The default mode network is disrupted in Parkinson's disease with visual hallucinations.

BACKGROUND: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinson's disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. METHODS: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. RESULTS: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. CONCLUSION: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher "connectivity" is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to "positive" symptom generation in PD.Contract grant sponsor: Research Grant Council of Hong Kong (General Research Fund awarded to Chua and McAlonan); Infrastructural support: National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and [Institute of Psychiatry] King's College London (McAlonan); Wellcome Trust; Contract grant number: 088324 (Rowe); National Institute for Health Research Cambridge Biomedical Research Centre (Suckling).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/hbm.2257

Epigenetic Age Acceleration Assessed with Human White-Matter Images

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample (n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρpheno = -0.119, p = 0.028), with evidence of shared genetic (ρgene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Visual hallucinations in Parkinson's disease : a multi-modal MRI investigation

Background Visual hallucinations (VH) are an important non-motor complication of Parkinson’s disease (PD) which carries a negative prognosis, but their biological basis is unclear. Multi-modal magnetic resonance imaging (MRI) can be used to evaluate structural and functional brain mechanisms underpinning VH in PD. Methods To assess cerebral microstructure and resting functional activities in patients with idiopathic PD and VH, I compared PD patients with VH (PDVH) and PD patients without VH (PDnonVH), while healthy controls (HC) were also recruited for comparison. Diffusion tensor imaging was used to calculate mean diffusivity (MD) and fractional anisotropy (FA). Structural MRI was used to calculate voxel-based intensity of grey matter (GM) and white matter (WM) across the entire brain and compared among groups. Furthermore, functional magnetic resonance imaging of the brain, acquired during rest, was processed to calculate the amplitude of low-frequency fluctuations (ALFF) and functional connectivity (FC) to inform a model of VH. In addition, hippocampal volume, shape, mean diffusivity and FC across the whole brain was further examined. Hippocampal dependent visual spatial memory performance was compared between groups, and predicted correlations with hippocampal microstructural indices and VH severity were tested. Results In the first study, PDVH had lower FA than both PDnonVH and HC in the right occipital lobe and left parietal lobe, but increased FA in the right infero-medial fronto-occipital fasciculus and posterior inferior longitudinal fasciculus. Moreover, PDVH patients showed less GM volume compared to PDnonVH in the right lingual gyrus of the occipital lobe. In the second study, PDVH patients compared to non-hallucinators showed lower ALFF in occipital lobes, with greater ALFF in temporo-parietal region, limbic lobe and right cerebellum. The PDVH group also showed alteration in functional connectivity between occipital region and corticostriatal regions. Finally in the third study, although there were no gross hippocampal volume and shape differences across groups, individuals with PDVH had higher diffusivity in hippocampus than PDnonVH and HC. Both PD groups had significantly poorer visuospatial memory compared to HC. Poorer visuospatial memory was correlated with higher hippocampal diffusivity in HC and more severe VH in the PDVH group.FC between hippocampus and primary visual cortex, dorsal/ventral visual pathways was also lower in PDVH than other groups, whereas FC between hippocampus and default mode network regions was greater in PDVH group compared to others. Conclusion Compared to PDnonVH groups, the PDVH group had multiple structural deficits in primary and associative visual cortices. In term of hemodynamic activity, the PDVH group had lower ALFF in occipital lobe, but greater ALFF in regions that comprise the dorsal visual pathway. Moreover, this lower ALFF in the primary visual cortex was accompanied by lower functional connectivity across components of the ventral/dorsal visual pathway in the PDVH group compared to the PDnonVH group. Moreover, evidence supporting a specific role for the hippocampus in PDVH was obtained. In the absence of gross macrostructural anomalies, hippocampal microstructure and functional connectivity was compromised in PDVH. I observed an association between visuospatial memory and hippocampal integrity and suggest that hippocampal pathology and consequent disruption in visuospatial memory plays a key contribution to VH in PD. Thus, in the PDVH group, "bottom-up" primary visual cortex and “top-down” visual association pathways and attentional networks appear to be disrupted.published_or_final_versionPsychiatryDoctoralDoctor of Philosoph

Altered hemodynamic activity in conduct disorder: a resting-state FMRI investigation.

Youth with conduct disorder (CD) not only inflict serious physical and psychological harm on others, but are also at greatly increased risk of sustaining injuries, developing depression or substance abuse, and engaging in criminal behaviors. The underlying neurobiological basis of CD remains unclear.The present study investigated whether participants with CD have altered hemodynamic activity under resting-state conditions.Eighteen medication-naïve boys with CD and 18 age- and sex- matched typically developing (TD) controls underwent functional magnetic resonance imaging (MRI) scans in the resting state. The amplitude of low-frequency fluctuations (ALFF) was measured and compared between the CD and TD groups.Compared with the TD participants, the CD participants showed lower ALFF in the bilateral amygdala/parahippocampus, right lingual gyrus, left cuneus and right insula. Higher ALFF was observed in the right fusiform gyrus and right thalamus in the CD participants compared to the TD group.Youth with CD displayed widespread functional abnormalities in emotion-related and visual cortical regions in the resting state. These results suggest that deficits in the intrinsic activity of resting state networks may contribute to the etiology of CD

ALFF result in participants with CD compared to TD participants.

<p>ALFF result in participants with CD compared to TD participants.</p

Multimodal MRI of the hippocampus in Parkinson's disease with visual hallucinations

Visual hallucinations carry poor prognosis in Parkinson’s disease. Here we tested the hypothesis that the hippocampus and visuospatial memory impairment play a central role in the pathology of PD with visual hallucinations. Multimodal magnetic resonance imaging of the brain was carried out in 12 people with PD and visual hallucinations; 15 PD individuals without hallucinations; and 14 healthy controls. Age, gender, cognitive ability, and education level were matched across the three groups. PD patients were taking dopaminergic medication. Hippocampal volume, shape, mean diffusivity (MD), and functional connectivity within the whole brain were examined. Visuospatial memory was compared between groups, and correlations with hippocampal MD, functional connectivity, and the severity of hallucinations were explored. There were no macrostructural differences across groups, but individuals with hallucinations had higher diffusivity in posterior hippocampus than the other two groups. Visuospatial memory was poorer in both PD groups compared to controls, and was correlated with hallucinations. Finally, hippocampal functional connectivity in the visual cortices was lower in those with hallucinations than other groups, and this correlated with visuospatial memory impairment. In contrast, functional connectivity between the hippocampus and default mode network regions and frontal regions was greater in the PD hallucinators compared to other groups. We suggest that hippocampal pathology, which disrupts visuospatial memory, makes a key contribution to visual hallucinations in PD. These findings may pave the way for future studies of imaging biomarkers to measure treatment response in those with PD who are most at risk of poor outcomes.link_to_OA_fulltex

Demographic characteristics and descriptive statistics for the CD and TD.

<p>SCARED = Screen for Child Anxiety Related Emotional Disorders; DSRS = Birleson Depression Self-Rating Scale. K-SADS-PL: the Schedule for Affective Disorder and Schizophrenia for School-Age Children-Present and Lifetime.</p><p>^a Chinese RMB (yuan) minimum monthly salary (per person).</p><p>Demographic characteristics and descriptive statistics for the CD and TD.</p