Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self‐control, underpinned by inferior fronto‐striatal deficits. Real‐time functional magnetic resonance neurofeedback (rtfMRI‐NF) allows participants to gain self‐control over dysregulated brain regions. Despite evidence for beneficial effects of electrophysiological‐NF on ADHD symptoms, no study has applied the spatially superior rtfMRI‐NF neurotherapy to ADHD. A randomized controlled trial tested the efficacy of rtfMRI‐NF of right inferior prefrontal cortex (rIFG), a key region that is compromised in ADHD and upregulated with psychostimulants, on improvement of ADHD symptoms, cognition, and inhibitory fMRI activation. To control for region‐specificity, an active control group received rtfMRI‐NF of the left parahippocampal gyrus (lPHG). Thirty‐one ADHD boys were randomly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI‐NF runs over 2 weeks. Feedback was provided through a video‐clip of a rocket that had to be moved up into space. A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life. Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11‐month follow‐up. Only the group targeting rIFG, however, showed a transfer effect, which correlated with ADHD symptom reductions, improved at trend level in sustained attention, and showed increased IFG activation during an inhibitory fMRI task. This proof‐of‐concept study demonstrates for the first time feasibility, safety, and shorter‐ and longer‐term efficacy of rtfMRI‐NF of rIFG in adolescents with ADHD. Hum Brain Mapp 38:3190–3209, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
Behavioral studies in rodents and humans have demonstrated deficits of spatial memory and orientation in bilateral vestibular failure (BVF). Our aim was to explore the functional consequences of chronic vestibular failure on different cognitive domains including spatial as well as non-spatial cognitive abilities. Sixteen patients with a unilateral vestibular failure (UVF), 18 patients with a BVF, and 17 healthy controls (HC) participated in the study. To assess the cognitive domains of short-term memory, executive function, processing speed and visuospatial abilities the following tests were used: Theory of Visual Attention (TVA), TAP Alertness and Visual Scanning, the Stroop Color-Word, and the Corsi Block Tapping Test. The cognitive scores were correlated with the degree of vestibular dysfunction and the duration of the disease, respectively. Groups did not differ significantly in age, sex, or handedness. BVF patients were significantly impaired in all of the examined cognitive domains but not in all tests of the particular domain, whereas UVF patients exhibited significant impairments in their visuospatial abilities and in one of the two processing speed tasks when compared independently with HC. The degree of vestibular dysfunction significantly correlated with some of the cognitive scores. Neither the side of the lesion nor the duration of disease influenced cognitive performance. The results demonstrate that vestibular failure can lead to cognitive impairments beyond the spatial navigation deficits described earlier. These cognitive impairments are more significant in BVF patients, suggesting that the input from one labyrinth which is distributed into bilateral vestibular circuits is sufficient to maintain most of the cognitive functions. These results raise the question whether BVF patients may profit from specific cognitive training in addition to physiotherapy.
Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.aggregation | conformational disease | electron tomography | protein assembly | prion
N-terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the Aβ peptide in Alzheimer's disease. We show herein that these two modifications significantly reduce the fibril length and the transition midpoint of thermal unfolding of the fibrils, but they do not substantially perturb the fibrillary peptide conformation. This observation implies that the N terminus of the unmodified peptide protects Aβ fibrils against mechanical stress and fragmentation and explains the high propensity of pE-modified peptides to form small and particularly toxic aggregates.
Positron emission tomography (PET) shows reduced binding of the dopamine D(2/3) antagonist [(11) C]raclopride in striatum of withdrawn psychostimulant abusers, but not consistently in patients with alcohol dependence (AD). We make first use of the high affinity ligand [(18) F]fallypride to obtain serial measures of D(2/3) receptor availability in striatal and extrastriatal regions of AD patients undergoing detoxification. Seventeen patients (mean age 44 ± 5y) with AD and 14 age-matched healthy volunteers participated. Each patient underwent [(18) F]fallypride PET upon hospital admission, and again 1-2 weeks later; two patients achieving abstinence, and two with substantial harm reduction had additional PET follow-up at 1 year. Dynamic 180-minute PET recordings were used for volume of interest (VOI)-based and voxel-wise analysis of [(18) F]fallypride binding potential (BP(ND) ). Mean baseline BP(ND) in striatum of the AD patients (15.7 ± 3.6) was unaltered during short-term follow-up, and did not differ from that in healthy controls (16.8 ± 3.0); however, BP(ND) was 10-20% lower in thalamus, hippocampus, and insular and temporal cortex of the AD patients (P < 0.05). Age-dependent declines in BP(ND) were very small in controls, but more pronounced and widespread in the AD group. Striatal and thalamic BP(ND) increased by 30% in four patients with long-term abstinence or reduced alcohol consumption. VOI-based [(18) F]fallypride PET analyses revealed group differences in D(2/3) receptor availability primarily in extra-striatal regions. Age-related loss of dopamine D(2/3) receptors was more pronounced in AD patients. Receptor availability was unaltered by acute withdrawal, but increased in the subgroup of patients with long-term follow-up, suggesting reversibility of receptor changes.
Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self-control, underpinned by inferior fronto-striatal deficits. We showed previously that 18 ADHD adolescents over 11 runs of 8.5 min of real-time functional magnetic resonance neurofeedback of the right inferior frontal cortex (rIFC) progressively increased activation in 2 regions of the rIFC which was associated with clinical symptom improvement. In this study, we used functional connectivity analyses to investigate whether fMRI-Neurofeedback of rIFC resulted in dynamic functional connectivity changes in underlying neural networks.Whole-brain seed-based functional connectivity analyses were conducted using the two clusters showing progressively increased activation in rIFC as seed regions to test for changes in functional connectivity before and after 11 fMRI-Neurofeedback runs. Furthermore, we tested whether the resulting functional connectivity changes were associated with clinical symptom improvements and whether they were specific to fMRI-Neurofeedback of rIFC when compared to a control group who had to self-regulate another region.rIFC showed increased positive functional connectivity after relative to before fMRI-Neurofeedback with dorsal caudate and anterior cingulate and increased negative functional connectivity with regions of the default mode network (DMN) such as posterior cingulate and precuneus. Furthermore, the functional connectivity changes were correlated with clinical improvements and the functional connectivity and correlation findings were specific to the rIFC-Neurofeedback group.The findings show for the first time that fMRI-Neurofeedback of a typically dysfunctional frontal region in ADHD adolescents leads to strengthening within fronto-cingulo-striatal networks and to weakening of functional connectivity with posterior DMN regions and that this may be underlying clinical improvement.
Two experiments are reported that use patients with visual extinction to examine how visual attention is influenced by action information in images. In Experiment 1 patients saw images of objects that were either correctly or incorrectly colocated for action, with the objects held by hands that were congruent or incongruent with those used premorbidly by the patients. The images were also shown from a 1st- and 3rd-person perspective. There was an overall reduction in extinction for objects colocated for action. In addition, there was an extra benefit when the objects were held in hands congruent with those used by the patients and when the objects were seen from a 1st-person perspective. This last result fits with an effect of motor simulation, over and above a purely visual effect based on positioning objects correctly for action. Experiment 2 showed that effects of hand congruence could emerge with images depicted from a 3rd-person perspective when patients saw themselves holding the objects. The data indicate 2 effects of action information on extinction: (a) an effect of colocating objects for action, which does not depend on a self-reference frame (a visual effect), and (b) an effect sensitive to object-hand congruence, which does depend on a self-reference frame (a motor-based effect). The self-reference frame is induced when stimuli are viewed from a 1st-person perspective and when an image of the self is seen from a 3rd-person perspective. Both visual and motor-based effects of action information facilitate the spread of attention across objects.
Actions taking place in the environment are critical for our survival. We review evidence on attention to action, drawing on sets of converging evidence from neuropsychological patients through to studies of the time course and neural locus of action-based cueing of attention in normal observers. We show that the presence of action relations between stimuli helps reduce visual extinction in patients with limited attention to the contralesional side of space, while the first saccades made by normal observers and early perceptual and attentional responses measured using electroencephalography/event-related potentials are modulated by preparation of action and by seeing objects being grasped correctly or incorrectly for action. With both normal observers and patients, there is evidence for two components to these effects based on both visual perceptual and motor-based responses. While the perceptual responses reflect factors such as the visual familiarity of the action-related information, the motor response component is determined by factors such as the alignment of the objects with the observer's effectors and not by the visual familiarity of the stimuli. In addition to this, we suggest that action relations between stimuli can be coded pre-attentively, in the absence of attention to the stimulus, and action relations cue perceptual and motor responses rapidly and automatically. At present, formal theories of visual attention are not set up to account for these action-related effects; we suggest ways that theories could be expected to enable action effects to be incorporated.
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