Marcus L.F. Janssen

Structural and Resting State Functional Connectivity of the Subthalamic Nucleus: Identification of Motor STN Parts and the Hyperdirect Pathway

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.

Hyperdopaminergic Status in Experimental Huntington Disease

Huntington disease has been linked to increased dopaminergic neurotransmission in the striatum, and clinical studies have demonstrated that the associated chorea can be treated with dopamine antagonist or dopamine-depleting drugs. The origin of this hyperdopaminergic status is unknown. Because substantia nigra pars compacta and the ventral tegmental area are the main sources of striatal dopamine input, we hypothesized that changes in these regions relate to striatal dopaminergic alterations. Here, in a recently generated transgenic rat Huntington disease model that shows progressive striatal neurodegeneration and chorea, we found evidence ofincreased dopamine levels in the striatum. We also demonstrate more dopaminergic cells in the substantia nigra pars compacta and ventral tegmental area in these rats. These results suggest that increased striatal dopamine comes from these 2 main nuclei, and that it is not necessarily related to shrinkage of the striatum. The findings implicate increased dopamine input from these nuclei in the pathogenesis of chorea in Huntington disease.

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 Huntingtons 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.

Subthalamic Nucleus High-Frequency Stimulation for Advanced Parkinson's Disease: Motor and Neuropsychological Outcome after 10 Years

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 Parkinsons 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 Parkinsons 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.

Automated gait analysis in bilateral parkinsonian rats and the role of L-DOPA therapy.

Gait disturbances and postural instability represent major sources of morbidity in Parkinsons disease (PD), and respond poorly to current treatment options. Some aspects of gait disturbances can be observed in rodent models of PD; however, knowledge regarding the stability of rodent gait patterns over time is lacking. Here we investigated the temporal constancy and reproducibility of gait patterns in neurologically intact and bilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, by using an automated quantitative gait analysis method (CatWalk). The bilateral neurotoxin injections into the medial forebrain bundle resulted in an average dopamine (DA) loss of 70% in each striata, which corresponds to the DA levels observed in moderate-mid stage human PD. Rats were tested weekly during one month, and we found that in intact rats all parameters investigated remained constant over multiple tests. The 6-OHDA lesioned rats were impaired in several aspects of gait, such as stride length, swing speed, stance duration, step cycle duration, and base of support. However the stance and step cycle deficits were transient, the performance of 6-OHDA lesioned rats were indistinguishable from control rats by the last test session with regard to these parameters. Finally, we found that administration of a single dose of levodopa (L-DOPA) to the 6-OHDA lesioned rats could counteract all but one observed deficits. Based on these findings we conclude that the gait pattern of intact rats is highly reproducible, 6-OHDA lesioned rats display impairments in gait, and L-DOPA can counteract most deficits seen in this model of experimental PD.

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 Parkinsons 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.

Changes in brainstem serotonergic and dopaminergic cell populations in experimental and clinical Huntington’s disease

The predominant motor symptom in Huntingtons disease (HD) is chorea. The patho-anatomical basis for the chorea is not well known, but a link with the dopaminergic system has been suggested by post-mortem and clinical studies. Our previous work revealed an increased number of dopamine-containing cells in the substantia nigra and ventral tegmental area in a transgenic rat model of HD (tgHD). Since there were no changes in the total number of cells in those regions, we hypothesized that changes in cell phenotype were taking place. Here, we tested this hypothesis by studying the dorsal raphe nucleus (DRN), which houses dopaminergic and non-dopaminergic (mainly serotonergic) neurons in tgHD rat tissue and postmortem HD human tissue. We found an increased number of dopamine and reduced number of serotonin-containing cells in the DRN of tgHD rats. Similar findings in postmortem HD brain tissue indicate that these changes also occur in patients. Further investigations in the tgHD animal tissue revealed the presence of dopaminergic cell bodies in the B6 raphe region, while in control animals exclusively serotonin-containing cells were found. These data suggest the existence of phenotype changes in monoaminergic neurons in the DRN in HD and shed new light on the neurobiology of clinical neurological symptoms such as chorea and mood changes.

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 Parkinsons 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.

Subthalamic neuronal responses to cortical stimulation

Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinsons 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.

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.