Imaging of the serotonergic system

Impulsive aggression is part of the BPD phenotype and yet little is known about its neurobiology. Reduced serotonergic activity has been associated with impulsive aggression in metabolite and pharmacologic challenge studies, e.g. hormone responses to fenfluramine that increases serotonergic activity were shown to be abnormal in personality disordered patients with impulsive aggression (Coccaro et al., 1989). However, the neuroanatomical locus of this serotonergic dysfunction is still unclear. Preclinical and human studies suggest that the orbital frontal cortex and anterior cingulate cortex play an inhibitory role in the regulation of aggression. FDG-PET in conjunction with serotonergic agents such as fenfluramine or meta -chlorophenylpiperazine (m -CPP) can be used to assess the function of the serotonergic system and localize brain areas of serotonergic dysfunction.

In a study using fenfluramine challenge and FDG-PET, Siever et al. (1999) investigated six outpatients (four males and two females) meeting criteria for Impulsive Aggressive Disorder, four of whom also met criteria for BPD. Impulsive-aggressive patients showed significantly less activity after fenfluramine as compared to placebo in the ventral medial frontal region, right middle and left upper cingulate gyrus, left lateral orbital and right dorsolateral prefrontal cortex. Blunted metabolic response in these regions to fenfluramine, which enhances serotonergic activity by direct release of serotonin, antagonism of serotonergic reuptake, and possibly direct receptor effects (Coccaro et al., 1996), may be related to reduced serotonergic modulation of inhibitory regions important in controlling impulsive aggression. These findings were replicated in a study of five patients with BPD and eight healthy controls (Soloff et al., 2000), which found reduced metabolism in response to fenfluramine as compared to placebo in right medial and orbital prefrontal cortex, left middle and superior temporal gyri, left parietal lobe, and left caudate body. This investigation also revealed baseline differences following placebo in large areas of the prefrontal cortex, namely reduced metabolism in right anterior frontal lobe, Brodmann areas 10 and 11 bilaterally, and right insula in BPD patients as compared to controls.

Using positron emission tomography in response to meta -chlorophenylpiperazine m -CPP), which acts as an agonist at serotonin receptors, New et al. (2002) investigated 12 personality disordered subjects (seven men and five women) with impulsive aggression, eight of whom had BPD, and 12 normal controls. Unlike normal subjects, patients with impulsive aggression did not show activation specifically in the left anteromedial orbital cortex in response to m -CPP. The anterior cingulate, normally activated by m -CPP, was deactivated in patients; in contrast, the posterior cingulate gyrus was activated in patients and deactivated in controls. In this study, no baseline differences in response to placebo were found. In a second study of this group, 27 male and female patients with BPD and 23 controls were investigated (New et al., 2003). At baseline, BPD men with physical aggression had less activity across the frontal cortex and cingulate gyrus as compared to BPD men with verbal aggression and controls. Verbally and physically aggressive BPD men had decreased activity specifically. Following m -CPP challenge, BPD men, but not women, revealed reduced activity across the frontal cortex as well as left cingulate gyrus, as compared to controls. Recently, a normalization of prefrontal cortex dysfunction by SSRI treatment (Fluoxetine 20 mg/day) could be shown in impulsive-aggressive BPD patients (New et al., 2004). Overall, pharmacologic challenge studies with fenfluramine and m -CPP revealed serotonergic dysfunction in prefrontal cortex as well as ACC; however, there seem to be important differences between male and female impulsive-aggressive BPD patients with men showing reduced prefrontal activity as a possible correlate of aggression.

Another method to assess serotonergic function in specific areas of the brain, is to use PET with the 5-HT precursor analogue α-[(11)C]methyl-L-tryptophan (α-[(11)C]MTrp). α-MTrp is taken up by 5-HT neurons, where it is trapped in the 5-HT synthesis precursor pool. The rate of trapping provides an index of 5-HT synthesis capacity (Chugani and Muzik, 2000). Leyton et al. (2001) measured brain regional α-[(11)C]MTrp trapping with positron emission tomography in 13 medication-free subjects with BPD (eight women and five men) and eleven healthy comparison subjects. Impulsivity was assessed by using a laboratory measure of behavioral disinhibition, go/no-go commission errors. Compared to healthy men, men with borderline personality disorder had significantly lower α-[(11)C]MTrp trapping in corticostriatal sites, including the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, and corpus striatum. In women with borderline personality disorder, significantly lower α-[(11)C]MTrp trapping was seen in fewer regions, but in both men and women negative correlations with impulsivity scores were identified in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum. It can be concluded that low 5-HT synthesis capacity in corticostriatal pathways may contribute to the development of impulsive behaviors in persons with borderline personality disorder. However, it should be pointed out that serotonin is not the only neurotransmitter thought to be involved in BPD. Disturbances in other neuro-chemical systems (e.g., the opioid and the HPA axis system) may underlie parts of the BPD symptomatology besides impulsivity (Skodol et al., 2002). Neuroimaging studies using tracers and/or challenges from these systems will be valuable for a better understanding of the roles these systems play in BPD.

Go to: