Sunovian. He is/has been involved in clinical trials conducted by Lilly & Shire. The present work is unrelated to the above grants and relationships. Jonna Kuntsi has given talks at educational events sponsored by Medice; all funds are received by King's College London and used for studies of ADHD. Theo Van Erp consulted for Roche Pharmaceuticals and has a contract with Otsuka Pharmaceutical, Ltd. Anders Dale is a Founder of CorTechs Labs, Inc. He serves on the Scientific Advisory Boards of CorTechs Labs and Human Longevity, Inc., and receives research funding through a Research Agreement with General Electric Healhcare. Paulo Mattos was on the speakers' bureau and/or acted as consultant for Janssen-Cilag, Novartis, and Shire in the previous five years; he also received travel awards to participate in scientific meetings from those companies. The ADHD outpatient program (Grupo de Estudos do Déficit de Atenção/Institute of Psychiatry) chaired by Dr. Mattos has also received research support from Novartis and Shire.The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Tobias Banaschewski served in an advisory or consultancy role for Actelion,

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high-dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract-based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H-MRS) in the left centrum semiovale (white matter) showed a reduction of N-acetylasparate/creatine indicative of axonal injury. Voxel-based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H-MRS only in the chemotherapy group. These results converge to suggest that high-dose adjuvant chemotherapy for breast cancer is associated with long-term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment.

Chemotherapy is associated with cognitive impairment in a subgroup of breast cancer survivors, but the neural circuitry underlying this side effect is largely unknown. Moreover, long-term impairment has not been studied well. In the present study, functional magnetic resonance imaging (fMRI) and neuropsychological testing were performed in breast cancer survivors almost 10 years after high-dose adjuvant chemotherapy (chemo group, n = 19) and in breast cancer survivors for whom chemotherapy had not been indicated (control group, n = 15). BOLD activation and performance were measured during an executive function task involving planning abilities (Tower of London) and a paired associates task for assessment of episodic memory. For the chemo group versus the control group, we found hyporesponsiveness of dorsolateral prefrontal cortex in the Tower of London, and of parahippocampal gyrus in the paired associates task. Also, the chemo group showed significantly impaired planning performance and borderline significantly impaired recognition memory as compared to findings in the control group. Whole-brain analyses demonstrated hyporesponsiveness of the chemo versus the control group in very similar regions of bilateral posterior parietal cortex during both the Tower of London and the paired associates task. Neuropsychological testing showed a relatively stable pattern of cognitive impairment in the chemo group over time. These results indicate that high-dose adjuvant chemotherapy is associated with long-term cognitive impairments. These impairments are underpinned by (a) task-specific hyporesponsiveness of dorsolateral prefrontal cortex and parahippocampal gyrus, and (b) a generalized hyporesponsiveness of lateral posterior parietal cortex encompassing attentional processing.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.