Marnie E. Shaw

Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study.

BACKGROUND This study examined cerebral function in posttraumatic stress disorder (PTSD) during the updating of working memory to trauma-neutral, verbal information. METHODS Ten PTSD and matched control subjects completed a visuoverbal target detection task involving continuous updating (Variable target condition) or no updating (Fixed target condition) of target identity, with updating activity estimated by condition comparison. RESULTS Normal updating activity using this paradigm involved bilateral activation of the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobe. The PTSD group lacked this activation in the left hemisphere and was significantly different from control subjects in this regard, but showed additional activation in the superior parietal lobe, bilaterally. CONCLUSIONS The pattern of parietal activation suggests a dependence on visuospatial coding for working memory representation of trauma-neutral, verbal information. Group differences in the relative involvement of the DLPFC indicate less dependence in PTSD on the executive role normally attributed to the left DLPFC for monitoring and manipulation of working memory content in posterior regions of the brain.

Reward-aversion circuitry in analgesia and pain: implications for psychiatric disorders.

Sensory and emotional systems normally interact in a manner that optimizes an organisms ability to survive using conscious and unconscious processing. Pain and analgesia are interpreted by the nervous system as aversive and rewarding processes that trigger specific behavioral responses. Under normal physiological conditions these processes are adaptive. However, under chronic pain conditions, functional alterations of the central nervous system frequently result in maladaptive behaviors. In this review, we examine: (a) the interactions between sensory and emotional systems involved in processing pain and analgesia in the physiological state; (b) the role of reward/aversion circuitry in pain and analgesia; and (c) the role of alterations in reward/aversion circuitry in the development of chronic pain and co‐morbid psychiatric disorders. These underlying features have implications for understanding the neurobiology of functional illnesses such as depression and anxiety and for the development and evaluation of novel therapeutic interventions.

Abnormal Functional Connectivity in Posttraumatic Stress Disorder

This study investigated the efficacy of a combined multivariate/resampling procedure for the analysis of PET activation studies. The covariance-based multivariate analysis was used to investigate distributed brain systems in posttraumatic stress disorder (PTSD) patients and matched controls during performance of a working memory task. The results were compared to univariate results obtained in an earlier study. We also examined whether the PTSD patients demonstrated a breakdown in functional connectivity that may be associated with working memory difficulties often experienced by these patients. A resampling procedure was used specifically to test the reliability of measured between-group effects, to avoid mistaken inference on the basis of random intersubject differences. Significant and reproducible differences in network connectivity were obtained for the two groups. The functional connectivity pattern of the patient group was characterized by relatively more activation in the bilateral inferior parietal lobes and the left precentral gyrus than the control group, and less activation in the inferior medial frontal lobe, bilateral middle frontal gyri and right inferior temporal gyrus. The resampling procedure provided direct evidence that working memory updating was abnormal in PTSD patients relative to matched controls. This work focuses on the need to identify extended brain networks (in addition to regionally specific changes) for the full characterization of brain responses in neuroimaging experiments. Our multivariate analysis explicitly measures the reliability of the patterns of functional connectivity we obtain and demonstrates the potential of such analyses for the study of brain network dysfunction in psychopathology.

Simulation of the effects of global normalization procedures in functional MRI.

We report on differences in sensitivity and false-positive rate across five methods of global normalization using resting-state fMRI data embedded with simulated activation. These methods were grand mean session scaling, proportional scaling, ANCOVA, a masking method, and an orthogonalization method. We found that global normalization by proportional scaling and ANCOVA decreased the sensitivity of the statistical analysis and induced artifactual deactivation even when the correlation between the global signal and the experimental paradigm was relatively low. The masking method and the orthogonalization method performed better from this perspective but are both restricted to certain experimental conditions. Based on the results of these simulations, we offer practical guidelines for the choice of global normalization method least likely to bias the experimental results.

Default network connectivity during a working memory task.

The default network exhibits correlated activity at rest and has shown decreased activation during performance of cognitive tasks. There has been little investigation of changes in connectivity of this network during task performance. In this study, we examined task‐related modulation of connectivity between two seed regions from the default network posterior cingulated cortex (PCC) and medial prefrontal cortex (mPFC) and the rest of the brain in 12 healthy adults. The purpose was to determine (1) whether connectivity within the default network differs between a resting state and performance of a cognitive (working memory) task and (2) whether connectivity differs between these nodes of the default network and other brain regions, particularly those implicated in cognitive tasks. There was little change in connectivity with the other main areas of the default network for either seed region, but moderate task‐related changes in connectivity occurred between seed regions and regions outside the default network. For example, connectivity of the mPFC with the right insula and the right superior frontal gyrus decreased during task performance. Increased connectivity during the working memory task occurred between the PCC and bilateral inferior frontal gyri, and between the mPFC and the left inferior frontal gyrus, cuneus, superior parietal lobule, middle temporal gyrus and cerebellum. Overall, the areas showing greater correlation with the default network seed regions during task than at rest have been previously implicated in working memory tasks. These changes may reflect a decrease in the negative correlations occurring between the default and task‐positive networks at rest. Hum Brain Mapp, 2011.

Evaluating subject specific preprocessing choices in multisubject fMRI data sets using data-driven performance metrics

This study investigated the possible benefit of subject specific optimization of preprocessing strategies in functional magnetic resonance imaging (fMRI) experiments. The optimization was performed using the data-driven performance metrics developed recently [Neuroimage 15 (2002), 747]. We applied numerous preprocessing strategies and a multivariate statistical analysis to each of the 20 subjects in our two example fMRI data sets. We found that the optimal preprocessing strategy varied, in general, from subject to subject. For example, in one data set, optimum smoothing levels varied from 16 mm (4 subjects), 10 mm (5 subjects), to no smoothing at all (1 subject). This strongly suggests that group-specific preprocessing schemes may not give optimum results. For both studies, optimizing the preprocessing for each subject resulted in an increased number of suprathresholded voxels in within-subject analyses. Furthermore, we demonstrated that we were able to aggregate the optimized data with a random effects group analysis, resulting in improved sensitivity in one study and the detection of interesting, previously undetected results in the other.

A systematic review and meta-analysis of longitudinal hippocampal atrophy in healthy human ageing

INTRODUCTION This review aimed to produce hippocampal atrophy rate estimates from healthy ageing studies as well as control samples from observational studies across the adult lifespan which can be used as benchmarks to evaluate abnormal changes in pathological conditions. METHODS The review followed PRISMA guidelines. PUBMED (to February 2014) was searched for longitudinal MRI studies reporting hippocampal atrophy or volume change in cognitively healthy individuals. Titles were screened and non-English, duplicate or irrelevant entries were excluded. Remaining record abstracts were reviewed to identify studies for full text retrieval. Full text was retrieved and screened against inclusion/exclusion criteria. Bibliographies and previous reviews were examined to identify additional studies. Data were summarised using meta-analysis and age, segmentation technique and study type were tested as potential moderators using meta-regression. It was hypothesised that population studies would produce higher atrophy rates than clinical observational studies. RESULTS The systematic search identified 4410 entries and 119 studies were retrieved with 58 failing selection or quality criteria, 30 were excluded as multiple reports and 3 studies were unsuitable for meta-analysis. The remaining 28 studies were included in the meta-analysis, n=3422, 44.65% male, 11,735 person-years of follow-up, mean age was 24.50 to 83 years. Mean total hippocampal atrophy for the entire sample was 0.85% per year (95% CI 0.63, 1.07). Age based atrophy rates were 0.38% per year (CI 0.14, 0.62) for studies with mean age <55 years (n=413), 0.98% (CI 0.27, 1.70) for 55 to <70 years (n=426), and 1.12% (CI 0.86, 1.38) for ≥70 years (n=2583). Meta-regression indicated age was associated with increased atrophy rates of 0.0263% (CI 0.0146, 0.0379) per year and automated segmentation approaches were associated with a reduced atrophy rate of -0.466% (CI -0.841, -0.090). Population studies were not associated with a significant effect on atrophy. Analyses of 11 studies separately measuring left and right hippocampal atrophy (n=1142) provided little evidence of laterality effects. While no study separately reported atrophy by gender, a number tested for gender effects and 2 studies reported higher atrophy in males. CONCLUSIONS Hippocampal atrophy rates increase with age with the largest increases occurring from midlife onwards. Manual segmentation approaches result in higher measured atrophy rates.

How anatomical asymmetry of human auditory cortex can lead to a rightward bias in auditory evoked fields

Auditory evoked fields and potentials, such as the N1 or the 40-Hz steady state response, are often stronger in the right compared to the left auditory cortex. Here we investigated whether a greater degree of cortical folding in left auditory cortex could result in increased MEG signal cancelation and a subsequent bias in MEG auditory signals toward the right hemisphere. Signal cancelation, due to non-uniformity of the orientations of underlying neural currents, affects MEG and EEG signals generated by any neuronal activity of reasonable spatial extent. We simulated MEG signals in patches of auditory cortex in seventeen subjects, and measured the relationships between underlying activity distribution, cortical non-uniformity, signal cancelation and resulting (fitted) dipole strength and position. Our results suggest that the cancelation of MEG signals from auditory cortex is asymmetric, due to underlying anatomy, and this asymmetry may result in a rightward bias in measurable dipole amplitudes. The effect was significant across all auditory areas tested, with the exception of planum temporale. Importantly, we also show how the rightward bias could be partially or completely offset by increased cortical area, and therefore increased cortical activity, on the left side. We suggest that auditory researchers are aware of the impact of cancelation and its resulting rightward bias in signal strength from auditory cortex. These findings are important for studies seeking functional hemispheric specialization in the auditory cortex with MEG as well as for integration of MEG with other imaging modalities.

Dysfunction of dorsolateral prefrontal cortex in antipsychotic-naïve schizophreniform psychosis.

Reports of abnormal activation of the dorsolateral prefrontal cortex (dlPFC) are common in functional neuroimaging studies of schizophrenia, although very few have examined brain activity in patients close to the onset of illness. In this H(2)(15)O PET study, eight young male patients with first-episode schizophreniform psychosis and age-matched control subjects performed a version of the Stroop task that we have previously shown to engage the middle-frontal gyrus. At the time of testing, patients were antipsychotic-naïve and were scanned within 1 week of initial contact with our clinical program. All patients received a later diagnosis of schizophrenia 6 months after participating in the study. Whole-brain (within-group) and region-of-interest (between-group) analyses were carried out and data underwent spatial reproducibility testing. Compared with healthy subjects, patients showed significantly greater reaction-time (RT) interference but normal RT accuracy on the Stroop task. This pattern correlated with significant under-activation of the posterior left middle-frontal gyri in the patient versus control group. These findings support an emerging model of impaired cognitive control in schizophrenia and suggest that there is significant dysfunction of the dlPFC close to the onset of illness that may coincide with, or be modulated by, the transition-to-illness phase.

Age-related cortical thinning in cognitively healthy individuals in their 60s: the PATH Through Life study

Although it is recognized that the human cortex thins with age, longitudinal estimates of thinning patterns specific to healthy young-old age (<75 years) individuals are lacking. Importantly, many neurodegenerative disorders first manifest between midlife and old age, and normative estimates may provide a reference for differential change associated with such disorders. Here, we provide longitudinal estimates of cortical thinning observed over 12 years in a large group (n = 396) of healthy individuals, aged 60-66 years at baseline scan, who were scanned with magnetic resonance imaging (1.5T) on 4 occasions. Longitudinal age-related thinning was observed across most of the cortices, with a mean change of -0.3% per year. We measured significant thinning in heteromodal association cortex, with less thinning in regions expected to atrophy later in life (e.g., primary sensory cortex). Men showed more extensive thinning than women. Our comparison of cross-sectional and longitudinal estimates adds to growing evidence that cross-sectional designs may underestimate age-related changes in cortical thickness.