All Publications

  • Region-specific associations between gamma-aminobutyric acid A receptor binding and cortical thickness in high-functioning autistic adults. Autism research : official journal of the International Society for Autism Research James, D., Lam, V. T., Jo, B., Fung, L. K. 2022


    The neurobiology of autism has been shown to involve alterations in cortical morphology and gamma-aminobutyric acid A (GABAA ) receptor density. We hypothesized that GABAA receptor binding potential (GABAA R BPND ) would correlate with cortical thickness, but their correlations would differ between autistic adults and typically developing (TD) controls. We studied 50 adults (23 autism, 27 TD, mean age of 27 years) using magnetic resonance imaging to measure cortical thickness, and [18 F]flumazenil positron emission tomography imaging to measure GABAA R BPND . We determined the correlations between cortical thickness and GABAA R BPND by cortical lobe, region-of-interest, and diagnosis of autism spectrum disorder (ASD). We also explored potential sex differences in the relationship between cortical thickness and autism characteristics, as measured by autism spectrum quotient (AQ) scores. Comparing autism and TD groups, no significant differences were found in cortical thickness or GABAA R BPND . In both autism and TD groups, a negative relationship between cortical thickness and GABAA R BPND was observed in the frontal and occipital cortices, but no relationship was found in the temporal or limbic cortices. A positive correlation was seen in the parietal cortex that was only significant for the autism group. Interestingly, in an exploratory analysis, we found sex differences in the relationships between cortical thickness and GABAA R BPND , and cortical thickness and AQ scores in the left postcentral gyrus. LAY SUMMARY: The thickness of the brain cortex and the density of the receptors associated with inhibitory neurotransmitter GABA have been hypothesized to underlie the neurobiology of autism. In this study, we found that these biomarkers correlate positively in the parietal cortex, but negatively in the frontal and occipital cortical regions of the brain. Furthermore, we collected preliminary evidence that the correlations between cortical thickness and GABA receptor density are sexdependent in a brain region where sensory inputs are registered.

    View details for DOI 10.1002/aur.2703

    View details for PubMedID 35261207

  • Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Molecular psychiatry Fung, L. K., Flores, R. E., Gu, M. n., Sun, K. L., James, D. n., Schuck, R. K., Jo, B. n., Park, J. H., Lee, B. C., Jung, J. H., Kim, S. E., Saggar, M. n., Sacchet, M. D., Warnock, G. n., Khalighi, M. M., Spielman, D. n., Chin, F. T., Hardan, A. Y. 2020


    The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

    View details for DOI 10.1038/s41380-020-0756-y

    View details for PubMedID 32376999

  • The Effects of Cortisol Administration on Emotion, Stress Reactivity, and Brain Activity in Depression Sudheimer, K., Duvio, D., James, D., Heinemeyer, E., Pirog, S., Williams, N., Schatzberg, A. ELSEVIER SCIENCE INC. 2019: S267
  • Cortisol Inhibition of Sadness-Induced Subgenual Cingulate Activity Sudheimer, K., Duvio, D., Heinemeyer, E., Williams, N., James, D., Schatzberg, A. NATURE PUBLISHING GROUP. 2018: S302
  • Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults NATURE Sorrells, S. F., Paredes, M. F., Ebrian-Silla, A. C., Sandoval, K., Qi, D., Kelley, K. W., James, D., Mayer, S., Chang, J., Auguste, K. I., Hang, E. C., Gutierrez, A. J., Kriegstein, A. R., Mathern, G. W., Oldham, M. C., Huang, E. J., Manuel Garcia-Verdugo, J., Yang, Z., Alvarez-Buylla, A. 2018; 555 (7696): 377-+


    New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

    View details for DOI 10.1038/nature25975

    View details for Web of Science ID 000427477100038

    View details for PubMedID 29513649

    View details for PubMedCentralID PMC6179355

  • Extensive migration of young neurons into the infant human frontal lobe SCIENCE Paredes, M. F., James, D., Gil-Perotin, S., Kim, H., Cotter, J. A., Ng, C., Sandoval, K., Rowitch, D. H., Xu, D., McQuillen, P. S., Garcia-Verdugo, J., Huang, E. J., Alvarez-Buylla, A. 2016; 354 (6308)
  • Patient-reported functioning in major depressive disorder THERAPEUTIC ADVANCES IN CHRONIC DISEASE IsHak, W., James, D. M., Mirocha, J., Youssef, H., Tobia, G., Pi, S., Collison, K. L., Cohen, R. M. 2016; 7 (3): 160–69


    Compared with the general population, patients with major depressive disorder (MDD) report substantial deficits in their functioning that often go beyond the clinical resolution of depressive symptoms. This study examines the impact of MDD and its treatment on functioning.From the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, we analyzed complete data of 2280 adult outpatients with MDD at entry and exit points of each level of antidepressant treatment and again 12 months post treatment. Functioning was measured using the Work and Social Adjustment Scale (WSAS).The results show that only 7% of patients with MDD reported within-normal functioning before treatment. The proportion of patients achieving within-normal functioning (WSAS) scores significantly increased after treatment. However, the majority of patients (>60%) were still in the abnormal range on functioning at exit. Although remitted patients had greater improvements compared with nonremitters, a moderate proportion of remitted patients continued to experience ongoing deficits in functioning after treatment (20-40%). Follow-up data show that the proportions of patients experiencing normal scores for functioning after 12 months significantly decreased from the end of treatment to the follow-up phase, from 60.1% to 49% (p < 0.0001), a finding that was particularly significant in nonremitters. Limitations of this study include the reliance on self-report of functioning and the lack of information on patients who dropped out.This study points to the importance of functional outcomes of MDD treatment as well as the need to develop personalized interventions to improve functioning in MDD.

    View details for DOI 10.1177/2040622316639769

    View details for Web of Science ID 000376684100003

    View details for PubMedID 27347363

    View details for PubMedCentralID PMC4907070

  • Quality of life in major depressive disorder before/after multiple steps of treatment and one-year follow-up ACTA PSYCHIATRICA SCANDINAVICA IsHak, W. W., Mirocha, J., James, D., Tobia, G., Vilhauer, J., Fakhry, H., Pi, S., Hanson, E., Nashawati, R., Peselow, E. D., Cohen, R. M. 2015; 131 (1): 51–60


    This study examines the impact of major depressive disorder (MDD) and its treatment on quality of life (QOL).From the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, we analyzed complete data of 2280 adult MDD out-patients at entry/exit of each level of antidepressant treatments and after 12 months of entry to follow-up. QOL was measured using the QOL Enjoyment and Satisfaction Questionnaire (Q-LES-Q). The proportions of patients scoring 'within-normal' QOL (within 10% of Q-LES-Q community norms) and those with 'severely impaired' QOL (>2 SD below Q-LES-Q community norms) were analyzed.Before treatment, no more than 3% of MDD patients experienced 'within-normal' QOL. Following treatment, statistically significant improvements were detected; however, the proportion of patients achieving 'within-normal' QOL did not exceed 30%, with >50% of patients experiencing 'severely impaired' QOL. Although remitted patients had greater improvements compared with non-remitters, 32-60% continued to experience reduced QOL. 12-month follow-up data revealed that the proportion of patients experiencing 'within-normal' QOL show a statistically significant decrease in non-remitters.Symptom-focused treatments of MDD may leave a misleading impression that patients have recovered when, in fact, they may be experiencing ongoing QOL deficits. These findings point to the need for investigating specific interventions to ameliorate QOL in MDD.

    View details for DOI 10.1111/acps.12301

    View details for Web of Science ID 000346337700015

    View details for PubMedID 24954156

    View details for PubMedCentralID PMC4267902