A multifaceted gradient in human cerebellum of structural and functional development.

The organization of the basic tissue and functional properties of the cerebellum across development is unknown. Combining several large datasets, we demonstrate in the human cerebellum a static tissue gradient in adults that mirrors a similar growth-rate gradient across development. Quantitative tissue metrics corroborate unique densities of certain lipids and proteins among lobules, and cerebellar structural development closely follows cerebellar functional properties through childhood.

Neurogenetic traits outline vulnerability to cortical disruption in Parkinson's disease.

The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson's disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex - such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.

Divergent connectomic organization delineates genetic evolutionary traits in the human brain.

The relationship between human brain connectomics and genetic evolutionary traits remains elusive due to the inherent challenges in combining complex associations within cerebral tissue. In this study, insights are provided about the relationship between connectomics, gene expression and divergent evolutionary pathways from non-human primates to humans. Using in vivo human brain resting-state data, we detected two co-existing idiosyncratic functional systems: the segregation network, in charge of module specialization, and the integration network, responsible for information flow. Their topology was approximated to whole-brain genetic expression (Allen Human Brain Atlas) and the co-localization patterns yielded that neuron communication functionalities-linked to Neuron Projection-were overrepresented cell traits. Homologue-orthologue comparisons using dN/dS-ratios bridged the gap between neurogenetic outcomes and biological data, summarizing the known evolutionary divergent pathways within the Homo Sapiens lineage. Evidence suggests that a crosstalk between functional specialization and information flow reflects putative biological qualities of brain architecture, such as neurite cellular functions like axonal or dendrite processes, hypothesized to have been selectively conserved in the species through positive selection. These findings expand our understanding of human brain function and unveil aspects of our cognitive trajectory in relation to our simian ancestors previously left unexplored.

In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline.

Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer's disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer's Coordinating Center cases providing three different LC measures (pigmentation, tangle density, and neuronal density), Braak staging, ß-amyloid, and longitudinal cognitive measures. Lower LC integrity was associated with elevated TAU deposition in the entorhinal cortex among unimpaired individuals consistent with postmortem correlations between LC tangle density and successive Braak staging. LC pigmentation ratings correlated with LC neuronal density but not with LC tangle density and were particularly worse at advanced Braak stages. In the context of elevated ß-amyloid, lower LC integrity and greater cortical tangle density were associated with greater TAU burden beyond the medial temporal lobe and retrospective memory decline. These findings support neuropathologic data in which early LC TAU accumulation relates to disease progression and identify LC integrity as a promising indicator of initial AD-related processes and subtle changes in cognitive trajectories of preclinical AD.

Cortical thickness across the lifespan in a Colombian cohort with autosomal-dominant Alzheimer's disease: A cross-sectional study.

INTRODUCTION: Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD). METHODS: Two hundred eleven participants (105 presenilin-1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers. RESULTS: Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. DISCUSSION: Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset.

Negative Impact of Sadness on Response Inhibition in Females: An Explicit Emotional Stop Signal Task fMRI Study.

Response inhibition is a critical cognitive ability underlying executive control over reactions to external cues, or inner requirements. Previous studies suggest that high arousal negative emotions (e.g., anger or fear) could impair response inhibition in implicit emotional stop signal tasks (eSSTs). However, studies exploring how low arousal negative emotions (e.g., sadness) influence response inhibition remain sparse. In the current study, 20 female college students performed an explicit eSST to explore the influence of sadness on response inhibition and its neural mechanism. Participants are instructed to press a button to sad or neutral facial stimuli while inhibiting their response during the presentation of a stop signal. Results showed that compared with neutral stimuli, sad stimuli were related to increased stop signal reaction time (SSRT) (i.e., worse response inhibition). Compared with neutral condition, higher activation during sad condition was found within the right superior frontal gyrus (SFG), right insula, right middle cingulate cortex (MCC), bilateral superior temporal gyrus (STG), left lingual gyrus, and right motor cortex. These findings indicated that sadness, like other negative emotions, may impair response inhibition in an explicit way and highlight the explicit eSST as a new paradigm to investigate the subtle interaction between negative emotion processing and cognitive control.

Central neurogenetic signatures of the visuomotor integration system.

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.

Associations of Widowhood and ß-Amyloid With Cognitive Decline in Cognitively Unimpaired Older Adults.

Importance: To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults. Objective: To determine whether widowhood status and level of brain ß-amyloid (ie, the Alzheimer disease pathologic protein) are additively or interactively associated with cognitive decline among cognitively unimpaired older adults. Design, Setting, and Participants: In this cohort study, 257 married, widowed, and unmarried (ie, never married, divorced, or separated) participants from the Harvard Aging Brain Study longitudinal cohort underwent baseline evaluation of neocortical ß-amyloid levels using Pittsburgh compound B positron emission tomography and 4 annual cognitive assessments. Data were collected from September 2010 to February 2017 and analyzed from July 2018 to July 2019. Main Outcomes and Measures: Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite. Results: Of the 257 participants, 153 (59.5%) were women, and the mean (SD) age was 73.5 (6.1) years; 145 participants (56.4%) were married (66 [45.5%] women), 77 (30.0%) were unmarried (56 [72.7%] women), and 35 (13.6%) were widowed (31 [88.6%] women). Compared with married participants, widowed participants demonstrated worsening cognitive performance after adjusting for age, sex, socioeconomic status, depression, and ß-amyloid levels (ß = -0.11; 95% CI, -0.19 to -0.04; P = .002) with no difference observed between married and unmarried participants. Furthermore, widowed participants with higher baseline ß-amyloid levels exhibited steeper cognitive decline (ß = -0.22; 95% CI, -0.42 to -0.03; P = .02), indicating both independent and interactive associations of ß-amyloid levels and widowhood with cognition. In a secondary model using dichotomous ß-amyloid-marital status groupings, the rate of cognitive decline among widowed participants with high ß-amyloid was nearly 3 times faster than among married participants with high ß-amyloid (widowed, high ß-amyloid: ß, -0.33; 95% CI, -0.46 to -0.19; P < .001; married, high ß-amyloid: ß, -0.12; 95% CI, -0.18 to -0.01; P < .001). Conclusions and Relevance: In a sample of cognitively unimpaired older adults, being widowed was associated with accelerated ß-amyloid-related cognitive decline during 3 years. Cognitively unimpaired, widowed older adults were particularly susceptible to Alzheimer disease clinical progression, emphasizing the need for increased research attention and evidenced-based interventions for this high-risk group.

Altered brain network organization in romantic love as measured with resting-state fMRI and graph theory.

Romantic love is a complex state that has been seen as similar to addiction. Previous task-based functional magnetic resonance imaging (fMRI) studies have shown that being in love is closely associated with functional brain changes in the reward and motivation system. However, romantic love-related functional connectivity network organization in resting-state fMRI has yet to be elucidated. To that end, here we used resting-state fMRI and graph theory to compare whole-brain functional network topology between an "in-love" group (n = 34, 16 females, currently in love and in a romantic relationship) and a "single" group (n = 32, 14 females, never in love and not in a romantic relationship). Compared to the single group, we found lower network segregation in the love group (i.e., lower small-worldness, mean clustering coefficient, and modularity), and these metrics were negatively associated with scores on the Passionate Love Scale (PLS) (an index of intense passionate/romantic love). Additionally, the love group displayed altered connectivity degree (reflecting the importance of a node): decreased degree in left angular gyrus and left medial orbitofrontal cortex, but increased degree in left fusiform gyrus. Furthermore, local efficiency or degree of these regions was significantly correlated to PLS scores. Taken together, results showed decreased overall brain functional segregation but enhanced emotional-social processing in romantic lovers. These findings provide the first evidence of love-related brain network organization changes and suggest similar but different brain network alterations between romantic love and addiction, providing new insights on the neural systems underlying romantic love.

Distance disintegration delineates the brain connectivity failure of Alzheimer's disease.

Alzheimer's disease (AD) is associated with brain network dysfunction. Network-based investigations of brain connectivity have mainly focused on alterations in the strength of connectivity; however, the network breakdown in AD spectrum is a complex scenario in which multiple pathways of connectivity are affected. To integrate connectivity changes that occur under AD-related conditions, here we developed a novel metric that computes the connectivity distance between cortical regions at the voxel level (or nodes). We studied 114 individuals with mild cognitive impairment, 24 with AD, and 27 healthy controls. Results showed that areas of the default mode network, salience network, and frontoparietal network display a remarkable network separation, or greater connectivity distances, from the rest of the brain. Furthermore, this greater connectivity distance was associated with lower global cognition. Overall, the investigation of AD-related changes in paths and distances of connectivity provides a novel framework for characterizing subjects with cognitive impairment; a framework that integrates the overall network topology changes of the brain and avoids biases toward unreferenced connectivity effects.

Neurofilament-lysosomal genetic intersections in the cortical network of stuttering.

The neurobiological underpinnings of stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent developments in the field have afforded researchers the ability to pinpoint several genetic profiles associated with stuttering, how these specific genetic backgrounds impact neuronal circuits and how they generate or facilitate the emergence of stuttered speech remains unknown. In this study, we identified the large-scale cortical network that characterizes stuttering using functional connectivity MRI and graph theory. We performed a spatial similarity analysis that examines whether the topology of the stuttering cortical network intersects with genetic expression levels of previously reported genes for stuttering from the protein-coding transcriptome data of the Allen Human Brain Atlas. We found that GNPTG - a gene involved in the mannose-6-phosphate lysosomal targeting pathways - was significantly co-localized with the stuttering cortical network. An enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization (NEFH, NEFL and INA). The relationship between lysosomal pathways, cytoskeleton organization, and stuttering, was investigated by comparing the genetic interactome between GNPTG and the neurofilament genes implicated in the current study. We found that genes of the interactome network, including CDK5, SNCA, and ACTB, act as functional links between lysosomal and neurofilament genes. These findings support the notion that stuttering is due to a lysosomal dysfunction, which has deleterious effects on the neurofilament organization of the speech neuronal circuits. They help to elucidate the intriguing, unsolved link between lysosomal mutations and the presence of stuttering.

Functional and Pathological Correlates of Judgments of Learning in Cognitively Unimpaired Older Adults.

Judgments of learning (JOL) pertain to introspective metamemory processes evaluating how well information is learned. Using a functional magnetic resonance imaging (fMRI) task, we investigated the neural substrates of JOL predictions in a group of 105 cognitively unimpaired older adults from the Harvard Aging Brain Study. Associations of JOL performance and its neural correlates with amyloid-ß (Aß) and tau pathology, two proteinopathies associated with Alzheimer's disease (AD) and aging, were also examined. We found that trials judged as learned well relative to trials judged as learned less well (high JOL > low JOL) engaged the ventromedial prefrontal cortex and precuneus, among other midline regions, in addition to bilateral hippocampi. In this cohort of older adults, greater levels of entorhinal tau deposition were associated with overestimation of memory performance and with lower fMRI signal in midline regions during predicted memory success. No associations with Aß were found. The findings suggest that tau pathology in unimpaired older adults may play a role in altered metamemory processes. We discuss our findings in light of the hypothesis that JOLs are partially dependent on a process involving attempts to retrieve a correct answer from memory, as well as implications for clinical research investigating unawareness of memory performance (i.e., anosognosia) in patients with AD dementia.

Decreased meta-memory is associated with early tauopathy in cognitively unimpaired older adults.

The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aß) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aß-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase.

Social Engagement and Amyloid-ß-Related Cognitive Decline in Cognitively Normal Older Adults.

OBJECTIVE: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-ß, the Alzheimer's disease (AD) pathologic marker. METHODS: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-ß was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-ß on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-ß on change in social engagement. RESULTS: Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-ß-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (ß = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (ß = 1.1, p = 0.02). This association was not modified by amyloid-ß, and there was no direct association of amyloid-ß with change in social engagement. CONCLUSIONS: Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.

Regional tau pathology and loneliness in cognitively normal older adults.

Loneliness is a perception of social and emotional isolation that increases in prevalence among older adults during the eighth decade of life. Loneliness has been associated with higher brain amyloid-ß deposition, a biologic marker of Alzheimer's disease, in cognitively normal older adults, suggesting a link with preclinical Alzheimer's disease pathophysiology. This study examined whether greater loneliness was associated with tau pathology, the other defining feature of Alzheimer's disease, in 117 cognitively normal older adults. Using flortaucipir positron emission tomography, we measured tau pathology in the entorhinal cortex, a region of initial accumulation in aging adults with or without elevated amyloid-ß, and in the inferior temporal cortex, a region of early accumulation typically associated with elevated amyloid-ß and memory impairment. Loneliness was measured by self-report using the 3-item UCLA-loneliness scale. We found that higher tau pathology in the right entorhinal cortex was associated with greater loneliness, controlling for age, sex, and apolipoprotein E ε4, the Alzheimer's disease genetic risk marker. This association remained significant after further adjustment for socioeconomic status, social network, depression and anxiety scores, and memory performance. There was no association of inferior temporal cortical or left entorhinal tau pathology with loneliness. Exploratory whole-brain surface maps supported these findings and identified additional clusters correlating loneliness and tau in the right fusiform gyrus. These results provide further support for loneliness as a socioemotional symptom in preclinical Alzheimer's disease.

Neurogenetic contributions to amyloid beta and tau spreading in the human cortex.

Tau and amyloid beta (Aß) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aß and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aß accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aß propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as 'axon related' and the Aß profile as 'dendrite related'. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aß in vivo propagation in the human brain.

Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals.

The biological mechanisms that link Beta-amyloid (Aß) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aß-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aß-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aß burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aß burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage.

Improving Relationships by Elevating Positive Illusion and the Underlying Psychological and Neural Mechanisms.

Romantic relationships are difficult to maintain novel and exciting for long periods of time, and individuals in love are known to engage in a variety of efforts to protect and maintain their romantic relationship. How to protect and maintain these relationships more effectively has, however, plagued people, psychologists, and therapists. Intimate partners typically perceive their relationship and their partners in a positive light or bias, a phenomenon called positive illusion. Interestingly, higher levels of positive illusion between partners have been associated with a decreased risk for relationship dissolution, as well as higher satisfaction, and less conflict or doubt in relationships. These findings indicate that elevating positive illusion amongst romantic partners may be of benefit and improve romantic relationships. In the present article, we discuss solving the paradox of positive illusion. As positive illusion may have relationship-enhancing attributes, we discuss the psychological and neural mechanisms that may underlie positive illusion. By elucidating the mechanisms underlying positive illusion, we shine a spotlight on potential future directions for research that aims to improve positive illusion and thus enhance the satisfaction and longevity of romantic relationships.

Definition of Substance and Non-substance Addiction.

Substance addiction (or drug addiction) is a neuropsychiatric disorder characterized by a recurring desire to continue taking the drug despite harmful consequences. Non-substance addiction (or behavioral addiction) covers pathological gambling, food addiction, internet addiction, and mobile phone addiction. Their definition is similar to drug addiction but they differ from each other in specific domains. This review aims to provide a brief overview of past and current definitions of substance and non-substance addiction, and also touches on the topic of diagnosing drug addiction and non-drug addiction, ultimately aiming to further the understanding of the key concepts needed for a foundation to study the biological and psychological underpinnings of addiction disorders.