Abstract

Beyond the Numbers: Expanding the Boundaries of Neuropsychology was Dr Perry's 2007 presidential address in the annual conference of the National Academy of Neuropsychology. In his address he discussed the achievements of the science of neuropsychology and highlighted some areas that exemplified the expansion of the boundaries of neuropsychology. These areas are: (i) the study of neuropsychological functioning in new or non-traditional populations, particularly seemingly healthy people and people with non-brain diseases; (ii) the interface of cognition and genetics; (iii) the use of the process approach as a means of understanding brain functioning; and (iv) a translational application to the science of neuropsychology.

My dear colleagues, tonight I am going to talk to you about the science of neuropsychology, because as we all know it is our science that informs and drives our clinical practice. It is clear that the science of neuropsychology has advanced beyond proof-of-concept studies. It is now universally accepted that neuropsychology offers a powerful and useful paradigm for understanding brain functioning and through this paradigm our community of researchers has made significant contributions to the understanding of dementia, epilepsy, AIDS, and how the brain influences other biological systems. These contributions have positively affected many peoples' lives, and as a result we have a rich past that we can be proud of. The future of neuropsychological science also offers great promise and opportunity. However, for us to realize our potential and be competitive with the technological advances of our colleagues from other branches of clinical neuroscience, we must move beyond our current comfort zone and expand the boundaries of our discipline and extend beyond our focus on numbers.

I believe that neuropsychology and neuropsychologists are well-positioned to take on a leading role in advancing cognitive science, because we fully embrace the importance of working in a collaborative fashion and facilitating interdisciplinary research. We recognize that many of the major advances in brain science are an outcome of working with scientists from a variety of disciplines. What results from our collaborative efforts is that the methodologies and instruments that were the exclusive province of a given discipline are now shared by several specialties. The advances that we have made to science have transformed and advanced the paradigm of neuropsychology while contributing to the perspective of other disciplines. The result of our contributions is that cognitive science now has new and powerful tools of inquiry. In other words, our contributions have enriched the disciplines of our colleagues and their contributions have allowed neuropsychology to expand our boundaries in ways unforeseen just a few years ago. For example, it had been suggested that when neuropsychologists first began applying brain-imaging techniques to study cognition that we misused the tools and confused artifact with real discovery. Now neuropsychologists are considered among the leading experts in the field and our contributions have improved the quality of the entire field of imaging by setting up a creative tension between neuropsychology, neurology, neurosurgery, psychiatry, and neuroradiology. This tension state has led to a paradigm shift in how imaging studies are conducted.

Neuropsychology brings many things to science such as a history replete with creativity, a true understanding of basic psychological principles, an appreciation for individual differences, a sophisticated understanding of psychometrics, a comprehensive knowledge of brain functioning, and an appreciation of the application of our work to understanding the human condition. Let me provide an example from the work of Andy Saykin and colleagues (2006) at Dartmouth. They studied three groups of people, one group with minor cognitive impairment (MCI), one group of healthy individuals who had normal neuropsychological profiles, but who had a high number of cognitive complaints and, a third group of neuropsychologically normal people without cognitive complaints. They found a similar pattern of decreased gray matter (GM) changes in frontal and medial temporal lobes in the MCI patients and healthy individuals with cognitive complaints. When they combined all the groups they also found that the degree of GM loss was associated with not only the memory complaints, but also with verbal memory performance deficits. These findings imply that there may be a pre-mild cognitive impairment state that can be identified by neuropsychologists in which early therapeutic opportunities exist for what otherwise would appear to the neurologist as a normal aging person. Taken alone, none of these assessment paradigms, be it clinical assessment, neuropsychological assessment, or imaging would have revealed a complete story about the relationship between cognitive complaints and neuropathological changes among the elderly. Combined together however, our colleagues' work illustrates what can be learned when a discipline expands beyond its comfort zone and expands its boundaries.

My friends, the science of neuropsychology has evolved beyond a science simply focused on psychometrics and numbers. We no longer see our role as explorers, who are in search of the ever-elusive hidden lesion. Now that we have taken down those partitions that limited us because of an allegiance to a particular neuropsychological battery or approach, we have become complete brain scientists who are the leaders in the practical application of clinical neuroscience, and our domain now ranges from the gene to phenotype.

As our science advances, so does our clinical practice. And as we expand our tool box beyond our traditional paper and pencil tests, the opportunities for an expanded clinical practice will be realized. One has to look only at the recently approved Current Procedural Terminology (CPT) code for functional brain mapping as an example of our progress. Neuropsychologists will be allowed to report neurofunctional brain mapping by magnetic resonance imaging in response to tests administered and correlate those findings to specific brain functions. Who would have thought the day would come where this would be acceptable?

There have been so many remarkable advances in neuropsychology over the past few years that we are barely able to adjust our methodologies to take full advantage of our transformed science. Tonight I would like to select several areas that I believe are particularly exciting and that exemplify the expansion of the boundaries of our science. These areas are: (i) the study of neuropsychological functioning in new or non-traditional populations, particularly seemingly healthy people and people with non-brain diseases; (ii) the interface of cognition and genetics; (iii) the use of the process approach as a means of understanding brain functioning; and (iv) a translational application to the science of neuropsychology. This is not intended to be an exhaustive list and perhaps not even the most representative of the new directions of our science but it is a sampling of areas that I am most familiar with and offer an example of the changing landscape of the science of neuropsychology. While I will present work from my laboratory and that of my colleagues, there are many outstanding examples of work from around the world.

The Study of Neuropsychological Functioning in New or Non-traditional Populations

It is well-established that neuropsychology plays a critical role in the science of brain disorders, but in recent years we have made far-reaching contributions in the areas of study of seemingly normal populations and in populations where the central disorder is focused on organs other than the brain. Take for example a study that we (Perry & Crean, 2005) completed several years ago in physicians who were cited by the California Medical Board for professional infractions, none of which were related to substance abuse or mental illness. In many cases it appeared that these individuals were nothing more than the wrong person in the wrong place at the wrong time. In fact, the California Medical Board was initially surprised that we chose to assess these individuals using a neuropsychological battery because it was anticipated that as physicians they would perform in the superior range of functioning. Although few, if any, of the 200 subjects complained of cognitive difficulties. We found that as a group their WAIS-R (Wechsler Adult Intelligence Scale-Revised) performance hovered below expectation and much of their performance was considerably below expectation given their educational status. In fact, up to 30% of the group scored at least one standard deviation below the mean on the Category Test and on a complex figure learning measure, and up to 42% scored at least one standard deviation below the expected mean on a Numerical Attention Test. I hardly think that one would argue that we lack ecological validity to support our claim that a surgeon who has difficulty copying the complex figure is vulnerable to performance problems when that performance requires accuracy of detail and eye–hand coordination.

Neuropsychology has also played an increasing central role in educating the scientific community about the relationship between general health status and cognition. This past year I have begun working with a bariatric population. This represents a new and needed population to study because over 70% of older adults in the USA are overweight or obese. In preparing to do this work I came across the work of Gunstad, Paul, Cohen, Tate, Spitznagel, & Gordon (2007). They have repeatedly found that obese individuals have impaired neuropsychological test performance compared with a normal weight group particularly on measures of executive functioning. They also show a moderate association between overall body mass index scores and neuropsychological test performance independent of obesity. Although these effects sizes are moderate, at best they show a consistency between weight and cognitive functioning, which provides an opportunity for neuropsychology to participate in public health initiatives by demonstrating a direct relationship between overall good health status and cognitive status. These are just a few examples of the contributions that neuropsychology has made to the understanding of the cognitive status of seemingly normal populations. Now I will switch to another very striking body of work that is still unfolding.

With the high rate of drug abuse in the world we have an epidemic of people who are infected with the Hepatitis C virus. Approximately 5 million Americans and 200 million people worldwide are infected. Soon after the discovery of the virus in 1989 (formally known as non-A non-B Hepatitis), the hepatology field was confronted with a relatively silent condition. Although the liver can begin to be damaged within as little as 15 days, the liver damage is neither revealed on common laboratory tests nor are patients symptomatic. The most common reason that patients were appearing in their physician's office, however, was because of their cognitive complaints. Their complaints were often disregarded because it was assumed that unless patients had cirrhosis they would not have cognitive problems and if they had cognitive complaints often described as “brain fog,” it was attributed to fatigue, depression, or their pre-morbid history of drug use.

Starting in approximately 2000 Robin Hilsabeck, then a post doctoral fellow working with myself and Tarek Hassanein, a noted hepatologist, began assessing patients for cognitive functioning in a tertiary care setting. In our original publication in 2002 (Hilsabeck, Perry, & Hassanein, 2002) we reported that patients with Hepatitis C virus, who were otherwise asymptomatic and not expected to show cognitive deficits, were in fact demonstrating impairment similar to patients with other liver disease, particularly in the area of attention and psychomotor speed. We also found that Hepatitis C appeared to have a second independent “hit” on the cognitive system compared to those people with other liver diseases.

Since our original paper, and an accompanying paper by Forton and coworkers (2002) in the journal Hepatology five short years ago, greater than 40 papers have been published from colleagues worldwide supporting our findings. Collectively most of the studies have found that there was little relationship between cognitive performance and viral load, genotype, liver enzymes abnormalities, history of IVDU (intravenous drug use), and alcohol use. Based upon our studies and the work of others we proposed that the pattern of deficits of the Hepatitis C group was consistent with what we see in other groups with known sub-cortical pathology. Our neuropsychological findings have now been supported by both spectroscopy work published by Scott Letendre, Igor Grant, and the UCSD HIV Neurobehavioral Research Center group (2007) that showed evidence of the virus trafficking into the basal ganglia and sub-cortical white matter. Because of the increasing contributions made by the field of neuropsychology to the understanding of liver disease, hepatology now holds us in high regard and recognizes our expertise in determining severity of illness, treatment efficacy, tracking improvement in quality of life among people with Hepatitis C and of course in assessing the cognitive functions of people with liver disease.

The contributions made by colleagues in the area of Hepatitis C have affects beyond hepatitis. For example, our group and others have made progress in understanding the effects of interferon treatment on cognition (Hilsabeck, Hassanein, Ziegler, Carlson, & Perry, 2005), an area of importance because interferon is used as the primary treatment for a number of medical diseases and the temporary cognitive and neuropsychiatric deficits are often cause for patients to prematurely withdraw from treatment. And now through a new generation of studies, such as Robin Hilsabeck's work on cytokines and cognition in Hepatitis C, neuropsychology is contributing to the understanding of the inflammatory process and its relationship to cognition.

So from seemingly normal populations who have behavioral problems to people with minor and transient medical conditions, like the migraine patients studied by Dr Sid O'Bryant, Marcus, Rains, & Penzien (2006), to populations with chronic medical disease like the lupus and emphysema populations studied by Dr Elizaeth Kozora (Kozora et al., 2005; Kozora, Emery, Kaplan, Wamboldt, Zhang, & Make, 2008), neuropsychology has increased the awareness of assessing cognitive functioning across the spectrum from seemingly healthy and intact adults to those who have systemic, non-neurological illness.

The Interface of Cognition and Genetics

Recent developments in DNA-based techniques have revolutionized the study of human behavioral genetics. It is through this exciting work that the important relationship between genetic factors and cognition is now widely acknowledged. Genetic research has established a strong case for the importance of genetic factors in many complex behavioral conditions. There is now overwhelming evidence for the existence of genetic influence on specific cognitive abilities. The actual localization and identification of genes underlying variation in cognitive abilities however has only just started.

Most neuropsychologists are familiar with the literature which indicates that specific genetic information (for example ApoE-E4) status may be important in identifying which individuals will progress to meet criteria for Alzheimer's Disease. ApoE-E4 has also been implicated in modifying outcome after traumatic brain injury, cardiovascular disease, and other cerebral events. Although the exact mechanism remains unknown, and there remains some question as to the strength of the association, APOE epsilon 4 allele possession is generally associated with an unfavorable cognitive outcome.

The story of ApoE-E4 is just one among the many emerging that demonstrates the increased role of genetics in understanding neuropsychological functioning. Most of my work has been in the area of cognition and neuropsychiatric disorders where abnormalities of dopamine regulation in the prefrontal and subcortices is the primary area of focus. It has been suggested that there is a potential susceptibility mechanism involving regulation of prefrontal dopamine, which is related to executive functioning and working memory. To study this, my laboratory and others are studying the relationship of a common functional polymorphism in the catechol-O-methyltransferase (COMT) gene to executive functioning in neuropsychiatric patients.

Within the COMT gene, the Val allele has been associated with a decrease in prefrontal dopamine and poorer cognitive functioning, with the exception being cognitive flexibility (Bilder et al., 2002). In contrast, the Met allele is associated with increased prefrontal dopamine and better executive functioning abilities. In a seminal study, Egan and colleagues (2001) at NIH determined that COMT genotype (specifically the Val/Val homozygote) was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test (WCST).

Dr Arpi Minassian followed-up on this work in bipolar manic subjects and again found the expected relationship between allele expression and WCST performance in an allele-related fashion in this diagnostic group. Dr Elizabeth Twamley, a UCSD colleague, is funded to study this further. She is finding the expected relationship between poorer performance on measures of executive functioning and the Val/Val homozygote allele, but she has also collected data to support a strong relationship between neuropsychological findings and poor functional ability among the Val/Val group when using a performance measure of functional ability called the UPSA—the UCSD Performance-Based Skills Assessment. This test requires subjects to engage in actual “real life” functions such as buying groceries, balancing a checkbook, and so forth. So now with the use of neuropsychological tools we can begin to draw together a model from genotype to phenotype in which neuropsychology sits in the fulcrum.

As neuroprotective interventions become available, early detection will increase in importance. The combination of genetic and neuropsychological strategies may prove useful for determining individuals at risk for disease before the onset of cognitive symptoms as well as to help predict treatment efficacy.

I now want to shift attention to the topic of the process approach to neuropsychology. The process approach has provided for an exciting area of research partly because it has allowed us to become creative in our thinking and as a result we have learned many things about brain functioning.

Use of the Process Approach to Further Neuropsychological Science

The first college that I attended was Clark University in Worcester, MA, USA. At that time the general orientation of the psychology program was “Organismic Developmental Theory,” an approach developed by the former chair of the department, Heinz Werner. This is the same Heinz Werner who wrote the now critically important paper in 1937 which is the basis of the process approach to neuropsychology. Edith Kaplan, a graduate of Clark University, has championed the “process approach” and has applied it to neuropsychology. The use of the process approach has been a major influence in my laboratory and offers a means of capturing information about brain functioning that might otherwise go undetected. There are three aspects of the process approach that I will discuss tonight: (i) Deconstructing existing measures—Here, I refer to the taking apart or modifying a test in order to better understand the underlying cognitive processes that are required to complete the function; (ii) the creation of new scoring systems that capture information on brain functioning that would otherwise be lost; and finally (iii) the development of new tasks using new techniques for analyzing data to engage in pattern analyses revealing data that has been largely overlooked. Collectively, these approaches are instrumental in revealing signatures that reflect underlying brain processes that might otherwise go unnoticed if we relied solely on numbers.

Let's begin with deconstructing new measures. As I mentioned earlier, the majority of my work has been in the study of the neuropsychology of severe psychiatric illness and no measure in this area has figured more prominently than the WCST. In fact, the early theories of dorsolateral prefrontal cortex deficits in schizophrenia patients were largely pinned on the fact that people with schizophrenia demonstrated WCST performance deficits. Yet, some people question whether the WCST deficits in patients with schizophrenia are not reflecting structural immutable impairment but rather epiphenomena such as amotivation, poor attention, and low intelligence. To address this question several authors studied and found that if you change the nature of test by adding additional instructions, coaching or financial incentive, not surprisingly, the performance deficits can be improved. These findings however, came under attack by neuropsychologists who pointed out that by providing subjects with extra instructions or telling the subject how the test works, dramatically affected the integrity of the WCST. So we threw our hat into this debate and introduced a simple strategy. Dr Eric Potterat and I (Perry, Potterat, & Braff, 2001) studied two groups of schizophrenia patients; one group received the standard instructions for the first 64 cards of the WCST. For the second group, in addition to telling them whether they were right or wrong after each card sort we asked “why did you put that there”? We provided no additional feedback. For the second 64 cards we introduced the experimental intervention to the first group that received the standard administration and removed the intervention to the second group that had initially received the intervention.

What we found was that the group that was simply asked why they placed the card in that location had significantly less perseverative responses than the group given the standard instructions without the additional question. Perhaps, most surprisingly, when this group was compared against a normal comparison group matched for age and education, their performance was equivalent. We also found that those who were first administered the standard WCST followed by instructions demonstrated a relative improvement in their WCST performance but not equal to the performance of those patients who were first administered the modified version. Our findings also confirmed the work of Rob Goldman and his colleagues (Tompkins, Goldman, & Axelrod, 1991) who demonstrated that if schizophrenia patients have already established an incorrect cognitive schema or have initially learned an erroneous response pattern they are less able to change even in the face of an intervention.

Consequently, in addition to illustrating how we can deconstruct a test without significantly affecting the underlying integrity of the measure, these results offer promise and an opportunity for neuropsychology to have input into rehabilitation strategies. For example, despite poor baseline cognitive performance, patients may be able to compensate for their deficits and improve performance when we provide a compensatory aid such as enhanced focus or attention to a task, which may “jump start” their fractured inhibitory processes. This is an example of a simple manipulation leading to a simple set of findings that offer rich clinical information and illustrate the wide-spread contributions that neuropsychology can make to clinical science.

Now let's turn to another way that the process approach can be used to creatively expand our science: Developing new scoring methods. This has been written by Amir Poreh (2006) who refers to this as the Composition Paradigm; where new indices are developed that reflect underlying cognitive constructs.

One area of major focus in past years in my laboratory has been to understand the cognitive basis of thought and language disorders observed in neuropsychiatric patients. To elicit observable examples of thought and language disorder we have used the Rorschach test. And it is from Rorschach protocols that one can observe the perseverative process unfold. In the mid-1990s, Edith Kaplan and I worked on a scoring system that was based in part on a paper that she and Bill Barr wrote on scoring perseverations on the Boston Naming Test (Barr, Bilder, Goldberg, Kaplan, & Mukherjee, 1989). Combining that work with the conceptual work of Martin Albert, Goldberg and Tucker, and others, I developed a perseveration scoring system called the Repetition and Perseveration Scale (RPS) and we applied it to Rorschach protocols (Perry, Potterat, Auslander, Kaplan, & Jeste, 1996). The scoring system classifies three types of repetitions or perseverations: The scoring system takes a while to understand but once learned is applicable to any written transcript. In fact, Dr Leeza Maron (Maron, Carlson, Minassian, & Perry, 2004) published a paper where this method was applied to verbal fluency data. I thought that I would demonstrate the utility of using such a method with the Rorschach by presenting a clinical case of a young woman who was referred to my clinic some years back for a second opinion. As can be easily seen in her protocol, there is a perseverative theme that runs through all of her responses and almost intrudes into the problem-solving process, interrupting the normal discourse that takes place in communication. We can trace how later responses are primed by earlier responses, suggesting that the semantic node is activated and easily elicited during a later response, exemplifying a fracture in the normal inhibitory process.

  • One that is scored for reoccurrence of objects or subjects;

  • One that is scored for a reoccurrence of an organizational framework;

  • The final one that is scored for a reoccurrence of a word.

We have further examined how this perseverative pattern is revealed at the level of visual processing through visual scanning. Visual scan paths provide a “real-time” and high-resolution index of the cognitive processing of visual information. In a series of studies by Dr Minassian (Minassian et al., 2005), we scanned Rorschach blots into the computer and presented them to schizophrenia patients. We then recorded visual scan paths via a high-frequency infrared camera. We found several interesting results. First, healthy normal people start at the fixation point and do a comparative analysis of the salient features. They use a sweeping visual scan path to analyze the entire blot. In contrast, people with schizophrenia appear to do several things: (i) they spend more time off the blot and do not focus upon the critical or salient detail and (ii) they tend to use a restricted visual processing approach where they “get stuck” on the small detail. Perhaps, the most interesting finding is that this restricted way of visually processing the blot is correlated with the number of perseverations on their Rorschach protocols using the RPS, suggesting that there is a vertical consistency between how someone is processing external information and synthesizing and reporting this information.

I believe that these studies exemplify what we can learn about brain functioning when we creatively assess underlying patterns that would otherwise be lost if we solely relied on aggregate data. So let us now turn to developing new tasks that rely on these new analyses. This work requires that we use sequential pattern analysis rather than summary scores to analyze data.

There have been many measures that have been based upon this approach, most notably from my colleague Dean Delis; these measures include the CVLT (California Verbal learning Test), the DKEFS (Delis Kaplan Executive Functioning Scale), the WAIS-RNI (Wechsler Adult Intelligence Scale-Revised as a Neuropsychology Instrument), and many others from places other than San Diego. The one that I would like to introduce to you is the two-choice guessing task that is named the Choice Task. The version that I will present to you was developed by Dr Martin Paulus.

The Choice Task is a simple task where a house is flanked by a person to the left and right on a computer screen. The subject is instructed to “predict” whether a car will be shown on the left or right side of the computer screen and to press a left or right button so that the person on the screen can meet up with the car. Unbeknownst to the subject, the computer program takes the response of the subject into account and determines a priori whether a response was “correct” or “incorrect.” One can set different contingencies so that we can study how one develops problem-solving strategies in response to different reinforcements in the environment.

We have applied the Choice Task to different neuropsyhciatric populations.

For example, we have published work on autistic adults and found that they respond to the environment when the environment is highly reinforcing. When the contingencies are low, they turn inwards and respond in a highly perseverative fashion (Minassian, Paulus, Lincoln, & Perry, 2007). Our work in bipolar manic patients (Minassian, Paulus, & Perry, 2004) revealed that if you reinforce the correct response the person with mania is more likely to continue to engage in the correct behavior, whereas the person with schizophrenia will initiate a behavioral strategy that is highly fixed, independent of contingencies, and resistant to change (Paulus, Perry, & Braff, 1999). Dr Paulus and colleagues (2002) studied amphetamine addicts on the Choice Task combined with imaging and found that they are less adaptive to switching after incorrect guesses. This behavioral pattern was related to reduced bilateral dorsolateral prefrontal cortex activation. Panic-disordered patients exhibited high unpredictability (switched more frequently) at low error rates suggesting that they are searching for different correct responses even when they are correct.

These studies demonstrate the wealth of information that can be obtained beyond the numbers when we apply new methodologies to the study of complex cognitive phenomena. The choice task is a simple task, yet one that offers a wealth of information and an opportunity to better understand the cognitive underpinnings of neuropsychiatric disorders.

Next, I would like to discuss an area that has emerged as a critically important opportunity for multidisciplinary collaboration and offers great promise to neuropsychology, which is translational studies.

A Translational Application to the Science of Neuropsychology

Translational studies typically refer to studies where human cognitive measures are developed or translated for use in primates and rodents. The utility of this approach is that cognition can be targeted in revamping neurobiological hypotheses, in screening drugs, and in establishing behavioral phenotypes of gene-targeted studies. Take for example the Conner's CPT. During the Conner's CPT the subject is required to click the mouse whenever any letter except the letter ‘X’ appears on the computer screen. Dr Jared Young and his colleagues (2004) have developed a version of the Five-choice Serial Reaction Time Task where genetically engineered and pharmacologically altered rodents are tested. When a single light cue appears in any one of the five holes, the animal responds for a reward, but if the light comes on in all the five holes it has to inhibit the response; thus the no-go condition. This is just one of a number of examples of cognitive measures that have been developed as an analog to a human measure.

However, the advances achieved in animal research on cognition can also direct the development of human cognitive measures, this is referred to as “reverse translational paradigm,” where the common behavioral paradigms that are used to test rodent behavior are revamped for use in humans. One such paradigm is known as the “open field test” (Geyer, Butcher, & Fite, 1985). In the open field test a rodent is placed in a novel environment and allowed to explore. Using an infrared video tracker one can then measure or quantify the characteristics of the animal's exploration in the environment.

What has been discovered using the open field test is that the exploratory patterns reveal a cognitive signature that reflects information at the anatomical, neurotransmitter, and genetic levels about how the animal explores its environment. So, how do we analyze these patterns? This analytical approach requires analyses of patterns rather than aggregate data. So I am going to digress for a moment to say a few words on the principles of chaos theory, which is the basis of our analyses.

The central principle discussed in chaos theory is the principle of fractals; that is a behavior that can be divided into parts, each of which is similar to the original object. Another basic principle is that seemingly random events have an order and if we can characterize this order we can characterize and study behaviors and cognitions that appear disorganized.

Returning to the open field test, we test mice in the open field environment and based upon the fractal dimension concept we analyze the xy coordinates to inform us about the sequence of their exploration. From the xy coordinates, the spatial scaling exponent spatial d is calculated. Spatial d measures the hierarchical and geometric organization of behavior and is calculated based on the principles of fractal geometry. Specifically, spatial d describes the degree to which the path taken within an enclosure by the subject is one-dimensional or two-dimensional. We can also quantify the predictability of their exploratory and motor patterns based upon dynamical entropy or h. The calculation of h, allows us to determine the degree to which behavior is observed along a continuum between complete order and disorder. Using the mouse behavioral pattern monitoring, or open field test, my colleagues led by Mark Geyer have reliably shown different profiles in genetically altered animals as well as profiles of animals administered different drugs that inform us about the role of different receptors in mediating exploratory behavior. We have recently translated this paradigm to be used with humans and refer to it as the human behavioral pattern monitor or hBPM.

The hBPM takes place in a 9' × 14' room that is novel to the human participants and is, therefore, like the rodent BPM, a novel and unfamiliar environment. Along the walls of the room, dispersed evenly on items of furniture, are 10 small objects. These were chosen because they are colorful, tactile, and can be manipulated and consequently invite human exploration. The toys provide an analog of the exploratory holes along the periphery of the rodent BPM. Participants are directed into the room with very little instruction or direction and are asked to wait for the experimenter to return. The hBPM session is 15 min long. Subjects are fitted with a ambulatory recording device called the Life Shirt (Vivometrics, 2002) that allows us to record a subject's acceleration movements. To generate xy coordinates, movements are recorded via a camera embedded in the ceiling. The continuous, high-frequency sampling of motor and exploratory activity allows us to calculate both spatial d and h.

Here is how it can be applied. It has been written that during acute and decompensated states, bipolar manic and schizophrenia patients present with similar symptoms, making it difficult to differentiate between the two diagnostic groups based upon their symptom presentation alone. We tested both bipolar manic and schizophrenia subjects in the hBPM and found distinct exploratory patterns for each groups. Bipolar manic subjects were characterized by increased motor activity in the hBPM and an exploratory pattern that was dominated by long straight movements during their exploration. Their h score was indicative of a highly entropic or disorganized pattern. In contrast, the schizophrenia patients as a group were significantly less active in the hBPM. Their exploratory pattern was also highly predictable but unlike the bipolar manic subject who had broad sweeping movements that led them to explore the entire room, the schizophrenia subjects tended to use a restricted pattern of exploration, not unlike the restricted scan path exploration that I presented to you earlier. In fact, our preliminary data suggest that there are significant associations between the exploratory patterns found in the hBPM and neuropsychological test performance on the measures of inhibition such as the CPT and the Stroop.

Consequently, we have distinct cognitively mediated behavioral profiles or signatures for each of the diagnostic groups. These profiles may reflect different underlying cognitive processes that are consistent, whether it is exploring a novel environment, or scanning a novel and ambiguous visual image. These preliminary results have been very promising and have led us to begin collecting exploratory profiles of different neuropsychiatric populations at various states of their illness and when they are treated with medications. Here we see that by expanding the traditional boundaries of neuropsychological assessment to include novel methods of studying cognition using a cross-species translational approach, we find that the seemingly random exploration of a novel environment is in fact not random, but guided by underlying cognitive processes. The next phase of this work is to deconstruct these processes, link them with other cognitive functions, and associate our findings with neurobiological and genetic information.

To summarize, I have presented you with a diverse collection of studies that illustrate some novel directions of neuropsychology. As we expand the boundaries of our field we will be redefining the populations that we study and the tasks that we use. Our efforts will require us to be collaborative and open to new technologies, new means of data analyses, and a willingness to tolerate the complexity and ambiguity involved in adapting these new techniques into a clinical and practical format.

I am confident that neuropsychology is poised to be cast into a central role in the understanding of brain functioning. Although we can barely imagine where our science will take us, I am certain that with creativity and a willingness to look beyond the numbers we will position ourselves to markedly influence the well-being of our patients and communities in ways we have yet to imagine.

In closing, I would like to personally thank people who have been so supportive to me throughout my career, both professionally and personally. I must begin by recognizing Dr Conan Kornetsky, who took me in to his psychopharmacology laboratory as an undergraduate 30 years ago when I worked across the hallway from Allan Mirsky, who is here in the audience. Dr Bob Heaton first supervised my training in neuropsychology and instilled in me the need to be diligent and careful. Dr Donald Viglione, my teacher and close friend who has always been there for me and has had my back through all my crazy schemes. Dr David Braff, who first brought me on as a post-doc at UCSD and provided me with the opportunity to learn about psychophysiology and to integrate that work with neuropsychology. Dr Eric Zillmer, former NAN President, introduced me to NAN and encouraged me to become involved in its governance. The NAN Board of Directors who has been so supportive and tolerant of me. Dr Ron Ruff, whose style, thoughtfulness, and sophistication have been a source of inspiration and support. Dr Jeff Barth, I can't begin to tell you how important his support has been to me. I remember Jeff sitting me down at lunch 8 years ago and saying, “you will be president of NAN someday and although I was flattered, I thought to myself that is the craziest idea that I have ever heard.” But he was right and I know that I could not have made it through this year without his reminding me of which “juice was worth the squeeze.” Thank you my friend. Dr Marc Norman, my colleague and friend who has had to put up with me and read my complaining e-mails at ungodly hours in the morning. Dr Arpi Minassian, I can't say enough about Arpi. We have worked side-by-side for many years. Much of the work that I present today is a reflection of her efforts and certainly a great deal of the creativity and sophistication is due to her merits. Dr Becky Crean, my wonderful partner, friend, and support. She has put up with so much and I know that under the best of circumstances that is asking a lot. And finally, my true inspiration, my children, Lucas and Olivia. There is nothing that I do where I don't draw from their love. Thank you all for your attention.

Funding

Some of the work described in this paper is supported by NIH grant R01-MH071916.

Conflict of Interest

None declared.

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Author notes

William Perry's presidential address at the Annual Conference of the National Academy of Neuropsychology in Scottsdale, Arizona, October 2007.