Neural correlates of the sound facilitation effect in the modified Simon task in older adults.

Introduction: The ability to resolve interference declines with age and is attributed to neurodegeneration and reduced cognitive function and mental alertness in older adults. Our previous study revealed that task-irrelevant but environmentally meaningful sounds improve performance on the modified Simon task in older adults. However, little is known about neural correlates of this sound facilitation effect. Methods: Twenty right-handed older adults [mean age = 72 (SD = 4), 11 female] participated in the fMRI study. They performed the modified Simon task in which the arrows were presented either in the locations matching the arrow direction (congruent trials) or in the locations mismatching the arrow direction (incongruent trials). A total of 50% of all trials were accompanied by task-irrelevant but environmentally meaningful sounds. Results: Participants were faster on the trials with concurrent sounds, independently of whether trials were congruent or incongruent. The sound effect was associated with activation in the distributed network of auditory, posterior parietal, frontal, and limbic brain regions. The magnitude of the behavioral facilitation effect due to sound was associated with the changes in activation of the bilateral auditory cortex, cuneal cortex, and occipital fusiform gyrus, precuneus, left superior parietal lobule (SPL) for No Sound vs. Sound trials. These changes were associated with the corresponding changes in reaction time (RT). Older adults with a recent history of falls showed greater activation in the left SPL than those without falls history. Conclusion: Our findings are consistent with the dedifferentiation hypothesis of cognitive aging. The facilitatory effect of sound could be achieved through recruitment of excessive neural resources, which allows older adults to increase attention and mental alertness during task performance. Considering that the SPL is critical for integration of multisensory information, individuals with slower task responses and those with a history of falls may need to recruit this region more actively than individuals with faster responses and those without a fall history to overcome increased difficulty with interference resolution. Future studies should examine the relationship among activation in the SPL, the effect of sound, and falls history in the individuals who are at heightened risk of falls.

Hand Dexterity Is Associated with the Ability to Resolve Perceptual and Cognitive Interference in Older Adults: Pilot Study.

The relationship between hand dexterity and inhibitory control across the lifespan is underexplored. In this pilot study, we examined inhibitory control using a modified Simon task. During the task, participants were presented with right- and left-pointing arrows located either on the right or the left parts of the screen. In the congruent trials, the arrow location and direction matched. In the incongruent trials, they mismatched, thus creating cognitive interference. In 50% of trials, the arrow presentation was accompanied by a task-irrelevant but environmentally meaningful sound that created perceptual interference. Hand dexterity was measured with the 9-hole peg test. Significantly faster reaction time (RT) on the modified Simon task (p < 0.001) was observed in younger adults, trials with concurrent sound stimuli, and congruent trials. Older adults who reported recent falls had greater difficulty resolving cognitive interference than older adults without recent falls. Hand dexterity significantly moderated the effect of sound on RT, but only in the group of older individuals. Interestingly, older individuals with reduced hand dexterity benefited from concurrent sounds more than those with better hand dexterity. Our findings suggest that task-irrelevant but environmentally meaningful sounds may increase alertness and enhance stimulus perception and recognition, thus improving motor performance in older individuals.

Predicting Upgrade of Ductal Carcinoma In Situ to Invasive Breast Cancer at Surgery With Ultrafast Imaging.

BACKGROUND. Biopsy-proven ductal carcinoma in situ (DCIS) lesions are often upgraded to invasive cancer at surgery. Therefore, accurate prediction of the likelihood of invasion is helpful for surgical planning, including the need for sentinel lymph node biopsy (SLNB). OBJECTIVE. The purpose of the present study was to investigate whether kinetic features of clinically available ultrafast MRI (UF-MRI) can predict upgrade of biopsy-proven DCIS to invasive cancer at surgical excision. METHODS. Consecutive patients with biopsy-proven pure DCIS lesions who underwent UF-MRI with conventional dynamic contrast-enhanced MRI (DCE-MRI) and subsequently underwent surgery between August 2019 and January 2021 were identified. Patient and lesion characteristics, biopsy method and pathology, and lesion features on mammography, ultrasound, DCE-MRI, and UF-MRI were assessed to determine predictors of upgrade to invasive cancer. The Fisher exact test and Kruskal-Wallis test were used for association analysis. RESULTS. In 68 patients (median age, 52.0 years; range, 31-79 years) with 68 biopsy-proven pure DCIS lesions, 26 lesions (38%) were upgraded from in situ to invasive cancer. An upgrade of DCIS to invasive cancer was significantly associated with a shorter time to enhancement (TTE) on preoperative UF-MRI (p = .03), with a threshold of 11 seconds providing maximum specificity (50%) and sensitivity (76%) for upgrade. Larger lesion size on DCE-MRI (p = .001) and mammography (p = .04) was also significantly associated with upgrade; an optimal predictive threshold of 4.4 cm on DCE-MRI yielded sensitivity of 88% and specificity of 56%. No other specific variables were significantly associated with upgrade after surgery. Logistic regression of selected features combined with TTE produced a higher AUC (0.85) in predicting upgrade to invasive disease than did each factor alone, but this result was not statistically significant. CONCLUSION. Preoperative UF-MRI TTE and lesion size on DCE-MRI and mammography show potential in predicting upgrade of DCIS to invasive cancer at surgery. CLINICAL IMPACT. UF-MRI provides useful information that can be used in surgical planning, including determination of the need to perform SLNB.

Active Surveillance for Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ.

Atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are relatively common breast lesions on the same spectrum of disease. Atypical ductal hyperblasia is a nonmalignant, high-risk lesion, and DCIS is a noninvasive malignancy. While a benefit of screening mammography is early cancer detection, it also leads to increased biopsy diagnosis of noninvasive lesions. Previously, treatment guidelines for both entities included surgical excision because of the risk of upgrade to invasive cancer after surgery and risk of progression to invasive cancer for DCIS. However, this universal management approach is not optimal for all patients because most lesions are not upgraded after surgery. Furthermore, some DCIS lesions do not progress to clinically significant invasive cancer. Overtreatment of high-risk lesions and DCIS is considered a burden on patients and clinicians and is a strain on the health care system. Extensive research has identified many potential histologic, clinical, and imaging factors that may predict ADH and DCIS upgrade and thereby help clinicians select which patients should undergo surgery and which may be appropriate for active surveillance (AS) with imaging. Additionally, multiple clinical trials are currently underway to evaluate whether AS for DCIS is feasible for a select group of patients. Recent advances in MRI, artificial intelligence, and molecular markers may also have an important role to play in stratifying patients and delineating best management guidelines. This review article discusses the available evidence regarding the feasibility and limitations of AS for ADH and DCIS, as well as recent advances in patient risk stratification.

Working memory updating in individuals with bipolar and unipolar depression: fMRI study.

Understanding neurobiological characteristics of cognitive dysfunction in distinct psychiatric disorders remains challenging. In this secondary data analysis, we examined neurobiological differences in brain response during working memory updating among individuals with bipolar disorder (BD), those with unipolar depression (UD), and healthy controls (HC). Individuals between 18-45 years of age with BD (n = 100), UD (n = 109), and HC (n = 172) were scanned using fMRI while performing 0-back (easy) and 2-back (difficult) tasks with letters as the stimuli and happy, fearful, or neutral faces as distractors. The 2(n-back) × 3(groups) × 3(distractors) ANCOVA examined reaction time (RT), accuracy, and brain activation during the task. HC showed more accurate and faster responses than individuals with BD and UD. Difficulty-related activation in the prefrontal, posterior parietal, paracingulate cortices, striatal, lateral occipital, precuneus, and thalamic regions differed among groups. Individuals with BD showed significantly lower difficulty-related activation differences in the left lateral occipital and the right paracingulate cortices than those with UD. In individuals with BD, greater difficulty-related worsening in accuracy was associated with smaller activity changes in the right precuneus, while greater difficulty-related slowing in RT was associated with smaller activity changes in the prefrontal, frontal opercular, paracingulate, posterior parietal, and lateral occipital cortices. Measures of current depression and mania did not correlate with the difficulty-related brain activation differences in either group. Our findings suggest that the alterations in the working memory circuitry may be a trait characteristic of reduced working memory capacity in mood disorders. Aberrant patterns of activation in the left lateral occipital and paracingulate cortices may be specific to BD.

Behavioral and neuroimaging evidence prodromal to major depressive disorder onset in a young adult without personal or family history of psychiatric disorder: Case report.

Background: Subthreshold symptoms of major depressive disorder (MDD) may be underreported due to stigma and/or cognitive impairment associated with this illness. Identifying objective behavioral and neural markers prodromal to MDD onset would help overcome this bias. This case study reports prospective behavioral and neuroimaging evidence prodromal to MDD onset in a young adult without prior personal or family history of psychiatric disorders who was identified during a longitudinal study of mood disorders. Methods: The participant completed the SCID-5 and other assessments of depression as well as the Vividness of Visual Imagery Questionnaire at baseline, 6-month follow-up, and 12-month follow-up. The participant completed the Emotion Intensity Rating task and high-resolution structural images were collected using magnetic resonance imaging (MRI) at baseline and 6-month follow-up. The levels of cortical myelin computed as the T1w/T2w ratio were used in a linear discriminant analysis (LDA) to predict participant's diagnostic status at baseline and 6-months. Results: The participant presented as a healthy control at baseline and 6-month but met criteria for MDD at the 12-month follow-up based on the SCID-5. The participant's visual imagery as well as the ability to correctly recognize neutral faces dramatically reduced from baseline to 6-month follow-up. The LDA classified the participant as an individual with depressive disorders at both baseline and 6-month follow-up despite the absence of either subthreshold or clinical symptoms of depression. Conclusions: While preliminary, the results suggest that the measures of cortical myelin, response to neutral and emotional facial expressions, and vividness of visual imagery could be prodromal to illness onset, whereas clinician-administered or self-reported measures of depression symptoms were uninformative.

The effects of mood disorders and childhood trauma on fear of positive and negative evaluation.

Fear of positive and negative evaluation is maladaptive and may result in psychosocial dysfunction. Although being diagnosed with mood disorders or experiencing childhood trauma may potentially affect fear of evaluation, previous studies examined this phenomenon mostly in social anxiety disorders. To fill this gap, we investigated the relationship between childhood trauma and fear of positive and negative evaluation in individuals with bipolar disorder (BD), depressive disorders (DD), and healthy controls (HC). 43 individuals with BD, 89 with DD, and 65 HC completed clinical interviews and self-report assessments. The relationship between participants' diagnoses and presence of trauma on fear of positive and negative evaluation was examined using ANCOVA. Independently of experiencing childhood trauma, fear of positive evaluation was significantly higher in individuals with mood disorders vs. HC. Fear of negative evaluation was significantly associated with diagnosis-by-trauma interaction. Significantly lower scores were observed in individuals with BD without childhood trauma compared to those with childhood trauma and individuals with DD. Compared to HC, more individuals with mood disorders experienced childhood trauma. While experiencing childhood trauma may increase vulnerability to mood disorders in general, it is especially detrimental for individuals with BD by increasing the risk for developing a fear of negative evaluation.

The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development.

The zebrafish kidney is conserved with other vertebrates, making it an excellent genetic model to study renal development. The kidney collects metabolic waste using a blood filter with specialized epithelial cells known as podocytes. Podocyte formation is poorly understood but relevant to many kidney diseases, as podocyte injury leads to progressive scarring and organ failure. zeppelin (zep) was isolated in a forward screen for kidney mutants and identified as a homozygous recessive lethal allele that causes reduced podocyte numbers, deficient filtration, and fluid imbalance. Interestingly, zep mutants had a larger interrenal gland, the teleostean counterpart of the mammalian adrenal gland, which suggested a fate switch with the related podocyte lineage since cell proliferation and cell death were unchanged within the shared progenitor field from which these two identities arise. Cloning of zep by whole genome sequencing (WGS) identified a splicing mutation in breast cancer 2, early onset (brca2)/fancd1, which was confirmed by sequencing of individual fish. Several independent brca2 morpholinos (MOs) phenocopied zep, causing edema, reduced podocyte number, and increased interrenal cell number. Complementation analysis between zep and brca2ZM_00057434 -/- zebrafish, which have an insertional mutation, revealed that the interrenal lineage was expanded. Importantly, overexpression of brca2 rescued podocyte formation in zep mutants, providing critical evidence that the brca2 lesion encoded by zep specifically disrupts the balance of nephrogenesis. Taken together, these data suggest for the first time that brca2/fancd1 is essential for vertebrate kidney ontogeny. Thus, our findings impart novel insights into the genetic components that impact renal development, and because BRCA2/FANCD1 mutations in humans cause Fanconi anemia and several common cancers, this work has identified a new zebrafish model to further study brca2/fancd1 in disease.

Production of haploid zebrafish embryos by in vitro fertilization.

The zebrafish has become a mainstream vertebrate model that is relevant for many disciplines of scientific study. Zebrafish are especially well suited for forward genetic analysis of developmental processes due to their external fertilization, embryonic size, rapid ontogeny, and optical clarity--a constellation of traits that enable the direct observation of events ranging from gastrulation to organogenesis with a basic stereomicroscope. Further, zebrafish embryos can survive for several days in the haploid state. The production of haploid embryos in vitro is a powerful tool for mutational analysis, as it enables the identification of recessive mutant alleles present in first generation (F1) female carriers following mutagenesis in the parental (P) generation. This approach eliminates the necessity to raise multiple generations (F2, F3, etc.) which involves breeding of mutant families, thus saving the researcher time along with reducing the needs for zebrafish colony space, labor, and the husbandry costs. Although zebrafish have been used to conduct forward screens for the past several decades, there has been a steady expansion of transgenic and genome editing tools. These tools now offer a plethora of ways to create nuanced assays for next generation screens that can be used to further dissect the gene regulatory networks that drive vertebrate ontogeny. Here, we describe how to prepare haploid zebrafish embryos. This protocol can be implemented for novel future haploid screens, such as in enhancer and suppressor screens, to address the mechanisms of development for a broad number of processes and tissues that form during early embryonic stages.