Sarah J. Hart

Emotional Priming Effects during Stroop Task Performance

The ability to make decisions within an emotional context requires a balance between two functionally integrated neural systems that primarily support executive control and affective processing. Several studies have demonstrated effects of emotional interference presented during an ongoing cognitive task, but it is unclear how activating the emotional circuitry prior to a cognitive task may enhance or disrupt the executive system. In this study we used fMRI to examine the effects of emotional priming on executive processing during a number Stroop task. Our results indicated that during trials with less executive requirements, there was a greater aversive emotional attenuation effect in a network of regions including the ventrolateral prefrontal cortex (vlPFC), insula and cingulate gyrus. This attenuation effect was counteracted during trials with increased executive demand, suggesting that while pre-activation of the emotional system may lead to an automatic attenuation of activity in multiple regions, requirements for executive function may override the aversive emotional attenuation effect. Furthermore, this override effect was found to be associated with faster reaction times during executive processing. These findings demonstrate that activity in the vlPFC, cingulate and insula is dynamically adjusted in order to optimize performance, and illustrate the importance of the timing of each systems engagement in determining how competing cognitive and emotional information is processed.

Visuospatial executive function in Turner syndrome: functional MRI and neurocognitive findings

Abstract Turner syndrome is a genetic disorder that results from an abnormal or missing X chromosome in females and is typically associated with impairments in visuospatial, but not verbal, information processing. These visuospatial processing impairments may be exacerbated with increased task demands, such as those engaged during working memory (WM). While previous studies have examined spatial WM function in Turner syndrome, none have directly compared the neural correlates of spatial and verbal WM processes across the encoding, maintenance and retrieval phases. We employed both neurocognitive assessments and functional MRI (fMRI) to examine the neural circuitry underlying both verbal and visuospatial WM functions in individuals with Turner syndrome and normal controls. We furthermore examined the vulnerability of task-related fMRI activation to distracters presented during WM maintenance. Fifteen healthy female volunteers and eight individuals with Turner syndrome performed a delayed-response WM task during fMRI scanning. Neurocognitive tests revealed impaired performance across both verbal and spatial domains in Turner syndrome, with greater impairment on tasks with WM demands. Frontoparietal regions in controls showed significantly sustained levels of activation during visuospatial WM. This sustained activation was significantly reduced in the group with Turner syndrome. Domain-specific activation of temporal regions, in contrast, did not differ between the two groups. Sensory distraction during the WM maintenance phase did not differentially alter frontoparietal activation between the two groups. The results reveal impaired frontoparietal circuitry recruitment during visuospatial executive processing in Turner syndrome, suggesting a significant role for the X chromosome in the development of these pathways.

Modulation of early and late event-related potentials by emotion

Although emotionally salient stimuli influence higher order information processing, the relative vulnerability of specific stages of cognitive processing to modulation by emotional input remains elusive. To test the temporal dynamics of emotional interference during executive function, we recorded event-related potentials (ERPs) while participants performed an effortful anticipation task with aversive emotional and neutral distracters. Participants were presented with a modified delayed Stroop task that dissociated the anticipation of an easier or more difficult task (instructional cues to attend to word vs. color) from the response to the Stroop stimulus, while aversive and neutral pictures were displayed during the delay period. Our results indicated a relative decrease in the amplitude of the contingent negative variation (CNV) during aversive trials that was greater during the early anticipatory phase than during the later response preparation phase, and greater during (the more difficult) color than word trials. During the initial stage of cue processing, there was also significant interaction between emotion and anticipatory difficulty on N1 amplitude, where emotional stimuli led to significantly enhanced negativity during color cues relative to word cues. These results suggest that earlier processes of orientation and effortful anticipation may reflect executive engagement that is influenced by emotional interference while later phases of response preparation may be modulated by emotional interference regardless of anticipatory difficulty.

Altered fronto-limbic activity in children and adolescents with familial high risk for schizophrenia

Early symptoms of schizophrenia tend to emerge during adolescence, hich is a critical period for development of executive and emotional processing. While individuals with familial high risk (FHR) for schizophrenia may show cognitive and emotional changes, the neural mechanisms underlying the development of these changes remain unclear. The goal of this study was to identify functional differences in fronto-striato-limbic regions in children with FHR. Functional magnetic resonance imaging (MRI) data were collected from 21 children with a first-degree family member with schizophrenia and 21 controls without FHR. Participants performed an emotional oddball task requiring both selective attention and suppression of task-irrelevant emotional information. During selective attention, the group with FHR showed enhanced activation in the inferior frontal gyrus and caudate, with decreases in middle frontal gyrus and insular activation. The FHR group also showed greater age-related recruitment of anterior cingulate, temporal and occipital cortical areas during selective attention. During emotional processing, the FHR group showed decreased anterior cingulate activation, with decreased age-related recruitment of inferior frontal, parietal and occipital areas. The results suggest that FHR for schizophrenia may be associated with abnormal hyperactivation and hypoactivation of the neural circuitry engaged during executive and emotional processing and with age-related changes in neural recruitment during adolescence.

Safety and efficacy of rivastigmine in children with Down syndrome: A double blind placebo controlled trial

Individuals with Down syndrome (DS) have decreased cholinergic function and an uneven profile of cognitive abilities, with more pronounced deficits in learning, memory, and expressive language. Cholinesterase inhibitors may improve cognitive function in adults and adolescents with DS, but studies in children with DS have been limited. This study aimed to: (i) investigate the safety and efficacy of rivastigmine treatment; (ii) build upon our open‐label studies in children with DS in a double‐blind, placebo‐controlled clinical trial; and (iii) investigate specific cognitive domains that may respond to rivastigmine treatment. We conducted a 20‐week double‐blind, placebo‐controlled trial to investigate the safety and efficacy of rivastigmine in 22 children and adolescents with DS aged 10–17 years. Safety measures included reports of adverse events, laboratory parameters, and electrocardiograms. Efficacy measures included parental assessments of adaptive behavior and executive function, and direct measures of language and memory. No group differences were found on safety measures and 22 of 24 participants that passed study screening completed the study. The results did not demonstrate evidence for significant improvement in aspects of cognition, language, or overall function in the children receiving rivastigmine. Our results suggest that rivastigmine is safe and well‐tolerated for children and adolescents with DS, but may not be effective for improving performance on the selected measures in this study. However, larger samples and/or alternate measures could possibly reveal improvements in cognitive function with rivastigmine treatment. Further research is needed to define a battery of cognitive measures that is sensitive to treatment effects in DS.

Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co‐occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight‐obesity, sleep apnea, congenital heart disease, and osteopenia‐osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision‐making and management of these medically complex individuals. The development of evidence‐based clinical guidance will require an expanded clinical knowledge‐base in order to move forward.

Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date

Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre‐clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on earlier pharmaceutical interventions, development of appropriate outcome measures, and greater collaboration between industry, academia, advocacy, and regulatory groups will be important for addressing limitations from prior studies and developing potential effective interventions for cognition in Down syndrome.

Communication of Psychiatric Risk in 22q11.2 Deletion Syndrome: A Pilot Project.

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an increased chance of developing a psychiatric disorder. While parents of children affected by 22q11.2DS typically receive counseling about risk for non-psychiatric health concerns, genetic counselors may be reluctant to discuss psychiatric risk. Further education of genetic counselors may be necessary to encourage discussion of psychiatric risk with these families. The goal of this project was to develop recommendations for genetic counselors to provide psychiatric risk information to families affected by 22q11.2DS. The recommendations were developed by synthesizing resources in the literature about risk communication. These recommendations were refined following an online focus group meeting with five health care professionals who were recruited for participation from 22q11.2DS clinics across the U.S.A. The focus group data revealed three themes related to discussion of psychiatric risk: 1) Stepwise approach, 2) Discussing treatment options and reducing risks, and 3) Addressing stigma. These recommendations may be used as a foundation for a future clinical protocol to encourage discussion about the risk for psychiatric illness at an earlier point in the diagnostic process for 22q11.2DS and to provide improved information, support and resources to affected families.

Measurement of Fronto-limbic Activity Using an Emotional Oddball Task in Children with Familial High Risk for Schizophrenia.

Adolescence is a critical developmental period where the early symptoms of schizophrenia frequently emerge. First-degree relatives of people with schizophrenia who are at familial high risk (FHR) may show similar cognitive and emotional changes. However, the neurological changes underlying the emergence of these symptoms remain unclear. This study sought to identify differences in frontal, striatal, and limbic regions in children and adolescents with FHR using functional magnetic resonance imaging. Groups of 21 children and adolescents at FHR and 21 healthy controls completed an emotional oddball task that relied on selective attention and the suppression of task-irrelevant emotional information. The standard oddball task was modified to include aversive and neutral distractors in order to examine potential group differences in both emotional and executive processing. This task was designed specifically to allow for children and adolescents to complete by keeping the difficulty and emotional image content age-appropriate. Furthermore, we demonstrate a technique for suitable fMRI registration for children and adolescent participants. This paradigm may also be applied in future studies to measure changes in neural activity in other populations with hypothesized developmental changes in executive and emotional processing.

Challenges in measuring the effects of pharmacological interventions on cognitive and adaptive functioning in individuals with Down syndrome: A systematic review

We systematically reviewed the measures used in pharmaceutical trials in children/adults with Down syndrome without dementia. Our purpose was to identify developmentally appropriate outcome measures capable of detecting changes in cognitive and adaptive functioning in this population. Eleven studies were included and used diverse outcome measures across the domains of language, memory, attention, behavior, and executive/adaptive functioning. Our results highlight the challenges in selecting measures capable of capturing improvements in pharmaceutical trials in individuals with DS. We offer suggestions to enhance future research, including: conducting studies with larger samples of participants with a range of developmental abilities; modifying existing/developing novel outcome measures; incorporating advances from related areas and DS observational studies; and considering alternative analytic techniques to characterize treatment effects.