Dopaminergic Mechanisms of Frontal Lobe Syndrome Following Traumatic Brain Injury
C. E. Dixon, P.I.

Frontal lobe syndrome is the hallmark functional response to virtually all magnitudes of traumatic brain injury (TBI) in humans. Frontal cortex activity is critically involved in "executive" cognitive functions including the generation and monitoring of strategic action, functions essential to complex goal-directed behavior that are frequently impaired following TBI. There is extensive evidence that dopaminergic lesions of the frontal cortex, innervated by mesocortical dopamine (DA) projections, can lead to persistent cognitive and behavioral deficits. However, there is a significant gap in the knowledge regarding the mechanisms of frontal lobe syndrome following TBI. Through a grant from the NIH, we are examining the cellular mechanisms of mesocortical dopaminergic deficits after TBI in a rodent model using biochemical indices of DA autoxidation and biochemical, molecular biological and immunohistochemical indices of DA metabolism and neurotransmission. Neurochemical and immunohistochemical markers of DA neurotransmission in the dopaminergic ventral tegmental/forebrain systems, as well as functional deficits, are being assessed at specific time points following injury. The effects of therapies that either reduce oxidative damage of DA terminals and/or chronically stimulate DA activity on neurochemical and immunohistologic markers, and on functional performance are being examined following TBI. Additional studies are examining the role of DA deficits on septohipocampal cholinergic deficits. Clinical studies are examining the relationship between early biochemical markers of DA activity to neuropsychological outcome measures specific to frontal lobe function will be evaluated in severe TBI patients. Lastly, a CDC-funded clinical study is being conducted to determine the efficacy of the psychstimulant amantadine on neuropsychological measures of frontal lobe function following TBI.

Four Week Sham	Four Week Injury

Figure 1 - Double immunostaining of tyrosine hydroxylase (Brown) and choline acetyltransferase (Blue) in the hind limb of the diagonal band. At 4-weeks post injury, there is a loss of TH positive fibers in cholinergic regions of the medial septal area.

Figure 2 - Daily administration of the dopamine agonist methylphenidate can attenuate cognitive (water maze performance) deficits after TBI.

Figure 3 - PET imaging of dopamine receptor subtype 2 activity measured prior to and after treatment with the dopaminergic agonist amantadine.

Figure 4 - Study design for an ongoing randomized clinical trial of amantadine treatment of frontal lobe deficits following TBI