Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have been extensively used to explore the functional neuroanatomy of cognitive functions. Here we review 275 PET and fMRI studies of attention (sustained, selective, Stroop, orientation, divided), perception (object, face, space/motion, smell), imagery (object, space/motion), language (written/spoken word recognition, spoken/no spoken response), working memory (verbal/numeric, object, spatial, problem solving), semantic memory retrieval (categorization, generation), episodic memory encoding (verbal, object, spatial), episodic memory retrieval (verbal, nonverbal, success, effort, mode, context), priming (perceptual, conceptual), and procedural memory (conditioning, motor, and nonmotor skill learning). To identify consistent activation patterns associated with these cognitive operations, data from 412 contrasts were summarized at the level of cortical Brodmann's areas, insula, thalamus, medial-temporal lobe (including hippocampus), basal ganglia, and cerebellum. For perception and imagery, activation patterns included primary and secondary regions in the dorsal and ventral pathways. For attention and working memory, activations were usually found in prefrontal and parietal regions. For language and semantic memory retrieval, typical regions included left prefrontal and temporal regions. For episodic memory encoding, consistently activated regions included left prefrontal and medial temporal regions. For episodic memory retrieval, activation patterns included prefrontal, medial temporal, and posterior midline regions. For priming, deactivations in prefrontal (conceptual) or extrastriate (perceptual) regions were consistently seen. For procedural memory, activations were found in motor as well as in non-motor brain areas. Analysis of regional activations across cognitive domains suggested that several brain regions, including the cerebellum, are engaged by a variety of cognitive challenges. These observations are discussed in relation to functional specialization as well as functional integration.

MRE11 by either MRN component or by MDC1 (Fig. 3C). However, upon immobilization of NBS1 or MRE11, the accumulation of the downstream factors MDC1 and 53BP1 was strongly impaired in the absence of H2AX (Fig. 3C). Recruitment of MDC1 by ATM 1300-3060 was similarly decreased, suggesting that phosphorylation of H2AX is an important step in recruiting and maintaining these factors at sites of damage (17, 19).To finally test whether individual repair factors are sufficient to induce a physiological DDR, we assessed the effect of immobilization on cell cycle progression (Fig. 4). Upon targeting of NBS1, MRE11, MDC1, or ATM, but not Chk1 or Chk2, to chromatin, cells accumulated in G 2 phase as determined by staining of pericentromeric heterochromatin with an antibody to phosphoS10H3 (Fig. 4A) (20). Cell cycle delay was confirmed by increased phosphorylation of retinoblastoma protein at Ser 807 /Ser 811 ( fig. S6). Furthermore, the cell cycle delay was sensitive to the presence of Chk2 and required ATM activity, suggesting involvement of the checkpoint kinase Chk2 (Fig. 4A). H2AX −/− cells were resistant to G 2 /M delays upon immobilization of repair factors (Fig. 4B). This observation is in line with the finding that cells lacking H2AX manifest a G 2 /M checkpoint defect after exposure to low doses of irradiation (21).We report here that activation of cellular DNA damage response pathways does not require DNA damage but can be triggered by stable association of single repair factors with chroma-tin. Our observations suggest that the physical interaction of DNA repair factors with chromatin is a key step in activation of the DDR signaling cascade, and that the observed buildup at DNA damage foci probably contributes appreciably to establishing the cellular response to damaged DNA (4). Our observation that immobilized downstream factors can recruit upstream components indicates that activation of a full DDR involves amplification via formation of multiple repair complexes and perpetuation of gH2AX phosphorylation. A critical role for signal amplification on DNA is also suggested by the findings that in the absence of gH2AX or MDC1, several repair factors, including NBS1 and 53BP1, are recruited to sites of double-strand breaks, but do not accumulate and are not efficiently retained (16, 19). Our observation of phosphorylation of several key components of the DDR, including H2AX, NBS1, and ATM, and the appearance of cell cycle delays upon tethering indicate that the observed cellular response mimics to a large extent the physiological DDR. Given the apparent importance of the physical interaction of DNA repair factors with chromatin, it will be essential to uncover the precise role of higher-order chromatin structure and chromatin-remodeling complexes in triggering the DDR.Process-specific training can improve performance on untrained tasks, but the magnitude of gain is variable and often there is no transfer at all. We demonstrate transfer to a 3-back test of working memory after 5 weeks of training in updating. The trans...

Human neuroimaging research on cognitive aging has brought significant advances to our understanding of the neural mechanisms underlying age-related cognitive decline and successful aging. However, interpreting age-related changes and differences in brain structure, activation, and functional connectivity is an ongoing challenge. Ambiguous terminology is a major source of this challenge. For example, the terms ‘compensation,’ ‘maintenance,’ and ‘reserve’ are used in different ways and researchers disagree about the kinds of evidence or patterns of results required to interpret findings related to these concepts. As such inconsistencies can impede theoretical and empirical progress, we here aim to clarify these key terms and to propose consensual definitions of maintenance, reserve, and compensation.

Five-year changes in episodic and semantic memory were examined in a sample of 829 participants (35-80 years). A cohort-matched sample (N=967) was assessed to control for practice effects. For episodic memory, cross-sectional analyses indicated gradual age-related decrements, whereas the longitudinal data revealed no decrements before age 60, even when practice effects were adjusted for. Longitudinally, semantic memory showed minor increments until age 55, with smaller decrements in old age as compared with episodic memory. Cohort differences in educational attainment appear to account for the discrepancies between cross-sectional and longitudinal data. Collectively, the results show that age trajectories for episodic and semantic memory differ and underscore the need to control for cohort and retest effects in cross-sectional and longitudinal studies, respectively.