I believe this work is highly cited for two reasons. First, it was the first study of its type—a longitudinal investigation of human brain plasticity after stroke. Because the logistics to accomplish the study were difficult—requiring functional imaging of stroke patients in the first 24-48 hours after stroke and then again at three to six months—it was also the only study of its type in the literature for years.

“The fMRI technique permits one to see the regions of the brain that are active during the performance of a given task— for example the movement or attempted movement of a hand that has been weakened by stroke.”

A second reason it is highly cited is that the findings have stood up over time. Novel ideas are cited frequently in the short term if they strike others in the field as interesting and plausible. In order to continue to be cited, however, a paper’s findings must be replicated and expanded across the scientific discipline.

For this work, our findings were initially replicated in an animal model. Subsequently, additional human studies, including studies using complementary techniques, were brought to bear on the principles that were demonstrated by the original work. The field overall was also expanding; brain plasticity has been one of the most intensively studied areas in neuroscience over the last several years.

The findings in this paper represented both a new observation and a new approach to a problem. The idea of brain plasticity following stroke had been in the literature for more than a decade. Cross-sectional brain imaging studies had reported comparisons of partially- or fully-recovered stroke patients with normal control subjects and showed that brain activation patterns were different between these groups, but the idea to investigate how those differences evolved over time was a new one.

We studied eight acute stroke patients with unilateral weakness in the first 24-48 hours after stroke and imaged their brains with functional magnetic resonance imaging (fMRI). The fMRI technique permits one to see the regions of the brain that are active during the performance of a given task—for example, the movement or attempted movement of a hand that has been weakened by stroke. We were able to show that the alteration in the brain’s motor system after stroke was not only different from normal control subjects, but that the differences changed over time.

The idea that the injury caused more than a static change led to the idea of a dynamic recovery process in which interaction between different brain regions—in particular the 2 hemispheres of the brain—might play different roles in the recovery at different time-points. Furthermore, any system that changes over time must have factors that influence its course.

New lines of inquiry followed. Our lab and others are attempting to elucidate the physiological stimuli that underlie the changes we see on brain imaging. Others are investigating the balance of excitation and inhibition that might influence the interaction between brain regions over the course of recovery. Advances in brain imaging and image analysis have further contributed to our ability to study neuroplasticity in stroke and other brain diseases.

Once fMRI became available in the hospital setting, questions of neuroanatomy and behavior that I had been pursuing with mentors J.P. Mohr, Jeffrey Binder, and Ronald Lazar, could be extended to the otherwise hidden processes of functional neuroanatomy in acute stroke recovery.

Clinical neuroscience is difficult. It must necessarily be undertaken in the highly variable and uncertain environment of clinical medicine. Unlike the strictly controlled settings of bench research and animal laboratories, to pursue rigorous science in the clinical milieu requires both extensive knowledge of the clinical spectrum of disease and a rigorous approach to study design in order to incorporate the intersubject variability into the experimental design and analysis. Our team has consequently expanded to include investigators with additional computational and technical expertise.

The notion that the brain is capable of reorganizing itself to achieve functional recovery has led to an intensive search for behavioral, technological, and pharmacological means to enhance the process. What has been interesting to consider is the spectrum of possibilities to achieve this goal.

It is yet to be determined whether low-tech, intensive, behavioral therapy such as targeted visual stimulation for visual restoration or constraint-induced (forced use) therapy for motor recovery are going to out-perform the highly technical and invasive technologies such as implantable cortical stimulators and cell therapies which are currently being tested.

As we learn more about the mechanisms underlying the recovery process, the full spectrum of ideas will need to be tested through rigorous clinical trial methodology. This will require financial support from government agencies, scientific organizations, industry, and private philanthropy.