Although each injury is necessarily unique, there are certain brain regions that are particularly vulnerable to damage including the frontal cortex and subfrontal white matter, the deeper

midline structures including the basal ganglia and diencephalon, the rostral brain stem, and the temporal lobes including the hippocampi. Certain neurotransmitter systems, particularly the catecholaminergic42 and cholinergic systems,54 are altered in TBI. Both of these systems play critical roles in a variety of domains important in behavioral homeostasis including arousal, cognition, reward behavior, and mood regulation. Inhibitors,research,lifescience,medical This profile of structural injury and neurochemical dysregulation Angiogenesis inhibitor occurs along a spectrum of injury severity, including “mild” injury.55 The correspondence between the neuropathophysiology of TBI and the common and disabling

neurobehavioral sequelae associated with it is now reviewed. Relationship Inhibitors,research,lifescience,medical of neurobiology of TBI to neurobehavioral sequelae of TBI As noted, there are several high-risk regions vulnerable to the effects of neurotrauma, but it is important to note that these Inhibitors,research,lifescience,medical brain regions are important nodal points in frontal-subcortical circuits that subserve cognition and social behavior. In particular, three major frontal-subcortical circuits have significant roles in nonmotor forms of behavior56 (Figure 2). A circuit arising in the dorsolateral prefrontal cortex modulates executive functions, such as working memory, decision making, problem Inhibitors,research,lifescience,medical solving, and mental flexibility. Another, arising from cells in the orbitofrontal cortex, plays a critical role in intuitive reflexive social behaviors and the capacity to self-monitor and self-correct in real time within a social context. A third circuit starting in the anterior cingulate modulates motivated and reward-related behaviors. Inhibitors,research,lifescience,medical Although not a frontal subcortical circuit, per se, circuits traversing medial temporal regions play critical roles in

episodic memory and new learning, as well as the smooth integration of emotional memory with current experience and real-time assessment of stimulus salience. Thus, the typical old regions vulnerable to damage associated with TBI overlap significantly with key regions and nodal points in these frontal subcortical circuits, making it readily apparent that problems with cognition, social comportment, and executive function, as well as an increased relative risk of specific psychiatric disorders would be common after TBI (Table I, Figure 3). Figure 2. Outline of frontal subcortical circuits relevant to common neurobehavioral sequelae of traumatic brain injury (TBI). Table I. Neural substrates of common sequelae of TBI. TBI, traumatic brain injury; PTSD; post-traumatic stress disorder; GABA, γ-aminobutyric acid Figure 3.