Julie Stout's Laboratory

Clinical & Cognitive Neuroscience Research

Research

The main topic of our research program is how the brain's neostriatum affects attentional and decisional processes. The neostriatum is a group of structures that lie deep in the brain (i.e., the basal ganglia), and have historically been associated with movement. This program is making progress in building an explanatory framework that links neostriatal physiology to specific predictions regarding cognition and movement. We have moved away from using traditional clinical neuropsychology methods, which tend to focus on test results as an indication of ability, to cognitive psychology methods, which reveal more dynamic processes associated with behavior.

Finding a Cure For Huntington’s Disease

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a normal polyglutamine (CAG) sequence on chromosome 4. Individuals with the disease typically begin to suffer from uncontrollable movements, psychiatric disturbance, and increasing cognitive impairment in their 40’s; with progressive decline leading to death within 15 to 20 years.

There is no cure for HD. Historically, research has focused on the development of compounds that provide symptomatic and palliative treatment for HD. As a result, intervention studies have targeted patients in later stages of the disease. The ultimate goal, however, is to identify effective treatments that will prevent or delay disease onset. Thus, the next step is to test potentially effective compounds in individuals that are known to have the HD gene, but are not yet clinically symptomatic. Such studies will allow researchers to detect drug effects that 1) delay the starting point at which individuals with the HD gene begin to deviate from healthy controls and/or 2) slow the rate of change in the earliest phases of HD.

Unfortunately, we currently know very little about what measures would be the most valid, reliable, feasible and sensitive to change in this population. The outcome measures that have been used to evaluate treatment effects in individuals clinically diagnosed with HD are not suitable for studies of high-functioning individuals who are not yet showing obvious clinical signs of HD. Thus far, there are no optimized measurement strategies for assessing treatment effects in pre-diagnostic and early HD, and this is essential for examining the effects of compounds for their ability to slow progression or delay the onset of the disease.

In the lab: The HD Toolkit Project

Early Detection of Behavioral Changes Associated with Imminent Huntington Disease

Huntington disease is an autosomal dominant disease that typically shows onset in adulthood and is fully penetrant. That is, individuals with the Huntington disease gene (an expansion of the CAG triplet repeat on the short arm of chromosome 4) have a 50% probability of passing on the Huntington gene to each of their offspring. There has been a long line of research documenting the presence of Huntington-related symptoms prior to the onset of chorea. These symptoms, which encompass psychiatric, cognitive, motor, and other behavioral and personality disturbances have been reported retrospectively in many clinical studies. Prospective documentation for these symptoms, and a timeline that defines the onset and progression of symptoms prior to meeting the chorea-defined diagnosis, has been much more elusive.

In the lab: PREDICT-HD

Risky Decision Making

The neostriatal structures function as components in brain circuits that have regionally specific constituents in the frontal lobes, with projections to the striatum, and then via additional structures, feed back into the same area of frontal cortex. Theories about this brain circuitry suggest that damage in the frontal cortical regions or in the other projection regions of the circuit can produce similar dysfunction of the circuit and thus behavioral disruptions may appear similar regardless of the level at which the neural circuit is disrupted.

Modeling of Decision Making

The Iowa Gambling Task has now become a very popular method of examining decision-making deficits exhibited by brain damaged, psychopathic, antisocial personality, and drug abusing populations. However, performance on this task is confounded by complex interdependencies between cognitive, motivational, and response processes, making it difficult to separate and identify the specific processes responsible for the observed behavioral deficits.

In the lab: NIDA

Huntington's & Parkinson's Diseases

We have made extensive use of two human neurodegenerative diseases, Parkinson disease (PD) and Huntington disease (HD) as model systems for studying the relationship between neostriatal brain circuits and adaptive behavior. The neostriatum is a group of structures in the brain that receive extensive inputs from all levels of the nervous system, including those known to process sensory, perceptual, motivational and emotional information, as well as higher level cognitive information related to goals and strategies. The most basic model of the role of the neostriatum in behavior is that it serves a gating or filtering role, allowing some inputs to cause a movement or other response, while preventing the influence of other less salient inputs. A version of this theory that provides greater detail is the action selection theory.

PD and HD have striking similarities and differences both in their behavioral expression and in their pathophysiology. Behaviorally, PD is associated with a personality style that is cautious, conservative, and deliberate, whereas HD is associated with disinhibited and emotionally erratic behavior. From the perspective of pathophysiology, in PD, the neostriatum is rendered less responsive to inputs due to depletion of the neurotransmitter dopamine. In Huntington's Disease, damage within the neostriatum leads to erratic cellular activity in the neostriatum, reducing fidelity of the coupling of multiple inputs to biased outputs in the motor system. The effect of this decreased neostriatal coupling of inputs to outputs may allow some incoming commands to gain undue influence over action selection, while others may fail to exact their normal effects.

In the lab: PD Study

Frontal behavior syndromes

Neurodegenerative diseases produce a broad array of behavioral disturbances, but the frequency and significance of these behaviors in everyday life is not known. In part, a conceptual framework for classifying these disturbances has been difficult to find, and in turn, there have been few effective measurement approaches that permit systematic study of these symptoms.

In 1992, a new instrument, published now as the Frontal Systems Behavior Scale (FrSBe, formerly the Frontal Lobe Personality Scale or FLOPS), was devised to measure a subset of behavior disturbances. The FrSBe is a behavioral rating scale was developed by identifying those behavioral disturbances associated with damage to frontal-striatal neural circuits.