Associations between cortical ß-amyloid burden, fornix microstructure and cognitive processing of faces, places, bodies and other visual objects in early Alzheimer's disease.

Using two imaging modalities, that is, Pittsburgh compound B (PiB) positron emission tomography (PET) and diffusion tensor imaging (DTI) the present study tested associations between cortical amyloid-beta (Aß) burden and fornix microstructural changes with cognitive deficits in early Alzheimer's disease (AD), namely deficits in working memory (1-back) processing of visual object categories (faces, places, objects, bodies and verbal material). Second, we examined cortical Aß associations with fornix microstructure. Seventeen early AD patients and 17 healthy-matched controls were included. Constrained spherical deconvolution-based tractography was used to segment the fornix and a control tract the central branch of the superior longitudinal fasciculus (CB-SLF) previously implicated in working memory processes. Standard uptake value ratios (SUVR) of Aß were extracted from 45 cortical/subcortical regions from the AAL atlas and subject to principal component analysis for data reduction. Patients exhibited (i) impairments in cognitive performance (ii) reductions in fornix fractional anisotropy (FA) and (iii) increases in a component that loaded highly on cortical Aß. There were no group differences in CB-SLF FA and in a component loading highly on subcortical Aß. Partial correlation analysis in the patient group showed (i) positive associations between fornix FA and performance for all the visual object categories and (ii) a negative association between the cortical Aß component and performance for the object categories but not for the remaining classes of visual stimuli. A subsequent analysis showed a positive association between overall cognition (performance across distinct 1-back task conditions) with fornix FA but no association with cortical Aß burden, in keeping with influential accounts on early onset AD. This indicates that the fornix degenerates early in AD and contributes to deficits in working memory processing of visual object categories; though it is also important to acknowledge the importance of prospective longitudinal studies with larger samples. Overall, the effect sizes of fornical degeneration on visual working memory appeared stronger than the ones related to amyloid burden.

Structural impairments in hippocampal and occipitotemporal networks specifically contribute to decline in place and face category processing but not to other visual object categories in healthy aging.

BACKGROUND: Functional neuroimaging studies have identified a set of nodes in the occipital-temporal cortex that preferentially respond to faces in comparison with other visual objects. By contrast, the processing of places seems to rely on parahippocampal cortex and structures heavily implicated in memory (e.g., the hippocampus). It has been suggested that human aging leads to decreased neural specialization of core face and place processing areas and impairments in face and place perception. METHODS: Using mediation analysis, we tested the potential contribution of micro- and macrostructure within the hippocampal and occipitotemporal systems to age-associated effects in face and place category processing (as measured by 1-back working memory tasks) in 55 healthy adults (age range 23-79 years). To test for specific contributions of the studied structures to face/place processing, we also studied a distinct tract (i.e., the anterior thalamic radiation [ATR]) and cognitive performance for other visual object categories (objects, bodies, and verbal material). Constrained spherical deconvolution-based tractography was used to reconstruct the fornix, the inferior longitudinal fasciculus (ILF), and the ATR. Hippocampal volumetric measures were segmented from FSL-FIRST toolbox. RESULTS: It was found that age associates with (a) decreases in fractional anisotropy (FA) in the fornix, in right ILF (but not left ILF), and in the ATR (b) reduced volume in the right and left hippocampus and (c) decline in visual object category processing. Importantly, mediation analysis showed that micro- and macrostructural impairments in the fornix and right hippocampus, respectively, associated with age-dependent decline in place processing. Alternatively, microstructural impairments in right hemispheric ILF associated with age-dependent decline in face processing. There were no other mediator effects of micro- and macrostructural variables on age-cognition relationships. CONCLUSION: Together, the findings support specific contributions of the fornix and right hippocampus in visuospatial scene processing and of the long-range right hemispheric occipitotemporal network in face category processing.

Frontoparietal microstructural damage mediates age-dependent working memory decline in face and body information processing: Evidence for dichotomic hemispheric bias mechanisms.

Age-associated damage in the microstructure of frontally-based connections (e.g. genu of the corpus callosum and superior longitudinal fasciculus) is believed to lead to impairments in processing speed and executive function. Using mediation analysis, we tested the potential contribution of callosal and frontoparietal association tracts to age-dependent effects on cognition/executive function as measured with 1-back working memory tasks for visual stimulus categories (i.e. faces and non-emotional bodies) in a group of 55 healthy adults (age range 23-79 years). Constrained spherical deconvolution-based tractography was employed to reconstruct the genu/prefrontal section of the corpus callosum (GCC) and the central/second branch of the superior longitudinal fasciculus (CB-SLF). Age was associated with (i) reductions in fractional anisotropy (FA) in the GCC and in the right and left CB-SLF and (iii) decline in visual object category processing. Mediation analysis revealed that microstructural damage in right hemispheric CB-SLF is associated with age-dependent decline in face processing likely reflecting the stimulus-specific/holistic nature of face processing within dedicated/specialized frontoparietal routes. By contrast, microstructural damage in left hemispheric CB-SLF associated with age-dependent decline in non-emotional body processing, consistent with the more abstract nature of non-emotional body categories. In sum, our findings suggest that frontoparietal microstructural damage mediates age-dependent decline in face and body information processing in a manner that reflects the hemispheric bias of holistic vs. abstract nature of face and non-emotional body category processing.

Drumming Motor Sequence Training Induces Apparent Myelin Remodelling in Huntington's Disease: A Longitudinal Diffusion MRI and Quantitative Magnetization Transfer Study.

BACKGROUND: Impaired myelination may contribute to Huntington's disease (HD) pathogenesis. OBJECTIVE: This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. METHODS: Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. RESULTS: MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. CONCLUSION: Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression.

Assessing the Role of the Left Dorsal Frontal Cortex in Working Memory Guidance: Attentional or Mnemonic? A Neurostimulation Study.

Perceptual selection can be guided by the contents of working memory (WM). Neuroimaging and neuropsychological data point to a role of a fronto-parietal and fronto-thalamic networks in WM guidance. Here we assessed the effect of transcranial direct current stimulation of the left dorsal frontal cortex (lDFC) in a combined WM/attention paradigm. We asked the extent to which the lDFC is implicated in mnemonic and selective attention functions during WM guidance of behavior. Observers were asked to keep information in memory while searching for a visual target, while the validity of WM contents for the search task varied. We tested the effects of lDFC-tDCS on the strength of WM guidance of search, whether any tDCS effect is dependent on the amount of WM load, and whether lDFC-tDCS primarily influences how WM contents are retained, the process of selective attention in search task, or both. Consistent with prior behavioral findings, we found that (i) selection of items that matched the contents of WM was facilitated relative to non-matching items and (ii) this WM guidance effect was reduced when the level processing/cognitive load in WM was higher. Notably, across two experiments we found that lDFC-tDCS modulated WM guidance of visual selection in the context of high processing loads in WM. No effects of tDCS were observed in WM accuracy. These findings suggest that the role of the left dorsal frontal cortex in WM guidance is associated with selective attentional control rather than mnemonic processing.

Myelin Breakdown in Human Huntington's Disease: Multi-Modal Evidence from Diffusion MRI and Quantitative Magnetization Transfer.

Huntington's disease (HD) leads to white matter (WM) degeneration that may be due to an early breakdown in axon myelination but in vivo imaging correlates of demyelination remain relatively unexplored in HD compared to other neurodegenerative diseases. This study investigated HD-related effects on a putative marker of myelin, the macromolecular proton fraction (MMPF) from quantitative magnetization transfer and on fractional anisotropy, axial and radial diffusivity from diffusion tensor MR-imaging. Microstructural differences were studied in WM pathways of the basal ganglia and motor systems known to be impaired in HD: the corpus callosum, the cortico-spinal tract, the anterior thalamic radiation, fibers between prefrontal cortex and caudate and between supplementary motor area and putamen. Principal component analysis was employed for dimensionality reduction. Patients showed reductions in a component with high loadings on MMPF in all WM pathways and a trend for increases in a component loading on axial and radial diffusivities but no differences in a component loading on fractional anisotropy. While patients' performance in executive functioning was impaired, their working memory span was preserved. Inter-individual differences in the diffusivity component correlated with patients' performance in clinical measures of the United Huntington Disease Rating Scale. In summary, HD-related reductions in MMPF suggest that myelin breakdown contributes to WM impairment in human HD and emphasize the potential of quantitative MRI metrics to inform about disease pathogenesis. Disease severity in manifest HD, however, was best captured by non-specific diffusivity metrics sensitive to multiple disease and age-related changes.

Thalamic control of human attention driven by memory and learning.

The role of the thalamus in high-level cognition-attention, working memory (WM), rule-based learning, and decision making-remains poorly understood, especially in comparison to that of cortical frontoparietal networks [1-3]. Studies of visual thalamus have revealed important roles for pulvinar and lateral geniculate nucleus in visuospatial perception and attention [4-10] and for mediodorsal thalamus in oculomotor control [11]. Ventrolateral thalamus contains subdivisions devoted to action control as part of a circuit involving the basal ganglia [12, 13] and motor, premotor, and prefrontal cortices [14], whereas anterior thalamus forms a memory network in connection with the hippocampus [15]. This connectivity profile suggests that ventrolateral and anterior thalamus may represent a nexus between mnemonic and control functions, such as action or attentional selection. Here, we characterize the role of thalamus in the interplay between memory and visual attention. We show that ventrolateral lesions impair the influence of WM representations on attentional deployment. A subsequent fMRI study in healthy volunteers demonstrates involvement of ventrolateral and, notably, anterior thalamus in biasing attention through WM contents. To further characterize the memory types used by the thalamus to bias attention, we performed a second fMRI study that involved learning of stimulus-stimulus associations and their retrieval from long-term memory to optimize attention in search. Responses in ventrolateral and anterior thalamic nuclei tracked learning of the predictiveness of these abstract associations and their use in directing attention. These findings demonstrate a key role for human thalamus in higher-level cognition, notably, in mnemonic biasing of attention.