Dysfunction of social cognition and behavior.

Review Article Address correspondence to Dr Bradford C. Dickerson, Frontotemporal Disorders Unit, Massachusetts General Hospital, 149 13th Street, Suite 2691, Charlestown, MA 02129, [email protected]. Relationship Disclosure: Dr Dickerson receives personal compensation as a consultant from FORUM Pharmaceuticals, Med Learning Group, and Merck & Company, Inc, and receives royalties from Oxford University Press. Unlabeled Use of Products/Investigational Use Disclosure: Dr Dickerson reports no disclosure. * 2015, American Academy of Neurology.

Dysfunction of Social Cognition and Behavior Bradford C. Dickerson, MD ABSTRACT Purpose of Review: Neurologists have generally paid relatively little attention to social behavior and its disorders. As a result, many individuals with suspected brain disorders primarily involving changes in social behavior have sought evaluations by psychiatrists or psychologists. This review summarizes recent findings from the growing field of social neuroscience and illustrates the relevance of this knowledge for the neurologist by reviewing contemporary research on frontotemporal dementia and its differential diagnosis. Recent Findings: An explosion of research over the past 10 to 15 years has illuminated specific psychological processes involved in core facets of social behavior and their neural bases. In parallel, knowledge of the genetics, neurobiology, neuroimaging features, and clinical phenomenology of frontotemporal dementia has grown dramatically. Summary: As the understanding of specific component processes involved in social behavior and their neural underpinnings deepen, neurologists may lead the way in using this knowledge to provide sophisticated evaluation and monitoring for patients with disorders of social behavior and ultimately may develop new therapeutic options to treat these brain disorders. Continuum (Minneap Minn) 2015;21(3):660–677.

INTRODUCTION People are among the most social of animals. We play, work, eat, and compete with one another. Yet people differ greatly from one another with regard to their tendencies to connect emotionally and empathize with others, infer the motivations or thoughts of others, maintain social networks, and follow common social norms. This normal variability in facets of sociability is increasingly being understood through the lens of neuroscience, but it presents challenges to the clinician who is confronted by the question of impaired social behavior in a patient. While abnormalities of social behavior have long been the domain of the psychiatrist, neurologists and neuropsychologists are increasingly recognizing the need to move beyond a focus on perception, action, and cognition and into the domain of social cognition and behavior. This review presents the author’s

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view of social behavior and its impairment, surveys the variability of normal social behavior, summarizes literature on the functional neuroanatomy of social behavior from a brain systems perspective, and discusses disordered social cognition and behavior and their assessment, with an emphasis on frontotemporal dementia (FTD). Another major illness of brain systems subserving social behavior, the autism spectrum disorders, is reviewed in the article ‘‘Neurodevelopmental Behavioral and Cognitive Disorders’’ by Shafali Jeste, MD, in this issue of . VARIABILITY IN NORMAL HUMAN SOCIAL BEHAVIOR Humans tend to maintain between 6 and 20 emotionally close relationships but vary substantially in their number of relatively weaker relationships.1 The size of social networks has been shown to decrease

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with age and increase with level of education, emotional intelligence, and self-monitoring abilities (people with high self-monitoring abilities, a personality construct, tend to modify their behavior substantially depending on the situational context). Yet contrary to what might be expected, no clear and consistent link exists between measures of personality, such as extraversion, and social network size.2,3 For humans, larger social networks confer benefits. Individuals who maintain more relationships experience positive health outcomes from lower rates of mortality4 to increased survival from heart attacks,5 whereas those who are more socially isolated are more susceptible to health problems.6 Although belonging to a larger social network results in demonstrable benefits, forming and managing more relationships requires investing more cognitive and emotional resources into relationships. Recent studies have begun to identify some of the neuroanatomic and neural system underpinnings of individual differences in social network size and related aspects of sociability.7 As in other domains of cognition, social information processing relies initially on attending to, perceiving, and decoding relevant cues. As with other types of information, the value of social information received through the senses is processed by primitive and rapid emotion-driven mechanisms; this firstlevel processing enables a rapid decision about whether to immediately approach or avoid another person, similarly to how objects are processed. Perceptual information about social stimuli is then more elaborately processed via mechanisms that may reach conscious awareness, including decoding the potential thoughts, emotions, and intentions of another person. This information is further embellished using knowledge (semantic memory) about social conContinuum (Minneap Minn) 2015;21(3):660–677

cepts and normative behavior appropriate for the context, as well as memory from past experiences. Once social information is perceived, decoded, and interpreted, a behavioral response can be selected, planned, and enacted, usually invoking executive and regulatory processes. These processes are reviewed in detail in this article, and their anatomic basis is discussed. Figure 5-1 illustrates the large-scale circuits involved in social behavior. SENSORY PERCEPTUAL SYSTEMS The exchange of information between individuals (social signals) necessarily engages multiple sensory systems involved in detecting and interpreting this information. In humans, the detection of socially relevant information relies heavily on visual and auditory processes in addition to somatosensory and, to a lesser degree, olfactory sensory processes.8 In the visual domain, a number of cortical regions are specialized for the processing of social information. Within the fusiform gyrus, a region called the fusiform face area is engaged by various visual stimuli but more robustly by faces, while the extrastriate body area in the lateral occipitotemporal cortex responds to images of parts of the body. Based on functional neuroimaging and human lesion studies, these processes appear to be bilateral but are usually right hemisphere dominant.9 The direction and movement of another person’s gaze and so-called ‘‘biological movement’’ (such as postures and gait) are processed by the superior temporal sulcus. This information is further processed along more rostral areas of the temporal cortex and prefrontal cortex to more fully interpret its meaning and relevance. The amygdala plays a central role in processing social visual information, receiving input from many of these regions as well as subcortical structures such as the superior

KEY POINTS

h People differ greatly from one another with regard to their tendencies to connect emotionally and empathize with others, infer the motivations or thoughts of others, maintain social networks, and follow common social norms. This normal variability in facets of sociability is increasingly being understood through the lens of neuroscience, but it presents challenges to the clinician who is confronted by the question of impaired social behavior in a patient.

h Larger social networks confer benefits. Individuals who maintain more relationships experience positive health outcomes from lower rates of mortality to increased survival from heart attacks, whereas those who are more socially isolated are more susceptible to health problems.

h The exchange of information between individuals (social signals) necessarily engages multiple sensory systems involved in detecting and interpreting this information. In humans, the detection of socially relevant information relies heavily on visual and auditory processes in addition to somatosensory and, to a lesser degree, olfactory sensory processes.



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FIGURE 5-1

A schematic of five large-scale brain networks subserving processes important for social behavior. Three networks are anchored in the amygdala (amygdala-based networks) and two are not (control networks). The amygdala is displayed in white, indicating that it is the hub of the three amygdala-based networks.

Regions of Interest With Abbreviations Perception network: lOFC = lateral orbitofrontal cortex; vTP = ventrolateral temporal pole; FG = fusiform gyrus; STS = superior temporal sulcus. Affiliation network: dTP = dorsomedial temporal pole; rACC = rostral anterior cingulate cortex; sgACC = subgenual anterior cingulate cortex; vmPFC = ventromedial prefrontal cortex; Ent = entorhinal cortex; Phip = parahippocampal cortex; vmStr = ventromedial striatum. Aversion network: cACC = caudal anterior cingulate cortex; Ins = insula; SII = somatosensory operculum; vlStr = ventrolateral striatum. Mentalizing network: dmPFC = dorsomedial prefrontal cortex; PCC = posterior cingulate cortex; Precun = precuneus; AngG = angular gyrus (temporoparietal junction). Mirror network: pSTS = posterior superior temporal sulcus; IPS = intraparietal sulcus; PreMC = premotor cortex. Hip = hippocampus; Amy = amygdala. 7

Reprinted with permission from Bickart KC, et al, Neuropsychologia. B 2014 Elsevier. www.sciencedirect.com/science/article/pii/S0028393214002760.

colliculus, which may process some of this visual information in a rapid and potentially unconscious fashion. Besides visual systems, other sensory systems are also critical to the processing of social signals. Auditory cortical regions, particularly unimodal and heteromodal regions in the superior temporal gyrus and sulcus bilaterally, respond more robustly to the sound of human voices than other sounds. Prosodic elements of speech perception appear to be processed by right temporal auditory regions. The touch of another person is processed not only by the somatosensory cortices but also the insular cortex,

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which is particularly important for decoding somatosensory stimuli as pleasant or unpleasant. Although seemingly much less important in humans than in many animals, the olfactory system also processes information relevant to social exchange. Heteromodal association and paralimbic cortical regions in the anterior temporal lobe and medial and orbital prefrontal cortex perform important integrative operations on this sensory information, decoding its meaning based on emotion, general knowledge (semantic memory), and past experience (episodic memory), as well as the present context, needs, and goals.



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MIRRORING AND THEORY OF MIND A number of investigators have discussed the potential importance of mirroring, or simulating other people’s actions in our own minds, as a means of communication.10 Some displays of behavior convey another person’s intended goals, while others convey their feelings. Observing someone else’s emotion or pain typically causes a mirroring reaction that is thought to duplicate their experience within oneself, extending in some cases to automatic mimicry of the other person’s facial expression and posture. Anatomically, the anterior insula and the anterior cingulate cortex are involved in our own experiences of emotion and in viewing others’ emotions; the inferior frontal gyrus and inferior parietal lobule are involved in both our own movements and in simulating others’ motor movements, including their facial displays. Asymmetries in some of these functions have been observed, leading some authorities to hypothesize that right-lateralized insula-cingulate activity is associated with arousal, sympathetic autonomic activity, and withdrawal (aversive) behavior, while left-lateralized activity is associated with relaxation, parasympathetic activity, and approach (appetitive or affiliative) behaviors. This instinctive aspect of empathy, which can be seen in many other species, is thought to be supplemented in humans by additional cognitive abilities important for communication, including consciously taking another person’s emotional perspective and making inferences about it, the so-called theory of mind. Theory of mind refers to one’s awareness that other individuals experience thoughts or feelings that are distinct from one’s own. These thoughts may include ideas about goals, plans for the future, memories from the past (cognitive theory of mind), or feelings about others’ emotional states. Cognitive theory Continuum (Minneap Minn) 2015;21(3):660–677

of mind, which is necessary to understand that another individual may think or believe something different from yourself, is at least in part supported by the inferior parietal cortex and posterior lateral temporal cortex (the temporoparietal junction, with a nondominant hemisphere bias). Additionally, the medial prefrontal cortex is engaged in both selfreferential thinking and imagining the perspective of others. Within the medial prefrontal cortex, a dorsal region is involved in taking another’s cognitive perspective and in representing the other person’s typical behavior traits, while a ventral medial prefrontal cortex region, which is highly interconnected with limbic structures, is thought to represent and reason about others’ emotions. CALCULATION OF SALIENCE AND VALUE In many situations, including social interactions, we rapidly process sensory information and attempt to determine what other people are thinking, feeling, or intending to do. With all of this information, how do we quickly determine what is most relevant? The determination of the salience of information depends on a network of limbic subcortical and cortical structures including the insula and anterior cingulate cortex, orbitofrontal cortex, amygdala, ventral striatum, and brainstem structures. The lateral orbitofrontal cortex and amygdala receive sensory information about social and emotional stimuli from temporal cortex visual areas, update the reinforcement value of these cues according to the social context, and subsequently guide attention to gather more information from the environment. Electrophysiologic recording studies in monkeys, for example, demonstrate neurons in the amygdala, lateral orbitofrontal cortex, and temporal lobe visual areas responsive to facial identity and changeable aspects of faces, such as expressions, eye gaze, and

KEY POINTS

h A number of investigators have discussed the potential importance of mirroring, or simulating other people’s actions in our own minds, as a means of communication. Some displays of behavior convey another person’s intended goals, while others convey their feelings.

h Theory of mind refers to one’s awareness that other individuals experience thoughts or feelings that are distinct from one’s own. These thoughts may include ideas about goals, plans for the future, memories from the past, or feelings about others’ emotional states.



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h We learn about social concepts from our own experience during development and from collective experiences shared through media or normative rules. Episodic memory systems are critical for learning and remembering information about other people and the contexts in which we have encountered them.

h Ultimately, all of the processing power that is used to understand other people is then put to use when we make decisions about how to act. In certain situations, substantial executive control and response inhibition may be necessary to regulate behavior appropriately for the context.

lip movement, which all serve as signals for social communication. Task-based functional MRI (fMRI) studies in humans demonstrate a similar topography of brain responses to socially salient features in the human face, such as facial expressions, eye gaze, and facial identity, and to perceived trustworthiness. Primary processing of sensory information is tuned by the salience system. For example, increased visual acuity is linked to enhanced activity in the amygdala and visual cortex including area V1,11 where the amygdala might directly modulate visual cortex responses to relevant stimuli. Structures including the insula and orbitofrontal cortex further create representation of value or salience. The insula is specifically involved in representing information about the internal milieu of the body at a given moment, thereby enabling the relevance of information to be determined in relation to a person’s current needs. Thus, the insula, particularly its anterior portion, is thought to play a central role in our experience of our own emotions (how we feel and what those feelings mean). The insula is also involved in representing other people’s emotional states (helping us understand what other people feel). The orbitofrontal cortex also contributes to the interpretation of information in the current context. In addition to representing the positive (rewarding) or negative (aversive) value of information, the orbitofrontal cortex continuously updates this value based on the outcome of actions. Many other structures are involved in approach and avoidance behavior, including the nucleus accumbens (reward) and amygdala (fear or threat). SOCIAL EPISODIC AND SEMANTIC MEMORY We learn about social concepts from our own experience during development and from collective experiences shared

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through media or normative rules. Episodic memory systems are critical for learning and remembering information about other people and the contexts in which we have encountered them. The hippocampus and other medial temporal lobe structures are critical for episodic memory for both social and nonsocial information. Semantic memory systems are essential for learning about societal rules, etiquette, and how to interpret others’ social signals. The anterior and ventrolateral temporal cortices, as well as medial and lateral prefrontal cortices and posterior cingulate/precuneus, are critical for these forms of memory. REGULATION OF COMPORTMENT AND SOCIAL DECISION MAKING Ultimately, all of the processing power that is used to understand other people is then put to use when we make decisions about how to act. In certain situations, substantial executive control and response inhibition may be necessary to regulate behavior appropriately for the context. The dorsolateral prefrontal cortex and ventrolateral prefrontal cortex are key regions that are critical to the regulation of emotion and play important roles in the execution of appropriate social behavior. The anterior cingulate cortex is also important for monitoring conflicts and errors as well as for response inhibition. Several investigators have recently developed highly consistent neurobehavioral models that implicate many of these structures in social judgment and decision making.12 These neural models for social judgment and decision making were derived primarily from lines of human neuroimaging and neuropsychological work examining the neural correlates of social interaction and morality. This body of work demonstrates a partial separation in the neural correlates of social affiliative and avoidant behaviors (ie, desires and actions to



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approach others versus feelings and actions to avoid others). Some regions associated with reward processing (eg, ventromedial prefrontal cortex, nucleus accumbens) are responsive in functional neuroimaging experiments to both images of family members and positive social feedback. In contrast, regions associated with avoidant behavior (eg, anterior insula, amygdala) demonstrate activation when stimuli of faces viewed are judged as untrustworthy and associated with negative social feedback. THE MOLECULES OF SOCIAL BEHAVIOR Below the level of brain regions and circuitry, certain neurochemicals are critical for social behavior. Oxytocin has been most widely studied, and appears to exert modulatory functions associated with prosocial behavior.13 Studies of the oxytocin receptor (OXTR),14 arginine vasopressin receptor 1A (AVPR1A),15 monoamine oxidase A (MAOA),16 and the serotonin receptor 5-HTT17 have shown that all of these receptors are involved in a variety of social behaviors. Oxytocin has undergone preliminary study in clinical trials for the treatment of impaired social function in several patient populations, including patients with FTD and autism.18,19 DISORDERS OF SOCIAL COGNITION Disorders of social cognition include frontotemporal dementia, autism, Williams syndrome (a neurodevelopmental syndrome associated with hypersocial behavior, due to a deletion on chromosome 7), schizophrenia and multiple other psychiatric illnesses, as well as developmental or acquired prosopagnosia, Capgras syndrome (a delusional syndrome in which a person believes their spouse or other family member or friend has been replaced by an identical-looking imposter, which can occur in patients with schizophrenia, dementia, traumatic brain inContinuum (Minneap Minn) 2015;21(3):660–677

jury, or other conditions), and focal brain lesions in key areas for social behavior.20 A new framework being developed by the National Institute of Mental Health, the Research Domain Criteria (RDoC), aims to change the focus of research on psychiatric illnesses to one heavily grounded in neuroscience. ‘‘Social Processes’’ is one of five major domains of behavior to be explored.21 Furthermore, in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),22 social cognition is one of the six cognitive domains that should be assessed in the diagnosis of major neurocognitive disorder (formerly called dementia in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]).23 A comprehensive review of these neuropsychiatric illnesses that affect social cognition is beyond the scope of this article. However, FTD is reviewed and its differential diagnosis considered, as it is one of the most relevant illnesses for many neurologists.24

KEY POINTS

h Certain neurochemicals are critical for social behavior; these include oxytocin, vasopressin, monoamine oxidase A, and serotonin. Studies of the normal neurochemical substrates of social behavior may lead to new ideas for the development of therapies for disorders of social behavior.

h The behavioral variant of frontotemporal dementia appears to be the most common variant of frontotemporal lobar degeneration.

Frontotemporal Dementia One of the most prominent disorders of social behavior that neurologists encounter is FTD. Although tremendous heterogeneity exists within this clinicopathologic spectrum, the behavioral variant of FTD (bvFTD) is most relevant to the current discussion. New international consensus diagnostic criteria were published in 2011,25 and are summarized in Table 5-1. bvFTD appears to be the most common variant of frontotemporal lobar degeneration (the term used to designate this family of neurodegenerative pathologies). The specific symptoms of this variant depend on the particular regions of frontotemporal cortical and frontostriatal brain systems that are involved as well as their laterality. Disinhibition is a common early symptom, and can manifest as socially inappropriate behavior such as overly familiar www.ContinuumJournal.com


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Social Cognition and Behavior KEY POINT

h Disinhibition, apathy, and loss of empathy are common early symptoms of frontotemporal dementia, and often manifest through changes in a person’s social interactions.

TABLE 5-1 Diagnostica Criteria for Behavioral Variant Frontotemporal Dementia b Evidence of neurodegenerative disease by progressive deterioration of cognition or behavior based on observation or history b Possible behavioral variant frontotemporal dementia (bvFTD) (at least three of the following must be present early [fewer than 3 years] in the course) Behavioral disinhibition: socially inappropriate behavior, loss of manners or decorum, impulsivity Apathy or inertia Loss of sympathy or empathy: diminished response to other people’s needs and feelings, diminished social interest Perseverative, stereotyped, or compulsive behavior: simple repetitive movements, complex compulsive or ritualistic behavior, stereotypy of speech Hyperorality and dietary changes: altered food preferences, binge eating or increased consumption of alcohol or cigarettes, oral exploration of inedible objects Neuropsychological profile of executive dysfunction with relative sparing of episodic memory and visuospatial skills b Probable bvFTD Meets criteria for possible bvFTD Exhibits functional decline Imaging results consistent with bvFTD: frontal and/or anterior temporal atrophy or hypometabolism or perfusion b bvFTD with definite frontotemporal lobar degeneration (FTLD) pathology Meets criteria for possible bvFTD Histopathologic evidence of FTLD on biopsy or autopsy Presence of a known pathogenic mutation b Exclusionary Criteria for bvFTD Pattern of deficits is better accounted for by another neuromedical disorder Behavioral disturbance is better accounted for by a psychiatric disorder Biomarkers strongly indicative of Alzheimer disease or another neurodegenerative process a

Modified from Rascovsky K, et al, Brain.25 B 2011 The Authors. brain.oxfordjournals.org/ content/134/9/2456.long.

interactions with strangers; loss of manners or violations of social normative behavior, such as public urination or changes in manners or other behavior during social meals; or impulsive actions such as unnecessary or excessive purchasing or shoplifting.26 Sometimes

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patients who are very active and jocular, and make rash decisions or go on spending sprees can be mistakenly diagnosed with mania or hypomania. Disinhibition appears to be related particularly to orbitofrontal and cingulo-opercular abnormalities in FTD.



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Another very common early symptom is apathy, including loss of interest in hobbies or leisure activities and social withdrawal; these behavioral changes are often mistaken for depression (Case 5-1). Yet patients with bvFTD do not usually exhibit sadness. They do not cry and talk about concerns, worries, or thoughts of worthlessness or hopelessness, and they do not usually exhibit the loss of appetite or sleep disturbance often seen in depression. Atrophy in the anterior cingulate cortex, dorsolateral prefrontal cortex, and striatum has been observed in association with apathy in bvFTD. Loss of empathy or sympathy toward one’s spouse, other family members, and friends is very common and can be subtle in some cases, depending in part on premorbid personality traits. These behavioral changes may concern family members for some time before it becomes obvious that something is wrong, which often occurs when the patient exhibits a highly unusual response to an event that almost universally provokes a vigorous uniform emotion in most people, such as the death of a close friend or family member or the birth of a child. Even under these circumstances, the behavior is commonly attributed to either depression or another psychiatric illness or to stress or a midlife crisis. Right anterior temporal cortex, anterior insula, and striatal abnormalities have been most consistently identified as related to loss of empathy. Compulsive, ritualistic, or repetitive behaviors are common in bvFTD, often early in the illness, and can be very distressing to family members. Examples of these symptoms include repetitive ‘‘projects’’ (eg, instead of writing her formerly floral, personalized greetings in holiday cards, a patient’s greetings became impersonal and repeated) or chores (eg, repeated emptying of trash), repetitive playing of card or computer games or watching of a particular televiContinuum (Minneap Minn) 2015;21(3):660–677

sion show. In some cases, these compulsive activities are carried on despite the presence of visitors or other salient social activities. Speech patterns may be stereotyped (eg, catchphrases, telling of stories as if by a script). Some of these symptoms appear similar to those of obsessive-compulsive disorder, but patients with bvFTD usually do not describe obsessive thoughts or any relief of such thoughts by a compulsive activity, as is typically described in primary obsessive-compulsive disorder. Some patients have very rigid routines that must be performed identically each day (often at a particular time, associated with clock watching); if these routines are disrupted, some patients become very upset. These symptoms may change as the disease progresses, in some cases becoming simpler. Simple repetitive behaviors include tapping or moving a limb, licking lips, picking skin, grunting, or moaning. These may appear similar to choreiform movements seen in dyskinetic movement disorders or tardive dyskinesia. Anatomic abnormalities associated with compulsive behaviors include striatal and anterior temporal atrophy. Changes in eating behavior are common, and may include altered food preferences (such as an increased sweet tooth or a rigid stereotypy in the foods eaten from day to day) or gluttonous or bingelike eating. Normative social eating conventions are often violated by actions such as rapid eating or stuffing food in the mouth, taking food from others’ plates, or belching. Patients may exhibit changes in the consumption of alcohol or cigarettes. Occasionally early in the course of the disease, but more often later, patients may explore inedible objects by placing them in their mouth, similar to the behavior seen in Klu ¨verBucy syndrome. Hypersexual behavior sometimes occurs. The neurobiological basis of changes in eating behavior in FTD has received little investigation but www.ContinuumJournal.com


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Case 5-1 A 58-year-old physician began having subtle difficulty at work. He was invited to give a lecture that would conventionally be 50 minutes, but after a 10-minute presentation, he concluded his talk and took his seat as if that were the usual routine. He was no longer loquacious with patients and colleagues as he had once been. He withdrew from his formerly active social life. He was still actively engaged in his home photography hobby, almost to a compulsive degree. At one event, he embarrassed his wife by cutting ahead of others in a food line and eating gluttonously. He began getting lost while driving home and seemed forgetful. His mother and maternal grandmother had suffered from dementia with an age of onset in their early 60s. His mother had received a diagnosis of Alzheimer disease but an autopsy was not performed. An initial office evaluation suggested the possibility of Alzheimer disease as he was not fully oriented, had difficulty drawing a clock, and had poor memory and executive dysfunction; his comportment was normal, although he spoke little. However, further neuropsychological testing demonstrated reduced acquisition and retrieval of lists of words but preserved storage on recognition memory testing, suggesting a frontal systems process. MRI and fluorodeoxyglucose positron

Imaging of the patient in Case 5-1. This 58-year-old man presented with behavioral symptoms (including apathy and impulsive eating) and executive dysfunction. A, Coronal T1-weighted MRI demonstrates bilateral (right greater than left) frontal, temporal, and parietal atrophy, quantified with a map of cortical thickness compared to controls. B, Fluorodeoxyglucose positron emission tomography (FDG-PET) shows prominent bilateral (right greater than left) frontal and temporal hypometabolism. The patient was found to have a Q300X (premature termination) mutation in progranulin (GRN). He exhibited a 5-year clinical course from first symptoms to death. Postmortem examination revealed the expected TAR DNA-binding proteinY43 (TDP-43) pathology.

FIGURE 5-2

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Continued from page 668 emission tomography (FDG-PET) scans showed abnormalities consistent with frontotemporal dementia (FTD) (Figure 5-2), and the diagnosis was made. Comment. This patient’s history was strongly consistent with impairment in social behavior, including his lack of understanding and violation of the normal rules of social behavior in his professional and personal life. He withdrew from colleagues and friends, which was not a manifestation of general apathy because he was still engaged in hobbies. Engagement in one of his hobbies was, in fact, increased to a compulsive degree. The clinician initially missed the diagnosis because the patient’s comportment in the office was normal and he exhibited multidomain cognitive impairment suggestive of Alzheimer disease. In this case, the presence of a progranulin (GRN) mutation was associated with more prominent parietal abnormalities than is typical in FTD, making diagnosis more difficult. Neuroimaging and genetic testing based on a strong family history solidified the diagnosis.

appears to involve the right-lateralized ventral anterior insula, striatum, and orbitofrontal cortex on structural MRI voxel-based morphometry. Another important clinical feature of bvFTD is lack of insight. This symptom was considered a core element of the Neary and colleagues27 diagnostic criteria but was not included in the new international consensus diagnostic criteria because it was thought to be too difficult to ascertain consistently. Nevertheless, it is well established that many patients with bvFTD, and some patients with semantic dementia, have a striking lack of insight even when confronted with obvious impairments. Clinically, this can be particularly challenging when the patient refuses to make office follow-up visits because he or she is convinced no problem exists. It may be one symptom that assists in differentiating FTD from psychiatric disorders, where insight is relatively preserved in many cases. Lack of insight in FTD has been associated with right-lateralized ventromedial prefrontal atrophy. Another a core feature of bvFTD is personality change. Alterations in personality can be prominent in bvFTD and in semantic dementia (Case 5-1). Although questionnaire-based instruments to assess classic dimensional personality traits are readily available, changes in personality might be best Continuum (Minneap Minn) 2015;21(3):660–677

understood clinically by considering more specific process-oriented functions contributing to personality traits. When faced with a family member who says ‘‘my spouse is not the person I married; his/her personality is completely different,’’ it is incumbent upon the clinician to probe further to ascertain the specific changes being described. Some symptoms may include changes in the expression or comprehension of emotion, social withdrawal or disinhibition, or loss of empathy (Case 5-2). In some cases, a previously gruff or aggressive individual becomes docile. The patient’s insight into these changes is often poor. Other symptoms that may also be described as personality changes include obsessive-compulsive behaviors, such as hoarding, and those involving changes in appetitive drives, such as sexual, eating, or drinking behaviors. Psychosis has been thought unusual in bvFTD, but since the discovery of the C9orf72 hexanucleotide repeat expansion in 2011, there have been multiple reports describing psychosis as an early clinical feature in patients with FTD who have this genetic mutation.28 At present, many experts consider it worthwhile to discuss testing for a C9orf72 mutation in a patient with FTD with psychotic features, especially if is the patient has a family history of neuropsychiatric illness.

KEY POINT

h The discovery of the C9orf72 expansion has highlighted the common presence of psychosis in patients with behavioral variant frontotemporal dementia as well as in family members without dementia who have this genetic mutation.



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h Patients with frontotemporal dementia are much more likely than those with other neurodegenerative diseases to have received an initial diagnosis of a psychiatric disorder, most commonly depression or bipolar disorder, but also occasionally schizophrenia, obsessive-compulsive disorder, or attention deficit hyperactivity disorder.

Differential diagnosis of frontotemporal dementia in relation to other disorders of social behavior. When an adult presents with disordered comportment or social conduct, the differential diagnosis is broad and must include toxic-metabolic conditions, infectious or inflammatory processes, and lipid-storage disorders or white matter degenerative diseases. Usually, however, in these disorders social cognitive or behavioral impairment is only one manifestation of a broader multidomain cognitive disorder, often accompanied by other neuropsychiatric or systemic symptoms. Both Huntington disease and Wilson disease may begin as a neuropsychiatric syndrome with obsessive-compulsive and manic symptoms with disordered social behavior, but these symptoms usually occur in the context of a movement disorder. Other neurodegenerative diseases, such as Alzheimer disease, progres-

sive supranuclear palsy, or corticobasal syndrome, may initially present similarly to bvFTD, although this is atypical. Focal brain lesions of the ventromedial prefrontal cortex, amygdala, cerebellum, and a number of other structures subserving social behavior as described above have been reported as causing disordered social behavior.8 Patients with FTD are much more likely than those with other neurodegenerative diseases to have received an initial diagnosis of a psychiatric disorder, most commonly depression or bipolar disorder, but also occasionally schizophrenia, obsessive-compulsive disorder, or attention deficit hyperactivity disorder. While these psychiatric conditions clearly may affect social behavior, important differences exist in behavior between patients with primary psychiatric disorders and patients with FTD.29 Generally, patients with FTD are unlikely to notice

Case 5-2 The wife of a previously generous, caring 28-year-old man with no neuropsychiatric history reported that he was unwilling to share an iPod given to them, selfishly listening to audio books. Previously a gregarious man, he increasingly spent time alone. He began making mistakes at work and drinking alcohol and smoking obsessively. His wife became pregnant, and after the baby was born, he seemed disinterested in spending time with his family. He lost his job and began having more difficulty doing complex tasks at home. His wife accompanied him to an evaluation with his primary care physician and reported his abnormal behavior. He had had a serious head injury with loss of consciousness in a car accident at age 12 and was otherwise healthy. Based on the office evaluation, he was diagnosed with depression. Subsequently, he was stopped by police for reckless driving while intoxicated and taken to an emergency department, where brain CT demonstrated temporal lobe encephalomalacia, attributed to childhood head trauma. He was admitted to a psychiatric hospital for 1 week, was diagnosed with severe depression and substance abuse, and underwent outpatient psychiatric treatment. Cognitive and functional decline progressed despite psychiatric treatment, and he was referred to a neurologist. The neurologic examination identified abnormal comportment, executive dysfunction, and anomia; he was diagnosed with behavioral variant frontotemporal dementia (bvFTD). Additional imaging revealed progressive frontal and anterior temporal atrophy (Figure 5-3). Comment. This patient’s initial symptoms were completely out of character for him, constituting serious personality change. His symptoms included loss of empathy/sympathy, social withdrawal, and behavior that violated social norms (socially inappropriate behavior). The development of such symptoms in an otherwise healthy individual may represent the new onset of a serious psychiatric disorder, such as schizophrenia or a related illness, or a neurologic disease such as a frontal lobe brain tumor or frontotemporal dementia. In a man this young, a primary psychiatric illness would be more

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Imaging and histology of the patient in Case 5-2. Serial MRI scans 3 years apart show rapid progression of frontotemporal atrophy in this man who died of frontotemporal dementia at age 33. A, A series of coronal fluid-attenuated inversion recovery (FLAIR) MRI images demonstrates left greater than right temporal lobe atrophy performed when he was 28 years old at a time when symptoms were clearly present but overall function was mildly impaired. B, A similar series of coronal T1-weighted MRI images performed when he was 31 years old demonstrates marked progression of frontal, insular, and temporal atrophy with parietal involvement at a time when the patient was minimally communicative and dependent for most activities of daily living. C, Postmortem histology demonstrated neuronal and glial cell loss with prominent tau immunohistochemical abnormalities (left), including Pick bodies (middle). The hematoxylin and eosin (H&E) stained sections (right) also clearly demonstrated cellular inclusions typical of Pick-type tauopathy.

FIGURE 5-3

common than a neurodegenerative disease, but the literature contains multiple case reports of FTD striking people this young, and the Massachusetts General Hospital Frontotemporal Disorders Unit multidisciplinary team has followed three patients with FTD in this age range. The evaluation should consider the types and severity of symptoms of social impairment and additional cognitive, affective, or motor symptoms. It should also include some form of brain imaging (ideally MRI and, if unrevealing, fluorodeoxyglucose positron emission tomography [FDG-PET]) as well as neuropsychological testing. Many patients with bvFTD are initially misdiagnosed as having a psychiatric illness.

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h The evaluation of a patient with serious personality change should consider the types and severity of symptoms of social impairment and additional cognitive, affective, or motor symptoms. It should also include some form of brain imaging (ideally MRI and, if unrevealing, fluorodeoxyglucose positron emission tomography) as well as neuropsychological testing. Many patients with behavioral variant frontotemporal dementia are initially misdiagnosed as having a psychiatric illness.

Case 5-3 A 57-year-old man with a history of bipolar disorder, well managed on lithium for many years, developed acute renal insufficiency, and lithium was discontinued during acute hospital medical management. He developed manic symptoms that were treated successfully with valproate. Several months after discharge, he was behaving differently than before and was now experiencing social withdrawal as well as generalized apathy, loss of empathy with family members, and difficulty starting and completing tasks. He was sent for an MRI and neuropsychological testing, which revealed mild bilateral dorsolateral prefrontal atrophy and evidence of executive dysfunction. A presumptive diagnosis of frontotemporal dementia (FTD) was made, and he was referred to a specialty clinic. Upon further evaluation, additional history revealed that he had never been a particularly empathic individual and that his social withdrawal appeared consistent with a broader apathy syndrome. There was no disinhibition, impulsivity, compulsivity, or changes in oral/eating behaviors. He had preserved insight and was distressed about loss of cognitive function. Thus, the clinical phenotype was not consistent with possible FTD. Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed cerebral metabolic activity that was within normal limits. Further review of the MRI indicated that sulci were widened in both dorsolateral parietal and frontal cortex without the frontal predominance initially suspected, a pattern reported in patients with bipolar disorder.30 Longitudinal follow-up over the subsequent 2 years demonstrated a gradual improvement in symptoms toward baseline with no evidence of progressive cognitive decline. Comment. It is critical that the neurologist consider prior psychiatric history when evaluating patients with suspected FTD. Many chronic psychiatric disorders involve abnormal cognitive function (especially working memory and executive function) and may be associated with apathy. When the clinical phenotype is atypical and MRI findings are not diagnostic, FDG-PET can be very valuable in further workup. Longitudinal follow-up with periodic reassessment is also fundamentally important.

and regret functional decline or to show remorse for offensive behavior, whereas patients with primary psychiatric states often will (with the exception of many individuals with psychosis) (Case 5-3). In the office, the spontaneous behavior of patients with FTD often differs from that of patients with psychiatric conditions; verbal or physical interruption is not unusual, as is a lack of concern for clinicians’ expectations. Diagnostic assessment of suspected frontotemporal dementia. It is critical that the history is obtained from a source very familiar with the patient, typically a spouse or other close relative. The

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history always needs to be interpreted in the context of the patient’s lifelong temperament, comportment, and habits. From a diagnostic perspective, it is essential to capture the chronology of symptoms, noting the approximate onset of the illness, and the timing, order, and progression of the symptoms. The illness may also be associated with falls and parkinsonian symptoms or with muscle wasting and weakness (which suggests coincident ALS and a more malignant prognosis). The physician should also inquire about prior psychiatric history and probe for symptoms and chronological patterns (such as lengthy duration,



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lack of progression, and discrete episodes interspersed with a normal state) that may point to a primary psychiatric disorder rather than FTD. These include chronic paranoia and delusions, longtime episodes of anxiety and depression, longstanding aloofness and awkwardness (spanning decades rather than a few years), recurring mania, depression, or distressing compulsions (compulsions in FTD are generally not accompanied by emotional distress). Structured instruments can be used to facilitate the history-taking process, including the use of specific FTD symptom inventories,31,32 the Frontal Behavioral Inventory,33 or the Neuropsychiatric Inventory (NPI).34 In addition, structured interviews targeting social and language symptoms in FTD35,36 and instruments to quantify disability in FTD37Y39 have been developed. In the initial office assessment of a patient with suspected FTD, a basic cognitive examination is essential. Most commonly used cognitive screening instruments, such as the Mini-Mental State Examination (MMSE), are insensitive to the cognitive and behavioral deficits of FTD. Office-based general cognitive testing instruments thought to be more sensitive to FTD include the Montreal Cognitive Assessment (MoCA)40 and Addenbrooke’s Cognitive Examination (ACE).41 The Frontal Assessment Battery42 is a brief (about 10-minute) cognitive and psychomotor assessment that has demonstrated sensitivity to FTD. A neurologic examination is essential, working especially to determine whether the patient has abnormalities in eye movements or gait, limb or buccofacial apraxia, extrapyramidal signs, primitive reflexes, or evidence of motor neuron disease. Impersistence and distractibility can present challenges during the neurologic examination. Most patients will have a normal physical examination in the early stages, or the examination may Continuum (Minneap Minn) 2015;21(3):660–677

show subtle signs suggestive of cerebral dysfunction, such as one or more of snout, sucking, rooting, or grasp reflexes. Neuropsychological and diagnostic testing in frontotemporal dementia syndromes. Neuropsychological assessment can be invaluable in patients suspected of having FTD spectrum disorders. Although some patients may perform adequately on brief office-based cognitive testing, typically performed by a neurologist, psychiatrist, geriatrician, or other physician, the neuropsychologist may be able to detect abnormalities on extended testing. In at least some very mild cases, however, reasonably extensive neuropsychological assessment can be normal.43 Torralva and colleagues44 have compiled a set of previously developed tests emphasizing ‘‘real-life’’ elements of executive function as well as social cognition. This test battery demonstrated higher sensitivity to mild FTD than many standard tests included in typical dementia neuropsychological batteries. Another similar approach was taken by Funkiewiez and colleagues,45 who assembled the Social Cognition and Emotional Assessment (SEA) and ultimately determined that a subset (facial emotion recognition and faux pas) of the original tests were most sensitive to bvFTD.45 Finally, the Interpersonal Reactivity Index46 is a standardized, 28-item questionnaire of empathy that yields a total score as well as scores on four subscales (perspective taking, fantasy, empathic concern, and personal distress). Contrasting the perspective taking and empathic concern subscales can help compare cognitive and emotional aspects of empathy.47 Neuroimaging is an important part of the diagnostic workup of suspected FTD and has made valuable contributions to our understanding of the specific subtype disorders. Both structural (MRI) and functional (PET, single-photon emission computed tomography [SPECT])

KEY POINTS

h Structured instruments can be used to facilitate the history-taking process, including the use of specific frontotemporal dementia symptom inventories, the Frontal Behavioral Inventory, or the Neuropsychiatric Inventory. In addition, structured interviews targeting social and language symptoms in frontotemporal dementia and instruments to quantify disability in frontotemporal dementia have been developed.

h A set of previously developed tests emphasizing ‘‘real-life’’ elements of executive function as well as social cognition have been compiled. This test battery demonstrated higher sensitivity to mild frontotemporal dementia than many standard tests included in typical dementia neuropsychological batteries.



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h Neuroimaging is an important part of the diagnostic workup of suspected frontotemporal dementia and has made valuable contributions to our understanding of the specific subtype disorders. Both structural (MRI) and functional (positron emission tomography and single-photon emission computed tomography) neuroimaging may be valuable for the investigation of anatomic, metabolic, or perfusion abnormalities in frontotemporal dementia.

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neuroimaging may be valuable for the investigation of anatomic, metabolic, or perfusion abnormalities in FTD. Amyloid PET imaging is increasingly being used to rule out atypical forms of Alzheimer disease; tau PET imaging is on the horizon.48 At present, no specific fluid biomarkers in either blood or CSF have been found that indicate the presence of FTD, with the exception of genetic testing for mutations in MAPT, GRN, or C9ORF72 under appropriate circumstances.49 THERAPY FOR SOCIAL COGNITIVE-BEHAVIORAL DISORDERS Although there have been very few randomized clinical trials evaluating treatments for disorders of social behavior, there is a small body of evidence and a larger body of empirical evidence drawn from clinical experience. Studies are beginning to evaluate pharmacologic therapies such as oxytocin, which is thought to be specifically prosocial, in patients with social impairment as a result of autism, schizophrenia, or FTD.50Y53 For all patients with bvFTD and most patients with other disorders of social cognition and behavior, a multidisciplinary team of specialists is invaluable.54 Treatment includes empiric pharmacologic and nonpharmacologic management of symptoms, management of comorbid conditions, psychosocial support, and education of the family and, in some cases, the patient.55 At present, no medications are approved for the symptomatic treatment of FTD, but many medications have demonstrated utility in small studies.56Y58 For example, selective serotonin reuptake inhibitors (SSRIs) or other antidepressants can modulate disinhibition or compulsive behavior, stimulants or prodopaminergic agents can sometimes reduce apathy or attentional impairment, and mood stabilizers or antipsychotics may ameliorate agitation and aggression. Yet, side

effects may outweigh benefits and always need close monitoring. Strategies for nonpharmacologic management of symptoms include behavioral management, speech and language, occupational, or physical therapy, and, in some cases, psychotherapy (for patient or family); social work assistance is also critical.59,60 Paid or volunteer companions, home health aides, and day programs or respite programs may play important roles in maintaining structured social engagement. The Association for Frontotemporal Degeneration (www.theaftd.org) or the Alzheimer’s Association (www.alz.org) can be invaluable. CONCLUSION Psychologists are increasingly illuminating the rich array of cognitive and affective processes involved in social interactions.61,62 The tools of neuroscience are providing valuable insights into the mechanisms of these interactions, including the activity and connectivity of large-scale neural networks of brain regions, the neurochemistry and receptor pharmacology of molecules critical for social behavior, and genetic variants that confer individual differences in numerous facets of social relations. Most neurologists are only beginning to consider how to evaluate patients with disorders of social behavior, which, until recently, have been a domain of the psychiatrist. The growth of the fields of the psychology and neuroscience of social behavior have begun to contribute important insights into our understanding of disorders of social behavior. Conditions such as FTD provide neurologists with examples of diseases with well-defined neuropathology that strike brain systems fundamentally involved in social behavior and afford the opportunity to use new tools for the detection of abnormalities in these circuits to



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Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.

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Oxytocin and Social Cognition.

Assessment of Social Cognition and Theory of Mind: Initial Validation of the Geneva Social Cognition Scale.

Oxytocin, social cognition and psychiatry.

Friends, friendlessness, and social cognition.

Social cognition in ravens.

The modified hole board--measuring behavior, cognition and social interaction in mice and rats.

The Global Cognition, Frontal Lobe Dysfunction and Behavior Changes in Chinese Patients with Multiple System Atrophy.

Social cognition in schizophrenia.

Social Cognition in Schizophrenia.

Social cognition in fishes.

Neuro-cognition and social-cognition: application to exercise rehabilitation.

Early-life single-episode sevoflurane exposure impairs social behavior and cognition later in life.

The Dynamic Reactance Interaction - How Vested Interests Affect People's Experience, Behavior, and Cognition in Social Interactions.

Reply to Cronin: Consistency between decision-making, gaze, and natural social behavior validates inferences on macaque social cognition.

Neural correlates of naturalistic social cognition: brain-behavior relationships in healthy adults.

Social brain circuitry and social cognition in infants born preterm.

Social cognition in cocaine addiction.

Stimulus independence, social cognition and consciousness.

Illness cognition and behavior: an experimental approach.

Oxytocin, testosterone, and human social cognition.

Functional perspectives on emotion, behavior, and cognition.

Intercorporeality as a theory of social cognition.