Heline Mirzakhanian

A Review of the Brain Structure Correlates of Successful Cognitive Aging

Unimpaired cognition is an important feature of successful aging. Differences in cognitive performance among healthy older adults may be related to differences in brain structure. The authors reviewed the literature to examine the relationship between brain-structure size and cognitive performance in older adults. Eighty-three percent of studies found at least one positive relationship between these factors; however, findings were variable. Positive relationships emerged most consistently between the hippocampal formation and global cognition and memory and between frontal measures and executive function. Additional longitudinal study is needed to further evaluate structure-cognition relationships in older adulthood and across the adult lifespan.

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study

Multisite neuroimaging studies can facilitate the investigation of brain‐related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Eρ2  = 0.82), inferior frontal gyrus (IFG; Eρ2  = 0.83), anterior cingulate cortex (ACC; Eρ2  = 0.76), insula ( Eρ2  = 0.85), and fusiform gyrus ( Eρ2  = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Eρ2  = 0.44), IFG ( Eρ2  = 0.48), ACC ( Eρ2  = 0.55), insula ( Eρ2  = 0.42), and fusiform gyrus ( Eρ2  = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Eρ2  = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta‐analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single‐site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level‐dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms. Hum Brain Mapp 36:2558–2579, 2015.

Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: Analysis from the North American Prodrome Longitudinal Study

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n=8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n=154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular.

Multisite reliability of MR-based functional connectivity

Abstract Recent years have witnessed an increasing number of multisite MRI functional connectivity (fcMRI) studies. While multisite studies provide an efficient way to accelerate data collection and increase sample sizes, especially for rare clinical populations, any effects of site or MRI scanner could ultimately limit power and weaken results. Little data exists on the stability of functional connectivity measurements across sites and sessions. In this study, we assess the influence of site and session on resting state functional connectivity measurements in a healthy cohort of traveling subjects (8 subjects scanned twice at each of 8 sites) scanned as part of the North American Prodrome Longitudinal Study (NAPLS). Reliability was investigated in three types of connectivity analyses: (1) seed‐based connectivity with posterior cingulate cortex (PCC), right motor cortex (RMC), and left thalamus (LT) as seeds; (2) the intrinsic connectivity distribution (ICD), a voxel‐wise connectivity measure; and (3) matrix connectivity, a whole‐brain, atlas‐based approach to assessing connectivity between nodes. Contributions to variability in connectivity due to subject, site, and day‐of‐scan were quantified and used to assess between‐session (test‐retest) reliability in accordance with Generalizability Theory. Overall, no major site, scanner manufacturer, or day‐of‐scan effects were found for the univariate connectivity analyses; instead, subject effects dominated relative to the other measured factors. However, summaries of voxel‐wise connectivity were found to be sensitive to site and scanner manufacturer effects. For all connectivity measures, although subject variance was three times the site variance, the residual represented 60–80% of the variance, indicating that connectivity differed greatly from scan to scan independent of any of the measured factors (i.e., subject, site, and day‐of‐scan). Thus, for a single 5 min scan, reliability across connectivity measures was poor (ICC=0.07–0.17), but increased with increasing scan duration (ICC=0.21–0.36 at 25 min). The limited effects of site and scanner manufacturer support the use of multisite studies, such as NAPLS, as a viable means of collecting data on rare populations and increasing power in univariate functional connectivity studies. However, the results indicate that aggregation of fcMRI data across longer scan durations is necessary to increase the reliability of connectivity estimates at the single‐subject level. HighlightsfcMRI (seed, matrix, ICD) is stable across 8 sites in a Traveling Subjects dataset.No major site, scanner manufacturer, or day‐of‐scan effects were found (GLM).No outlier sites were found (leave‐one‐site‐out analysis of variance).Reliability substantially improves when averaging data over multiple days.Data can be combined across sites to increase power without impacting reliability.

Compensatory Brain Activity during Encoding among Older Adults with Better Recognition Memory for Face-Name Pairs: An Integrative Functional, Structural, and Perfusion Imaging Study

Many neuroimaging studies interpret the commonly reported findings of age-related increases in frontal response and/or increased bilateral activation as suggestive of compensatory neural recruitment. However, it is often unclear whether differences are due to compensation or reflective of other cognitive or physiological processes. This study aimed to determine whether there are compensatory age-related changes in brain systems supporting successful associative encoding while taking into account potentially confounding factors including age-related differences in task performance, atrophy, and resting perfusion. Brain response during encoding of face-name pairs was measured using functional magnetic resonance imaging in 10 older and nine young adults and was correlated with memory performance. During successful encoding, older adults demonstrated increased frontal and decreased occipital activity as well as greater bilateral involvement relative to the young. Findings remained significant after controlling for age-related cortical atrophy and hypoperfusion. Among the older adults, greater response was associated with better memory performance. Cognitive aging may involve recruitment of compensatory mechanisms to improve performance or prevent impairment. Results extend previous findings by suggesting that age-related alterations in activation cannot be attributed to the commonly observed findings of poorer task performance, reduced resting perfusion, or cortical atrophy among older adults.

A preliminary study of interactive questioning methods to assess and improve understanding of informed consent among patients with schizophrenia

Growing recognition of the inadequacy of traditional methods of providing informed consent, especially for individuals vulnerable to impaired decisional capacity, has spurred recent interest in how to assess and improve components of consent-related decision making. In this preliminary study, we aimed to compare different methods of interactive questioning during presentation of research consent information among patients with schizophrenia. Patients were randomized to receive either standard administration (SA) of a consent form or one of two interactive questioning methods: Corrective Feedback (CF), in which the correct answer was provided following the participants response, or Errorless Learning (EL), in which correct answers were provided just prior to the question. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) was used to measure understanding, appreciation, reasoning, and expression of a choice following presentation of the consent form. There was no significant effect of condition (SA vs. EL vs. CF) on any of the components of decisional capacity. Understanding scores measured during the consent process were higher than those measured afterward, but the two scores were highly correlated. Thus, the results of this randomized study suggest that interactive questioning neither helped nor harmed understanding, appreciation, or reasoning among patients with schizophrenia. Other considerations, however, may favor use of such methods in the consenting process.

Ethical implications for clinical practice and future research in "at risk" individuals.

The last 15 years have witnessed a shift in schizophrenia research with increasing interest in earlier stages of illness with the hope of early intervention and ultimately prevention of psychotic illness. Large-scale longitudinal studies have identified clinical and biological risk factors associated with increased risk of psychotic conversion, which together with symptomatic and demographic risk factors may improve the power of prediction algorithms for psychotic transition. Despite these advances, 45-70% of at risk subjects in most samples do not convert to frank psychosis, but continue to function well below their age matched counterparts. The issue is of utmost importance in light of the upcoming DSM-V and the possible inclusion of the attenuated psychotic symptoms syndrome (APSS) diagnosis, with clinical and ethical implications. Clinical considerations include feasibility of reliably diagnosing the at risk state in non-academic medical centers, variable psychotic conversion rates, a non-uniform definition of conversion and extensive debate about treatment for individuals with an ill-defined outcome. On the ethical side, diagnosing APSS could lead to unnecessary prescribing of antipsychotics with long-term deleterious consequences, slow research by providing a false sense of comfort in the diagnosis, and have psychosocial implications for those who receive a diagnosis. Thus it may be prudent to engage at risk populations early and to use broad-spectrum treatments with low risk benefit ratios to relieve functional impairments, while simultaneously studying all subsets of the at risk population.

Schizophrenia Patients Lack Normal Positive Correlation Between Age and Brain Response During Verbal Learning

OBJECTIVE To investigate the differences in the relationship of age to brain function among individuals with schizophrenia and a healthy comparison group. The authors hypothesized that the correlation with age would be more strongly negative among schizophrenia patients, particularly in the frontal cortex. DESIGN Cross-sectional measures of functional MRI (fMRI) brain response were correlated with age in both groups. SETTING Participants came to university research facilities for testing. PARTICIPANTS The authors analyzed data from 30 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia or schizoaffective disorder ranging in age from 25 to 68 years and 14 healthy comparison participants ranging in age from 21 to 70 years. MEASUREMENTS Brain response during word pair learning was measured with fMRI in each voxel of the brain. This measure was correlated with age within each group and the correlations were compared across groups in regions of interest determined a priori and based on a whole-brain analysis. In exploratory analyses, the authors examined the interaction of task performance with age and study group. RESULTS The correlations between age and brain response were more positive in the healthy group than in the schizophrenia group in several regions, including right lateral prefrontal cortex and clusters in midline precuneus and right superior temporal gyrus. Interactions with task performance suggest that age effects on brain function relate differently to cognitive output in patients and comparison participants. CONCLUSIONS There is no strong evidence that functional brain response during learning changes significantly with age among schizophrenia patients, in contrast to findings of positive associations with age among healthy individuals.

Brains of Optimistic Older Adults Respond Less to Fearful Faces

The authors examined the neural correlates of emotion processing and how they relate to individual differences in optimism among older adults. Brain response during processing of fearful faces was measured by functional magnetic resonance imaging in 16 older adults and was correlated with level of optimism. Greater optimism was associated with reduced activation in the fusiform gyrus and frontal regions, which may reflect decreased salience of negative emotional information or better emotion regulation among optimistic individuals. Relationships persisted after taking into account cortical thickness, amygdala volume, and resting perfusion. Findings have potential implications for the promotion of successful aging.

Biomarkers in psychosis: an approach to early identification and individualized treatment

Numerous biomarkers for somatic disorders are used in routine medical practice. Yet, despite remarkable advances in mental health research, we are not able to identify biomarkers with established clinical utility for mental disorders such as schizophrenia. While identification and characterization of biomarkers are crucial first steps in this process, their predictive diagnostic and treatment utility need to be better developed for clinical practice. The heterogeneity of psychotic disorders etiologically, pathologically and symptomatically presents both a challenge and an opportunity for the use of biomarkers in clinical practice. Simply said, a single biomarker might not exist that necessitates the search for a biomarker profile. In this review we discuss research findings in light of such an approach. We summarize some examples of emerging biomarkers in early psychosis research and delineate how these can be applied to a clinical setting to inform treatment on an individual basis fostering a personalized treatment approach.