Cortico-basal control of action selection

 

Control and flexible modification of behavior, termed executive control, are essential to functioning in a dynamic environment.  Executive control impairments have been described in several neuropsychiatric conditions, including schizophrenia, Parkinson's disease, ADHD, and others.  These impairments have been found to have significant effects on daily functioning, including employment and the ability to live independently.  Understanding the etiology of these deficits in patient populations, however, requires a precise understanding of how executive control is instantiated in the healthy brain.

We are currently investigating the neural networks involved in the control of action during performance of two oculomotor tasks, with a specific focus on fronto-striatal pathways.  We are investigating both functional and anatomical connections between these regions using a combination of functional MRI and diffusion weighted imaging.  Studying cognitive control of saccadic eye movements holds a particular advantage over studying other response systems as the underlying neural circuitry has been well-mapped in non-human primates and the subtle dynamics of saccadic eye movements have been investigated in human and non-human psychophysiological research.  This basic knowledge of how the brain instantiates such a movement gives us a unique leverage on understanding how the brain controls, inhibits, and monitors these movements. We are using two oculomotor paradigms to investigate these questions.

The saccadic search-step paradigm requires making a saccade to a visual target unless the target jumps to an alternate location.  On such trials, the subject is instructed to inhibit the response to the first target and redirect gaze towards the second.  This task is similar to the better-known stop-signal or countermanding paradigm, and formal mathematical modeling has shown that the latency to redirect the movement, called the target step reaction time (TSRT), can be estimated.  Along with measures of response inhibition, this paradigm allows for investigation of subtle error-based performance adjustments (e.g. error corrections) and reaction time adjustments based on trial history (e.g. post-error slowing).   The neural basis of performance in this task has been investigated in non-human primates, with an emphasis on the frontal eye fields (FEF) and medial frontal cortex.  Further, the known circuitry of the saccadic eye movement system would predict an important role for basal ganglia structures in inhibiting a response and monitoring whether a response was one's intended outcome.  This role, however, has yet to be fully-elucidated in either humans or non-human primates.

In our second paradigm, the saccade capture task, subjects are instructed to look at a target.  Sometimes, a sudden and unexpected item can appear elsewhere that needs to be ignored.  Often, attention is "captured", and gaze is directed towards the irrelevant item.  The frequency of "capture" is a good measure of distractibility and very likely depends on the integrity of pathways that connect the striatium with cortical structures, such as the FEF. Indeed, in a recent Transcranial Magnetic Stimulation study, we showed that stimulation of FEF altered the proportion of trials in which attention was captured by a distractor.

Given the well-established role of dysfunction in frontal cortex and basal ganglia in neuropsychiatric conditions associated with executive control impairments, delineating the role of these regions in saccadic search-step and capture task performance would contribute importantly to our understanding of these cognitive deficits in patient populations.

Neural basis of cognitive control symptoms in schizophrenia

Executive control and flexible modification of behaviour on the basis of feedback are essential to adaptive functioning in a dynamic environment. Schizophrenia is associated with impairments in a range of cognitive functions that underlie behavioural flexibility. These deficits predict functional outcome better than clinical symptoms, are observed before formal onset of the illness, and have been found in healthy relatives of patients. Thus, these cognitive impairments are thought to reflect underlying vulnerability towards the disease and are major targets for pharmacotherapy. We are examining the etiology of executive control impairments in patients with schizophrenia and their healthy first-degree relatives, using the double-step task in combination with eye tracking and functional magnetic resonance imaging (fMRI). Furthermore, we are using diffusion tensor imaging (DTI) and 1-proton spectroscopy (1H-MRS).

By generating understanding of mechanisms, which underlie disrupted cognitive control in schizophrenia, new avenues for behavioural and pharmacological treatment can be created. The potential benefit to society in the future is considerable if the findings lead to optimization of treatment strategies and accurate predictions of treatment response.

 

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