Working Memory Recovery in Adolescents with Concussion: Longitudinal fMRI Study.

Background: Understanding the behavioral and neural underpinnings of the post-concussion recovery of working memory function is critically important for improving clinical outcomes and adequately planning return-to-activity decisions. Previous studies provided inconsistent results due to small sample sizes and the use of a mixed population of participants who were at different post-injury time points. We aimed to examine working memory recovery during the first 6 months post-concussion in adolescents. Methods: We used functional magnetic resonance imaging (fMRI) to scan 45 concussed adolescents [CONCs] at baseline (<10 days post-concussion) and at 6 months post-concussion. Healthy control adolescents [HCs; n = 32] without a history of concussion were scanned once. During the scans, participants performed one-back and two-back working memory tasks with letters as the stimuli and angry, happy, neutral, and sad faces as distractors. Results: All affected adolescents were asymptomatic and cleared to return to activity 6 months after concussion. Working memory recovery was associated with faster and more accurate responses at 6 months vs. baseline (p-values < 0.05). It was also characterized by significant difficulty-related activation increases in the left inferior frontal gyrus (LIFG) and the left orbitofrontal cortex (LOFC) at 6 months vs. baseline. Although the activation differences between one-back and two-back were comparable between HCs and CONCs at 6 months, HCs had more pronounced activation in the LIFG than concussed adolescents. Conclusions: Post-concussion recovery is associated with significant performance improvements in speed and accuracy, as well as the normalization of brain responses in the LIFG and LOFC during the n-back task. The observed patterns of LOFC activation might reflect compensatory strategies to distribute neural processing and reduce neural fatigue post-concussion.

Neural correlates of the sound facilitation effect in the modified Simon task in older adults.

Introduction: The ability to resolve interference declines with age and is attributed to neurodegeneration and reduced cognitive function and mental alertness in older adults. Our previous study revealed that task-irrelevant but environmentally meaningful sounds improve performance on the modified Simon task in older adults. However, little is known about neural correlates of this sound facilitation effect. Methods: Twenty right-handed older adults [mean age = 72 (SD = 4), 11 female] participated in the fMRI study. They performed the modified Simon task in which the arrows were presented either in the locations matching the arrow direction (congruent trials) or in the locations mismatching the arrow direction (incongruent trials). A total of 50% of all trials were accompanied by task-irrelevant but environmentally meaningful sounds. Results: Participants were faster on the trials with concurrent sounds, independently of whether trials were congruent or incongruent. The sound effect was associated with activation in the distributed network of auditory, posterior parietal, frontal, and limbic brain regions. The magnitude of the behavioral facilitation effect due to sound was associated with the changes in activation of the bilateral auditory cortex, cuneal cortex, and occipital fusiform gyrus, precuneus, left superior parietal lobule (SPL) for No Sound vs. Sound trials. These changes were associated with the corresponding changes in reaction time (RT). Older adults with a recent history of falls showed greater activation in the left SPL than those without falls history. Conclusion: Our findings are consistent with the dedifferentiation hypothesis of cognitive aging. The facilitatory effect of sound could be achieved through recruitment of excessive neural resources, which allows older adults to increase attention and mental alertness during task performance. Considering that the SPL is critical for integration of multisensory information, individuals with slower task responses and those with a history of falls may need to recruit this region more actively than individuals with faster responses and those without a fall history to overcome increased difficulty with interference resolution. Future studies should examine the relationship among activation in the SPL, the effect of sound, and falls history in the individuals who are at heightened risk of falls.

Hand Dexterity Is Associated with the Ability to Resolve Perceptual and Cognitive Interference in Older Adults: Pilot Study.

The relationship between hand dexterity and inhibitory control across the lifespan is underexplored. In this pilot study, we examined inhibitory control using a modified Simon task. During the task, participants were presented with right- and left-pointing arrows located either on the right or the left parts of the screen. In the congruent trials, the arrow location and direction matched. In the incongruent trials, they mismatched, thus creating cognitive interference. In 50% of trials, the arrow presentation was accompanied by a task-irrelevant but environmentally meaningful sound that created perceptual interference. Hand dexterity was measured with the 9-hole peg test. Significantly faster reaction time (RT) on the modified Simon task (p < 0.001) was observed in younger adults, trials with concurrent sound stimuli, and congruent trials. Older adults who reported recent falls had greater difficulty resolving cognitive interference than older adults without recent falls. Hand dexterity significantly moderated the effect of sound on RT, but only in the group of older individuals. Interestingly, older individuals with reduced hand dexterity benefited from concurrent sounds more than those with better hand dexterity. Our findings suggest that task-irrelevant but environmentally meaningful sounds may increase alertness and enhance stimulus perception and recognition, thus improving motor performance in older individuals.

The Role of Puberty and Sex on Brain Structure in Adolescents With Anxiety Following Concussion.

BACKGROUND: Adolescence represents a window of vulnerability for developing psychological symptoms following concussion, especially in girls. Concussion-related lesions in emotion regulation circuits may help explain these symptoms. However, the contribution of sex and pubertal maturation remains unclear. Using the neurite density index (NDI) in emotion regulation tracts (left/right cingulum bundle [CB], forceps minor [FMIN], and left/right uncinate fasciculus), we sought to elucidate these relationships. METHODS: No adolescent had a history of anxiety and/or depression. The Screen for Child Anxiety Related Emotional Disorders and Children's Depression Rating Scale were used at scan to assess anxiety and depressive symptoms in 55 concussed adolescents (41.8% girls) and 50 control adolescents with no current/history of concussion (44% girls). We evaluated if a mediation-moderation model including the NDI (mediation) and sex or pubertal status (moderation) could help explain this relationship. RESULTS: Relative to control adolescents, concussed adolescents showed higher anxiety (p = .003) and lower NDI, with those at more advanced pubertal maturation showing greater abnormalities in 4 clusters: the left CB frontal (p = .002), right CB frontal (p = .011), FMIN left-sided (p = .003), and FMIN right-sided (p = .003). Across all concussed adolescents, lower NDI in the left CB frontal and FMIN left-sided clusters partially mediated the association between concussion and anxiety, with the CB being specific to female adolescents. These effects did not explain depressive symptoms. CONCLUSIONS: Our findings indicate that lower NDI in the CB and FMIN may help explain anxiety following concussion and that adolescents at more advanced (vs less advanced) status of pubertal maturation may be more vulnerable to concussion-related injuries, especially in girls.

Working memory updating in individuals with bipolar and unipolar depression: fMRI study.

Understanding neurobiological characteristics of cognitive dysfunction in distinct psychiatric disorders remains challenging. In this secondary data analysis, we examined neurobiological differences in brain response during working memory updating among individuals with bipolar disorder (BD), those with unipolar depression (UD), and healthy controls (HC). Individuals between 18-45 years of age with BD (n = 100), UD (n = 109), and HC (n = 172) were scanned using fMRI while performing 0-back (easy) and 2-back (difficult) tasks with letters as the stimuli and happy, fearful, or neutral faces as distractors. The 2(n-back) × 3(groups) × 3(distractors) ANCOVA examined reaction time (RT), accuracy, and brain activation during the task. HC showed more accurate and faster responses than individuals with BD and UD. Difficulty-related activation in the prefrontal, posterior parietal, paracingulate cortices, striatal, lateral occipital, precuneus, and thalamic regions differed among groups. Individuals with BD showed significantly lower difficulty-related activation differences in the left lateral occipital and the right paracingulate cortices than those with UD. In individuals with BD, greater difficulty-related worsening in accuracy was associated with smaller activity changes in the right precuneus, while greater difficulty-related slowing in RT was associated with smaller activity changes in the prefrontal, frontal opercular, paracingulate, posterior parietal, and lateral occipital cortices. Measures of current depression and mania did not correlate with the difficulty-related brain activation differences in either group. Our findings suggest that the alterations in the working memory circuitry may be a trait characteristic of reduced working memory capacity in mood disorders. Aberrant patterns of activation in the left lateral occipital and paracingulate cortices may be specific to BD.

Behavioral and neuroimaging evidence prodromal to major depressive disorder onset in a young adult without personal or family history of psychiatric disorder: Case report.

Background: Subthreshold symptoms of major depressive disorder (MDD) may be underreported due to stigma and/or cognitive impairment associated with this illness. Identifying objective behavioral and neural markers prodromal to MDD onset would help overcome this bias. This case study reports prospective behavioral and neuroimaging evidence prodromal to MDD onset in a young adult without prior personal or family history of psychiatric disorders who was identified during a longitudinal study of mood disorders. Methods: The participant completed the SCID-5 and other assessments of depression as well as the Vividness of Visual Imagery Questionnaire at baseline, 6-month follow-up, and 12-month follow-up. The participant completed the Emotion Intensity Rating task and high-resolution structural images were collected using magnetic resonance imaging (MRI) at baseline and 6-month follow-up. The levels of cortical myelin computed as the T1w/T2w ratio were used in a linear discriminant analysis (LDA) to predict participant's diagnostic status at baseline and 6-months. Results: The participant presented as a healthy control at baseline and 6-month but met criteria for MDD at the 12-month follow-up based on the SCID-5. The participant's visual imagery as well as the ability to correctly recognize neutral faces dramatically reduced from baseline to 6-month follow-up. The LDA classified the participant as an individual with depressive disorders at both baseline and 6-month follow-up despite the absence of either subthreshold or clinical symptoms of depression. Conclusions: While preliminary, the results suggest that the measures of cortical myelin, response to neutral and emotional facial expressions, and vividness of visual imagery could be prodromal to illness onset, whereas clinician-administered or self-reported measures of depression symptoms were uninformative.

The role of sleep quality on white matter integrity and concussion symptom severity in adolescents.

BACKGROUND: Sleep problems are common after concussion; yet, to date, no study has evaluated the relationship between sleep, white matter integrity, and post-concussion symptoms in adolescents. Using self-reported quality of sleep measures within the first 10 days of injury, we aimed to determine if quality of sleep exerts a main effect on white matter integrity in major tracts, as measured by diffusion Magnetic Resonance Imaging (dMRI), and further examine whether this effect can help explain the variance in post-concussion symptom severity in 12- to 17.9-year-old adolescents. METHODS: dMRI data were collected in 57 concussed adolescents (mean age[SD] = 15.4[1.5] years; 41.2 % female) with no history of major psychiatric diagnoses. Severity of post-concussion symptoms was assessed at study entry (mean days[SD] = 3.7[2.5] days since injury). Using the Pittsburgh Sleep Quality Index (PSQI), concussed adolescents were divided into two groups based on their quality of sleep in the days between injury and scan: good sleepers (PSQI global score ≤ 5; N = 33) and poor sleepers (PSQI global score > 5; N = 24). Neurite Orientation Dispersion and Dispersion Index (NODDI), specifically the Neurite Density Index (NDI), was used to quantify microstructural properties in major tracts, including 18 bilateral and one interhemispheric tract, and identify whether dMRI differences existed in good vs poor sleepers. Since the interval between concussion and neuroimaging acquisition varied among concussed adolescents, this interval was included in the analysis along with an interaction term with sleep groups. Regularized regression was used to identify if quality of sleep-related dMRI measures correlated with post-concussion symptom severity. Due to higher reported concussion symptom severity in females, interaction terms between dMRI and sex were included in the regularized regression model. Data collected in 33 sex- and age-matched non-concussed controls (mean age[SD] = 15.2[1.5]; 45.5 % female) served as healthy reference and sex and age were covariates in all analyses. RESULTS: Relative to good sleepers, poor sleepers demonstrated widespread lower NDI (18 of the 19 tracts; FDR corrected P < 0.048). This group effect was only significant with at least seven days between concussion and neuroimaging acquisition. Post-concussion symptoms severity was negatively correlated with NDI in four of these tracts: cingulum bundle, optic radiation, striato-fronto-orbital tract, and superior longitudinal fasciculus I. The multiple linear regression model combining sex and NDI of these four tracts was able to explain 33.2 % of the variability in symptom severity (F[7,49] = 4.9, P < 0.001, Adjusted R2 = 0.332). Relative to non-concussed controls, poor sleepers demonstrated lower NDI in the cingulum bundle, optic radiation, and superior longitudinal fasciculus I (FDR corrected P < 0.040). CONCLUSIONS: Poor quality of sleep following concussion is associated with widespread lower integrity of major white matter tracts, that in turn helped to explain post-concussion symptom severity in 12-17.9-year-old adolescents. The effect of sleep on white matter integrity following concussion was significant after one week, suggesting that acute sleep interventions may need this time to begin to take effect. Our findings may suggest an important relationship between good quality of sleep in the days following concussion and integrity of major white matter tracts. Moving forward, researchers should evaluate the effectiveness of sleep interventions on white matter integrity and clinical outcomes following concussion.

Resting State Functional Connectivity between Dorsal Attentional Network and Right Inferior Frontal Gyrus in Concussed and Control Adolescents.

Concussion among adolescents continues to be a public health concern. Yet, the differences in brain function between adolescents with a recent concussion and adolescents with no history of concussion are not well understood. Although resting state functional magnetic resonance imaging (fMRI) can be a useful tool in examining these differences, few studies have used this technique to examine concussion in adolescents. Here, we investigate the differences in the resting state functional connectivity of 52 adolescents, 38 with a concussion in the previous 10 days (mean age = 15.6; female = 36.8%), and 14 controls with no concussion history (mean age = 15.1; female = 57.1%). Independent component analysis and dual regression revealed that control adolescents had significantly greater functional connectivity between the dorsal attention network (DAN) and right inferior frontal gyrus (RIFG) compared to concussed adolescents (p-corrected < 0.001). Specifically, there was a positive DAN-RIFG connectivity in control, but not concussed, adolescents. Our findings indicate that concussion is associated with disrupted DAN-RIFG connectivity, which may reflect a general, nonspecific response to injury.

The effects of mood disorders and childhood trauma on fear of positive and negative evaluation.

Fear of positive and negative evaluation is maladaptive and may result in psychosocial dysfunction. Although being diagnosed with mood disorders or experiencing childhood trauma may potentially affect fear of evaluation, previous studies examined this phenomenon mostly in social anxiety disorders. To fill this gap, we investigated the relationship between childhood trauma and fear of positive and negative evaluation in individuals with bipolar disorder (BD), depressive disorders (DD), and healthy controls (HC). 43 individuals with BD, 89 with DD, and 65 HC completed clinical interviews and self-report assessments. The relationship between participants' diagnoses and presence of trauma on fear of positive and negative evaluation was examined using ANCOVA. Independently of experiencing childhood trauma, fear of positive evaluation was significantly higher in individuals with mood disorders vs. HC. Fear of negative evaluation was significantly associated with diagnosis-by-trauma interaction. Significantly lower scores were observed in individuals with BD without childhood trauma compared to those with childhood trauma and individuals with DD. Compared to HC, more individuals with mood disorders experienced childhood trauma. While experiencing childhood trauma may increase vulnerability to mood disorders in general, it is especially detrimental for individuals with BD by increasing the risk for developing a fear of negative evaluation.

Vestibular/ocular motor symptoms in concussed adolescents are linked to retrosplenial activation.

Following concussion, adolescents often experience vestibular and ocular motor symptoms as well as working memory deficits that may affect their cognitive, academic and social well-being. Complex visual environments including school activities, playing sports, or socializing with friends may be overwhelming for concussed adolescents suffering from headache, dizziness, nausea and fogginess, thus imposing heightened requirements on working memory to adequately function in such environments. While understanding the relationship between working memory and vestibular/ocular motor symptoms is critically important, no previous study has examined how an increase in working memory task difficulty affects the relationship between severity of vestibular/ocular motor symptoms and brain and behavioural responses in a working memory task. To address this question, we examined 80 adolescents (53 concussed, 27 non-concussed) using functional MRI while performing a 1-back (easy) and 2-back (difficult) working memory tasks with angry, happy, neutral and sad face distractors. Concussed adolescents completed the vestibular/ocular motor screening and were scanned within 10 days of injury. We found that all participants showed lower accuracy and slower reaction time on difficult (2-back) versus easy (1-back) tasks (P-values < 0.05). Concussed adolescents were significantly slower than controls across all conditions (P < 0.05). In concussed adolescents, higher vestibular/ocular motor screening total scores were associated with significantly greater differences in reaction time between 1-back and 2-back across all distractor conditions and significantly greater differences in retrosplenial cortex activation for the 1-back versus 2-back condition with neutral face distractors (P-values < 0.05). Our findings suggest that processing of emotionally ambiguous information (e.g. neutral faces) additionally increases the task difficulty for concussed adolescents. Post-concussion vestibular/ocular motor symptoms may reduce the ability to inhibit emotionally ambiguous information during working memory tasks, potentially affecting cognitive, academic and social functioning in concussed adolescents.

The Relationship Between Default Mode and Dorsal Attention Networks Is Associated With Depressive Disorder Diagnosis and the Strength of Memory Representations Acquired Prior to the Resting State Scan.

Previous research indicates that individuals with depressive disorders (DD) have aberrant resting state functional connectivity and may experience memory dysfunction. While resting state functional connectivity may be affected by experiences preceding the resting state scan, little is known about this relationship in individuals with DD. Our study examined this question in the context of object memory. 52 individuals with DD and 45 healthy controls (HC) completed clinical interviews, and a memory encoding task followed by a forced-choice recognition test. A 5-min resting state fMRI scan was administered immediately after the forced-choice task. Resting state networks were identified using group Independent Component Analysis across all participants. A network modeling analysis conducted on 22 networks using FSLNets examined the interaction effect of diagnostic status and memory accuracy on the between-network connectivity. We found that this interaction significantly affected the relationship between the network comprised of the medial prefrontal cortex, posterior cingulate cortex, and hippocampal formation and the network comprised of the inferior temporal, parietal, and prefrontal cortices. A stronger positive correlation between these two networks was observed in individuals with DD who showed higher memory accuracy, while a stronger negative correlation (i.e., anticorrelation) was observed in individuals with DD who showed lower memory accuracy prior to resting state. No such effect was observed for HC. The former network cross-correlated with the default mode network (DMN), and the latter cross-correlated with the dorsal attention network (DAN). Considering that the DMN and DAN typically anticorrelate, we hypothesize that our findings indicate aberrant reactivation and consolidation processes that occur after the task is completed. Such aberrant processes may lead to continuous "replay" of previously learned, but currently irrelevant, information and underlie rumination in depression.

Aberrant levels of cortical myelin distinguish individuals with depressive disorders from healthy controls.

The association between depressive disorders and measures reflecting myelin content is underexplored, despite growing evidence of associations with white matter tract integrity. We characterized the T1w/T2w ratio using the Glasser atlas in 39 UD and 47 HC participants (ages = 19-44, 75% female). A logistic elastic net regularized regression with nested cross-validation and a subsequent linear discriminant analysis conducted on held-out samples were used to select brain regions and classify patients vs. healthy controls (HC). True-label model performance was compared against permuted-label model performance. The T1w/T2w ratio distinguished patients from HC with 68% accuracy (p < 0.001; sensitivity = 63.8%, specificity = 71.5%). Brain regions contributing to this classification performance were located in the orbitofrontal cortex, anterior cingulate, extended visual, and auditory cortices, and showed statistically significant differences in the T1w/T2w ratio for patients vs. HC. As the T1w/T2w ratio is thought to characterize cortical myelin, patterns of cortical myelin in these regions may be a biomarker distinguishing individuals with depressive disorders from HC.

White matter abnormalities in adults with bipolar disorder type-II and unipolar depression.

Discerning distinct neurobiological characteristics of related mood disorders such as bipolar disorder type-II (BD-II) and unipolar depression (UD) is challenging due to overlapping symptoms and patterns of disruption in brain regions. More than 60% of individuals with UD experience subthreshold hypomanic symptoms such as elevated mood, irritability, and increased activity. Previous studies linked bipolar disorder to widespread white matter abnormalities. However, no published work has compared white matter microstructure in individuals with BD-II vs. UD vs. healthy controls (HC), or examined the relationship between spectrum (dimensional) measures of hypomania and white matter microstructure across those individuals. This study aimed to examine fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) across BD-II, UD, and HC groups in the white matter tracts identified by the XTRACT tool in FSL. Individuals with BD-II (n = 18), UD (n = 23), and HC (n = 24) underwent Diffusion Weighted Imaging. The categorical approach revealed decreased FA and increased RD in BD-II and UD vs. HC across multiple tracts. While BD-II had significantly lower FA and higher RD values than UD in the anterior part of the left arcuate fasciculus, UD had significantly lower FA and higher RD values than BD-II in the area of intersections between the right arcuate, inferior fronto-occipital and uncinate fasciculi and forceps minor. The dimensional approach revealed the depression-by-spectrum mania interaction effect on the FA, RD, and AD values in the area of intersection between the right posterior arcuate and middle longitudinal fasciculi. We propose that the white matter microstructure in these tracts reflects a unique pathophysiologic signature and compensatory mechanisms distinguishing BD-II from UD.

Protocol for a machine learning algorithm predicting depressive disorders using the T1w/T2w ratio.

The T1w/T2w ratio is a novel magnetic resonance imaging (MRI) measure that is thought to be sensitive to cortical myelin. Using this novel measure requires developing novel pipelines for the data quality assurance, data analysis, and validation of the findings in order to apply the T1w/T2w ratio for classification of disorders associated with the changes in the myelin levels. In this article, we provide a detailed description of such a pipeline as well as the reference to the scripts used in our recent report that applied the T1w/T2w ratio and machine learning to classify individuals with depressive disorders from healthy controls.

Prefrontal cortical activation during working memory task anticipation contributes to discrimination between bipolar and unipolar depression.

Distinguishing bipolar disorder (BD) from major depressive disorder (MDD) is clinically challenging, especially during depressive episodes. While both groups are characterized by aberrant working memory and anticipatory processing, the role of these processes in discriminating BD from MDD remains unexplored. In this study, we examine how brain activation corresponding to anticipation of and performance on easy vs. difficult working memory tasks with emotional stimuli contributes to discrimination among BD, MDD, and healthy controls (HC). Depressed individuals with BD (n = 18), MDD (n = 23), and HC (n = 23) were scanned while performing a working memory task in which they had to first anticipate performance on 1-back (easy) or 2-back (difficult) tasks with happy, fearful, or neutral faces, and then, perform the task. Anticipation-related and task-related brain activation was measured in the whole brain using functional magnetic resonance imagining. We used an elastic-net regression for variable selection, and a random forest classifier for BD vs. MDD classification. The former selected the activation differences (1-back minus 2-back) in the lateral and medial prefrontal cortices (PFC) during task anticipation and performance on the working memory tasks with fearful and neutral faces as variables relevant for BD vs. MDD classification. BD vs. MDD were classified with 70.7% accuracy (p < 0.01) based on the neuroimaging measures alone, with 80.5% accuracy (p = 0.001) based on clinical measures alone, and with 85.4% accuracy (p < 0.001) based on clinical and neuroimaging measures together. These findings suggest that PFC activation during working memory task anticipation and performance may be an important biological marker distinguishing BD from MDD.

The impact of familial risk and early life adversity on emotion and reward processing networks in youth at-risk for bipolar disorder.

A recently developed risk calculator for bipolar disorder (BD) accounts for clinical and parental psychopathology. Yet, it is understood that both familial predisposition and early life adversity contribute to the development of BD. How the interplay between these two factors influence emotion and reward processing networks in youth at risk for BD remains unclear. In this exploratory analysis, offspring of BD parents performed emotion and reward processing tasks while undergoing a fMRI scan. Risk calculator score was used to assess risk for developing BD in the next 5 years. Environmental risk was tabulated using the Stressful Life Events Schedule (SLES). Emotion and reward processing networks were investigated for genetic and/or environment interactions. Interaction effects were found between risk calculator scores, negative SLES score and activity in right amygdala and bilateral fusiform gyri during the emotion processing task, as well as activity in the fronto-, striatal, and parietal regions during the reward processing task. Our findings are preliminary; however, they support the unique and interactive contributions of both familial and environmental risk factors on emotion and reward processing within OBP. They also identify potential neural targets to guide development of interventions for youth at greatest risk for psychiatric disorders.

Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

The role of the right prefrontal cortex in recognition of facial emotional expressions in depressed individuals: fNIRS study.

BACKGROUND: Depressed individuals often perceive neutral facial expressions as emotional. Neurobiological underpinnings of this effect remain unclear. We investigated the differences in prefrontal cortical (PFC) activation in depressed individuals vs. healthy controls (HC) during recognition of emotional and neutral facial expressions using functional near infrared spectroscopy (fNIRS). METHOD: In Experiment 1, 33 depressed individuals and 20 HC performed the Emotion Intensity Rating task in which they rated intensity of facial emotional expressions. In Experiment 2, a different set of participants (18 depressed individuals and 16 HC) performed the same task while their PFC activation was measured using fNIRS. RESULTS: Both experiments showed that depressed individuals were slower and less accurate in recognizing neutral, but not happy or fearful, facial emotional expressions. Experiment 2 revealed that lower accuracy for neutral facial emotional expressions was associated with lower right PFC activation in depressed individuals, but not HC. In addition, depressed individuals, compared to HC, had lower right PFC activation during recognition of happy facial expressions. LIMITATIONS: Relatively small sample size CONCLUSIONS: Recognition of neutral facial expressions is impaired in depressed individuals. Greater impairment corresponds to lower right PFC activation during neutral face processing. Recognition of happy facial expressions is comparable for depressed individuals and HC, but the former have significantly lower right PFC activation. Taken together, these findings suggest that the ability of depressed individuals to discriminate neutral and emotional signals in the environment may be affected by aberrant functioning of right PFC.

Baseline and follow-up activity and functional connectivity in reward neural circuitries in offspring at risk for bipolar disorder.

Bipolar disorder (BD) is a serious psychiatric illness with demonstrated abnormalities in reward processing circuitry. Examining this circuitry in youth at familial risk for BD may provide further insight into the underlying mechanisms of BD development. In this study, we compared offspring of bipolar parents (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 36), and offspring of healthy parents (OHP, n = 39) during a functional magnetic resonance imaging reward processing task. Elastic net regression analyses identified 26 activity, functional connectivity (FC), and demographic variables that explained 34.24% of the variance in group (λ = 0.224). ANOVA and post-hoc analyses revealed that OBP had significantly lower right ventral striatum-left caudal anterior cingulate FC to loss (OBP versus OCP: p = 0.028, OBP versus OHP: p = 0.015) and greater right pars orbitalis-left (OBP versus OCP: p = 0.003, OBP versus OHP: p = 0.036) and -right (OBP versus OCP: p = 0.001, OBP versus OHP: p = 0.038) orbitofrontal cortex FC to reward versus OCP and OHP, respectively. These findings were not affected by non-BD psychopathology, psychotropic medication use, or symptomatology. There were no changes in, or relationships between, neuroimaging or symptom measures at follow-up (mean(SD) = 2.70(1.22) year inter-scan interval) in a subset of youth with follow-up data (OBP, n = 14; OCP, n = 8; OHP, n = 19). These findings suggest that lower right ventral striatum-left caudal anterior cingulate FC to loss and greater right pars orbitalis-orbitofrontal cortex FC to reward may be trait-level neural markers that may reflect risk for BD in at-risk youth. These findings comprise important steps toward identifying neural markers of BD risk, which may enhance early identification and guide interventions for youth at familial risk for BD.

White matter - emotion processing activity relationships in youth offspring of bipolar parents.

BACKGROUND: Early detection of Bipolar Disorder (BD) is critical for targeting interventions to delay or prevent illness onset. Yet, the absence of objective BD biomarkers makes accurately identifying at-risk youth difficult. In this study, we examined how relationships between white matter tract (WMT) structure and activity in emotion processing neural circuitry differentiate youth at risk for BD from youth at risk for other psychiatric disorders. METHODS: Offspring (ages 8-17) of parents with BD (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 30), and offspring of healthy parents (OHP, n = 24) underwent diffusion tensor and functional magnetic resonance imaging while performing an emotional face processing task. Penalized and multiple regression analyses included GROUP(OBP,OCP)xWMT interactions as main independent variables, and emotion processing activity as dependent variables, to determine significant group differences in WMT-activity relationships. RESULTS: 8 GROUPxWMT interaction variables contributed to 16.5% of the variance in amygdala and prefrontal cortical activity to happy faces. Of these, significant group differences in slopes (inverse for OBP, positive for OCP) existed for the relationship between forceps minor radial diffusivity and rostral anterior cingulate activity (p = 0.014). Slopes remained significantly different in unmedicated youth without psychiatric disorders (p = 0.017) and were moderated by affective lability symptoms (F(1,29) = 5.566, p = 0.036). LIMITATIONS: Relatively small sample sizes were included. CONCLUSIONS: Forceps minor radial diffusivity-rostral anterior cingulate activity relationships may reflect underlying neuropathological processes that contribute to affectively labile youth at risk for BD and may help differentiate them from youth at risk for other psychiatric disorders.