A wealth of data has implicated the limbic system, in particular the amygdala and its connections, with conditioned fear in animals and anxiety disorders in humans. These studies have pointed to a complex hierarchical control of autonomic and somatic fear related behavior, with multiple interacting feed forward and feedback loops. Anatomical structures that have been implicated in the fear processing network include the paralimbic and limbic cortices, ventral striatum, amygdala, ventral pallidum, bed nucleus of the stria terminalis, dorsal and midline thalamic nuclei, the anterior, ventromedial and dorsal premammillary hypothalamic nuclei, and somatic and autonomic efffector loci in the periaqueductal gray and pontine and medullary reticular formation. Although there has been a rapid expansion of our understanding about the structural connectivity of fear circuitry, much less is known about the functional dynamics of the network. Progress in our understanding of the expression of fear and stress related behaviors have only begun to offer significant insights into the understanding of the pathophysiology of the anxiety and mood disorders.

MacLean drew on phylogenetic and anthropomorphic data to support his hypothesis that the pathophysiologic basis of many psychiatric symptoms was likely to be found in the connections between the recently evolved neocortex and more ancient parts of the brain. In his triune brain theory, he suggested that the limbic cortex was responsible for emotional experience and that dual processing in neocortical and limbic networks led to the dichotomy in human experience between what we know and what we feel. In the realm of psychopathology, obsessive compulsive disorder (OCD), is the prime example of this dichotomy. OCD is a complex neuropsychiatric disorder of unkown etiology whose cardinal symptoms include intrusive thoughts and images that cause anxiety (obsessions) and repetitive motor or cognitive behaviors (compulsions) that are performed to reduce the anxiety associated with the obsessions. Functional imaging studies have repeatedly demonstrated hypermetabolic activity in medial and orbital frontal cortex, ventral striatum and dorsal thalamus in resting and provoked paradigms. Eighty five percent of patients respond to a combination of serotonin reuptake inhibitors and repetitive exposure to the feared stimulus accompanied by preventing compulsive behaviors or avoidance.

Recent advances in radiosurgery and deep brain stimulation have allowed us to approach neuroanatomical targets that were heretofore thought to be unaccesssible. Our collaborative group is currently following 45 patients with intractable OCD who have undergone gamma capsulotomy and an additional 15 patients who have had deep brain capsular stimulation. Bilateral 4x6 mm gamma lesions in the midcapsular region resulted in minimal symptomatic improvement. A second bilateral lesion placed immediately ventral to the first, led to significant clinical improvement in 55% of patients with minimal adverse effects. There is a strong correlation between lesion size and treatment response. Additional basic neuroanatomical and electrophysiologic studies are needed to define the mechanism of action of DBS and radiosurgical lesioning and to further our understanding of the functional neuroanatomy of the relevant circuitry.