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http://dx.doi.org/10.1037/0000064-004 APA Handbook of Psychopathology: Vol. 1. Psychopathology: Understanding, Assessing, and Treating Adult Mental Disorders, J. N. Butcher (Editor-in-Chief) Copyright © 2018 by the American Psychological Association. All rights reserved.

Neuropsychology is commonly defined as the study of brain–behavior relationships. Although the field of neuropsychology was once based in the assess- ment of individuals with neurological disorders, the need and usefulness of neuropsychological assessment in the mental health field has gained widespread acceptance (Yozawitz, 1986). With the increased use of neuropsychological assessment with psychiatric populations came a growing appre- ciation of the cognitive sequelae, both subtle and profound, within psychiatric conditions (Heaton, Baade, & Johnson, 1978). Today, neuropsycho- logical assessment is commonly used to inform diagnostic and treatment outcomes in neurological, psychiatric, and mixed populations (Hebben & Milberg, 2009).

The sheer number of individuals affected by psychiatric conditions is striking, particularly when considered within the context of substantial disability associated with mental illness. Recent published figures from the World Health Organiza- tion (2001) estimate that 450 million individuals are affected by a mental or behavioral disorder; however, this figure is likely now far surpassed. Updated prevalence figures (Kessler et al., 2009) suggest that, although variable across countries, a diagnosis of any Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiat- ric Association, 1994) condition was present for 18.1%–36.1% of those assessed. The pervasiveness

of cognitive impairment associated with psychiatric conditions underscores the need to understand and intervene with what is likely to be a major cause of disability in these conditions.

INTRODUCTION

In this chapter, we present numerous men- tal health conditions with associated cognitive impairment. However, the reasons why these conditions are associated with cognitive impair- ment is less clear. In the attempt to understand cognitive impairment within the context of psy- chopathology, one is faced with the challenge of considering whether measurable cognitive impair- ment is the result of fundamental neuropathology due to the mental health condition or, alterna- tively, whether cognitive impairment in one or more domains is reflective of more diffuse impair- ment co-occurring with the psychiatric condi- tion. For example, many of the mental health disorders discussed in this chapter are associated with memory dysfunction. However, is memory impairment fundamental to, and reflective of neu- robiological dysfunction in, these disorders? Or are these problems indicative of a deficit in core cognitive functions (e.g., attention, information processing) resulting in bottom-up dysfunction? Or do more generalized cognitive deficits perhaps commonly co-occur with, yet are in fact separate

C h a P t e r 4

Examination of nEurological and nEuropsychological

fEaturEs in psychopathology Colleen E. Jackson and William P. Milberg

Dr. Jackson was supported by a Department of Veterans Affairs Fellowship in Advanced Geriatrics during a portion of her work on this chapter. This chapter was authored by employees of the United States government as part of official duty and is considered to be in the public domain. Any views expressed herein do not necessarily represent the views of the United States government, and the authors’ participation in the work is not meant to serve as an official endorsement.

APA Handbook of Psychopathology: Psychopathology: Understanding, Assessing, and Treating Adult Mental Disorders, edited by J. N. Butcher and J. M. Hooley Copyright © 2018 American Psychological Association. All rights reserved.

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from, these conditions? We raise this as a criti- cal point in interpreting the neuropsychological, neurological, and neuropathological literature as it relates to psychopathology.

Because many different mental health condi- tions may present with one or more similar areas of cognitive dysfunction, neuropsychological results cannot be used to diagnose mental disorders. Rather, the information obtained through a neu- ropsychological evaluation may offer significant insight into an individual’s cognitive strengths and weaknesses and may be used to inform treatment recommendations and guide educational and voca- tional planning.

Evolving conceptualizations of psychopathol- ogy and neuroscience have transitioned focus from symptom-based diagnoses to a greater emphasis on transdiagnostic commonalities (i.e., shared dimen- sions of brain–behavior relationships; McTeague, 2016). Although not the focus of this chapter, we believe that the evolving diagnostic approaches described in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM–5; American Psychiatric Association, 2013) and the Research Domain Criteria (see Krueger & DeYoung, 2016) have relevance to the broader issue of conceptualizing cognition and neuropathology across psychopathological conditions. Evidence supports common neurobiological abnormalities in related disorders (Baker et al., 2014; Etkin & Wager, 2007) as well as across more diverse diag- nostic groups (Goodkind et al., 2015). Common genetic polymorphisms are also associated with a number of different psychiatric conditions (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013).

This chapter presents an up-to-date review of the most common mental health conditions presenting with cognitive dysfunction using a DSM–5 frame- work. Chapter sections are separated by diagnosis, with associated cognitive, neurological, and neu- ropathological dysfunction. Although we strive to present the most relevant evidence of impairment associated with the individual conditions presented in this chapter, we strongly encourage the reader to consider all evidence within a broader, transdiag- nostic framework.

Challenges in the Assessment of Cognition The assessment of cognition has a number of chal- lenges. These challenges exist in all assessment contexts; however, they may be particularly salient when working with individuals with a mental health condition.

Motivation and effort are of particular concern in neuropsychological assessment. Suboptimal motivation can potentially complicate interpretation of assessment results and in some instances lead to an invalid examination. The role of secondary gain, including internal (e.g., receiving attention or care) or external factors (e.g., financial compensa- tion, reduced obligations at work), should also be considered. These factors may reduce a person’s motivation to perform in a manner consistent with his or her true capabilities (Heilbronner, Sweet, Morgan, Larrabee, & Millis, 2009). In the field of neuropsychology, measures of symptom validity (symptom validity tests) and performance valid- ity (performance validity tests) are used to provide an objective assessment of motivation and effort (Larrabee, 2012). Similarly, the use of embedded symptom validity test measures in psychological assessment (e.g., the Minnesota Multiphasic Person- ality Inventory—2—Restructured Form) also offers standardized, objective measurement of motivation and effort. Standardized assessment of motivation and effort is of particular importance with psychiat- ric populations because factors related to psychiatric conditions may affect an individual’s ability to put forth full and consistent effort.

Neuropsychological assessment must also con- sider the extent to which an individual’s perfor- mance is reflective of his or her current pathology versus baseline cognitive abilities. This is typically described in terms of a deficit in one or more cog- nitive domains relative to estimated baseline (i.e., premorbid) abilities. Such abilities may be predicted on the basis of sociodemographic information (e.g., Barona equation, which incorporates patient age, sex, race, education, occupation, geographic region of residence, and urban vs. rural residence; Barona, Reynolds, & Chastain, 1984) or objective assessment (e.g., Wechsler Adult Intelligence Scale; Wechsler, 1987). The process of distinguishing

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between baseline functioning and cognitive changes attributable to a psychiatric disorder may be espe- cially complicated because many psychiatric condi- tions begin early in life and may lack a clear point of onset, making it difficult to estimate premorbid cognitive abilities.

Using neuropsychological assessment to clarify cognitive functioning is further complicated when two or more psychiatric conditions co-occur (e.g., anxiety and depression). As discussed further later in this chapter, many psychiatric conditions produce similar cognitive profiles, making it challenging to attribute specific deficits to a particular disorder in cases of multiple co-occurring conditions. We encourage readers to reflect on these challenges as they consider neuropsychological and neurological findings within psychiatric populations.

Cognitive Domains and Associated Brain Regions Before discussing the unique, and at times overlap- ping, cognitive impairments associated with mental health conditions, we feel it is pertinent to present descriptions of the cognitive domains included in this chapter. Although we briefly mention relevant brain structures associated with cognitive domains, this summary is not intended to be exhaustive. Readers are reminded that cognitive functions exist within a highly networked system, and although damage in a particular region may result in cogni- tive dysfunction, this does not necessarily indicate a direct structure-to-function relationship (Hebben & Milberg, 2009).

Attention. Attention extends well beyond the fundamental ability to encode information. Rather, attention is more appropriately defined and concep- tualized as a multipart process that includes (a) sen- sory selection, described as the filtering of relevant and irrelevant information, as well as the focusing and automatic shifting between incoming informa- tion; (b) response selection, which includes initiat- ing a response, inhibition of unselected responses, and active switching; (c) attentional capacity, which is dependent on arousal, effort, and motivation; and (d) sustained performance, which describes the ability to maintain attention, although performance

is influenced by vigilance and fatigability (Strauss, Sherman, & Spreen, 2006).

Assessment and description of attentional processes is complicated by a number of factors, including inconsistent use of terminology and overlap in attentional processes both conceptually (i.e., attentional processes cannot be evaluated in isolation and there is frequent overlap with other neurocognitive domains, such as executive func- tion) and in practice (i.e., frequent overlap in atten- tional processes assessed in a given test; Strauss et al., 2006).

Executive functioning. Perhaps even more so than attention, executive functioning represents the use of a single term to describe a multitude of func- tions. Multiple authors in the past 10 to 15 years have attempted to define the core aspects of execu- tive functioning (e.g., Baron, 2004; Gioia, Isquith, Guy, & Kenworthy, 2000; Lezak, Howieson, & Loring, 2004), with most authors describing a system that functions in a supervisory capacity and enables the execution of purposeful and goal- directed actions. This type of functioning is dependent on the ability to plan, respond, and flex- ibly adjust in response to changing information. Consequently, impairments in executive function- ing may result in alterations in social comportment, judgment, decision making, organizing and execut- ing behaviors, modifying and switching, and aspects of memory (J. G. Scott & Schoenberg, 2011).

Damage to the prefrontal lobes, particularly the orbital and medial regions, has consistently been associated with behavioral and personality changes. However, damage to limbic structures (e.g., amygdala), thalamic nuclei, and right hemisphere structures may also result in notable changes in per- sonality (e.g., apathy) and behavior (e.g., planning, organization, and execution).

Verbal and nonverbal memory. Memory includes three component processes: (a) encoding (the pro- cessing of information to be stored), (b) consolida- tion (strengthening of representations while stored), and (c) retrieval (accessing stored information). The studies included in this chapter typically focus on the encoding and retrieval of consciously learned and recalled information (i.e., declarative memory).

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Multiple brain regions are implicated in memory, including the temporal lobes, medial temporal struc- tures (i.e., hippocampus, entorhinal and perirhinal cortices, amygdala), diencephalon (i.e., thalamus, hypothalamus), and basal forebrain (see Kolb & Whishaw, 2003).

Visuospatial functioning. Visuospatial functioning encompasses higher order vision abilities, includ- ing visuoperception (i.e., identifying the object) and spatial processing (i.e., identifying the location of the object). A dorsal visual pathway, projecting from the primary visual field through the parietal lobe, has been shown to be involved in spatial process- ing, resulting in deficits in locating objects in space and hemispatial neglect. In contrast, a ventral visual pathway, connecting the striate and temporal lobe, has been associated with object identification; dam- age to this pathway results in impairments in face and object recognition.

Language. The assessment of language typically includes evaluation, whether formal or informal, of fluency, comprehension, and repetition. In addition, assessment of receptive and expressive vocabulary, naming, and word generation (i.e., phonemic [let- ter] and semantic [category] fluency) are commonly

included. The left hemisphere contains many of the critical areas for language production, including speech output (e.g., Broca’s area in the left prefrontal region) and comprehension (e.g., Wernicke’s area in the left temporoparietal region). Access to semantic information, on which naming tasks and semantic word generation tasks are dependent, is commonly associated with the functioning of the left anterior temporal lobe. In contrast, phonemic generation tasks are more broadly mediated by frontal- executive systems.

Motor functioning. Motor functioning is com- monly assessed via standardized tasks requiring manual dexterity and motor speed. However, it should also be noted that many motor tasks are also affected by attention, executive functioning, and visuospatial abilities.

Neurological and Neuropathological Factors Associated With Psychopathology In an effort to provide relevant background to understanding associated neuropathological cor- relates of psychiatric disorders, we present a brief reference table that provides an overview of relevant brain regions and associated functions and disorders (Table 4.1). Readers are encouraged to refer back to

TABLE 4.1

Relevant Brain Regions and Associated Functions and Disorders

Brain region and structure Function and involvement in mental

health conditions

Relevant mental health conditions

Limbic system Amygdalaa Sense and identify fear and anxiety; initiate

emotional response Anxiety disorders

Anterior cingulate cortexb Self-monitoring; motivation; sustained attention Depression; bipolar disorder; schizophrenia Cingulate gyrusa Involved in the emotional response Anxiety disorders Hippocampusa Potentially affected by neurochemical alterations Depression; bipolar disorder; posttraumatic stress

disorder Insular cortex Internal regulation system controlling

visceromotor, neuroendocrine, pulmonary systems, pain

Posttraumatic stress disorder; social anxiety disorder

Orbitofrontal cortexb Involved in the emotional response Depression; bipolar disorder; anxiety disorders Thalamusb Involved in emotional responding, homeostasis Depression; bipolar disorder Frontal cortexb Involved in control of the behavioral response;

social awareness Depression; bipolar disorder; anxiety disorders

Note. aBlumenfeld (2010). bHarrison (2002).

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this table as they progress through the neurological and neuropathological subsections relevant to each disorder. In addition, the role of soft neurologi- cal signs, describing abnormal motor, sensory, or integrative motor–sensory presentations that do not localize to a central nervous system lesion (Rossi, De Cataldo, et al., 1990), are also presented when relevant. Examples include motor impairments, such as dyspraxia (difficulty carrying out voluntary move- ments), dyskinesia (problems in movement), and impairments in sensory abilities such as left–right discrimination and stereognosis (the ability to per- ceive and recognize the form of an object without seeing it).

In the sections that follow, we describe several psychiatric conditions with prominent neuropsy- chological and neurological features: major depres- sive disorder, bipolar disorder, panic disorder, social phobia, generalized anxiety disorder, posttraumatic stress disorder (PTSD), and schizophrenia.

MAJOR DEPRESSIVE DISORDER

Major depressive disorder (MDD) is one of the most common mental health conditions in the United States, with a prevalence estimate of 6.7% among all U.S. adults (Substance Abuse and Mental Health Services Administration, 2014). Cognitive deficits associated with MDD, including attention, executive functioning, psychomotor and processing speed, and verbal and visual memory (immediate and delayed) are associated with psychosocial impair- ment (see Evans, Iverson, Yatham, & Lam, 2014, for a review).

Neuropsychological Findings

Intellectual functioning. The effect of MDD on intellectual functioning has been a topic of uncer- tainty for decades. Inconsistent findings may be, at least in part, attributable to variability in the clini- cal severity of the patient group, use of measures to assess intellectual functioning, and poorly matched control samples. The existence of intellectual dif- ferences between patients with MDD and healthy controls is equivocal; patients with MDD have been found to have IQs lower than (Sørensen, Sæbye, Urfer-Parnas, Mortensen, & Parnas, 2012), equal

to (Granick, 1963), and greater than (Robertson & Taylor, 1985) normal controls. In addition, research comparing currently depressed individuals, previ- ously depressed but currently euthymic individuals, and controls who have never been depressed has found that a history of depression (either current or lifetime) was associated with significantly worse per- formance on tests of global cognition (i.e., Dementia Rating Scale and Mini-Mental State Examination; Koenig et al., 2015).

The role of premorbid intellectual functioning on conferring risk for the development of depres- sion is also an area of extensive study. Higher child- hood cognitive abilities have been associated with fewer symptoms of depression and anxiety during adulthood (Hatch et al., 2007; Koenen et al., 2009). Cognitive reserve, conceptualized as a factor that may confer protection from or vulnerability for the clinical expression of sequelae associated with brain pathology (Stern, 2009), has been proposed as a fac- tor influencing risk for the development of depres- sion and other neuropsychiatric disorders (Barnett, Salmond, Jones, & Sahakian, 2006).

Attention and executive functioning. Attention and executive functioning are consistently identi- fied as areas of impairment among individuals with MDD. A systematic review and meta-analysis identi- fied high rates of reduced concentration and inde- cisiveness among individuals with MDD (Trivedi & Greer, 2014). This study also noted the not incon- sequential effects on function associated with these attentional impairments. Specific effects on selective attention (Landrø, Stiles, & Sletvold, 2001), work- ing memory (Cotrena, Branco, Shansis, & Fonseca, 2016; Landrø et al., 2001), focused and divided attention (Cotrena et al., 2016), and processing speed (Koenig et al., 2015) have also been identified.

MDD is also associated with deficits in aspects of executive functioning (e.g., Gohier et al., 2009). For example, Lee, Hermens, Porter, and Redoblado- Hodge (2012) identified small to medium effect size differences between patients experiencing their first episode of MDD and healthy controls on measures of attentional switching (Hedges’s g = .22) and cog- nitive flexibility (Hedges’s g = .53). Similarly, other meta-analyses have found MDD to be reliably asso- ciated with impaired performance on measures of

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executive functioning (Snyder, 2013; Wagner, Doer- ing, Helmreich, Lieb, & Tadić, 2012). There is also evidence that greater depression symptom severity may be associated with more impaired executive functioning (McDermott & Ebmeier, 2009).

Learning and memory. Reductions in learning and memory are prominent cognitive effects associated with MDD (Koenig et al., 2015). In fact, deficits in episodic memory are arguably the most prominent disturbance associated with depression (Zakzanis, Leach, & Kaplan, 1998). For example, Landrø et al. (2001) identified significantly worse verbal delayed memory (i.e., worse performance on seven sub- tasks, including a list learning paradigm, associative learning task, and short story, with delayed recall 4–5 minutes and 24 hours after initial exposure) among MDD patients compared with controls. Meta- analytic findings based on 14 studies of patients who varied in MDD duration also identified a posi- tive relationship between symptom severity and worse verbal episodic memory (weighted M = .31), but not visuospatial memory (weighted population effect size r = .11; McDermott & Ebmeier, 2009). In contrast, Lee et al. (2012) identified significant deficits in visual learning and memory in a sample of individuals in a first episode of MDD (Hedges’s g = .53)

Visuospatial functioning. Visuospatial impair- ment is less commonly identified among individuals with MDD; however, Koenig et al. (2015) reported significantly worse visuospatial abilities, includ- ing construction using colored blocks and drawing of simple and complex figures, among a sample of older adults (mean age = 72.51 years) with a history of depression, either current or lifetime, than among individuals without a history of depression. In addi- tion, Rossi, Stratta, et al. (1990) identified signifi- cantly worse performance among young to middle aged (mean age = 47 years) severely depressed patients than among controls on the Rey Complex Figure Task (J. E. Meyers & Meyers, 1995) copy and immediate recall trials.

Language. Phonemic fluency (i.e., a measure of the ability to generate words beginning with an identified letter; also referred to as letter fluency) has repeatedly been identified as an area of impairment

among individuals with MDD (Koenig et al., 2015; Landrø et al., 2001; Lee et al., 2012). Cross-sectional (Fossati, Amar, Raoux, Ergis, & Allilaire, 1999) and meta-analytic (Wagner et al., 2012) findings with patients with unipolar depression identified signifi- cant impairment in semantic fluency (i.e., a measure of the ability to generate words belonging to a spe- cific category). However, there is noted variability across studies, including assessment of verbal flu- ency (see Henry & Crawford, 2005, for a review and meta-analysis). Specifically, Henry and Crawford (2005) identified generally greater impairment on measures of semantic relative to phonemic fluency. However, when examining studies in which assess- ment of both semantic and phonemic fluency were included for the same participants, the deficit for semantic fluency was only marginally larger than the deficit for phonemic fluency (rs = .43 for semantic fluency and .39 for phonemic fluency), which was interpreted as suggesting a more generalized flu- ency deficit. Notably, a meta-analysis of 14 studies concluded that symptom severity is not significantly associated with poorer semantic memory (weighted population effect size r = .17; McDermott & Ebmeier, 2009).

Motor and sensory functioning. Psychomotor dis- turbance (i.e., slowing or retardation vs. agitation) is one of the only objectively measurable symptoms of endogenous depression (see Schrijvers, Hulstijn, & Sabbe, 2008, and Sobin & Sackeim, 1997, for reviews). Psychomotor retardation and agitation are not mutually exclusive. For example, a study of 23 hospitalized depressed patients identified increased frequency of self-touching but decreased direct eye contact, smiling, and eyebrow movement (Jones & Pansa, 1979). In addition, task complex- ity does not appear to modulate psychomotor symptoms, because Sabbe, Hulstijn, van Hoof, and Zitman (1996; Sabbe, Hulstijn, van Hoof, Tuynman- Qua, & Zitman, 1999) identified fine motor slowing on both less demanding tests (e.g., drawing lines and simple figures) and tests with greater cognitive effort (e.g., tasks requiring coordination, visuospa- tial storage, planning, and sequencing).

Evidence has suggested that age may influ- ence psychomotor disturbances, such that patients younger than age 40 are more likely to experience

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psychomotor retardation, and patients older than age 40 are more likely to experience agitation (Hamilton, 1967; Winokur, Morrison, Clancy, & Crowe, 1973). Sex may also affect psychomotor symptoms, although the findings are equivocal, and evidence ranges from suggesting that males experi- ence greater psychomotor retardation than females (Avery & Silverman, 1984; Winokur et al., 1973), females experience greater psychomotor retardation than males (Khan, Gardner, Prescott, & Kendler, 2002; Kornstein et al., 2000), to a lack of sex- dependent differences (Hildebrandt, Stage, & Kragh-Soerensen, 2003a, 2003b).

Changes in speech output are also commonly noted among depressed patients. Increased speech pause time (Greden, Albala, Smokler, Gardner, & Carroll, 1981; Hoffmann, Gonze, & Mendlewicz, 1985; Nilsonne, 1987; Szabadi, Bradshaw, & Besson, 1976), paucity of speech, slowed responses, mono- tonic phrases, and poor articulation (Hoffmann et al., 1985) are more frequently seen in depressed patients than in controls. Cannizzaro, Harel, Reilly, Chappell, and Snyder (2004) also identified a cor- relation between Hamilton Depression Rating Scale score (Hamilton, 1967) and slower speaking rate and reduced pitch variation.

One of the greatest concerns related to psycho- motor slowing among depressed individuals may be the association between psychomotor retarda- tion and slowed motor response and decision times (Lapierre & Butter, 1980). This finding may have real-world application in the performance of tasks such as driving, which requires rapid cognitive and motor responses. Bulmash et al. (2006) found that, after controlling for age and sleepiness, depressed, nonmedicated outpatients exhibited slower steering reaction times than did controls. They also had an increased number of crashes when tested on a driv- ing simulator.

Cognitive Functioning After Major Depressive Disorder Remission Findings reflect a persistence of cognitive deficits during MDD remission (Hammar, Lund, & Hugdahl, 2003; Neu, Kiesslinger, Schlattmann, & Reischies, 2001). Specific findings have identified continued impairment in attention (Bora, Harrison, Yücel, &

Pantelis, 2013; Paelecke-Habermann, Pohl, & Leplow, 2005) and executive functioning (Boeker et al., 2012; Paelecke-Habermann et al., 2005). The persistence of cognitive deficits after remission has been hypothesized to reflect trait features associ- ated with chronic MDD (e.g., Hammar et al., 2003; Paelecke-Habermann et al., 2005). In addition, others have proposed possible relations between the duration of illness and structural brain changes (e.g., Sheline, Sanghavi, Mintun, & Gado, 1999), which may also explain persisting deficits.

Interestingly, there is also evidence to support improvement in some aspects of cognitive function- ing during MDD remission. For example, memory deficits appear to be related to depression severity and, as a result, performances improve after remis- sion (Biringer et al., 2007; Boeker et al., 2012; Gualtieri, Johnson, & Benedict, 2006; Paelecke- Habermann et al., 2005). Notably, the literature examining cognitive functioning during remission is complicated by variable definitions to establish the extent of symptom remission, diverse methodological strategies, and heterogeneous clinical characteristics of patients (see Hasselbalch, Knorr, & Kessing, 2011, for a review).

Cognitive Effects Associated With Late-Life Major Depressive Disorder Late-life depression, defined as MDD in adults older than age 60, is of tremendous clinical con- cern. These individuals present with notable cogni- tive impairment that is significant in its own right. Impairments related to depression may also mask or confound the assessment and diagnosis of other neurological conditions affecting cognition (e.g., dementia). The nature of cognitive impairments associated with the onset of depression after age 60 appears to be broad, with noted deficits in process- ing speed and executive functioning (Alexopoulos, 2002). Additional deficits in psychomotor impair- ment (Beheydt et al., 2015), episodic memory, and visuospatial abilities are also commonly identified (Butters et al., 2004).

As with their younger counterparts, depressed older adults continue to experience cognitive symp- toms, particularly on executive tasks, processing speed, and working memory, after remission of

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mood symptoms (Butters et al., 2000; Nebes et al., 2003). In fact, treatment with pharmacotherapy has been found to have a limited effect on cogni- tion in depressed older adults (B. S. Meyers, Mattis, Gabriele, & Kakuma, 1991). Cognitive abilities also appear to be related to future symptomatology and functional outcomes; poor executive functioning in depressed older adults has been shown to predict greater functional disability (Kiosses & Alexopoulos, 2005).

Neurological and Neuropathological Findings

Neuropathology. Multiple neuropathological changes have been associated with MDD in adults. Frontal, midbrain, and limbic regions are most consistently implicated, with evidence of decreased volume in the frontotemporal region (Vasic et al., 2015), prefrontal cortex (PFC), dorsolateral prefron- tal cortex (DLPFC), subgenual region of the anterior cingulate cortex (ACC), basal ganglia, amygdala, and hippocampus (Campbell & MacQueen, 2006). There is also decreased density of neurons in the hippocampus (Tsopelas et al., 2011), orbito- frontal cortex (Cotter, Hudson, & Landau, 2005; Rajkowska et al., 1999), and PFC (Cotter et al., 2002; Rajkowska et al., 1999). In addition, a reduc- tion in the number and density of pyramidal cells in the orbitofrontal cortex and ACC and reductions in pyramidal cell volumes in the DLPFC (see Kim, Nunes, Oliveira, Young, & Lafer, 2016, for a review) have been described.

MDD has also been associated with altered brain network functioning. Specifically, relative to control participants, functional neuroimaging with individ- uals with MDD has demonstrated decreased activity in the DLPFC and increased activity in the ventro- lateral PFC (Brody, Barsom, Bota, & Saxena, 2001). Furthermore, there is evidence of particular abnor- malities in ACC and DLPFC inputs from the amyg- dala (Drevets, 2000), as well as reduced cerebral blood flow in the ACC and bilateral parahippocam- pal areas, with increased blood flow in the frontopa- rietal and striatal regions (Vasic et al., 2015).

Meta-analytic findings from fluorodeoxyglucose– positron emission tomography studies identified

lower metabolism in bilateral insula, left lentiform nucleus putamen, and right caudate and cingulate gyrus; however, right thalamus pulvinar and declive of the posterior limb and left culmen of vermis in the anterior lobe were significantly increased (Su et al., 2014). Furthermore, evidence of decreased metabolic activity during depressive episodes has also been identified in the DLPFC, dorsomedial PFC, subgenual region of the ACC, basal ganglia, and hippocampus, and increased activity has been identified in the ventrolateral and orbital PFC and amygdala (Davidson, Pizzagalli, Nitschke, & Putnam, 2002).

Soft neurological signs associated with MDD. Evidence has suggested that hypoesthesia of the malleolus (i.e., reduced sense of touch on the bony projections on the ankle) may be a soft neurological sign associated with MDD (Livianos et al., 2015). However, other studies have failed to identify signifi- cant differences in soft neurological signs between individuals with MDD and healthy controls using standard soft sign assessments, including motor coordination, sensory integration, and disinhibition (Zhao et al., 2013).

Conclusions Interpreting findings from the MDD literature is complicated by considerable variability in partici- pant inclusion/exclusion criteria, depression severity within patient groups, and control of factors with potential cognitive and/or neurologic sequelae (e.g., medications, psychotic symptoms) (Evans et al., 2014). Additionally, the role of effort and engage- ment must be considered when evaluating individu- als with MDD. For example, Rohling, Green, Allen, and Iverson (2002) found that depression had no effect on objective cognitive and psychomotor tests once patients with suboptimal effort were excluded from analyses.

BIPOLAR DISORDER

Bipolar disorder is a disabling illness (Harvey, Wingo, Burdick, & Baldessarini, 2010) associated with significant functional impairment during acute and remitted stages. In addition, bipolar disorder is

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a challenging condition to treat, and relapse rates are high even after psychopharmacological interven- tion. For example, Gitlin, Swendsen, Heller, and Hammen (1995) found that 37% of participants diagnosed with bipolar disorder and followed in an outpatient clinic experienced a recurrence of a manic or depressive episode within 1 year. More- over, two thirds of individuals who relapsed experi- enced multiple relapses.

Per the diagnostic criteria of the DSM–5 (Ameri- can Psychiatric Association, 2013), bipolar I disor- der is characterized by the occurrence of at least one manic episode, with many individuals also experi- encing one or more depressive episodes. Diagnosis of bipolar II requires current or past hypomanic episode as well as current or past major depressive episode.

Cognitive impairment in bipolar disorder is not a core diagnostic criterion. However, given evidence of neurocognitive deficits across all stages of bipolar illness (manic, depressed, and euthymic), neurocog- nitive deficits have been proposed as an endopheno- type (Hasler, Drevets, Gould, Gottesman, & Manji, 2006). Further evidence for this proposal comes from findings indicating that first-degree relatives of individuals with bipolar disorder, who are pre- sumably at particularly elevated risk of developing a mood disorder, perform worse on tasks of verbal declarative memory as well as on some aspects of executive functioning (Robinson & Ferrier, 2006). This finding has been interpreted as suggesting that cognitive impairment may be a trait vulnerability factor for bipolar disorder that is present before the onset of clinical symptoms and that worsens as the illness progresses.

Neuropsychological Findings

Intellectual functioning. Research on intellectual functioning among patients with bipolar disorder has generally suggested that they perform about as well as healthy controls (e.g., Mann-Wrobel, Carreno, & Dickinson, 2011). However, some reports have suggested that bipolar patients may have premorbid intellectual deficits. For example, Trotta, Murray, and MacCabe (2015) identified small yet significant deficits in premorbid intellectual

functioning when it was assessed retrospectively, but not prospectively.

Attention and executive functioning. Multiple aspects of attention, including sustained atten- tion, psychomotor speed, and processing speed, have consistently been identified as impairments among individuals with bipolar disorder relative to healthy control participants (Kurtz & Gerraty, 2009). Vrabie et al. (2015) identified significantly worse performance on measures of attention, psy- chomotor speed, and processing speed, regardless of disease stage (manic–hypomanic, depressed, or euthymic). In meta-analytic comparisons between healthy control participants and euthymic bipolar patients, small effect size differences were identified for auditory attention, and moderate to large effect size differences were identified for sustained visual vigilance and speeded visual scanning (Arts, Jabben, Krabbendam, & van Os, 2008; Bora, Yucel, & Pantelis, 2009; Kurtz & Gerraty, 2009). Bonnín et al. (2012) similarly found that subsyndromic euthymic bipolar patients demonstrated slower psychomo- tor speed relative to healthy controls. In this study, even asymptomatic euthymic patients demonstrated significantly worse performance, relative to healthy controls, on measures of psychomotor and process- ing speed.

Comparisons between healthy controls and depressed bipolar patients have revealed deficits in visual scanning (Kurtz & Gerraty, 2009), as well as large effect size differences in processing speed (Gallagher, Gray, Watson, Young, & Ferrier, 2014). Large effect size differences were also found in com- parisons between healthy controls and individuals in mixed or manic states for sustained attention and rapid visual scanning (Kurtz & Gerraty, 2009).

Deficits in working memory have also been con- sistently identified across different bipolar states, including euthymia (Bora et al., 2009; Kurtz & Gerraty, 2009; Vrabie et al., 2015), mania– hypomania (Vrabie et al., 2015), and depression (Gallagher et al., 2014; Vrabie et al., 2015). Con- sistent impairments in executive functioning are similarly found across bipolar states (Martínez-Aran, Vieta, Reinares, et al., 2004; Vrabie et al., 2015). Rel- ative to healthy controls, euthymic bipolar patients

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demonstrated impairments in multiple aspects of executive functioning, including large effect size dif- ferences in working memory (Robinson & Ferrier, 2006), inhibition, and set shifting (Arts et al., 2008; Bora et al., 2009; Kurtz & Gerraty, 2009), as well as moderate to large effect size differences for concep- tual shifting, novel problem solving, perseveration (Bora et al., 2009; Kurtz & Gerraty, 2009; Robinson & Ferrier, 2006), speeded set shifting, sustained visual and auditory attention, and response inhibition (Robinson & Ferrier, 2006). Furthermore, Martínez- Arán, Vieta, Colom, et al. (2004) reported signifi- cantly worse performance on multiple measures of executive functioning among remitted patients in a euthymic state, even after controlling for the effects of subclinical symptomatology, age, and premorbid IQ. Even among subsyndromic euthymic bipolar patients, Bonnín et al. (2012) identified worse per- formance on set switching. Moderate effect size differences in set switching (d = 0.64) have been identified among depressed and mixed or manic bipolar patients, and large effect size differences in perseverations among mixed or manic bipolar patients have also been noted (Kurtz & Gerraty, 2009).

Learning and memory. Deficits in verbal learn- ing and memory are commonly and consistently identified among patients with bipolar disorder, regardless of their clinical state (Gallagher et al., 2014; Goswami et al., 2006; Martínez-Arán, Vieta, Reinares, et al., 2004; Robinson & Ferrier, 2006). Kurtz and Gerraty (2009) identified large effect size differences in verbal learning for euthymic, mixed or manic, and depressed patient groups, as well as large effect size differences in delayed recall for mixed or manic patients and moderate differences for euthymic patients. Bonnín et al. (2012) also identi- fied verbal learning and recall deficits in subsyn- dromic euthymic bipolar patients and asymptomatic patients, relative to healthy controls, and Malhi et al. (2007) reported more pronounced deficits in verbal memory during episodes of hypomania and depression among patients diagnosed with bipolar I disorder. Interestingly, Vrabie et al. (2015) found that manic patients showed greater verbal memory deficits than depressed, mixed, and euthymic

subgroups. Deficits in nonverbal memory have also been identified in bipolar patient groups (Bora et al., 2009), and Martínez-Arán, Vieta, Reinares, et al. (2004) reported differences between depressed patients and controls in visual learning as well as differences between both acute clinical groups and controls in visual recall.

Visuospatial functioning. Deficits in visual per- ception and visuospatial functioning in individuals with bipolar disorder are comparatively less severe relative to well-established attention, executive func- tioning, and memory deficits. Meta-analytic findings focused on patients in the euthymic stage of bipolar disorder have demonstrated small to moderate effect size differences relative to healthy controls on mea- sures of visuoperception (i.e., copying a complex figure and ability to reproduce visually presented designs using colored blocks; Arts et al., 2008; Kurtz & Gerraty, 2009). In addition, Gallagher, Gray, and Kessels (2015) reported differences among indi- viduals in a depressive episode, relative to healthy controls, on an object-location binding task.

Language. Impairment within the language domain is quite variable and dependent on the cog- nitive task and stage of the disease. For example, the existence of differences between semantic and phonemic fluency (ability to generate words belonging to a particular category or starting with a particular letter, respectively) among patients in the euthymic stage of bipolar disorder is equivocal, with some studies reporting greater impairment in semantic fluency (Arts et al., 2008; Martínez-Arán, Vieta, Colom, et al., 2004; Robinson & Ferrier, 2006), some studies reporting greater impairment in phonemic fluency (Bonnín et al., 2012), and some studies reporting comparable impairment in both (Kurtz & Gerraty, 2009). Furthermore, although Vrabie et al. (2015) reported worse performance on both semantic and phonemic fluency tasks across bipolar stages, individuals in a depressive stage were more impaired relative to other bipolar patients and healthy controls. Additional findings further sup- port impairment in both phonemic and semantic fluency among patients in mixed or manic stages (Kurtz & Gerraty, 2009), as well as impairment in

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phonemic fluency among patients in a depressed stage (Kurtz & Gerraty, 2009; Martínez-Arán, Vieta, Reinares, et al., 2004).

Motor and sensory functioning. Evidence of structural changes in the cerebellum (Baldaçara et al., 2011; Moorhead et al., 2007) has supported recent evidence of impaired implicit motor learning (i.e., learning a sequence of button presses with- out instruction) in bipolar patients compared with healthy controls (Chrobak et al., 2015).

Neurological and Neuropathological Findings

Neuropathology. Neuropathological changes in patients with bipolar disorder have implicated reduced hippocampal volume (Quigley et al., 2015) and frontal cortical volume (Abé et al., 2015; López-Larson, DelBello, Zimmerman, Schwiers, & Strakowski, 2002), as well as reduced gray and white matter volumes in the posterior cingulate bilaterally, right thalamus, cerebellum bilaterally, and left posterior limb of the internal capsule (Sani et al., 2016; see Haldane & Frangou, 2004, for a review).

Soft neurological signs associated with bipolar disorder. Soft neurological signs appear to be significantly increased among patients with bipolar disorder compared with healthy controls (Goswami et al., 2007; Nasrallah, Tippin, & McCalley-Whitters, 1983; Negash et al., 2004). Among a sample of euthymic patients with bipolar disorder, prevalence of soft neurological signs was high, with 54% dem- onstrating parkinsonism, 27% reporting akathisia, and 11% presenting with dyskinetic movements (Goswami et al., 2006). In addition, Mrad, Wassim Krir, Ajmi, Gaha, and Mechri (2016) reported higher prevalence and scores on a measure of soft neuro- logical signs among euthymic patients with bipolar disorder and their psychiatrically healthy siblings, compared with unrelated control participants.

Conclusions Multiple clinical factors have been associated with neuropsychological dysfunction in bipolar disorder. Broadly, greater cognitive impairment has been associated with worse course of illness, particularly

with respect to the number of manic episodes, hospitalizations, and length of illness (Robinson & Ferrier, 2006), which is likely attributable to a complex combination of genetic, environmental, neurodevelopmental, and medication-related fac- tors, as well as possible medical or psychiatric comorbidities (Balanzá-Martínez et al., 2010). Specifically, longer duration of illness and greater number of hospitalizations, suicide attempts, and manic episodes have been associated with greater memory dysfunction, and longer duration of illness was associated with diminished attention, slowness, and perseveration (Martínez-Arán, Vieta, Colom, et al., 2004). Significant clinical heterogeneity, including symptom severity, predominating symp- toms (mania or depression), age at symptom onset, duration of illness (Robinson & Ferrier, 2006), number of prior manic or depressive episodes (Nehra, Chakrabarti, Pradhan, & Khehra, 2006), duration of clinical stages (manic, depression, and euthymia), and other comorbidities complicate interpretation of the literature. In addition, many of these clinical factors, as well as other methodologi- cal and statistical factors, and within-participant factors (e.g., engagement, self-esteem, sensitivity to perceived feedback) may exert a potential influence on cognitive function (Porter, Robinson, Malhi, & Gallagher, 2015).

ANXIETY DISORDERS

The DSM–5 includes a number of conditions under the umbrella of anxiety disorders, including panic disorder, social phobia, and generalized anxiety disorder, as well as a number of less commonly diagnosed or studied conditions not described in detail here. Anxiety disorders cost the United States billions in health care costs (Greenberg et al., 1999), and they are also associated with significant func- tional disability (e.g., Alonso et al., 2004), particu- larly among those with social anxiety and multiple anxiety disorders (Hendriks et al., 2014).

Patients commonly report cognitive symptoms of varying severity with anxiety. Although the pres- ence and severity of cognitive problems on formal objective testing varies, a number of key similarities, including deficits in complex attention, executive

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functioning, encoding, and free retrieval of infor- mation, are present across the spectrum of anxiety disorders. We focus our discussion on cognitive symptoms associated with panic disorder, social phobia, and generalized anxiety disorder.

Neuropsychological Findings

Intellectual functioning. The evidence support- ing differences in estimated intellectual functioning between individuals with anxiety and healthy con- trols is minimal. In a study comparing individuals with panic disorder, individuals with social phobia, and healthy controls, Asmundson, Stein, Larsen, and Walker (1994) found no difference between anxiety disorder patients and healthy controls on measures of vocabulary or similarities as measured by the Wechsler Adult Intelligence Scales—Revised. However, this study did identify significant dif- ferences between the clinical groups and healthy controls on a measure of visuoconstruction (i.e., creating designs using colored blocks; Asmundson et al., 1994).

Attention and executive functioning. Deficits in cognitive processing speed on a task requiring the transcription of digit–symbol pairs has been identified among individuals with social phobia (O’Toole, Pedersen, Hougaard, & Rosenberg, 2015). However, on a less complicated visual process- ing task (Trails A completion time and accuracy), Airaksinen, Larsson, and Forsell (2005) found no differences in performance between individuals with any anxiety disorder compared with healthy control participants. Similarly, there were no identified dif- ferences between anxiety subtypes on this measure (Airaksinen et al., 2005). It would appear, on the basis of these findings, that task complexity plays a role in visual processing performance. Executive dysfunction, particularly set-shifting completion time, has also been identified among individu- als with anxiety more generally (Airaksinen et al., 2005), as well as specifically among individuals with panic disorder (L. J. Cohen et al., 1996).

Learning and memory. Verbal memory deficits have been identified in numerous patient groups, including individuals with social phobia (Airaksinen

et al., 2005; Asmundson et al., 1994; O’Toole et al., 2015; although see Sachs et al., 2004), and panic disorder (Airaksinen et al., 2005; Asmundson et al., 1994). In fact, in the sample of patients examined by Asmundson et al. (1994), approximately 22% of those diagnosed with social phobia and 50% of individuals diagnosed with panic disorder were at least 2 or more standard deviations below the mean on a word-list learning task. Evidence has also sup- ported deficits in nonverbal memory among patients with social phobia compared with healthy controls matched for education and general cognitive ability (O’Toole et al., 2015).

Visuospatial functioning. Visuospatial deficits, including construction accuracy (O’Toole et al., 2015), visuospatial processing (e.g., block design; Asmundson et al., 1994, L. J. Cohen et al., 1996), and cube drawing (Hollander et al., 1996), have been identified among individuals with social phobia.

Language. Decreased verbal fluency, including reduced phonemic (Airaksinen et al., 2005; O’Toole et al., 2015) and semantic fluency (O’Toole et al., 2015), has been identified among individuals with social phobia.

Motor and sensory functioning. No specific defi- cits in motor or sensory functioning are commonly reported among individuals with social phobia or panic disorder.

Neurological and Neuropathological Findings

Neuropathology. Structural abnormalities involv- ing the cingulate cortex, precentral gyrus, precu- neus, and temporal and frontal gyrus (De Bellis et al., 2002; Strawn et al., 2013) have been identified in individuals with generalized anxiety disorder. Functional abnormalities have also been identi- fied in this group, including resting state abnor- malities involving amygdala circuits (Etkin, Prater, Schatzberg, Menon, & Greicius, 2009; Liu et al., 2015), as well as task-related changes in PFC and ACC (see Mochcovitch, da Rocha Freire, Garcia, & Nardi, 2014, for a review).

Among those diagnosed with panic disorder, structural changes in the amygdala (Massana et al.,

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2003a), parahippocampal gyrus, caudate nucleus, basal ganglia, insula (Lai, 2011; Massana et al., 2003b), ACC, and frontal and temporal areas (Asami et al., 2008; Han et al., 2008; Sobanski et al., 2010) have been identified. Functional abnormalities during functional MRI have also been identified in many of these regions. Specifi- cally, increased activation in the amygdala, insula, and hippocampus during the presentation of ago- raphobic-specific stimuli (Wittmann et al., 2011), and increased activation in the right inferior frontal area and cingulate cortex during panic anticipation and imagery exposure (Bystritsky et al., 2001) have been identified. Furthermore, abnormal functional connectivity within the default mode network (Y. W. Shin et al., 2013) and salience network (Pannekoek et al., 2013) have also been high- lighted. Interestingly, evidence has not pointed to a clear pattern of structural changes associated with social phobia (e.g., Potts, Davidson, Krishnan, & Doraiswamy, 1994).

Soft neurological signs associated with anxiety disorders. Soft neurological signs, including cube drawing and mirror movement impairments, have been identified among individuals with social pho- bia (Hollander et al., 1996).

Conclusions Deficits in attention, executive functioning, learning and memory, visuospatial functioning, and language have been identified among patients with social anxiety and panic disorder. However, the literature examining neurocognitive functioning in these populations is relatively small and may benefit from further examination using clinical and experimental paradigms, with particular attention to symptom severity and comorbid conditions.

POSTTRAUMATIC STRESS DISORDER

The cognitive sequelae and related neuroimaging correlates of PTSD have been studied extensively. We present a brief review here; however, we also refer the reader to several excellent review references detailing this topic (Aupperle, Melrose, Stein, & Paulus, 2012; Hayes, Vanelzakker, & Shin, 2012; Qureshi et al., 2011; Vasterling & Brewin, 2005).

Neuropsychological Findings

Intellectual functioning. Pretrauma intelligence has been found to predict PTSD diagnosis after trauma exposure (see Bomyea, Risbrough, & Lang, 2012, for a review). In addition, PTSD symptom severity, as measured by the Clinician Administered PTSD Scale (Blake et al., 1995), has been found to be negatively correlated with estimated IQ (Gurvits et al., 2000), suggesting that it is not simply the dichotomous diagnosis but rather the potential severity of the symptoms that may contribute to a reduction in per- formance on measures assessing intelligence.

Attention and executive functioning. Deficits in attention and executive functioning are com- monly identified among individuals with PTSD (B. E. Cohen et al., 2013; Koso & Hansen, 2006). For example, Jenkins, Langlais, Delis, and Cohen (2000) identified worse performance on measures of sustained attention, digit span, processing speed (i.e., rapid transcription of digit–symbol pairs), and set shifting among rape survivors with and without PTSD. Vasterling et al. (2002) similarly identified impairments in basic (i.e., Digit Span), and sus- tained attention on the Continuous Performance Test among Vietnam veterans with PTSD; sus- tained attention deficits were similarly found among Operation Desert Storm (Vasterling, Brailey, Constans, & Sutker, 1998) and Bosnian combat veterans with PTSD (Koso & Hansen, 2006).

Learning and memory. Studies have also indicated that individuals with PTSD performed significantly worse on verbal learning (B. E. Cohen et al., 2013; Vasterling et al., 2002; Yehuda, Golier, Tischler, Stavitsky, & Harvey, 2005) and memory trials (Yehuda et al., 2005). Nonverbal learning has been shown to be impaired among veterans with PTSD (Vasterling et al., 1998), although not consistently (e.g., Gilbertson et al., 2006).

Visuospatial functioning. Visuospatial functioning has been less well studied among individuals with PTSD.

Language. Significantly worse semantic fluency, relative to healthy controls, has been identified among adults with PTSD (B. E. Cohen et al., 2013). In addition, Koso and Hansen (2006) identified

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impairment among veterans with PTSD, relative to age and IQ-matched trauma-exposed veterans with- out PTSD, on a sentence completion task.

Motor and sensory functioning. Assessment of motor and sensory functioning that is independent of processing speed or executive demands has been less well studied among individuals with PTSD.

Neurological and Neuropathological Findings

Neuropathology. The literature examining neu- ropathological markers among individuals with anxiety has largely focused on those with PTSD. Structural abnormalities in this diagnostic group are typified by reduced anterior cingulate (e.g., Rauch et al., 2003) and hippocampal volumes (Gurvits et al., 1996; although see Golier et al., 2005). The literature examining functional changes among indi- viduals with PTSD is also quite extensive (see Hayes et al., 2012, for a review). A number of functional imaging studies have identified increased activ- ity in the amygdala in response to trauma-related stimuli (Pissiota et al., 2002; L. M. Shin et al., 2004) and trauma-unrelated affective stimuli (L. M. Shin et al., 2005). However, these findings are not uni- versal (e.g., Hayes et al., 2011). Similarly, findings are also mixed with regard to hippocampal activity in those with PTSD, such that there is evidence for both increased (Thomaes et al., 2009) and decreased (Bremner et al., 2003; Hayes et al., 2011) activity in response to emotionally salient stimuli. Dysfunction in neural circuits involved in attention and emo- tional processing has also been identified, specifi- cally increased dorsolateral and ventromedial PFC activity in response to threat stimuli (Hayes, Labar, Petty, McCarthy, & Morey, 2009) and reduced dorso- lateral PFC activity in response to nonthreat stimuli (Hayes et al., 2009; Morey, Petty, Cooper, Labar, & McCarthy, 2008).

Soft neurological signs associated with PTSD. Among both combat veterans and women with a history of childhood sexual abuse, individu- als with PTSD had a greater than average number of soft neurological signs than individuals with similar trauma exposure without PTSD. Furthermore, PTSD

symptom severity, as assessed using the Clinician Administered PTSD Scale (Blake et al., 1995), was significantly correlated with an average number of soft neurological signs (Gurvits et al., 2000).

Conclusions Overall, the literature supports significant neuro- cognitive effects associated with PTSD, including deficits in verbal learning and memory, rapid infor- mation processing, attention, and working memory (J. C. Scott et al., 2015). However, examination of the PTSD literature highlights several challenges in interpreting existing findings. The role of symptom severity is one that must be considered, particularly because it has been found to be significantly associ- ated with worse performance on multiple aspects of cognitive functioning, even after adjusting for demo- graphics (L. J. Cohen et al., 2013). Furthermore, the potential influence of comorbid conditions, includ- ing depression and other anxiety disorders, is one that must be considered both clinically and in evalu- ating the literature.

SCHIZOPHRENIA

The literature examining cognitive factors associated with schizophrenia and psychotic spectrum disor- ders is extensive; the reader is referred to several well-written review articles for additional informa- tion (Barch & Sheffield, 2014; Madre et al., 2016; Tolman & Kurtz, 2012). The relationship between cognitive deficits and functional impairment among individuals with schizophrenia has been well sup- ported (Green, Kern, & Heaton, 2004), and concep- tualization of cognitive deficits as discrete areas of weakness is now being replaced by a view reflect- ing a more global deficit across cognitive domains (Gold & Dickinson, 2013).

In addition, although a full review of these find- ings is outside the scope of this chapter, it is worth noting that evidence from the second phase of the North American Prodrome Longitudinal Study (Seidman et al., 2016) has indicated that attention, working memory, and declarative memory abilities may be strong predictors of conversion to psycho- sis among those considered to be clinically high risk. Investigators in this study have suggested that

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interventions targeting neurocognitive functioning may be particularly important among those at high risk for psychosis.

Neuropsychological Findings

Intellectual functioning. Meta-analysis has dem- onstrated impairments in premorbid (Woodberry, Giuliano, & Seidman, 2008) and current intellectual functioning among individuals with schizophre- nia. Compared with healthy control participants, Woodberry et al. (2008) reported a 0.5 standard deviation impairment in premorbid intelligence in individuals who went on to develop psychotic symp- toms. Comparisons between individuals with schizo- phrenia and control samples have reflected medium to large effect sizes (Heinrichs & Zakzanis, 1998).

Attention and executive functioning. Impairments on tasks requiring auditory attention (i.e., Digit Span), psychomotor speed (i.e., Trails A), rapid alternation between sets of information (i.e., Trails B), and sustained attention (e.g., Continuous Performance Test) are commonly identified among individuals with schizophrenia (Heinrichs & Zakzanis, 1998). Deficits in working memory are among the most commonly reported in schizophre- nia (see Forbes, Carrick, McIntosh, & Lawrie, 2009, for a review; Van Snellenberg et al., 2016). Given a lack of difference between phonological and visuo- spatial working memory functioning, a more general- ized deficit in the central executive resource system, responsible for maintaining and modulating informa- tion over time, has been proposed to explain working memory impairments in this population (Barch & Sheffield, 2014). Finally, performance on more complex measures of executive functioning requir- ing novel problem solving, flexibility, and learning from feedback (i.e., the Wisconsin Card Sorting Task) is frequently impaired in this clinical group (Heinrichs & Zakzanis, 1998). However, findings from this meta-analytic study have also noted a rela- tionship between the Wisconsin Card Sorting Task and intelligence, suggesting that impaired perfor- mance on this test may be a reflection of low general intellectual abilities (Heinrichs & Zakzanis, 1998).

Learning and memory. Impairments in verbal declarative memory are consistently reported among

individuals with schizophrenia (see Stone & Hsi, 2011, for a review), with effect sizes ranging from 1.0 to 1.5 standard deviations below comparison populations (Cirillo & Seidman, 2003; Heinrichs & Zakzanis, 1998). Deficits are greatest in the learn- ing and encoding stage of memory (Cirillo & Seidman, 2003), relative to retrieval and recognition. Nonverbal memory performance is also impaired within this group, but greater heterogeneity across studies suggests that performance within this spe- cific domain may be less reliable relative to verbal memory deficits (Heinrichs & Zakzanis, 1998).

Visuospatial functioning. Visuospatial functioning is less commonly assessed in studies on schizophre- nia. Heinrichs and Zakzanis (1998) reported moder- ate effect sizes, in the range of 0.46 for Block Design, 0.60 for Line Orientation (judgment of line angles), and 0.61 for Facial Recognition, relative to compari- son groups. Similar effect sizes were also reported by Dickinson, Ramsey, and Gold (2007).

Language. Performance on verbal fluency mea- sures is also reflective of significant impairment (large Cohen’s d; Dickinson et al., 2007; Heinrichs & Zakzanis, 1998).

Motor and sensory functioning. Dickinson et al. (2007) reported moderate (finger tapping bilater- ally) to large (grooved pegboard bilaterally) effect sizes between individuals with schizophrenia and control samples. In addition, there is evidence of greater involuntary dyskinetic movement abnor- malities among children with multiple antecedents of schizophrenia (e.g., dyskinetic movements, psy- chotic-like experiences), who are considered to be at increased risk of future schizophrenia spectrum disorders, compared with children without such antecedents (MacManus et al., 2012).

Neurological and Neuropathological Findings

Neuropathology. Meta-analysis of 52 cross- sectional and 16 longitudinal studies identified reductions in both whole brain and hippocampal volume, as well as increased ventricular volume, in individuals with schizophrenia compared with healthy controls (Steen, Mull, McClure, Hamer, &

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Lieberman, 2006). Evidence of abnormal neural connectivity was identified in both first-episode and chronic schizophrenia patients; however, there is considerable heterogeneity between studies (see Wheeler & Voineskos, 2014, for a review).

Soft neurological signs associated with schizophrenia. The literature on neurological soft signs in schizophrenia is extensive, with demon- strated relationships to structural and functional abnormalities (see Hüfner, Frajo-Apor, & Hofer, 2015, for a review). Total score on a measure of neu- rological soft signs, including sensory integration, motor coordination, motor sequencing, and other neurological impairments, was positively correlated with aspects of cognition, including spatial working memory and complex set shifting in both controls and individuals with schizophrenia (Arabzadeh et al., 2014). Furthermore, Bachmann, Degen, Geider, and Schröder (2014) described variability in neurological soft signs over the course of the disor- der, although these soft signs were in almost all cases found to decrease alongside psychiatric symptoms.

Conclusions The literature focused on cognitive factors associated with schizophrenia is rich and evolving. Given the strong relationship between cognition and functional impairment within this population, there is a criti- cal need to improve the ability to address cognitive deficits and their effects on daily activities and social functioning (Green, 2016). The development of cog- nitive remediation programs focused on schizophre- nia is an area of great interest, and such programs have demonstrated effectiveness in this population (see Kaneko & Keshavan, 2012, for a review).

CONCLUSION

Cognitive dysfunction within the context of psy- chopathology is common and may contribute to the high rates of functional impairment found within psychiatric groups. Comparisons across psychiatric conditions underscore a number of common areas of cognitive dysfunction, including attention, memory, and execution of complex cognitive tasks (i.e., exec- utive functioning). Given these overlapping areas of dysfunction, neuropsychological assessment cannot,

at this time, function as a diagnostic test for psycho- pathology. However, neuropsychological assessment has the potential to clarify cognitive strengths and weaknesses, inform treatment, and contribute to dif- ferential diagnosis.

Because future research and clinical efforts are likely to be informed by a transdiagnostic approach, understanding common mechanisms of dysfunction from both cognitive and neurological–neuropathological views will be of increasing importance. Incorporating neuropsy- chological assessment into mental health treatment has the potential to contribute to improving the understanding of the cognitive impairments asso- ciated with psychiatric conditions and to use this knowledge to inform the treatment of individuals with these conditions.

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