Depression refers to a set of prevalent (Kessler et al. 1994), extremely debilitating disorders (Murray and Lopez 1997) that can be characterized by a triad of symptoms: extreme anhedonia (complete loss of pleasure from previously pleasurable activities), depressed mood, and low energy. Other cognitive symptoms (e.g., pessimistic thoughts, feelings of guilt, low self-esteem and suicidal ideations) and somatic symptoms (e.g., sleep and psychomotor disturbances, food-intake and body-weight dysregulation) are also often present. Unipolar major depression is the leading cause of disability worldwide; a contribution almost three times that of chronic obstructive pulmonary disease (Lopez and Murray 1998). Depression is associated with a high mortality due to suicide (Joukamaa et al. 2001) and increases in mortality in comorbid somatic disorders such as cardiovascular disorders or cancer (Glassman and Shapiro 1998; Wulsin et al. 1999). Neuroscientific research in the last decade has led to a more complete conceptualization of depression as a complex interaction of genetic susceptibility and environmental factors (Berton et al. 2006; Berton and Nestler 2006; Nestler et al. 2002; Svenningsson et al 2006; Wong and Licinio 2001). Traditional methods of alleviating depression largely stem from serendipitous observations of antidepressant effects of substances such as iproniazid (originally developed as a treatment for tuberculosis) or imipramine (originally developed as a treatment for schizophrenia). In particular, increasing levels of monoamine neurotransmitters in the synaptic cleft are associated with improvements of depressive symptoms. This insight led to a more targeted drug discovery process, resulting in drugs with fewer side effects, such as SSRI's. A better understanding of the phal (Nemeroff et al. 1996; Richelson 2003; Roose and Schatzberg 2005). These medication treatments, in conjunction with certain methods of psychotherapy, are effective at alleviating depressive symptomatology in most patients. However, these treatments do not work for all patients. A sizable minority of patients does not respond. Indeed, 17−21% of patients suffering from major depression have a poor outcome after two years, and 8−13% have a poor outcome even after five years of treatment (Winokur et al. 1993). These patients thus do not respond to any known treatment combination including electroconvulsive therapy, and are thus referred to as "treatment resistant" patients. This underserved population has had little hope of recovering from this disease. Psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain, many of which may be unrelated to depression. It might be that more focused, targeted treatment approaches that modulate specific networks in the brain will prove a more effective approach to help treatment-resistant patients. In other words, whereas existing depression treatments approach this disease as a general brain dysfunction, a more complete and appropriate treatment will arise from thinking of depression as a dysfunction of specific brain networks that mediate mood and reward signals, in particular, the cortical-limbic- thalamic-striatal network (Mayberg 2002). This conceptualization leads to novel ideas about targeted neuromodulatory treatments which have been researched in the last decade.