Frontotemporal dementia (FTD) is a neurodegenerative disorder

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1 EXPERIMENTAL STUDIES Alterations of the Sense of Humanness in Right Hemisphere Predominant Frontotemporal Dementia Patients Mario F. Mendez, MD, PhD, and Gerald T. H. Lim, MD Objective: To evaluate the sense of humanness in frontotemporal dementia (FTD) patients with right hemispheric involvement. Background: Early in the course, FTD is often asymmetric, and those with predominant right frontotemporal disease have disproportionate disturbances in social behavior and empathy. A disruption in a sense of humanness may underlie these behavioral disturbances. Method: Sixteen patients with asymmetric FTD on functional neuroimaging underwent recognition tests of facial masking, humananimal morphing, and facial distortion. Additional tests evaluated facial discrimination and the recognition of famous faces, facial emotions, and animate inanimate differences. Results: On the distorted and morphed face tasks, 8 FTD patients with predominant right hemisphere involvement were significantly more likely to call morphed and distorted faces human as compared with both 8 FTD patients with predominant left hemisphere involvement and normal controls. The FTD groups did not differ on thresholds for recognizing masked faces or on other face recognition measures. Conclusions: In FTD, right hemispheric involvement may alter the threshold for judging someone as human independent of the recognition of faces or facial affect. These results suggest that a specific sense of humanness facilitates a person recognition network in the right frontotemporal region of the brain. Key Words: frontotemporal dementia, faces, prosopagnosia, semantic knowledge (Cog Behav Neurol 2004;17: ) Received October 13, 2003; revised May 3, 2004; accepted May 26, David Geffen School of Medicine at UCLA, The University of California at Los Angeles, Los Angeles, California Reprints: M. F. Mendez, Neurobehavior Unit (116AF), VA Greater Los Angeles Healthcare, Wilshire Blvd, Los Angeles, CA ( Mmendez@UCLA.edu). Copyright 2004 by Lippincott Williams & Wilkins Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by lobar atrophy of anterior parts of the brain and impairments in interpersonal conduct. 1 These manifestations are most prominent in FTD with asymmetric involvement of the right orbitofrontal-temporal region. 2,3 FTD patients with predominant right hemisphere disease develop personality changes consistent with a loss of feeling for other human beings, 2,3 and the drawings of FTD patients with right temporal disease are suggestive of a decreased sense of the humanness for others. 4 Humanness may be a specific property of the human brain. It may be part of a person recognition network in the right hemisphere, predominantly in the temporal lobe, that involves the processing of human faces. 5 8 This network also includes theory of mind or the appreciation that others have attitudes and feelings Additionally, semantic information appears to be organized into an animate category and a person-specific subcategory in the right temporal region. 5,12 15 The presence of an intermediate humanness category in a person recognition network would have evolutionary significance and would be critical for social cognition and behavior. This study investigated the sense of humanness in patients with early, asymmetric FTD using computerized presentations of filmstrips. The expectation was that FTD patients with right hemispheric involvement (FTD-R) would have altered thresholds for assessing the humanness of faces, compared with FTD patients with left hemisphere involvement (FTD-L) and normal controls. Additionally, this study aimed to show that these altered thresholds were not caused by differences in facial recognition, facial emotion, or a generally altered threshold for responding to facial stimuli. METHODS Subjects The participants were community-based, moderately impaired patients who presented for a neurologic evaluation because of personality changes. They underwent a complete examination including neuroimaging and were diagnosed with FTD based on Clinical Consensus Criteria. 1 These patients had the insidious onset of a progressive decline in social and personal behavior along with emotional shallowness or unconcern and decreased insight into their disease. 1 None of the patients met criteria for other frontotemporal lobar degeneration (FTLD) syndromes, such as semantic dementia or progressive nonfluent aphasia, 1 and none had a family history of FTLD. The diagnosis of FTD also required the presence of isolated Cog Behav Neurol Volume 17, Number 3, September

2 Mendez and Lim Cog Behav Neurol Volume 17, Number 3, September 2004 frontal, temporal, or frontotemporal lobe changes or hypoperfusion on single photon emission computer tomography (SPECT) (Fig. 1). The presence of frontotemporal predominant atrophy on magnetic resonance imaging was supportive but not necessary for the diagnosis. Sixteen asymmetric FTD patients were identified and included in the study. Hemispheric asymmetry was determined by the presence of significant differences in hemispheric perfusion on SPECT as determined by the neuroimager. Eight FTD patients had predominantly right hemispheric involvement (FTD-R), and 8 had predominantly left hemispheric involvement (FTD-L). The 8 FTD-L patients had language changes including word-finding difficulty and anomia, but not sufficient to interfere with the testing or with comprehension of the testing instructions. The FTD patients were additionally compared with 24 age-matched normal controls on the computerized tasks (Table 1). These controls were adults, usually spouses or relatives of the patients, without a history of neurologic or ophthalmologic problems. Other measures were administered to the FTD patients. Dementia severity was based on the estimated duration of disease and the Clinical Dementia Rating Scale (CDR). 16 The FIGURE 1. Single photon emission tomography images (Tc- 99m HMPAO). A, Example of asymmetric hypoperfusion in the right hemisphere in a frontotemporal dementia patient (FTD- R). B, Example of asymmetric hypoperfusion in the left hemisphere in a frontotemporal dementia patient (FTD-L). TABLE 1. Frontotemporal Dementia (FTD): Patient Characteristics FTD-R: Right Hemisphere Predominant FTD by SPECT FTD-L: Left Hemisphere Predominant FTD by SPECT Normal Controls Numbers Sex (M/F) 4/4 4/4 12/12 Education in years 16.8 (3.2) a 15.0 (1.8) 16.6 (2.7) Estimated age of onset 56.9 (9.6) 53.6 (9.5) range 39 to 72 range 45 to 71 Age at testing 58.4 (8.9) 56.6 (8.4) 55.3 (7.6) a Mean, with standard deviation in parentheses. CDR is minimally dependent on language, visuospatial, or other cognitive deficits and includes an assessment of functional impairment. The evaluation included the Mini-Mental Status Examination (MMSE), 17 verbal fluency (animals), short-version Boston Naming Test (15-item version), constructions (copy of a circle, rhombus, overlapping rectangles, cube), and the Consortium to Establish a Registry in Alzheimer s Disease (CERAD) memory test. 18 The patients had 4 specific face tests: 1. Famous Faces Recognition Test. Twenty-four photographs of famous people were presented for naming or for identification by describing a major associated feature of the individual, eg, movie actor, president, or world leader. 19 The patients were also asked to state whether each unrecognized face looked familiar, and any yes answer was followed by predetermined recognition questions regarding the famous person. 2. The Benton Facial Recognition Test, Short Form. 20 The patients were asked to match front-view photographs with six photographs presented either in front-view, three-quarters view, or in different lighting. 3. Recognition of Facial Emotions. Ekman and Friesen s (1976) Pictures of Facial Affect were used to measure sensitivity to facial expressions of emotion. 21 The test consisted of a subset of 48 pictures from the original 110 blackand-white images of faces of men and women expressing happiness, sadness, anger, surprise, fear, and disgust. The participants verbal responses were recorded by the examiner. 4. An animate inanimate discrimination task. A subset of 20 black-and-white drawings from the Snodgrass and Vanderwart set (1980) were used to depict animal and inanimate items. 22 The FTD patients were asked to name the item and indicate whether living or nonliving Lippincott Williams & Wilkins

3 Cog Behav Neurol Volume 17, Number 3, September 2004 Humanness in Right Hemisphere FTD Procedures The 16 FTD patients underwent computerized tests of human facial recognition (Fig. 2). 23 Part I assessed the threshold of face recognition. The comparison was between a masked image and a human face. Part II assessed the threshold to recognition of humans versus animals in morphed faces. Part III assessed the threshold for recognition of human compared with distorted or alien faces. These 3 tasks involved presentation of filmstrips consisting of sequences of 15 images. The stills of the filmstrips showed a gradual transition to and from a human face. The 30 filmstrips were randomly presented. Each part contained 10 filmstrips, and each of the 10 filmstrip presentations contained 5 trials in ascending order and 5 trials in descending order. Participants were instructed to press yes or no keys when they felt that each image was definitely a human face. Their responses advanced the film- FIGURE 2. A, Example of masked face filmstrip (part I). B, Example of human-animal morphed filmstrip (part II). C, Example of distorted faces filmstrip (Part III) Lippincott Williams & Wilkins 135

4 Mendez and Lim Cog Behav Neurol Volume 17, Number 3, September 2004 strip to the next still. Average threshold scores were obtained for each of the three parts. RESULTS The 2 patient groups did not differ in age, sex, years of education, or measures of dementia severity (Table 1). Although the difference did not reach statistical significance when compared with the FTD-R group, the FTD-L group had lower MMSE, category fluency, and confrontational naming scores on these language-dependent measures (Table 2). Both FTD groups had low delayed word list recall scores. The two FTD groups did not differ on the other neuropsychological tests including Famous Faces Recognition, Benton Facial Recognition, Recognition of Facial Emotions, or Animate Inanimate Recognition. On the computerized tests of facial recognition, the FTD-R patients called more morphed and distorted faces definitely a human face compared with the FTD-L patients and the normal controls (Table 3). The three groups were compared with one-way analysis of variance (ANOVA) tests. On part I, there were no differences on human face recognition TABLE 2. Frontotemporal Dementia Patients Neuropsychological Test Results: Means (Standard Deviations) for Right (FTD-R) and Left Predominant (FTD-L) Groups Tests FTD-R FTD-L CDR a 1.6 (0.9) a 1.3 (0.8) a MMSE b 26.0 (2.4) 22.8 (3.5) b Category fluency (animals/minute) 11.5 (3.5) 7.6 (3.6) d Boston Naming Test (15-item version) 11.4 (2.8) 9.4 (2.2) d CERAD c memory test (10 words) Trials I III (30) 13.4 (6.7) 12.2 (2.4) Delayed word list recall (10) 4.5 (3.2) d 2.3 (2.3) d True false memory recognition test (20) 17.2 (2.2) 17.5 (2.9) Constructions (circle, rhombus, rectangles, cube) 10.3 (0.8) 10.4 (0.9) Famous Faces Recognition (n = 24) 20.1 (2.0) 21.1 (1.4) Benton Facial Recognition (n = 54) 42.5 (2.1) 44.1 (2.2) Pictures of Facial Affect (n = 48) 34.3 (1.5) 36.9 (2.1) Animate Inanimate Discrimination (n = 20) a Clinical Dementia Rating Scale. 16 Both groups mildly to moderately impaired. b Mini-Mental State Examination. 17 FTD-L group below 24, suggested cutoff for dementia. c Consortium to Establish a Registry in Alzheimer s Disease. 18 d Less than first percentile compared to normal age-adjusted controls. 18,49 Comparison norms for face tests included: Famous Face Recognition, 21.4 (2.4); Benton Face Recognition, 45.4 (4.0); and Pictures of Facial Affect, 37.2 (4.3). There are no norms for Animate Inanimate Discrimination. TABLE 3. Frontotemporal Dementia (FTD): Computerized Test Results a FTD-R: Right Hemisphere Predominant FTD by SPECT or PET FTD-L: Left Hemisphere Predominant FTD by SPECT or PET Normal Controls Part I 7.34 (0.89) 7.41 (0.83) 7.39 (0.74) Part II 6.38 (0.92) b 7.63 (0.92) 7.46 (0.66) Part III 5.13 (0.83) b 6.25 (0.89) 6.04 (0.81) a The lower the number, the lower the threshold for describing filmstrip images as looking like human faces (max = 15). b Significantly lower thresholds for calling morphed (part II) or distorted (part III) faces definitely a human face. thresholds between the groups. On part II, there was a between-group difference [F(2,37) = 7.05, P < 0.01] with post hoc Tukey-B and Scheffé tests at the 0.05 level showing significant differences between the FTD-R patients and the FTD-L patients and between the FTD-R patients and the normal controls. On part III, there was a between-group difference [F(2,37) = 4.58, P < 0.05] with post hoc Tukey-B and Scheffé at 0.05 level showing significant differences between the FTD-R patients and the FTD-L patients and between the FTD-R patients and the normal controls. DISCUSSION In this study, frontotemporal dementia patients with predominant right hemisphere involvement were overinclusive in describing morphed or distorted faces as human. This inclusiveness was independent of the ability to recognize and discriminate faces, interpret facial emotions, or appreciate the distinction between living and nonliving things. The results of this study suggest that FTD and other diseases can disturb a right frontotemporal network for person recognition by affecting an innate sense of humanness in the brain. 4,5 Loss of social awareness and loss of feeling for other human beings are core diagnostic features of FTD. 1 Those patients with asymmetric right frontotemporal involvement have more disturbed social behavior than FTD patients with asymmetric left frontotemporal involvement. 2,3 FTD-R patients are impaired in their ability to empathize with others and may even manifest sociopathic behaviors. 3,24,25 A decreased sense of humanness from right frontotemporal dysfunction could underlie some of these behaviors. 4 Support for an appreciation of humanness as part of a person recognition network comes from documented right frontotemporal systems for human faces, facial emotions, knowledge of living things and persons, and the concept of theory of mind. Prior investigations suggest that the right hemisphere is involved in a sequence of stages leading to the Lippincott Williams & Wilkins

5 Cog Behav Neurol Volume 17, Number 3, September 2004 Humanness in Right Hemisphere FTD appreciation of other people. The right inferior occipitotemporal fusiform gyrus face area is selectively involved in the perception of human faces, 6,7,26 and the right anterotemporal lobe and amygdala contribute to the recognition of human faces The right superior temporal gyrus, amygdala, and orbitofrontal cortex respond to facial emotions and contribute to a sense of familiarity of faces. 7,8,30 35 The appreciation of humanness may facilitate the transition from facial perception to the recognition of human faces and facial emotions. There are functionally segregated, discrete regions in the right anterior temporal lobe for semantic knowledge of living things, including people. 36,37 Right anterior temporal lesions disproportionately impair knowledge of living things as compared with knowledge of inanimate objects. 12,15,38 42 This deficit in animate knowledge may be limited to subordinate categories such as distinctions of land animals, sea animals, fruits and vegetables, and people. 5,43 Although knowledge of people is bilateral, 5,44,45 the right side is particularly important for person recognition because of linkages to the recognition of faces and facial emotions. 5 Right anterior temporal lesions or dementia can impair access to person-specific knowledge of faces, facial emotions, voice, and other modalities. 5,13,27,38,46 A sense of humanness elicited by the recognition of faces and facial emotions may mediate access to person-specific knowledge. A sense of the humanness of others could be the mechanism that elicits theory of mind. This term refers to the ability to accurately represent the mental state of another individual. 9 Theory of mind facilitates inferences about the feelings of others, a critical prerequisite for experiencing empathy. 10 It can be disturbed in FTD patients and those with orbital-medial or dorsolateral prefrontal and amygdalar lesions, especially on the right. 9 11,47 Theory of mind appears to be part of a more extensive network for person recognition involving the right frontal lobe and its temporal and cingulate connections. A sense of humanness may not only lead to but also help bind the elements of this network. There are alternative explanations for the results of this study that do not invoke a sense of humanness. Although the possible effects of face perception and facial emotional recognition were excluded, this study did not control for the effects of empathy and theory of mind. Another potential variable is greater disinhibition in responding among the FTD-R patients compared with the FTD-L patients. This potential explanation is unlikely because the presentations were counterbalanced, and there were no group differences on part I, the masking task. This study initially expected the FTD-R patients to be underinclusive rather than overinclusive in calling faces human. The unexpected overinclusiveness, however, may indicate that the sense of humanness becomes less discriminating and more diffuse. Finally, because most of the FTD-R patients had right temporal hypoperfusion, the group differences could indicate more right temporal than right frontal involvement. The relatively small number of subjects makes this determination difficult; a larger study is needed to explore quadrant differences. The literature and this study suggest that a sense of humanness, which is damaged in FTD-R, facilitates a right hemisphere network for person recognition and appreciation. Much of human social cognition may depend on recognizing humanness. This attribute has evolutionary value, and there is evidence that preverbal infants already distinguish between humans and mammals within the animate domain. 48 This preliminary study proposes that facial and emotional perception elicits a sense of humanness that enables access to personspecific knowledge, theory of mind, and empathy. Clearly, more research is needed to establish the existence of a sense of humanness, especially in relation to theory of mind and empathy. REFERENCES 1. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51: Edwards-Lee T, Miller BL, Benson DF, et al. The temporal variant of frontotemporal dementia. Brain. 1997;120: Miller BL, Chang L, Mena I, et al. Progressive right frontotemporal degeneration: clinical, neuropsychological and SPECT characteristics. Dementia. 1993;3: Mendez MF, Perryman KM. 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