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 ...

University of North Carolina at Chapel Hill School of Medicine

Duke University Medical Center

Phosducin and phosducin-like protein (PhLP) bind G protein betagamma subunits and regulate their activity. This report describes a previously uncharacterized binding partner unique to PhLP that was discovered by coimmunoprecipitation coupled with mass spectrometric identification. Chaperonin containing tailless complex polypeptide 1 (CCT), a cytosolic chaperone responsible for the folding of many cellular proteins, binds PhLP with a stoichiometry of one PhLP per CCT complex. Unlike protein-folding substrates of CCT, which interact only in their nonnative conformations, PhLP binds in its native state. Native PhLP competes directly for binding of protein substrates of CCT and thereby inhibits CCT activity. Overexpression of PhLP inhibited the ability of CCT to fold newly synthesized beta-actin by 80%. These results suggest that the interaction between PhLP and CCT may be a means to regulate CCT-dependent protein folding or alternatively, to control the availability of PhLP to modulate G protein signaling.

Regulatory interaction of phosducin-like protein with the cytosolic chaperonin complex.

The properties of the KcsA channel were investigated using a combination of tryptophan scanning of the two transmembrane helices followed by random mutagenesis at targeted residues. The tryptophan mutants were subjected to two screens: oligomeric stability and ability to complement the K+ uptake deficiency of the TK2420 Escherichia coli strain. Oligomeric stability is affected primarily by mutations at sites that border on and interact with the selectivity filter, while the complementation assays identified residues at the crossing point of the inner helices. Sites identified by the complementation assay in the tryptophan screen were subjected to random mutagenesis and selection by complementation. We have found two mutants, A108S and A108T, which have dramatically increased open probability while retaining the basic property of oligomeric stability.

Opening the KcsA K+ channel: tryptophan scanning and complementation analysis lead to mutants with altered gating.

Several recent studies using functional magnetic resonance imaging (fMRI) during recognition memory tests have suggested that the ability to neuromodulate as a function of cognitive demand may be impaired in older adults due to age-related cell loss and neural volume reduction in memory specific regions. In the current study, older adults (ages 59-77) were tested with fMRI during a delayed-recognition task in which memory load for faces was varied across trials. Activity was greater in amplitude for three- versus one-face stimuli within the superior, middle, and inferior frontal gyri, intraparietal sulcus, and fusiform gyrus. It was concluded that the ability to modulate activity with increasing load is preserved in older adults despite reductions in neural volume.

Increasing memory load modulates regional brain activity in older adults as measured by fMRI.

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.

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

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 system's engagement in determining how competing cognitive and emotional information is processed.

Emotional priming effects during Stroop task performance.

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.

Modulation of early and late event-related potentials by emotion.

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.

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

This study examines influences of climate variability on spruce beetle (Dendroctonus rufipennis) outbreak across northwestern Colorado during the period 1650 2011 CE. Periods of broad-scale outbreak reconstructed using documentary records and tree rings were dated to 1843-1860, 1882-1889, 1931-1957, and 2004-2010. Periods of outbreak were compared with seasonal temperature, precipitation, vapor pressure deficit (VPD), the Palmer Drought Severity Index (PDSI), and indices of ocean-atmosphere oscillation that include the El Niño Southern Oscillation (ENSO), Pacific Decadal Oscillation (PDO), and Atlantic Multidecadal Oscillation (AMO). Classification trees showed that outbreaks can be predicted most successfully from above average annual AMO values and above average summer VPD values, indicators of drought across Colorado. Notably, we find that spruce beetle outbreaks appear to be predicted best by interannual to multidecadal variability in drought, not by temperature alone. This finding may imply that spruce beetle outbreaks are triggered by decreases in host tree defenses, which are hypothesized to occur with drought stress. Given the persistence of the AMO, the shift to a positive AMO phase in the late 1990s is likely to promote continued spruce beetle disturbance.

Drought induces spruce beetle (Dendroctonus rufipennis) outbreaks across northwestern Colorado.

In the western United States, mountain pine beetles (MPBs) have killed pine trees across 71,000 km(2) of forest since the mid-1990s, leading to widespread concern that abundant dead fuels may increase area burned and exacerbate fire behavior. Although stand-level fire behavior models suggest that bark beetle-induced tree mortality increases flammability of stands by changing canopy and forest floor fuels, the actual effect of an MPB outbreak on subsequent wildfire activity remains widely debated. To address this knowledge gap, we superimposed areas burned on areas infested by MPBs for the three peak years of wildfire activity since 2002 across the western United States. Here, we show that the observed effect of MPB infestation on the area burned in years of extreme fire appears negligible at broad spatial extents. Contrary to the expectation of increased wildfire activity in recently infested red-stage stands, we found no difference between observed area and expected area burned in red-stage or subsequent gray-stage stands during three peak years of wildfire activity, which account for 46% of area burned during the 2002-2013 period. Although MPB infestation and fire activity both independently increased in conjunction with recent warming, our results demonstrate that the annual area burned in the western United States has not increased in direct response to bark beetle activity. Therefore, policy discussions should focus on societal adaptation to the effects of recent increases in wildfire activity related to increased drought severity.

Area burned in the western United States is unaffected by recent mountain pine beetle outbreaks.

Understanding disturbance interactions and their ecological consequences remains a major challenge for research on the response of forests to a changing climate. When, where, and how one disturbance may alter the severity, extent, or occurrence probability of a subsequent disturbance is encapsulated by the concept of linked disturbances. Here, we evaluated 1) how climate and forest habitat variables, including disturbance history, interact to drive 2000s spruce beetle (Dendroctonus rufipennis) infestation of Engelmann spruce (Picea engelmannii) across the Southern Rocky Mountains; and 2) how previous spruce beetle infestation affects subsequent infestation across the Flat Tops Wilderness in northwestern Colorado, which experienced a severe landscape-scale spruce beetle infestation in the 1940s. We hypothesized that drought and warm temperatures would promote infestation, whereas small diameter and non-host trees, which may reflect past disturbance by spruce beetles, would inhibit infestation. Across the Southern Rocky Mountains, we found that climate and forest structure interacted to drive the 2000s infestation. Within the Flat Tops study area we found that stands infested in the 1940s were composed of higher proportions of small diameter and non-host trees ca. 60 years later. In this area, the 2000s infestation was constrained by a paucity of large diameter host trees (> 23 cm at diameter breast height), not climate. This suggests that there has not been sufficient time for trees to grow large enough to become susceptible to infestation. Concordantly, we found no overlap between areas affected by the 1940s infestation and the current infestation. These results show a severe spruce beetle infestation, which results in the depletion of susceptible hosts, can create a landscape template reducing the potential for future infestations.

Negative feedbacks on bark beetle outbreaks: widespread and severe spruce beetle infestation restricts subsequent infestation.

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.

Sarah J. Hart

Department of Psychiatry

University of North Carolina at Chapel Hill School of Medicine

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

Sarah J. Hart

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Psychiatry

University of North Carolina at Chapel Hill School of Medicine

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

Department of Psychiatry