In der universitären Akut-Neurorehabilitation Inselspital (NREH) werden zur Zeit ausschliesslich Menschen mit akuten Hirnverletzungen rehabilitiert. Ab 2017 sollen zusätzlich Personen mit M. Parkinson (PmP) und neuer DeepBrainStimulation Implantation (DBS) während einer Dauer von maximal drei Wochen stationär rehabilitiert werden. Aktuell wird von circa 30 Personen pro Jahr ausgegangen. Die Rehabilitation dieser Patienten ist für alle Mitarbeiterinnen der Abteilung neu. Folglich ist die vertiefte Auseinandersetzung mit den Rollen und den Aufgaben der
The study included 79 participants subdivided into 4 groups. Patients with PD were divided into a PD- DBS group (DBS plus best medical treatment) and a PD-BMT group (best medical treatment only). The DBS group underwent deepbrainstimulation after the first testing. Patients received bilateral magnetic resonance (MR)-based, stereotactic DBS surgery. The optimum electrode position within the STN was as- sessed intraoperatively in the awake patient, applying macrostimulation to test for motor improvement and side effects. A small minority of PD patients with anx- iety disorder underwent DBS surgery under general anesthesia. Postoperative MR imaging (MRI) was used to exclude perioperative structural lesions and to reas- sure correct electrode position. Starting with standard DBS parameters (60 μs impulse duration at 130 Hz), the voltage was gradually increased over 1–2 weeks and stimulation parameters adjusted individually. In parallel, dopaminergic therapy was decreased gradu- ally [ 34 , 35 ]. Community-dwelling patients complain- ing of cognitive problems who came to the memory outpatient clinic for assessment of a possible cogni- tive disorder were included in the study. Mild cogni- tive impairment (MCI) was defined according to the Petersen criteria [ 32 ].
Aachen University, Aachen, Germany
Abstract: Deepbrainstimulation (DBS) has become a well-accepted therapy to treat movement disorders, including Parkinson’s disease, essential tremor, and dystonia. Long-term follow-up studies have demonstrated sustained improvement in motor symptoms and quality of life. DBS offers the opportunity to selectively modulate the targeted brain regions and related networks. Moreover, stimulation can be adjusted according to individual patients’ demands, and stimula- tion is reversible. This has led to the introduction of DBS as a treatment for further neurological and psychiatric disorders and many clinical studies investigating the efficacy of stimulating various brain regions in order to alleviate severe neurological or psychiatric disorders includ- ing epilepsy, major depression, and obsessive–compulsive disorder. In this review, we provide an overview of accepted and experimental indications for DBS therapy and the corresponding anatomical targets.
Since its introduction more than 25 years ago (Benabid et al. 1987 ), deepbrainstimulation (DBS) for movement disorders has become an efficient and widely used tool in the therapeutic armamentarium of various neurological conditions. Parkinson disease (PD), tremor, dystonia, epi- lepsy, and obsessive–compulsive disorder (OCD) are indications for treatment with deepbrainstimulation. Table 1 summarizes approved indications for each system. A typical DBS system consists of an electrode that is placed into the targeted cerebral structure, an implantable pulse generator (IPG), and an extension that connects the electrode to the IPG. The IPG itself consists of a case that houses a battery and electronic circuitry, which generates the electric signal going to the brain.
The basal ganglia (BG) are involved in gait. This notion is exemplified by observations that gait is disturbed by most diseases that affect the BG. However, it is unclear in what way the BG are activated during gait. One method to investigate the activity of the BG is to record local field potentials (LFPs) from electrodes placed in the BG for therapeutic purposes. Nowadays, the globus pallidus internum (GPi) represents the target for deepbrainstimulation (DBS) in dystonia. LFPs recorded from this area have been shown to delineate activity associated with dystonic cramps but also activity which may be relevant for certain types of movement. In this study we recorded LFPs from DBS electrodes implanted into the GPi of eight patients with dystonia during walking on a treadmill machine and compared these data with data acquired during rest (sitting and standing). There was no difference in the power of frequency bands during the sitting and standing conditions. LFP power in the theta (4-8 Hz), alpha (8-12 Hz) and gamma (60-90 Hz) frequency bands was higher during walking than during the resting conditions. Beta (15-25 Hz) frequencies were the only frequencies that were down-regulated during walking. The amplitude of the theta and alpha frequency bands was modulated during the gait cycle. These data shed light on the function of the BG in patients with dystonia and demonstrate that, during gait, their overall activity increases in a specific way without showing increases of narrow frequency bands.
For more than twenty years deepbrainstimulation (DBS) is being used in patients with movement disorders, predominantly in refractory Parkinson’s disease (PD) followed by dystonia and essential tremor (ET). More than 75.000 patients worldwide have undergone DBS ever since . In the last couple of years, new manufacturers have entered the market and DBS is currently under investigation for indications such as major depression, obsessive-compulsive disorder or epilepsy . All DBS systems include hand-held therapy controllers that patients obtain for home-use. With this technical device, patients are able to switch stimulation off and on, to in- or decrease it within a small range and to check the battery status of their implantable pulse generator (IPG). The latter is necessary in order to have invasive IPG exchange in time without therapy loss. Currently, the Medtronic Access controller is the most commonly used DBS patient controller. In practice, we observed that especially elderly patients refuse to use the controller or encounter some difficulties when they try to operate the device. However, to the best of our knowledge, no research has been done on the usability of DBS patient controllers.
Deepbrainstimulation (DBS) is an effective and widely used treatment option for various movement disorders such as Parkinson’s disease (PD), tremor, or dystonia( 1 , 2 ). Many efforts have been made to study the clinical side effects of chronic stimulation and the peri-procedural risks, also complications are well-characterized ( 3 – 7 ). However, there is limited data available on the potential damage to brain parenchyma through the implanted electrodes and leads in the course of DBS therapy. Histopathological autopsy studies on brains of DBS patients have been performed to assess the long-term structural effects of DBS electrodes and leads on brain tissue ( 8 – 13 ). The largest study, examining 26 post-mortem brains of DBS patients, showed only mild to moderate gliosis to DBS lead placement ( 13 ). Another study analyzed brain tissue of 10 patients treated with DBS up to 7.5 years and found minor axonal changes around the DBS electrode ( 14 ). Two retrospective studies analyzing postoperative MRI scans (with a maximum of 3 months after DBS surgery) have detected transient white matter changes, whose origin and significance remain uncertain ( 15 , 16 ). Englot and colleagues found T2 signal hyperintensity surrounding DBS leads on postoperative MRI scans in 6.3% of 239 implants in 133 patients ( 15 ). The changes were considered to be non-infectious and non- hemorrhagic, but instead as a reactive and inflammatory tissue response. They were considered to be transient in nature and could not be correlated to a clinical manifestation of symptoms or worsening of stimulation effects ( 15 , 16 ).
Keywords: Tourette syndrome, thalamus, deepbrainstimulation
Tourette syndrome (TS) is a complex chronic neu- ropsychiatric disorder characterized by motor and vo- cal tics. Motor tics are sudden, repetitive, stereotyped movements such as eye blinking, facial twitching, and head or shoulder movements, whereas vocal or phon- ic tics are sounds produced by moving air through the nose, mouth, or throat (e.g. coughing and throat clear- ing) as well as repeating syllables, words, or phras- es . TS typically has an onset in early childhood, and boys are more commonly affected than girls. Symp- toms usually start with transient bouts of simple motor tics. Tics can become more “complex” in nature and appear to be purposeful. A ﬂeeting feeling of relief often follows performance of a tic or a series of tics [2, 3]. Tics typically follow a waxing and waning pattern of severity, intensity, and frequency . Tic severi- ty usually peaks between 8 and 12 years of age, with many patients showing a marked reduction in severity by the end of adolescence [5–7]. Approximately 20% of children with TS continue to experience a moder-
(COMT) inhibitors are another recommended medication for PD. They can be applied for the later stages of the disease. Blocking the COMT enzyme prevents the breakdown of L-Dopa, and therefore, helps L-Dopa to last longer. Nonetheless, sometimes, in particular in late stages of PD, medications would lose their efficacy and the patient has to undergo a surgery. Two surgical approaches, which are generally used for PD, are Pallidotomy and Thalamotomy (Utter & Basso, 2008; Benabid et al., 1987; Miocinovic et al., 2013; Speelman & Bosch, 1998). In Pallidotomy, the hyperactive Globus Pallidus (GP) is taken away by surgical possess. The permanent GP removal helps in returning the balance to brain motor circuit. It eliminates rigidity and significantly reduces tremor, bradykinesia, and balance problems. In Thalamotomy, some parts of the thalamus, which are believed to be involved in passing the impaired motor commands from BG to the cortex, are removed by surgical process. Removing these parts of the thalamus, solely, alleviates the tremor and shaking problem (Duval et al., 2005). Because of the narrowed therapeutic effect on PD (just for tremor) (Duval et al., 2005), Thalamotomy is not the most recommended surgery for PD patients. In addition, it is notable that even though Thalamotomy and Pallidotomy are still applied in clinics, because of the high risk of after surgery side effects, they are the least frequent treatments for PD. However, another type of surgery which is called deepbrainstimulation has been found to be much safer and has much fewer side effects. It was first developed in the 1980s and since then has become the most prevalent treatment especially for the late stage PD (Benabid et al., 1987; Benabid, 2003; Benabid & Torres, 2012; Miocinovic et al., 2013).
In the following, the main resulting scientific issues and clinical applications will be addressed. First, one can conclude that more studies assessing the role of dopamine and deepbrainstimulation on motor learning in Parkinson’s disease are needed as there is a gap in literature for this topic. Therapeutic implications could arise from future work in this field: for example, in a cross-over design one could investigate the role of DBS in retention of motor learning, which would be relevant for enhancing rehabilitative processes to improve activities of daily living. Second, this study highlights the utility of connectomics to understand function of targeted networks and mechanisms of DBS. This methodology has been gaining relevance in the past years, as it is not invasive and increasingly accessible. Future studies should investigate the role of network modulation of individual connectivity profiles through DBS and associated changes in movement kinematics and cognitive aspects of movement execution in Parkinson’s disease. To this end, Parkinson’s disease patients could perform the visuomotor task as described in Neumann et al., 2018 and undergo fMRI scans on and off DBS. Third, investigating the functionality of neural circuits and networks is highly relevant to optimise targeted treatments such as deepbrainstimulation. With increasing quality of clinically available MRI scans, DBS targets may be chosen based on connectivity measures relating to circuit connections. Furthermore, the long-term goal would be to adapt stimulation to “real-time” necessities in a closed loop fashion either by becoming active only when needed or even by switching active contacts depending on the required circuit modulation. To transfer these concepts to current practice, more research is required.
Keywords: Tourette syndrome, thalamus, deepbrainstimulation
Tourette syndrome (TS) is a complex chronic neu- ropsychiatric disorder characterized by motor and vo- cal tics. Motor tics are sudden, repetitive, stereotyped movements such as eye blinking, facial twitching, and head or shoulder movements, whereas vocal or phon- ic tics are sounds produced by moving air through the nose, mouth, or throat (e.g. coughing and throat clear- ing) as well as repeating syllables, words, or phras- es . TS typically has an onset in early childhood, and boys are more commonly affected than girls. Symp- toms usually start with transient bouts of simple motor tics. Tics can become more “complex” in nature and appear to be purposeful. A fleeting feeling of relief often follows performance of a tic or a series of tics [2, 3]. Tics typically follow a waxing and waning pattern of severity, intensity, and frequency . Tic severi- ty usually peaks between 8 and 12 years of age, with many patients showing a marked reduction in severity by the end of adolescence [5–7]. Approximately 20% of children with TS continue to experience a moder-
Currently available treatment methods for major depression (MD) and schizophrenia (SZ) yield unsatisfactory results and as a consequence, a considerable portion of patients remains therapy- resistant. Conceptualization of psychiatric disorders as representations of dysfunctional neural networks has led to investigating new causal therapeutic interventions such as deepbrainstimulation (DBS), an approach that has been granted a humanitarian device exemption for severe obsessive-compulsive disorder and is tested for MD and SZ. Despite initial promising findings, recent trials for antidepressant DBS showed no efficacy warranting further research, including preclinical studies, to improve DBS settings. This thesis aimed to elucidate optimal DBS targets and parameters on anti-depressant efficacy and to test a preventive approach of DBS application in the context of SZ using valid rat models of both dysfunctions: i) Chronic-
Deepbrainstimulation (DBS) of the subthalamic nucleus is an established treatment for severe motor complications in Parkinson dis- ease (PD), and since it is usually a lifelong therapy, it is essential to carefully evaluate beneficial and inadvertent effects in the long term. Studies demonstrate a remarkable improvement of motor symptoms in PD patients, whereas psychosocial impacts of DBS surgery includ- ing social adjustment, coping strategies, and mental health –related quality of life may be variable. 1-4 It is particularly difficult to determine
The aim of the studies was to establish a methodological framework for connectomic analyses in the context of deepbrainstimulation. Both fields of study – connectomic analyses and deepbrainstimulation – require a substantial amount of expertise and methodological skills. Until now, to the best of our knowledge, no software package is available that covers both fields of study and focuses on the combination of DBS with connectomics. The final goal of the three studies that led to this dissertation was to establish such a framework and an accompanying software package. The result was published as the software Lead DBS and its first extension Lead Connectome online under www.lead-dbs.org. To gather the necessary expertise in both fields of study, in a first step, a connectomic analysis-framework was established in two consecutive studies that focused on i) the combined analysis of structural and functional connectivity and ii) on the estimation of a structural- functional group connectome in MNI space. In parallel, the second aim was covered by a third study that aimed at precisely locating DBS electrode placement based on postoperative magnetic resonance or computed tomography imaging. This last study laid the groundwork for Lead DBS, whereas the methodology established in the first two studies was integrated into Lead DBS via the extension Lead Connectome. Methodologies from both fields of study are now freely available to the broader scientific community in a seamlessly integrated software package that is based on the MATLAB programming environment (the Mathworks, MA, USA).
programming the electric current applied to the brain. Loss of therapeutic efficacy may occur due to hardware failures in DBS systems. DBS systems are challenging to troubleshoot, and the underlying error is not always clear. Our group at the Medical University of Vienna worked on the development of a new troubleshooting tool, called surface electrography (SEG). The underlying principle of SEG is the measurement of the voltage between two electrodes on the patient. The electrodes are connected to an oscilloscope, which plots a curve of the recorded voltage against time. This work focuses on exploring the value of SEG in a test bench setting by simulating various hardware failures and comparing the results to reference patient data. The parameters are evaluated in regard to changes in the recorded signal compared to baseline measurements of the intact DBS system. Five parameters were found helpful in diagnosing the recorded signal; the unipolar voltage-amplitude, the curve shape, the bipolar signal, the header contact signal, and the signal stability. It was
The efficacy of vmPFC-DBS to affect depressive- and anhedonia-like behavior was tested, as well as its reward-manipulating potential. In the FST, 2-way ANOVA showed an effect for treatment (F (1,20) =7.448, p<0.05), while phenotype had no effect (F (1,20) =2.8712, p=0.106) and phenotype ✕ treatment interaction did not reach significance (F (1,20) =3.324, p=0.086). As for the SCT, there was a main effect for stimulation (F (1,20) =10.75, p<0.05). Phenotype had no effect (F (1,20) =0.166, p=0.688) and no interaction was found between both factors (F (1,20) =0.11, p=0.743) (Fig. 3). A 2x6 ANOVA on threshold shift data showed a main effect for treatment (F (5,35) =36.483, p<0.001) but not for phenotype (F (5,35) =2.073, p=0.193) and there was no interaction between factors (F (5,35) =1.191, p=0.334) (Fig. 4). Holm-Sidak post hoc analysis revealed a left shift of the R/F function after D-amph treatment in FSL and FRL when compared to all other treatments (p<0.05). There was no significant curve shift with any other treatment.
DBS therapy consists of chronic local electrical stimulation of discrete brain targets through an implanted wire bundle electrode with multiple contacts and a small implanted subcutaneous, externally programmable pulse generator. The primary targets for DBS in PD are specific regions of the STN, GPi or the ventral striatum. During DBS surgery, electrodes are stereotactically placed into the brain, guided by neuroimaging and/or electrophysiological recording. These electrodes contain four separate contacts, spaced 0.5– 1.5 mm apart along their distal end. An internal pulse generator, which is similar to a cardiac pacemaker, is simultaneously or subsequently implanted, usually in the subclavicular region, and connected to the electrode (Bronstein et al., 2011). In bilateral DBS, two independent single-channel stimulators or a single dual-channel stimulator can be used. Multi-site DBS lead implantations can be done during single surgical sessions or as staged procedures. Different aspects of the stimulation can be controlled via telemetric adjustments of the pulse generator, including the choice of electrode contacts, the stimulation voltage or current, the width of the stimulation pulses, and the frequency of stimulation. The stimulation parameters vary between patients, stimulation targets and specific disorders, but typically, pulses are delivered at 60–185 Hz, with an amplitude of less than 4 V, and a pulse width between 60 and 200 µs (Wichmann & DeLong, 2016; Elias et al., 2007; Hristova et al., 2000).
through keeping nerve cell excitation and inhibition in balance (Boulanger 2009). When the abnormal secretion of cytokines appears, it could, for instance, lead to an interruption in this normal neuroplastic function or an imbalance of this regulation as well as neurogenesis. Considering the characteristics of the maternal Poly(I:C) injection model, which only show schizophrenic-like behavior in adult offspring (Vuillermot et al. 2010), such inconsistency between cell density and cytokine productions could be explained by the variations in age. The animals sacrificed for cytokine testing (PND 90) were much younger than those sacrificed for cell counting (PND 120). Furthermore, our previous study confirmed that the production of TNF-α and IL-1β derived from microglia, in the PND 128, was enhanced in the Poly(I:C) offspring in microglia sorted from the hippocampus (Mattei et al. 2014). Also these rats were older than the ones we used for cytokine measures. There is a possibility that age might have an effect. It is also worth noting that microglia are not the only source of inflammatory cytokines，peripheral cytokines crossing blood-brain barrier (BBB); activation of astrocytes and dendritic cells entering brain tissue under CNS inflammatory conditions can contribute to the upregulation of cytokines as well (Geissmann et al. 2010).
The identification of universal and orthography-specific dyslexic brain activation abnormalities has the potential to substantially improve and extend our neurobiological under- standing of developmental dyslexia [Frost, 2012]. So far, most neurocognitive models of developmental dyslexia [e.g., Demonet et al., 2004; McCandliss and Noble, 2003; Pugh et al., 2001; Sandak et al., 2004] are based on findings from English-language studies. In light of this Anglo-centric research, Share  pointed to the extreme ambiguity of the English spelling-sound correspondence and critically emphasized the significant influence of this “outlier” orthog- raphy on previous theoretical conceptualizations of reading and dyslexia. Therefore, it is of specific interest whether these previous findings of functional brain abnormalities can be generalized to dyslexic readers of other, more regular orthog- raphies. Besides the high relevance for the research domain, this topic is all the more relevant for practice. That is, differ- ent neurobiological manifestations of dyslexia in DO and SO would have an impact on the identification of at-risk chil- dren, prevention, diagnosis, and remediation.
In contrast, bottom-up or sensory stimulation treatments need less conscious awareness about the deficits on hand, forcing up their effectiveness in neglect therapy settings. They are consistent with the view of neglect as a multimodal disorder resulting from a disturbed representation of multimodal spatial coordinates and a common spatial reference frame (Karnath, 1994a; Karnath & Dieterich, 2006; Kerkhoff & Schenk, 2012; Kerkhoff, 2001; Kerkhoff, 2003). This reference frame is assumed to be constituted by different sensory inputs, i.e. visual and auditory inputs, motor efference copies, eye and neck muscle proprioceptive and vestibular information, which are transformed in a multimodal, higher order space representation including the own body in relation to the exterior surrounding field. According to the authors, it is hypothesized to be anatomically represented in the multisensory superior temporal cortex, the temporo-parietal junction as well as the insular cortex (Karnath & Dieterich, 2006; Bottini et al., 2001), whereas damage to these areas is mostly associated with neglect symptoms. As these different sensory inputs are injected into that multisensory spatial frame, changing the “weight” of specific sensory inputs by specific manipulations can be utilized to improve neglect associated deficits by correcting this disturbed reference frame in neglect (Kerkhoff, 2001). Based on this assumption, bottom-up sensory stimulation techniques are capable to ameliorate multimodal deficits even in a crossmodal way (see below).