BAL HARBOUR, FLA—Advances in neuroimaging—particularly when they are combined with innovative application of established tools of psychology such as the Five-Factor Model of Personality—are enabling researchers to map the neuroanatomy of personality.

Leading the way is an enhanced understanding of frontotemporal lobar degeneration, a clinical disorder in which pathological personality traits are expressed in ways not typically seen in other forms of dementia. Recent studies conducted at the University of California, San Francisco (UCSF), Memory and Aging Center indicate that the loss of positive personality traits such as empathy, which helps characterize frontotemporal lobar degeneration, may result largely from damage to specific regions of the brain—namely, the right posterior temporo-occipital junction, the right orbitofrontal cortex, and right temporal structures such as the superior temporal sulcus.

Previous studies had already established that the neuroanatomy of such functions as language and memory can be studied using objective methods. According to the researchers, clear associations between the brain and behavior can also be delineated. This is just one initial step in the process of investigating the neural basis of personality, said Katherine P. Rankin, PhD, Assistant Professor of Neuropsychology at UCSF and a clinical neuropsychologist at the Memory and Aging Center.

“For decades, even centuries, neurologists have been making excellent qualitative descriptions of various [clinical populations], carefully detailing their changes in behavior and social function,” she said in an interview with Neuropsychiatry Reviews. “But until very recently, we haven’t had the tools to quantitatively link these behaviors to specific changes in the brain across large groups of patients.”

VOXEL BY VOXEL

“Based on clinical experience and case studies,” stated Dr. Rankin, “we’ve always had our suspicions” that certain behavior changes are attributable to right-temporal lobe damage. “But we haven’t been able to reliably establish a one-to-one correspondence—where we see that, for instance, patients with a lot of damage in the superior temporal sulcus are statistically more likely to have difficulty reading facial emotions. Though these relationships have been suggested in controls using functional imaging, we had never really had that level of structure-function specificity with these clinical populations.”

To determine a direct correlation between abnormal personality changes and specific regions of the brain, Dr. Rankin turned to an established neuroimaging technique—voxel-based morphometry—and applied it in a novel way. Typically, researchers use voxel-based morphometry to measure the amount of brain atrophy in frontotemporal dementia patients and compare the results with those of controls. The investigators would base assumptions about the differences in behavior between these two groups on the extent of atrophy in the brains of the frontotemporal dementia patients. However, Dr. Rankin and a few other researchers in the field of neurodegenerative disease have applied this imaging technique by conducting a voxel-by-voxel comparison.

“It’s basically a regression analysis, looking in an unbiased way at whether there are particular areas of the brain where the atrophy covaries with the behavior that you’ve measured,” she explained. “To my knowledge, there have been only about five or six papers that have been published so far using this method. But I think this technique is going to be a gold mine.” Dr. Rankin presented her latest findings at the 16th Annual Meeting of the American Neuropsychiatric Association as part of the “Neuropsychiatry of Personality and Its Disorders” symposium.

“NOT THE SAME PERSON”

While the future looks quite promising for continued gains in neuroimaging research, this approach currently has important clinical implications for patients with frontotemporal lobar degeneration and the clinicians and family members caring for them, in Dr. Rankin’s view. “I wish I could get the word out to everybody who sees patients, whether they’re a neurologist, primary care physician, or marital counselor, that frontotemporal lobar degeneration can often start with personality change,” she said.

Such symptoms can occur in individuals who are in their mid to late 40s; the earliest age of disease onset that Dr. Rankin has seen was 36. The average age of onset is young compared with what has been observed in Alzheimer’s disease and other, more traditional dementias. Dr. Rankin recommends to caregivers that if they see an individual who has a significant change in his or her approach to life—if the personality changes, if behavior changes, if he or she does something distinctly out of character—that person needs to be assessed for dementia.

She has found that many of these patients are referred for psychological counseling or psychiatric treatment and in some cases are hospitalized for psychiatric reasons. It can be years before they are diagnosed with frontotemporal lobar degeneration—in part because many caregivers do not realize that the first signs of dementia can be behavioral and that the disorder does not necessarily have to start with cognitive symptoms, according to Dr. Rankin.

“A lot of these patients will undergo cognitive assessment and perform beautifully on executive function tests,” she said. “Yet their family members say things like, ‘They’re not the same person.’”

SEEKING THE RIGHT TOOL

Frontotemporal lobar degeneration encompasses several subtypes, each with distinct anatomic features and functional/behavioral disorders. More than half of all frontotemporal lobar degeneration cases involve frontotemporal dementia, the right or bilateral frontal variant that is marked by such characteristics as emotional deficits, apathy, and impulsivity. Nearly 20% of cases involve semantic dementia, the temporal variant that is marked by language disorder (including progressive loss of verbal and visual meaning—ie, semantic loss) and such behavioral abnormalities as mental rigidity. Patient populations for both of these subtypes are approximately two-thirds male; patients with a third subtype, primary progressive aphasia—the left frontal variant that represents about one quarter of all frontotemporal lobar degeneration cases—are disproportionately female (60%).

In terms of personality changes, core diagnostic features of frontotemporal dementia include a decline in social interpersonal conduct, impairment in the regulation of personal conduct, and emotional blunting—all occurring early and frequently prior to the appearance of any cognitive changes. Supportive diagnostic features of semantic dementia include loss of empathy and narrowed preoccupations. When Dr. Rankin began doing research in this area, she found that investigators had not operationalized these changes, making it difficult to measure patients’ symptoms. Eventually, she discovered that such changes can provide not only key clinical information useful in differential diagnosis but also a mechanism for studying the neuroanatomic structures of personality using an atrophy model.

The study of personality in frontotemporal lobar degeneration poses several challenges to the researcher, as Dr. Rankin learned. First, it raises the question of whether the concept of “personality” even applies to persons with brain damage, forcing investigators to drop any a priori assumptions about the etiology of abnormal personality features. In addition, the frequent lack of insight by patients regarding their predicament means researchers must seek innovative methods, ruling out such standard tools as self-report questionnaires and clinical interviews. Finally, she said, because this is clinical research, which makes it impossible to randomize patients to their diagnostic group, it can be difficult to infer causality. The use of an atrophy model requires cautious interpretation of brain-behavior associations.

“Because such complex behaviors as ‘personality’ are certainly the result of multiple distributed networks of functional circuits, one must be careful not to say, ‘This is where extroversion is located in the brain,’” she stated.

These limitations led Dr. Rankin to consider applying the Five-Factor Model of Personality as a diagnostic tool (see Sidebar). Use of the Five-Factor Model in personality disorders is based on the recognition that although personality is highly variable among people, it remains fairly consistent in normal individuals once it is formed, usually by early adulthood. Therefore, investigators can hypothesize that uniform changes in a clinical population arise from a pathological process inherent to that disease, Dr. Rankin explained. In patients with neurodegenerative disease, change from previous personality can be more diagnostically important than current personality.

Largely for procedural reasons, Dr. Rankin ultimately applied the Interpersonal Adjective Scales personality model, which focuses on just two of the five dimensions comprising the Five-Factor Model—extraversion and agreeableness. However, Dr. Rankin credits the Five-Factor Model with helping her solve some of the challenges of studying personality in frontotemporal lobar degeneration.

“The Five-Factor Model, as far as I’m concerned, and I think as far as most personality researchers would be concerned, is the predominant personality theory,” she said. “The constructs measured by every other personality instrument, every other theory, have been shown to be accounted for by the Five-Factor theory. And that’s true about this measure [the Interpersonal Adjectives Scales] as well…. So I’m a big fan. I think that the NEO [Neuroticism, Extraversion, Openness] Personality Inventory [based on the Five-Factor Model] is a fabulous instrument; it really is the most comprehensive.”

EARLY-WARNING SCREEN

One goal Dr. Rankin has for this particular area of research is to develop tools that clinicians could easily administer to a family member. “If the clinician had the family member fill this [questionnaire] out on a patient—sort of the ‘before and the after,’ how the patient used to be versus how he or she is now—it’s likely that the clinician could actually document a significant personality change that would serve as a red flag.”

It is at this point in the diagnostic process, according to Dr. Rankin’s scenario, that a neuropsychiatrist or another specialist in neurodegenerative disease would be consulted. “I don’t think these tools are sensitive enough yet, at least in their current form” to confirm a diagnosis of frontotemporal lobar degeneration, she emphasized. “I don’t think that would be clinically responsible. Diagnosis should come from a full work-up by people who are expert in neurodegenerative disease; they have to do the full clinical interview, cognitive testing, and MRI.

“But personality testing can actually be an adjunct to that diagnostic process, if there is confusion. And it even can be used as an early-warning screen by somebody who’s not an expert.”

—Fred Balzac

Suggested Reading
Rankin KP, Kramer JH, Mychack P, Miller BL. Double dissociation of social functioning in frontotemporal dementia. Neurology. 2003;60:266-271.
Rankin KP, Baldwin E, Pace-Savitsky C, et al. Self awareness and personality change in dementia. J Neurol Neurosurg Psychiatry. 2005;76:632-639.
Rankin KP, Rosen HJ, Kramer JH, et al. Right and left medial orbitofrontal volumes show an opposite relationship to agreeableness in FTD. Dement Geriatr Cogn Disord. 2004;17:328-332.
Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546-1554.

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