders including addiction. Here we review the rationale of DBS in addiction and the selection of possible targets. We then consider evidence from animal models as well as human case studies. We conclude that DBS in particular of the nucleus accumbens (NAcc) represents a promising treatment option in addiction which deserves further investigation.

It is well established that deep brain stimulation (DBS) of the subthalamic nucleus (STN) has beneficial effects on motor symptoms of Parkinson’s disease (PD). Unfortunately, these can be overshadowed by psychiatric side effects, including depression and suicide. The underlying mechanism is unknown, but it is generally believed that low mood is related to a dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system. Recent animal experiments have demonstrated that bilateral STN DBS with clinically relevant parameters (130 Hz, 60 μs, 100–200 μA) inhibits 5-HT neurotransmission in the brain. In anaesthetized rats bilateral STN DBS caused a significant inhibition of 5-HT neuronal activity in the dorsal raphe nucleus (DRN). Moreover, both unilateral and bilateral STN DBS inhibited 5-HT release in the forebrain of anaesthetized and freely moving rats. A direct STN projection to the DRN does not exist, making a multisynaptic pathway most likely. On the basis of increased expression of c-Fos, a marker of neuronal activity, it was found that the medial prefrontal cortex and lateral habenula potentially mediate the inhibitory effect of STN DBS on the DRN 5-HT system. Previously these two brain regions have been extensively described in inhibitory control of DRN 5-HT neurons. Behavioural evaluation showed that bilateral STN DBS also induced depressive-like behaviour in the forced swim test and increased interaction in the social interaction test. Interestingly, depressive-like behaviour could be prevented by treatment with a 5-HT reuptake inhibitor. Thus, STN DBS induced inhibition of 5-HT transmission via a multisynaptic anatomical pathway may underlie the development of psychiatric complications such as depression. STN DBS treated patients with these symptoms may benefit from drug treatment focusing on 5-HT transmission.

Movement disability in advanced Parkinson's disease (PD) can be treated by high frequency stimulation (HFS) of the subthalamic nucleus (STN) but some patients experience psychiatric side-effects including depression, which is strongly linked to decreases in 5-hydroxytryptamine (5-HT). The current study investigated the effect of bilateral STN HFS on extracellular 5-HT in brain regions of anesthetized and freely moving rats as measured with microdialysis. Parallel in vivo electrophysiological experiments allowed a correlation of changes in extracellular 5-HT with the firing of 5-HT neurons. Bilateral STN HFS decreased (by up to 25%) extracellular levels of 5-HT in both striatum and medial prefrontal cortex of anesthetized rats. STN HFS also decreased extracellular 5-HT in the medial prefrontal cortex of freely moving rats. This decrease in extracellular 5-HT persisted after turning off the stimulation, and was present in dopamine-denervated rats. As with changes in extracellular 5-HT, in anesthetized rats STN HFS evoked a decrease in the in vivo firing of midbrain raphe 5-HT neurons that also persisted after cessation of stimulation. These data provide neurochemical evidence for an inhibition of 5-HT neurotransmission by STN HFS, which may contribute to its psychiatric side effects and guide therapeutic options. © 2011.

The proinflammatory cytokine tumor necrosis factor-α (TNF-α) is well recognized as a key player in nociceptive signaling. Yet, therapeutic capitalization of this knowledge requires a better understanding of how TNF receptors (TNFR) contribute to pain. To address this question, we studied TNFR expression in the chronic sciatic nerve constriction (CCI) model of neuropathic pain. CCI and sham operated rats received two subcutaneous injections (one immediately after surgery, the other on postoperative day 5) containing either saline, GABA-reuptake inhibitor (NO-711), insulin-like growth factor-1 (IGF-1), ZVAD or thalidomide. Mechanical (using von Frey filaments) and thermal hypersensitivity (Hargreaves test) were assessed preoperatively and weekly during the first four postoperative weeks. Spinal cord dorsal horn samples were collected from animals that were sacrificed at 2 weeks and 4 weeks after surgery, and analyzed for TNFR1 and TNFR2 mRNA levels by qPCR and protein levels by Western blot. Compared to saline, all applied drug treatments resulted in a faster recovery from mechanical and thermal hypersensitivity, yet in a potency order of thalidomide > ZVAD = IGF-1 > NO-711. CCI resulted in increased TNFR1 and TNFR2 mRNA and protein levels in the ipsilateral dorsal horn. Thalidomide was the only treatment that attenuated these increases. Finally, animals that showed a poor behavioral recovery were characterized by a significantly higher TNFR1/TNFR2 mRNA ratio. These data show that differential expression of TNFR in the dorsal horn is associated with recovery from pain in this model and suggest that the analgesic effects of thalidomide may act via this mechanism.

Tourette syndrome is a chronic neuropsychiatric disorder characterized by motor and vocal tics. In the majority of cases, tics are associated by behavioral disorders such as obsessive-compulsive behavior. First symptoms typically appear in early childhood. Mostly symptoms disappear when adulthood is reached. Treatment options consist of behavioral therapy and medication. In refractory cases, surgery may be an option. In the past, several attempts have been made to treat therapy-refractory patients through neurosurgical ablative procedures. In 1999, deep brain stimulation was introduced as a novel treatment option for patients with intractable Tourette syndrome. Up until now, five brain areas have been used or suggested as potential target areas for deep brain stimulation in Tourette syndrome. In the majority of the published cases, there is a clear effect on tics but most studies consist of only a limited number of patients. A strict patient selection is absolutely mandatory. There is a need for double-blinded multicenter trials with inclusion of more patients.

Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinson's disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation-induced behavioral side effects, by using motor cortex stimulation.We describe the results of subthalamic nucleus neuronal responses to stimulation of the hand area of the motor cortex and evaluate the safety of this novel technique.Responses differed between regions within the subthalamic nucleus. In the anterior and lateral electrode at dorsal levels of the subthalamic nucleus, an early excitation (∼5-45 ms) and subsequent inhibition (45-105 ms) were seen. The lateral electrode also showed a late excitation (∼125-160 ms). Focal seizures were observed following motor cortex stimulation.To prevent seizures the current density should be lowered, so that motor cortex stimulation-evoked responses can be safely used during deep brain stimulation surgery.

Lumbar disc hernia (LDH) is a leading cause of chronic pain in adults. The underlying pathology of chronic pain after discectomy remains unclear. Chronic local inflammation is considered to underlie painful symptomatology. In this context, we investigated tumor necrosis factor (TNF)-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) expression at the time of surgery in LDH patients and correlated it with the severity of postoperative pain. We analyzed protein and mRNA levels from muscle, ligamentum flavum (LF), annulus fibrosus (AF), and nucleus pulposus (NP) in LDH patients and scoliosis patients (SP), who served as controls. Pain assessment with the visual analogue scale (VAS) was performed 1 day before surgery and 6 weeks and 12 months postoperatively. TNF-α protein levels were detected in AF, LF, and NP in all LDH patients, but not in SP. TNF-α mRNA was significantly greater in LDH patients than in SP; ie, 5-fold in AF, 3-fold in NP, and 2-fold in LF. For NP, TNF-α protein levels correlated with VAS scores (r = 0.54 at 6-week and r = 0.65 at 12-month follow-up). Also, TNFR1 protein levels in NP positively correlated with VAS scores (r = 0.75 at 6-week and r = 0.80 at 12-month follow-up). However, TNFR2 protein levels in AF negatively correlated with VAS scores (r = −0.60 at 6 weeks and r = −0.60 at 12 months follow-up). These data indicate that TNF-α levels could determine the clinical outcome in LDH patients after discectomy. Moreover, the opposite correlation of TNF receptors with pain sensation suggests that an unbalanced expression plays a role in the generation of pain.

Bilateral stimulation of the subthalamic nucleus (STN) is an accepted treatment for advanced Parkinson's disease (PD) refractory to medical therapy.1 Despite motor improvement, postoperative changes in mood and behaviour have been reported.2 Besides a direct influence of STN stimulation, other factors such as changes in medication and maladaptation to motor improvement might be involved. Here we report a PD patient successfully treated with bilateral STN stimulation but showing postoperative gradual worsening of psychological status. By using a single case experiment design (SCED) we tried to find out whether these problems were stimulation-related. The patient is a 56-year-old woman with a 13-year history of PD. Before surgery, (neuro)psychological evaluation was normal, besides a slight depressive elevation (Beck Depression Inventory (BDI) total score=13 with scores from 10 to 16 indicating mild depression).3 Psychiatric evaluation, however, revealed no psychopathology. The patient underwent a one-staged bilateral stereotactical implantation of electrodes4 and was discharged with stimulation at pole 1 monopolar, pulse width 90 μs, frequency 130 Hz, 1.5 V right and 1.2 V left. In the 20 months following surgery, stimulation was adjusted up to 3.0 V bilaterally, to optimise motor function. During follow-up at 3, 6 and 12 months postoperatively, the patient increasingly complained of various psychological symptoms including depression, …

International audience; Ten years ago deep brain stimulation (DBS) has been introduced as an alternative and promising treatment option for patients suffering from severe Tourette syndrome (TS). It seemed timely to develop a European guideline on DBS by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). For a narrative review a systematic literature search was conducted and expert opinions of the guidelines group contributed also to the suggestions. Of 63 patients reported so far in the literature 59 had a beneficial outcome following DBS with moderate to marked tic improvement. However, randomized controlled studies including a larger number of patients are still lacking. Although persistent serious adverse effects (AEs) have hardly been reported, surgery-related (e.g., bleeding, infection) as well as stimulation-related AEs (e.g., sedation, anxiety, altered mood, changes in sexual function) may occur. At present time, DBS in TS is still in its infancy. Due to both different legality and practical facilities in different European countries these guidelines, therefore, have to be understood as recommendations of experts. However, among the ESSTS working group on DBS in TS there is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients. It is highly recommended to perform DBS in the context of controlled trials.

A new consensus statement, written by an international panel of experts, seeks to standardize the use of neurosurgery for psychiatric disorders and to enhance patient safety. Although the approach is noble, some recommendations are overly conservative, whereas others might be more appropriate for regulatory authorities.

The nucleus accumbens (NAc) is gaining interest as a target for deep brain stimulation (DBS) in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. In animal models, it has been shown that DBS of the NAc changes impulsive action. Here, we tested the hypothesis that a change in impulsive action by DBS of the NAc is associated with changes in dopamine levels. Rats received stimulating electrodes either in the NAc core or shell, and underwent behavioral testing in a reaction time task. In addition, in a second experiment, the effect of DBS of the NAc core and shell on extracellular dopamine and serotonin levels was assessed in the NAc and medial prefrontal cortex. Control subjects received sham surgery. We have found that DBS of the NAc shell stimulation induced more impulsive action but less perseverative checking. These effects were associated with increased levels of dopamine and serotonin in the NAc, but not in the medial prefrontal cortex. DBS of the NAc core had no effect on impulsive action, but decreased perseverative responses indicative of a better impulse control. In these subjects, no effects were found on neurotransmitter levels. Our data point out that DBS of the NAc shell has negative effects on impulsive action which is accompanied by increases of dopamine and serotonin levels in the NAc, whereas DBS of the NAc core has beneficial behavioral effects.