White Matter Changes after Neurobehavioral Therapy for Functional Seizures.

OBJECTIVE: We aimed to prospectively quantify changes in white matter morphology after neurobehavioral therapy (NBT) for functional seizures (FS) using neurite orientation dispersion and density imaging (NODDI). We hypothesized that patients with FS would exhibit white matter plasticity in the uncinate fasciculus, fornix/stria terminalis, cingulum, and corticospinal tract following NBT that would correlate with improvements in affective symptoms, postconcussive symptoms, and quality of life (QOL). METHODS: Forty-two patients with traumatic brain injury (TBI) and FS (TBI+FS) underwent NBT and provided pre-/postintervention neuroimaging and behavioral data; 47 controls with TBI without FS (TBI-only) completed the same measures but did not receive NBT. Changes in neurite density, orientation dispersion (orientation dispersion index [ODI]), and extracellular free water (FW) were compared between groups. RESULTS: Significant ODI increases in the left uncinate fasciculus in TBI+FS (mean difference = 0.017, p = 0.039) correlated with improvements in posttraumatic symptoms (r = -0.395, p = 0.013), QOL (r = 0.474, p = 0.002), emotional well-being (r = 0.524, p < 0.001), and energy (r = 0.474, p = 0.002). In TBI-only, ODI decreased (mean difference = -0.008, p = 0.047) and FW increased (mean difference = 0.011, p = 0.003) in the right cingulum. FW increases correlated with increased psychological problems (r = 0.383, p = 0.013). In TBI+FS, NBT resulted in FS decreases of 3.5 seizures per week. None of the imaging changes correlated with FS frequency. INTERPRETATION: We identified white matter changes after NBT in patients with FS that were associated with improved psychosocial functioning. NODDI could be incorporated into future mechanistic assessments of interventions in patients with FS. ANN NEUROL 2023;94:350-365.

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

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

One-year follow-up of neurobehavioral therapy in functional seizures or epilepsy with traumatic brain injury: A nonrandomized controlled trial.

OBJECTIVE: Patients with traumatic brain injury (TBI) often present with seizures (functional and/or epileptic), but treatments for patients with TBI and seizures are limited. We examined treatment phase and 1-year post-enrollment outcomes following neurobehavioral therapy (NBT) for patients with TBI + functional seizures (FS) and TBI + epilepsy. METHODS: In this multicenter, prospective, three-group, nonrandomized, controlled trial, with 1-year post-enrollment follow-up, three cohorts of adults were recruited: TBI + video-electroencephalography (EEG)-confirmed FS (n = 89), TBI + EEG-confirmed epilepsy (n = 29), and chart/history-confirmed TBI without seizures (n = 75). Exclusion criteria were recent psychotic or self-injurious behavior, current suicidal ideation, pending litigation or long-term disability, active substance use disorder, and inability to participate in study procedures. TBI + FS and TBI + epilepsy groups completed NBT for seizures, an evidence-based, 12-session, multimodal psychotherapy, whereas TBI without seizures participants received standard medical care. The primary outcome was change in seizure frequency; secondary outcomes were changes in mental health, TBI-related symptoms, disability, and quality of life. RESULTS: Reductions in average monthly seizures occurred during treatment in TBI + FS participants (p = .002) and were significant from baseline (mean = 16.75; 95% confidence interval [CI] = 11.44-24.53) to 12 months post-enrollment (mean = 7.28, 95% CI = 4.37-12.13, p = .002, d = .38). Monthly seizures decreased during treatment in TBI + epilepsy participants (p = .002); reductions were not statistically significant from baseline (mean = 2.38, 95% CI = 1.12-5.04) to 12-month postenrollment (mean = .98, 95% CI = .40-2.42, p = .07, d = .22). Regarding treatment-phase changes in secondary outcome measures, TBI + FS participants improved significantly on 10 of 19 variables (52.6%), TBI + epilepsy participants improved on five of 19 (26.3%), and TBI-only comparisons improved on only one of 19 (5.3%). SIGNIFICANCE: NBT benefited patients with TBI + FS and TBI + epilepsy. Improvements were demonstrated at 1 year post-enrollment in those with TBI + FS. NBT may be a clinically useful treatment for patients with seizures.

Psychometric and adherence considerations for high-frequency, smartphone-based cognitive screening protocols in older adults.

OBJECTIVE: The psychometric rigor of unsupervised, smartphone-based assessments and factors that impact remote protocol engagement is critical to evaluate prior to the use of such methods in clinical contexts. We evaluated the validity of a high-frequency, smartphone-based cognitive assessment protocol, including examining convergence and divergence with standard cognitive tests, and investigating factors that may impact adherence and performance (i.e., time of day and anticipated receipt of feedback vs. no feedback). METHODS: Cognitively unimpaired participants (N = 120, Mage = 68.8, 68.3% female, 87% White, Meducation = 16.5 years) completed 8 consecutive days of the Mobile Monitoring of Cognitive Change (M2C2), a mobile app-based testing platform, with brief morning, afternoon, and evening sessions. Tasks included measures of working memory, processing speed, and episodic memory. Traditional neuropsychological assessments included measures from the Preclinical Alzheimer's Cognitive Composite battery. RESULTS: Findings showed overall high compliance (89.3%) across M2C2 sessions. Average compliance by time of day ranged from 90.2% for morning sessions, to 77.9% for afternoon sessions, and 84.4% for evening sessions. There was evidence of faster reaction time and among participants who expected to receive performance feedback. We observed excellent convergent and divergent validity in our comparison of M2C2 tasks and traditional neuropsychological assessments. CONCLUSIONS: This study supports the validity and reliability of self-administered, high-frequency cognitive assessment via smartphones in older adults. Insights into factors affecting adherence, performance, and protocol implementation are discussed.

Reduced Subjective Cognitive Concerns With Neurobehavioral Therapy in Functional Seizures and Traumatic Brain Injury.

OBJECTIVE: Functional seizures are common among people with traumatic brain injury (TBI). Subjective cognitive concerns refer to a person's own perception of problems with cognitive functioning in everyday life. The authors investigated the presence and correlates of subjective cognitive concerns and the response to neurobehavioral therapy among adults with TBI and functional seizures (TBI+FS group). METHODS: In this observational study, participants in the TBI+FS group (N=47) completed a 12-session neurobehavioral therapy protocol for seizures, while participants in the comparison group (TBI without seizures) (N=50) received usual treatment. Subjective cognitive concerns, objective cognition, mental health, and quality of life were assessed before and after treatment. Data collection occurred from 2018 to 2022. RESULTS: Baseline subjective cognitive concerns were reported for 37 (79%) participants in the TBI+FS group and 20 (40%) participants in the comparison group. In a multivariable regression model in the TBI+FS group, baseline global mental health (ß=-0.97) and obsessive-compulsive symptoms (ß=-1.01) were associated with subjective cognitive concerns at baseline. The TBI+FS group had fewer subjective cognitive concerns after treatment (η2=0.09), whereas the TBI comparison group showed a nonsignificant increase in subjective cognitive concerns. CONCLUSIONS: Subjective cognitive concerns are common among people with TBI and functional seizures and may be related to general mental health and obsessive-compulsive symptoms. Evidence-based neurobehavioral therapy for functional seizures is a reasonable treatment option to address such concerns in this population, although additional studies in culturally diverse samples are needed. In addition, people with functional seizures would likely benefit from rehabilitation specifically targeted toward cognitive functioning.

Altered fronto-limbic-motor response to stress differs between functional and epileptic seizures in a TBI model.

BACKGROUND AND OBJECTIVES: Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES emergence and occurrence after TBI may be linked to aberrant neurobehavioral stress responses. We hypothesized that neural activity signatures in response to a psychosocial stress task would differ between TBI + FS and TBI + ES after controlling for TBI status (TBI-only). METHODS: In the current multicenter study, participants were recruited prospectively from Rhode Island Hospital, Providence Rhode Island Veterans Administration Medical Center, and the University of Alabama at Birmingham Medical Center. Previous diagnoses of TBI, ES, and FS were verified based on data collected from participants, medical chart and record review, and, where indicated, results of EEG and/or video-EEG confirmatory diagnosis. TBI + ES (N = 21) and TBI + FS (N = 21) were matched for age and sex and combined into an initial group (TBI + SZ; N = 42). A TBI-only group (N = 42) was age and sex matched to the TBI with seizures (TBI + SZ) group. All participants completed an fMRI control math task (CMT) and stress math task (SMT) based on the Montreal Imaging Stress Task (MIST). RESULTS: The TBI + SZ group (n = 24 female) did not differ in mood or anxiety severity compared to TBI-only group (n = 24 female). However, TBI + FS group (n = 11 female) reported greater severity of these symptoms compared to TBI + ES (n = 13 female). The linear mixed effects analysis identified neural responses that differed between TBI-only and TBI + SZ during math performance within the left premotor cortex and during auditory feedback within bilateral prefrontal cortex and hippocampus/amygdala regions. Additionally, neural responses differed between TBI + ES and TBI + FS during math performance within the right dorsolateral prefrontal cortex and bilateral amygdala during auditory feedback within the supplementary motor area. All tests comparing neural stress responses to psychiatric symptom severity failed to reach significance. DISCUSSION: Controlling for TBI and seizure status, these findings implicate specific nodes within frontal, limbic, and sensorimotor networks that may maintain functional neurological symptoms and possibly distinguish FS from ES. This study provides class II evidence of differences in neural responses to psychosocial stress between ES and FS after TBI.

Compensatory strategy use in diverse older adults with subjective cognitive complaints.

OBJECTIVES: The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx White (NLW), Black, and Latinx American older adults. METHOD: 807 older adults (Mage = 65.38, 62.7% female) were recruited through Amazon's Mechanical Turk (MTurk) and Qualtrics Panel to complete questionnaires on SCC and CS use. Kruskall-Wallis tests were used to evaluate differences in SCC across groups given non-normal distributions. Analysis of variance (ANOVA) was used to evaluate group differences in CS use. The PROCESS macro for SPSS was used to examine whether demographic factors moderated the relationship between SCC and CS use. RESULTS: NLWs reported higher levels of SCC and greater overall use of CS in comparison to Latinx and Black individuals. Several demographic and psychosocial factors including age, ethno-racial group, education, and anxiety level were found to be associated with CS use. Education was found to moderate the association between SCC and CS use. CONCLUSION: Inconsistent with prior studies, our study found that NLWs reported the highest levels of SCC. CS were used across all racial/ethnic groups, but the frequency of CS use may be impacted by education level. While all education groups increased their CS in response to higher levels of SCC, this increase was more substantial for those with lower levels of education. Future work should consider individuals' cultural and educational background when examining SCC and/or developing CS-based intervention for the aging population.

Relationship between intrinsic network connectivity and psychiatric symptom severity in functional seizures.

BACKGROUND: Traumatic brain injury (TBI) may precipitate the onset of functional seizures (FSs). Many patients with FS report at least one prior TBI, and these patients typically present with more severe psychiatric comorbidities. TBI and psychopathology are linked to changes in neural network connectivity, but their combined effects on these networks and relationship to the effects of FS remain unclear. We hypothesised that resting-state functional connectivity (rsFC) would differ between patients with FS and TBI (FS+TBI) compared with TBI without FS (TBI only), with variability only partially explained by the presence of psychopathology. METHODS: Patients with FS+TBI (n=52) and TBI only (n=54) were matched for age and sex. All participants completed psychiatric assessments prior to resting-state functional MRI at 3 T. Independent component analysis identified five canonical rsFC networks related to emotion and motor functions. RESULTS: Five linear mixed-effects analyses identified clusters of connectivity coefficients that differed between groups within the posterior cingulate of the default mode network, insula and supramarginal gyrus of the executive control network and bilateral anterior cingulate of the salience network (all α=0.05, corrected). Cluster signal extractions revealed decreased contributions to each network for FS+TBI compared to TBI only. Planned secondary analyses demonstrated correlations between signal and severity of mood, anxiety, somatisation and global functioning symptoms. CONCLUSIONS: These findings indicate the presence of aberrant connectivity in FS and extend the biopsychosocial network model by demonstrating that common aetiology is linked to both FS and comorbidities, but the overlap in affected networks varies by comorbid symptoms.

Longitudinal post-shunt outcomes in idiopathic normal pressure hydrocephalus with and without comorbid Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) is highly comorbid with idiopathic normal pressure hydrocephalus (iNPH) and may diminish the benefits of shunting; however, findings in this area are mixed. We examined postoperative outcomes, with emphases on cognition and utilization of novel scoring procedures to enhance sensitivity. METHODS: Using participant data from an iNPH outcome study at Butler Hospital, a mixed effect model examined main and interaction effects of time since surgery (baseline, 3 months, 12 months, and 24-60 months) and AD comorbidity (20 iNPH and 11 iNPH+AD) on activities of daily living (ADLs) and iNPH symptoms. Regression modeling explored whether baseline variables predicted improvements 3 months postoperatively. RESULTS: There were no group differences in gait, incontinence, and global cognition over time, and neither group showed changes in ADLs. Cognitive differences were observed postoperatively; iNPH patients showed stable improvements in working memory (p = 0.012) and response inhibition (p = 0.010), while iNPH + AD patients failed to maintain initial gains. Regarding predicting postoperative outcomes, baseline AD biomarkers did not predict shunt response at 3 months; however, older age at surgery predicted poorer cognitive outcomes (p = 0.04), and presurgical Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (p = 0.035) and Mini-Mental Status Examination (MMSE) scores (p = 0.009) predicted improvements incontinence. CONCLUSION: iNPH + AD may be linked with greater declines in aspects of executive functioning postoperatively relative to iNPH alone. While baseline AD pathology may not prognosticate shunt response, younger age appears linked with postsurgical cognitive improvement, and utilizing both brief and comprehensive cognitive measures may help predict improved incontinence. These results illustrate the potential benefits of surgery and inform postoperative expectations for those with iNPH + AD.

Regional brain atrophy and aberrant cortical folding relate to anxiety and depression in patients with traumatic brain injury and psychogenic nonepileptic seizures.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are characterized by multifocal and global abnormalities in brain function and connectivity. Only a few studies have examined neuroanatomic correlates of PNES. Traumatic brain injury (TBI) is reported in 83% of patients with PNES and may be a key component of PNES pathophysiology. In this study, we included patients with TBI preceding the onset of PNES (TBI-PNES) and TBI without PNES (TBI-only) to identify neuromorphometric abnormalities associated with PNES. METHODS: Adults diagnosed with TBI-PNES (n = 62) or TBI-only (n = 59) completed psychological questionnaires and underwent 3-T magnetic resonance imaging. Imaging data were analyzed by voxel- and surface-based morphometry. Voxelwise general linear models computed group differences in gray matter volume, cortical thickness, sulcal depth, fractal dimension (FDf), and gyrification. Statistical models were assessed with permutation-based testing at 5000 iterations with the Threshold-Free Cluster Enhancement toolbox. Logarithmically scaled p-values corrected for multiple comparisons using familywise error were considered significant at p < .05. Post hoc analyses determined the association between structural and psychological measures (p < .05). RESULTS: TBI-PNES participants demonstrated atrophy of the left inferior frontal gyrus and the right cerebellum VIII. Relative to TBI-only, TBI-PNES participants had decreased FDf in the right superior parietal gyrus and decreased sulcal depth in the left insular cortex. Significant clusters were positively correlated with global assessment of functioning scores, and demonstrated varying negative associations with measures of anxiety, depression, somatization, and global severity of symptoms. SIGNIFICANCE: The diagnosis of PNES was associated with brain atrophy and reduced cortical folding in regions implicated in emotion processing, regulation, and response inhibition. Cortical folds primarily develop during the third trimester of pregnancy and remain relatively constant throughout the remainder of one's life. Thus, the observed aberrations in FDf and sulcal depth could originate early in development. The convergence of environmental, developmental, and neurobiological factors may coalesce to reflect the neuropathophysiological substrate of PNES.

Safety and Tolerability of APOE Genotyping and Disclosure in Cognitively Normal Volunteers From the Butler Alzheimer's Prevention Registry.

AIMS: Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease that ultimately results in total loss of cognitive and functional independence in older adults. This study aimed to examine the safety and tolerability of APOE disclosure in community-dwelling, cognitively normal (CN) older adults from the Butler Alzheimer's Prevention Registry (BAPR), and to determine whether APOE disclosure impacted participant's decisions to participate in AD clinical research. METHODS: 186 (N = 106 ∊4 non-carriers, 80 ∊4 carriers) CN older adults aged 58-78 from the BAPR completed 2 visits: one for psychological readiness screening and genotyping and one for APOE disclosure. Online follow-ups were completed 3 days, 6 weeks, and 6 months post-disclosure. Primary outcomes were scores on self-report measures of depression, anxiety, impact of events, and perceived risk of AD, along with enrollment in AD clinical trials. RESULTS: ∊4 carriers and non-carriers did not differ significantly on measures of depression, anxiety, or suicidal ideation over the 6-month follow-up period. ∊4 carriers reported higher impact of disclosure than non-carriers immediately after disclosure, but both groups' scores on impact of events measures remained sub-clinical. ∊4 carriers and non-carriers were equally likely to participate in AD research after disclosure, with genotype-dependent differences in type of clinical trial enrollment. CONCLUSIONS: APOE genotyping and disclosure was safe and well tolerated in a group of CN, community-dwelling older adults, who were pre-screened after volunteering for AD research through BAPR. Implications for the inclusion of APOE genotyping and disclosure at AD clinical trial sites are discussed.

Diagnostic delay in functional seizures is associated with abnormal processing of facial emotions.

PURPOSE: In patients with functional seizures (FS), delay in diagnosis (DD) may negatively affect outcomes. Altered brain responses to emotional stimuli have been shown in adults with FS. We hypothesized that DD would be associated with differential fMRI activation in emotion processing circuits. METHODS: Fifty-two adults (38 females) with video-EEG confirmed FS prospectively completed assessments related to symptoms of depression (BDI-II), anxiety (BAI), post-traumatic stress disorder (PCL-S), a measure of how their symptoms affect day-to-day life (GAF), and fMRI at 3T with emotional faces task (EFT). During fMRI, subjects indicated "male" or "female" via button press while implicitly processing happy, sad, fearful, and neutral faces. Functional magnetic resonance imaging (FMRI) response to each emotion was modeled and group analyses were performed in AFNI within pre-specified regions-of-interest involved in emotion processing. A median split (507 days) defined short- (s-DD) and long-delay diagnosis (l-DD) groups. Voxelwise regression analyses were also performed to examine linear relationship between DD and emotion processing. FMRI signal was extracted from clusters showing group differences and Spearman's correlations assessed relationships with symptom scores. RESULTS: Groups did not differ in FS age of onset, sex distribution, years of education, TBI characteristics, EFT in-scanner or post-test performance, or scores on the GAF, BDI-II, BAI, and PCL-S measures. The s-DD group was younger than l-DD (mean age 32.6 vs. 40.1; p = 0.022) at the time of study participation. After correcting for age, compared to s-DD, the l-DD group showed greater fMRI activation to sad faces in the bilateral posterior cingulate cortex (PCC) and to neutral faces in the right anterior insula. Within-group linear regression revealed that with increasing DD, there was increased fMRI activation to sad faces in the PCC and to happy faces in the right anterior insula/inferior frontal gyrus (AI/IFG). There were positive correlations between PCC response to sad faces and BDI-II scores in the l-DD group (rho = 0.48, p = 0.012) and the combined sample (rho = 0.30, p = 0.029). Increased PCC activation to sad faces in those in the l-DD group was associated with worse symptoms of depression (i.e. higher BDI-II score). CONCLUSIONS: Delay in FS diagnosis is associated with fMRI changes in PCC and AI/IFG. As part of the default mode network, PCC is implicated in mood control, self-referencing, and other emotion-relevant processes. In our study, PCC changes are linked to depression. Future studies should assess the effects of interventions on these abnormalities.

Discrepancy-Based Evidence for Loss of Thinking Abilities (DELTA): Development and Validation of a Novel Approach to Identifying Cognitive Changes.

OBJECTIVE: To develop and validate the Discrepancy-based Evidence for Loss of Thinking Abilities (DELTA) score. The DELTA score characterizes the strength of evidence for cognitive decline on a continuous spectrum using well-established psychometric principles for improving detection of cognitive changes. METHODS: DELTA score development used neuropsychological test scores from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (two tests each from Memory, Executive Function, and Language domains). We derived regression-based normative reference scores using age, gender, years of education, and word-reading ability from robust cognitively normal ADNI participants. Discrepancies between predicted and observed scores were used for calculating the DELTA score (range 0-15). We validated DELTA scores primarily against longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Functional Activities Questionnaire (FAQ) scores (baseline assessment through Year 3) using linear mixed models and secondarily against cross-sectional Alzheimer's biomarkers. RESULTS: There were 1359 ADNI participants with calculable baseline DELTA scores (age 73.7 ± 7.1 years, 55.4% female, 100% white/Caucasian). Higher baseline DELTA scores (stronger evidence of cognitive decline) predicted higher baseline CDR-SOB (ΔR2 = .318) and faster rates of CDR-SOB increase over time (ΔR2 = .209). Longitudinal changes in DELTA scores tracked closely and in the same direction as CDR-SOB scores (fixed and random effects of mean + mean-centered DELTA, ΔR2 > .7). Results were similar for FAQ scores. High DELTA scores predicted higher PET-Aß SUVr (ρ = 324), higher CSF-pTau/CSF-Aß ratio (ρ = .460), and demonstrated PPV > .9 for positive Alzheimer's disease biomarker classification. CONCLUSIONS: Data support initial development and validation of the DELTA score through its associations with longitudinal functional changes and Alzheimer's biomarkers. We provide several considerations for future research and include an automated scoring program for clinical use.

White matter integrity and functional predictors of response to repetitive transcranial magnetic stimulation for posttraumatic stress disorder and major depression.

BACKGROUND: Recent evidence suggests that therapeutic repetitive transcranial magnetic stimulation (TMS) is an effective treatment for pharmacoresistant posttraumatic stress disorder (PTSD) and comorbid major depressive disorder (MDD). We recently demonstrated that response to 5 Hz TMS administered to the dorsolateral prefrontal cortex was predicted by functional connectivity of the medial prefrontal (MPFC) and subgenual anterior cingulate cortex (sgACC). This functionally-defined circuit is a novel target for treatment optimization research, however, our limited knowledge of the structural pathways that underlie this functional predisposition is a barrier to target engagement research. METHODS: To investigate underlying structural elements of our previous functional connectivity findings, we submitted pre-TMS diffusion-weighted imaging data from 20 patients with PTSD and MDD to anatomically constrained tract-based probabilistic tractography (FreeSurfer's TRActs Constrained by UnderLying Anatomy). Averaged pathway fractional anisotropy (FA) was extracted from four frontal white matter tracts: the forceps minor, cingulum, anterior thalamic radiations (ATRs), and uncinate fasciculi. Tract FA statistics were treated as explanatory variables in backward regressions testing the relationship between tract integrity and functional connectivity coefficients from MPFC and sgACC predictors of symptom improvement after TMS. RESULTS: FA in the ATRs was consistently associated with symptom improvement in PTSD and MDD (Bonferroni-corrected p < .05). CONCLUSION: We found that structural characteristics of the ATR account for significant variance in individual-level functional predictors of post-TMS improvement. TMS optimization studies should target this circuit either in stand-alone or successive TMS stimulation protocols.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study.

INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network.

OBJECTIVE: White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. METHODS: The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. RESULTS: Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. INTERPRETATION: Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.

White matter integrity correlates with depressive symptomatology in temporal lobe epilepsy.

RATIONALE: White matter abnormalities occur in both temporal lobe epilepsy (TLE) and depression, but there is limited research examining the depression-white matter association in depressed individuals with TLE. This study examined the relationship between white matter integrity (WMI) and depression including the influence of age at seizure onset, in adults with TLE, TLE and depression, and depression only. METHODS: Thirty-one adults were in one of three groups: TLE without depression (TLE; n=11), TLE with depression (TLE+DEP; n=9), and depression without TLE (DEP; n=11). Participants completed structured interviews for depression diagnosis and severity. White matter integrity was estimated based on fractional anisotropy (FA) calculated in frontotemporolimbic (FTL) and non-FTL regions in the JHU DTI atlas. RESULTS: In adults with TLE (n=20), depressive symptomology was significantly correlated with FA in non-FTL regions and trended toward significance in FTL regions. These associations were found in FTL (statistically significant) and non-FTL (trended toward significance) regions in participants with childhood seizure onset but not in those with adolescent/adult seizure onset. CONCLUSIONS: Current results suggest that WMI, within FTL and non-FTL regions, are associated with depressive symptomology in adults with TLE. This association may be most notable in those with childhood-onset epilepsy. These findings could have important implications for the conceptualization and clinical care of neuropsychiatric comorbidities in TLE.

Age exacerbates HIV-associated white matter abnormalities.

Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23-79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.

Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Brain network entropy, depression, and quality of life in people with traumatic brain injury and seizure disorders.

OBJECTIVE: Traumatic brain injury (TBI) often precedes the onset of epileptic (ES) or psychogenic nonepileptic seizures (PNES) with depression being a common comorbidity. The relationship between depression severity and quality of life (QOL) may be related to resting-state network complexity. We investigated these relationships in adults with TBI-only, TBI + ES, or TBI + PNES using Sample Entropy (SampEn), a measure of physiologic signals complexity. METHODS: Adults with TBI-only (n = 60), TBI + ES (n = 21), or TBI + PNES (n = 56) completed the Beck Depression Inventory-II (BDI-II; depression symptom severity) and QOL in Epilepsy (QOLIE-31) assessments and underwent resting-state functional magnetic resonance imaging (rs-fMRI). SampEn values derived from six resting state functional networks were calculated per participant. Effects of group, network, and group-by-network-interactions for SampEn were investigated with a mixed-effects model. We examined relationships between BDI-II, QOL, and SampEn of each of the networks. RESULTS: Groups did not differ in age, but there was a higher proportion of women with TBI + PNES (p = 0.040). TBI + ES and TBI-only groups did not differ in BDI-II or QOLIE-31 scores, while the TBI + PNES group scored worse on both measures. The fixed effects of the model revealed significant differences in SampEn values across networks (lower SampEn for the frontoparietal network compared to other networks). The likelihood ratio test for group-by-network-interactions was significant (p = 0.033). BDI-II was significantly negatively associated with Overall QOL scale scores in all groups, and significantly negatively associated with network SampEn values only in the TBI + PNES group. SIGNIFICANCE: Only TBI + PNES had significant relationships between depression symptom severity and network SampEn values indicating that the resting state network complexity is related to depression severity in this group but not in TBI + ES or TBI-only. PLAIN LANGUAGE SUMMARY: The brain has a complex network of internal connections. How well these connections work may be affected by TBI and seizures and may underlie mental health symptoms including depression; the worse the depression, the worse the quality of life. Our study compared brain organization in people with TBI, people with epilepsy after TBI, and people with nonepileptic seizures after TBI. Only people with nonepileptic seizures after TBI showed a relationship between how organized their brain connections were and how bad was their depression. We need to better understand these relationships to develop more impactful, effective treatments.