Christina Young

All Publications

• Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra. Annals of clinical and translational neurology Plastini, M. J., Abdelnour, C., Young, C. B., Wilson, E. N., Shahid-Besanti, M., Lamoureux, J., Andreasson, K. I., Kerchner, G. A., Montine, T. J., Henderson, V. W., Poston, K. L. 2024

  Abstract

  More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD.Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra.Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2 (3) = 13.87, p = 0.003).Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

  View details for DOI 10.1002/acn3.52034

  View details for PubMedID 38436140

• Speech patterns during memory recall relates to early tau burden across adulthood. Alzheimer's & dementia : the journal of the Alzheimer's Association Young, C. B., Smith, V., Karjadi, C., Grogan, S. M., Ang, T. F., Insel, P. S., Henderson, V. W., Sumner, M., Poston, K. L., Au, R., Mormino, E. C. 2024

  Abstract

  Early cognitive decline may manifest in subtle differences in speech.We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined.Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between β-amyoid-positive (Aβ+) and -negative (Aβ-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions.Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology.Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

  View details for DOI 10.1002/alz.13731

  View details for PubMedID 38348772

• Reliability of remote National Alzheimer's Coordinating Center Uniform Data Set data. Alzheimer's & dementia (Amsterdam, Netherlands) Smith, V., Younes, K., Poston, K. L., Mormino, E. C., Young, C. B. 2023; 15 (4): e12498

  Abstract

  The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) neuropsychological battery is being used to track cognition in participants across the country, but it is unknown if scores obtained through remote administration can be combined with data obtained in person.The remote UDS battery includes the blind version of the Montreal Cognitive Assessment (MoCA), Number Span, Semantic and Phonemic Fluency, and Craft Story. For these tests, we assessed intraclass correlation coefficients (ICCs) between in-person and remote scores in 3838 participants with both in-person and remote UDS assessments, and we compared annual score changes between modalities in a subset that had two remote assessments.All tests exhibited moderate to good reliability between modalities (ICCs = 0.590-0.787). Annual score changes were also comparable between modalities except for Craft Story Immediate Recall, Semantic Fluency, and Phonemic Fluency.Our findings generally support combining remote and in-person scores for the majority of UDS tests.

  View details for DOI 10.1002/dad2.12498

  View details for PubMedID 38034852

  View details for PubMedCentralID PMC10687343

• Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study. Movement disorders : official journal of the Movement Disorder Society Kerestes, R., Laansma, M. A., Owens-Walton, C., Perry, A., van Heese, E. M., Al-Bachari, S., Anderson, T. J., Assogna, F., Aventurato, Í. K., van Balkom, T. D., Berendse, H. W., van den Berg, K. R., Betts, R., Brioschi, R., Carr, J., Cendes, F., Clark, L. R., Dalrymple-Alford, J. C., Dirkx, M. F., Druzgal, J., Durrant, H., Emsley, H. C., Garraux, G., Haroon, H. A., Helmich, R. C., van den Heuvel, O. A., João, R. B., Johansson, M. E., Khachatryan, S. G., Lochner, C., McMillan, C. T., Melzer, T. R., Mosley, P. E., Newman, B., Opriessnig, P., Parkes, L. M., Pellicano, C., Piras, F., Pitcher, T. L., Poston, K. L., Rango, M., Roos, A., Rummel, C., Schmidt, R., Schwingenschuh, P., Silva, L. S., Smith, V., Squarcina, L., Stein, D. J., Tavadyan, Z., Tsai, C. C., Vecchio, D., Vriend, C., Wang, J. J., Wiest, R., Yasuda, C. L., Young, C. B., Jahanshad, N., Thompson, P. M., van der Werf, Y. D., Harding, I. H. 2023

  Abstract

  Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated.To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group.Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated.Overall, people with PD had a regionally smaller posterior lobe (dmax  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17).We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  View details for DOI 10.1002/mds.29611

  View details for PubMedID 37964373

• Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer`s disease. medRxiv : the preprint server for health sciences Younes, K., Smith, V., Johns, E., Carlson, M. L., Winer, J., He, Z., Henderson, V. W., Greicius, M. D., Young, C. B., Mormino, E. C. 2023

  Abstract

  Understanding psychiatric symptoms in Alzheimer`s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is unknown. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory, and composite scores for memory, executive function, and language; using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 858 individuals (age=73.9±7.7 years, 434(50%) females) were included, comprising 438 cognitively unimpaired (CU) (53.4%) and 420 impaired (CI) participants (48.9%). In the full cohort analysis, right temporal tau was associated with worse behavior (B(SE)=7.19 (2.9), p-value=0.01) and left temporal tau was associated with worse language (B(SE)=1.4(0.2), p-value<0.0001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, four patterns of tau PET uptake were observed: anterior temporal, typical AD, typical AD with frontal involvement, and posterior. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Behavioral and socioemotional measures are needed to understand right-sided asymmetry in AD.

  View details for DOI 10.1101/2023.11.10.23296836

  View details for PubMedID 37986964

  View details for PubMedCentralID PMC10659470

• Generative Adversarial Network-Enhanced Ultra-Low-Dose [18F]-PI-2620 tau PET/MRI in Aging and Neurodegenerative Populations. AJNR. American journal of neuroradiology Chen, K. T., Tesfay, R., Koran, M. E., Ouyang, J., Shams, S., Young, C. B., Davidzon, G., Liang, T., Khalighi, M., Mormino, E., Zaharchuk, G. 2023

  Abstract

  BACKGROUND AND PURPOSE: With the utility of hybrid tau PET/MR imaging in the screening, diagnosis, and follow-up of individuals with neurodegenerative diseases, we investigated whether deep learning techniques can be used in enhancing ultra-low-dose [18F]-PI-2620 tau PET/MR images to produce diagnostic-quality images.MATERIALS AND METHODS: Forty-four healthy aging participants and patients with neurodegenerative diseases were recruited for this study, and [18F]-PI-2620 tau PET/MR data were simultaneously acquired. A generative adversarial network was trained to enhance ultra-low-dose tau images, which were reconstructed from a random sampling of 1/20 (approximately 5% of original count level) of the original full-dose data. MR images were also used as additional input channels. Region-based analyses as well as a reader study were conducted to assess the image quality of the enhanced images compared with their full-dose counterparts.RESULTS: The enhanced ultra-low-dose tau images showed apparent noise reduction compared with the ultra-low-dose images. The regional standard uptake value ratios showed that while, in general, there is an underestimation for both image types, especially in regions with higher uptake, when focusing on the healthy-but-amyloid-positive population (with relatively lower tau uptake), this bias was reduced in the enhanced ultra-low-dose images. The radiotracer uptake patterns in the enhanced images were read accurately compared with their full-dose counterparts.CONCLUSIONS: The clinical readings of deep learning-enhanced ultra-low-dose tau PET images were consistent with those performed with full-dose imaging, suggesting the possibility of reducing the dose and enabling more frequent examinations for dementia monitoring.

  View details for DOI 10.3174/ajnr.A7961

  View details for PubMedID 37591771

• Atypical child-parent neural synchrony is linked to negative family emotional climate and children's psychopathological symptoms. The American psychologist Su, H., Young, C. B., Han, Z. R., Xu, J., Xiong, B., Zhou, Z., Wang, J., Hao, L., Yang, Z., Chen, G., Qin, S. 2023

  Abstract

  Family emotional climate is fundamental to children's well-being and mental health. Family environments filled with negative emotions may lead to increased psychopathological symptoms in the child through dysfunctional child-parent interactions. Single-brain paradigms have uncovered changes in brain systems and networks related to negative family environments, but how the neurobiological reciprocity between child and parent brains is associated with children's psychopathological symptoms remains unknown. Here, we first investigated the relation between family emotional climate and children's psychopathological symptoms in 395 child-parent dyads. Using a naturalistic movie-watching functional magnetic resonance imaging technique in a subsample of 50 child-parent dyads, we further investigated the neurobiological underpinnings of how family emotional climates are associated with children's psychopathological symptoms through child-parent neural synchrony. Children from negative family emotional climate experienced significantly more severe psychopathological symptoms. In comparison to child-stranger dyads, child-parent dyads exhibited higher intersubject correlations in the dorsal and ventral portions of the medial prefrontal cortex (mPFC), and greater concordance of activity with widespread regions critical for socioemotional skills. Critically, negative family emotional climate was associated with decreased intersubject functional correlation between the ventral-mPFC and the hippocampus during movie watching in child-parent dyads, which further accounted for higher children's internalizing symptoms. Together, our findings provide insights into the neurobiological mechanisms that negative family environments can cause and maintain psychopathological symptoms in children through atypical child-parent neural synchrony. This has important implications for a better understanding of how child-parent connections may mediate the relation between environmental risks and developmental outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

  View details for DOI 10.1037/amp0001173

  View details for PubMedID 37439757

• APOE effects on regional tau in preclinical Alzheimer's disease. Molecular neurodegeneration Young, C. B., Johns, E., Kennedy, G., Belloy, M. E., Insel, P. S., Greicius, M. D., Sperling, R. A., Johnson, K. A., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative, A4 Study Team 2023; 18 (1): 1

  Abstract

  BACKGROUND: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Abeta+) remains unclear.METHODS: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Abeta-, 1323 Abeta+) and tau PET data were available for a subset of 447 participants (55 Abeta-, 392 Abeta+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Abeta+CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).RESULTS: APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Abeta+CU, e2 and e4 were associated with reduced (-12 centiloidsper allele) and greater (+15 centiloidsper allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Abeta+s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Abeta+ADNI participants.CONCLUSIONS: APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Abeta+individuals.

  View details for DOI 10.1186/s13024-022-00590-4

  View details for PubMedID 36597122

• Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi-site cohort. Alzheimer's & dementia (Amsterdam, Netherlands) Young, C. B., Mormino, E. C., Poston, K. L., Johnson, K. A., Rentz, D. M., Sperling, R. A., Papp, K. V. 2023; 15 (1): e12414

  Abstract

  Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n=3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short-term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow-up period provides additional insights into early Alzheimer's disease processes.

  View details for DOI 10.1002/dad2.12414

  View details for PubMedID 36950699

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• Tau positron emission tomography in preclinical Alzheimer's disease. Brain : a journal of neurology Insel, P. S., Young, C. B., Aisen, P. S., Johnson, K. A., Sperling, R. A., Mormino, E. C., Donohue, M. C. 2022

  Abstract

  Rates of tau accumulation in cognitively unimpaired older adults are subtle with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid beta-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts, and how these patterns relate to amyloid burden, in order to design optimal tau endpoints for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (N=447), the Alzheimer's Disease Neuroimaging Initiative (N=420), and the Harvard Aging Brain Study (N=190), we attempt to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts, when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern - inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid beta levels. For participants with highly elevated baseline amyloid beta levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala, and 16% fusiform. At mildly elevated levels of baseline amyloid beta, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation), to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.

  View details for DOI 10.1093/brain/awac299

  View details for PubMedID 35962782

• Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease. JAMA neurology Young, C. B., Winer, J. R., Younes, K., Cody, K. A., Betthauser, T. J., Johnson, S. C., Schultz, A., Sperling, R. A., Greicius, M. D., Cobos, I., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative and the Harvard Aging Brain Study, Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J. C., Perrin, R. J., Shaw, L. M., Khachaturian, Z., Carrillo, M., Potter, W., Barnes, L., Bernard, M., Gonzalez, H., Ho, C., Hsiao, J. K., Jackson, J., Masliah, E., Masterman, D., Okonkwo, O., Ryan, L., Silverberg, N., Fleisher, A., Sacrey, D. T., Fockler, J., Conti, C., Veitch, D., Neuhaus, J., Jin, C., Nosheny, R., Ashford, M., Flenniken, D., Kormos, A., Montine, T., Rafii, M., Raman, R., Jimenez, G., Donohue, M., Gessert, D., Salazar, J., Zimmerman, C., Cabrera, Y., Walter, S., Miller, G., Coker, G., Clanton, T., Hergesheimer, L., Smith, S., Adegoke, O., Mahboubi, P., Moore, S., Pizzola, J., Shaffer, E., Harvey, D., Forghanian-Arani, A., Borowski, B., Ward, C., Schwarz, C., Jones, D., Gunter, J., Kantarci, K., Senjem, M., Vemuri, P., Reid, R., Fox, N. C., Malone, I., Thompson, P., Thomopoulos, S. I., Nir, T. M., Jahanshad, N., DeCarli, C., Knaack, A., Fletcher, E., Tosun-Turgut, D., Chen, S. R., Choe, M., Crawford, K., Yuschkevich, P. A., Das, S., Koeppe, R. A., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Franklin, E., Bernhardt, H., Taylor-Reinwald, L., Korecka, M., Figurski, M., Neu, S., Nho, K., Risacher, S. L., Apostolova, L. G., Shen, L., Foroud, T. M., Nudelman, K., Faber, K., Wilmes, K., Thal, L., Johnson, K. A., Sperling, R. A. 2022

  Abstract

  Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated beta-amyloid (A+).Design, Setting, and Participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n=447; ADNI, n=433; HABS, n=190; and Wisconsin, n=328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.Results: The 447 A4 participants (A+ group, 392; and normal beta-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867=-2.597; P=.03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

  View details for DOI 10.1001/jamaneurol.2022.0676

  View details for PubMedID 35435938

• Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson's disease. Brain : a journal of neurology Cai, W., Young, C. B., Yuan, R., Lee, B., Ryman, S., Kim, J., Yang, L., Henderson, V. W., Poston, K. L., Menon, V. 2022

  Abstract

  Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease (PD), but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in PD by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 msec resolution) fMRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 PD patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signaling in frontoparietal-basal ganglia circuits in PD patients OFF medication. Importantly, aberrant signaling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in PD patients. These findings were specific to causal signaling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signaling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in PD. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in PD patients OFF medication. However, dopaminergic medication in PD patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.

  View details for DOI 10.1093/brain/awac007

  View details for PubMedID 35357463

• Prevalence Rates of Amyloid Positivity-Updates and Relevance. JAMA neurology Young, C. B., Mormino, E. C. 1800

  View details for DOI 10.1001/jamaneurol.2021.5225

  View details for PubMedID 35099511

• Neuroimaging approaches to cognition in Parkinson's disease. Progress in brain research Montaser-Kouhsari, L., Young, C. B., Poston, K. L. 2022; 269 (1): 257-286

  Abstract

  While direct visualization of Lewy body accumulation within the brain is not yet possible in living Parkinson's disease patients, brain imaging studies offer insights into how the buildup of Lewy body pathology impacts different regions of the brain. Unlike biological biomarkers and purely behavioral research, these brain imaging studies therefore offer a unique opportunity to relate brain localization to cognitive function and dysfunction in living patients. Magnetic resonance imaging studies can reveal physical changes in brain structure as they relate to different cognitive domains and task specific impairments. Functional imaging studies use a combination of task and resting state magnetic resonance imaging, as well as positron emission tomography and single photon emission computed tomography, and can be used to determine changes in blood flow, neuronal activation and neurochemical changes in the brain associated with PD cognition and cognitive impairments. Other unique advantages to brain imaging studies are the ability to monitor changes in brain structure and function longitudinally as patients progress and the ability to study changes in brain function when patients are exposed to different pharmacological manipulations. This is particularly true when assessing the effects of dopaminergic replacement therapy on cognitive function in Parkinson's disease patients. Together, this chapter will describe imaging studies that have helped identify structural and functional brain changes associated with cognition, cognitive impairment, and dementia in Parkinson's disease.

  View details for DOI 10.1016/bs.pbr.2022.01.008

  View details for PubMedID 35248197

• Decreased reward-related brain function prospectively predicts increased substance use. Journal of abnormal psychology Bart, C. P., Nusslock, R., Ng, T. H., Titone, M. K., Carroll, A. L., Damme, K. S., Young, C. B., Armstrong, C. C., Chein, J., Alloy, L. B. 2021; 130 (8): 886-898

  Abstract

  Substance use and addiction are prominent global health concerns and are associated with abnormalities in reward sensitivity. Reward sensitivity and approach motivation are supported by a fronto-striatal neural circuit including the orbitofrontal cortex (OFC), ventral striatum (VS), and dorsal striatum (DS). Although research highlights abnormalities in reward neural circuitry among individuals with problematic substance use, questions remain about whether such use arises from excessively high, or excessively low, reward sensitivity. This study examined whether reward-related brain function predicted subsequent substance use course. Participants were 79 right-handed individuals (Mage = 21.52, SD = 2.19 years), who completed a monetary incentive delay (MID) fMRI task, and follow-up measures assessing substance use frequency and impairment. The average duration of the follow-up period was 9.1 months. Regions-of-interest analyses focused on the reward anticipation phase of the MID. Decreased activation in the VS during reward anticipation predicted increased substance use frequency at follow-up. Decreased DS activation during reward anticipation predicted increased substance use frequency at follow-up, but this finding did not pass correction for multiple comparisons. Analyses adjusted for relevant covariates, including baseline substance use and the presence or absence of a lifetime substance use disorder prior to MRI scanning. Results support the reward hyposensitivity theory, suggesting that decreased reward-related brain function is a risk factor for increased substance use. Results have implications for understanding the pathophysiology of problematic substance use and highlight the importance of the fronto-striatal reward circuit in the development and maintenance of addiction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

  View details for DOI 10.1037/abn0000711

  View details for PubMedID 34843292

• Latent brain state dynamics and cognitive flexibility in older adults. Progress in neurobiology Lee, B., Cai, W., Young, C. B., Yuan, R., Ryman, S., Kim, J., Santini, V., Henderson, V. W., Poston, K. L., Menon, V. 2021: 102180

  Abstract

  Cognitive impairment in older adults is a rapidly growing public health concern as the elderly population dramatically grows worldwide. While it is generally assumed that cognitive deficits in older adults are associated with reduced brain flexibility, quantitative evidence has been lacking. Here, we investigate brain flexibility in healthy older adults (ages 60-85) using a novel Bayesian switching dynamical system algorithm and ultrafast temporal resolution (490msec) whole-brain fMRI data during performance of a Sternberg working memory task. We identify latent brain states and characterize their dynamic temporal properties, including state transitions, associated with encoding, maintenance, and retrieval. Crucially, we demonstrate that brain inflexibility is associated with slower and more fragmented transitions between latent brain states, and that brain inflexibility mediates the relation between age and cognitive inflexibility. Our study provides a novel neurocomputational framework for investigating latent dynamic circuit processes underlying brain flexibility and cognition in the context of aging.

  View details for DOI 10.1016/j.pneurobio.2021.102180

  View details for PubMedID 34627994

• Influence of Common Reference Regions on Regional Tau Patterns in Cross-Sectional and Longitudinal [18F]-AV-1451 PET Data. NeuroImage Young, C. B., Landau, S. M., Harrison, T. M., Poston, K. L., Mormino, E. C., ADNI 2021: 118553

  Abstract

  Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal [18F]-AV1451 PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

  View details for DOI 10.1016/j.neuroimage.2021.118553

  View details for PubMedID 34487825

• High cerebrospinal amyloid-beta 42 is associated with normal cognition in individuals with brain amyloidosis ECLINICALMEDICINE Sturchio, A., Dwivedi, A. K., Young, C. B., Malm, T., Marsili, L., Sharma, J. S., Mahajan, A., Hill, E. J., El Andaloussi, S., Poston, K. L., Manfredsson, F. P., Schneider, L. S., Ezzat, K., Espay, A. J. 2021; 38

  View details for DOI 10.1016/j.eclinm.2021.100988

  View details for Web of Science ID 000691266400004

• High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine Sturchio, A., Dwivedi, A. K., Young, C. B., Malm, T., Marsili, L., Sharma, J. S., Mahajan, A., Hill, E. J., Andaloussi, S. E., Poston, K. L., Manfredsson, F. P., Schneider, L. S., Ezzat, K., Espay, A. J. 2021; 38: 100988

  Abstract

  Brain amyloidosis does not invariably predict dementia. We hypothesized that high soluble 42-amino acid β amyloid (Aβ42) peptide levels are associated with normal cognition and hippocampal volume despite increasing brain amyloidosis.This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year. All subjects were evaluated between June 2010 and February 2019. Brain amyloid positivity was defined as positron emission tomography-based standard uptake value ratio (SUVR) ≥1.08 for [18] F-florbetaben or 1.11 for [18]F-florbetapir, with higher SUVR indicating more brain amyloidosis. Analyses were adjusted for age, sex, education, APOE4, p-tau, t-tau, and centiloids levels.Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. In adjusted analysis, there was a larger absolute effect size of soluble Aβ42 than SUVR for NC (0.82 vs. 0.40) and MCI (0.60 vs. 0.26) versus AD. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26; p < 0.001) or MCI (1.42; p = 0.006). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume.Normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis.Please refer to the Funding section at the end of the article.

  View details for DOI 10.1016/j.eclinm.2021.100988

  View details for PubMedID 34505023

  View details for PubMedCentralID PMC8413261

• Socioeconomic Disparities Affect Children's Amygdala-Prefrontal Circuitry via Stress Hormone Response. Biological psychiatry Tian, T., Young, C. B., Zhu, Y., Xu, J., He, Y., Chen, M., Hao, L., Jiang, M., Qiu, J., Chen, X., Qin, S. 2021

  Abstract

  BACKGROUND: The socioeconomic status (SES) of a family can affect almost all aspects of a child's life, including health and current and future achievement. The potential adverse effects of low SES on children's emotional development are thought to result from proximal factors such as stress. The underlying neurobiological mechanisms, however, remain elusive.METHODS: The effect of SES on children's integrative cortisol secretion and its modulations on emotion-related brain systems and connectivity were examined in children aged 6 to 12 years. In study 1, we investigated the relationship between SES and cortisol secretion in 239 children. In study 2, using resting-state and task-dependent functional magnetic resonance imaging in a subsample of 50 children, we investigated how SES affects children's amygdala-prefrontal functional organization through cortisol secretion.RESULTS: Children from lower SES exhibited lower cortisol secretion, considering basal cortisol, nocturnal cortisol activity during sleep, and cortisol awakening response, which mediated higher amygdala nuclei intrinsic functional connectivity with the medial and dorsolateral prefrontal cortex (PFC). Critically, these children also exhibited higher task-evoked ventromedial PFC activity through higher intrinsic connectivity of the centromedial amygdala with the medial PFC. They also exhibited higher functional coupling of the centromedial amygdala with the dorsolateral PFC when processing negative emotions.CONCLUSIONS: This study demonstrates that SES shapes children's amygdala-prefrontal circuitry through stress-sensitive cortisol secretion, with the most prominent effect in the centromedial amygdala's functional coordination with the ventromedial and dorsolateral PFC involved in processing negative emotions. Our findings provide important insight into the neurobiological etiology underlying how socioeconomic disparities shape children's emotional development.

  View details for DOI 10.1016/j.biopsych.2021.02.002

  View details for PubMedID 33832707

• PROSPECTIVE EFFECTS OF A GROUP-BASED MOTHER-DAUGHTER INTERVENTION FOR AFRICAN AMERICAN ADOLESCENT GIRLS ON MENTAL HEALTH SYMPTOMS AND SEXUALLY TRANSMITTED INFECTIONS Kendall, A., Young, C., Bray, B., Emerson, E., Freels, S., Donenberg, G. BMJ PUBLISHING GROUP. 2020: 1106–7

  View details for DOI 10.1136/jim-2020-MW.117

  View details for Web of Science ID 000582669400133

• Changes in Externalizing and Internalizing Symptoms Among African American Female Adolescents Over 1 Year Following a Mother-Daughter Sexual Health Intervention JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY Kendall, A. D., Young, C. B., Bray, B. C., Emerson, E. M., Freels, S., Donenberg, G. R. 2020; 88 (6): 495–503

  Abstract

  African American female adolescents face disparities compared with White peers in the interrelated areas of mental health symptoms and sexually transmitted infection (STI) acquisition. IMARA (Informed, Motivated, Aware and Responsible about AIDS) is a group-based mother-daughter intervention addressing these factors among African American teenagers. Previous work demonstrated that female adolescents who received IMARA were 43% less likely than controls to evidence a new STI at 1 year. This report aimed to provide the 1st test of IMARA on externalizing and internalizing symptoms and an exploratory analysis of whether symptom improvements were associated with the protective effect of treatment against future STIs.Female African Americans aged 14-18 years (M = 16; N = 199) were randomly assigned to IMARA or a health promotion control group matched for time and structure. They completed the Youth Self-Report of externalizing and internalizing symptoms at baseline and at 6 and 12 months and were tested for STIs at baseline and 12 months; positive cases were treated. Hierarchical linear modeling tested symptom change over time, including the moderating effects of baseline symptoms.Among participants who entered with high versus lower externalizing symptoms, those who received IMARA showed a slightly greater decrease in externalizing scores relative to the control (p = .035). For these youth, symptom improvements appeared to be associated with IMARA's protective effect against new STIs. Treatment was not associated with internalizing symptom change (p > .05).IMARA shows promise in modestly reducing self-reported externalizing symptoms, although only for participants with high scores at baseline. The possibility that externalizing symptom improvement is linked with reduced STI acquisition warrants future examination. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

  View details for DOI 10.1037/ccp0000491

  View details for Web of Science ID 000535193100001

  View details for PubMedID 32134286

• Amygdala subnuclei volume in bipolar spectrum disorders: Insights from diffusion-based subsegmentation and a high-risk design. Human brain mapping Damme, K. S., Alloy, L. B., Young, C. B., Kelley, N. J., Chein, J., Ng, T. H., Titone, M. K., Black, C. L., Nusslock, R. 2020

  Abstract

  Amygdala abnormalities are widely documented in bipolar spectrum disorders (BSD). Amygdala volume typically is measured after BSD onset; thus, it is not known whether amygdala abnormalities predict BSD risk or relate to the disorder. Additionally, past literature often treated the amygdala as a homogeneous structure, and did not consider its distinct subnuclei and their differential connectivity to other brain regions. To address these issues, we used a behavioral high-risk design and diffusion-based subsegmentation to examine amygdala subnuclei among medication-free individuals with, and at risk for, BSD. The behavioral high-risk design (N = 114) included low-risk (N = 37), high-risk (N = 47), and BSD groups (N = 30). Diffusion-based subsegmentation of the amygdala was conducted to determine whether amygdala volume differences related to particular subnuclei. Individuals with a BSD diagnosis showed greater whole, bilateral amygdala volume compared to Low-Risk individuals. Examination of subnuclei revealed that the BSD group had larger volumes compared to the High-Risk group in both the left medial and central subnuclei, and showed larger volume in the right lateral subnucleus compared to the Low-Risk group. Within the BSD group, specific amygdala subnuclei volumes related to time since first episode onset and number of lifetime episodes. Taken together, whole amygdala volume analyses replicated past findings of enlargement in BSD, but did not detect abnormalities in the high-risk group. Examination of subnuclei volumes detected differences in volume between the high-risk and BSD groups that were missed in the whole amygdala volume. Results have implications for understanding amygdala abnormalities among individuals with, and at risk for, a BSD.

  View details for DOI 10.1002/hbm.25021

  View details for PubMedID 32386113

• Emotion-based brain mechanisms and predictors for SSRI and CBT treatment of anxiety and depression: a randomized trial NEUROPSYCHOPHARMACOLOGY Gorka, S. M., Young, C. B., Klumpp, H., Kennedy, A. E., Francis, J., Ajilore, O., Langenecker, S. A., Shankman, S. A., Craske, M. G., Stein, M. B., Phan, K. 2019; 44 (9): 1639–48

  View details for DOI 10.1038/s41386-019-0407-7

  View details for Web of Science ID 000475474900017

• Using Machine Learning to Characterize Circuit-Based Subtypes in Mood and Anxiety Disorders Young, C., Harati, S., Ball, T., Williams, L. ELSEVIER SCIENCE INC. 2019: S310

  View details for DOI 10.1016/j.biopsych.2019.03.786

  View details for Web of Science ID 000472661000759

• The Impact of Family History of Depression on the Relation Between Episodic Memory Encoding and Intrinsic Hippocampal Connectivity Young, C., Talati, A., Posner, J., Weissman, M. M., Shankman, S. ELSEVIER SCIENCE INC. 2019: S243

  View details for DOI 10.1016/j.biopsych.2019.03.615

  View details for Web of Science ID 000472661000592

• Emotion-based brain mechanisms and predictors for SSRI and CBT treatment of anxiety and depression: A randomized trial. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Gorka, S. M., Young, C. B., Klumpp, H., Kennedy, A. E., Francis, J., Ajilore, O., Langenecker, S. A., Shankman, S. A., Craske, M. G., Stein, M. B., Luan Phan, K. 2019

  Abstract

  Mechanisms and predictors for the successful treatment of anxiety and depression have been elusive, limiting the effectiveness of existing treatments and curtailing the development of new interventions. In this study, we evaluated the utility of three widely used neural probes of emotion (experience, regulation, and perception) in their ability to predict symptom improvement and correlate with symptom change following two first-line treatments-selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy (CBT). Fifty-five treatment-seeking adults with anxiety and/or depression were randomized to 12 weeks of SSRI or CBT treatment (ClinicalTrials.gov identifier: NCT01903447). Functional magnetic resonance imaging (fMRI) was used to examine frontolimbic brain function during emotion experience, regulation, and perception, as probed by the Emotion Regulation Task (ERT; emotion experience and regulation) and emotional face assessment task (EFAT; emotion perception). Brain function was then related to anxiety and depression symptom change. Results showed that both SSRI and CBT treatments similarly attenuated insula and amygdala activity during emotion perception, and greater treatment-related decrease in insula and amygdala activity was correlated with greater reduction in anxiety symptoms. Both treatments also reduced amygdala activity during emotion experience but brain change did not correlate with symptom change. Lastly, greater pre-treatment insula and amygdala activity during emotion perception predicted greater anxiety and depression symptom improvement. Thus, limbic activity during emotion perception is reduced by both SSRI and CBT treatments, and predicts anxiety and depression symptom improvement. Critically, neural reactivity during emotion perception may be a non-treatment-specific mechanism for symptom improvement.

  View details for PubMedID 31060042

• Dynamic Temporal Inflexibility of the Frontoparietal Network Predicts Depression Severity and Treatment Response in Internalizing Psychopathologies Young, C., Chen, T., Zhang, Y., Klumpp, H., Phan, K., Menon, V. ELSEVIER SCIENCE INC. 2018: S196–S197

  View details for Web of Science ID 000432466300491

• Brain hyper-connectivity and operation-specific deficits during arithmetic problem solving in children with developmental dyscalculia. Developmental science Rosenberg-Lee, M., Ashkenazi, S., Chen, T., Young, C. B., Geary, D. C., Menon, V. 2015; 18 (3): 351-372

  Abstract

  Developmental dyscalculia (DD) is marked by specific deficits in processing numerical and mathematical information despite normal intelligence (IQ) and reading ability. We examined how brain circuits used by young children with DD to solve simple addition and subtraction problems differ from those used by typically developing (TD) children who were matched on age, IQ, reading ability, and working memory. Children with DD were slower and less accurate during problem solving than TD children, and were especially impaired on their ability to solve subtraction problems. Children with DD showed significantly greater activity in multiple parietal, occipito-temporal and prefrontal cortex regions while solving addition and subtraction problems. Despite poorer performance during subtraction, children with DD showed greater activity in multiple intra-parietal sulcus (IPS) and superior parietal lobule subdivisions in the dorsal posterior parietal cortex as well as fusiform gyrus in the ventral occipito-temporal cortex. Critically, effective connectivity analyses revealed hyper-connectivity, rather than reduced connectivity, between the IPS and multiple brain systems including the lateral fronto-parietal and default mode networks in children with DD during both addition and subtraction. These findings suggest the IPS and its functional circuits are a major locus of dysfunction during both addition and subtraction problem solving in DD, and that inappropriate task modulation and hyper-connectivity, rather than under-engagement and under-connectivity, are the neural mechanisms underlying problem solving difficulties in children with DD. We discuss our findings in the broader context of multiple levels of analysis and performance issues inherent in neuroimaging studies of typical and atypical development.

  View details for DOI 10.1111/desc.12216

  View details for PubMedID 25098903

  View details for PubMedCentralID PMC4320038

• Amygdala subregional structure and intrinsic functional connectivity predicts individual differences in anxiety during early childhood. Biological psychiatry Qin, S., Young, C. B., Duan, X., Chen, T., Supekar, K., Menon, V. 2014; 75 (11): 892-900

  Abstract

  Early childhood anxiety has been linked to an increased risk for developing mood and anxiety disorders. Little, however, is known about its effect on the brain during a period in early childhood when anxiety-related traits begin to be reliably identifiable. Even less is known about the neurodevelopmental origins of individual differences in childhood anxiety.We combined structural and functional magnetic resonance imaging with neuropsychological assessments of anxiety based on daily life experiences to investigate the effects of anxiety on the brain in 76 young children. We then used machine learning algorithms with balanced cross-validation to examine brain-based predictors of individual differences in childhood anxiety.Even in children as young as ages 7 to 9, high childhood anxiety is associated with enlarged amygdala volume and this enlargement is localized specifically to the basolateral amygdala. High childhood anxiety is also associated with increased connectivity between the amygdala and distributed brain systems involved in attention, emotion perception, and regulation, and these effects are most prominent in basolateral amygdala. Critically, machine learning algorithms revealed that levels of childhood anxiety could be reliably predicted by amygdala morphometry and intrinsic functional connectivity, with the left basolateral amygdala emerging as the strongest predictor.Individual differences in anxiety can be reliably detected with high predictive value in amygdala-centric emotion circuits at a surprisingly young age. Our study provides important new insights into the neurodevelopmental origins of anxiety and has significant implications for the development of predictive biomarkers to identify children at risk for anxiety disorders.

  View details for DOI 10.1016/j.biopsych.2013.10.006

  View details for PubMedID 24268662

  View details for PubMedCentralID PMC3984386

• Cortico-limbic-striatal Reactivity in Depression and its Relationship with Anhedonia Young, C. B., Nusslock, R., Keller, J., Schatzberg, A. F., Menon, V. ELSEVIER SCIENCE INC. 2014: 196S

  View details for Web of Science ID 000334101801188

• Brain hyper-connectivity and operation-specific deficits during arithmetic problem solving in children with developmental dyscalculia DEVELOPMENTAL SCIENCE Rosenberg-Lee, M., Ashkenazi, S., Chen, T., Christina, Y. B., Geary, D. C., Menon, V. 2014: 351–72

  Abstract

  Developmental dyscalculia (DD) is marked by specific deficits in processing numerical and mathematical information despite normal intelligence (IQ) and reading ability. We examined how brain circuits used by young children with DD to solve simple addition and subtraction problems differ from those used by typically developing (TD) children who were matched on age, IQ, reading ability, and working memory. Children with DD were slower and less accurate during problem solving than TD children, and were especially impaired on their ability to solve subtraction problems. Children with DD showed significantly greater activity in multiple parietal, occipito-temporal and prefrontal cortex regions while solving addition and subtraction problems. Despite poorer performance during subtraction, children with DD showed greater activity in multiple intra-parietal sulcus (IPS) and superior parietal lobule subdivisions in the dorsal posterior parietal cortex as well as fusiform gyrus in the ventral occipito-temporal cortex. Critically, effective connectivity analyses revealed hyper-connectivity, rather than reduced connectivity, between the IPS and multiple brain systems including the lateral fronto-parietal and default mode networks in children with DD during both addition and subtraction. These findings suggest the IPS and its functional circuits are a major locus of dysfunction during both addition and subtraction problem solving in DD, and that inappropriate task modulation and hyper-connectivity, rather than under-engagement and under-connectivity, are the neural mechanisms underlying problem solving difficulties in children with DD. We discuss our findings in the broader context of multiple levels of analysis and performance issues inherent in neuroimaging studies of typical and atypical development.

  View details for DOI 10.1111/desc.12216

  View details for PubMedCentralID PMC4320038

• Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways. Journal of psychiatric research Keller, J., Young, C. B., Kelley, E., Prater, K., Levitin, D. J., Menon, V. 2013; 47 (10): 1319-1328

  Abstract

  Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia. We found that trait anhedonia was negatively correlated with pleasantness ratings of music stimuli and with activation of key brain structures involved in reward processing, including nucleus accumbens (NAc), basal forebrain and hypothalamus which are linked by the medial forebrain bundle to the ventral tegmental area (VTA). Brain regions important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with trait anhedonia. Furthermore, effective connectivity between NAc, VTA and paralimbic areas, that regulate emotional reactivity to hedonic stimuli, was negatively correlated with trait anhedonia. Our results indicate that trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and related limbic and paralimbic systems involved in reward processing. Critically, this association can be detected even in individuals without psychiatric illness. Our findings have important implications both for understanding the neurobiological basis of anhedonia and for the treatment of anhedonia in psychiatric disorders.

  View details for DOI 10.1016/j.jpsychires.2013.05.015

  View details for PubMedID 23791396

• Hippocampal-Prefrontal Engagement and Dynamic Causal Interactions in the Maturation of Children's Fact Retrieval JOURNAL OF COGNITIVE NEUROSCIENCE Cho, S., Metcalfe, A. W., Young, C. B., Ryali, S., Geary, D. C., Menon, V. 2012; 24 (9): 1849-1866

  Abstract

  Children's gains in problem-solving skills during the elementary school years are characterized by shifts in the mix of problem-solving approaches, with inefficient procedural strategies being gradually replaced with direct retrieval of domain-relevant facts. We used a well-established procedure for strategy assessment during arithmetic problem solving to investigate the neural basis of this critical transition. We indexed behavioral strategy use by focusing on the retrieval frequency and examined changes in brain activity and connectivity associated with retrieval fluency during arithmetic problem solving in second- and third-grade (7- to 9-year-old) children. Children with higher retrieval fluency showed elevated signal in the right hippocampus, parahippocampal gyrus (PHG), lingual gyrus (LG), fusiform gyrus (FG), left ventrolateral PFC (VLPFC), bilateral dorsolateral PFC (DLPFC), and posterior angular gyrus. Critically, these effects were not confounded by individual differences in problem-solving speed or accuracy. Psychophysiological interaction analysis revealed significant effective connectivity of the right hippocampus with bilateral VLPFC and DLPFC during arithmetic problem solving. Dynamic causal modeling analysis revealed strong bidirectional interactions between the hippocampus and the left VLPFC and DLPFC. Furthermore, causal influences from the left VLPFC to the hippocampus served as the main top-down component, whereas causal influences from the hippocampus to the left DLPFC served as the main bottom-up component of this retrieval network. Our study highlights the contribution of hippocampal-prefrontal circuits to the early development of retrieval fluency in arithmetic problem solving and provides a novel framework for studying dynamic developmental processes that accompany children's development of problem-solving skills.

  View details for Web of Science ID 000307045400004

  View details for PubMedID 22621262

• Immature integration and segregation of emotion-related brain circuitry in young children PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Qin, S., Young, C. B., Supekar, K., Uddin, L. Q., Menon, V. 2012; 109 (20): 7941-7946

  Abstract

  The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing children compared with twenty-four 19- to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry.

  View details for DOI 10.1073/pnas.1120408109

  View details for Web of Science ID 000304369800076

  View details for PubMedID 22547826

  View details for PubMedCentralID PMC3356602

• The Neurodevelopmental Basis of Math Anxiety PSYCHOLOGICAL SCIENCE Young, C. B., Wu, S. S., Menon, V. 2012; 23 (5): 492-501

  Abstract

  Math anxiety is a negative emotional reaction to situations involving mathematical problem solving. Math anxiety has a detrimental impact on an individual's long-term professional success, but its neurodevelopmental origins are unknown. In a functional MRI study on 7- to 9-year-old children, we showed that math anxiety was associated with hyperactivity in right amygdala regions that are important for processing negative emotions. In addition, we found that math anxiety was associated with reduced activity in posterior parietal and dorsolateral prefrontal cortex regions involved in mathematical reasoning. Multivariate classification analysis revealed distinct multivoxel activity patterns, which were independent of overall activation levels in the right amygdala. Furthermore, effective connectivity between the amygdala and ventromedial prefrontal cortex regions that regulate negative emotions was elevated in children with math anxiety. These effects were specific to math anxiety and unrelated to general anxiety, intelligence, working memory, or reading ability. Our study identified the neural correlates of math anxiety for the first time, and our findings have significant implications for its early identification and treatment.

  View details for DOI 10.1177/0956797611429134

  View details for PubMedID 22434239

• Burnout in Premedical Undergraduate Students ACADEMIC PSYCHIATRY Young, C., Fang, D., Golshan, S., Moutier, C., Zisook, S. 2012; 36 (1): 11-16

  Abstract

  There has been growing recognition that medical students, interns, residents and practicing physicians across many specialties are prone to burnout, with recent studies linking high rates of burnout to adverse mental health issues. Little is known about the trajectory and origins of burnout or whether its roots may be traced to earlier in medical training, specifically, during undergraduate studies. Here, the authors surveyed undergraduates at UC San Diego (UCSD) to assess the relationship of burnout to premedical status while controlling for depression severity.Undergraduate students at UCSD were invited to participate in a web-based survey, consisting of demographic questions; the Maslach Burnout Inventory Student Survey (MBI-SS), which gauged the three dimensions of burnout; and the nine-item Patient Health Questionnaire (PHQ-9), to assess depression severity.A total of 618 premedical students and 1,441 non-premedical students completed the questionnaire. Premedical students had greater depression severity and emotional exhaustion than non-premedical students, but they also exhibited a greater sense of personal efficacy. The burnout differences were persistent even after adjusting for depression. Also, premedical women and Hispanic students had especially high levels of burnout, although differences between groups became nonsignificant after accounting for depression.Despite the limitations of using a burnout questionnaire not specifically normed for undergraduates, the unique ethnic characteristics of the sample, and the uncertain response rate, the findings highlight the importance of recognizing the unique strains and mental health disturbances that may be more common among premedical students than non-premedical students. Results also underscore the close relationship between depression and burnout, and point the way for subsequent longitudinal, multi-institutional studies that could help identify opportunities for prevention and intervention.

  View details for Web of Science ID 000300753100004

  View details for PubMedID 22362430

• Multivariate Searchlight Classification of Structural Magnetic Resonance Imaging in Children and Adolescents with Autism BIOLOGICAL PSYCHIATRY Uddin, L. Q., Menon, V., Young, C. B., Ryali, S., Chen, T., Khouzam, A., Minshew, N. J., Hardan, A. Y. 2011; 70 (9): 833-841

  Abstract

  Autism spectrum disorders (ASD) are neurodevelopmental disorders with a prevalence of nearly 1:100. Structural imaging studies point to disruptions in multiple brain areas, yet the precise neuroanatomical nature of these disruptions remains unclear. Characterization of brain structural differences in children with ASD is critical for development of biomarkers that may eventually be used to improve diagnosis and monitor response to treatment.We use voxel-based morphometry along with a novel multivariate pattern analysis approach and searchlight algorithm to classify structural magnetic resonance imaging data acquired from 24 children and adolescents with autism and 24 age-, gender-, and IQ-matched neurotypical participants.Despite modest voxel-based morphometry differences, multivariate pattern analysis revealed that the groups could be distinguished with accuracies of approximately 90% based on gray matter in the posterior cingulate cortex, medial prefrontal cortex, and bilateral medial temporal lobes-regions within the default mode network. Abnormalities in the posterior cingulate cortex were associated with impaired Autism Diagnostic Interview communication scores. Gray matter in additional prefrontal, lateral temporal, and subcortical structures also discriminated between groups with accuracies between 81% and 90%. White matter in the inferior fronto-occipital and superior longitudinal fasciculi, and the genu and splenium of the corpus callosum, achieved up to 85% classification accuracy.Multiple brain regions, including those belonging to the default mode network, exhibit aberrant structural organization in children with autism. Brain-based biomarkers derived from structural magnetic resonance imaging data may contribute to identification of the neuroanatomical basis of symptom heterogeneity and to the development of targeted early interventions.

  View details for DOI 10.1016/j.biopsych.2011.07.014

  View details for Web of Science ID 000296228000010

  View details for PubMedID 21890111

  View details for PubMedCentralID PMC3191298

• Functional dissociations between four basic arithmetic operations in the human posterior parietal cortex: A cytoarchitectonic mapping study NEUROPSYCHOLOGIA Rosenberg-Lee, M., Chang, T. T., Young, C. B., Wu, S., Menon, V. 2011; 49 (9): 2592-2608

  Abstract

  Although lesion studies over the past several decades have focused on functional dissociations in posterior parietal cortex (PPC) during arithmetic, no consistent view has emerged of its differential involvement in addition, subtraction, multiplication, and division. To circumvent problems with poor anatomical localization, we examined functional overlap and dissociations in cytoarchitectonically defined subdivisions of the intraparietal sulcus (IPS), superior parietal lobule (SPL) and angular gyrus (AG), across these four operations. Compared to a number identification control task, all operations except addition, showed a consistent profile of left posterior IPS activation and deactivation in the right posterior AG. Multiplication and subtraction differed significantly in right, but not left, IPS and AG activity, challenging the view that the left AG differentially subserves retrieval during multiplication. Although addition and multiplication both rely on retrieval, multiplication evoked significantly greater activation in right posterior IPS, as well as the prefrontal cortex, lingual and fusiform gyri, demonstrating that addition and multiplication engage different brain processes. Comparison of PPC responses to the two pairs of inverse operations: division versus multiplication and subtraction versus addition revealed greater activation of left lateral SPL during division, suggesting that processing inverse relations is operation specific. Our findings demonstrate that individual IPS, SPL and AG subdivisions are differentially modulated by the four arithmetic operations and they point to significant functional heterogeneity and individual differences in activation and deactivation within the PPC. Critically, these effects are related to retrieval, calculation and inversion, the three key cognitive processes that are differentially engaged by arithmetic operations. Our findings point to distribute representation of these processes in the human PPC and also help explain why lesion and previous imaging studies have yielded inconsistent findings.

  View details for DOI 10.1016/j.neuropsychologia.2011.04.035

  View details for Web of Science ID 000293611600034

  View details for PubMedID 21616086

  View details for PubMedCentralID PMC3165023

• Depression in Asian American and Caucasian undergraduate students JOURNAL OF AFFECTIVE DISORDERS Young, C. B., Fang, D. Z., Zisook, S. 2010; 125 (1-3): 379-382

  Abstract

  Depression is a serious and often under-diagnosed and undertreated mental health problem in college students which may have fatal consequences. Little is known about ethnic differences in prevalence of depression in US college campuses. This study compares depression severity in Asian-American and Caucasian undergraduate students at the University of California San Diego (UCSD).Participants completed the nine item Patient Health Questionnaire and key demographic information via an anonymous online questionnaire.Compared to Caucasians, Asian-Americans exhibited significantly elevated levels of depression. Furthermore, Korean-American students were significantly more depressed than Chinese-American, other minority Asian-American, and Caucasian students. In general, females were significantly more depressed than males. Results were upheld when level of acculturation was considered.The demographic breakdown of the student population at UCSD is not representative to that of the nation.These findings suggest that outreach to female and Asian-American undergraduate students is important and attention to Korean-American undergraduates may be especially worthwhile.

  View details for DOI 10.1016/j.jad.2010.02.124

  View details for Web of Science ID 000281377100055

  View details for PubMedID 20303181