James C. Root

Cancer- and Cancer Treatment–Associated Cognitive Change: An Update on the State of the Science

Cognitive changes associated with cancer and cancer treatments have become an increasing concern. Using breast cancer as the prototype, we reviewed the research from neuropsychological, imaging, genetic, and animal studies that have examined pre- and post-treatment cognitive change. An impressive body of research supports the contention that a subgroup of patients is vulnerable to post-treatment cognitive problems. We also propose that models of aging may be a useful conceptual framework for guiding research in this area and suggest that a useful perspective may be viewing cognitive change in patients with cancer within the context of factors that influence the trajectory of normal aging.

Hippocampal structural changes across the menstrual cycle

Magnetic resonance imaging (MRI) in association with Jacobian‐modulated voxel‐based morphometry (VBM) was used to test for regional variation in gray matter over the menstrual cycle. T1‐weighted anatomical images were acquired using a spoiled gradient recalled acquisition sequence in 21 women. Each subject was scanned twice: once during the postmenstrual late‐follicular phase (Days 10–12 after onset of menses), and once during the premenstrual late‐luteal phase (1–5 days before the onset of menses). Gray matter was relatively increased in the right anterior hippocampus and relatively decreased in the right dorsal basal ganglia (globus pallidus/putamen) in the postmenstrual phase. Verbal declarative memory was increased in the postmenstrual vs. premenstrual phase. This first report of human brain structural plasticity associated with the endogenous menstrual cycle extends well‐established animal findings of hormone‐mediated hippocampal plasticity to humans, and has implications for understanding alterations in cognition and behavior across the menstrual cycle.

Human fear-related motor neurocircuitry

Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans.

Overgeneralized autobiographical memory and future thinking in combat veterans with posttraumatic stress disorder

BACKGROUND Studies show that individuals with Posttraumatic Stress Disorder (PTSD) tend to recall autobiographical memories with decreased episodic specificity. A growing body of research has demonstrated that the mechanisms involved in recalling autobiographical memories overlap considerably with those involved in imagining the future. Although shared autobiographical deficits in remembering the past and imagining the future have been observed in other clinical populations, this has yet to be examined in PTSD. This study examined whether, compared to combat trauma-exposed individuals without PTSD, those with combat-related PTSD would be more likely to generate overgeneralized autobiographical memories and imagined future events. METHOD Operation Enduring/Iraqi Freedom (OEF/OIF) veterans with and without PTSD were presented with neutral word cues and were instructed to generate memories or imagine future autobiographical events. Responses were digitally recorded and were coded for level of episodic specificity and content related to combat trauma. RESULTS Individuals with PTSD were more likely to generate overgeneral autobiographical memories and future events than individuals without PTSD, and were more likely to incorporate content associated with combat when remembering the past or thinking about the future. LIMITATION Limitations of the study include a cross-sectional design, precluding causality; the lack of a non-trauma exposed group, relatively small sample, and almost all-male gender of participants, limiting the generalizability to other populations. CONCLUSION These findings suggest that individuals with PTSD show similar deficits when generating personal past and future events, which may represent a previously unexamined mechanism involved in the maintenance of PTSD symptoms.

Detection of inadequate effort on the California Verbal Learning Test-Second edition: Forced choice recognition and critical item analysis

The Forced Choice Recognition (FCR) and the Critical Item Analysis (CIA) indices of the California Verbal Learning Test-II (CVLT-II) have been identified by the CVLT-II test developers as potentially useful, brief screening indicators of effort in neuropsychological assessment. This retrospective study analyzes performance on these measures in three groups: (1) clinically referred individuals; (2) forensically referred individuals not suspected of inadequate effort; and (3) forensically referred individuals whose performance on freestanding tests of effort suggested inadequate effort. Performances on FCR were analyzed for their relation to actual memory impairment and with regard to concrete and abstract distractor endorsement. FCR and CIA performances were analyzed for agreement with formal tests of inadequate effort and their test characteristics. Incremental validity was assessed by hierarchical logistic regression with previously identified indices for detection of inadequate effort on the CVLT. Results indicate that (1) FCR and CIA performances are not related to decreased memory performance; (2) FCR and CIA indices exhibit higher specificity and lower sensitivity, with higher positive predictive value than negative predictive value; and (3) FCR and CIA indices exhibit modest incremental validity with previously identified indices. Implications for use of FCR and CIA indices in inadequate effort detection are discussed

Differential activity of subgenual cingulate and brainstem in panic disorder and PTSD

Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects.

Diurnal cortisol amplitude and fronto-limbic activity in response to stressful stimuli

The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response.

Frontolimbic function and cortisol reactivity in response to emotional stimuli

Frontolimbic structures involved in fear conditioning have also been associated with hypothalamic–pituitary–adrenal (HPA)-axis modulation, including amygdaloid, hippocampal, and ventromedial prefrontal cortex regions. Although HPA-axis function and endocrine changes have been investigated in the context of stress provocation, much research has not been conducted using functional neuroimaging in the study of the HPA axis and frontolimbic function in response to emotional stimuli. Using functional magnetic resonance imaging, the association of blood-oxygen-level dependent signal with salivary cortisol in response to an emotional visual scene paradigm was investigated, with prescan and postscan salivary cortisol analyzed as a covariate of interest during specific conditions. Cortisol reactivity to the paradigm was positively associated with amygdalar and hippocampal activity and negatively associated with ventromedial prefrontal cortex activity in conditions involving emotional imagery.

Left hemisphere specialization for response to positive emotional expressions : A divided output methodology

An extensive literature credits the right hemisphere with dominance for processing emotion. Conflicting literature finds left hemisphere dominance for positive emotions. This conflict may be resolved by attending to processing stage. A divided output (bimanual) reaction time paradigm in which response hand was varied for emotion (angry; happy) in Experiments 1 and 2 and for gender (male; female) in Experiment 3 focused on response to emotion rather than perception. In Experiments 1 and 2, reaction time was shorter when right-hand responses indicated a happy face and left-hand responses an angry face, as compared to reversed assignment. This dissociation did not obtain with incidental emotion (Experiment 3). Results support the view that response preparation to positive emotional stimuli is left lateralized.

Cancer, coping, and cognition: a model for the role of stress reactivity in cancer-related cognitive decline

Cognitive decline and accompanying neurological changes associated with non‐CNS cancer diagnosis and treatment have been increasingly identified in a subset of patients. Initially believed to be because of neurotoxic effects of chemotherapy exposure, observation of cognitive decline in patients not treated with chemotherapy, cancer‐diagnosed individuals prior to treatment, and patients receiving alternative treatment modalities (surgery, endocrine therapy, and radiation) has led to the investigation of additional potential etiologies and moderating factors. Stressful experiences have long been posited as a contributor to these cognitive changes. Through reciprocal connectivity with peripheral systems, the brain maintains a dynamic circuitry to adapt to stress (allostasis). However, overuse of this system leads to dysregulation and contributes to pathophysiology (allostatic load). At this time, little research has been conducted to systematically examine the role of allostatic load in cancer‐related cognitive dysfunction.