The purpose of this protocol is to test a comprehensive model of the underlying knowledge representations stored in the human prefrontal cortex developed by the principal investigator. Utilizing a variety of standardized and experimental neuropsychological tasks and techniques, we will investigate hypotheses regarding the role of the dorsolateral prefrontal cortex in planning, problem-solving, and reasoning and the ventromedial prefrontal cortex in social cognition and emotional processing. We will ascertain the relationship between so-called "cold" cognitive processes such as planning and "hot" social processes such as attitude formation and specific brain regions within the prefrontal cortex. Besides cognitive paradigms, we will use skin conductance and event-related EEG recording techniques when subjects are performing selected cognitive tasks in order to determine the relationship between autonomic and central nervous system markers of emotional modulation and speed/duration of processing and task performance. The data we collect in this protocol will be of value in 1) Developing a model of the forms of knowledge representation stored in the human prefrontal cortex; 2) Developing outcome measures for drug and behavioral treatments for disorders of prefrontal cortex functions; and, 3) Developing biologically plausible computer models of the cognitive sub-components stored in the human prefrontal cortex that compose the complex skills referred to above.

• INCLUSION AND EXCLUSION CRITERIA:

Controls: Healthy normal controls matched to specific patient groups for age, education, gender, and race to be recruited by advertisement from the community or from among friends and relatives of the patient. Individuals with a neurological or psychiatric history or medical condition that would compromise our interpretation of the test results will not be included.

Patients: Patients will be selected from referrals to the Cognitive Neuroscience Section, the NIH Clinical Center, and from referrals recruited through approved advertisement in appropriate media and medical journals.

All patients must have a diagnosed CNS disorder with lesions localization (when suspected) verified by CT or MRI scanning available from the referring physician or completed at the NIH Clinical Center. Subjects without neurological, neuropsychological, and imaging evidence compatible with one of the recruited diagnoses will be excluded from the study as will subjects who cannot cooperate with neuropsychological testing (based on family report and the report of the referring healthcare professional).

The bulk of the patients recruited for this protocol with have focal or degenerative lesions of the HPFC. We also will recruit patients with non-frontal lesions in order to determine the specificity of the deficit we observe in patients with HPFC lesions. These patients will undergo the same testing but are not expected to have marked cognitive deficits on tests of frontal lobe function.

Patients with different basal ganglia disorders or limbic system lesions are included because their lesions involve differing subsets of subcortical structures that are thought to play an important role in the automatic activation of stored plans and social behavior. Another prediction from the SEC model is that patients with basal ganglia disorders will have deficits primarily on over-learned components of tasks that require visuomotor interaction (e.g., a visuomotor serial reaction time task) but have spared performance on higher level cognitive planning tasks that don't require simple visuomotor responses.

The bulk of the patients will be patients with focal penetrating head injuries who will be seen here at the NIH as part of a newly funded study to be conducted primarily, but not solely, at the National Naval Medical Center. Patients with dementing disorders (e.g., frontotemporal dementia) are suitable for assessment of the structure of knowledge, and in particular, the systematic general breakdown of social and non-social SEC knowledge representation. Patients with focal lesions (e.g., dorsolateral frontal) will be studied to assess damage to specific sub-components of the structured event complex model. Occasionally, single cases will be intensively studied due to a unique behavioral presentation (see above for a lengthier description).

A durable power of attorney will be appointed if the patient is unable to make decisions about any or all aspects of this protocol. In the past in our protocols, this has almost always been the spouse.

The age range of the brain-damaged patients will be determined on entrance into the protocol. An equal number of left and right unilateral lesions will be sought for determination of laterality differences. Patients with lesions limited to (rather than simply including) the frontal lobe will also be especially sought.

Minors (ages 6-17) are included in this protocol in order to examine 3 specific questions: (1) What is the distinction in retrievable SEC knowledge (e.g., plans or social rules) learned prior to adolescence from that subsequent to adolescence?; (2) Does learning and development of all aspects of social cognition require an intact prefrontal cortex?; and (3) Will some effects of early prefrontal cortex lesions only appear after the age of 14? The first question will be addressed by studying healthy normal children before the age of 14 on experimental social cognition and planning tasks slightly modified from those used with adults (see the six studies described above). The second question will be addressed by studying single cases and groups of children with prefrontal cortex lesions on social cognition tasks before and after the age of 14. The third question will be addressed by studying children with prefrontal cortex lesions incurred before the age of 14 both before and after the age of 14 on social cognition, meta-cognition, and planning tasks.