In 1848, railway construction foreman Phineas Gage survived a freak accident that put an iron bar right through his skull, but the damage to his frontal lobes led to dramatic alterations in his personality.

In 1861, physician Paul Broca reported on a patient who lost the ability to speak due to a small lesion in the left side of his brain.

And in 1957, a famous patient referred to in medical literature as "HM" became globally amnesic (unable to form new memories) following brain surgery for epilepsy.

These individuals, whose cognitive and behavioral abilities were lost or altered due to destruction of specific areas of brain tissue, are just a few of what UI neuropsychologist Daniel Tranel terms "glorious examples"—the anecdotal cases that underpinned early scientific understanding of the roles different brain regions play in complex human behavior.

"For 150 years our field of behavioral neurology and cognitive neuroscience was built on famous case studies like this," says Tranel, UI professor of neurology and psychology. "The downside is that you are never sure if the particulars of these individual patients can be generalized to all human brains."

Strength in numbers

The desire to move cognitive neuroscience beyond reliance on anecdotal evidence from individual cases spurred Tranel and other UI researchers to establish the Iowa Neurological Patient Registry. The registry collects multiple instances of patients who have experienced brain damage as a result of injury, illness, or surgery, and helps researchers determine if lesions in one specific brain area always produce the same cognitive or behavioral deficits.

"If all people with injuries to the front of their brain, for example, from all causes—disease, trauma, surgery—all have the same personality change, that starts to be a pretty convincing argument that that part of the brain is required for the ability that's been lost," Tranel explains.

The one-of-a-kind registry was established in 1982 under the leadership of renowned husband-and-wife neurologists Antonio and Hanna Damasio, who were then faculty members in the UI Department of Neurology. Tranel, who was a graduate student when the registry started, has been with the program for its entire history and assumed the role of director in 2005, when the Damasios left Iowa for the University of Southern California in Los Angeles.

Over three decades, the registry has enrolled thousands of patients, collecting brain scans that map the patients' brain lesions and compiling medical histories, demographic information, and neuropsychological test results that assess cognitive function and deficit for each participant. The registry currently has more than 500 active members who are available to participate in new cognitive studies.

The fundamental soundness of the lesion-deficit approach lies in what Tranel calls its "inferential strength"—the simple fact that when a part of the brain is removed or destroyed and the patient loses a function, you can infer that this area is necessary for the function.

Unlike animal studies where identical brain lesions can be created in a large group of genetically matched animals to produce a highly controlled experimental model, registry patients are unique individuals who acquired their brain lesions as a result of accident or illness. Registry patients vary widely with respect to age, gender, education, and other demographic factors, and no two registry patients will have identical brain lesions.

The extensive size of the Iowa registry allows researchers to overcome, and even capitalize on, this variation among patients. The neuroimaging data allow scientists to form cohorts of patients whose brain lesions occur in the same location in the brain. Patients with matched overlapping brain lesions are then compared with study participants who don't have lesions in that area for deficits in cognition or behavior, allowing the researchers to hone in on brain areas that are critical for particular cognitive functions.

Methods converge

While the registry was growing through the 1980s and ’90s, another tool for investigating brain function burst onto the research scene. Since the mid-1990s, functional brain imaging, which detects brain activity during cognitive tasks, has developed into a highly popular research tool. Studies using this technique have implicated different brain areas in all kinds of human behavior, from memory formation and language acquisition to personality disorders, addiction, and even political and religious persuasion.

These separate avenues of brain-behavior research—functional imaging and the lesion-deficit method—are now starting to converge, as functional imaging researchers look to the registry data and the inferential strength of the lesion-deficit approach as a definitive tool for testing many of the intriguing ideas about brain function raised by functional imaging studies.

"Every major university now does functional magnetic resonance imaging (fMRI) studies. Cognitive neuroscience is accruing fMRI data at an overwhelming pace, but that approach has well-known limitations. The lesion method remains an indispensable complement in understanding structure-function relationships in the human brain," says Ralph Adolphs, Bren Professor of Psychology and Neuroscience at California Institute of Technology.

Adolphs was a UI faculty member and colleague of Tranel's and the Damasios' prior to his move in 2004 to Caltech, where he heads the Emotion and Social Cognition Laboratory. Adolphs also retains an adjunct appointment in the UI Department of Neurology and continues to collaborate with Tranel on studies using registry data to investigate brain function.

"The University of Iowa’s registry is a gold mine for all of cognitive neuroscience. In terms of the sample size, the depth of neuropsychological assessment, and the care of neuroanatomical characterization, I know of nothing like it in the world," he says.

In recent years, the registry has allowed researchers to identify specific parts of the brain that are required for a multitude of human behaviors, emotions, and cognitive processes, including decision-making and addiction, self-awareness, gullibility, and the ability to feel fear.

Getting old together

Recently, one of the registry's most famous patients, referred to as “Eliot” in Antonio Damasio's books, stopped by Tranel's office just to say hello.

"I've known him my entire career," Tranel says. "He was one of the first patients we ever studied, so he's watched me go from a grad student to the guy running the place."

For Tranel, these long-term doctor-patient relationships are a key reason for the registry's success. He notes that because the research is done within the context of clinicians providing care and treatment to patients, the studies are focused on discovering ways to improve treatments for people affected by brain injury and disease.

Another important feature, he says, is that the majority of registry participants are Iowans.

"The registry works because of Iowa—you could not do this in a big city. These patients are very willing to participate in research studies, they are very loyal to the UI and they tend to stay put—meaning that they are easy to contact over many years," he says.

The fact that the registry continues to grow while retaining many of its participants as they age also opens up exciting avenues of research that have the potential to uncover findings that will be important as men and women continue to live longer and remain active in their senior years.

"One of the really interesting future directions we plan to explore is how the natural aging process has affected our patients," Tranel says. "Some of our patients do incredibly well following even serious brain injury. On the other hand, some patients are in care centers. These different outcomes can occur even when these patients have the same lesion and the same cognitive deficit. Understanding those differences has really important implications for recovery, intervention, and treatment."