Neural Substrates Associated With Fatigue Symptom In Fibromyalgia

Many patients with fibromyalgia (FM) experience fatigue, but the associated biological mechanisms have not been delineated. We aimed to investigate the neural signatures associated with fatigue severity in patients with FM using MRI. We consecutively recruited 138 patients with FM and collected their clinical profiles and brain-MRI data. We categorized the patients into 3 groups based on their fatigue severity. Using voxel-based morphometry analysis and trend analysis, we first identified neural structures showing volumetric changes associated with fatigue severity, and further explored their seed-to-voxel structural covariance networks (SCNs). Results showed decreased bilateral thalamic volumes were associated with higher severity of fatigue. There was a more widespread distribution of the thalamic SCNs to the frontal, parietal, subcortical, and limbic regions in patients with higher fatigue severity. In addition, increased right inferior temporal cortex volumes were associated with higher severity of fatigue. The right inferior temporal seed showed more SCNs distributions over the temporal cortex and a higher strength of SCNs to the bilateral occipital cortex in patients with higher fatigue severity. The thalamus and the right inferior temporal cortex as well as their altered interactions with cortical and subcortical regions comprise the neural signatures of fatigue in FM.

An in vivo pig model for testing novel PET radioligands targeting cerebral protein aggregates

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-β or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated α-synuclein, which is seen in, e.g., Parkinson's Disease. Access to a large animal model with α-synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here established a pig model with cerebral injections of α-synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimer's disease (AD) or dementia with Lewy body (DLB) into the pig's brain using minimally invasive surgery and validated against saline injections. In the absence of a suitable α-synuclein radioligand, we validated the model with an unselective amyloid-β tracer [11C]PIB, which has a high affinity for β-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier function was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in α-synuclein-preformed-fibrils-injected regions compared to the saline-injected regions. The [11C]PIB uptake was the same in the occipital cortex, cerebellum, DLB-homogenate, and saline-injected regions. With its large brains and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.

Systemic deficiency of GM1 ganglioside in Parkinson’s disease tissues and its relation to the disease etiology

Following our initial reports on subnormal levels of GM1 in the substantia nigra and occipital cortex of Parkinson’s disease (PD) patients, we have examined additional tissues from such patients and found these are also deficient in the ganglioside. These include innervated tissues intimately involved in PD pathology such as colon, heart and others, somewhat less intimately involved, such as skin and fibroblasts. Finally, we have analyzed GM1 in peripheral blood mononuclear cells, a type of tissue apparently with no direct innervation, and found those too to be deficient in GM1. Those patients were all afflicted with the sporadic form of PD (sPD), and we therefore conclude that systemic deficiency of GM1 is a characteristic of this major type of PD. Age is one factor in GM1 decline but is not sufficient; additional GM1 suppressive factors are involved in producing sPD. We discuss these and why GM1 replacement offers promise as a disease-altering therapy.

Neural correlates of perceiving and interpreting engraved prehistoric patterns as human production: effect of archaeological expertise.

It has been suggested that engraved abstract patterns dating from the Middle and Lower Palaeolithic served as means of representation and communication. Identifying the brain regions involved in visual processing of these engravings can provide insights into their function. In this study, brain activity was measured during perception of the earliest known Palaeolithic engraved patterns and compared to natural patterns mimicking human-made engravings. Participants were asked to categorise marks as being intentionally made by humans or due to natural processes (e.g. erosion, root etching). To simulate the putative familiarity of our ancestors with the marks, the responses of expert archaeologists and control participants were compared, allowing characterisation of the effect of previous knowledge on both behaviour and brain activity in perception of the marks. Besides a set of regions common to both groups and involved in visual analysis and decision-making, the experts exhibited greater activity in the inferior part of the lateral occipital cortex, ventral occipitotemporal cortex, and medial thalamic regions. These results are consistent with those reported in visual expertise studies, and confirm the importance of the integrative visual areas in the perception of the earliest abstract engravings. The attribution of a natural rather than human origin to the marks elicited greater activity in the salience network in both groups, reflecting the uncertainty and ambiguity in the perception of, and decision-making for, natural patterns. The activation of the salience network might also be related to the process at work in the attribution of an intention to the marks. The primary visual area was not specifically involved in the visual processing of engravings, which argued against its central role in the emergence of engraving production.

Receptor architecture of macaque and human early visual areas: not equal, but comparable

Existing cytoarchitectonic maps of the human and macaque posterior occipital cortex differ in the number of areas they display, thus hampering identification of homolog structures. We applied quantitative in vitro receptor autoradiography to characterize the receptor architecture of the primary visual and early extrastriate cortex in macaque and human brains, using previously published cytoarchitectonic criteria as starting point of our analysis. We identified 8 receptor architectonically distinct areas in the macaque brain (mV1d, mV1v, mV2d, mV2v, mV3d, mV3v, mV3A, mV4v), and their respective counterpart areas in the human brain (hV1d, hV1v, hV2d, hV2v, hV3d, hV3v, hV3A, hV4v). Mean densities of 14 neurotransmitter receptors were quantified in each area, and ensuing receptor fingerprints used for multivariate analyses. The 1st principal component segregated macaque and human early visual areas differ. However, the 2nd principal component showed that within each species, area-specific differences in receptor fingerprints were associated with the hierarchical processing level of each area. Subdivisions of V2 and V3 were found to cluster together in both species and were segregated from subdivisions of V1 and from V4v. Thus, comparative studies like this provide valuable architectonic insights into how differences in underlying microstructure impact evolutionary changes in functional processing of the primate brain and, at the same time, provide strong arguments for use of macaque monkey brain as a suitable animal model for translational studies.

When You Do Not Get the Whole Picture: Scene Perception After Occipital Cortex Lesions

Background: Occipital cortex lesions (OCLs) typically result in visual field defects (VFDs) contralateral to the damage. VFDs are usually mapped with perimetry involving the detection of point targets. This, however, ignores the important role of integration of visual information across locations in many tasks of everyday life. Here, we ask whether standard perimetry can fully characterize the consequences of OCLs. We compare performance on a rapid scene discrimination task of OCL participants and healthy observers with simulated VFDs. While the healthy observers will only suffer the loss of part of the visual scene, the damage in the OCL participants may further compromise global visual processing.Methods: VFDs were mapped with Humphrey perimetry, and participants performed two rapid scene discrimination tasks. In healthy participants, the VFDs were simulated with hemi- and quadrant occlusions. Additionally, the GIST model, a computational model of scene recognition, was used to make individual predictions based on the VFDs.Results: The GIST model was able to predict the performance of controls regarding the effects of the local occlusion. Using the individual predictions of the GIST model, we can determine that the variability between the OCL participants is much larger than the extent of the VFD could account for. The OCL participants can further be categorized as performing worse, the same, or better as their VFD would predict.Conclusions: While in healthy observers the extent of the simulated occlusion accounts for their performance loss, the OCL participants’ performance is not fully determined by the extent or shape of their VFD as measured with Humphrey perimetry. While some OCL participants are indeed only limited by the local occlusion of the scene, for others, the lesions compromised the visual network in a more global and disruptive way. Yet one outperformed a healthy observer, suggesting a possible adaptation to the VFD. Preliminary analysis of neuroimaging data suggests that damage to the lateral geniculate nucleus and corpus callosum might be associated with the larger disruption of rapid scene discrimination. We believe our approach offers a useful behavioral tool for investigating why similar VFDs can produce widely differing limitations in everyday life.

Early neural activity changes associated with visual conscious perception

The neural mechanisms of visual conscious perception have been investigated for decades. However, the spatiotemporal dynamics associated with the earliest neural responses following consciously perceived stimuli are still poorly understood. Using a dataset of intracranial EEG recordings, the current study aims to investigate the neural activity changes associated with the earliest stages of visual conscious perception. Subjects (N=10, 1,693 grey matter electrode contacts) completed a continuous performance task in which individual letters were presented in series and subjects were asked to press a button when they saw a target letter. Broadband gamma power (40-115Hz) dynamics were analyzed in comparison to baseline prior to stimulus and contrasted for target trials with button presses and non-target trials without button presses. Regardless of event type, we observed early gamma power changes within 30-150 ms from stimulus onset in a network including increases in bilateral occipital, fusiform, frontal (including frontal eye fields), and medial temporal cortex, increases in left lateral parietal-temporal cortex, and decreases in the right anterior medial occipital cortex. No significant differences were observed between target and non-target stimuli until >150 ms post-stimulus, when we saw greater gamma power increases in left motor and premotor areas, suggesting a possible role of these later signals in perceptual decision making and/or motor responses with the right hand. The early gamma power findings suggest a broadly distributed cortical visual detection network that is engaged at early times tens of milliseconds after signal transduction from the retina.

The Effect of Low-Intensity Daily Walking Activity on Cognitive and Brain Function in Older Adults

Physical activity is an effective intervention to prevent or delay cognitive decline and dementia in older adults; however, many have difficulty achieving recommended moderate- to vigorous-intensity guidelines. This study examined the impact of low-intensity daily walking activity on executive cognitive and brain function in 66 older adults (mean age=67.26 ; SD=6.04). Daily walking activity was measured using a step activity monitor and brain function was assessed using functional magnetic resonance imaging during the Flanker task. Analyses included whole and region of interest (ROI) in the right middle frontal gyrus (RMFG), occipital cortex (OCC) and anterior cingulate (ACC). Partial correlations were performed between step activity, behavioral performance, and ROI activation, adjusting for age and education. Most of the step activity was in the low-intensity range. No associations were observed between step activity and task performance (p>.05). Task-related activation occurred in the RMFG, lateral OCC and paracingulate (p<.01). Increased activation in the RMFG was associated with greater amount r(62)=.390, p=.001, duration r(62)=.309, p=.013 and frequency r(62)=.327, p=.007 of step activity. Stratification by sex revealed a positive association between amount of step activity and RMFG activation in women r(44)= .360, p=.014, but not men. Whole brain correlation revealed that amount of step activity was positively associated with precuneus activation (p<.01), an area impacted early in Alzheimer’s disease. These results support the benefits of low intensity daily walking activity on prefrontal function in older adults and suggest the importance of designing attainable and sustainable physical activity interventions to promote brain health in older adults.