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 emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3.

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders involving emotional disruptions. One such pathway - the uncinate fasciculus - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity with the orbitofrontal cortex remains unknown. Here we asked if the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution fMRI, we found that reduced integrity of the UF is related to elevated BOLD fMRI activation of the DG/CA3 subregions of the hippocampus during emotional lure discrimination. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that greater activation in this network (possibly driven by CA3 recurrent collaterals) is associated with memory errors. Based on this work we suggest that the UF is one pathway that may allow the OFC to exert control on this network and improve discrimination of emotional experiences, although further work is necessary to fully evaluate this possibility. This work provides novel insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional 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.

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.

White Matter Connectivity in Youth at Risk for Serious Mental Illness: A Longitudinal Analysis.

Longitudinal changes in white matter connectivity were assessed in a sample of youth at-risk for serious mental illness (n=183; age 12-25). Diffusion tensor imaging (DTI) was acquired at baseline and 12 months from youth recruited across two sites and classified as healthy controls (n=36), familial risk (n=30), mild-symptoms (n=41), attenuated syndromes (n=70), or transition (n=9) based on clinical assessments. Fractional anisotropy (FA) and mean diffusivity (MD) values were derived for the whole brain white matter, forceps minor, anterior cingulate, anterior thalamic radiations, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and uncinate fasciculus. MANCOVA analysis controlling for site, sex, and age showed no significant group differences in FA and MD at baseline or at 12 months. Linear mixed effects analysis showed a significant effect for time for most white matter tracts, but no effect for group, or group by time interaction. Transdiagnostic risk groups have similar profiles of WM connectivity and similar rates of change over time.

Uncinate fasciculus white matter connectivity related to impaired social perception and cross-sectional and longitudinal symptoms in patients with schizophrenia spectrum psychosis.

Dysfunctional social-emotional perception in patients with schizophrenia can result in adverse clinical symptoms and poorer long-term outcomes. The white matter tracts that interact among a number of brain regions have an important role to play. However, few neuroimaging studies focus on the effects of white matter connectivity on social-emotional perception in schizophrenia and its impact on patients' clinical symptoms and long-term outcomes. Forty-one patients with schizophrenia spectrum psychosis and 42 healthy controls underwent structural magnetic resonance imaging. The white matter fractional anisotropy values of the emotion recognition areas, the bilateral anterior thalamic radiation, inferior longitudinal fasciculus, cingulum bundle, superior longitudinal fasciculus, and uncinate fasciculus were compared between patients with schizophrenia spectrum psychosis and healthy controls. Social-emotional perception levels and symptom severity at baseline and after 1 year were examined. A group analysis showed that white matter connectivity was significantly lower in the bilateral anterior thalamic radiation, cingulum bundle, right inferior longitudinal fasciculus, and uncinate fasciculus of patients with schizophrenia spectrum psychosis compared to the healthy controls. Contrastingly, a correlation analysis revealed that larger right uncinate fasciculus fractional anisotropy values were associated with lower social-emotional perception levels in patients with schizophrenia spectrum psychosis. Additionally, the white matter fractional anisotropy values of the right uncinate fasciculus showed a significant positive correlation with the severity of positive symptoms at baseline and with poor outcomes after 1 year. The findings of the present study suggest that impaired social-emotional perception in patients with schizophrenia spectrum psychosis is associated with larger white matter connectivity of the uncinate fasciculus, which is also associated with more severe symptoms at baseline and after 1-year. These results suggest that the uncinate fasciculus could affect the pathophysiology of schizophrenia.

A multimodal imaging study of brain structural correlates of schizotypy dimensions using the MSS.

Schizotypy is a multidimensional construct of subclinical schizophrenia-like behavioural traits and cognition. The recently developed multidimensional schizotypy scale (MSS) provides an improved psychometric assessment of the three main dimensions (positive, negative, and disorganised). We tested the hypothesis that the three dimensions are related to brain structural variation in the precuneus and fronto-thalamo-striatal system in a new non-clinical healthy cohort to support a dimensional model of the psychosis spectrum. We analysed data from 104 subjects with Multidimensional Schizotypy Scale (MSS) phenotyping and 3 Tesla magnetic resonance images using voxel-based morphometry (VBM) applying CAT12 software, and diffusion-tensor imaging (DTI) with TBSS in FSL to test for correlations with MSS scores. MSS subscales and total score were negatively associated with GMV in brain areas including the medial prefrontal cortex, anterior cingulate cortex, and lateral prefrontal and orbital cortex. MSS schizotypy was associated with white matter integrity in anterior thalamic radiation, uncinate fasciculus, and superior longitudinal fasciculus. Our findings provide first direct evidence for an association of schizotypy (as a psychosis risk phenotype) and the fronto-thalamo-striatal system, in both grey and white matter with regionally diverging effects across single dimensions. This provides new evidence arguing for the fronto-striatal system (rather than precuneus) in schizotypy.

Youth with elevated psychopathic traits exhibit structural integrity deficits in the uncinate fasciculus.

Youth with elevated psychopathic traits represent a particularly severe subgroup of adolescents characterized by extreme behavioral problems and exhibit comparable neurocognitive deficits as adult offenders with psychopathic traits. A consistent finding among adults with elevated psychopathic traits is reduced white matter structural integrity of the right uncinate fasciculus (UF). The UF is a major white matter tract that connects regions of the anterior temporal lobe (i.e., the amygdala) to higher-order executive control regions, including the ventromedial prefrontal cortex. However, the relationship between youth psychopathic traits and structural integrity of the UF has been mixed, with some studies identifying a negative relationship between adolescent psychopathy scores and FA in the UF, and others identifying a positive relationship. Here, we investigated structural integrity of the left and right UF using fractional anisotropy (FA) in a large sample of n = 254 male adolescent offenders recruited from maximum-security juvenile correctional facilities. Psychopathic traits were assessed using the Hare Psychopathy Checklist: Youth Version (PCL:YV). Consistent with hypotheses, interpersonal and affective traits (i.e., PCL:YV Factor 1 and Facet 1 scores) were associated with reduced FA in the right UF. Additionally, lifestyle traits (i.e., PCL:YV Facet 3 scores) were associated with increased FA in the left UF. Results are consistent with previously published studies reporting reduced FA in the right UF in adult psychopathic offenders and increased left UF FA in youth meeting criteria for certain externalizing disorders.

Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome.

BACKGROUND: This cohort study utilized diffusion tensor imaging tractography to compare the uncinate fasciculus and inferior longitudinal fasciculus in children with Phelan-McDermid syndrome with age-matched controls and investigated trends between autism spectrum diagnosis and the integrity of the uncinate fasciculus and inferior longitudinal fasciculus white matter tracts. METHODS: This research was conducted under a longitudinal study that aims to map the genotype, phenotype, and natural history of Phelan-McDermid syndrome and identify biomarkers using neuroimaging (ClinicalTrial NCT02461420). Patients were aged three to 21 years and underwent longitudinal neuropsychologic assessment over 24 months. MRI processing and analyses were completed using previously validated image analysis software distributed as the Computational Radiology Kit (http://crl.med.harvard.edu/). Whole-brain connectivity was generated for each subject using a stochastic streamline tractography algorithm, and automatically defined regions of interest were used to map the uncinate fasciculus and inferior longitudinal fasciculus. RESULTS: There were 10 participants (50% male; mean age 11.17 years) with Phelan-McDermid syndrome (n = 8 with autism). Age-matched controls, enrolled in a separate longitudinal study (NIH R01 NS079788), underwent the same neuroimaging protocol. There was a statistically significant decrease in the uncinate fasciculus fractional anisotropy measure and a statistically significant increase in uncinate fasciculus mean diffusivity measure, in the patient group versus controls in both right and left tracts (P ≤ 0.024). CONCLUSION: Because the uncinate fasciculus plays a critical role in social and emotional interaction, this tract may underlie some deficits seen in the Phelan-McDermid syndrome population. These findings need to be replicated in a larger cohort.

Neural networks in bottom up 'experiential emotion regulation'.

Emotion regulation influences how and when we experience emotion, impacting our sense of self and well being. While previous brain research on emotion regulation has focused on gray matter correlates of emotion regulation, this study represents a first exploratory study on white matter integrity of brain networks of 'emotional approach' as a bottom up experiential emotion regulation-strategy. Responding to the gap between cognitive and affective approaches of emotion regulation, pertaining to some of the daily emotional stressors, the present study investigates brain pathways of individual differences in 'emotional approach', or the tendency to affectively acknowledge, understand and express emotional experience (cf. [1]). Diffusion tensor magnetic resonance imaging (DTI-MRI) measures of fractional anisotropy (FA) and mean diffusion (MD) evaluated dispositional emotion regulation in a group of 21 women with a 'high emotional approach' (HEA) (N = 11) and a 'low emotional approach' (LEA) (N = 10). HEA exhibited more FA of the cingulum, supporting emotion processing and emotion regulation, whereas LEA correlated to a higher FA in the right corticospinal tracts, supporting automatic action tendencies and a higher FA in the superior longitudinal fasciculus (SLF), supporting cognitive control and monitoring of emotion. LEA also correlated with an increase in MD in the body (p. = 0.05) and in the splenium of the corpus callosum (CC). A higher FA in the inferior longitudinal fasciculus (IFL) may indicate higher visual- affective integration within emotion processing, whereas more MD in the body and splenium of the CC decreases interhemispheric integration of emotional information within emotion processing and emotion regulation.