Incidence and Management of Hardware-Related Wound Infections in Spinal Cord, Peripheral Nerve Field, and Deep Brain Stimulation Surgery: A Single-Center Study.

INTRODUCTION: Neuromodulation using deep brain stimulation (DBS), spinal cord stimulation (SCS), and peripheral nerve field stimulation (PNFS) to treat neurological, psychiatric, and pain disorders is a rapidly growing field. Infections related to the implanted hardware are among the most common complications and result in health-related and economic burden. Unfortunately, conservative medical therapy is less likely to be successful. In this retrospective study, we aimed to identify characteristics of the infections and investigated surgical and antimicrobial treatments. METHODS: A retrospective analysis was performed of patients with an infection related to DBS, SCS, and/or PNFS hardware over an 8-year period at our institution. Data were analyzed for type of neurostimulator, time of onset of infection following the neurosurgical procedure, location, and surgical treatment strategy. Surgical treatment of infections consisted of either a surgical wound revision without hardware removal or a surgical wound revision with partial or complete hardware removal. Data were further analyzed for the microorganisms involved, antimicrobial treatment and its duration, and clinical outcome. RESULTS: Over an 8-year period, a total of 1,250 DBS, 1,835 SCS, and 731 PNFS surgeries were performed including de novo system implantations, implanted pulse generator (IPG) replacements, and revisions. We identified 82 patients with infections related to the neurostimulator hardware, representing an incidence of 3.09% of the procedures. Seventy-one percent of the patients had undergone multiple surgeries related to the neurostimulator prior to the infection. The infections occurred after a mean of 12.2 months after the initial surgery. The site of infection was most commonly around the IPG, especially in DBS and SCS. The majority (62.2%) was treated by surgical wound revision with simultaneous partial or complete removal of hardware. Microbiological specimens predominantly yielded Staphylococcus epidermidis (39.0%) and Staphylococcus aureus (35.4%). After surgery, antimicrobials were given for a mean of 3.4 weeks. The antimicrobial regime was significantly shorter in patients with hardware removal in comparison to those who only had undergone surgical wound revision. One intracranial abscess occurred. No cases of infection-related death, sepsis, bacteremia, or intraspinal abscesses were found. CONCLUSION: Our data did show the predominance of S. epidermidis and S. aureus as etiologic organisms in hardware-related infections. Infections associated with S. aureus most likely required (partial) hardware removal. Aggressive surgical treatment including hardware removal shortens the duration of antimicrobial treatment. Clear strategies should be developed to treat hardware-related infections to optimize patient management and reduce health- and economic-related burden.

High-frequency stimulation of the subthalamic nucleus induces a sustained inhibition of serotonergic system via loss of cell phenotype.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment for Parkinson's disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters' homeostasis in neurons, which is known as "neurotransmitter respecification". Herein, we addressed if neurotransmitter respecification could be a mechanism by which DBS suppresses the serotonergic function in the dorsal raphe nucleus (DRN) leading to mood changes. We infused transgenic 5-HT-Cre (ePET-Cre) mice with AAV viruses to achieve targeted expression of eYFP and the genetically encoded calcium indicator GCaMP6s in the DRN prior to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Mice received bilateral DBS electrodes in the STN and an optic fiber in the DRN for calcium photometry. MPTP-treated mice demonstrated behavioral and histological PD phenotype, whereas all STN-DBS animals exhibited an increased immobility time in the forced swim test, reduced calcium activity, and loss of tryptophan hydroxylase-2 expression in the DRN. Given the prominent role of calcium transients in mediating neurotransmitter respecification, these results suggest a loss of serotonergic phenotype in the DRN following STN-DBS. These findings indicate that loss of serotonergic cell phenotype may underlie the unwanted depressive symptoms following STN-DBS.

High-frequency stimulation of the subthalamic nucleus modulates neuronal activity in the lateral habenula nucleus.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is often used to treat movement disability in advanced Parkinson's disease, but some patients experience debilitating psychiatric effects including depression. Interestingly, HFS of the STN modulates 5-HT neurons in the dorsal raphe nucleus (DRN) which are linked to depression, but the neural substrate of this effect is unknown. Here, we tested the effect of STN stimulation on neuronal activity in the lateral habenula nucleus (LHb), an important source of input to DRN 5-HT neurons and also a key controller of emotive behaviours. LHb neurons were monitored in anaesthetized rats using single-unit extracellular recording, and localization within the LHb was confirmed by juxtacellular labelling. HFS of the STN (130 Hz) evoked rapid changes in the firing rate of the majority of LHb neurons tested (38 of 68). Some LHb neurons (19/68) were activated by HFS, while others (19/68), distinguished by a higher basal firing rate, were inhibited. LHb neurons that project to the DRN were identified using antidromic activation and collision testing (n = 17 neurons). Some of these neurons (5/17) were also excited by HFS of the STN, and others (7/17) were inhibited although this was only a statistical trend. In summary, HFS of the STN modulated the firing of LHb neurons, including those projecting to the DRN. The data identify that the STN impacts on the LHb-DRN pathway. Moreover, this pathway may be part of the circuitry mediating the psychiatric effects of STN stimulation experienced by patients with Parkinson's disease.

Changes in 5-HT2A receptor expression in untreated, de novo patients with Parkinson's disease.

BACKGROUND: Serotonin (5-HT) has long been implied in the pathophysiology of Parkinson's disease (PD). In addition, the 5-HT2A receptor is associated with the regulation of motor function and mood. OBJECTIVE: To assess regional 5-HT2A receptor expression in unmedicated patients with de novo PD. METHODS: Eight de novo, drug naïve patients with PD and eight healthy control subjects underwent a single photon emission computed tomography (SPECT) scan with the highly selective 5-HT2A radioligand 123I-5-I-R91150. RESULTS: In de novo PD patients 5-HT2A receptor binding was significantly reduced in the anterior striatum and the premotor cortex in PD patients compared to controls. In addition, occipital binding was elevated in PD patients. No changes in 5-HT2A receptor binding were found in the prefrontal and parietal cortex. CONCLUSION: In de novo PD patients, 5-HT2A receptor expression is changed in key areas of the basal ganglia-thalamocortical motor circuit and occipital cortex. This suggests altered 5-HT neurotransmission to contribute to development of PD motor and non-motor symptoms.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: Why so successful?

The subthalamic nucleus (STN), historically referred to as the corpus Luysii, is a relatively small nucleus located in the junction between the diencephalon and midbrain. An important discovery was made in the late 1980s by Miller and DeLong putting the focus on the STN demonstrating abnormal hyperactivity in this area in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated non-human primates. Shortly after, Benazzouz and colleagues showed STN deep brain stimulation (DBS) to significantly improve MPTP induced parkinsonian symptoms, including rigidity and bradykinesia in monkeys. In the same year, Pollak et al. were the first to publish a French case report describing the potential of STN DBS in a patient with advanced Parkinson's disease (PD) in whom they observed improvement of akinesia. Many other prospective studies showed similar improvements of motor symptoms and the lowering of required levodopa dosage. The great success of STN DBS for the treatment of advanced PD is underlined by the growing number of patients treated. STN DBS also provided additional insight into the role of the STN, which is important not only in motor control but also in cognitive and emotional functions.

Neuromodulation in psychiatric disorders.

Psychiatric disorders are worldwide a common cause of severe and long-term disability and socioeconomic burden. The management of patients with psychiatric disorders consists of drug therapy and/or psychotherapy. However, in some patients, these treatment modalities do not produce sufficient therapeutic effects or induce intolerable side effects. For these patients, neuromodulation has been suggested as a potential treatment modality. Neuromodulation includes deep brain stimulation, vagal nerve stimulation, and transcranial magnetic and electrical stimulation. The rationale for neuromodulation is derived from the research identifying neurobiologically localized substrates for refractory psychiatric symptoms. Here, we review the clinical data on neuromodulation in the major psychiatric disorders. Relevant data from animal models will also be discussed to explain the neurobiological basis of the therapy.

Mild dopaminergic lesions are accompanied by robust changes in subthalamic nucleus activity.

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.

A combined in vivo neurochemical and electrophysiological analysis of the effect of high-frequency stimulation of the subthalamic nucleus 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.

High frequency stimulation of the subthalamic nucleus increases c-fos immunoreactivity in the dorsal raphe nucleus and afferent brain regions.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is the neurosurgical therapy of choice for the management of motor deficits in patients with advanced Parkinson's disease, but this treatment can elicit disabling mood changes. Our recent experiments show that in rats, HFS of the STN both inhibits the firing of 5-HT (5-hydroxytryptamine; serotonin) neurons in the dorsal raphe nucleus (DRN) and elicits 5-HT-dependent behavioral effects. The neural circuitry underpinning these effects is unknown. Here we investigated in the dopamine-denervated rat the effect of bilateral HFS of the STN on markers of neuronal activity in the DRN as well as DRN input regions. Controls were sham-stimulated rats. HFS of the STN elicited changes in two 5-HT-sensitive behavioral tests. Specifically, HFS increased immobility in the forced swim test and increased interaction in a social interaction task. HFS of the STN at the same stimulation parameters, increased c-fos immunoreactivity in the DRN, and decreased cytochrome C oxidase activity in this region. The increase in c-fos immunoreactivity occurred in DRN neurons immunopositive for the GABA marker parvalbumin. HFS of the STN also increased the number of c-fos immunoreactive cells in the lateral habenula nucleus, medial prefrontal cortex but not significantly in the substantia nigra. Collectively, these findings support a role for circuitry involving DRN GABA neurons, as well as DRN afferents from the lateral habenula nucleus and medial prefrontal cortex, in the mood effects of HFS of the STN.

Cerebellar nuclei are activated by high-frequency stimulation of the subthalamic nucleus.

The cerebellum, primarily considered a pure motor structure, is increasingly considered to play a role in behaviour and cognition. In a similar manner, there is increasing evidence that the basal ganglia are involved in non-motor processes. Recently a direct connection between the cerebellum and the basal ganglia has been shown to exist. High-frequency stimulation (HFS) of the subthalamic nucleus (STN) has become an accepted treatment in advanced Parkinson's disease (PD). We performed HFS of the STN in rats to evaluate the neuronal activation in the deep cerebellar nuclei (DCbN) using c-Fos immunohistochemistry. We found an increased c-Fos expression in the DCbN. Previously, we have shown that STN HFS in rats leads to decreased impulsive behaviour and our findings now suggest a link with increased DCbN activity. This is in line with our previous work showing that decreased DCbN activity is accompanied by disruptive behaviour. We suggest that the DCbN play a role in the selection of relevant information on which a behavioural response is based. The connection between the cerebellum and the basal ganglia may imply a role for the cerebellum in behavioural aspects of disorders of the basal ganglia.

Serotonin-dependent depression in Parkinson's disease: a role for the subthalamic nucleus?

Depression is the most common neuropsychiatric co-morbidity in Parkinson's disease (PD). The underlying mechanism of depression in PD is complex and likely involves biological, psychosocial and therapeutic factors. The biological mechanism may involve changes in monoamine systems, in particular the serotonergic (5-hydroxytryptamine, 5-HT) system. It is well established that the 5-HT system is markedly affected in the Parkinsonian brain, with evidence including pathological loss of markers of 5-HT axons as well as cell bodies in the dorsal and median raphe nuclei of the midbrain. However, it remains unresolved whether alterations to the 5-HT system alone are sufficient to confer vulnerability to depression. Here we propose low 5-HT combined with altered network activity within the basal ganglia as critically involved in depression in PD. The latter hypothesis is derived from a number of recent findings that highlight the close interaction between the basal ganglia and the 5-HT system, not only in motor but also limbic functions. These findings include evidence that clinical depression is a side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN), a treatment option in advanced PD. Further, it has recently been demonstrated that STN DBS in animal models inhibits 5-HT neurotransmission, and that this change may underpin depressive-like side effects. This review provides an overview of 5-HT alterations in PD and a discussion of how these changes might combine with altered basal ganglia network activity to increase depression vulnerability.

The subthalamic nucleus: From response selection to execution.

The involvement of the subthalamic nucleus in physiological and pathological motor behaviour has now largely been established. Clinical observations in patients suffering from Parkinson disease treated with Deep Brain Stimulation of the STN show that these patients can suffer from postoperative changes in non-motor behaviour mainly involving alterations in cognitive functions. The involvement of the STN in cognition has initially been demonstrated by non-human studies investigating the effects of STN lesions and stimulations on cognitive parameters. In the present review, we discuss the findings of these preclinical studies on cognitive parameters and outline the anatomical and functional place of the STN in the basal ganglia cognitive circuit.