Decreased uncinate fasciculus integrity in functional seizures following traumatic brain injury.

OBJECTIVE: The uncinate fasciculus (UF) has been implicated previously in contributing to the pathophysiology of functional (nonepileptic) seizures (FS). FS are frequently preceded by adverse life events (ALEs) and present with comorbid psychiatric symptoms, yet neurobiological correlates of these factors remain unclear. To address this gap, using advanced diffusion magnetic resonance imaging (dMRI), UF tracts in a large cohort of patients with FS and pre-existing traumatic brain injury (TBI + FS) were compared to those in patients with TBI without FS (TBI-only). We hypothesized that dMRI measures in UF structural connectivity would reveal UF differences when controlling for TBI status. Partial correlation tests assessed the potential relationships with psychiatric symptom severity measures. METHODS: Participants with TBI-only (N = 46) and TBI + FS (N = 55) completed a series of symptom questionnaires and MRI scanning. Deterministic tractography via diffusion spectrum imaging (DSI) was implemented in DSI studio (https://dsi-studio.labsolver.org) with q-space diffeomorphic reconstruction (QSDR), streamline production, and manual segmentation to assess bilateral UF integrity. Fractional anisotropy (FA), radial diffusivity (RD), streamline counts, and their respective asymmetry indices (AIs) served as estimates of white matter integrity. RESULTS: Compared to TBI-only, TBI + FS participants demonstrated decreased left hemisphere FA and RD asymmetry index (AI) for UF tracts (both p < .05, false discovery rate [FDR] corrected). Additionally, TBI + FS reported higher symptom severity in depression, anxiety, and PTSD measures (all p < .01). Correlation tests comparing UF white matter integrity differences to psychiatric symptom severity failed to reach criteria for significance (all p > .05, FDR corrected). SIGNIFICANCE: In a large, well-characterized sample, participants with FS had decreased white matter health after controlling for the history of TBI. Planned follow-up analysis found no evidence to suggest that UF connectivity measures are a feature of group differences in mood or anxiety comorbidities for FS. These findings suggest that frontolimbic structural connectivity may play a role in FS symptomology, after accounting for prior ALEs and comorbid psychopathology severity.

A meta-analysis on the uncinate fasciculus in depression.

Aberrant microstructure of the uncinate fasciculus (UNC), a white matter (WM) tract implicated in emotion regulation, has been hypothesized as a neurobiological mechanism of depression. However, studies testing this hypothesis have yielded inconsistent results. The present meta-analysis consolidates evidence from 44 studies comparing fractional anisotropy (FA) and radial diffusivity (RD), two metrics characterizing WM microstructure, of the UNC in individuals with depression (n = 5016) to healthy individuals (n = 18 425). We conduct meta-regressions to identify demographic and clinical characteristics that contribute to cross-study heterogeneity in UNC findings. UNC FA was reduced in individuals with depression compared to healthy individuals. UNC RD was comparable between individuals with depression and healthy individuals. Comorbid anxiety explained inter-study heterogeneity in UNC findings. Depression is associated with perturbations in UNC microstructure, specifically with respect to UNC FA and not UNC RD. The association between depression and UNC microstructure appears to be moderated by anxiety. Future work should unravel the cellular mechanisms contributing to aberrant UNC microstructure in depression; clarify the relationship between UNC microstructure, depression, and anxiety; and link UNC microstructure to psychological processes, such as emotion regulation.

The right uncinate fasciculus supports verbal short-term memory in aphasia.

Verbal short-term memory (STM) deficits are associated with language processing impairments in people with aphasia. Importantly, the integrity of STM can predict word learning ability and anomia therapy gains in aphasia. While the recruitment of perilesional and contralesional homologous brain regions has been proposed as a possible mechanism for aphasia recovery, little is known about the white-matter pathways that support verbal STM in post-stroke aphasia. Here, we investigated the relationships between the language-related white matter tracts and verbal STM ability in aphasia. Nineteen participants with post-stroke chronic aphasia completed a subset of verbal STM subtests of the TALSA battery including nonword repetition (phonological STM), pointing span (lexical-semantic STM without language output) and repetition span tasks (lexical-semantic STM with language output). Using a manual deterministic tractography approach, we investigated the micro- and macrostructural properties of the structural language network. Next, we assessed the relationships between individually extracted tract values and verbal STM scores. We found significant correlations between volume measures of the right Uncinate Fasciculus and all three verbal STM scores, with the association between the right UF volume and nonword repetition being the strongest one. These findings suggest that the integrity of the right UF is associated with phonological and lexical-semantic verbal STM ability in aphasia and highlight the potential compensatory role of right-sided ventral white matter language tracts in supporting verbal STM after aphasia-inducing left hemisphere insult.

Examining the role of the uncinate fasciculus in proper noun naming: awake brain tumor resections and stereo EEG targeted electrical stimulation multiple case study.

While there is strong evidence from lesion and functional imaging studies implicating the left anterior temporal pole (LTP) in naming unique entities, less is known about white matter tracts in category-specific naming. We present evidence that implicates the uncinate fasciculus (UF) in proper noun naming. First, we describe two patients with left LTP gliomas who developed category specific worsening in proper noun naming in real time during awake surgery when the UF was surgically involved . We then describe a third case involving targeted electrical stimulation of the UF using stereo-electroencephalography (sEEG) that resulted in category specific naming disturbance for proper nouns..

White matter connectivity in uncinate fasciculus accounts for visual attention span in developmental dyslexia.

The present study aimed to investigate the role of connectivity disruptions in two fiber pathways, the uncinate fasciculus (UF) and the frontal aslant tract (FAT), in developmental dyslexia and determine the relationship between the connectivity of these pathways and behavioral performance in children with dyslexia. A total of 26 French children with dyslexia and 31 age-matched control children were included. Spherical deconvolution tractography was used to reconstruct the two fiber pathways. Hindrance-modulated oriented anisotropy (HMOA) was used to measure the connectivity of each fiber pathway in both hemispheres. Only boys with dyslexia showed reduced HMOA in the UF compared to control boys. Furthermore, HMOA of the UF correlated with individual differences in the visual attention span in participants with dyslexia. All significant results found in HMOA of the UF were verified in fractional anisotropy (FA) of the UF using standard diffusion imaging model. This study suggests a differential sex effect on the connectivity disruption in the UF in developmental dyslexia. It also indicates that the UF may play an essential role in the visual attention span deficit in developmental dyslexia.

Reduced structural integrity of the uncinate fasciculus in incarcerated women scoring high on psychopathy.

Both men and women scoring high on psychopathy exhibit similar structural and functional neural abnormalities, including reduced volume of the orbitofrontal cortex (OFC) and reduced hemodynamic activity in the amygdala during affective processing experimental paradigms. The uncinate fasciculus (UF) is a white matter (WM) tract that connects the amygdala to the OFC. Reduced structural integrity of the UF, measured via fractional anisotropy (FA), is commonly associated with men scoring high on psychopathy. However, only one study to date has investigated the relationship between psychopathic traits and UF structural integrity in women, recruiting participants from a community sample. Here, we investigated whether Hare Psychopathy Checklist-Revised (PCL-R) facet scores (measuring interpersonal, affective, lifestyle/behavioral, and antisocial psychopathic traits, respectively) were associated with reduced FA in the left and right UF in a sample of 254 incarcerated women characterized by a wide range of psychopathy scores. We observed that PCL-R Facet 3 scores, assessing lifestyle/behavioral psychopathic traits, were associated with reduced FA in the left and right UF, even when controlling for participant's age and history of previous substance use. The results obtained in the current study help improve our understanding of structural abnormalities associated with women scoring high on psychopathy. Specifically, reduced UF structural integrity may contribute to some of the deficits commonly associated with women scoring high on psychopathy, including emotion dysregulation.

Asymmetry Matters: Diffusion Tensor Tractography of the Uncinate Fasciculus in Children with Verbal Memory Deficits.

BACKGROUND AND PURPOSE: Verbal declarative memory performance relies on frontotemporal connectivity. The uncinate fasciculus is a major association tract connecting the frontal and temporal lobes. Hemispheric asymmetries contribute to various cognitive and neurobehavioral abilities. Here we investigated microstructural alterations and hemispheric asymmetry of the uncinate fasciculus and their possible correlation to memory performance of children with learning disorders attributed to verbal memory deficits. MATERIALS AND METHODS: Two groups of right-handed children with learning disorders attributed to verbal memory deficits and typically developing children (n = 20 and 22, respectively) underwent DTI on a 1.5T scanner. Tractography of the uncinate fasciculus in both hemispheres was performed, and fractional anisotropy and diffusivity indices (radial diffusivity, axial diffusivity, and trace) were obtained. The asymmetry index was calculated. Verbal memory was assessed using subsets of the Stanford Binet Intelligence Scale, 4th edition, a dyslexia assessment test, and the Illinois test of Psycholinguistic Abilities. Correlation between diffusion metrics and verbal memory performance was investigated in the learning disorders group. Also, hemispheric differences in each group were tested, and between-group comparisons were performed. RESULTS: Children with learning disorders showed absence of the normal left-greater-than-right asymmetry of fractional anisotropy and the normal right-greater-than-left asymmetry of radial diffusivity seen in typically developing children. Correlation with verbal memory subsets revealed that the higher the fractional anisotropy and asymmetry index, the better the rapid naming performance (P <.05) was. CONCLUSIONS: These findings demonstrated microstructural aberrations with reduction of hemispheric asymmetry of the uncinate fasciculus, which could disrupt the normal frontotemporal connectivity in children with learning disorders attributed to verbal memory deficits. This outcome gives more understanding of pathologic mechanisms underlying this disorder.

Right uncinate fasciculus supports socioemotional sensitivity in health and neurodegenerative disease.

The uncinate fasciculus (UF) connects fronto-insular and temporal gray matter regions involved in visceral emotional reactivity and semantic appraisal, but the precise role of this tract in socioemotional functioning is not well-understood. Using the Revised-Self Monitoring (RSMS) informant questionnaire, we examined whether fractional anisotropy (FA) in the right UF corresponded to socioemotional sensitivity during face-to-face interactions in 145 individuals (40 healthy older adults [NC], and 105 patients with frontotemporal lobar degeneration [FTLD] syndromes in whom this tract is selectively vulnerable, including 31 behavioral variant frontotemporal dementia [bvFTD], 39 semantic variant primary progressive aphasia [svPPA], and 35 nonfluent variant primary progressive aphasia [nfvPPA]). Voxelwise and region-of-interest-based DWI analyses revealed that FA in the right but not left UF significantly predicted RSMS score in the full sample, and in NC and svPPA subgroups alone. Right UF integrity did not predict RSMS score in the bvFTD group, but gray matter volume in the right orbitofrontal cortex adjacent to the UF was a significant predictor. Our results suggest that better socioemotional sensitivity is specifically supported by right UF white matter, highlighting a key neuro-affective relationship found in both healthy aging and neurologically affected individuals. The finding that poorer socioemotional sensitivity corresponded to right UF damage in svPPA but was more robustly influenced by gray matter atrophy adjacent to the UF in bvFTD may have important implications for endpoint selection in clinical trial design for patients with FTLD.

Right arcuate fasciculus and left uncinate fasciculus abnormalities in young smoker.

Previous diffusion tensor imaging (DTI) studies had investigated the white matter (WM) integrity abnormalities in smokers. Exposure to nicotine disrupts neurodevelopment during adolescence, possibly by disrupting the trophic effects of acetylcholine. However, little is known about the diffusion parameters of specific fibre bundles at multiple locations in young smokers. Thirty-seven young smokers and 29 age-, education- and gender-matched healthy non-smokers participated in this study. Automated Fibre Quantification (AFQ) was employed to investigate the WM microstructure in young smokers by integrating multiple indices. Diffusion parameters, that is, fractional anisotropy (FA), axial diffusion (AD), radial diffusion (RD) and mean diffusion (MD), were calculated at 100 points along the length of 18 major brain tracts. The relationships between neuroimaging differences and smoking behaviours were explored, including Fagerström Test of Nicotine Dependence (FTND) and pack-years. Compared with non-smokers, young smokers showed significantly increased FA, AD and decreased RD in the left uncinate fasciculus (UF) and right thalamic radiation (TR), increased AD, RD and decreased FA in the right arcuate fasciculus (Arc). Correlation analyses revealed that FA values of the left UF and RD values of the right Arc were negatively correlated with FTND score in smokers and FA values of the right Arc were positively correlated with FTND scores. Positive correlation was observed between AD values of the left UF and pack-years in smokers. The findings enhanced our understanding of the potential effect of adolescent smoking on WM microstructure.

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

BACKGROUND: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle. METHODS: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls. RESULTS: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally. CONCLUSIONS: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure. IMPACT: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.

Individual differences in white matter of the uncinate fasciculus and inferior fronto-occipital fasciculus: possible early biomarkers for callous-unemotional behaviors in young children with disruptive behavior problems.

BACKGROUND: Callous-unemotional (CU) behaviors are important for identifying severe patterns of conduct problems (CP). One major fiber tract implicated in the development of CP is the uncinate fasciculus (UF), which connects amygdala and orbitofrontal cortex (OFC). The goals of the current study were to (a) explore differences in the white matter microstructure in the UF and other major fiber tracks between young typically developing (TD) children and those with a disruptive behavior disorder (DBD) and (b) explore, within the DBD group, whether individual differences in these white matter tracts relate to co-occurring CP and CU behaviors. METHODS: Participants included 198 young children (69% boys, Mage = 5.66 years; 80% Latinx; 48.5% TD). CU behaviors and CP were measured via a combination of teacher/parent ratings. Non-invasive diffusion-weighted imaging (DWI) was used to measure fractional anisotropy (FA), an indirect indicator of white matter properties. RESULTS: Relative to TD children, children in the DBD group had reduced FA on four out of the five fiber tracks we examined (except for cingulum and right ILF), even after accounting for whole brain FA, sex, movement, parental income, and IQ. Within the DBD group, no associations were found between CP and reduced white matter integrity across any of the fiber tracks examined. However, we found that even after accounting for CP, ADHD symptomology, and a host of covariates (whole brain FA, sex, movement, parental income, and IQ), CU behaviors were independently related to reduced FA in bilateral UF and left inferior fronto-occipital fasciculus (IFOF) in the DBD group, but this was not the case for TD children. CONCLUSIONS: Alterations in the white matter microstructure within bilateral UF and left IFOF may be biomarkers of CU behaviors, even in very young children.

Sex matters: association between callous-unemotional traits and uncinate fasciculus microstructure in youths with conduct disorder.

Among youths with conduct disorder, those with callous-unemotional traits are at increased risk for persistent antisocial behaviour. Although callous-unemotional traits have been found to be associated with white-matter brain abnormalities, previous diffusion imaging studies were conducted in small samples, preventing examination of potential sex by callous-unemotional traits interaction effects on white matter. Here, we used tract-based spatial statistics at a whole-brain level and within regions of interest to compare the white matter correlates of callous-unemotional traits in female vs. male youths with conduct disorder, in a sample (n = 124) recruited through a multi-site protocol. A sex-specific association between callous-unemotional traits and white matter was found in the left uncinate fasciculus, where callous-unemotional traits were positively associated with axial diffusivity in males, while an opposite pattern was found in females. These findings are in line with previous studies suggesting that the uncinate fasciculus is a key tract implicated in the development of psychopathy, but also add to recent evidence showing that sexual dimorphism needs to be taken into account when examining the structural correlates of mental disorders in general, and callous-unemotional traits in conduct disorder in particular.

The uncinate fasciculus in individuals with and at risk for bipolar disorder: A meta-analysis.

BACKGROUND: Bipolar disorder (BD) is a severe mental disorder, characterized by prominent mood swings and emotion regulation (ER) deficits. The uncinate fasciculus (UF), a white matter tract connecting the amygdala and the ventral prefrontal cortex, has been implicated in ER. Aberrancies in UF microstructure may be an endophenotype associated with increased risk for BD. However, studies in individuals with BD and their first-degree relatives (REL) have yielded inconsistent findings. This meta-analysis takes a region-of-interest approach to consolidate the available evidence and elucidate the role of the UF in the risk-architecture of BD. METHODS: Using web-based search engines, we identified diffusion tensor imaging (DTI) studies focusing on the left and right UF and conducted meta-analyses comparing fractional anisotropy (FA) and radial diffusivity (RD) between BD or REL and healthy control participants (HC). RESULTS: We included 32 studies (nBD=1186, nREL=289, nHC=2315). Compared to HC, individuals with BD showed lower FA in the right (WMD=-0.31, p<0.0001) and left UF (WMD=-0.21, p = 0.010), and higher RD in the right UF (WMD=0.32, p = 0.009). We found no significant differences between REL and HC. In the right but not left UF, REL showed higher FA than BD (p = 0.043). CONCLUSION: Our findings support aberrant UF microstructure, potentially related to alterations in myelination, as a mechanism, but not as an endophenotype of BD. However, given the limited power in the REL subsample, the latter finding must be considered preliminary. Studies examining the role of the UF in individuals at familial risk for BD are warranted.

The Topography of the Frontal Terminations of the Uncinate Fasciculus Revisited Through Focused Fiber Dissections: Shedding Light on a Current Controversy and Introducing the Insular Apex as a Key Anatomoclinical Area.

BACKGROUND: Recent studies advocate a connectivity pattern wider than previously believed of the uncinate fasciculus that extends to the ventrolateral and dorsolateral prefrontal cortices. These new percepts on the connectivity of the tract suggest a more expansive role for the uncinate fasciculus. Our aim was to shed light on this controversy through fiber dissections. METHODS: Twenty normal adult human formalin-fixed cerebral hemispheres were used. Focused dissections on the insular, orbitofrontal, ventromedial, ventrolateral, and dorsolateral prefrontal areas were performed to record the topography of the frontal terminations of the uncinate fasciculus. RESULTS: Three discrete fiber layers were consistently disclosed: the first layer was recorded to terminate at the posterior orbital gyrus and pars orbitalis, the second layer at the posterior two thirds of the gyrus rectus, and the last layer at the posterior one third of the paraolfactory gyrus. The insular apex was documented as a crucial landmark regarding the topographic differentiation of the uncinate and occipitofrontal fasciculi (i.e., fibers that travel ventrally belong to the uncinate fasciculus whereas those traveling dorsally are occipitofrontal fibers). CONCLUSIONS: The frontal terminations of the uncinate fasciculus were consistently documented to project to the posterior orbitofrontal area. The area of the insular apex is introduced for the first time as a crucial surface landmark to effectively distinguish the stems of the uncinate and occipitofrontal fasciculi. This finding could refine the spatial resolution of awake subcortical mapping, especially for insular lesions, and improve the accuracy of in vivo diffusion tensor imaging protocols.

Uncinate fasciculus and its cortical terminals in aphasia after subcortical stroke: A multi-modal MRI study.

Aphasia, one of the most common cognitive impairments after stroke, is commonly considered to be a cortical deficit. However, many studies have reported cases of post subcortical stroke aphasia (PSSA). The pathology and recovery mechanism of PSSA remain unclear. This study aimed to investigate PSSA mechanism through a multimodal magnetic resonance imaging (MRI) approach and a two-session study design (baseline and one month after treatment). Thirty-six PSSA patients and twenty-four matched healthy controls (HC) were included. All patients had subcortical infarctions involving left subcortical white matter for 1 to 6 months. The patients underwent MRI scan and Western Aphasia Battery (WAB) examination before and after one month's comprehensive treatment. Region-wise lesion-symptom mapping (RLSM), tractography, fractional anisotropy (FA), and amplitude of low-frequency fluctuations (ALFF) analysis were conducted. After MRI preprocessing and exclusion, FA analysis included 35 patients pre-treatment and 16 patients post-treatment. ALFF analysis included 30 patients pre-treatment and 14 patients post-treatment. We found: 1) the amount of damage in the left uncinate fasciculus (UF) was associated with WAB aphasia quotient (AQ); 2) the left UF FA and left temporal pole (TP) ALFF were decreased and positively correlated with WAB-AQ, spontaneous speech, and naming in PSSA patients; and 3) PSSA patients showed increased left TP ALFF when their language ability recovered after treatment. The left TP ALFF change was positively correlated with AQ change. Our results demonstrate the importance of left UF and left TP (one of the cortical terminals of the left UF) in PSSA pathology and recovery. These results may further provide support for the disconnection theory in the mechanism of PSSA.

Degeneration of core neural tracts for emotional regulation in a patient with traumatic brain injury: A case report.

RATIONALE: Several brain structures, including the orbital prefrontal cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, amygdala, and anterior cingulate cortex, are considered key structures in the neural circuitry underlying emotion regulation. We report on a patient showing behavior changes and degeneration of core neural tracts for emotional regulation following traumatic brain injury (TBI). PATIENT CONCERNS: A 51-year-old male patient suffered an in-car accident. The patient lost consciousness for approximately 30 days, and his Glasgow Coma Scale score was 3. He underwent stereotactic drainage for traumatic intraventricular and intracerebral hemorrhages. At approximately 6.5-year after onset, he began to show disinhibition behaviors such as shouting with anger, which worsened over time. At approximately 8-year after onset, he showed severe depression signs and disinhibition, including violence. DIAGNOSES: The patient who showed delayed-onset behavioral changes (disinhibition and depression). INTERVENTIONS: Diffusion tensor imaging data were acquired at 3 months and 8 years after TBI onset. OUTCOMES: The patient showed degeneration of core neural tracts for emotional regulation that was associated with delayed behavioral changes following TBI. On both 3-month and 8-year diffusion tensor tractographies (DTTs), the right dorsolateral prefronto-thalamic tract, ventrolateral prefronto-thalamic tract, orbital prefronto-thalamic tract, uncinate fasciculus, and both cinguli were reconstructed whereas other neural tracts were not reconstructed. Compared with the 3-month DTT, all reconstructed neural tracts on the 8-year DTT were narrow, except for the left cingulum, which showed new transcallosal fibers between both anterior cingula. The fractional anisotropy and tract volume of all reconstructed neural tracts were lower on the 8-year DTT than the 3-month DTT, except for the tract volume of left cingulum. LESSONS: The evaluation of dorsolateral, ventrolateral, and orbital prefronto-thalamic tract, uncinate fasciculus, and cingulum using follow-up DTTs is useful when a patient with TBI shows delayed-onset behavioral problems.

Integrity of the uncinate fasciculus is associated with the onset of bipolar disorder: a 6-year followed-up study.

Patients with Bipolar Disorder (BD) are associated with aberrant uncinate fasciculus (UF) that connects amygdala-ventral prefrontal cortex (vPFC) system, but the casual relationship is still uncertain. The research aimed to investigate the integrity of UF among offspring of patients with BD and investigate its potential causal association with subsequent declaration of BD. The fractional anisotropy (FA) and mean diffusivity (MD) of UF were compared in asymptomatic offspring (AO, n = 46) and symptomatic offspring (SO, n = 45) with a parent with BD, and age-matched healthy controls (HCs, n = 35). Logistic regressions were performed to assess the predictive effect of UF integrity on the onset of BD. The three groups did not differ at baseline in terms of FA and MD of the UF. Nine out of 45 SO developed BD over a follow-up period of 6 years, and the right UF FA predicted the onset of BD (p = 0.038, OR = 0.212, 95% CI = 0.049-0.917). The ROC curve revealed that the right UF FA predicted BD onset (area-under-curve = 0.859) with sensitivity of 88.9% and specificity of 77.3%. The complementary whole-brain tract-based spatial statistics (TBSS) showed that widespread increases of FA were found in the SO group compared with HCs, but were not associated with the onset of BD. Our data provide evidence supporting the causal relationship between the white matter structural integrity of the amygdala-vPFC system and the onset of BD in genetically at-risk offspring of BD patients.

Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable Patterns of Maternal Signals.

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

Short strides to important findings: A short interval longitudinal study of sleep quality, psychological distress and microstructure changes to the uncinate fasciculus in early adolescents.

BACKGROUND: Developmental studies have shown adolescence is a period of ongoing white matter (WM) development, reduced sleep quality and the onset of many mental disorders. Findings indicate the WM development of the uncinate fasciculus (UF), a WM tract suggested to play a key role in mental disorders, continues throughout adolescence. While these studies provide valuable information, they are limited by long intervals between scans (1 to 4 years) leaving researchers and clinicians to infer what may be occurring between time-points. To allow inferences to be made regarding the impact that sleep quality may be having on WM development, longitudinal studies with much shorter between-scan intervals are required. METHODS: The current study reports longitudinal data of self-reported sleep quality (PSQI), diffusion tensor imaging (DTI) measures of WM development and psychological distress (K10) for n = 64 early adolescents spanning the first twelve months (four time-points; Baseline, 4, 8, & 12 months) of the Longitudinal Adolescent Brain Study (LABS) study currently underway at the Thompson Institute. RESULTS: Generalised Estimating Equation analysis showed a significant relationship between sleep quality and psychological distress over the four time-points. Reduced radial diffusivity and increased fractional anisotropy of the UF is also reported with increasing age suggesting that ongoing myelination is occurring. Adding sleep quality to the model, however, negatively impacted this myelination process. CONCLUSION: These findings represent an important step towards elucidating how sleep, psychological distress and maturation of the UF may co-develop during early adolescence.