Integrative hierarchical models have sought to account for the extensive comorbidity between various internalizing disorders in terms of broad individual difference factors these disorders share. However, such models have been developed largely on the basis of self-report and diagnostic symptom data. Toward the goal of linking such models to neurobiological systems, we review studies that have employed variants of the affect-modulated startle paradigm to investigate emotional processing in internalizing disorders as well as personality constructs known to be associated with these disorders. Specifically, we focus on four parameters of startle reactivity: fear-potentiated startle, inhibition of startle in the context of pleasant stimuli, context-potentiated startle, and general startle reactivity. On the basis of available data, we argue that these varying effects index differing neurobiological processes related to mood and anxiety disorders that are interpretable from the standpoint of dimensional models of the internalizing spectrum. Further, we contend that these empirical findings can feed back into and help reshape conceptualizations of internalizing disorders in ways that make them more amenable to neurobiological analysis. Keywords Startle blink; internalizing disorders; neurobiology of internalizing disorders Linking Dimensional Models of Internalizing Psychopathology to Neurobiological Systems: Affect-Modulated Startle as an Indicator of Fear and Distress Disorders and Affiliated TraitsIn the two decades that have passed since the finding of affect-modulated startle was initially reported in humans (Vrana, Spence, & Lang, 1988), an extensive literature has developed on the use of this measure for investigating affective individual differences in relation to psychopathology (cf. Grillon & Baas, 2003;Cook, 1999;Patrick & Bernat, 2006). In particular, startle reflex modulation has been examined in relation to traits associated with fear, neuroticism, and negative affectivity, and in relation to disorders involving an excess of emotional reactivity (e.g., phobias, panic, post-traumatic stress, and depression) as well as those Correspondence concerning this article may be addressed either to Uma Vaidyanathan or Christopher Patrick, Department of Psychology, University of Minnesota, Elliott Hall, 75 East River Road, Minneapolis, MN 55455. vaidy017@umn.edu, cpatrick@umn.edu.. Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/journals/bul. NIH Public Access Author ManuscriptPsychol Bull. Author manuscript; available in ...

Measures of fearfulness and measures of psychopathy show positive and negative associations, respectively, with startle reflex potentiation during unpleasant picture viewing. We tested the hypothesis that a common bipolar trait dimension underlies these differing associations. Blink responses to noise probes were recorded during pleasant, neutral, and unpleasant pictures in 88 undergraduates assessed with a battery of self-report scales indexing fear and psychopathy/ fearlessness. A significant positive association was found between an omnibus index of fear, consisting of scores on the first component from a PCA of these various scales, and startle potentiation during aversive picture viewing. This association was most robust, across participants overall and within gender subgroups, for scenes that were most directly threatening. Implications for psychophysiological research on individual differences and psychopathology are discussed.The potentiation of the startle blink reflex in the presence of aversive stimuli is a welldocumented finding in both animal and human literatures. Research with humans has provided evidence of individual differences in the magnitude of this effect. One line of research has demonstrated positive associations between the degree of aversive startle potentiation and measures of dispositional fear and negative affect. Another has demonstrated negative associations between the magnitude of aversive startle potentiation and psychopathy (psychopathic personality), a clinical construct believed to entail deficits in fear reactivity. The current study was undertaken to bridge these two lines of research by investigating the relationship between affective modulation of the startle blink reflex and a bipolar trait dimension defined by measures of dispositional fear on one hand, and measures of fearlessness/psychopathy on the other. The primary study hypothesis was that aversive startle potentiation would serve as a continuous physiological indicator of this bipolar trait dimension. Potentiated Startle as an Index of FearContemporary theories of emotion consider motivational states to be organized around two basic survival systems, one defensive and the other appetitive in nature (Lang, Bradley, & Cuthbert, 1997). The defensive system is activated in situations in which an organism is threatened or endangered. Studies of animals have shown that threatening stimuli activate subcortical circuitry in the brain including the basolateral and central nuclei of the amygdala (e.g. Campeau and Davis, 1995;Sananes and Davis, 1992). The central nucleus of the amygdala in turn projects to other brain areas that mobilize (depending upon the circumstances) varying defensive responses, including freezing, active flight (Fanselow, 1994), fear bradycardia (e.g. Kapp, Frysinger, Gallagher, & Haselton, 1979) increase (e.g. LeDoux, 1990), and potentiation of the startle response (e.g. Davis, 2000). From this perspective, individual differences in fear and negative affect can be conceptualized as variations ...

Prior research has demonstrated deficits in defensive reactivity (indexed by potentiation of the startle blink reflex) in psychopathic individuals. However, the basis of this association remains unclear, as diagnostic criteria for psychopathy encompass two distinct phenotypic components that may reflect differing neurobiological mechanisms – an affective-interpersonal component, and an antisocial deviance component. Likewise, the role of defensive response deficits in antisocial personality disorder (APD), a related but distinct syndrome, remains to be clarified. The current study examined affective priming deficits in relation to factors of psychopathy and symptoms of APD using startle reflex methods in 108 adult male prisoners. Deficits in blink reflex potentiation during aversive picture viewing were found in relation to the affective-interpersonal (Factor 1) component of psychopathy, and to a lesser extent in relation to the antisocial deviance (Factor 2) component of psychopathy and symptoms of APD—but only as a function of their overlap with affective-interpersonal features of psychopathy. These findings provide clear evidence that deficits in defensive reactivity are linked specifically to the affective-interpersonal features of psychopathy, and not the antisocial deviance features represented most strongly in APD.

Recent empirical investigations utilizing male prisoners have begun to validate clinical conceptualizations of primary and secondary psychopathy subtypes. We extended this literature by identifying similar psychopathic subtypes in female prisoners on the basis of personality structure using model-based cluster analysis. Secondary psychopaths (n = 39) were characterized by personality traits of negative emotionality and low behavioral constraint, an early onset of antisocial and criminal behavior, greater substance use and abuse, more violent behavior and institutional misconduct, and more mental health problems including symptoms of post-traumatic stress disorder and suicide attempts. Primary psychopaths (n = 31) exhibited few distinguishing personality features but were prolific criminals especially in regards to non-violent crime, and exhibited relatively few mental health problems despite substantial exposure to traumatic events. The results support alternative etiological pathways to antisocial and criminal behavior that are evident in personality structure as well as gender similarities and differences in the manifestation of psychopathic personalities.

Objective-Comorbidity poses a major challenge to conventional methods of diagnostic classification. While dimensional models of psychopathology have shed some light on this issue, the reason for inter-relationships among dimensions is unclear. The current study attempted to utilize an alternative approach to characterizing patterns of comorbidity among common mental disorders by modeling them instead as clusters by using latent class analysis.Method-Latent class analyses (LCA) of DSM diagnoses from two nationally representative epidemiological samples -the National Comorbidity Survey (NCS) and National Comorbidity Survey -Replication (NCS-R) datasets were undertaken.Results-Within each dataset, LCA yielded five latent classes exhibiting distinctive profiles of diagnostic comorbidity: a fear class (all phobias and panic disorder); a distress class (depression, generalized anxiety disorder, dysthymia); an externalizing class (alcohol and drug dependence, conduct disorder); a multimorbid class (highly elevated rates of all disorders); and a few disorders class (very low probability of all disorders). While some disorders were relatively specific to certain classes, others (major depression, PTSD, social phobia) appeared to be evident across all classes. Profiles for the five classes were highly similar across the two samples. When bipolar I disorder was added to the LCA models, in both samples, it occurred almost exclusively in the multimorbid class.Conclusions-Comorbidity among mental disorders in the general population appears to occur in a finite number of distinct patterns. This finding has important implications for efforts to refine existing diagnostic classification schemes, as well as for research directed at elucidating the etiology of mental disorders.The phenomenon of comorbidity poses a serious challenge to traditional psychiatric classification systems such as the DSM and the ICD, which conceptualize mental disorders as discrete pathologic conditions. Factor analytic studies have characterized observed co-© 2010 Elsevier Inc. All rights reserved.Correspondence to: Uma Vaidyanathan. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. occurrence among common mental disorders in terms of two correlated but distinct factors of internalizing (subsuming two interrelated subdimensions of "fear" and "anxious-misery") and externalizing (antisocial and addictive disorders) [1]. However, the basis of the moderately large correlation between factors of internalizing and externalizing (i.e., the sources of overlap between disorders in one domain and the other) remains uncl...

Several EEG parameters are potential endophenotypes for different psychiatric disorders. The present study consists of a comprehensive behavioral- and molecular-genetic analysis of such parameters in a large community sample (N = 4,026) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric heritability estimates ranged from .49 to .85, with a median of .78. The additive effect of all SNPs (SNP heritability) varied across electrodes. Although individual SNPs were not significantly associated with EEG parameters, several genes were associated with delta power. We also obtained an association between the GABRA2 gene and beta power (p < .014), consistent with findings reported by others, although this did not survive Bonferroni correction. If EEG parameters conform to a largely polygenic model of inheritance, larger sample sizes will be required to detect individual variants reliably.

This article provides an introductory overview of the investigative strategy employed to evaluate the genetic basis of 17 endophenotypes examined as part of a 20-year data collection effort from the Minnesota Center for Twin and Family Research. Included are characterization of the study samples, descriptive statistics for key properties of the psychophysiological measures, and rationale behind the steps taken in the molecular genetic study design. The statistical approach included (a) biometric analysis of twin and family data, (b) heritability analysis using 527,829 single nucleotide polymorphisms (SNPs), (c) genome-wide association analysis of these SNPs and 17,601 autosomal genes, (d) follow-up analyses of candidate SNPs and genes hypothesized to have an association with each endophenotype, (e) rare variant analysis of nonsynonymous SNPs in the exome, and (f) whole genome sequencing association analysis using 27 million genetic variants. These methods were used in the accompanying empirical articles comprising this special issue, Genome-Wide Scans of Genetic Variants for Psychophysiological Endophenotypes.

Current initiatives such as the National Institute of Mental Health's Research Domain Criteria project aim to reorganize classification of mental disorders along neurobiological lines. Here, we describe how consideration of findings from psychiatric research employing two physiological measures with distinct neural substrates--the startle blink reflex and the error-related negativity (ERN)--can help to clarify relations among disorders entailing salient anxiety or depressive symptomatology. Specifically, findings across various studies and reviews reveal distinct patterns of association for both the startle blink reflex and the ERN with three key domains of psychopathology: (1) Fear (or phobic) disorders (distinguished by increased startle to unpleasant stimuli, but normal-range ERN). (2) Non-phobic anxiety disorders and negative affect (associated with increased ERN, increased startle across all types of emotional stimuli and increased baseline startle) and, more tentatively (3) Major depression (for which patterns of response for both startle and ERN appear to vary, as a function of severity and distinct symptomatology). Findings from this review point to distinct neurobiological indicators of key psychopathology domains that have been previously demarcated using personality and diagnostic data. Notably, these indicators exhibit more specificity in their relations with these three domains than has been seen in quantitative-dimensional models. Implications of these findings are discussed.