We believe that DBS to the ventral striatum, and in particular, the nucleus accumbens, will be a promising and efficacious treatment of severe depression. Our hypothesis is based on three lines of reasoning: (1) the ventral striatum is heavily implicated in both normal and abnormal reward processes, (2) the nucleus accumbens acts as a ‘motivation gateway’ between limbic systems involved in emotion and systems involved in motor control, and (3) the ventral striatum is uniquely located to modulate activity in other regions of the brain. These arguments are described in detail below.
First, the ventral striatum, and in particular the nucleus accumbens, is a central region for processing reward and pleasure information. Increases in nucleus accumbens neuron activity and dopamine release are observed during expectations and experience of rewards (Adinoff, 2004; de la Fuente-Fernandez et al, 2002; Doyon et al, 2005; Schultz, 2004). Converging evidence of the accumbens’ role in reward processing comes from neuroimaging studies, which show increases in ventral striatal activity associated with euphoric responses to dextroamphetamine (Drevets et al, 2001), cocaine-induced euphoria (Breiter et al, 1997), monetary reward (Cohen et al, 2005; Knutson et al, 2001a; O’Doherty et al, 2001), pleasurable responses to music (Blood and Zatorre, 2001), and viewing attractive face (Aharon et al, 2001). Recent evidence demonstrates that the ventral striatum exhibits abnormal activity following administration of dextroamphetamine in patients with major depression, compared with activity observed in healthy control subjects (Tremblay et al, 2005). Furthermore, data exploring a specific role of the nucleus accumbens within the limbic system demonstrate that the reward system is dysfunctional in mice submitted to social defeat stress, a dysfunction which is reset by chronic administration of an antidepressant (Berton et al, 2006). Together, these findings demonstrate that the nucleus accumbens is a critical center for the experience of reward and pleasure, and that this region is dysfunctional in patients who suffer from depression.
Second, the nucleus accumbens acts as a gateway to transmit, and therefore enhance or degrade, information from emotion centers of the brain to motor control regions of the brain. For example, depleting dopamine from the shell region of the nucleus accumbens in rats severely impairs their ability to engage in reward-seeking behaviors (Ito et al, 2004). Human neuroimaging studies have shown that the ventral striatum is very active during reward seeking behaviors (Juckel et al, 2006; Knutson et al, 2001b, 2003), and this activation is reduced in certain clinical populations; for example, patients with schizophrenia (Juckel et al, 2006). Thus, the nucleus accumbens mediates motivational behavior related to obtaining rewards. This is particularly relevant to the treatment of depression because anhedonia, which can be conceptualized as lack of reward motivated behavior, is one of the key defining symptoms of the disorder.
Third, the ventral striatum is in a particularly unique position to modulate activity in many other regions of the brain. The nucleus accumbens receives projections from midbrain regions that produce dopamine such as the ventral tegmental area, from regions involved in emotion such as the amygdala, orbitofrontal cortex, and medial prefrontal cortex, from motor regions such as the dorsal caudate and globus pallidus, and from regions involved in memory such as the hippocampus (Nauta and Domesick, 1984). The accumbens in turn indirectly projects to cortical regions including Cg25 and medial prefrontal cortex, the ventral pallidum, the thalamus, amygdala, and hypothalamus (Jones and Mogenson, 1980; Kelley and Stinus, 1984; Mogenson et al, 1983). Many of these regions are also implicated in normal and abnormal emotion processing,
especially the medial prefrontal cortex and Cg25, suggesting a network of tightly anatomically and functionally connected regions (Mayberg, 1997). These connections can be GABA-ergic (inhibitory) or glutamatergic (excitatory).
Thus, stimulating the nucleus accumbens can modulate neural activity in other emotion and motivation centers of the brain.
First, the ventral striatum, and in particular the nucleus accumbens, is a central region for processing reward and pleasure information. Increases in nucleus accumbens neuron activity and dopamine release are observed during expectations and experience of rewards (Adinoff, 2004; de la Fuente-Fernandez et al, 2002; Doyon et al, 2005; Schultz, 2004). Converging evidence of the accumbens’ role in reward processing comes from neuroimaging studies, which show increases in ventral striatal activity associated with euphoric responses to dextroamphetamine (Drevets et al, 2001), cocaine-induced euphoria (Breiter et al, 1997), monetary reward (Cohen et al, 2005; Knutson et al, 2001a; O’Doherty et al, 2001), pleasurable responses to music (Blood and Zatorre, 2001), and viewing attractive face (Aharon et al, 2001). Recent evidence demonstrates that the ventral striatum exhibits abnormal activity following administration of dextroamphetamine in patients with major depression, compared with activity observed in healthy control subjects (Tremblay et al, 2005). Furthermore, data exploring a specific role of the nucleus accumbens within the limbic system demonstrate that the reward system is dysfunctional in mice submitted to social defeat stress, a dysfunction which is reset by chronic administration of an antidepressant (Berton et al, 2006). Together, these findings demonstrate that the nucleus accumbens is a critical center for the experience of reward and pleasure, and that this region is dysfunctional in patients who suffer from depression.
Second, the nucleus accumbens acts as a gateway to transmit, and therefore enhance or degrade, information from emotion centers of the brain to motor control regions of the brain. For example, depleting dopamine from the shell region of the nucleus accumbens in rats severely impairs their ability to engage in reward-seeking behaviors (Ito et al, 2004). Human neuroimaging studies have shown that the ventral striatum is very active during reward seeking behaviors (Juckel et al, 2006; Knutson et al, 2001b, 2003), and this activation is reduced in certain clinical populations; for example, patients with schizophrenia (Juckel et al, 2006). Thus, the nucleus accumbens mediates motivational behavior related to obtaining rewards. This is particularly relevant to the treatment of depression because anhedonia, which can be conceptualized as lack of reward motivated behavior, is one of the key defining symptoms of the disorder.
Third, the ventral striatum is in a particularly unique position to modulate activity in many other regions of the brain. The nucleus accumbens receives projections from midbrain regions that produce dopamine such as the ventral tegmental area, from regions involved in emotion such as the amygdala, orbitofrontal cortex, and medial prefrontal cortex, from motor regions such as the dorsal caudate and globus pallidus, and from regions involved in memory such as the hippocampus (Nauta and Domesick, 1984). The accumbens in turn indirectly projects to cortical regions including Cg25 and medial prefrontal cortex, the ventral pallidum, the thalamus, amygdala, and hypothalamus (Jones and Mogenson, 1980; Kelley and Stinus, 1984; Mogenson et al, 1983). Many of these regions are also implicated in normal and abnormal emotion processing,
especially the medial prefrontal cortex and Cg25, suggesting a network of tightly anatomically and functionally connected regions (Mayberg, 1997). These connections can be GABA-ergic (inhibitory) or glutamatergic (excitatory).
Thus, stimulating the nucleus accumbens can modulate neural activity in other emotion and motivation centers of the brain.