Over the last decades, extensive basic and clinical knowledge has been acquired on the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease (PD). It is now clear that mechanisms involved in the effects of this therapy are far more complex than previously anticipated. At frequencies commonly used in clinical practice, neural elements may be excited or inhibited and novel dynamic states of equilibrium are reached. Electrode contacts used for chronic DBS in PD are placed near the dorsal border of the nucleus, a highly cellular region. DBS may thus exert its effects by modulating these cells, hyperdirect projections from motor cortical areas, afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques may allow us to identify these structures optimizing surgical targeting. In this review, we provide an update on mechanisms and the neural elements modulated by STN DBS.

Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive-like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN.

A promising direction in the research on Alzheimer’s Disease (AD) is the identification of biomarkers that better inform the disease progression of AD. However, the performance of amyloid-based biomarkers in predicting cognitive performance has been shown to be suboptimal. We hypothesise that neuronal loss could better inform cognitive impairment. We have utilised the 5xFAD transgenic mouse model that displays AD pathology at an early phase, already fully manifested after 6 months. We have evaluated the relationships between cognitive impairment, amyloid deposition, and neuronal loss in the hippocampus in both male and female mice. We observed the onset of disease characterized by the emergence of cognitive impairment in 6-month-old 5xFAD mice coinciding with the emergence of neuronal loss in the subiculum, but not amyloid pathology. We also showed that female mice exhibited significantly increased amyloid deposition in the hippocampus and entorhinal cortex, highlighting sex-related differences in the amyloid pathology of this model. Therefore, parameters based on neuronal loss might more accurately reflect disease onset and progression compared to amyloid-based biomarkers in AD patients. Moreover, sex-related differences should be considered in studies involving 5xFAD mouse models.

Deep brain stimulation is a treatment for Parkinson’s disease and other related disorders, involving the surgical placement of electrodes in the deeply situated basal ganglia or thalamic structures. Good clinical outcome requires accurate targeting. However, due to limited visibility of the target structures on routine clinical MR images, direct targeting of structures can be challenging. Non-clinical MR scanners with ultra-high magnetic field (7T or higher) have the potential to improve the quality of these images. This technology report provides an overview of the current possibilities of visualizing deep brain stimulation targets and their related structures with the aid of ultra-high field MRI. Reviewed studies showed improved resolution, contrast- and signal-to-noise ratios at ultra-high field. Sequences sensitive to magnetic susceptibility such as T2* and susceptibility weighted imaging and their maps in general showed the best visualization of target structures, including a separation between the subthalamic nucleus and the substantia nigra, the lamina pallidi medialis and lamina pallidi incompleta within the globus pallidus and substructures of the thalamus, including the ventral intermediate nucleus (Vim). This shows that the visibility, identification and even subdivision of the small deep brain stimulation targets benefit from increased field strength. Although ultra-high field MR imaging is associated with increased risk of geometrical distortions, it has been shown that these distortions can be avoided or corrected to the extent where the effects are limited. The availability of ultra-high field MR scanners for humans seems to provide opportunities for a more accurate targeting for deep brain stimulation in patients with Parkinson’s disease and related disorders.