For chrisbenjamin: Discussion post - Future of social psychology

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Social Neuroscience: A Neuropsychological Perspective

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Abstract and Keywords

This chapter discusses the human lesion approach for understanding the mechanisms of social processes. It begins with a description of the lesion method, which allows researchers to explore the association between focal damage to a particular brain region and impairment in a clearly defined cognitive-behavioral function. In humans, the lesion method is used to study individuals who have incurred focal brain damage naturally as a result of external insult (e.g., car accident, bullet wound) or due to specific kinds of disease or damage (e.g., cerebrovascular disease, surgical treatment of epilepsy, tumor resection). The chapter goes on to present some notable examples of lesion-method research in the field of social neuroscience.

Keywords: human lesion approach, social processes, cognitive behavior, social neuroscience, lesion method research

Introduction In 1992, the term social neuroscience was used in an influential paper emphasizing the importance of investigating and explaining social behavior through multiple levels of analysis, including not only social psychological constructs but also neural systems (Cacioppo & Bernston, 1992). By now, social neuroscience is a burgeoning field that has literally exploded in size and scope over the past several years, spawning new journals, new specialty areas, and dedicated textbooks such as the one in which this chapter appears.

Social Neuroscience: A Neuropsychological Perspective

Janelle Beadle and Daniel Tranel The Oxford Handbook of Social Neuroscience Edited by Jean Decety and John T. Cacioppo

Print Publication Date: Sep 2011 Subject: Psychology, Cognitive Neuroscience, Social Psychology Online Publication Date: Sep 2012 DOI: 10.1093/oxfordhb/9780195342161.013.0005

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It is interesting to consider briefly why this might be the case. A few contributing factors would seem to include: (1) During the 1990s, the World Wide Web became a widely available and highly accessible tool. This development gave social an entirely new meaning, expanding virtually overnight and by many orders of magnitude the realm of interactions that persons can have with each other. (2) The decade of the ‘90s also witnessed the emergence of functional neuroimaging, especially functional magnetic resonance imaging (fMRI), as a readily available and widely used tool in cognitive neuroscience. This development paved the way for entire species of researchers—who often would have identified previously with groups such as social and/or physiological psychology—to deem themselves neuroscientists. (3) We also note that studying the myriad functions that fall under the rubric of social has enormous intuitive appeal and almost automatic vernacular intrigue. Discovering the brain’s “moral compass” has a charm to it that is hard to match with, say, discovering the neural basis of visual attention. (4) Finally, the past two decades have witnessed a rediscovery of emotion, and the reinsertion of emotion into the lineup of topics considered acceptable as proper domains of neuroscientific inquiry. Much of this resurgence can be traced to the influential and paradigm-shifting theoretical framework that Antonio Damasio explicated in a series of books published in the mid to late 1990s, especially Descartes’ Error (1994) and The Feeling of What Happens (1999). Emotion is tightly intertwined with all manner of social processes and functions, a fact underscored by the numerous studies that have shown similar neural systems underpinning emotional and social processes. Hence, the reinstatement of emotion as a popular topic of neuroscientific investigation has also catalyzed the rapid expansion of the field of social neuroscience.

In short, the neuroscientific study of social processes has become increasingly fashionable and more and more widely practiced. This has led to a whole host of exciting new discoveries, many of whose importance for neuroscience and for the fundamental understanding of human health and disease is immediately obvious. As one prominent example, researchers studying the neural basis of loneliness (a state of psychological suffering due to perceived social isolation) have discovered that lonely people are more likely to experience a variety of negative health issues and diseases, including impairments in sleep, depression, cardiovascular disease, and even Alzheimer’s disease (Cacioppo et al., 2002; Hawkley, Masi, Berry, & Cacioppo, 2006; Paul, Ayis, & Ebrahim, 2006). As the baby boomer population grows older, researchers have also become very interested in the effects of aging on brain systems involved in social functioning, and how these changes may affect real-world decision making.

Along with this, recent work has highlighted related changes in the domain of emotion. For example, older adults are less able than younger adults to recognize stimuli with negative content (e.g., Moreno, Borod, Welkowitz, & Alpert, 1993; Sullivan & Ruffman, 2004) and may experience negative emotion with less frequency and intensity (e.g., Gross, Carstensen, Pasupathi, Tsai, Skorpen, & Hsu, 1997). This functional change may be a consequence of neurological changes—for example, reduced brain activity has been found in the amygdala of older adults (in comparison to younger adults) when they are viewing negatively valenced pictures (Mather et al., 2004). There is evidence that some

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older adults may have difficulty making advantageous financial decisions, and this has been documented in the laboratory (Denburg, Tranel, & Bechara, 2005) as well as in real- world settings such as targeting of older persons through telemarketing (American Association of Retired Persons [AARP], 1996). It is thought that aging-related changes in decision-making behavior may be a result of degeneration to particular brain structures, with the prefrontal cortex being most often implicated (Denburg et al., 2007). Thus, this domain of inquiry is not only important and interesting in its own right; it is also highly relevant to the fundamental knowledge base that is necessary for conquering diseases and promoting health. We would also note that many variables that are social in kind, are modifiable and amenable to intervention and change (unlike, say, genetic variables), and this means that there is enormous potential for developing programs that could prevent or alter the course of disease. Hence, scientific knowledge in this domain has enormous practical potential.

Against this background, it is interesting to ponder the role of traditional neuropsychological approaches to the study of social neuroscience. This is especially intriguing in the wake of the tsunami of functional imaging studies that has hit the literature over the past decade, and that continues more or less unabated. Does traditional neuropsychology have anything to contribute in this context? What are some of the important questions that neuropsychology can answer, and might even be positioned uniquely to answer? We have prepared the following chapter with these overarching questions in mind.

At the outset, we would like to point out that the lesion method remains a fundamental and indispensable scientific approach to the study of brain-behavior relationships in cognitive neuroscience, and we and others have underscored this message in several recent articles (e.g., Chatterjee, 2005; Fellows, Heberlein, Morales, Shivde, Waller, & Wu, 2005; Hernandez, Denburg, & Tranel, 2009; Koenigs, Tranel, & Damasio, 2007; Poldrack, 2006; Rorden & Karnath, 2004). What investigators like Brenda Milner (Milner, 1972) gleaned from a single case of profound anterograde amnesia can now be systematically studied in sufficiently large groups of such patients and where careful experimental control over neuropsychological and neuroanatomical variables is possible. Historically, lesion studies have often provided the first source of evidence for specific brain-behavior relationships (e.g., hippocampus and memory in patient H.M.) that are later validated with converging evidence from other methods. Today, as in decades past, findings from lesion studies still continue to inspire and set the agenda for other approaches. Also, the lesion method remains an ideal approach for fleshing out clinical and real-world observations and characterizations of behavioral phenomena. The lesion method also affords a means to test, at the systems level, the necessity of a particular structure in (not just correlated with or involved in) a cognitive process and provides uniquely complementary information to results from imaging and animal studies.

We can be more specific. While the lesion method has both shared and unique inferential pitfalls with other methods, the lesion method, in neurological patients, confers particular investigational and inferential advantages relative to other approaches (e.g., fMRI, animal

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studies). An obvious but often overlooked advantage is the possibility of conducting in- depth experiments on higher order cognitive abilities whose temporal and social characteristics are not currently amenable to other approaches. Especially in the domain of social processes, the core behaviors under scrutiny are decidedly human and decidedly social (other people are often involved). Many of the relevant experiments concern linguistic descriptions and high-level, face-to-face social interactions among people.

To be sure, there are challenges associated with studying social behaviors in laboratory settings and there are limitations on the extent to which real-world conditions can be simulated in the laboratory. But the confines of a magnetic resonance scanner introduce even more restrictions (e.g., difficulty implementing online social interactive tasks requiring expressive and pragmatic language use such as gesture, scanner noise). Studying the behaviors of patients with acquired brain damage provides an accessible and ecologically valid means of establishing brain-behavior relationships related to the domains of social functioning. Moreover, data from lesion studies of neurological patients are uniquely positioned to facilitate the translation of scientific knowledge into clinical application, as the research participants are in many cases the same individuals who would benefit from such clinical interventions.

To fully understand the mechanisms of social behavior, a multilevel approach that incorporates a variety of scientific methods which measure both macro- and micro- structural levels of a specific behavior should be used (Cacioppo & Bernston, 1992; Sarter, Bernston, & Cacioppo, 1996; Cacioppo, Bernston, Sheridan, & McClintock, 2000). A very complex social behavior can be explained succinctly at the level of higher-order cognitive mechanisms through social-psychological constructs which specify the mediating and moderating roles of various aspects of the individual’s personality, life experience, and interaction with social groups over time. This same social behavior can be further understood by examining the individual’s genetic makeup and determining how their genes may have interacted with their environment over time. For example, the interaction of genes that predispose an individual for developing a disease in combination with a socially distressing environment can increase the overall risk of a disease. As one instance, men with a positive family history of hypertension who also had high cardiovascular reactivity (high cardiac reactivity to stress) and significant life stressors showed higher levels of blood pressure than those who had a positive family history of hypertension but did not have high cardiovascular reactivity or significant life stress (Light et al., 1999). Functional neuroimaging serves as a useful tool to examine normal, healthy human brain function at the level of brain systems. Through functional neuroimaging, researchers are able to discern the network of brain areas involved in a specific psychological process in an online fashion. While the human lesion method is used to investigate the necessity of a brain region for a particular function, functional neuroimaging adds additional information by specifying the network of brain areas involved in a particular brain function. However, like all scientific techniques, there are limitations to the functional neuroimaging approach. Although the BOLD response is on the order of 6 to 8 seconds, it still does not reflect the time course of a neuron’s action potential. Another limitation of this method is that it is difficult to design an appropriate

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control task that accounts for all mechanistic aspects of an experimental task except for the one process that is specific to the experimental task. Another type of methodology— the animal lesion study—can directly complement a human lesion study through the method of experimentally lesioning a particular focal brain area of interest in the animal which can then be compared to the outcome of a similar naturally occurring lesion in a human lesion study. However, one limitation of animal lesion studies specific to the domain of social neuroscience is that although animals do engage in many of the same social behaviors as humans, it is difficult to measure their personal experience. Despite this limitation, research has examined some social behaviors that are shared by humans and animals such as communication with others through distress vocalizations (Carden & Hofer, 1990) and participation in conflict between social groups (Keeley, 1996; Goodall et al., 1979), making it a relevant methodology to study social behavior.

In short, a multilevel approach is the most optimal way to fully understand the mechanisms of social processes, and the human lesion approach provides an extremely valuable method by which to obtain information about social processes. We are excited to outline in this chapter the specific reasons why this is the case. In the following section, we take up that venture, and elaborate some of the nuts and bolts of the modern practice of the lesion method. The chapter then moves to a section in which we present some especially notable examples of lesion-method research in the field of social neuroscience.

The Lesion Method

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As already alluded to, the lesion method in cognitive neuroscience confers a number of distinct advantages over other approaches, and it stands alone among experimental methods in that it can determine the necessity of a given brain region for a specific function. Using the lesion method, researchers can explore the association between focal damage to a particular brain region and impairment in a clearly defined cognitive- behavioral function. In this way, a hypothesis about a particular brain-behavior relationship can be tested. If damage to a particular brain region results in impairment to a particular cognitive-behavioral function, it is concluded that the brain region is necessary (albeit not necessarily sufficient) for that function. There are variations across laboratories in the way the lesion method is conducted, and the following describes how this method is practiced in our laboratory (H. Damasio & A. Damasio, 2003).

In humans, the lesion method is used to study individuals who have incurred focal brain damage naturally as a result of external insult (e.g., car accident, bullet wound) or due to specific kinds of disease or damage (e.g., cerebrovascular disease, surgical treatment of epilepsy, tumor resection). Lesion studies often examine patients whose lesions were caused by stroke, herpes simplex encephalitis, surgical ablation of benign tumors, specific cases of head trauma, or surgical treatment of epilepsy. Naturally occurring lesions do not affect each region of the brain equally. Rather, different types of brain insults tend to produce damage preferentially in certain areas of the brain. For example, herpes simplex encephalitis tends to affect limbic system structures; surgical treatment of epilepsy typically involves the anterior-mesial temporal lobes; and cerebrovascular accidents more commonly affect the perisylvian regions fed by the middle cerebral artery.

Case Study vs. Group Study Approach

Case Study Approach In its origin, the lesion method was a case study approach which involved the study of a patient with a particular lesion and a particular behavioral deficit. More recently, the lesion method has evolved to include group studies of patients who have lesions in similar locations or similar behavioral deficits (where either the common lesion site or the common behavioral deficit can be used as the independent variable). However, the case study method is still a valuable technique, especially to document rare and theoretically significant cases that help the scientific community to better understand the functional organization of the brain (Editorial, 2004). Patients who fall under the rubric of a case study tend to have a rare (typically focal) lesion or a behavioral deficit that is clear, specific, and stable over time. The behavioral performance of the patient often does not overlap with, or even come close to overlapping with, that of the group of comparison participants. Oftentimes, the magnitude of the difference between the patient’s performance and the performance of healthy comparison participants is standardized in the form of a z-score (Editorial, 2004). To demonstrate the specificity of the deficit, the

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patient should show normal performance on a variety of other neuropsychological measures that do not tap into the processing demands required by the deficient ability.

A case study shares many similar methodological considerations to a group study. The patient should have a focal, specific lesion. A direct comparison should be made to a group of brain-damaged patients who have a focal lesion in a different location but with a similar size, etiology, and chronicity (time since lesion onset), with similar demographic characteristics (e.g., sex, age), and with similar performance on other measures of cognitive functioning (e.g., IQ, memory, language) that do not directly relate to the behavioral deficit being measured. In many cases, the patient should also be compared to a group of normal, healthy comparison participants matched on similar demographic and cognitive characteristics. (A comparison of “target” lesion patients to brain-damaged and healthy comparison participants is ideal, however, there are many examples of exceptions to this, whereby one or the other of these comparison groups is sufficient. And in some cases, the behavioral profile of the target patient is so obvious and so far from normal that a comparison group is unnecessary.) Anatomical information about the patient’s lesion should be described and quantified using statistical imaging analysis techniques (see below for discussion).

A recent case study serves as an example of how the examination of a patient with a rare lesion can aid in our understanding of an important neuroanatomical circuit (Feinstein et al., 2009). This study describes the case of Roger, a man with a rare lesion encompassing virtually the entire limbic system. Since brain injury typically only affects part of the limbic system, this study is unique in that the damage includes more or less the entire system. The study serves as a useful model of the case study approach, as exemplified in its nuanced description of Roger’s cognitive and emotional functioning which is measured through standardized neuropsychological measurement, rigorously designed experimental tests, and rich anecdotal observations. A holistic picture of Roger’s functioning becomes evident, and it is revealed that his primary deficits are a temporally graded retrograde amnesia (spanning 10 years before the brain injury to onset) that affects both episodic and semantic memory, as well as a severe anterograde amnesia for declarative verbal and nonverbal information. In contrast, Roger shows predominantly spared function on tests of intelligence, language, and visual function. The patient’s brain damage is carefully described by a trained neuroanatomist, who delineates the damage to each portion of the limbic system as well as explicitly noting any damage that has occurred outside of the limbic system. An in-depth description of the neuroanatomy of the patient’s lesion in a case study is critical to its functional interpretation, as even focal lesions can produce damage to regions outside the area of interest. (And we would add that this component of case reports is often underreported and underspecified, which, ultimately, does a disservice to the field because it becomes impossible to compare cases across laboratories, reconcile discrepant findings, and the like.) A compelling example of such a predicament is the case of Phineas Gage, where, because the patient never came to autopsy (and obviously was not studied with modern neuroimaging tools), there has

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continued a vigorous (and, ultimately, unsolvable) debate about the particulars of his lesion—for example, was it bilateral? Which prefrontal structures were damaged? (Damasio, Grabowski, Frank, Galaburda, & Damasio, 1994; Macmillan, 2000; Ratiu & Talos, 2004).

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Group Study Approach The traditional group study approach examines a sample of patients with a specific lesion location or behavioral deficit. To begin with, it is often important that all patients in the study have a lesion that is the chronic phase of recovery (at least three months after the onset) and that the lesion is stable (non-progressing). Mixing patients with evolving lesions and patients with stable lesions creates noise and adds to the chances of not finding reliable brain-behavior relationships. Selection of patients for the target group (or patients with damage to the region of interest) is based upon the degree to which the patient’s lesion matches the following criteria: location, size, laterality (right-sided, left- sided, bilateral) and etiology (cause: stroke, surgery to remove epileptic foci, tumor resection, etc.). Oftentimes, researchers attempt to restrict the etiology of their sample, such as including only cases of lesions due to cerebrovascular disease or surgical resection of benign tumors, in order to reduce the effect of how different types of brain insults can cause different effects in the brain. Next, a comparison group is selected, comprised by patients who have focal damage to a brain region outside the target region but of similar size, etiology, and chronicity. Finally, another comparison group comprised by healthy, normal participants is selected. The two comparison groups are matched to the target group on particular demographic characteristics (e.g., age, sex, education, handedness) as well as general cognitive functions (e.g., intelligence, language, memory).

A more recent type of group study approach—the voxel-wise symptom-lesion analysis— employs an exploratory analysis that examines all voxels in the brain to determine which particular brain-damaged region is most significantly associated with a cognitive deficit. This methodology can be used when the researchers do not have an a priori hypothesis of the relationship between a brain area and a function. Patients with a variety of different lesion locations and sizes are included in the sample and a particular cognitive or emotional function of interest is examined. The scores of the patients in the sample on the cognitive/emotional function are represented along a continuum (if possible, depending on the fidelity of the measurement). An example of this type of approach is seen in a study that uses a voxel-wise analysis to examine the neural correlates of naming and recognition of concrete entities (Rudrauf, Mehta, Bruss, Tranel, Damasio, & Grabowski, 2008).

There are advantages to both the case study and group study approach when studying lesion-deficit relationships. The primary advantage of the case study approach is that it allows the researcher to further understand the brain’s functional organization. If a small, focal lesion results in a specific behavioral deficit, it can be concluded that a specific brain area is necessary for a given function. This same conclusion can not be made in group studies where there is overlapping damage to a particular region because it is unclear what role the damage to the other areas may play. Another advantage of the case study approach is that it allows a more precise anatomical description of lesion location and extent. For a single case study it is not necessary, as in the group approach, to average across the lesions of a group of patients when performing the anatomical analysis. A limitation of the case study approach is that as a result of individual variability

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in brain structure and function, personality characteristics, cognitive abilities, and other idiosyncratic factors, a focal lesion to a particular brain area may produce a behavioral deficit in some individuals but not others. Another limitation of the case study approach is that some lesions may produce a behavioral deficit that is functionally relevant yet is subtle and thus undetectable due to a lack of power. Group studies that involve a large sample of patients with damage to a particular brain region help to ameliorate some of these issues by providing greater power to detect a difference between the target patient group and a comparison group. Another advantage of group studies is that the neural correlates of a particular function can be explored without having an a priori prediction of the particular brain regions involved in the function. This type of analysis can be accomplished through voxel-based analyses where the role that each and every voxel in the brain may play in a specific behavioral function is considered (at least insofar as what the lesion sampling has covered; see the next section for more details about this issue).

Multiple Case Study Approach A powerful approach, that blends some of the strengths of the case study method with those of the group approach, is the multiple case study design. This entails the selection of a number of patients who, typically, have demonstrated a very robust, severe impairment in a particular function and have a focal lesion to a particular region of the brain. This type of approach affords more statistical power than a case study because a greater number of patients are investigated; moreover, the reliability of the finding is more certain. At the same time, this approach may allow the researcher to have greater specificity in determining the lesion-deficit relationship than in a group study approach, because it focuses on those patients with the most severe impairment rather than on patients with functional deficits that vary along a spectrum of severity as in group studies. Also, because all of the cases are presented individually in some depth, the investigators can include and consider nuances and idiosyncracies of the patients that would be left out or masked by group means in a group-level approach. An example of this approach is described in a multiple case study of six patients with a consistent, severe impairment in their knowledge of locative prepositions (e.g., in, on, around ) and brain damage to the left posterior frontal operculum, white matter subjacent to this region, and the white matter located underneath the inferior parietal operculum (described in Study 2, Tranel & Kemmerer, 2004). The patients all showed significant impairments in their naming of actions, and some of the patients also had deficits in naming concrete entities (e.g., persons, animals, fruits). However, the researchers found a double dissociation between naming and conceptual knowledge, because the patients’ conceptual knowledge for actions and concrete entities was mostly intact. In summary, the multiple case study approach is a useful, statistically powerful way to examine the lesion-deficit relationship in instances where there are multiple patients with severe impairments in a particular function and focal brain damage to a particular region of the brain, but where individual details of the cases are important and can be preserved in the presentation of the data.

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Lesion Method Analysis Techniques

An important component of the lesion method is the description and quantification of the anatomy of the patient’s lesion in order to examine the association between a specific brain region and a cognitive or emotional function. The development of magnetic resonance imaging (MRI) technology has allowed researchers to image the structure of the brain, making regions of brain damage visible to the naked eye as well as quantifiable by various measurement techniques. Through the examination of MRI images, researchers are able to determine the location and size of gray and white matter lesions. Methods have been developed to image a single patient’s brain as well as to compare lesion characteristics across a group of patients with brain damage. Our laboratory uses the Brainvox system which allows for three-dimensional visualization and analysis of MRI images of patients with lesions (Frank, Damasio, & Grabowski, 1997). Using the MAP-3 tool within Brainvox, lesions from each patient are manually transferred to the shared space of a normal reference brain, taking into account proximity to sulcal and gyral landmarks.

Statistical analysis of group lesion studies typically involves either region of interest analysis (ROI) or voxel-wise analysis. ROI analysis is primarily utilized when there is a specific (a priori) hypothesis about a brain region’s involvement in a particular function. The target participant group is selected on the basis of specific, focal damage that is (relatively) isolated to a region of interest. Another comparison group of patients is then selected, who have circumscribed brain damage to regions outside of the target region of interest. Participants are then dichotomized on the basis of having a target lesion (yes/no) and having a behavioral deficit (yes/no). Statistical tests compare these four groups: lesion/deficit, lesion/no-deficit, no-lesion/deficit, and no-lesion/no-deficit. An advantage of ROI analysis is that fewer statistical comparisons need to be conducted than in voxel-wise analysis, and therefore there is higher statistical power to be able to detect differences between groups.

When there is no a priori prediction about the involvement of a particular brain area for a function or if the researcher wants to do an exploratory investigation of which brain areas might be involved in a particular function, a voxel-wise analysis is a better fit. In this type of analysis, the relationship between a lesion and a deficit at each voxel in the brain is examined. Consequently, using voxel-wise analysis, there is better spatial resolution than in the ROI method to detect exactly which region of the brain results in a deficit for the function of interest. This is different from the ROI method which examines a clearly defined anatomical region as a whole rather than examining it at a more fine-grained voxel-wise level. A limitation of the voxel-wise approach is that because there are thousands of voxels in the brain, numerous statistical comparisons need to be performed and therefore there is a concern about how multiple comparisons may result in a high false positive rate. In this case, it is difficult to determine whether the voxels implicated in the deficit are truly related to the deficit or if they have occurred due to random

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chance. However, there are statistical methods available to help account for the effect of multiple comparisons.

The ROI approach has been used frequently in our laboratory to examine the relationship between a lesion to a particular brain region and a deficit in a particular function (e.g., Damasio, Grabowski, Tranel, Hichwa, & Damasio, 1996; Damasio, Tranel, Grabowski, Adolphs, & Damasio, 2004). A lesion overlap difference map (M3) is created that examines the overlap between a lesion and a functional deficit at the level of each voxel to determine areas of maximum overlap of lesion and deficit. More specifically, an M3 lesion-deficit analysis is performed such that at each voxel, the number of subjects with a lesion (L) and deficit (D) specified as N is subtracted by the number of subjects with a lesion (L) and no deficit (∼D) specified as N . This can be expressed as a joint probability such that the proportion of lesion subjects with a deficit is subtracted by the number of lesion subjects without a deficit and then multiplied by the number of subjects in the entire sample:(1a)

A statistical assumption of the null hypothesis is that the two variables of interest are independent of each other. Applied to this specific case, this means that the presence of a lesion at a specific location does not influence the rate at which a deficit will appear. Based upon this assumption, equation 1a can be transformed so that it is expressed as the joint probability of two independent variables:(1b)

Furthermore, this equation can be transformed by factoring out Prop (L) to result in the final product:(1c)

The M3 method is limited in its ability to make statistical inferences in certain cases. This becomes particularly evident when there is no relationship between the lesion location and a particular functional deficit. The arithmetic outcome is shifted based upon the difference between the proportion of subjects with a deficit versus no deficit. In addition, the outcome is highly dependent on the number of lesions at a particular voxel location and the number of subjects in the sample. Consequently, the resulting outcome becomes inflated locally (due to the proportion of lesions at that particular voxel) or globally (due to the number of subjects in the sample.) Another important issue to consider is that the lesion coverage at each voxel is heterogeneous due to the natural occurrence of lesions in some areas but not others. An alternative approach to M3 is the “lesion proportion difference” measure called PM3, which is the proportion of subjects with a lesion among those with a deficit minus the proportion of subjects with a lesion among those with no deficit (utilized in Karnath, Fruhmann Berger, Zopf, & Kuker, 2004; described in Rudrauf et al., 2008). This method advances the M3 method by centering the probability distribution corresponding to the null hypothesis around zero, accounting for uneven numbers of subjects who have deficits in comparison to subjects who have no

L∼D

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deficits and cancelling the global effect of the number of subjects in the sample. The PM3 is defined as:

It is important to note that methods like MAP3 and PM3 methods are purely descriptive in nature because they are not thresholded at a specific statistical criterion (Rudrauf et al., 2008). Instead, these methods typically employ a uniform cutoff to determine which scores truly indicate a deficit based upon the consideration of false positives (Damasio et al., 2004).

Methods have been developed to conduct inferential statistical analyses in group lesion studies. In the context of the M3 and PM3 methods, novel techniques have been devised for threshold methods that were initially only descriptive in nature (Rudrauf et al., 2008). Statistical methods are typically tailored to the characteristics of the data being examined. If the behavioral impairment is expressed in a binary manner (e.g., presence or absence of an emotion-processing deficit), a binomial test is most appropriate (reviewed in Rorden, Karnath, & Bonilha, 2007.) The most frequently used binomial test is the Yates corrected chi-square test, an approximation of the Fisher exact test. However, this statistical test may not be entirely appropriate for lesion data and therefore an alternative statistical test, called the Liebermeister test (Liebermeister, 1877), has been suggested. This test is similar to the Fisher exact test in its calculation but it offers better sensitivity (Seneta & Phipps, 2001).

If a behavioral impairment instead exists on a continuum, typically a t-test or an analysis of variance (ANOVA) is used (Bates et al., 2003). However, in the case of voxel-wise analysis, the t-test or ANOVA may not be the most effective statistical test to use (discussed in Rorden et al., 2007). Voxel-wise analysis involves the computation of a statistical test comparing each and every voxel, resulting in thousands of tests. Consequently, it is difficult to determine whether the statistical assumptions of a t-test are upheld for each test. These include that the data are normally distributed, represented on an interval scale and that the two groups of interest have comparable variance. The t-test is also not suitable when the mean is not representative of the sample, as in cases where the sample is skewed. Finally, oftentimes behavioral deficits are measured by scales that do not accurately represent an interval. For example, in a scale that is not expressed on an interval, the difference between two points on the scale may not mean the same thing as the difference between two other points on the scale. Typically when these assumptions are violated, researchers use a Wilcoxon-Mann- Whitney test (Mann & Whitney, 1947; Wilcoxon, 1945) or the robust rank order test (Fligner & Policello, 1981). However, these tests are not always entirely appropriate for lesion data because they assume that the data have a similar shape and range and that they are drawn from symmetrical distributions. A more recently developed test—the Brunner-Munzel test—(Brunner & Munzel, 2000) helps to remedy some of these problems by using a rank order test that is assumption free. When there are at least 10

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observations in each group, it generates a statistic that is normal, and when the groups are smaller than 10 it uses an additional permutation test to approximate the precise p value (Neubert & Brunner, 2007).

When conducting voxel-wise analyses, it is important to account for the effect of multiple comparisons, or in other words, to control for family-wise error rate (the chance of making a Type 1 error). The Bonferroni correction is a frequently used method that conservatively controls for family-wise error. Because the comparisons in voxel-wise analysis are not independent, some researchers have asserted that this method is too conservative because of its acceptance of a higher Type II error than is necessary to produce the least amount of Type I error. An alternative to this method is the false discovery rate (FDR) thresholding approach, which is thought to provide better power than the Bonferroni correction while still controlling for the ratio of false alarms to hits (for application to lesion method see: Bates et al., 2003; Friston, 2000; Rorden & Karnath, 2004).

Limitations of the Lesion Method

Although the lesion-deficit approach is a powerful methodology, there are limitations that derive from both issues of practicality as well as functional resolution. One limitation of the lesion method is practical, and has to do with access to patients. The lesion method is often conducted within the context of a medical center because scientists will need access to neurological patients. Other necessities include neuropsychological testing facilities and structural imaging facilities. It helps to have a continuous referral of new patients from clinicians. Another limitation of the lesion method is a consequence of the functional resolution of the method. Typically, even small, focal lesions may not affect a single functional unit of the brain but rather may affect brain tissue that is involved in multiple functions. Lesion overlap analysis or voxel-wise studies aid in providing more precision, but there are limitations in these methods as well. A related issue derives from the fact that certain cognitive functions may recruit more than one brain area. Consequently, damage to a single brain area may not necessarily completely impair function because the individual is able to rely on other brain structures in the functional system. Furthermore, individual differences in the function and anatomy of the brain may become more pronounced after lesion onset, thus making it difficult to make general conclusions about the function of a particular brain area across subjects.

Another important limitation of the lesion method derives from the fact that when researchers conduct the lesion method in humans, the lesions are not made experimentally (as in animal research), and lesions do not occur in all areas of the brain with equal frequency. In particular, there are specific regions of the brain that are frequently affected by brain injury and other regions that are rarely affected. For example, in cases of traumatic brain injury due to an automobile accident or a concussion, portions of the frontal lobes (especially orbital) and temporal lobes are most

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often affected. Cerebrovascular accidents such as ischemic or hemorrhagic strokes typically affect perisylvian regions fed by the middle cerebral artery. Herpes simplex encephalitis damages limbic system structures (especially medial temporal and cingulate regions) and surgical treatment for epilepsy involves the removal of portions of the anterior mesial temporal lobes. A pictorial representation of the brain regions sampled in one of our lesion studies (Rudrauf et al., 2008) is presented in Figure 5.1.

Another limitation has to do with connectivity. In general, lesion studies have not accounted very well for the effect of white matter damage that often occurs as a result of brain injury, and that can obviously produce functional deficits. It is important to recognize that the brain functions as a system of interconnected parts, including gray matter as well as the white matter fiber tracts that

connect various cortical regions (Friston, 2000). In the past, researchers have been limited by technological constraints that made it difficult to consider the effects of gray and white matter damage simultaneously. Recently, progress on this issue has been facilitated by the advent of diffusion tensor imaging (DTI), which enables the visualization and even some degree of quantification of damage to white matter fiber tracts (Jones, 2008). Novel statistical techniques that allow researchers to utilize probability maps of the various types of fiber tracts (projection, commissural, and association) that are registered to a normal reference brain atlas have also facilitated analyses of connectivity issues. One particular method that uses this approach is generalized lesion-symptom mapping (GLSM), which incorporates information about white matter fiber tracts from DTI-based tractographic atlases in order to conduct lesion- deficit analyses at both a tract-wise and voxel-wise level (Rudrauf, Mehta, & Grabowski, 2008). In a study illustrating the validity of this approach, the researchers choose to examine a fiber tract system that has been very well documented both anatomically and functionally—the geniculo-calcarine visual pathway. The researchers compared the results of a gray matter analysis alone versus an analysis of gray matter and white matter damage in 149 patients with right homonymous visual field deficits following focal brain damage. The analysis revealed that although analysis of gray matter alone implicated several regions in the temporal lobe, when fiber tract information was included only damage to the optic radiations predicted the visual field defects. This example illustrates

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Fig. 5.1 Voxel-wise approach to the lesion method in humans, showing a “lesion coverage map.” The lesion coverage at each voxel based on a sample of 129 patients with brain damage is represented on a reference brain, and keyed by the color bar (ranging from 1 lesion to 9 or more at any given voxel). Left lateral, ventral, and right lateral views are depicted.

Reproduced from Rudrauf, D., Mehta, S., Bruss, J., Tranel, D., Damasio, H., & Grabowski, T. J. (2008), with permission of Elsevier.

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the importance of considering the effects of white matter damage on functional deficits. Consideration of the connectivity of brain regions may lead to a more accurate understanding of the association between a lesion and a deficit.

Application of the Lesion Method to Social Neuroscience In what follows, we present several examples from the recent literature, in which the lesion method has been used in particularly compelling fashion to tackle issues in the field of social neuroscience. Again, we would underscore that these examples provide notable illustrations of how the lesion method can inform questions in this field in ways that are especially convincing and in some respects, unattainable with other methods.

Moral Judgment

Philosophers have debated the mechanisms of moral judgment for many years, but only recently has the field of neuroscience attempted to examine the neural underpinnings of moral judgment through functional neuroimaging and lesion studies (Greene, Sommerville, Nystrom, Darley, & Cohen, 2001; Koenigs et al., 2007). Although moral decision-making theory has been long dominated by cognitive models that describe moral decision making as a process of rational deliberation, more recently researchers have hypothesized that moral judgments may also be a consequence of emotional responses (Valdesolo & DeSteno, 2006). Some evidence for this idea stems from behavioral work that has shown that an induction of an affective state can change how someone makes a moral decision (Valdesolo & DeSteno, 2006) as well as descriptions of how moral decision making is impaired in neurological populations with emotional disturbances (Eslinger, Grattan, Damasio, & Damasio, 1992). Additional evidence for the role of emotion in moral judgment derives from functional neuroimaging studies which conclude that there is heightened brain activity in areas related to emotional functioning, in particular the ventromedial prefrontal cortex (VMPC), when healthy, normal participants make moral decisions (Greene et al., 2001).

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To further the understanding of the neural correlates of moral judgments and the role of emotion in moral reasoning, a lesion study was conducted using a region of interest approach to examine whether the ventromedial prefrontal cortex was necessary to make normal moral judgments (Koenigs et al., 2007). The study examined moral judgments in a target group of six patients with focal brain damage to the ventromedial prefrontal cortex, and severe acquired impairments in social emotional processing. The lesions in the target group

were overlayed on a reference brain to convey the commonality of damage in the ventromedial prefrontal region (Figure 5.2.) The behavior of the target group was compared to a group of 12 patients with brain damage to regions outside of the target region of interest as well as a group of 12 normal comparison participants. Both groups were matched to the target group on education, sex, handedness, and age (and, for the brain-damaged group, chronicity of lesion). Participants made moral judgments by deciding whether they would engage in a behavior depicted in two critical types of scenarios: “personal” scenarios (highly emotional vignettes requiring a participant to choose between an emotionally distressing act that will save several people or a less emotional act that will only save one person) and “impersonal” scenarios (vignettes in which the participant must choose between saving one versus many people from a more distant, impersonal vantage point). Strikingly, a greater proportion of patients with damage to the ventromedial prefrontal cortex made utilitarian judgments for a subset of

“personal” scenarios. After closer examination, it was revealed that this subset of personal scenarios also produced high disagreement among the comparison groups; these scenarios were denoted as “high-conflict personal scenarios” by Koenigs and colleagues. The high-conflict personal scenarios pitted two very difficult choices against each other. However, one of the choices was clearly more emotionally salient. For example, in one decision you must either smother your baby to save several other people or let the baby cry and several people will be killed. In these emotionally charged scenarios, the patients with damage to the VMPC made the utilitarian choice—i.e., they

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Fig. 5.2 Lesion overlap map of VMPC patients who participated in a moral judgment study. The lesions of 6 VMPC patients are displayed in mesial views and coronal slices. The color bar indicates the number of overlapping lesions at each voxel.

Reproduced from Koenigs, M., Young, L., Adolphs, R., Tranel, D., Cushman, F., Hauser, M., et al. (2007), with permission of Nature Publishing Group.

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chose to smother their own baby to save the lives of several others. It is well documented that patients with damage to the VMPC have a severe reduction in their capacity for social emotions (e.g., compassion, empathy, guilt). Consequently, their utilitarian choices may be the result of an inactive emotional system that prevents them from experiencing the emotional distress and disgust that normal, healthy individuals experience when engaging in morally reprehensible acts.

Empathy

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Empathy, which refers to the ability to understand and adopt the feelings of other individuals, is an inherently social construct, centering on our ability to relate to other people. Although the construct of empathy has been studied for several decades in the field of psychology, within the field of social neuroscience researchers are just beginning to understand the neural systems that subserve the experience of empathy (Eslinger, 1998; Preston & de Waal, 2002; Singer, 2006). Most of this research has focused on the neural correlates of empathic function in normal, healthy adults. The numerous neuroscientific theories of empathy that have emerged contain a common theme: empathy for others occurs through the embodied simulation of our own emotional experiences and the sensory and motor responses that make up these experiences such as hugging, crying, or smiling (e.g., Bastiaansen, Thioux, & Keysers, 2009). At a more basic level, studies have shown that similar neural mechanisms are involved in personal sensory experience and the observation of the sensory experience of others. For example, in a functional neuroimaging study, the anterior insula and nearby frontal operculum were activated in the observation of another person expressing food-related disgust or pleasure and the experience of personally tasting food from these various categories (Jabbi, Swart, & Keysers, 2007). The same brain areas were involved in viewing facial expressions of the emotion of disgust and then smelling disgusting odors (Wicker, Keysers, Plailly, Royet, Gallese, & Rizzolatti, 2003). Similarly, the personal experience of physical pain (e.g., a moderately painful electric stimulation), and the knowledge that another person (a loved one) is experiencing this same type of pain, also recruit the anterior insula as well as the anterior cingulate (Singer, Seymour, O’Doherty, Kaube, Dolan, & Frith, 2004). Results from these studies have pointed to a neural circuit important for empathy, which includes secondary somatosensory and premotor cortices used to simulate the sensory and motor components of others’ experiences, and the anterior insula and the anterior cingulate, which are involved in experiencing the emotions others (Singer, 2006; Bastiaansen et al., 2009). There is also evidence that the right hemisphere may be preferentially involved in empathy, although this could be modulated by sex so that women show a right hemisphere preference more so than men (e.g., Rueckert & Naybar, 2008).

Many different neurological and psychiatric illnesses result in (and, for some psychiatric diseases, may in part be caused by) poor empathy. Examples include patients with brain damage to the ventromedial prefrontal cortex, frontotemporal dementia, autism, psychopathy, and schizophrenia (Eslinger, 1998; Rankin et al., 2006; Blair, 2008; Shamay- Tsoory, Shur, Harari, & Levkovitz, 2007). In addition, recent research has found that healthy older adults may experience decreased empathy in comparison to younger adults (Bailey, Henry, & Von Hippel, 2008; Schieman & Van Gundy, 2000). In particular, a small number of studies have found that older adults experience lower cognitive empathy, or the ability to adopt the mental perspective (or “put oneself in the shoes”) of another person (Bailey et al., 2008). In patients with focal brain damage, empathy has primarily been measured through anecdotal reports of family members or through questionnaires rated by the patient or family members of the patient that assess empathy as a general tendency in daily life (Eslinger, 1998; Shamay-Tsoory, Tomer, Berger, & Aharon-Peretz,

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2003; Shamay-Tsoory, Tomer, Berger, Goldsher, & Aharon-Peretz, 2005). These studies have implicated the orbitofrontal and ventromedial prefrontal cortices as brain regions that are necessary for empathy.

There are two primary limitations to the research that has examined empathy in patients with neurological disease: Empathy has not been measured implicitly and “online,” and empathic experience in real time has not been measured. Explicit measurement of empathy may be problematic because previous studies have shown that patients with brain damage (particularly those with damage to the frontal lobe) are able to use their intact social “factual” knowledge to reason their way through the questionnaires. Moreover, such patients are notorious for having poor insight, making their self-reports of rather questionable validity in the first place. Thus, such patients may give the impression of being normal when they clearly are not (Barrash, Tranel, & Anderson, 2000; Saver & Damasio, 1991.) Implicit measurement may aid in the understanding of empathy because it allows the researcher to measure the construct of empathy in a way that is more naturalistic and less likely to produce socially desirable responses. One example of a way in which to measure empathy implicitly would be to assess behavior in a live empathy-provoking situation and measure whether patients respond similarly to normal individuals.

We designed a study which attempts to address some of the limitations of previous work to further understand the neural underpinnings of empathy. This study assessed online empathic experience both implicitly and explicitly. Participants included patients with adult-onset brain damage to the ventromedial prefrontal cortex. The study contained two parts: first, the induction of online empathy and second, the assessment of empathy through implicit and explicit measurements. The participants’ behavior on a social economic decision-making game that they played against other people served as an implicit measure of prosocial behavior. Explicit measurement of empathy occurred through the self-report assessment of the patient’s current empathic state at regular intervals throughout the experiment as well as the measurement of trait empathy, or empathy as a general tendency.

In order to understand how empathy was induced in this experiment, the context of this naturalistic deception experiment must first be understood. Participants were told that they would be playing an economic game (where they would make decisions about money) against a series of two different opponents through a hands-free intercom system. The participant played against one opponent at a time and this opponent was located in a separate testing room. The “opponent” was actually a voice recording of a community theater actor of a similar age to the patient. During the course of the experiment, unbeknownst to the participant, a naturalistic neutral emotion induction and empathic induction would occur. Right before the neutral induction the participant rated their current feelings which served as a baseline for their empathic feelings during the experiment. Participants were asked to, “Indicate to what extent you feel this way right now, that is, at the present moment,” on a scale from 1 (very slightly or not at all) to 5

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(extremely). The two items designed to assess empathic concern included “sympathetic” and “compassionate.”

Both inductions occurred in an implicit manner. The neutral induction occurred by the participant overhearing through the intercom a conversation of neutral content between the research assistant and the participant’s opponent as they talked about the events of their day (actually a voice recording). Following this induction, the participant rated their online feelings and then played the game against their first opponent. After the first game, the participant rated their current feelings again which served as a baseline of their feelings before the empathic induction took place. This second baseline was measured to determine their current feelings immediately before the empathic induction. Following this, the empathic induction took place and this included the participant overhearing a conversation between the research assistant and the second opponent who revealed that today was the anniversary of his son’s death (in a voice recording).

The game played in the current study was the Repeated Fixed Opponent variant of the Ultimatum Game (UG). The UG is a well-studied social economic decision-making game that has been used in contexts ranging from marketing to neuroscience (Kahneman, Knetsch, & Thaler, 1986; Sanfey, Rilling, Aronson, Nystrom, & Cohen, 2003; Koenigs & Tranel, 2007). This game poses a common bargaining scenario whereby a seller makes a final offer (often called an ultimatum) to a buyer (e.g. “The loaf of bread costs $3—take it or leave it”) and the buyer can either accept it, or reject it and leave it on the bargaining table. We designed our experiment so that the participant would make an offer to their opponent that could range from $1–9 (e.g. “You get $5 and I get $5”). Their opponent (actually a series of voice recordings) would then choose to either accept or reject the offer. If the offer is accepted, both persons receive the proposed division of money but if the offer is rejected, neither person receives any money. In the traditional 1-Shot version of the UG, in which the participant plays against a different opponent over every round, offers that are less than half of the total are often rejected, and offers that are 20% or less than the total are rejected at a rate of about 50% (Guth, Schmittberger, & Schwarze, 1982). Rationally, it may not be clear why a person would ever reject an offer, because some money is better than no money. However, theorists have proposed that rejections may occur due to the prevalent awareness of the norm of fairness which exists across many cultures (Roth, Prasnikar, Okuno-Fujiwara, & Zamir, 1991; Fehr & Fischbacher, 2003) and violations of this norm provoke anger (Pillutla & Murnighan, 1996). This response of negative emotion due to unfair behavior fits nicely in the context of findings that this game engages the insula, in which functional brain activity covaries as a response of the fairness of the offer (Sanfey et al., 2003), and with findings that the ventromedial prefrontal cortex (which plays a role in emotion regulation) is important for normal behavior during the UG (Koenigs & Tranel, 2007).

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The Repeated Fixed Opponent Ug In the Repeated Fixed Opponent UG, the participant plays against the same “fixed” opponent for several rounds as compared to the 1-Shot version in which a participant plays against a different opponent for each round. This version of the UG was chosen for three reasons: (1) It allows for an effective empathic induction, (2) it allows for the empathic induction to be believable, (3) it allows for a measurement of social interaction over time rather than at just one time point.

The Repeated Fixed Opponent version of the UG has not been studied much, and particularly has not been studied in older adults. Prior to conducting the empathy experiment with patients with damage to the ventromedial prefrontal cortex, we conducted a pilot study to further understand how younger and older adults play the Repeated Fixed Opponent UG. The participants in this study included twenty pairs of healthy, normal younger adults (N = 40) aged 24–45 years and twenty pairs of healthy, normal older adults (N = 40) aged 55–81 years. Age-matched pairs (younger vs. younger, older vs. older) played against each other. In this pilot study, the pairs included two real opponents (rather than voice recordings as described in the previous study) and participants were located in two different testing rooms and made their offers and responses orally through a hands-free intercom system.

When participants were offered a share of equal to or greater than half of the total, the older and younger groups behaved similarly, accepting virtually all offers. However, when participants were made offers of less than half of the total, an age difference in behavior emerged. Older adults rejected offers of less than half of the total at a significantly higher rate than younger adults (Figure 5.3). Since there is evidence that one

aspect of empathy—cognitive empathy—may be decreased in late life, the study next investigated whether there was an association between empathy as a general tendency and rejection rate of offers less than half of the total. Cognitive empathy was measured using the Perspective Taking subscale of the Interpersonal Reactivity Index, a well- studied self-report measure of trait empathy (Davis, 1980). A significant inverse relationship was found between empathy and rejection rate of offers less than half the

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Fig. 5.3 Mean rejection rate (%) on the Repeated Fixed Opponent Ultimatum Game for all offers less than half of the total (less than $5) as a function of age group (younger adult, older adult). Error bars reflect standard error of the mean.

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total, with high rejection rates being associated with low levels of empathy. Due to a decreased capacity to adopt the mental state of others, older adults may not realize how their high rejection behavior may cause the other person to become upset and may instead be focused on their own emotions.

The Online Empathic Response of Patients With Damage to the Ventromedial Prefrontal Cortex During the online empathic induction, patients with damage to the ventromedial prefrontal cortex reported that they experienced moderate empathic concern towards their opponent. In particular, while undergoing the online induction, the patients’ responses ranged from “a little” empathic concern to “quite a bit” of empathic concern with the modal response being “moderate” empathic concern. In comparison to their feelings of empathic concern in the control (neutral) condition, patients reported greater empathic concern during the online empathy condition (modal response = 1 point change from neutral to empathic condition). At an individual subject level, the number of patients with damage to the ventromedial prefrontal cortex that endorsed feelings of “moderate” to “quite a bit” of empathy during the empathic condition was greater than that of the neutral condition. In summary, patients with damage to the ventromedial prefrontal cortex reported that they experienced online empathic concern for another person.

However, a strikingly different pattern emerged in the implicit measure of empathic behavior (the Ultimatum Game.) The patients did not show an increase in empathic behavior during the empathy condition, but rather behaved very similarly in both the neutral and empathic conditions (Figure 5.4). In the neutral condition, patients with damage to the ventromedial prefrontal cortex gave an average of $4.43 (SD = .56) out of $10 to their opponent, and in the empathic condition the patients gave virtually an identical amount of $4.45 (SD = .74). Consequently, although the patients reported an increase in their online experience of empathy during the empathic condition, they did not show empathic behavior.

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Fig. 5.4 Mean offer amount ($) given by each patient with ventromedial prefrontal damage (N = 6) on a measure of empathic behavior (the Repeated Fixed

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The preliminary results of this study indicate that patients with damage to

the ventromedial prefrontal cortex do not experience online empathy towards others. An implicit measure of empathic behavior (the Ultimatum Game) demonstrated that patients did not show empathy towards a person who was suffering (the man who had lost his son). Although the patients did rate that they felt some level of empathy during the induction, these ratings may be more reflective of social desirability effects than actual empathic feelings. A previous study found that patients are able to access factual social knowledge, which enables them to appear emotionally and socially competent on a number of off-line tasks—in short, to “talk a good game” (Saver & Damasio, 1991), while in real-world settings these patients demonstrate clear social impairments (e.g., Anderson, Barrash, Bechara, & Tranel, 2006).

Sex Differences

At a large-scale macroscopic level, the brains of men and women are very similar. Closer inspection, though, reveals some striking differences between men and women in the ways in which various brain structures relate to cognitive and behavioral functions. Obviously, it is important for both men and women to be able to navigate the social world effectively, but individuals of each sex may have somewhat different goals. To begin with, women bear children, and this central and basic function likely sets the agenda for the individual and societal goals of many women. Men do not bear children and may often be driven by an agenda that emphasizes the acquisition and maintenance of resources and power. The ventromedial prefrontal cortex and amygdala are especially important for social-emotional processing. Recent evidence suggests that the left-sided and right-sided components of these structures may serve different functions in men versus women.

The Ventromedial Prefrontal Cortex To investigate whether sex plays a role in the functional asymmetry of the ventromedial prefrontal cortex (VMPC), we examined same sex pairs with unilateral lesions of similar location and extent in the VMPC, but located in a different hemisphere (Tranel, Damasio, Denburg, & Bechara, 2005). The participants included two male pairs and one female pair, and each pair had one patient with unilateral damage to the right side and another patient with unilateral damage to the left side. An additional two women with right-sided damage to the VMPC were included and although an exact left-sided match for these women could not be found, these two patients were compared to the males with right- sided damage. Three key functions of the VMPC were examined: social conduct, emotional processing/personality, and decision making. Structured rating scales were completed by collaterals (family members/friends of the patient) and neuropsychologists to assess social conduct. Social conduct was determined by the degree of change from pre- to post- brain injury in the domains of social status, employment status, and interpersonal functioning. Emotional processing and personality were assessed through

Opponent Ultimatum Game) as a function of induction type (neutral, empathic). Error bars reflect standard deviation.

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self-report ratings of the patient on the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory-2 as well as the Iowa Scales of Personality Change. Decision making was measured by the Iowa Gambling Task (IGT), which represents a decision-making environment that is similar to the real world in that it takes into account factors such as reward, punishment, and uncertainty.

A functional asymmetry in the VMPC was demonstrated as a result of sex. Males showed impaired function only when they had incurred right-sided unilateral damage to the VMPC but not when they had left-sided unilateral damage. The reverse pattern was seen in females: Females with left-sided unilateral damage to the VMPC showed severe functional impairments, but females with right-sided unilateral damage to the VMPC did not. This finding was interpreted to mean that the two genders may rely on differential strategies in the domains of social conduct, emotional processing/personality, and decision making. Such evidence suggests that the right VMPC and amygdala in men and the left VMPC and amygdala in women are important for social-emotional functioning, possibly reflecting differing social strategies and divergent social goals. Potentially, the left-sided dominance observed in women reflects a need for expertise in interpersonal relationships (and this could be related to factors such as the need to bear and rear children, maintenance of in-group cohesion, etc.), whereas the right-sided dominance observed in men could reflect a need for expertise in intergroup relations (e.g., warfare, out-group relations, leverage of critical resources, etc.).

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The Amygdala The amygdala plays an important role in the detection of emotional signals in the social environment. It is involved in recognition of emotional facial expressions (Adolphs, 2002, 2003), processing social information (Hariri, Tessitore, Mattay, Fera, & Weinberger, 2002) and the enhancement of emotional information in memory (Buchanan & Adolphs, 2004; LaBar & Cabeza, 2006). The role of the amygdala extends to the domain of real-world decision making where it detects emotional signals in the environment in order to guide behavior. Additional convergent evidence comes from the finding that patients with bilateral damage to the amygdala are impaired on a task of complex decision making, the Iowa Gambling Task (Bechara, Damasio, Damasio, & Lee, 1999). Not only is the amygdala crucial for social and emotional functioning, but its hemispheric-related functionality may differ between the sexes. For example, during the encoding of emotionally arousing material, the relationship between amygdala activation and memory for emotional material was the strongest in the right amygdala in males but in the left amygdala in females (Cahill et al., 2001; Canli & Gabrieli, 2004). We have studied whether there is sex-related functional asymmetry of the amygdala through the investigation of four patients with unilateral damage to the amygdala (Tranel & Bechara, 2009).

A case-matched lesion approach was utilized whereby a pair of men with unilateral amygdala damage (1 right amygdala, 1 left amygdala) were contrasted and a pair of women with unilateral amygdala damage (1 right amygdala, 1 left amygdala) were contrasted. Neuroanatomical analysis revealed that the four patients all had major damage to the amygdala unilaterally. The patients were assessed on the domains of social conduct, emotional processing/personality, and decision making through the same procedures specified in Tranel and colleagues (2005). We found preliminary evidence for a sex-related asymmetry of the amygdala: The man with right-sided damage to the amygdala showed severe impairments in social/emotional functioning (but the man with left-sided damage to the amygdala did not), whereas the woman with left-sided damage to the amygdala showed impairments in these domains, but the woman with right-sided damage did not. These results are considered to be preliminary because this is the first study of its kind and the sample size was small. However, the strength of these findings lies in the specificity of the case-based matching that allows for a direct comparison of how damage to the right or left amygdala affects socio-emotional function while accounting for shared nonspecific factors across patients, such as taking neurological medicine and going through brain surgery.

Altogether, the studies summarized in this section provide intriguing evidence that there is a sex-related functional asymmetry in the ventromedial prefrontal cortex and the amygdala, two areas crucial for socio-emotional functioning. The directionality of this pattern is the same in both brain areas: males-right, females-left. This work emphasizes the importance of examining the effect of sex on the functional architecture of the brain, particularly within the domain of social and emotional functioning. Evolutionarily, sex- related functional differences in the brain’s emotion system may have developed based upon the differential needs the physical and social environment placed on each sex. For

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example, left-sided dominance may have evolved in women because of their involvement in raising children and maintaining unity within their social group, whereas right-sided dominance may have been more beneficial to men in their need to moderate relations between tribes and compete for resources.

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Concluding Comments As the field of social neuroscience came into existence and rapidly grew into a major subdiscipline within cognitive neuroscience, it has, not surprisingly, attracted a large and growing number of constituents. This has fueled, in turn, a welter of new data, elaborate new theoretical frameworks, and, as with many of the challenging topics in cognitive neuroscience, a whole host of new questions. Many of these questions have profound practical significance. For example: Are utilitarian social decisions best made by eschewing emotion and using cold, hard reasoning? How do social emotions such as empathy and embarrassment shape and influence interpersonal interactions? Is social isolation a risk factor for neurological disease? Are there differences between men and women in the manner in which neural structures are specialized for social processing? These and many similar kinds of questions will shape the research agenda in this field for years to come.

The lesion method in social neuroscience has played a major role in pushing the field forward, and it will continue to be a key contributor. The lesion method, especially as exemplified by critical case studies, has often opened entirely new avenues of work, for example, by raising important and provocative questions about putative brain-behavior relationships (e.g., Is the ventromedial prefrontal cortex necessary for social emotions and moral reasoning?). The modern practice of the lesion method has capitalized on powerful new tools for lesion-deficit analysis (e.g., voxel-based lesion-symptom mapping), as well as unique patient resources (e.g., the Neurological Patient Registry at the University of Iowa), to yield robust conclusions about brain-behavior relationships. It is our hope that this knowledge will catalyze breakthroughs in understanding the more fundamental neural mechanisms behind cognition and behavior. In turn, progress towards the diagnosis, treatment, cure, and prevention of neurological and psychiatric disease may be realized.

Not so long ago, the rubric of social neuroscience was yet to be invented (cf. Cacioppo & Bernston, 1992). Now, this topic has become so popular and fashionable that it can be the hinge point for a dedicated Handbook, such as the one in which this chapter appears. As this happens, it is interesting to witness how frequently the modern literature ends up recapitulating themes that were articulated so eloquently by the forefathers of our field, especially William James (1918) and Charles Darwin (see 1989). For example, those scientists from many generations past clearly recognized and appreciated the central role that emotion plays in human existence and social interaction, and we are very pleased that our contemporaries have become similarly enamored. In a world that is ever more social, this development can only be a good thing, and we have every reason to be sanguine that social neuroscience will mature into a cornerstone field within cognitive neuroscience.

Authors’ note:

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This chapter was supported by NINDS P50 NS19632 and NIDA R01 DA022549.

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Janelle Beadle

Janelle Beadle, Department of Neurology and Program of Neuroscience, University of Iowa.

Daniel Tranel

Daniel Tranel is a professor in the Department of Neurology and Psychology at the University of Iowa in Iowa City, IA.

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