Behavioral skill practice as a predictor of mood and family functioning in adolescents with bipolar and depressive mood disorders: Results of a 6-month randomized trial of family-focused therapy.

OBJECTIVE: Behavioral interventions require considerable practice of treatment skills in between therapy sessions. The effects of these treatments may vary with the degree to which patients are able to implement these practices. In offspring of parents with bipolar and major depressive disorders, we examined whether youth who frequently practiced communication and problem-solving skills between family-focused therapy (FFT) sessions had less severe mood symptoms and better psychosocial functioning over 6 months than youth who practiced less frequently. METHODS: We randomly assigned offspring (ages 12-19) of parents with mood disorders to 12 sessions of FFT plus a mobile app that encouraged the practice of communication, problem-solving and mood management skills (FFT-MyCoachConnect [MCC] condition) or 12 sessions of FFT with an app that only allowed for tracking of symptoms and stress (FFT-Track condition). Independent evaluators assessed youths' mood and psychosocial functioning at 9-week intervals over 27 weeks. Clinicians rated participants' between-session skill practice at each FFT session. RESULTS: FFT-MCC was associated with more frequent skill practice than FFT-Track over 18 weeks of treatment. Skill practice was associated with reductions in youths' mood instability and perceptions of family conflict over 27 weeks in both app conditions. Skill practice mediated the effects of app condition on youths' mood instability and family functioning. CONCLUSIONS: Mobile applications as adjuncts to family therapy for youth with mood disorders can help increase skill practice. These findings provide preliminary causal evidence for behavioral skill practice improving mood symptoms and family functioning among youth with mood disorders.

Functional magnetic resonance imaging (fMRI) as adjunct for planning laser interstitial thermal therapy (LITT) near eloquent structures.

LITT is a minimally-invasive laser ablation technique used to treat a wide variety of intracranial lesions. Difficulties performing intraoperative mapping have limited its adoption for lesions in/near eloquent regions. In this institutional case series, we demonstrate the utility of fMRI-adjunct planning for LITT near language or motor areas. Six out of 7 patients proceeded with LITT after fMRI-based tractography determined adequate safety margins for ablation. All underwent successful ablation without new or worsening postoperative symptoms requiring adjuvant corticosteroids, including those with preexisting deficits. fMRI is an easily accessible adjunct which may potentially reduce chances of complications in LITT near eloquent structures.

Neural changes in youth at high risk for bipolar disorder undergoing family-focused therapy or psychoeducation.

BACKGROUND: Patients with mood disorders may benefit from psychosocial interventions through changes in brain networks underlying emotion processing. In this study, we used functional magnetic resonance imaging (fMRI) to investigate treatment-related changes in emotion processing networks in youth at familial high risk for bipolar disorder (BD). METHODS: Youth, ages 9-17, were randomly assigned to family-focused therapy for high-risk youth (FFT-HR) or an active comparison treatment, Enhanced Care (EC). Before and after these 4-month treatments, participants underwent fMRI while viewing happy, fearful, and calm facial expressions. Twenty youth in FFT-HR and 20 in EC were included in analyses of pre- to post-treatment changes in activation across the whole brain. Significant clusters were assessed for correlation with mood symptom improvement. RESULTS: In the dorsolateral prefrontal cortex (DLPFC), activation increased from pre- to post-treatment in the FFT-HR group and decreased in the EC group. Insula activation decreased in the FFT-HR group and did not change in the EC group. Across both treatments, decreasing activation in the hippocampus and amygdala was correlated with pre- to post-treatment improvement in hypomania, while increasing activation in the DLPFC was correlated with pre- to post-treatment improvement in depression. DISCUSSION: Psychosocial treatment addresses abnormalities in emotion regulation networks in youth at high risk for BD. Increased prefrontal cortex activation suggests enhanced emotion regulation from pre- to post-treatment with FFT-HR. Improvements in family interactions may facilitate the development of prefrontal resources that provide protection against future mood episodes.

Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 ).

OBJECTIVES: This report describes the first comparative double-blind, placebo-controlled trial of levothyroxine (L-T4 ) and triiodothyronine (T3 ) as adjunctive treatments in rapid cycling bipolar disorder. METHODS: Thirty-two treatment-resistant, rapid cycling patients who had failed a trial of lithium were randomized into three treatment arms: L-T4 , T3 , or placebo. They were followed for ≥4 months with weekly clinical and endocrine assessments. RESULTS: There were no statistically significant differences between the groups in age, gender, duration of illness, or thyroid status. Markov chain analyses were employed to assess treatment effects on cycling patterns among mood states (euthymia, depression, mania, and mixed). Within groups, post-treatment the L-T4 group spent significantly less time depressed or in a mixed state and greater time euthymic. The T3 and placebo groups did not differ significantly pre- and post-treatment in any mood state, although the pattern of effects was the same for the T3 group as for the L-T4 group. Between groups, the L-T4 group had a significantly greater increase in time euthymic and decrease in time in the mixed state than the placebo group. Other group differences were not significant, although they were in the expected direction. CONCLUSIONS: The findings in this first double-blind study directly comparing the effects of L-T4 and T3 therapy against placebo provide evidence for the benefit of adjunctive L-T4 in alleviating resistant depression, reducing time in mixed states and increasing time euthymic. Adjunctive T3 did not show statistically significant evidence of benefit over placebo in reducing the time spent in disturbed mood states.

Presurgical language fMRI: Mapping of six critical regions.

Language mapping is a key goal in neurosurgical planning. fMRI mapping typically proceeds with a focus on Broca's and Wernicke's areas, although multiple other language-critical areas are now well-known. We evaluated whether clinicians could use a novel approach, including clinician-driven individualized thresholding, to reliably identify six language regions, including Broca's Area, Wernicke's Area (inferior, superior), Exner's Area, Supplementary Speech Area, Angular Gyrus, and Basal Temporal Language Area. We studied 22 epilepsy and tumor patients who received Wada and fMRI (age 36.4[12.5]; Wada language left/right/mixed in 18/3/1). fMRI tasks (two × three tasks) were analyzed by two clinical neuropsychologists who flexibly thresholded and combined these to identify the six regions. The resulting maps were compared to fixed threshold maps. Clinicians generated maps that overlapped significantly, and were highly consistent, when at least one task came from the same set. Cases diverged when clinicians prioritized different language regions or addressed noise differently. Language laterality closely mirrored Wada data (85% accuracy). Activation consistent with all six language regions was consistently identified. In blind review, three external, independent clinicians rated the individualized fMRI language maps as superior to fixed threshold maps; identified the majority of regions significantly more frequently; and judged language laterality to mirror Wada lateralization more often. These data provide initial validation of a novel, clinician-based approach to localizing language cortex. They also demonstrate clinical fMRI is superior when analyzed by an experienced clinician and that when fMRI data is of low quality judgments of laterality are unreliable and should be withheld. Hum Brain Mapp 38:4239-4255, 2017. © 2017 Wiley Periodicals, Inc.

Assessment of grammar optimizes language tasks for the intracarotid amobarbital procedure.

PURPOSE: A previous study showed that assessment of language laterality could be improved by adding grammar tests to the recovery phase of the intracarotid amobarbital procedure (IAP) (Polczynska et al. 2014). The aim of this study was to further investigate the extent to which grammar tests lateralize language function during the recovery phase of the IAP in a larger patient sample. METHODS: Forty patients with drug-resistant epilepsy (14 females, thirty-two right-handed, mean age 38.5years, SD=10.6) participated in this study. On EEG, 24 patients had seizures originating in the left hemisphere (LH), 13 in the right hemisphere (RH), and 4 demonstrated mixed seizure origin. Thirty participants (75%) had bilateral injections, and ten (25%) had unilateral injections (five RH and five LH). Based on results from the encoding phase, we segregated our study participants to a LH language dominant and a mixed dominance group. In the recovery phase of the IAP, the participants were administered a new grammar test (the CYCLE-N) and a standard language test. We analyzed the laterality index measure and effect sizes in the two tests. KEY FINDINGS: In the LH-dominant group, the CYCLE-N generated more profound language deficits in the recovery phase than the standard after injection to either hemisphere (p<0.001). At the same time, the laterality index for the grammar tasks was still higher than for the standard tests. Critically, the CYCLE-N administered in the recovery phase was nearly as effective as the standard tests given during the encoding phase. SIGNIFICANCE: The results may be significant for individuals with epilepsy undergoing IAP. The grammar tests may be a highly efficient measure for lateralizing language function in the recovery phase.

Electroencephalography correlates of spatial working memory deficits in attention-deficit/hyperactivity disorder: vigilance, encoding, and maintenance.

In the current study we sought to dissociate the component processes of working memory (WM) (vigilance, encoding and maintenance) that may be differentially impaired in attention-deficit/ hyperactivity disorder (ADHD). We collected electroencephalographic (EEG) data from 52 children with ADHD and 47 typically developing (TD) children, ages 7-14 years, while they performed a spatial Sternberg working memory task. We used independent component analysis and time-frequency analysis to identify midoccipital alpha (8-12 Hz) to evaluate encoding processes and frontal midline theta (4-7 Hz) to evaluate maintenance processes. We tested for effects of task difficulty and cue processing to evaluate vigilance. Children with ADHD showed attenuated alpha band event-related desynchronization (ERD) during encoding. This effect was more pronounced when task difficulty was low (consistent with impaired vigilance) and was predictive of memory task performance and symptom severity. Correlated with alpha ERD during encoding were alpha power increases during the maintenance period (relative to baseline), suggesting a compensatory effort. Consistent with this interpretation, midfrontal theta power increases during maintenance were stronger in ADHD and in high-load memory conditions. Furthermore, children with ADHD exhibited a maturational lag in development of posterior alpha power whereas age-related changes in frontal theta power deviated from the TD pattern. Last, subjects with ADHD showed age-independent attenuation of evoked responses to warning cues, suggesting low vigilance. Combined, these three EEG measures predicted diagnosis with 70% accuracy. We conclude that the interplay of impaired vigilance and encoding in ADHD may compromise maintenance and lead to impaired WM performance in this group.

Role of the Wada test and functional magnetic resonance imaging in preoperative mapping of language and memory: two atypical cases.

The Wada test is an invasive procedure used to determine cerebral memory and language dominance as well as risk of cognitive deficits following neurosurgery. However, the potential risks of Wada testing have led some to consider foregoing Wada testing in candidates for resective epilepsy surgery with right hemispheric seizure onset. We present two atypical cases in which the Wada test showed unexpected memory and language lateralization. These cases underscore the importance of functional magnetic resonance in which imaging and Wada examination in right-handed individuals even when the lesion would not suggest atypical language representation.

Grey Matter Reshaping of Language-Related Regions Depends on Tumor Lateralization.

A brain tumor in the left hemisphere can decrease language laterality as assessed through fMRI. However, it remains unclear whether or not this decreased language laterality is associated with a structural reshaping of the grey matter, particularly within the language network. Here, we examine if the disruption of the language hubs exclusively affects the macrostructural properties of the contralateral homologues or whether it affects both hemispheres. This study uses voxel-based morphometry applied to high-resolution MR T1-weighted MPRAGE images from 31 adult patients' left hemisphere, which is dominant for language. Eighteen patients had brain tumors in the left hemisphere, and thirteen had tumors in the right hemisphere. A cohort of 71 healthy individuals matched with respect to age and sex was used as a baseline. We defined 10 ROIs per hemisphere involved in language function. Two separate repeated-measure ANOVAs were conducted with the volume per region as the dependent variable. For the patients, tumor lateralization (right versus left) served as a between-subject factor. The current study demonstrated that the presence of a brain tumor generates global volumetric changes affecting the left language regions and their contralateral homologues. These changes are mediated by the lateralization of the lesion. Our findings suggest that functional mechanisms are supported by the rearrangement of the grey matter.

Early Family Intervention for Youth at Risk for Bipolar Disorder: Psychosocial and Neural Mediators of Outcome.

BACKGROUND: The impairing neurodevelopmental course of bipolar disorder (BD) suggests the importance of early intervention for youth in the beginning phases of the illness. OBJECTIVE: We report the results of a 3-site randomized trial of family-focused therapy for youth at high-risk (FFT-HR) for BD, and explore psychosocial and neuroimaging variables as mediators of treatment effects. METHODS: High-risk youth (<18 years) with major depressive disorder or other specified BD, active mood symptoms, and a family history of BD were randomly assigned to 4 months of FFT-HR (psychoeducation, communication and problem-solving skills training) or 4 months of enhanced care psychoeducation. Adjunctive pharmacotherapy was provided by study psychiatrists. Neuroimaging scans were conducted before and after psychosocial treatments in eligible participants. Independent evaluators interviewed participants every 4-6 months over 1-4 years regarding symptomatic outcomes. RESULTS: Among 127 youth (mean 13.2 ± 2.6 years) over a median of 98 weeks, FFT-HR was associated with longer intervals prior to new mood episodes and lower levels of suicidal ideation than enhanced care. Reductions in perceived family conflict mediated the effects of psychosocial interventions on the course of mood symptoms. Among 34 participants with pre-/post-treatment fMRI scans, youth in FFT-HR had (a) stronger resting state connectivity between ventrolateral PFC and anterior default mode network, and (b) increased activity of dorsolateral and medial PFC in emotion processing and problem-solving tasks, compared to youth in enhanced care. CONCLUSION: FFT-HR may delay new mood episodes in symptomatic youth with familial liability to BD. Putative treatment mechanisms include neural adaptations suggestive of improved emotion regulation.

Grey matter reshaping of language-related regions depends on tumor lateralization.

A brain tumor in the left hemisphere can decrease language laterality as assessed with fMRI. However, it remains unclear whether or not this decreased language laterality is associated with a structural reshaping of the grey matter, particularly within the language network. Here, we examine if the disruption of language hubs exclusively affects macrostructural properties of contralateral homologues (as suggested by previous research), or whether it affects both hemispheres. This study uses voxel-based morphometry applied to high-resolution MR T1-weighted MPRAGE images from 31 adult patients left-dominant for language. Eighteen patients had brain tumors in the left hemisphere, and 13 had tumors in the right hemisphere. A cohort of 71 healthy individuals matched on age and sex was used as a baseline. We defined 10 ROIs per hemisphere known to subserve language function. Two separate repeated-measures ANOVAs were conducted with the volume per region as the dependent variables. For the patients, tumor lateralization (right versus left) served as a between-subject factor. The current study demonstrated that the presence of a brain tumor generates a global volumetric change affecting left language regions and their contralateral homologues. These changes are mediated by the lateralization of the lesion. Our findings suggest that compensatory functional mechanisms are supported by the rearrangement of the grey matter, although future longitudinal research should determine the temporal course of such changes.

A Randomized Clinical Trial of Technology-Enhanced Family-Focused Therapy for Youth in the Early Stages of Mood Disorders.

Objective: Family-focused therapy (FFT) is associated with enhanced outcomes in youth with bipolar and depressive disorders, but has not been evaluated in conjunction with mobile health tools. In symptomatic adolescents whose parents had histories of mood disorders, we examined whether the effects of telehealth-based FFT were augmented by mobile health apps that emphasized mood tracking and family coping skills. Method: Participants (aged 13-19 years) had active mood symptoms and a parent with major depressive or bipolar disorder. Participants received 12 sessions in 18 weeks of telehealth FFT, with random assignment to (1) a mobile app (MyCoachConnect, MCC) that enabled mood tracking, reviews of session content, and text reminders to practice mood management and family communication skills (FFT-MCC); or (2) a mobile app that enabled mood tracking only (FFT-Track). Independent evaluators assessed youth every 9 weeks over 6 months on depressive symptoms (primary outcome), anxiety, and psychosocial functioning. Results: Participants (N = 65; mean age 15.8 ± 1.6 years) significantly improved in depressive symptoms over 6 months (F1,170 = 45.02, p < .0001; ή2 = 0.21, 95% CI = 0.11-0.31), but there were no effects of treatment condition or treatment by time interactions on depression scores. When secondary outcome measures were considered, the subgroup of youth with bipolar spectrum disorders showed greater improvements in anxiety and global functioning in FFT-MCC compared with FFT-Track. Conclusion: Youth in the early stages of mood disorder may benefit from FFT enhanced by mobile health apps. Collaborations between researchers and information technologists on mobile app design and user experience may lead to increases in engagement among adolescents. Clinical trial registration information: Technology Enhanced Family Treatment; https://clinicaltrials.gov/; NCT03913013.

Mood Instability in Youth at High Risk for Bipolar Disorder.

OBJECTIVE: Mood instability is associated with the onset of bipolar disorder (BD) in youth with a family history of the illness. In a clinical trial with youth at high risk for BD, we examined the association between mood instability and symptomatic, psychosocial, and familial functioning over an average of 2 years. METHOD: Youth (aged 9-17 years) with major depressive disorder or other specified BD, current mood symptoms, and a family history of BD were rated by parents on a mood instability scale. Participants were randomly assigned to 4 months of family-focused therapy or enhanced care psychoeducation, both with medication management as needed. Independent evaluators rated youth every 4-6 months for up to 4 years on symptom severity and psychosocial functioning, whereas parents rated mood instability of the youth and levels of family conflict. RESULTS: High-risk youth (N = 114; mean age 13.3 ± 2.6 years; 72 female) were followed for an average of 104.3 ± 65.8 weeks (range, 0-255 weeks) after randomization. Youth with other specified BD (vs major depressive disorder), younger age, earlier symptom onset, more severe mood symptoms, lower psychosocial functioning, and more familial conflict over time had higher mood instability ratings throughout the study period. Mood instability mediated the association between baseline diagnosis and mother/offspring conflict at follow-up (Z = 2.88, p = .004, αß = 0.19, 95% CI = 0.06-0.32). Psychosocial interventions did not moderate these associations. CONCLUSION: A questionnaire measure of mood instability tracked closely with symptomatic, psychosocial, and family functioning in youth at high risk for BD. Interventions that are successful in reducing mood instability may enhance long-term outcomes among high-risk youth. CLINICAL TRIAL REGISTRATION INFORMATION: Early Intervention for Youth at Risk for Bipolar Disorder; https://clinicaltrials.gov/; NCT01483391.

Characterizing physiological high-frequency oscillations using deep learning.

Objective.Intracranially-recorded interictal high-frequency oscillations (HFOs) have been proposed as a promising spatial biomarker of the epileptogenic zone. However, HFOs can also be recorded in the healthy brain regions, which complicates the interpretation of HFOs. The present study aimed to characterize salient features of physiological HFOs using deep learning (DL).Approach.We studied children with neocortical epilepsy who underwent intracranial strip/grid evaluation. Time-series EEG data were transformed into DL training inputs. The eloquent cortex (EC) was defined by functional cortical mapping and used as a DL label. Morphological characteristics of HFOs obtained from EC (ecHFOs) were distilled and interpreted through a novel weakly supervised DL model.Main results.A total of 63 379 interictal intracranially-recorded HFOs from 18 children were analyzed. The ecHFOs had lower amplitude throughout the 80-500 Hz frequency band around the HFO onset and also had a lower signal amplitude in the low frequency band throughout a one-second time window than non-ecHFOs, resembling a bell-shaped template in the time-frequency map. A minority of ecHFOs were HFOs with spikes (22.9%). Such morphological characteristics were confirmed to influence DL model prediction via perturbation analyses. Using the resection ratio (removed HFOs/detected HFOs) of non-ecHFOs, the prediction of postoperative seizure outcomes improved compared to using uncorrected HFOs (area under the ROC curve of 0.82, increased from 0.76).Significance.We characterized salient features of physiological HFOs using a DL algorithm. Our results suggested that this DL-based HFO classification, once trained, might help separate physiological from pathological HFOs, and efficiently guide surgical resection using HFOs.

Knowledge gaps for functional outcomes after multilobar resective and disconnective pediatric epilepsy surgery: Conference Proceedings of the Patient-Centered Stakeholder Meeting 2019.

For children with medication-resistant epilepsy who undergo multilobar or hemispheric surgery, the goal of achieving seizure freedom is met with a variety of potential functional consequences, both favorable and unfavorable. However, there is a paucity of literature that comprehensively addresses the cognitive, medical, behavioral, orthopedic, and sensory outcomes across the lifespan following large epilepsy surgeries in childhood, leaving all stakeholders underinformed with regard to counseling and expectations. Through collaboration between clinicians, researchers, and patient/caregiver stakeholders, the "Functional Impacts of Large Resective or Disconnective Pediatric Epilepsy Surgery: Identifying Gaps and Setting PCOR Priorities" meeting was convened on July 18, 2019, to identify gaps in knowledge and inform various patient-centered research initiatives. Clinicians and researchers with content expertise presented the best available data in each functional domain which is summarized here. As a result of the meeting, the top three consensus priorities included research focused on postoperative: (1) hydrocephalus; (2) mental health issues; and (3) literacy and other educational outcomes. The proceedings of this meeting mark the first time research on functional outcomes after resective and disconnective pediatric epilepsy surgery has been codified and shared among multidisciplinary stakeholders. This joint initiative promotes continued collaboration in the field and ensures that advancements align with actual patient and family needs and experiences. Collaboration around common objectives will lead to better informed counseling around postoperative expectations and management for children undergoing epilepsy surgery.

Longitudinal relationship between maternal distress and pediatric mood symptoms in youth with mood disorders.

Parents of a child with a mood disorder report significant levels of distress and burden from caregiving. This study examined whether maternal distress varies over time with levels of mood symptoms in youth with mood disorders, and whether expressed emotion (EE) and family functioning moderate these associations. We recruited youth (ages 9-17 years) with mood disorders and familial risk for bipolar disorder (BD) for a randomized trial of family-focused therapy compared to standard psychoeducation. Participants were assessed every 4-6 months for up to 4 years. Using repeated-measures mixed effects modeling, we examined the longitudinal effects of youths' mood symptoms and maternal distress concurrently, as well as whether each variable predicted the other in successive study intervals. Secondary analyses examined the moderating effects of EE and ratings of family cohesion and adaptability on maternal distress. In sample of 118 youth-mother dyads, levels of self-reported parental distress decreased over time, with no differences between treatment conditions. Youths' depressive symptoms and, most strongly, mood lability were associated with greater maternal distress longitudinally; however, maternal distress did not predict youths' mood symptoms or lability. The effect of youth symptoms on maternal distress was greater among mothers who were high EE. Family cohesion was associated with reduced concurrent ratings of maternal distress, whereas family adaptability was associated with reduced maternal distress at successive follow-ups. While maternal distress decreases over time as youths' symptoms decrease, mothers of youth with mood disorders experience significant distress that is directly linked to the youths' depressive symptom severity and lability. Improved family functioning appears to be an important mechanism by which to intervene.

Development and Open Trial of a Technology-Enhanced Family Intervention for Adolescents at Risk for Mood Disorders.

AIM: Integrating psychosocial interventions with mobile apps may increase treatment engagement among adolescents. We examined the user experience, uptake, and clinical effects of a mobile-enhanced family-focused therapy (FFT) among adolescents at risk for mood disorders. METHOD: We created a mobile app containing 12 lesson plans corresponding to content of weekly FFT sessions, with modules concerning mood management, family communication and problem-solving. We pilot tested the app in an open trial of FFT (12 sessions in 18 weeks) for adolescents who had active depressive or hypomanic symptoms, a parent with mood disorder, and at least one parent who expressed high levels of criticism. Teens and parents made daily and weekly ratings of youths' moods, amount of parent/offspring criticism, and practice of FFT psychoeducational, communication or problem-solving skills. Independent evaluators interviewed adolescents at baseline and every 9 weeks over 27 weeks to measure symptom trajectories. RESULTS: Participants were adolescents (n=22; mean age 15.4 ± 1.8 years; 45.5% female) and their 34 parents. Completion of requested app assessment and skill practices averaged 46%-65% among adolescents and parents over 18 weeks of treatment. Adolescents showed significant improvement in clinician-rated depression scores over 27 weeks (Cohen's d=1.58, 95% CI, 0.83 to 2.32) and reported reductions in the amount of perceived criticism expressed by parents. LIMITATIONS: The uncontrolled design limits inferences about whether the mobile app augmented the effects of FFT on moods or family relationships. CONCLUSIONS: Mobile applications may enhance users' responses to family therapy and provide clinicians with information regarding clinical status. Clinicaltrials.gov NCT03913013.

Changes in Intrinsic Brain Connectivity in Family-Focused Therapy Versus Standard Psychoeducation Among Youths at High Risk for Bipolar Disorder.

OBJECTIVE: We compared intrinsic network connectivity in symptomatic youths at high risk (HR) for bipolar disorder (BD) and healthy comparison (HC) youths. In HR youths, we also investigated treatment-related changes in intrinsic connectivity after family-focused therapy for high-risk youths (FFT-HR) vs standardized family psychoeducation. METHOD: HR youths (N = 34; age 9-17 years; mean 14 years, 56% girls and 44% boys) with depressive and/or hypomanic symptoms and at least 1 first- or second-degree relative with BD I or II were randomly assigned to 4 months of FFT-HR (12 sessions of psychoeducation, communication, and problem-solving skills training) or enhanced care (EC; 3 family and 3 individual psychoeducation sessions). Before and after 4 months of treatment, participants underwent resting state functional magnetic resonance imaging (rs-fMRI). A whole-brain independent component analysis compared rs-fMRI networks in HR youths and 30 age-matched HC youths at a pretreatment baseline. Then we identified pretreatment to posttreatment (4-month) changes in network connectivity in HR youths receiving FFT-HR (n = 16) or EC (n = 18) and correlated these changes with depression improvement. RESULTS: At baseline, HR youths had greater connectivity between the ventrolateral prefrontal cortex (VLPFC) and the anterior default mode network (aDMN) than did HCs (p = .004). Over 4 months of treatment, FFT-HR-assigned HR youths had increased VLPFC-aDMN connectivity from pre- to posttreatment (p = .003), whereas HR youths in EC showed no significant change over time (p = .11) (treatment by time interaction, t31 = 3.33, 95% CI = 0.27-1.14, p = .002]. Reduction in depression severity over 4 months inversely correlated with enhanced anterior DMN (r = -0.71) connectivity in the FFT-HR but not in the EC (r = -0.07) group (z = -2.17, p = .015). CONCLUSION: Compared to standard psychoeducation, FFT-HR is associated with stronger connectivity between the VLPFC and aDMN, suggesting possible enhancements of self-awareness, illness awareness, and emotion regulation. CLINICAL TRIAL REGISTRATION INFORMATION: Early Intervention for Youth at Risk for Bipolar Disorder; https://clinicaltrials.gov/; NCT01483391.

Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.

OBJECTIVE: Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. METHODS: Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. RESULTS: With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. SIGNIFICANCE: This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Executive function in pediatric bipolar disorder and attention-deficit hyperactivity disorder: in search of distinct phenotypic profiles.

Often, there is diagnostic confusion between bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) in youth due to similar behavioral presentations. Both disorders have been implicated as having abnormal functioning in the prefrontal cortex; however, there may be subtle differences in the manner in which the prefrontal cortex functions in each disorder that could assist in their differentiation. Executive function is a construct thought to be a behavioral analogy to prefrontal cortex functioning. We provide a qualitative review of the literature on performance on executive function tasks for BD and ADHD in order to determine differences in task performance and neurocognitive profile. Our review found primary differences in executive function in the areas of interference control, working memory, planning, cognitive flexibility, and fluency. These differences may begin to establish a pediatric BD profile that provides a more objective means of differential diagnosis between BD and ADHD when they are not reliably distinguished by clinical diagnostic methods.