-
[show abstract]
[hide abstract]
ABSTRACT: To better understand the development and exacerbation of late-life anxiety, we tested a risk model positing that trait negative affect (NA) characteristics would interact with cognitive functioning, thereby increasing some older adults' risk for increased anxiety symptoms. The moderator-mediator model consisted of measures of NA, cognitive functioning, and their interaction, as predictors of later Hamilton Anxiety Rating Scale scores (HARS) via a mediational process, subjective memory concerns (SMCs). Older adults (aged 65-years and over; Mage=76.7 years, SD=6.90 years) completed evaluations four times over approximately 18 months. A latent growth curve model including Anxiety Sensitivity Index total score (ASI), Mattis Dementia Rating Scale-2 (DRS) total raw score, the ASI×DRS interaction, a SMC measure as mediator, HARS intercept (scores at times 3 and 4), and HARS slope provided good fit. The ASI×DRS-2 interaction at Time 1 predicted HARS slope score (β=-.34, p<.05). When ASI score was high, stronger cognitive functioning was associated with fewer anxiety symptoms. The indirect effect of ASI score predicting HARS score 18-months later through the SMC mediator was statistically significant (β=.08, p<.05). Results suggest that the cognitive functioning changes associated with aging might contribute to the development of anxiety symptoms in older adults with specific NA traits. Implications for predicting and preventing late life anxiety disorders are discussed.
Journal of anxiety disorders 04/2013; · 2.68 Impact Factor
-
Nathan Hantke,
Kristy A Nielson, John L Woodard,
Leslie M Guidotti Breting,
Alissa Butts,
Michael Seidenberg,
J Carson Smith,
Sally Durgerian,
Melissa Lancaster,
Monica Matthews,
Michael A Sugarman,
Stephen M Rao
[show abstract]
[hide abstract]
ABSTRACT: Previous studies suggest that task-activated functional magnetic resonance imaging (fMRI) can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively "Stable" or "Declining" based on ≥1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with Apolipoprotein E (APOE) ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R2 = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R2 = .285; C index = .787), whereas the addition of EM did not (R2 = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer's disease. (JINS, 2012, 18, 1-11).
Journal of the International Neuropsychological Society 11/2012; · 2.76 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer's disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
Biochimica et Biophysica Acta 03/2012; 1822(3):442-56. · 4.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Functional magnetic resonance imaging (fMRI) allows for dynamic observation of the neural substrates of cognitive processing, which makes it a valuable tool for studying brain changes that may occur with both normal and pathological aging. fMRI studies have revealed that older adults frequently exhibit a greater magnitude and extent activation of the blood-oxygen-level-dependent signal compared to younger adults. This additional activation may reflect compensatory recruitment associated with functional and structural deterioration of neural resources. Increased activation has also been associated with several risk factors for Alzheimer's disease (AD), including the apolipoprotein ε4 allele. Longitudinal studies have also demonstrated that fMRI may have predictive utility in determining which individuals are at the greatest risk of developing cognitive decline. This chapter will review the results of a number of task-activated fMRI studies of older adults, focusing on both healthy aging and neuropathology associated with AD. We also discuss models that account for cognitive aging processes, including the hemispheric asymmetry reduction in older adults (HAROLD) and scaffolding theory of aging and cognition (STAC) models. Finally, we discuss methodological issues commonly associated with fMRI research in older adults.
Current topics in behavioral neurosciences. 09/2011; 10:113-36.
-
J Carson Smith,
Kristy A Nielson, John L Woodard,
Michael Seidenberg,
Matthew D Verber,
Sally Durgerian,
Piero Antuono,
Alissa M Butts,
Nathan C Hantke,
Melissa A Lancaster,
Stephen M Rao
[show abstract]
[hide abstract]
ABSTRACT: The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event-related functional magnetic resonance imaging during fame discrimination. Significantly greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients, (P=0.03), suggesting PA may enhance memory-related caudate activation in aMCI.
Psychiatry Research 07/2011; 193(1):60-2. · 2.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer's disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65-85) cognitively intact adults. A cross-sectional design was used with four groups (n=17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous>unfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline.
NeuroImage 01/2011; 54(1):635-44. · 5.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Person recognition can be accomplished through several modalities (face, name, voice). Lesion, neurophysiology and neuroimaging studies have been conducted in an attempt to determine the similarities and differences in the neural networks associated with person identity via different modality inputs. The current study used event-related functional-MRI in 17 healthy participants to directly compare activation in response to randomly presented famous and non-famous names and faces (25 stimuli in each of the four categories). Findings indicated distinct areas of activation that differed for faces and names in regions typically associated with pre-semantic perceptual processes. In contrast, overlapping brain regions were activated in areas associated with the retrieval of biographical knowledge and associated social affective features. Specifically, activation for famous faces was primarily right lateralized and famous names were left-lateralized. However, for both stimuli, similar areas of bilateral activity were observed in the early phases of perceptual processing. Activation for fame, irrespective of stimulus modality, activated an extensive left hemisphere network, with bilateral activity observed in the hippocampi, posterior cingulate, and middle temporal gyri. Findings are discussed within the framework of recent proposals concerning the neural network of person identification.
Brain and Cognition 02/2010; 72(3):491-8. · 3.17 Impact Factor
-
John L Woodard,
Michael Seidenberg,
Kristy A Nielson,
J Carson Smith,
Piero Antuono,
Sally Durgerian,
Leslie Guidotti,
Qi Zhang,
Alissa Butts,
Nathan Hantke,
Melissa Lancaster,
Stephen M Rao
[show abstract]
[hide abstract]
ABSTRACT: Few studies have examined the extent to which structural and functional MRI, alone and in combination with genetic biomarkers, can predict future cognitive decline in asymptomatic elders. This prospective study evaluated individual and combined contributions of demographic information, genetic risk, hippocampal volume, and fMRI activation for predicting cognitive decline after an 18-month retest interval. Standardized neuropsychological testing, an fMRI semantic memory task (famous name discrimination), and structural MRI (sMRI) were performed on 78 healthy elders (73% female; mean age = 73 years, range = 65 to 88 years). Positive family history of dementia and presence of one or both apolipoprotein E (APOE) ε4 alleles occurred in 51.3% and 33.3% of the sample, respectively. Hippocampal volumes were traced from sMRI scans. At follow-up, all participants underwent a repeat neuropsychological examination. At 18 months, 27 participants (34.6%) declined by at least 1 SD on one of three neuropsychological measures. Using logistic regression, demographic variables (age, years of education, gender) and family history of dementia did not predict future cognitive decline. Greater fMRI activity, absence of an APOE ε4 allele, and larger hippocampal volume were associated with reduced likelihood of cognitive decline. The most effective combination of predictors involved fMRI brain activity and APOE ε4 status. Brain activity measured from task-activated fMRI, in combination with APOE ε4 status, was successful in identifying cognitively intact individuals at greatest risk for developing cognitive decline over a relatively brief time period. These results have implications for enriching prevention clinical trials designed to slow AD progression.
Journal of Alzheimer's disease: JAD 01/2010; 21(3):871-85. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Person identification represents a unique category of semantic knowledge that is commonly impaired in Alzheimer's disease (AD), but has received relatively little investigation in patients with mild cognitive impairment (MCI). The current study examined the retrieval of semantic knowledge for famous names from three time epochs (recent, remote, and enduring) in two participant groups: 23 amnestic MCI (aMCI) patients and 23 healthy elderly controls. The aMCI group was less accurate and produced less semantic knowledge than controls for famous names. Names from the enduring period were recognized faster than both recent and remote names in both groups, and remote names were recognized more quickly than recent names. Episodic memory performance was correlated with greater semantic knowledge particularly for recent names. We suggest that the anterograde memory deficits in the aMCI group interferes with learning of recent famous names and as a result produces difficulties with updating and integrating new semantic information with previously stored information. The implications of these findings for characterizing semantic memory deficits in MCI are discussed. (JINS, 2009, 15, 9-18.).
Journal of the International Neuropsychological Society 02/2009; 15(1):9-18. · 2.76 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Subjective memory complaints (SMCs) are part of the diagnostic criteria for Mild Cognitive Impairment (MCI), yet little is known about their etiology. In some previous studies, no direct relation has been found between SMCs and objective memory performance, yet significant correlations have been identified between SMCs and psychological factors such as depression and anxiety. In the current study, we examined whether negative affect moderated the relation between objective memory functioning and SMCs in a sample of healthy, non-demented participants aged 65 and older. As predicted, several negative affect measures moderated the relationship between objective cognitive functioning and SMCs. In the absence of objective memory impairment as indexed by the Rey Auditory Verbal Learning Test (RAVLT) and the Dementia Rating Scale-2nd Edition (DRS-2), higher levels of negative affect were associated with increased levels of SMCs. Moreover, a lower order negative affect factor, anxiety sensitivity, significantly moderated the relation between objective memory functioning and SMCs, after controlling for higher order measures of general negative affectivity. Findings suggest that negative affect, particularly anxiety sensitivity, distorts the subjective appraisal of one's own memory, such that people high on negative affect factors report more episodes of forgetting, even in the absence of objective cognitive impairments.
Journal of the International Neuropsychological Society 04/2008; 14(2):327-36. · 2.76 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Anxiety sensitivity (AS), a cognitive risk factor for anxiety disorders, was evaluated in a homogeneous obsessive-compulsive disorder (OCD) sample. A total of 280 individuals with OCD completed measures. Evaluation of the Anxiety Sensitivity Index revealed a latent structure that was congruent with previous studies showing a single higher order and three lower order factors, although greater variance was accounted for by the general factor than in a previous study. AS was significantly associated with OCD symptom severity after controlling for other putative cognitive risk factors, although the additional variance explained was small. Variability in the relationship of AS to OCD symptom severity was found across OCD symptom subgroups. Results suggest that AS might be an important aspect of OCD-relevant cognition for specific OCD subgroups, and the need for experimental evaluation is discussed.
Assessment 03/2008; 15(3):351-63. · 2.01 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although significant empirical support exists for both cognitive and neurobiological models of obsessive-compulsive disorder (OCD), there have been few efforts to integrate findings. In this investigation, we attempted to link models by examining relationships between performance on information processing tasks posited to be markers of OCD-related neuropathology and a self-report measure of excessive thought-focused attention (cognitive self-consciousness; CSC). Congruent with predictions and prior research, OCD patients' performance was impaired in comparison to an anxious control group on the Serial Reaction Time (SRT) Task, a measure of implicit procedural learning. Following completion of the SRT, participants' awareness of the embedded stimulus pattern was assessed. As predicted, participants with OCD demonstrated superior performance on this task. Scoring on a measure of CSC correlated with performance on both tasks, although the amount of variance accounted for was modest. Evaluation of OCD symptom subgroups revealed greater procedural learning impairment in a hoarding subgroup. Implications for theory and treatment are discussed.
Behaviour Research and Therapy 02/2008; 46(1):48-61. · 3.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory's greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed.
Journal of Cognitive Neuroscience 08/2007; 19(7):1113-24. · 5.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recent neuroimaging research shows that older adults exhibit recruitment, or increased activation on various cognitive tasks. The current study evaluated whether a similar pattern also occurs in semantic memory by evaluating age-related differences during recognition of Recent (since the 1990s) and Enduring (1950s to present) famous names. Fifteen healthy older and 15 healthy younger adults performed the name recognition task with a high and comparable degree of accuracy, although older adults had slower reaction time in response to Recent famous names. Event-related functional MRI showed extensive networks of activation in the two groups including posterior cingulate, right hippocampus, temporal lobe and left prefrontal regions. The Recent condition produced more extensive activation than the Enduring condition. Older adults had more extensive and greater magnitude of activation in 15 of 20 regions, particularly for the Recent condition (15 of 15; 7 of 15 also differed for Enduring); young adults did not show greater activation magnitude in any region. There were no group differences for non-famous names, indicating that age differences are task-specific. The results support and extend the existing literature to semantic memory tasks, indicating that older adult brains use functional recruitment to support task performance, even when task performance accuracy is high.
Neurobiology of aging 11/2006; 27(10):1494-504. · 5.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Investigations of obsessive–compulsive disorder (OCD) have increasingly emphasized the role of cognition in symptom development and maintenance. In the present study, relationships between parent and adolescent child OCD symptoms and OCD cognition measures were explored to elucidate how OCD related beliefs and OCD symptoms might develop. One hundred and twenty-six non-clinical parent–adolescent pairs completed measures of OCD symptoms, OCD related beliefs and metacognitive beliefs (cognitive self-consciousness [CSC], the tendency to focus attention on thought processes). A significant indirect relationship was found between parent OCD symptoms and adolescent OCD symptoms through specific adolescent OCD related beliefs. Contrary to expectations, parent and adolescent CSC were not correlated. Although findings were limited by the correlational and cross-sectional design, implications of the observed associations for theory and treatment are discussed. Copyright © 2006 John Wiley & Sons, Ltd.
Clinical Psychology & Psychotherapy 05/2006; 13(3):153 - 162. · 1.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The negative appraisal of commonly experienced intrusive thoughts is posited to play an important role in obsessive-compulsive disorder (OCD), although why some people focus on thought experiences and have difficulties dismissing intrusions is not well understood. To elucidate how intrusive thoughts might become obsessional problems, relations between thought-focused attention (cognitive self-consciousness; CSC), implicit sequence learning and OCD were evaluated in individuals with OCD (n=43) and in a nonclinical comparison group (n=41). Impaired performance on a serial reaction time test, but enhanced recognition of the embedded stimulus pattern, was predicted for the OCD group based on hypothesized nonconscious processing differences. Predicted differences were found and CSC score predicted reaction time and pattern recognition. CSC might be a consequence of conscious processing gating problems that increase thought salience and the likelihood of the negative appraisal of intrusive thoughts. Implications for theory and treatment are discussed.
Journal of Anxiety Disorders 02/2006; 20(4):389-407. · 2.96 Impact Factor
-
Frederick S Sierles,
Amy C Brodkey,
Lynn M Cleary,
Frederick A McCurdy,
Matthew Mintz,
Julia Frank,
D Joanne Lynn,
Jason Chao,
Bruce Z Morgenstern,
William Shore, John L Woodard
[show abstract]
[hide abstract]
ABSTRACT: While exposure to and attitudes about drug company interactions among residents have been studied extensively, relatively little is known about relationships between drug companies and medical students.
To measure third-year medical students' exposure to and attitudes about drug company interactions.
In 2003, we distributed a 64-item anonymous survey to 1143 third-year students at 8 US medical schools, exploring their exposure and response to drug company interactions. The schools' characteristics included a wide spectrum of ownership types, National Institutes of Health funding, and geographic locations. In 2005, we conducted a national survey of student affairs deans to measure the prevalence of school-wide policies on drug company-medical student interactions.
Monthly frequency of students' exposure to various activities and gifts during clerkships, and attitudes about receiving gifts.
Overall response rate was 826/1143 (72.3%), with range among schools of 30.9%-90.7%. Mean exposure for each student was 1 gift or sponsored activity per week. Of respondents, 762/818 (93.2%) were asked or required by a physician to attend at least 1 sponsored lunch. Regarding attitudes, 556/808 (68.8%) believed gifts would not influence their practices and 464/804 (57.7%) believed gifts would not affect colleagues' practices. Of the students, 553/604 (80.3%) believed that they were entitled to gifts. Of 183 students who thought a gift valued at less than $50 was inappropriate, 158 (86.3%) had accepted one. The number of students who simultaneously believed that sponsored grand rounds are educationally helpful and are likely to be biased was 452/758 (59.6%). Students at 1 school who had attended a seminar about drug company-physician relationships were no more likely than the nonattending classmates to show skepticism. Of the respondents, 704/822 (85.6%) did not know if their school had a policy on these relationships. In a national survey of student affairs deans, among the 99 who knew their policy status, only 10 (10.1%) reported having school-wide policies about these interactions.
Student experiences and attitudes suggest that as a group they are at risk for unrecognized influence by marketing efforts. Research should focus on evaluating methods to limit these experiences and affect the development of students' attitudes to ensure that physicians' decisions are based solely on helping each patient achieve the greatest possible benefit.
JAMA The Journal of the American Medical Association 10/2005; 294(9):1034-42. · 30.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous neuroimaging studies examining recognition of famous faces have identified activation of an extensive bilateral neural network [Gorno Tempini, M. L., Price, C. J., Josephs, O., Vandenberghe, R., Cappa, S. F., Kapur, N. et al. (1998). The neural systems sustaining face and proper-name processing. Brain, 121, 2103-2118], including the medial temporal lobe (MTL) and specifically the hippocampal complex [Haist, F., Bowden, G. J., & Mao, H. (2001). Consolidation of human memory over decades revealed by functional magnetic resonance imaging. Nature Neuroscience, 4, 1139-1145; Leveroni, C. L., Seidenberg, M., Mayer, A. R., Mead, L. A., Binder, J. R., & Rao, S. M. (2000). Neural systems underlying the recognition of familiar and newly learned faces. Journal of Neuroscience, 20, 878-886]. One model of hippocampal functioning in autobiographical, episodic memory retrieval argues that the hippocampal complex remains active in retrieval tasks regardless of time or age of memory (multiple trace theory, MTT), whereas another proposal posits that the hippocampal complex plays a time-limited role in retrieval of autobiographical memories. The current event-related fMRI study focused on the medial temporal lobe and its response to recognition judgments of famous names from two distinct time epochs (1990s and 1950s) in 15 right-handed healthy older adults (mean age=70 years). A pilot study with an independent sample of young and older subjects ensured that the stimuli were representative of a recent and remote time period. Increased MR signal activity was observed on a bilateral basis for both the hippocampus and parahippocampal gyrus (PHG) during recognition of familiar names from both the recent and remote time periods when compared to non-famous names. However, the impulse response functions in the right hippocampus and right PHG demonstrated a differential response to stimuli from different time epochs, with the 1990s names showing the greatest MR signal intensity change, followed by the 1950s names, followed by foils. The finding that recognition of famous names produced significant bilateral MTL activation regardless of time epoch relative to foils provides support for the MTT model. However, the finding of a temporal gradient in the right MTL also provides support for the HC model, given the greater MTL response associated with recently famous names relative to remotely famous names.
Neuropsychologia 01/2005; 43(5):693-703. · 3.64 Impact Factor
-
Journal of Clinical and Experimental Neuropsychology 07/2004; 26(4):577-86. · 2.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The proportion of students matching into psychiatry (PMP) at each medical school results from a complex interplay between extrinsic (e.g., national trends, geographic region) and intrinsic factors (e.g., the quality of psychiatric education). The goal of the study was to learn the extent to which regional and local extrinsic factors (and one intrinsic factor) influenced PMP at medical schools in the U.S. from 1999 to 2001.
The authors obtained data about these factors from deans of student affairs, the National Resident Matching Program (NRMP), American Medical Association (AMA), Association of American Medical Colleges (AAMC), American Psychiatric Association (APA), and Harvard University's HealthSystem Consortium.
The best predictor of a school's PMP is the PMP of the prior year for that particular school. Local and regional extrinsic factors were not significantly associated with PMP. There was a modest inverse correlation between PMP and the proportion of international medical graduates (IMGs) in psychiatry residency.
The authors infer that intrinsic factors are most important for recruitment, and they make recommendations for addressing these factors.
Academic Psychiatry 02/2003; 27(4):260-8. · 0.81 Impact Factor
