Biology subjects

Georgiou-Karistianis, N.

Publications and source records attributed to Georgiou-Karistianis, N..

6 recordsLinked to original sources

bioRxiv2025

Temporal Dynamics of Depression in Premanifest Huntington's Disease: A Network Dysconnection Approach

Background and objectivesDepression emerges years before motor signs in Huntington"s disease gene expansion carriers (HDGECs), yet how directional connectivity patterns evolve over time and relate to depression trajectories remains unknown. We hypothesized HDGECs with depression history would show accelerated grey matter atrophy and disinhibition of striatal-to-default mode network connections over time. MethodsThe study utilised the largest longitudinal study of premanifest HD, TrackOn-HD, including structural and resting-state brain scans. HDGECs were stratified by depression history and followed over three annual assessments. Analyses focused on 8 predefined regions spanning striatal and default mode network regions. Here, we applied spectral dynamic causal modelling to examine effective connectivity, alongside voxel-based morphometry of grey matter atrophy and linear mixed models of depressive symptoms. Spectral DCM employed Bayesian model reduction with free energy thresholds [≥]0.95 for strong evidence of connectivity changes. ResultsThe study included 105 HDGECs (53 females, mean age = 43, mean CAG = 43). Depression-related network dysconnection operated independently of regional grey matter atrophy, with HDGECs exhibiting widespread striatal volume loss but no differential atrophy patterns between depression groups. Larger posterior cingulate cortex volumes predicted increased depression severity specifically in HDGECs with depression history, across both Beck Depression Inventory-II ({beta} = 36.79, 95% CI = 2.33-71.25, p =.041) and Hospital Anxiety and Depression Scale-Depression Subscale ({beta} = 27.31, 95% CI = 11.12-43.50, p =.002). Spectral dynamic causal models explained 88.6% of variance in depression groups and 90.4% in non-depression groups. Longitudinal effective connectivity analyses revealed distinct dysconnection profiles: HDGECs with depression history showed widespread interhemispheric alterations including progressive inhibitory changes of striatal-DMN circuits and aberrant hippocampal regulatory control, while those without depression exhibited more focal dysconnection. These patterns occurred despite no group differences in grey matter atrophy trajectories over 24 months. DiscussionDepression in HDGECs emerges through network dysconnection that operates independently of regional atrophy. Functional alterations may precede detectable structural breakdown and represent pathological responses to subclinical neurodegenerative processes, suggesting functional connectivity markers may serve as early indicators of depression vulnerability in premanifest HD.

neuroscience↗

bioRxiv2021

The responsiveness of gait and balance outcomes to disease progression in Friedreich ataxia

ObjectiveTo identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA) we administered a battery of potential measures three times over a 12-month period. MethodsSixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, six months and 12 months. Outcomes included: GAITRite(R) spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25 Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. ResultsSenseWear Armband daily step count had the largest effect size of all the variables over six months (SRM=-0.615), while the PST medial-lateral index had the largest effect size (SRM=0.829) over 12 months. The FARS USS (SRM=0.824) and BBS (SRM=-0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p<0.001, SRM=-1.429). ConclusionsThe FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

neuroscience↗

bioRxiv2020

Perceptual Degradation Affects Stop-Signal Performance in Normal Healthy Adults

During stop-signal task performance, little is known how the quality of visual information of the go stimuli may indirectly affect the interplay between the go and stop processes. In this study, we assessed how perceptual degradation of the visual go stimuli affect response inhibition. Twenty-six healthy individuals (mean age 33.34 {+/-} 9.61) completed a modified 12-minute stop-signal task, where V and Y letters were used as visual go stimuli. The stimuli were subjected to four levels of perceptual degradation using Gaussian smoothing, to parametrically manipulate stop difficulty across low, intermediate-1, intermediate-2 and high difficulty conditions. On 33% of trials, the stop-signal (50ms audio tone) followed a go stimulus after a stop-signal delay, which was individually adjusted for each participant. As predicted, we found that with increased level of stop difficulty (little perceptual degradation), reaction times on go trials and the proportion of successful behavioural inhibitions on stop trials (P(i)) decreased in normal healthy adults. Contrary to our predictions, there was no effect of increased stop difficulty on the number of correct responses on go trials and reaction times on stop trials. Overall, manipulation of the completion time of the go process via perceptual degradation has been partially successful, whereby increased stop difficulty differentially affected P(i) and SSRT. These findings have implications for the relationship between the go and stop processes and the horse-race model, which may be limited in explaining the role of various cortico-basal ganglia loops in modulation of response inhibition. HighlightsO_LIManipulation of the completion time of the go process is partially successful C_LIO_LIPerceptual degradation differentially affects stop-signal performance C_LIO_LIIncreased stop difficulty (easy go) results in lower P(i) C_LIO_LIIncreased stop difficulty (easy go) has no effect on SSRT C_LIO_LIHorse-race model does not fully explain basal ganglia involvement in inhibition C_LI

neuroscience↗

bioRxiv2018

Compensation Related Utilization of Neural Circuits Hypothesis Model in Response Inhibition in Premanifest Huntington’s Disease

During premanifest stages of Huntingtons disease (pre-HD), individuals typically show increased functional brain activity thought to compensate for widespread brain anomalies. What remains unknown, is to disentangle whether increased functional brain activity reflects compensation or whether it is more of a product of HD-related pathological processes. We used a quantitative model of compensation, known as the CRUNCH (Compensation-Related Utilization of Neural Circuits Hypothesis) to characterise compensatory function in pre-HD using functional magnetic resonance imaging (fMRI). To test CRUNCH predictions, pre-HD individuals (n = 15) and age- and gender-matched controls (n = 15) performed a modified stop-signal task that incremented in four levels of stop difficulty (low, intermediate-1, intermediate-2, and high). Our results did not support the critical assumption of the CRUNCH model - controls did not show increased fMRI activity with increased level of stop difficulty. By contrast, controls showed decreased fMRI activity with increased stop difficulty in right inferior frontal gyrus pars triangularis and right caudate nucleus. Relative to controls, pre-HD individuals showed increased fMRI activity in right inferior frontal gyrus pars triangularis at intermediate-2 and high level of stop difficulty, which is the opposite effect to that predicted by the CRUNCH model. Contrary to the CRUNCH prediction, the pre-HD group showed decreased fMRI activity in right caudate nucleus at low level of stop difficulty, compared with controls. Further to this, fMRI activity patterns in right inferior frontal gyrus pars triangularis and right caudate nucleus were not accompanied by a decline in the number of successful behavioural stops in pre-HD. We therefore suggest that the CRUNCH model does not apply to characterise compensatory processes associated with response inhibition in pre-HD.\n\nHighlightsO_LICRUNCH does not apply to characterise compensation during stop-signal in pre-HD\nC_LIO_LIDeficits in inhibitory control in pre-HD occur 25 years prior to clinical diagnosis\nC_LIO_LICRUNCH may show signs of selective reporting\nC_LI

neuroscience↗

bioRxiv2018

Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA

BackgroundFriedreich ataxia is a recessively inherited, progressive neurological disease characterised by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of pathology in these structures.\n\nMethodsUsing in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n=20) and healthy controls (n=18) over a two-year period.\n\nResultsThe longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Moreover, atrophy was maximal in individuals early in the disease course, while the rate of iron concentration increased with disease progression.\n\nConclusionsProgressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

neuroscience↗

bioRxiv2018

To CRUNCH or not to CRUNCH: Task Difficulty Affects Functional Brain Reorganisation during Visuospatial Working Memory Performance in Premanifest Huntington’s Disease

Presymptomatic Huntingtons disease (pre-HD) individuals tend to increase functional brain activity to compensate for HD-related brain anomalies. We used a quantitative model of compensation, known as the CRUNCH (Compensation-Related Utilization of Neural Circuits Hypothesis) to explicitly characterise compensation in pre-HD. We acquired functionalmagnetic resonance imaging (fMRI) data (n = 15 pre-HD; n = 15 controls) during performance of an 18-minute fMRI visuospatial working memory task with low, intermediate-1, intermediate-2, and high memory loads. Consistent with the CRUNCH prediction, pre-HD individuals showed decreased fMRI activity in left intraparietal sulcus at high memory load, compared to healthy controls who showed increased fMRI activity in left intraparietal sulcus at high memory load. Contrary to the other CRUNCH prediction, the pre-HD group did not show compensatory increase in fMRI activity at lower levels of memory loads in left intraparietal sulcus. Our findings provide partial support for the validity of CRUNCH in pre-HD.\n\nHighlightsO_LIVisuospatial working memory deficits in pre-HD occur 25 years prior to predicted disease onset\nC_LIO_LITask demands differentially affect fMRI activity in left intraparietal sulcus\nC_LIO_LICRUNCH can partially apply in Huntingtons disease\nC_LI

neuroscience↗