A cautionary tale on the effects of different covariance structures in linear mixed effects modeling of fMRI data.

With the steadily increasing abundance of longitudinal neuroimaging studies with large sample sizes and multiple repeated measures, questions arise regarding the appropriate modeling of variance and covariance. The current study examined the influence of standard classes of variance-covariance structures in linear mixed effects (LME) modeling of fMRI data from patients with pediatric mild traumatic brain injury (pmTBI; N = 181) and healthy controls (N = 162). During two visits, participants performed a cognitive control fMRI paradigm that compared congruent and incongruent stimuli. The hemodynamic response function was parsed into peak and late peak phases. Data were analyzed with a 4-way (GROUP×VISIT×CONGRUENCY×PHASE) LME using AFNI's 3dLME and compound symmetry (CS), autoregressive process of order 1 (AR1), and unstructured (UN) variance-covariance matrices. Voxel-wise results dramatically varied both within the cognitive control network (UN>CS for CONGRUENCY effect) and broader brain regions (CS>UN for GROUP:VISIT) depending on the variance-covariance matrix that was selected. Additional testing indicated that both model fit and estimated standard error were superior for the UN matrix, likely as a result of the modeling of individual terms. In summary, current findings suggest that the interpretation of results from complex designs is highly dependent on the selection of the variance-covariance structure using LME modeling.

Parkinson's disease cerebrovascular reactivity pattern: A feasibility study.

A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson's disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO2) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice.

Dynamic Functional Connectivity in Pediatric Mild Traumatic Brain Injury.

Resting-state fMRI can be used to identify recurrent oscillatory patterns of functional connectivity within the human brain, also known as dynamic brain states. Alterations in dynamic brain states are highly likely to occur following pediatric mild traumatic brain injury (pmTBI) due to the active developmental changes. The current study used resting-state fMRI to investigate dynamic brain states in 200 patients with pmTBI (ages 8-18 years, median = 14 years) at the subacute (∼1-week post-injury) and early chronic (∼ 4 months post-injury) stages, and in 179 age- and sex-matched healthy controls (HC). A k-means clustering analysis was applied to the dominant time-varying phase coherence patterns to obtain dynamic brain states. In addition, correlations between brain signals were computed as measures of static functional connectivity. Dynamic connectivity analyses showed that patients with pmTBI spend less time in a frontotemporal default mode/limbic brain state, with no evidence of change as a function of recovery post-injury. Consistent with models showing traumatic strain convergence in deep grey matter and midline regions, static interhemispheric connectivity was affected between the left and right precuneus and thalamus, and between the right supplementary motor area and contralateral cerebellum. Changes in static or dynamic connectivity were not related to symptom burden or injury severity measures, such as loss of consciousness and post-traumatic amnesia. In aggregate, our study shows that brain dynamics are altered up to 4 months after pmTBI, in brain areas that are known to be vulnerable to TBI. Future longitudinal studies are warranted to examine the significance of our findings in terms of long-term neurodevelopment.

Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms.

Approximately one third of non-hospitalized coronavirus disease of 2019 (COVID-19) patients report chronic symptoms after recovering from the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some of the most persistent and common complaints of this post-acute COVID-19 syndrome (PACS) are cognitive in nature, described subjectively as "brain fog" and also objectively measured as deficits in executive function, working memory, attention, and processing speed. The mechanisms of these chronic cognitive sequelae are currently not understood. SARS-CoV-2 inflicts damage to cerebral blood vessels and the intestinal wall by binding to angiotensin-converting enzyme 2 (ACE2) receptors and also by evoking production of high levels of systemic cytokines, compromising the brain's neurovascular unit, degrading the intestinal barrier, and potentially increasing the permeability of both to harmful substances. Such substances are hypothesized to be produced in the gut by pathogenic microbiota that, given the profound effects COVID-19 has on the gastrointestinal system, may fourish as a result of intestinal post-COVID-19 dysbiosis. COVID-19 may therefore create a scenario in which neurotoxic and neuroinflammatory substances readily proliferate from the gut lumen and encounter a weakened neurovascular unit, gaining access to the brain and subsequently producing cognitive deficits. Here, we review this proposed PACS pathogenesis along the gut-brain axis, while also identifying specific methodologies that are currently available to experimentally measure each individual component of the model.

Electric field distribution predicts efficacy of accelerated intermittent theta burst stimulation for late-life depression.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for late-life depression (LLD) but may have lower rates of response and remission owing to age-related brain changes. In particular, rTMS induced electric field strength may be attenuated by cortical atrophy in the prefrontal cortex. To identify clinical characteristics and treatment parameters associated with response, we undertook a pilot study of accelerated fMRI-guided intermittent theta burst stimulation (iTBS) to the right dorsolateral prefrontal cortex in 25 adults aged 50 or greater diagnosed with LLD and qualifying to receive clinical rTMS. Methods: Participants underwent baseline behavioral assessment, cognitive testing, and structural and functional MRI to generate individualized targets and perform electric field modeling. Forty-five sessions of iTBS were delivered over 9 days (1800 pulses per session, 50-min inter-session interval). Assessments and testing were repeated after 15 sessions (Visit 2) and 45 sessions (Visit 3). Primary outcome measure was the change in depressive symptoms on the Inventory of Depressive Symptomatology-30-Clinician (IDS-C-30) from Visit 1 to Visit 3. Results: Overall there was a significant improvement in IDS score with the treatment (Visit 1: 38.6; Visit 2: 31.0; Visit 3: 21.3; mean improvement 45.5%) with 13/25 (52%) achieving response and 5/25 (20%) achieving remission (IDS-C-30 < 12). Electric field strength and antidepressant effect were positively correlated in a subregion of the ventrolateral prefrontal cortex (VLPFC) (Brodmann area 47) and negatively correlated in the posterior dorsolateral prefrontal cortex (DLPFC). Conclusion: Response and remission rates were lower than in recently published trials of accelerated fMRI-guided iTBS to the left DLPFC. These results suggest that sufficient electric field strength in VLPFC may be a contributor to effective rTMS, and that modeling to optimize electric field strength in this area may improve response and remission rates. Further studies are needed to clarify the relationship of induced electric field strength with antidepressant effects of rTMS for LLD.

Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The clinical and physiologic time course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects. A priori study hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months postinjury, which would be inversely associated with age at injury. METHODS: Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurologic, psychiatric, or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 T MRI) evaluations within 11 days (subacute visit [SA]) and at 4 months (early chronic visit [EC]) postinjury. Age- and sex-matched healthy controls (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1). RESULTS: A total of 208 patients with pmTBI (age = 14.4 ± 2.9; 40.4% female) and 176 HC (age = 14.2 ± 2.9; 42.0% female) were included in the final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus; d = -0.49) and hippocampal volumes (d = -0.24) observed for pmTBI, but not associated with age at injury. Hippocampal volume recovery was mediated by loss of consciousness/posttraumatic amnesia. Significantly greater postconcussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%). DISCUSSION: Current findings indicate that structural brain abnormalities may persist up to 4 months post-pmTBI and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiologic recovery post-pmTBI. In contrast, there was no evidence for age-at-injury effects or physiologic correlates of persistent symptoms in our sample.

Microbiome-gut-brain dysfunction in prodromal and symptomatic Lewy body diseases.

Lewy body diseases, such as Parkinson's disease and dementia with Lewy bodies, vary in their clinical phenotype but exhibit the same defining pathological feature, α-synuclein aggregation. Microbiome-gut-brain dysfunction may play a role in the initiation or progression of disease processes, though there are multiple potential mechanisms. We discuss the need to evaluate gastrointestinal mechanisms of pathogenesis across Lewy body diseases, as disease mechanisms likely span across diagnostic categories and a 'body first' clinical syndrome may better account for the heterogeneity of clinical presentations across the disorders. We discuss two primary hypotheses that suggest that either α-synuclein aggregation occurs in the gut and spreads in a prion-like fashion to the brain or systemic inflammatory processes driven by gastrointestinal dysfunction contribute to the pathophysiology of Lewy body diseases. Both of these hypotheses posit that dysbiosis and intestinal permeability are key mechanisms and potential treatment targets. Ultimately, this work can identify early interventions targeting initial disease pathogenic processes before the development of overt motor and cognitive symptoms.

Multicompartmental models and diffusion abnormalities in paediatric mild traumatic brain injury.

The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicates that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples. The current study collected diffusion MRI data in consecutively recruited patients (n = 203; 8-18 years old) and age and sex-matched healthy controls (n = 170) in a prospective cohort design. Patients were evaluated subacutely (1-11 days post-injury) as well as at 4 months post-injury (early chronic phase). Healthy participants were evaluated at similar times to control for neurodevelopment and practice effects. Clinical findings indicated persistent symptoms at 4 months for a significant minority of patients (22%), along with residual executive dysfunction and verbal memory deficits. Results indicated increased fractional anisotropy and reduced mean diffusivity for patients, with abnormalities persisting up to 4 months post-injury. Multicompartmental geometric models indicated that estimates of intracellular volume fractions were increased in patients, whereas estimates of free water fractions were decreased. Critically, unique areas of white matter pathology (increased free water fractions or increased neurite dispersion) were observed when standard assumptions regarding parallel diffusivity were altered in multicompartmental models to be more biologically plausible. Cross-validation analyses indicated that some diffusion findings were more reproducible when ∼70% of the total sample (142 patients, 119 controls) were used in analyses, highlighting the need for large-sample sizes to detect abnormalities. Supervised machine learning approaches (random forests) indicated that diffusion abnormalities increased overall diagnostic accuracy (patients versus controls) by ∼10% after controlling for current clinical gold standards, with each diffusion metric accounting for only a few unique percentage points. In summary, current results suggest that novel multicompartmental models are more sensitive to paediatric mild traumatic brain injury pathology, and that this sensitivity is increased when using parameters that more accurately reflect diffusion in healthy tissue. Results also indicate that diffusion data may be insufficient to achieve a high degree of objective diagnostic accuracy in patients when used in isolation, which is to be expected given known heterogeneities in pathophysiology, mechanism of injury and even criteria for diagnoses. Finally, current results indicate ongoing clinical and physiological recovery at 4 months post-injury.

Test-Retest Reliability of a Semi-Structured Interview to Aid in Pediatric Traumatic Brain Injury Diagnosis.

OBJECTIVE: Retrospective self-report is typically used for diagnosing previous pediatric traumatic brain injury (TBI). A new semi-structured interview instrument (New Mexico Assessment of Pediatric TBI; NewMAP TBI) investigated test-retest reliability for TBI characteristics in both the TBI that qualified for study inclusion and for lifetime history of TBI. METHOD: One-hundred and eight-four mTBI (aged 8-18), 156 matched healthy controls (HC), and their parents completed the NewMAP TBI within 11 days (subacute; SA) and 4 months (early chronic; EC) of injury, with a subset returning at 1 year (late chronic; LC). RESULTS: The test-retest reliability of common TBI characteristics [loss of consciousness (LOC), post-traumatic amnesia (PTA), retrograde amnesia, confusion/disorientation] and post-concussion symptoms (PCS) were examined across study visits. Aside from PTA, binary reporting (present/absent) for all TBI characteristics exhibited acceptable (≥0.60) test-retest reliability for both Qualifying and Remote TBIs across all three visits. In contrast, reliability for continuous data (exact duration) was generally unacceptable, with LOC and PCS meeting acceptable criteria at only half of the assessments. Transforming continuous self-report ratings into discrete categories based on injury severity resulted in acceptable reliability. Reliability was not strongly affected by the parent completing the NewMAP TBI. CONCLUSIONS: Categorical reporting of TBI characteristics in children and adolescents can aid clinicians in retrospectively obtaining reliable estimates of TBI severity up to a year post-injury. However, test-retest reliability is strongly impacted by the initial data distribution, selected statistical methods, and potentially by patient difficulty in distinguishing among conceptually similar medical concepts (i.e., PTA vs. confusion).

Distant histories of mild traumatic brain injury exacerbate age-related differences in white matter properties.

We examined associations of distant histories of mild traumatic brain injury (mTBI) with non-linear and linear trajectories of white matter (WM) properties across a wide age range (23-77). Diffusion tensor imaging (DTI) data obtained from 171 Veterans with histories of clinically diagnosed mTBIs and 115 controls were subjected to tractography, isolating 20 major WM tracts. Non-linear and linear effects of age on each tract's diffusion properties were examined in terms of their interactions with group (mTBI and control). The non-linear model revealed 7 tracts in which the mTBI group's DTI metrics rapidly deviated from control trajectories in middle and late adulthoods, despite the injuries having occurred in the late 20s, on average. In contrast, no interactions between prior injuries and age were detected when examining linear trajectories. Distant mTBIs may thus accelerate normal age-related trajectories of WM degeneration much later in life. As such, life-long histories of head trauma should be assessed in all patients in their mid-to-late adulthoods, whether neurologically healthy or presenting with seemingly unrelated neuropathology.

Specific White Matter Tracts and Diffusion Properties Predict Conversion From Mild Cognitive Impairment to Alzheimer's Disease.

Identifying biomarkers that can assess the risk of developing Alzheimer's Disease (AD) remains a significant challenge. In this study, we investigated the integrity levels of brain white matter in 34 patients with mild cognitive impairment (MCI) who later converted to AD and 53 stable MCI patients. We used diffusion tensor imaging (DTI) and automated fiber quantification to obtain the diffusion properties of 20 major white matter tracts. To identify which tracts and diffusion measures are most relevant to AD conversion, we used support vector machines (SVMs) to classify the AD conversion and non-conversion MCI patients based on the diffusion properties of each tract individually. We found that diffusivity measures from seven white matter tracts were predictive of AD conversion with axial diffusivity being the most predictive diffusion measure. Additional analyses revealed that white matter changes in the central and parahippocampal terminal regions of the right cingulate hippocampal bundle, central regions of the right inferior frontal occipital fasciculus, and posterior and anterior regions of the left inferior longitudinal fasciculus were the best predictors of conversion from MCI to AD. An SVM based on these white matter tract regions achieved an accuracy of 0.75. These findings provide additional potential biomarkers of AD risk in MCI patients.

Brainstem damage is associated with poorer sleep quality and increased pain in gulf war illness veterans.

AIMS: Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. MATERIALS AND METHODS: We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. KEY FINDINGS: Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. SIGNIFICANCE: These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.

Brainstem atrophy in Gulf War Illness.

BACKGROUND: Gulf War Illness (GWI) is a condition that affects about 30 % of veterans who served in the 1990-91 Persian Gulf War. Given its broad symptomatic manifestation, including chronic pain, fatigue, neurological, gastrointestinal, respiratory, and skin problems, it is of interest to examine whether GWI is associated with changes in the brain. Existing neuroimaging studies, however, have been limited by small sample sizes, inconsistent GWI diagnosis criteria, and potential comorbidity confounds. OBJECTIVES: Using a large cohort of US veterans with GWI, we assessed regional brain volumes for their associations with GWI, and quantified the relationships between any regional volumetric changes and GWI symptoms. METHODS: Structural magnetic resonance imaging (MRI) scans from 111 veterans with GWI (Age = 49 ±â€¯6, 88 % Male) and 59 healthy controls (age = 51 ±â€¯9, 78 % male) were collected at the California War Related Illness and Injury Study Center (WRIISC-CA) and from a multicenter study of the Parkinson's Progression Marker Initiative (PPMI), respectively. Individual MRI volumes were segmented and parcellated using FreeSurfer. Regional volumes of 19 subcortical, 68 cortical, and 3 brainstem structures were evaluated in the GWI cohort relative to healthy controls. The relationships between regional volumes and GWI symptoms were also assessed. RESULTS: We found significant subcortical atrophy, but no cortical differences, in the GWI group relative to controls, with the largest effect detected in the brainstem, followed by the ventral diencephalon and the thalamus. In a subsample of 58 veterans with GWI who completed the Chronic Fatigue Scale (CFS) inventory of Centers for Disease Control and Prevention (CDC), smaller brainstem volumes were significantly correlated with increased severities of fatigue and depressive symptoms. CONCLUSION: The findings suggest that brainstem volume may be selectively affected by GWI, and that the resulting atrophy could in turn mediate or moderate GWI-related symptoms such as fatigue and depression. Consequently, the brain stem should be carefully considered in future research focusing on GWI pathology.

Diffusion tensor tractography of brainstem fibers and its application in pain.

Evaluation of brainstem pathways with diffusion tensor imaging (DTI) and tractography may provide insights into pathophysiologies associated with dysfunction of key brainstem circuits. However, identification of these tracts has been elusive, with relatively few in vivo human studies to date. In this paper we proposed an automated approach for reconstructing nine brainstem fiber trajectories of pathways that might be involved in pain modulation. We first performed native-space manual tractography of these fiber tracts in a small normative cohort of participants and confirmed the anatomical precision of the results using existing anatomical literature. Second, region-of-interest pairs were manually defined at each extracted fiber's termini and nonlinearly warped to a standard anatomical brain template to create an atlas of the region-of-interest pairs. The resulting atlas was then transformed non-linearly into the native space of 17 veteran patients' brains for automated brainstem tractography. Lastly, we assessed the relationships between the integrity levels of the obtained fiber bundles and pain severity levels. Fractional anisotropy (FA) measures derived using automated tractography reflected the respective tracts' FA levels obtained via manual tractography. A significant inverse relationship between FA and pain levels was detected within the automatically derived dorsal and medial longitudinal fasciculi of the brainstem. This study demonstrates the feasibility of DTI in exploring brainstem circuitries involved in pain processing. In this context, the described automated approach is a viable alternative to the time-consuming manual tractography. The physiological and functional relevance of the measures derived from automated tractography is evidenced by their relationships with individual pain severities.

White Matter Asymmetry: A Reflection of Pathology in Traumatic Brain Injury.

Comparisons of white matter (WM) fractional anisotropy (FA) values between mild traumatic brain injury (mTBI) patients and controls have revealed inconsistencies in the directions of the resulting FA changes. To address these discrepancies, we examined hemispheric FA symmetry levels across WM tracts in 150 mTBI patients relative to 96 military controls. Automated fiber quantification was used to extract 18 WM tracts with 100 FA values, which were used to compute correlation strengths between the nine bilateral tract pairs. The Fisher z-transformed Pearson's r values were entered into an analysis of covariance examining the effects of group (mTBI and controls) and age on symmetry levels within each tract pair. The mTBI group displayed lower symmetry levels in the corticospinal tract and the inferior longitudinal fasciculus. Interactions between age and group were detected in the inferior fronto-occipital (IFOF), uncinate (UF), and superior longitudinal fasciculi (SLF). A similar pattern emerged in the IFOF and the UF, revealing age-related symmetry decreases in the mTBI patients despite stable levels of symmetry across ages in controls. In contrast, although the control group's symmetry levels actually increased with age in the SLF, no age-related symmetry changes were detected across the mTBI participants. Here, we proposed WM symmetry measures as a potential means of circumventing directional inconsistencies of trauma-related FA changes, as well as capturing more within-tract and within-subject variances of diffusion tensor imaging (DTI) metrics. Further, we demonstrated the method's utility in detecting mTBI-specific effects and their associated interactions with age.

Fronto-Parietal gray matter and white matter efficiency differentially predict intelligence in males and females.

While there are minimal sex differences in overall intelligence, males, on average, have larger total brain volume and corresponding regional brain volumes compared to females, measures that are consistently related to intelligence. Limited research has examined which other brain characteristics may differentially contribute to intelligence in females to facilitate equal performance on intelligence measures. Recent reports of sex differences in the neural characteristics of the brain further highlight the need to differentiate how the structural neural characteristics relate to intellectual ability in males and females. The current study utilized a graph network approach in conjunction with structural equation modeling to examine potential sex differences in the relationship between white matter efficiency, fronto-parietal gray matter volume, and general cognitive ability (GCA). Participants were healthy adults (n = 244) who completed a battery of cognitive testing and underwent structural neuroimaging. Results indicated that in males, a latent factor of fronto-parietal gray matter was significantly related to GCA when controlling for total gray matter volume. In females, white matter efficiency and total gray matter volume were significantly related to GCA, with no specificity of the fronto-parietal gray matter factor over and above total gray matter volume. This work highlights that different neural characteristics across males and females may contribute to performance on intelligence measures. Hum Brain Mapp 37:4006-4016, 2016. © 2016 Wiley Periodicals, Inc.

Aberrant development of post-movement beta rebound in adolescents and young adults with fetal alcohol spectrum disorders.

Dependent on maternal (e.g. genetic, age) and exposure (frequency, quantity, and timing) variables, the effects of prenatal alcohol exposure on the developing fetus are known to vary widely, producing a broad range of morphological anomalies and neurocognitive deficits in offspring, referred to as fetal alcohol spectrum disorders (FASD). Maternal drinking during pregnancy remains a leading risk factor for the development of intellectual disabilities in the US. While few functional findings exist today that shed light on the mechanisms responsible for the observed impairments in individuals with FASD, animal models consistently report deleterious effects of early alcohol exposure on GABA-ergic inhibitory pathways. The post-motor beta rebound (PMBR), a transient increase of 15-30 Hz beta power in the motor cortex that follows the termination of movement, has been implicated as a neural signature of GABA-ergic inhibitory activity. Further, PMBR has been shown to be a reliable predictor of age in adolescents. The present study sought to investigate any differences in the development of PMBR between FASD and control groups. Beta event-related de-synchronization (ERD) and movement-related gamma synchronization (MRGS), although not clearly linked to brain maturation, were also examined. Twenty-two participants with FASD and 22 age and sex-matched controls (12-22 years old) underwent magnetoencephalography scans while performing an auditory oddball task, which required a button press in response to select target stimuli. The data surrounding the button presses were localized to the participants' motor cortices, and the time courses from the locations of the maximally evoked PMBR were subjected to wavelet analyses. The subsequent analysis of PMBR, ERD, and MRGS revealed a significant interaction between group and age in their effects on PMBR. While age had a significant effect on PMBR in the controls, no simple effects of age were detected in the FASD group. The FASD group additionally displayed decreased overall ERD levels. No group or age effects on MRGS were detected. The described findings provide further evidence for broad impairments in inhibitory processes in adolescents with FASD, possibly related to aberrant development of GABA-ergic pathways.

Quantity yields quality when it comes to creativity: a brain and behavioral test of the equal-odds rule.

The creativity research community is in search of a viable cognitive measure providing support for behavioral observations that higher ideational output is often associated with higher creativity (known as the equal-odds rule). One such measure has included divergent thinking: the production of many examples or uses for a common or single object or image. We sought to test the equal-odds rule using a measure of divergent thinking, and applied the consensual assessment technique to determine creative responses as opposed to merely original responses. We also sought to determine structural brain correlates of both ideational fluency and ideational creativity. Two-hundred forty-six subjects were subjected to a broad battery of behavioral measures, including a core measure of divergent thinking (Foresight), and measures of intelligence, creative achievement, and personality (i.e., Openness to Experience). Cortical thickness and subcortical volumes (e.g., thalamus) were measured using automated techniques (FreeSurfer). We found that higher number of responses on the divergent thinking task was significantly associated with higher creativity (r = 0.73) as independently assessed by three judges. Moreover, we found that creativity was predicted by cortical thickness in regions including the left frontal pole and left parahippocampal gyrus. These results support the equal-odds rule, and provide neuronal evidence implicating brain regions involved with "thinking about the future" and "extracting future prospects."

Functional brain networks contributing to the Parieto-Frontal Integration Theory of Intelligence.

The refinement of localization of intelligence in the human brain is converging onto a distributed network that broadly conforms to the Parieto-Frontal Integration Theory (P-FIT). While this theory has received support in the neuroimaging literature, no functional magnetic resonance imaging study to date has conducted a whole-brain network-wise examination of the changes during engagement in tasks that are reliable measures of general intelligence (e.g., Raven's Progressive Matrices Test; RPM). Seventy-nine healthy subjects were scanned while solving RPM problems and during rest. Functional networks were extracted from the RPM and resting state data using Independent Component Analysis. Twenty-nine networks were identified, 26 of which were detected in both conditions. Fourteen networks were significantly correlated with the RPM task. The networks' spatial maps and functional connectivity measures at 3 frequency levels (low, medium, & high) were compared between the RPM and rest conditions. The regions involved in the networks that were found to be task related were consistent with the P-FIT, localizing to the bilateral medial frontal and parietal regions, right superior frontal lobule, and the right cingulate gyrus. Functional connectivity in multiple component pairs was differentially affected across all frequency levels during the RPM task. Our findings demonstrate that functional brain networks are more stable than previously thought, and maintain their general features across resting state and engagement in a complex cognitive task. The described spatial and functional connectivity alterations that such components undergo during fluid reasoning provide a network-wise framework of the P-FIT that can be valuable for further, network based, neuroimaging inquiries regarding the neural underpinnings of intelligence.