The habenula in Parkinson's disease: Anatomy, function, and implications for mood disorders - A narrative review.

Parkinson's disease (PD), a widespread neurodegenerative disorder, often coexists with mood disorders. Degeneration of serotonergic neurons in brainstem raphe nuclei have been linked to depression and anxiety. Additionally, the locus coeruleus and its noradrenergic neurons are among the first areas to degenerate in PD and contribute to stress, emotional memory, motor, sensory, and autonomic symptoms. Another brain region of interest is habenula, which is especially related to anti-reward processing, and its function has recently been linked to PD and to mood-related symptoms. There are several neuroimaging studies that investigated role of the habenula in mood disorders. Differences in habenular size and hemispheric symmetry were found in healthy controls compared to individuals with mood disorders. The lateral habenula, as a link between the dopaminergic and serotonergic systems, is thought to contribute to depressive symptoms in PD. However, there is only one imaging study about role of habenula in mood disorders in PD, although the relationship between PD and mood disorders is known. There is little known about habenula pathology in PD but given these observations, the question arises whether habenular dysfunction could play a role in PD and the development of PD-related mood disorders. In this review, we evaluate neuroimaging techniques and studies that investigated the habenula in the context of PD and mood disorders. Future studies are important to understand habenula's role in PD patients with mood disorders. Thus, new potential diagnostic and treatment opportunities would be found for mood disorders in PD.

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.

The role of neurotransmitter systems in mediating deep brain stimulation effects in Parkinson's disease.

Deep brain stimulation (DBS) is among the most successful paradigms in both translational and reverse translational neuroscience. DBS has developed into a standard treatment for movement disorders such as Parkinson's disease (PD) in recent decades, however, specific mechanisms behind DBS's efficacy and side effects remain unrevealed. Several hypotheses have been proposed, including neuronal firing rate and pattern theories that emphasize the impact of DBS on local circuitry but detail distant electrophysiological readouts to a lesser extent. Furthermore, ample preclinical and clinical evidence indicates that DBS influences neurotransmitter dynamics in PD, particularly the effects of subthalamic nucleus (STN) DBS on striatal dopaminergic and glutamatergic systems; pallidum DBS on striatal dopaminergic and GABAergic systems; pedunculopontine nucleus DBS on cholinergic systems; and STN-DBS on locus coeruleus (LC) noradrenergic system. DBS has additionally been associated with mood-related side effects within brainstem serotoninergic systems in response to STN-DBS. Still, addressing the mechanisms of DBS on neurotransmitters' dynamics is commonly overlooked due to its practical difficulties in monitoring real-time changes in remote areas. Given that electrical stimulation alters neurotransmitter release in local and remote regions, it eventually exhibits changes in specific neuronal functions. Consequently, such changes lead to further modulation, synthesis, and release of neurotransmitters. This narrative review discusses the main neurotransmitter dynamics in PD and their role in mediating DBS effects from preclinical and clinical data.

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.

Surgical nuances and placement of subgaleal drains for supratentorial procedures-a prospective analysis of efficacy and outcome in 150 craniotomies.

BACKGROUND: For supratentorial craniotomy, surgical access, and closure technique, including placement of subgaleal drains, may vary considerably. The influence of surgical nuances on postoperative complications such as cerebrospinal fluid leakage or impaired wound healing overall remains largely unclear. With this study, we are reporting our experiences and the impact of our clinical routines on outcome in a prospectively collected data set. METHOD: We prospectively observed 150 consecutive patients undergoing supratentorial craniotomy and recorded technical variables (type/length of incision, size of craniotomy, technique of dural and skin closure, type of dressing, and placement of subgaleal drains). Outcome variables (subgaleal hematoma/CSF collection, periorbital edema, impairment of wound healing, infection, and need for operative revision) were recorded at time of discharge and at late follow-up. RESULTS: Early subgaleal fluid collection was observed in 36.7% (2.8% at the late follow-up), and impaired wound healing was recorded in 3.3% of all cases, with an overall need for operative revision of 6.7%. Neither usage of dural sealants, lack of watertight dural closure, and presence of subgaleal drains, nor type of skin closure or dressing influenced outcome. Curved incisions, larger craniotomy, and tumor size, however, were associated with an increase in early CSF or hematoma collection (p < 0.0001, p = 0.001, p < 0.01 resp.), and larger craniotomy size was associated with longer persistence of subgaleal fluid collections (p < 0.05). CONCLUSIONS: Based on our setting, individual surgical nuances such as the type of dural closure and the use of subgaleal drains resulted in a comparable complication rate and outcome. Subgaleal fluid collections were frequently observed after supratentorial procedures, irrespective of the closing technique employed, and resolve spontaneously in the majority of cases without significant sequelae. Our results are limited due to the observational nature in our single-center study and need to be validated by supportive prospective randomized design.

Effect of Intrastriatal 6-OHDA Lesions on Extrastriatal Brain Structures in the Mouse.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor and non-motor symptoms. The underlying pathology of non-motor symptoms is poorly understood. Discussed are pathological changes of extrastriatal brain structures. In this study, we characterized histopathological alterations of extrastriatal brain structures in the 6-hydroxydopamine (6-OHDA) PD animal model. Lesions were induced by unilateral stereotactic injections of 6-OHDA into the striatum or medial forebrain bundle of adult male mice. Loss of tyrosine hydroxylase positive (TH+) fibers as well as glia activation was quantified following stereological principles. Loss of dopaminergic innervation was further investigated by western-blotting. As expected, 6-OHDA injection into the nigrostriatal route induced retrograde degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc), less so within the ventral tegmental area. Furthermore, we observed a region-specific drop of TH+ projection fiber density in distinct cortical regions. This pathology was most pronounced in the cingulate- and motor cortex, whereas the piriform cortex was just modestly affected. Loss of cortical TH+ fibers was not paralleled by microglia or astrocyte activation. Our results demonstrate that the loss of dopaminergic neurons within the substantia nigra pars compacta is paralleled by a cortical dopaminergic denervation in the 6-OHDA model. This model serves as a valuable tool to investigate mechanisms operant during cortical pathology in PD patients. Further studies are needed to understand why cortical dopaminergic innervation is lost in this model, and what functional consequence is associated with the observed denervation.

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.

Deep brain stimulation of the rostromedial tegmental nucleus: An unanticipated, selective effect on food intake.

The rostromedial tegmental nucleus (RMTg) is a relatively newly described brainstem structure. The RMTg is extensively connected to both dopaminergic (DA) and serotoninergic key areas and it fulfills a pivotal role in the regulation of mesolimbic and nigrostriatal DA release. The RMTg may directly influence DA- and 5-HT associated motor and possibly also mood related behavior, the latter of which has not yet been well described. The current study explored the consequences of RMTg manipulation on DA- and 5-HT related behavior through the application of RMTg deep brain stimulation (DBS) with both high and low frequency stimulation (LFS and HFS). We used a wide array of motor and mood tests to assess changes in behavior. RMTg DBS did not change behavioral outcomes in the Skinner box task, nor in the Catwalk, the sucrose intake test, the open field test, the elevated zero maze, or the place preference test, but LFS did induce a significant decrease in food intake. This seems to be a selective effect as no motor or anxiety changes were observed that could lead to attenuated food intake. This finding not only underlines the RMTg's braking effect on the VTA, but possibly also on the forebrain, where GABA-ergic RMTg efferent may cause suppression of feeding in the lateral hypothalamus.

Deep Brain Stimulation of the Rat Subthalamic Nucleus Induced Inhibition of Median Raphe Serotonergic and Dopaminergic Neurotransmission.

AIM: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) relieves motor dysfunction in advanced Parkinson's disease (PD). However, STN DBS treated patients can experience unpleasant and debilitating psychiatric side effects such as depression and impulsivity. The neural basis of these psychiatric effects has been linked to a dysfunction of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission. STN DBS inhibited activity of 5-HT cell bodies in the dorsal raphe nucleus (DRN). Another important 5-HT source is located in the median raphe nucleus (MRN), which also contains a population of dopamine neurons. The effects of STN DBS on the MRN are unknown. Here, we test the hypothesis that STN DBS reduces 5-HT and dopaminergic function in the MRN, which may contribute to the psychiatric side effects of STN stimulation. MATERIAL AND METHODS: Bilateral STN DBS was applied in a freely moving rat model. Following STN DBS, rats were sacrificed and the brains were processed for c-Fos, 5-HT and tyrosine hydroxylase (TH) immunohistochemistry. RESULTS: We found that STN DBS significantly lowered c-Fos expression compared to non-stimulated controls indicating reduced neuronal activity. Moreover, the mean optical density values of 5-HT and TH cells in the MRN was significantly lower compared to controls. CONCLUSION: These results show that STN DBS inhibits 5-HT and dopamine neurotransmission in the MRN.

Current perspectives on deep brain stimulation for severe neurological and psychiatric disorders.

Deep brain stimulation (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 stimulation 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 including 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.

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.

Does probe's eye subthalamic nucleus length on T2W MRI correspond with microelectrode recording in patients with deep brain stimulation for advanced Parkinson's disease?

AIM: Subthalamic nucleus (STN) deep brain stimulation (DBS) has become a well-accepted treatment for patients with advanced Parkinson's disease (PD). During surgical planning for DBS, the length of the STN is taken into account and verified during microelectrode recording (MER) intraoperatively. Here, we addressed the question to which extent the length of the STN measured with the T2 weighted MRI in the probe's eye view corresponded with the intraoperatively determined length of the STN with MER. MATERIAL AND METHODS: We included 10 consecutive Parkinson's disease patients who underwent STN DBS surgery. The length of the STN in the probe's eye view mode was calculated along the trajectory of the central MER electrode crossing the STN. RESULTS: Our analysis showed no statistical difference between the length of the STN measured with the T2 weighted probe's eye view mode and the MER (right STN length 5.8 ± 0.9 mm MRI vs. 6.3 ± 0.5 mm MER, p > 0.05; left STN length 5.6 ± 0.4 mm MRI vs 5.8 ± 1 mm MER, p > 0.05). CONCLUSION: This means that the entry and the exit of the STN can be adequately estimated using the probe's eye view preoperatively.

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.

Motor and non-motor behaviour in experimental Huntington's disease.

In this study, we investigated motor and non-motor behaviour in the transgenic rat model of Huntington's disease (tgHD). In particular, we were interested in the development and changes of motor and non-motor features (anxiety, motivation and hedonia) of disease over time and their interactions. We found tgHD animals to be hyperkinetic in the open field test compared to their wild-type littermates at all ages tested, which was accompanied by reduced anxiety-like behaviour in the open field test and the elevated zero maze, but not in the home cage emergence test. No major changes were found in hedonia (sucrose intake test) and motivation for food (food intake test). Our data suggest that hyperkinetic features and reduced-anxiety in the tgHD rats are associated behaviours and are seen in the earlier stages of the disease.

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.

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.

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.