The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

The impact of physiological noise on hemodynamic-derived estimates of directed functional connectivity.

Measuring the strength of directed functional interactions between brain regions is fundamental to understand neural networks. Functional near-infrared spectroscopy (fNIRS) is a suitable method to map directed interactions between brain regions but is based on the neurovascular coupling. It, thus, relies on vasomotor reactivity and is potentially biased by non-neural physiological noise. To investigate the impact of physiological noise on fNIRS-based estimates of directed functional connectivity within the rostro-caudal hierarchical organization of the prefrontal cortex (PFC), we systematically assessed the effects of pathological perturbations of vasomotor reactivity and of externally triggered arterial blood pressure (aBP) fluctuations. Fifteen patients with unilateral stenosis of the internal carotid artery (ICA) underwent multi-channel fNIRS during rest and during metronomic breathing, inducing aBP oscillations at 0.1 Hz. Comparisons between the healthy and pathological hemispheres served as quasi-experimental manipulation of the neurovascular system's capability for vasomotor reactivity. Comparisons between rest and breathing served as experimental manipulation of two different levels of physiological noise that were expected to differ between healthy and pathological hemispheres. In the hemisphere affected by ICA stenosis, the rostro-caudal hierarchical organization of the PFC was compromised reflecting the pathological effect on the vascular and neural level. Breathing-induced aBP oscillations biased the magnitude of directed interactions in the PFC, but could be adjusted using either the aBP time series (intra-individual approach) or the aBP-induced fNIRS signal variance (inter-individual approach). Multi-channel fNIRS, hence, provides a sound basis for analyses of directed functional connectivity as potential bias due to physiological noise can be effectively controlled for.

Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development.

Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.