Intrinsic Infant Hippocampal Function Supports Inhibitory Processing.

Impaired cerebral inhibition is commonly observed in neurodevelopmental disorders and may represent a vulnerability factor for their development. The hippocampus plays a key role in inhibition among adults and undergoes significant and rapid changes during early brain development. Therefore, the structure represents an important candidate region for early identification of pathology that is relevant to inhibitory dysfunction. To determine whether hippocampal function corresponds to inhibition in the early postnatal period, the present study evaluated relationships between hippocampal activity and sensory gating in infants 4-20 weeks of age (N = 18). Resting-state functional magnetic resonance imaging was used to measure hippocampal activity, including the amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF. Electroencephalography during a paired-stimulus paradigm was used to measure sensory gating (P50). Higher activity of the right hippocampus was associated with better sensory gating (P50 ratio), driven by a reduction in response to the second stimulus. These findings suggest that meaningful effects of hippocampal function can be detected early in infancy. Specifically, higher intrinsic hippocampal activity in the early postnatal period may support effective inhibitory processing. Future work will benefit from longitudinal analysis to clarify the trajectory of hippocampal function, alterations of which may contribute to the risk of neurodevelopmental disorders and represent an intervention target.

Hippocampal, basal ganglia and olfactory connectivity contribute to cognitive impairments in Parkinson's disease.

Cognitive impairment is increasingly recognized as a characteristic feature of Parkinson's disease (PD), yet relatively little is known about its underlying neurobiology. Previous investigations suggest that dementia in PD is associated with subcortical atrophy, but similar studies in PD with mild cognitive impairment have been mixed. Variability in cognitive phenotypes and diversity of PD symptoms suggest that a common neuropathological origin results in a multitude of impacts within the brain. These direct and indirect impacts of disease pathology can be investigated using network analysis. Functional connectivity, for instance, may be more sensitive than atrophy to decline in specific cognitive domains in the PD population. Fifty-eight participants with PD underwent a neuropsychological test battery and scanning with structural and resting state functional MRI in a comprehensive whole-brain association analysis. To investigate atrophy as a potential marker of impairment, structural gray matter atrophy was associated with cognitive scores in each cognitive domain using voxel-based morphometry. To investigate connectivity, large-scale networks were correlated with voxel time series and associated with cognitive scores using distance covariance. Structural atrophy was not associated with any cognitive domain, with the exception of visuospatial measures in primary sensory and motor cortices. In contrast, functional connectivity was associated with attention, executive function, language, learning and memory, visuospatial, and global cognition in the bilateral hippocampus, left putamen, olfactory cortex, and bilateral anterior temporal poles. These preliminary results suggest that cognitive domain-specific networks in PD are distinct from each other and could provide a network signature for different cognitive phenotypes.

Functional magnetic resonance imaging of headache: Issues, best-practices, and new directions, a narrative review.

OBJECTIVE: To ensure readers are informed consumers of functional magnetic resonance imaging (fMRI) research in headache, to outline ongoing challenges in this area of research, and to describe potential considerations when asked to collaborate on fMRI research in headache, as well as to suggest future directions for improvement in the field. BACKGROUND: Functional MRI has played a key role in understanding headache pathophysiology, and mapping networks involved with headache-related brain activity have the potential to identify intervention targets. Some investigators have also begun to explore its use for diagnosis. METHODS/RESULTS: The manuscript is a narrative review of the current best practices in fMRI in headache research, including guidelines on transparency and reproducibility. It also contains an outline of the fundamentals of MRI theory, task-related study design, resting-state functional connectivity, relevant statistics and power analysis, image preprocessing, and other considerations essential to the field. CONCLUSION: Best practices to increase reproducibility include methods transparency, eliminating error, using a priori hypotheses and power calculations, using standardized instruments and diagnostic criteria, and developing large-scale, publicly available datasets.

Hemodynamic responses are abnormal in isolated cervical dystonia.

Neuroimaging studies using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting the changes in blood oxygenation levels, are advancing our understanding of the pathophysiology of dystonia. Neurobiological disturbances in dystonia, however, may affect neurovascular coupling and impact the interpretability of fMRI studies. We evaluated here whether the hemodynamic response patterns during a behaviorally matched motor task are altered in isolated cervical dystonia (CD). Twenty-five CD patients and 25 healthy controls (HCs) underwent fMRI scanning during a paced finger tapping task (nondystonic task in patients). Imaging data were analyzed using a constrained principal component analysis-a statistical method that combines regression analysis and principal component analysis and enables the extraction of task-related functional networks and determination of the spatial and temporal hemodynamic response patterns associated with the task performance. Data from three patients and two controls were removed due to excessive movement. No significant differences in demographics or motor performance were observed. Three task-associated functional brain networks were identified. During task performance, reduced hemodynamic responses were seen in a sensorimotor network and in a network that included key nodes of the default mode, executive control and visual networks. During rest, reductions in hemodynamic responses were seen in the cognitive/visual network. Lower hemodynamic responses within the primary sensorimotor network in patients were correlated with the increased dystonia severity. Pathophysiological disturbances in isolated CD, such as alterations in inhibitory signaling and dopaminergic neurotransmission, may impact neurovascular coupling. Not accounting for hemodynamic response differences in fMRI studies of dystonia could lead to inaccurate results and interpretations.

Childhood Metabolic Biomarkers Are Associated with Performance on Cognitive Tasks in Young Children.

OBJECTIVE: To evaluate the hypothesis that metabolic measures (fasting glucose, insulin, and Homeostatic Model of Assessment for Insulin Resistance [HOMA-IR] levels) are inversely associated with performance on cognitive tasks using data from young (4- to 6-year-old), typically developing, healthy children. STUDY DESIGN: Data were obtained from children participating in the Healthy Start study, a pre-birth cohort in Colorado. HOMA-IR, glucose, and insulin values were centered and scaled using the study sample means and SD. Thus, they are reported in number of SD units from the mean. Fully corrected T scores for inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort test), and receptive language (Picture Vocabulary test) were obtained via the National Institutes of Health Toolbox cognition battery. RESULTS: Children included in this analysis (n = 137) were 4.6 years old, on average. Per 1-SD unit, fasting glucose (B = -2.0, 95% CI -3.5, -0.5), insulin (B = -1.7, 95% CI -3.0, -0.4), and HOMA-IR values (B = -1.8, 95% CI -3.1, -0.5) were each significantly and inversely associated with inhibitory control (P < .05 for all, respectively). Fasting glucose levels were also inversely associated with cognitive flexibility (B = -2.0, 95% CI -3.7, -0.2, P = .03). CONCLUSIONS: Our data suggest that metabolic health may impact fluid cognitive function in healthy, young children.

The epileptic network and cognition: What functional connectivity is teaching us about the childhood epilepsies.

Our objective was to summarize and evaluate the rapidly expanding body of literature studying functional connectivity in childhood epilepsy. In the self-limited childhood epilepsies, awareness of cognitive comorbidities has been steadily increasing, and recent advances in our understanding of the network effects of these disorders promise insights into the underlying neurobiology. We reviewed publications addressing functional connectivity in children with epilepsy with an emphasis on studies of children with self-limited childhood epilepsies. The majority of studies have been published in the past 10 years and predominantly examine childhood epilepsy with centrotemporal spikes and childhood absence epilepsy. Cognitive network alterations are commonly observed across the childhood epilepsies. Some of these effects appear to be nonspecific to epilepsy syndrome or even to category of neurological disorder. Other patterns, such as changes in the connectivity of cortical language areas in childhood epilepsy with centrotemporal spikes, provide clues to the underlying cognitive deficits seen in affected children. The literature to date is dominated by general observations of connectivity patterns without a priori hypotheses. These data-driven studies build an important foundation for hypothesis generation and are already providing useful insights into the neuropathology of the childhood epilepsies. Future work should emphasize hypothesis-driven approaches and rigorous clinical correlations to better understand how the knowledge of network alterations can be applied to guidance and treatment for the children in our clinics.

Association of Working Memory With Distributed Executive Control Networks in Schizophrenia.

OBJECTIVE: Working memory impairments represent a core cognitive deficit in schizophrenia, predictive of patients' daily functioning, and one that is unaffected by current treatments. To address this, working memory is included in the MATRICS Consensus Cognitive Battery (MCCB), a standardized cognitive battery designed to facilitate drug development targeting cognitive symptoms. However, the neurobiology underlying these deficits in MCCB working memory is currently unknown, mirroring the poor understanding in general of working memory deficits in schizophrenia. METHODS: Twenty-eight participants with schizophrenia were administered working memory tests from the MCCB and examined with resting-state functional MRI. Intrinsic connectivity networks were estimated with independent component analysis. Each voxel's time series was correlated with each network time series, creating a feature vector for voxel-level connectivity analysis. This feature vector was associated with working memory by using the distance covariance statistic. RESULTS: The neurobiology of MCCB working memory tests largely followed the multicomponent model of working memory but revealed unexpected differences. The dorsolateral prefrontal cortex was not associated with working memory. The central executive system was instead associated with delocalized right and left executive control networks. The phonologic loop within the multicomponent model, a subsystem involved in storing linguistic information, was associated with connectivity to the left temporoparietal junction and inferior frontal gyrus. However, connections to the language network did not predict working memory test performance. CONCLUSIONS: These results provide supporting evidence for the multicomponent model of working memory in terms of the biology underlying MCCB findings.

Alpha7 Nicotinic Receptors as Therapeutic Targets in Schizophrenia.

While current treatments for schizophrenia often provide much relief for positive symptoms such as hallucinations, other symptoms, particularly cognitive deficits, persist and contribute to substantial suffering and reduced quality of life for patients. In searching for novel therapeutic avenues to treat cognitive deficits in schizophrenia, recent work is exploring nicotinic receptor neurobiology. Supported by a large body of evidence, with contributions from studies of smoking behaviors, genetics, receptor distribution and function, animal models and nicotinic effects on illness symptoms, the alpha7 nicotinic receptor has emerged as a potential therapeutic target. Despite promise in early clinical trials, however, no drug targeting nicotinic systems has succeeded in larger phase 3 trials. Following a brief review of nicotinic receptor biology and the evidence that has led to pursuit of alpha7 nicotinic agonism as a therapeutic strategy, this review will provide an update on the status of recent trials, discuss potential issues that may have contributed to negative outcomes, and point to new directions and promising advances in developing alpha7 nicotinic receptor-based treatment for cognitive symptoms in schizophrenia. IMPLICATIONS: By examining alpha7 nicotinic receptor biology and recent efforts to target the receptor in clinical trials, it is hoped that investigators will be motivated to explore novel, promising directions focusing on the receptor as a strategy to treat cognitive symptoms in schizophrenia.

Exposure to maternal diabetes in utero and offspring eating behavior: The EPOCH study.

The risk of becoming overweight among offspring exposed to gestational diabetes (GDM) in utero is two-fold higher than in the general population. The responsible mechanisms are likely multifactorial, with some evidence that GDM exposure alters brain satiety signaling, which may impact eating behavior. To better understand these effects, we investigated the relationship between GDM exposure, eating behavior, and total energy intake in 268 adolescents from the Exploring Perinatal Outcomes among Children cohort, who were exposed (n = 50) or not exposed (n = 217) to GDM in utero. Eating behavior was measured by the Eating in the Absence of Hunger in Children and Adolescents (EAH-C) questionnaire, which included subscale scores for Negative Affect, External Stimuli, and Fatigue/Boredom. Total energy intake (kcal/day) was derived from the Block Kid's Food Questionnaire. The associations between GDM exposure and the outcomes of total score and each EAH-C subscale were evaluated in separate multivariable models. In addition to the main predictor, GDM, the models included a GDM-by-sex interaction term and were adjusted for important covariates. The associations between EAH-C total and subscale scores and the outcome of total energy intake were also tested in separate multivariable models. Female offspring exposed to GDM in utero (vs unexposed males and females) were more likely to continue eating beyond satiation due to feelings of boredom and fatigue (ß = 0.47, 95% CI: 0.11, 0.83), and in general (EAH-C total score; ß = 4.20, 95% CI: 0.56, 7.86) compared to unexposed males. All EAH-C subscale and total scores were significantly, positively associated with higher energy intake (p < 0.05 for all, respectively). Our findings highlight the need for further investigation into the possible early life programming of eating behaviors by GDM exposure in utero.