Search

Introduction Decision-making and learning impairments are core characteristics of a wide range of psychiatric disorders--such as major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia--and are linked to their specific [...], Background: Decision-making alterations are present in psychiatric illnesses like major depressive disorder (MDD), obsessivecompulsive disorder (OCD), and schizophrenia, linked to symptoms of the respective disorders. We sought to analyze unique and shared decision-making alterations in these disorders, which is crucial for early diagnosis and treatment, especially given potential comorbidities. Methods: Using 2 computational modelling approaches--logistic regression and hierarchical Bayesian modelling--we analyzed alterations in model-based and model-free decision-making in a transdiagnostic cohort of patients with MDD, OCD, or schizophrenia. Our aim was to identify disorder-specific and shared alterations and their associations with symptoms. Results: We included 23 patients with MDD, 25 patients with OCD, 27 patients with schizophrenia, and 25 controls. Overall, participants of all groups relied on model-free decision-making. Patients with schizophrenia had the lowest learning rate and highest switching rate, indicating low perseverance. Furthermore, patients with OCD were more random in both task stages than controls and patients with MDD. All patient groups exhibited more randomness in responses than controls, with the schizophrenia group showing the highest levels. Increased model- free behaviour correlated with elevated depressive symptoms, and more model-based decision-making was linked to lower anhedonia levels across all patient groups. Limitations: The sample size in each group was small. Conclusion: This study highlights disorder-specific and shared decision-making alterations among people with MDD, OCD, or schizophrenia. Our findings suggest that anhedonia and depressive symptoms, which are present in all 3 disorders, share underlying behavioural mechanisms. Improving model-based behaviour may be a target for intervention and treatment. Furthermore, completely random behaviour in the 2-step task appears to distinctly differentiate patients with schizophrenia in remission.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p

Functional connectivity of blood oxygenation level dependent signal fluctuations (BOLD-FC) is decreased in Alzheimer's disease (AD), and suggested to reflect reduced coherence in neural population activity; however, as both neuronal and vascular-hemodynamic processes underlie BOLD signals, impaired perfusion might also contribute to reduced BOLD-FC; 42 AD patients and 27 controls underwent simultaneous PET/MR imaging. Resting-state functional MRI assessed BOLD co-activity to quantify BOLD-FC, pulsed arterial spin labeling (pASL) assessed cerebral blood flow (CBF) as proxy for vascular hemodynamics, and 18F-fluorodeoxyglucose PET assessed glucose metabolism (GluMet) to index neuronal activity. Patients' BOLD-FC, CBF, and GluMet were reduced within the same precuneal parietal regions. BOLD-FC was positively associated with mean CBF, specifically in patients and controlled for GluMet levels, suggesting that BOLD-FC reductions correlate with pASL-derived hypoperfusion in AD, independently from 18F-fluorodeoxyglucose PET-derived hypometabolism. Data indicate that impaired vascular hemodynamic processes contribute to reduced BOLD connectivity in AD.

Background: Early regulatory problems (RPs), i.e., problems with crying, sleeping, and/or feeding during the first years, increase the risk for avoidant personality traits in adulthood, associated with social withdrawal and anxiety. Even more, RPs are linked with functional alterations in the adult default mode and salience networks, comprising the brain's allostatic‐interoceptive system (AIS) and playing a role in social interactions. We investigated whether RPs assessed in infancy are associated with difficulties in adult peer relationships mediated by functional alterations of the AIS. Methods: As part of a large case‐controlled prospective study, 42 adults with previous RPs and 70 matched controls (mean age = 28.48, SD = 2.65, 51% male) underwent fMRI during rest. The analysis focused on the intrinsic functional connectivity (iFC) of key nodes of the AIS. Peer relationship quality was assessed via a semi‐structured Life Course Interview and the YASR scale. In these same individuals, RPs were assessed at ages 5, 20 and 56 months. Results: RPs in infancy were associated with lower‐quality peer relationships and enhanced functional connectivity of the AIS nodes in adulthood, with a stronger effect for multiple and persistent RPs compared with transient‐multiple or single‐persistent RPs. Importantly, iFC changes of the dorsal mid insula, a primary interoceptive cortex with frontal and temporal regions, mediated the relationship between early RPs and adult peer relationship quality. Conclusions: Results indicate long‐lasting social and neural changes associated with early RPs. Our findings further implicate the AIS in both interoceptive and social processes, while indicating the need for early screening of early RPs. [ABSTRACT FROM AUTHOR]

The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer's disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events.

Despite substantial neuroscience research in the last decade revealing the claustrum's prominent role in mammalian forebrain organization, as evidenced by its extraordinarily widespread connectivity pattern, claustrum studies in humans are rare. This is particularly true for studies focusing on claustrum connections. Two primary reasons may account for this situation: First, the intricate anatomy of the human claustrum located between the external and extreme capsule hinders straightforward and reliable structural delineation. In addition, the few studies that used diffusion‐weighted‐imaging (DWI)‐based tractography could not clarify whether in vivo tractography consistently and reliably identifies claustrum connections in humans across different subjects, cohorts, imaging methods, and connectivity metrics. To address these issues, we combined a recently developed deep‐learning‐based claustrum segmentation tool with DWI‐based tractography in two large adult cohorts: 81 healthy young adults from the human connectome project and 81 further healthy young participants from the Bavarian longitudinal study. Tracts between the claustrum and 13 cortical and 9 subcortical regions were reconstructed in each subject using probabilistic tractography. Probabilistic group average maps and different connectivity metrics were generated to assess the claustrum's connectivity profile as well as consistency and replicability of tractography. We found, across individuals, cohorts, DWI‐protocols, and measures, consistent and replicable cortical and subcortical ipsi‐ and contralateral claustrum connections. This result demonstrates robust in vivo tractography of claustrum connections in humans, providing a base for further examinations of claustrum connectivity in health and disease. [ABSTRACT FROM AUTHOR]

IntroductionChanges in intrinsic functional connectivity (iFC) have been reported at various stages of the Alzheimer's disease (AD) spectrum. We aimed to investigate such alterations over a variety of large-scale intrinsic brain networks (iBNs) across the spectrum of amyloid β positivity and uncover their relation to cognitive impairment.MethodsEight iBNs were defined from resting-state functional magnetic resonance imaging data. In amyloid β-positive healthy subjects, prodromal, and AD patients (N = 70), within-network iFC (intra-iFC) and between-network iFC (inter-iFC) were correlated with scores of cognitive impairment.ResultsAcross all iBNs, a general degradation in intra-iFC along the scale of cognitive impairment severity was found. Only subtle changes in inter-iFC were identified.DiscussionAcross the AD spectrum, changes in iFC that are strongly related to cognitive impairment occur within an extensive variety of networks.

Very early Alzheimer's disease (AD) - i.e., AD at stages of mild cognitive impairment (MCI) and mild dementia - is characterized by progressive structural and neuropathologic changes, such as atrophy or tangle deposition in medial temporal lobes, including hippocampus and entorhinal cortex and also adjacent amygdala. While progressively disrupted intrinsic connectivity of hippocampus with other brain areas has been demonstrated by many studies, amygdala connectivity was rarely investigated in AD, notwithstanding its known relevance for emotion processing and mood disturbances, which are both important in early AD. Intrinsic functional connectivity (iFC) patterns of hippocampus and amygdala overlap in healthy persons. Thus, we hypothesized that increased alteration of iFC patterns along AD is not limited to the hippocampus but also concerns the amygdala, independent from atrophy. To address this hypothesis, we applied structural and functional resting-state MRI in healthy controls (CON, n = 33) and patients with AD in the stages of MCI (AD-MCI, n = 38) and mild dementia (AD-D, n = 36). Outcome measures were voxel-based morphometry (VBM) values and region-of-interest-based iFC maps of basolateral amygdala, which has extended cortical connectivity. Amygdala VBM values were progressively reduced in patients (CON > AD-MCI and AD-D). Amygdala iFC was progressively reduced along impairment severity (CON > AD-MCI > AD-D), particularly for hippocampus, temporal lobes, and fronto-parietal areas. Notably, decreased iFC was independent of amygdala atrophy. Results demonstrate progressively impaired amygdala intrinsic connectivity in temporal and fronto-parietal lobes independent from increasing amygdala atrophy in very early AD. Data suggest that early AD disrupts intrinsic connectivity of medial temporal lobe key regions, including that of amygdala.

Amyloid-β pathology (Aβ) and impaired cognition characterize Alzheimer's disease (AD); however, neural mechanisms that link Aβ-pathology with impaired cognition are incompletely understood. Large-scale intrinsic connectivity networks (ICNs) are potential candidates for this link: Aβ-pathology affects specific networks in early AD, these networks show disrupted connectivity, and they process specific cognitive functions impaired in AD, like memory or attention. We hypothesized that, in AD, regional changes of ICNs, which persist across rest- and cognitive task-states, might link Aβ-pathology with impaired cognition via impaired intrinsic connectivity. Pittsburgh compound B (PiB)-positron emission tomography reflecting in vivo Aβ-pathology, resting-state fMRI, task-fMRI, and cognitive testing were used in patients with prodromal AD and healthy controls. In patients, default mode network's (DMN) functional connectivity (FC) was reduced in the medial parietal cortex during rest relative to healthy controls, relatively increased in the same region during an attention-demanding task, and associated with patients' cognitive impairment. Local PiB-uptake correlated negatively with DMN connectivity. Importantly, corresponding results were found for the right lateral parietal region of an attentional network. Finally, structural equation modeling confirmed a direct influence of DMN resting-state FC on the association between Aβ-pathology and cognitive impairment. Data provide evidence that disrupted intrinsic network connectivity links Aβ-pathology with cognitive impairment in early AD.

There is striking overlap between the spatial distribution of amyloid-β pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-β and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-β plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-β exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-β on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-β and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-β on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-β distributions. Here we compared spatial patterns of amyloid-β-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-β and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-β aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-β-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-β pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-β-plaque concentration. The local negative association between amyloid-β and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-β on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-β and intrinsic connectivity, with the distribution of amyloid-β pathology following functional connectivity gradients within and across intrinsic networks.

In Alzheimer's disease (AD), recent findings suggest that amyloid-β (Aβ)-pathology might start 20-30 years before first cognitive symptoms arise. To account for age as most relevant risk factor for sporadic AD, it has been hypothesized that lifespan intrinsic (i.e., ongoing) activity of hetero-modal brain areas with highest levels of functional connectivity triggers Aβ-pathology. This model induces the simple question whether in older persons without any cognitive symptoms intrinsic activity of hetero-modal areas is more similar to that of symptomatic patients with AD or to that of younger healthy persons. We hypothesize that due to advanced age and therefore potential impact of pre-clinical AD, intrinsic activity of older persons resembles more that of patients than that of younger controls. We tested this hypothesis in younger (ca. 25 years) and older healthy persons (ca. 70 years) and patients with mild cognitive impairment and AD-dementia (ca. 70 years) by the use of resting-state functional magnetic resonance imaging, distinct measures of intrinsic brain activity, and different hierarchical clustering approaches. Independently of applied methods and involved areas, healthy older persons' intrinsic brain activity was consistently more alike that of patients than that of younger controls. Our result provides evidence for larger similarity in intrinsic brain activity between healthy older persons and patients with or at-risk for AD than between older and younger ones, suggesting a significant proportion of pre-clinical AD cases in the group of cognitively normal older people. The observed link of aging and AD with intrinsic brain activity supports the view that lifespan intrinsic activity may contribute critically to the pathogenesis of AD.

Background and Hypothesis Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. Study Design We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. Study Results We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. Conclusions Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia. [ABSTRACT FROM AUTHOR]