Deep brain stimulation of the central thalamus restores arousal and motivation in a zolpidem-responsive patient with akinetic mutism after severe brain injury.

After severe brain injury, zolpidem is known to cause spectacular, often short-lived, restorations of brain functions in a small subgroup of patients. Previously, we showed that these zolpidem-induced neurological recoveries can be paralleled by significant changes in functional connectivity throughout the brain. Deep brain stimulation (DBS) is a neurosurgical intervention known to modulate functional connectivity in a wide variety of neurological disorders. In this study, we used DBS to restore arousal and motivation in a zolpidem-responsive patient with severe brain injury and a concomitant disorder of diminished motivation, more than 10 years after surviving hypoxic ischemia. We found that DBS of the central thalamus, targeted at the centromedian-parafascicular complex, immediately restored arousal and was able to transition the patient from a state of deep sleep to full wakefulness. Moreover, DBS was associated with temporary restoration of communication and ability to walk and eat in an otherwise wheelchair-bound and mute patient. With the use of magnetoencephalography (MEG), we revealed that DBS was generally associated with a marked decrease in aberrantly high levels of functional connectivity throughout the brain, mimicking the effects of zolpidem. These results imply that 'pathological hyperconnectivity' after severe brain injury can be associated with reduced arousal and behavioral performance and that DBS is able to modulate connectivity towards a 'healthier baseline' with lower synchronization, and, can restore functional brain networks long after severe brain injury. The presence of hyperconnectivity after brain injury may be a possible future marker for a patient's responsiveness for restorative interventions, such as DBS, and suggests that lower degrees of overall brain synchronization may be conducive to cognition and behavioral responsiveness.

Magnetoencephalography to measure the effect of contact point-specific deep brain stimulation in Parkinson's disease: A proof of concept study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for disabling fluctuations in motor symptoms in Parkinson's disease (PD) patients. However, iterative exploration of all individual contact points (four in each STN) by the clinician for optimal clinical effects may take months. OBJECTIVE: In this proof of concept study we explored whether magnetoencephalography (MEG) has the potential to noninvasively measure the effects of changing the active contact point of STN-DBS on spectral power and functional connectivity in PD patients, with the ultimate aim to aid in the process of selecting the optimal contact point, and perhaps reduce the time to achieve optimal stimulation settings. METHODS: The study included 30 PD patients who had undergone bilateral DBS of the STN. MEG was recorded during stimulation of each of the eight contact points separately (four on each side). Each stimulation position was projected on a vector running through the longitudinal axis of the STN, leading to one scalar value indicating a more dorsolateral or ventromedial contact point position. Using linear mixed models, the stimulation positions were correlated with band-specific absolute spectral power and functional connectivity of i) the motor cortex ipsilateral tot the stimulated side, ii) the whole brain. RESULTS: At group level, more dorsolateral stimulation was associated with lower low-beta absolute band power in the ipsilateral motor cortex (p = .019). More ventromedial stimulation was associated with higher whole-brain absolute delta (p = .001) and theta (p = .005) power, as well as higher whole-brain theta band functional connectivity (p = .040). At the level of the individual patient, switching the active contact point caused significant changes in spectral power, but the results were highly variable. CONCLUSIONS: We demonstrate for the first time that stimulation of the dorsolateral (motor) STN in PD patients is associated with lower low-beta power values in the motor cortex. Furthermore, our group-level data show that the location of the active contact point correlates with whole-brain brain activity and connectivity. As results in individual patients were quite variable, it remains unclear if MEG is useful in the selection of the optimal DBS contact point.

Cortical and Subcortical Changes in MEG Activity Reflect Parkinson's Progression over a Period of 7 Years.

In this study of early functional changes in Parkinson's disease (PD), we aimed to provide a comprehensive assessment of the development of changes in both cortical and subcortical neurophysiological brain activity, including their association with clinical measures of disease severity. Repeated resting-state MEG recordings and clinical assessments were obtained in the context of a unique longitudinal cohort study over a seven-year period using a multiple longitudinal design. We used linear mixed-models to analyze the relationship between neurophysiological (spectral power and functional connectivity) and clinical data. At baseline, early-stage (drug-naïve) PD patients demonstrated spectral slowing compared to healthy controls in both subcortical and cortical brain regions, most outspoken in the latter. Over time, spectral slowing progressed in strong association with clinical measures of disease progression (cognitive and motor). Global functional connectivity was not different between groups at baseline and hardly changed over time. Therefore, investigation of associations with clinical measures of disease progression were not deemed useful. An analysis of individual connections demonstrated differences between groups at baseline (higher frontal theta, lower parieto-occipital alpha2 band functional connectivity) and over time in PD patients (increase in frontal delta and theta band functional connectivity). Our results suggest that spectral measures are promising candidates in the search for non-invasive markers of both early-stage PD and of the ongoing disease process.

Longitudinal consistency of source-space spectral power and functional connectivity using different magnetoencephalography recording systems.

Longitudinal analyses of magnetoencephalography (MEG) data are essential for a full understanding of the pathophysiology of brain diseases and the development of brain activity over time. However, time-dependent factors, such as the recording environment and the type of MEG recording system may affect such longitudinal analyses. We hypothesized that, using source-space analysis, hardware and software differences between two recordings systems may be overcome, with the aim of finding consistent neurophysiological results. We studied eight healthy subjects who underwent three consecutive MEG recordings over 7 years, using two different MEG recordings systems; a 151-channel VSM-CTF system for the first two time points and a 306-channel Elekta Vectorview system for the third time point. We assessed the within (longitudinal) and between-subject (cross-sectional) consistency of power spectra and functional connectivity matrices. Consistency of within-subject spectral power and functional connectivity matrices was good and was not significantly different when using different MEG recording systems as compared to using the same system. Importantly, we confirmed that within-subject consistency values were higher than between-subject values. We demonstrated consistent neurophysiological findings in healthy subjects over a time span of seven years, despite using data recorded on different MEG systems and different implementations of the analysis pipeline.

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson's disease.

BACKGROUND: Notwithstanding the large improvement in motor function in Parkinson's disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role. OBJECTIVE: We studied whether apathy in DBS-treated PD patients could be a stimulation effect. METHODS: In 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy. RESULTS: Average apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex. CONCLUSIONS: The present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.

Awakening after a sleeping pill: Restoring functional brain networks after severe brain injury.

Some patients with severe brain injury show short-term neurological improvements, such as recovery of consciousness, motor function, or speech after administering zolpidem, a GABA receptor agonist. The working mechanism of this paradoxical phenomenon remains unknown. In this study, we used electroencephalography and magnetoencephalography to investigate a spectacular zolpidem-induced awakening, including the recovery of functional communication and the ability to walk in a patient with severe hypoxic-ischemic brain injury. We show that cognitive deficits, speech loss, and motor impairments after severe brain injury are associated with stronger beta band connectivity throughout the brain and suggest that neurological recovery after zolpidem occurs with the restoration of beta band connectivity. This exploratory work proposes an essential role for beta rhythms in goal-directed behavior and cognition. It advocates further fundamental and clinical research on the role of increased beta band connectivity in the development of neurological deficits after severe brain injury.

Motor effects of deep brain stimulation correlate with increased functional connectivity in Parkinson's disease: An MEG study.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established symptomatic treatment in Parkinson's disease, yet its mechanism of action is not fully understood. Locally in the STN, stimulation lowers beta band power, in parallel with symptom relief. Therefore, beta band oscillations are sometimes referred to as "anti-kinetic". However, in recent studies functional interactions have been observed beyond the STN, which we hypothesized to reflect clinical effects of DBS. Resting-state, whole-brain magnetoencephalography (MEG) recordings and assessments on motor function were obtained in 18 Parkinson's disease patients with bilateral STN-DBS, on and off stimulation. For each brain region, we estimated source-space spectral power and functional connectivity with the rest of the brain. Stimulation led to an increase in average peak frequency and a suppression of absolute band power (delta to low-beta band) in the sensorimotor cortices. Significant changes (decreases and increases) in low-beta band functional connectivity were observed upon stimulation. Improvement in bradykinesia/rigidity was significantly related to increases in alpha2 and low-beta band functional connectivity (of sensorimotor regions, the cortex as a whole, and subcortical regions). By contrast, tremor improvement did not correlate with changes in functional connectivity. Our results highlight the distributed effects of DBS on the resting-state brain and suggest that DBS-related improvements in rigidity and bradykinesia, but not tremor, may be mediated by an increase in alpha2 and low-beta functional connectivity. Beyond the local effects of DBS in and around the STN, functional connectivity changes in these frequency bands might therefore be considered as "pro-kinetic".

Functional connectivity between resting-state networks reflects decline in executive function in Parkinson's disease: A longitudinal fMRI study.

Deficits in cognitive functioning are a common yet poorly understood symptom in Parkinson's disease (PD). Recent studies have highlighted the importance of (dynamic) interactions between resting-state networks for cognition, which remains understudied in PD. We investigated how altered (dynamic) functional interactions between brain networks relate to cognitive dysfunction in PD patients. In this fMRI study, 50 PD patients (mean age 65.5 years ± 6.27) on dopaminergic medication were studied cross-sectionally, and of this cohort 31 PD patients were studied longitudinally. MRI imaging and neuropsychological testing was performed at two time points, with a follow-up duration of approximately three years. Functional connectivity within and between seven resting-state networks was calculated (both statically and dynamically) and correlated with four neuropsychological test scores; a combined score of (four) executive tasks, a motor perseveration, memory, and category fluency task. Cognitive dysfunction was determined based on a longitudinal sample of age-matched healthy controls (n = 13). PD patients showed dysfunction on six out of seven cognitive tasks when compared to healthy controls. Severity of executive dysfunction was correlated with higher static and lower dynamic functional connectivity between deep gray matter regions and the frontoparietal network (DGM-FPN). Over time, declining executive function was related to increasing static DGM-FPN connectivity, together with changes of connectivity involving the dorsal attention network (amongst others with the ventral attention network). Static functional connectivity between the ventral and dorsal attention network correlated with motor perseveration. Our findings demonstrate that in PD patients, dysfunctional communication between (i) subcortical, fronto-parietal and attention networks mostly underlies worsening of executive functioning, (ii) attention networks are involved in motor perseveration.

Distance to white matter tracts is associated with deep brain stimulation motor outcome in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in patients with Parkinson's disease (PD). However, the underlying mechanism of tremor suppression is not well understood. Stimulation of white matter tracts, such as the dentatorubrothalamic tract (DRT), might be involved. Also, side effects, including dysarthria, might result from (unwanted) stimulation of white matter tracts in proximity to the STN. The aim of this study was to establish an association between stimulation effect on tremor and dysarthria and stimulation location relative to relevant white matter tracts. METHODS: In 35 PD patients in whom a bilateral STN DBS system was implanted, the authors established clinical outcome measures per electrode contact. The distance from each stimulation location to the center of the DRT, corticopontocerebellar tract, pyramidal tract (PT), and medial lemniscus was determined using diffusion-weighted MRI data. Clinical outcome measures were subsequently related to the distances to the white matter tracts. RESULTS: Patients with activated contacts closer to the DRT showed increased tremor improvement. Proximity of activated contacts to the PT was associated with dysarthria. CONCLUSIONS: Proximity to specific white matter tracts is associated with tremor outcome and side effects in DBS. This knowledge can help to optimize both electrode placement and postsurgical electrode contact selection. Presurgical white matter tract visualization may improve targeting and DBS outcome. These findings are of interest not only for treatment in PD, but potentially also for other (movement) disorders.

A systematic review of MEG-based studies in Parkinson's disease: The motor system and beyond.

Parkinson's disease (PD) is accompanied by functional changes throughout the brain, including changes in the electromagnetic activity recorded with magnetoencephalography (MEG). An integrated overview of these changes, its relationship with clinical symptoms, and the influence of treatment is currently missing. Therefore, we systematically reviewed the MEG studies that have examined oscillatory activity and functional connectivity in the PD-affected brain. The available articles could be separated into motor network-focused and whole-brain focused studies. Motor network studies revealed PD-related changes in beta band (13-30 Hz) neurophysiological activity within and between several of its components, although it remains elusive to what extent these changes underlie clinical motor symptoms. In whole-brain studies PD-related oscillatory slowing and decrease in functional connectivity correlated with cognitive decline and less strongly with other markers of disease progression. Both approaches offer a different perspective on PD-specific disease mechanisms and could therefore complement each other. Combining the merits of both approaches will improve the setup and interpretation of future studies, which is essential for a better understanding of the disease process itself and the pathophysiological mechanisms underlying specific PD symptoms, as well as for the potential to use MEG in clinical care.

Clinical correlates of quantitative EEG in Parkinson disease: A systematic review.

OBJECTIVE: To assess the relevance of quantitative EEG (qEEG) measures as outcomes of disease severity and progression in Parkinson disease (PD). METHODS: Main databases were systematically searched (January 2018) for studies of sufficient methodologic quality that examined correlations between clinical symptoms of idiopathic PD and cortical (surface) qEEG metrics. RESULTS: Thirty-six out of 605 identified studied were included. Results were classified into 4 domains: cognition (23 studies), motor function (13 studies), responsiveness to interventions (7 studies), and other (10 studies). In cross-sectional studies, EEG slowing correlated with global cognitive impairment and with diffuse deterioration in other domains. In longitudinal studies, decreased dominant frequency and increased θ power, reflecting EEG slowing, were biomarkers of cognitive deterioration at an individual level. Results on motor dysfunction and treatment yielded contrasting findings. Studies on functional connectivity at an individual level and longitudinal studies on other domains or on connectivity measures were lacking. CONCLUSION: qEEG measures reflecting EEG slowing, particularly decreased dominant frequency and increased θ power, correlate with cognitive impairment and predict future cognitive deterioration. qEEG could provide reliable and widely available biomarkers for nonmotor disease severity and progression in PD, potentially promoting early diagnosis of nonmotor symptoms and an objective monitoring of progression. More studies are needed to clarify the role of functional connectivity and network analyses.

Changes in resting-state directed connectivity in cortico-subcortical networks correlate with cognitive function in Parkinson's disease.

OBJECTIVE: The pathophysiological mechanisms underlying Parkinson's disease (PD)-related cognitive decline and conversion to PD dementia are poorly understood. In the healthy human brain, stable patterns of posterior-to-anterior cortical information flow have recently been demonstrated in the higher frequency bands using magnetoencephalography (MEG). In this study we estimated PD-related changes in information flow patterns, as well as the contribution of subcortical regions. METHODS: Resting-state MEG recordings were acquired in moderately advanced PD patients (n=34; mean Hoehn and Yahr-stage 2.5) and healthy controls (n=12). MEG signals were projected to both cortical and subcortical brain regions, following which we estimated the balance between incoming and outgoing information flow per region. RESULTS: In PD patients, compared to controls, preferential beta band information outflow was significantly higher for the basal ganglia and frontotemporal cortical regions, and significantly lower for parieto-occipital regions. In addition, in patients, low preferential information outflow from occipital regions correlated with poor global cognitive performance. CONCLUSION: In the PD brain, a shift in balance towards more anterior-to-posterior beta band information flow takes place and is associated with poorer cognitive performance. SIGNIFICANCE: Our results indicate that a reversal of the physiological posterior-to-anterior information flow may be an important mechanism in PD-related cognitive decline.

Influence of the Steric Bulk and Solvent on the Photoreactivity of Ruthenium Polypyridyl Complexes Coordinated to l-Proline.

Ruthenium polypyridyl complexes are good candidates for photoactivated chemotherapy (PACT) provided that they are stable in the dark but efficiently photosubstitute one of their ligands. Here the use of the natural amino acid l-proline as a protecting ligand for ruthenium-based PACT compounds is investigated in the series of complexes Λ-[Ru(bpy)2(l-prol)]PF6 ([1a]PF6; bpy = 2,2'-bipyridine and l-prol = l-proline), Λ-[Ru(bpy)(dmbpy)(l-prol)]PF6 ([2a]PF6 and [2b]PF6; dmbpy = 6,6'-dimethyl-2,2'-bipyridine), and Λ-[Ru(dmbpy)2(l-prol)]PF6 ([3a]PF6). The synthesis of the tris-heteroleptic complex bearing the dissymmetric proline ligand yielded only two of the four possible regioisomers, called [2a]PF6 and [2b]PF6. Both isomers were isolated and characterized by a combination of spectroscopy and density functional theory calculations. The photoreactivity of all four complexes [1a]PF6, [2a]PF6, [2b]PF6, and [3a]PF6 was studied in water (H2O) and acetonitrile (MeCN) using UV-vis spectroscopy, circular dichroism spectroscopy, mass spectrometry, and 1H NMR spectroscopy. In H2O, upon visible-light irradiation in the presence of oxygen, no photosubstitution took place, but the amine of complex [1a]PF6 was photooxidized to an imine. Contrary to expectations, enhancing the steric strain by the addition of two ([2b]PF6) or four ([3a]PF6) methyl substituents did not lead, in phosphate-buffered saline (PBS), to ligand photosubstitution. However, it prevented photoxidation, probably as a consequence of the electron-donating effect of the methyl substituents. In addition, whereas [2b]PF6 was photostable in PBS, [2a]PF6 quantitatively isomerized to [2b]PF6 upon light irradiation. In pure MeCN, [2a]PF6 and [3a]PF6 showed non-selective photosubstitution of both the l-proline and dmbpy ligands, whereas the non-strained complex [1a]PF6 was photostable. Finally, in H2O-MeCN mixtures, [3a]PF6 showed selective photosubstitution of l-proline, thus demonstrating the active role played by the solvent on the photoreactivity of this series of complexes. The role of the solvent polarity and coordination properties on the photochemical properties of polypyridyl complexes is discussed.

A comparative morphological, electrophysiological and functional analysis of axon regeneration through peripheral nerve autografts genetically modified to overexpress BDNF, CNTF, GDNF, NGF, NT3 or VEGF.

The clinical outcome of microsurgical repair of an injured peripheral nerve with an autograft is suboptimal. A key question addressed here is: can axon regeneration through an autograft be further improved? In this article the impact of six neurotrophic factors (BDNF, CNTF, GDNF, NGF, NT3 or VEGF) on axon regeneration was compared after delivery to a 1cm long nerve autograft by gene therapy. To distinguish between early and late effects, regeneration was assessed at 2 and 20weeks post-surgery by histological, electrophysiological and functional analysis. BDNF, GDNF and NGF exhibited a spectrum of effects, including early stimulatory effects on axons entering the autograft and excessive axon growth and Schwann cell proliferation at 20weeks post-surgery. Persistent expression of these factors in autografts interfered with target cell reinnervation and functional recovery in a modality specific way. Autografts overexpressing VEGF displayed hypervascularization, while grafts transduced with CNTF and NT3 were indistinguishable from control grafts. These three factors did not have detectable pro-regenerative effects. In conclusion, autograft-based repair combined with gene therapy for three of the six growth factors investigated (BDNF, GDNF, NGF) showed considerable promise since these factors enhanced modality specific axon outgrowth in autografts. The remarkable and selective effects of BDNF, GDNF and NGF on motor or sensory regeneration will be exploited in future experiments that aim to carefully regulate their temporal and spatial expression since this has the potential to overcome the adverse effects on long-distance regeneration observed after uncontrolled delivery.