Biology subjects

Larcher, K.

Publications and source records attributed to Larcher, K..

5 recordsLinked to original sources

bioRxiv2018

Connectome architecture, gene expression and functional co-activation shape the propagation of misfolded proteins in neurodegenerative disease

It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinsons disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding and prion-like propagation of endogenous -synuclein via axonal projections. However, the mechanisms that translate local \"synucleinopathy\" to large-scale network dysfunction and atrophy remain unknown. Here we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity and gene expression, and to predict sequential volume loss due to neurodegeneration. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence -synuclein concentration and local regional vulnerability. Functional co-activation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.

neuroscience↗

bioRxiv2018

Ghrelin enhances food odor conditioning in healthy humans: an fMRI study

Vulnerability to obesity includes eating in response to food cues, which acquire incentive value through conditioning. The conditioning process is largely subserved by dopamine, theorized to encode the discrepancy between expected and actual rewards, known as the reward prediction error (RPE). Ghrelin is a gut-derived homeostatic hormone that triggers hunger and eating. Despite extensive evidence that ghrelin stimulates dopamine, it remains unknown in humans if ghrelin modulates food cue learning. Here we show using functional magnetic resonance imaging that intravenously administered ghrelin increased RPE-related activity in dopamine-responsive areas during food odor conditioning in healthy volunteers. Participants responded faster to food odor-associated cues and perceived them to be more pleasant following ghrelin injection. Ghrelin also increased functional connectivity between hippocampus and ventral striatum. Our work demonstrates that ghrelin promotes the ability of cues to acquire incentive salience, and has implications for the development of vulnerability to obesity.

neuroscience↗

bioRxiv2017

Central Role of Cognitive Control Networks in Weight Loss During Voluntary Calorie Restriction

Insufficient responses to hypocaloric diets have been attributed to hormonal adaptations that override self-control of food intake. We tested this hypothesis by measuring brain fMRI reactivity to food cues and circulating energy-balance hormones in 24 overweight/obese participants before, and 1 and 3 months after starting a calorie restriction diet. Increased activity in prefrontal regions at month 1 correlated with weight loss at months 1 and 3. Weight loss was also correlated with increased plasma ghrelin and decreased leptin at month 1, and these changes were associated with greater food cue reactivity in reward-related brain regions. However, the reduction in leptin did not counteract weight loss; indeed, it was correlated with further weight loss at month 3. Activation in a network of prefrontal regions associated with self-control could contribute to individual differences in weight loss and maintenance, whereas we failed to find that the hormonal adaptations play a major role.

neuroscience↗

bioRxiv2017

Network Connectivity Predicts Cortical Thinning and Cognitive Decline in Early Parkinson’s Disease

Parkinsons Disease (PD) is a progressive neurodegenerative disorder characterized by motor and cognitive deficits. The neurodegenerative process is thought to move stereotypically from the brainstem up to the cerebral cortex, possibly reflecting the spread of toxic alpha-synuclein molecules. Using a large, longitudinal, multi-center database of de novo PD patients, we tested whether focal reductions in cortical thickness could be explained by disease spread from a subcortical \"disease reservoir\" along the brains connectome. PD patients (n=105) and matched controls (n=57) underwent T1-MRI at entry and one year later. Over this period, PD patients demonstrated significantly greater loss of cortical thickness than healthy controls in parts of the left occipital and bilateral frontal lobes and right somatomotor-sensory cortex. Cortical regions with greater connectivity (measured functionally or structurally) to a \"disease reservoir\" evaluated via MRI at baseline demonstrated greater atrophy one year later. The atrophy pattern in the ventral frontal lobes resembled one described in certain cases of Alzheimers disease. Moreover, a multiple linear regression model suggested that cortical thinning was associated with impaired cognitive function at follow-up. Our findings suggest that disease propagation to the cortex in PD follows neural connectivity, and that disease spread to the cortex may herald the onset of cognitive impairment.

neuroscience↗

bioRxiv2017

Anatomical And Functional Organization Of The Human Substantia Nigra And Its Connections

We investigated the anatomical and functional organization of the human substantia nigra (SN) using diffusion and functional MRI data from the Human Connectome Project. We identified a tripartite connectivity-based parcellation of SN with a limbic, cognitive and motor arrangement. The medial SN connects with limbic striatal and cortical regions and encodes value (greater response to monetary wins than losses during fMRI), while the ventral SN connects with associative regions of cortex and striatum and encodes salience (equal response to wins and losses). The lateral SN connects with somatomotor regions of striatum and cortex and also encodes salience. Connectivity within the value-coding medial SN network was associated with a measure of decisional impulsivity, while the salience-coding ventral SN network was associated with motor impulsivity. In sum, there is anatomical and functional heterogeneity of human SN, and separate SN networks underpin value versus salience coding, and impulsive choice versus impulsive action.

neuroscience↗