ISSN / EISSN : 0006-8950 / 1460-2156
Published by: Oxford University Press (OUP) (10.1093)
Total articles ≅ 16,823
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Exaggerated bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus (STN) of patients with Parkinson’s disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the STN local field potential (LFP) in Parkinson’s disease, and that together these different states predict motor impairment with high fidelity. LFPs were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the STN. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. LFPs were analysed using Hidden Markov Modelling to identify transient spectral states with frequencies under 40 Hz. Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional LFP states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all LFP states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients’ hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone. We conclude that multiple spectral states in the STN LFP have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how LFP feedback can be made more informative in closed-loop deep brain stimulation systems.
Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangle was measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden reveal significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we find similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu Ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer’s disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
Although recent clinical trials targeting amyloid-β (Aβ) in Alzheimer’s disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with Aβ metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to either Aβ or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 Aβ-negative cognitively unimpaired individuals, 71 Aβ-positive cognitively unimpaired individuals, 78 Aβ-positive cognitively impaired individuals, 63 Aβ-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal Aβ (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all Aβ-positive groups compared with subjects without Aβ pathology (p < 0.01). In addition, there were significant associations between plasma GFAP with higher Aβ-PET signal in all Aβ-positive groups, but also in cognitively normal individuals with normal Aβ values (p < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict Aβ-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for Aβ-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p < 0.05) and correlated with Aβ-PET only in Aβ-positive cognitively impaired individuals (p = 0.005). Finally, plasma GFAP was associated with both longitudinal Aβ-PET and cognitive decline, and mediated the effect of Aβ-PET on tau-PET burden, suggesting that astrocytosis secondary to Aβ aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain Aβ pathology but not tau aggregation, even in cognitively normal individuals with a normal Aβ status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to Aβ pathology.
In Parkinson’s disease (PD) patients, beta (β) and gamma (γ) oscillations are altered in the basal ganglia, and this abnormality contributes to the pathophysiology of bradykinesia. However, it is unclear whether β and γ rhythms at the primary motor cortex (M1) level influence bradykinesia. Transcranial alternating current stimulation (tACS) can modulate cortical rhythms by entraining endogenous oscillations. We tested whether β- and γ-tACS on M1 modulate bradykinesia in PD patients by analyzing the kinematic features of repetitive finger tapping, including movement amplitude, velocity, and sequence effect, recorded during β-, γ-, and sham tACS. We also verified whether possible tACS-induced bradykinesia changes depended on modifications in specific M1 circuits, as assessed by short-interval intracortical inhibition (SICI) and short-latency afferent inhibition (SAI). Patients were studied OFF and ON dopaminergic therapy. Results were compared to those obtained in a group of healthy subjects (HS). In patients, movement velocity significantly worsened during β-tACS and movement amplitude improved during γ-tACS, while the sequence effect did not change. In addition, SAI decreased (reduced inhibition) during β-tACS and SICI decreased during both γ- and β-tACS in PD. The effects of tACS were comparable between OFF and ON sessions. In patients OFF therapy, the degree of SICI modulation during β- and γ-tACS correlated with movement velocity and amplitude changes. Moreover, there was a positive correlation between the effect of γ-tACS on movement amplitude and motor symptoms severity. Our results show that cortical β and γ oscillations are relevant in the pathophysiology of bradykinesia in PD and that changes in inhibitory GABA-A-ergic interneuronal activity may reflect compensatory M1 mechanisms to counteract bradykinesia. In conclusion, abnormal oscillations at the M1 level of the basal ganglia-thalamo-cortical network play a relevant role in the pathophysiology of bradykinesia in PD.
Spreading depolarizations (SD) are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply-demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure (ICP) are also prevalent in injured brain. Here, using a mouse model of large hemispheric ischemic stroke, we show that mild and brief ICP elevations (20 or 30 mmHg for just 3 minutes) potently trigger SDs in ischemic penumbra (4-fold increase in SD occurrence). We also show that 30 mmHg ICP spikes as brief as 30 seconds are equally effective. In contrast, sustained ICP elevations to the same level for 30 minutes do not significantly increase the SD rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger an SD. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the ICP spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply-demand mismatch. These hemodynamic changes during ICP spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, higher rate of ICP spikes was associated with SD clusters in a retrospective series of patients with aneurysmal subarachnoid hemorrhage with strong temporal correspondence. Altogether, our data show that ICP spikes, even when mild and brief, are capable of triggering SDs. Aggressive prevention of ICP spikes may help reduce SD occurrence and improve outcomes after brain injury.
After spinal cord injury (SCI), macrophages can exert either beneficial or detrimental effects depending on their phenotype. Aside from their critical role in inflammatory responses, macrophages are also specialized in the recognition, engulfment, and degradation of pathogens, apoptotic cells, and tissue debris. They promote remyelination and axonal regeneration by removing inhibitory myelin components and cellular debris. However, excessive intracellular presence of lipids and dysregulated intracellular lipid homeostasis result in the formation of foamy macrophages. These develop a pro-inflammatory phenotype that may contribute to further neurological decline. Additionally, myelin-activated macrophages play a crucial role in axonal dieback and retraction. Here, we review the opposing functional consequences of phagocytosis by macrophages in SCI, including remyelination and regeneration versus demyelination, degeneration, and axonal dieback. Furthermore, we discuss how targeting the phagocytic ability of macrophages may have therapeutic potential for the treatment of SCI.
Neuropathic pain is a major health problem that affects up to 7–10% of the population worldwide. Currently, neuropathic pain is difficult to treat due to its elusive mechanisms. Here we report that orphan G protein-coupled receptor 151 (GPR151) in nociceptive sensory neurons controls neuropathic pain induced by nerve injury. GPR151 was mainly expressed in nonpeptidergic C-fiber dorsal root ganglion (DRG) neurons and highly upregulated after nerve injury. Importantly, conditional knockout of Gpr151 in adult nociceptive sensory neurons significantly alleviated chronic constriction injury (CCI)-induced neuropathic pain-like behavior but did not affect basal nociception. Moreover, GPR151 in DRG neurons was required for CCI-induced neuronal hyperexcitability and upregulation of colony-stimulating factor 1 (CSF1), which is necessary for microglial activation in the spinal cord after nerve injury. Mechanistically, GPR151 coupled with P2X3 ion channels and promoted their functional activities in neuropathic pain-like hypersensitivity. Knockout of Gpr151 suppressed P2X3-mediated calcium elevation and spontaneous pain behavior in CCI mice. Conversely, overexpression of Gpr151 significantly enhanced P2X3-mediated calcium elevation and DRG neuronal excitability. Furthermore, knockdown of P2X3 in DRGs reversed CCI-induced CSF1 upregulation, spinal microglial activation, and neuropathic pain-like behavior. Finally, the co-expression of GPR151 and P2X3 was confirmed in small-diameter human DRG neurons, indicating the clinical relevance of our findings. Together, our results suggest that GPR151 in nociceptive DRG neurons plays a key role in the pathogenesis of neuropathic pain and could be a potential target for treating neuropathic pain.
Published: 9 July 2021
The diversity of cognitive deficits and neuropathological processes associated with dementias has encouraged divergence in pathophysiological explanations of disease. Here, we review an alternative framework that emphasises convergent critical features of cognitive pathophysiology. Rather than the loss of “memory centres” or “language centres”, or singular neurotransmitter systems, cognitive deficits are interpreted in terms of aberrant predictive coding in hierarchical neural networks. This builds on advances in normative accounts of brain function, specifically the Bayesian integration of beliefs and sensory evidence in which hierarchical predictions and prediction errors underlie memory, perception, speech and behaviour. We describe how analogous impairments in predictive coding in parallel neurocognitive systems can generate diverse clinical phenomena, including the characteristics of dementias. The review presents evidence from behavioural and neurophysiological studies of perception, language, memory and decision-making. The re-formulation of cognitive deficits in terms of predictive coding has several advantages. It brings diverse clinical phenomena into a common framework; it aligns cognitive and movement disorders; and it makes specific predictions on cognitive physiology that support translational and experimental medicine studies. The insights into complex human cognitive disorders from the predictive coding framework may therefore also inform future therapeutic strategies.