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Introduction

Some individuals are abnormally aggressive. That is, they respond with disproportionate retaliation as compared to the provocation and they can escalate their behavior to violate the safety and well-being of others. The behavior is repeated over the individual lifespan resulting in severe consequences for the aggressor ranging from job loss and divorce to severe injury and jail time. The loss in occupational and social functioning in these individuals and damage to victims calls for systematic study of individuals who express repeated aggression. A phenotype is a readily observable trait (e.g., brown eyes). The phenotype of aggressive behavior is also observable, though not as readily; still, teachers can point to the kids who initiated many physical fights this school year and friends know of their aggressive buddy who flew into a rage at the bar. Through interviews and tasks, we too, can identify the aggressive phenotype and our aim is to study the multiple factors that are related to this particular behavior.

 

The multifactorial nature of problem behaviors

This figure represents the different contributions to disorders of aggression and substance use, which we call problem behaviors since they often appear together (most violent crimes occur under the influence of substances) and result in serious public health concerns.

 

 

Developing an Inhibitory Paradigm: Just say No?

Is it possible to just say "No" and avoid all those things we want but we know are bad for us? If it was only that simple! Studies have shown that people vary in their ability to say "No" to things they want to do even if these things are damaging to them. We set out to study how the word No! is perceived by people and processed in their brain. The words No! and Yes! are involved in learning to prohibit or encourage behavior. We hypothesized that these are emotional words, activating neural circuits involved with emotional control. Functional magnetic resonance imaging was used to record brain activity while people were hearing these words. Results showed that No and Yes were associated with opposite brain-behavior responses; while No was perceived as a negative word, produced a slowing of behavior, and evoked a negative signal in the orbitofrontal cortex (part of the frontal cortex), the word Yes was perceived as a positive word and produced faster response times, and evoked a positive signal in the same frontal region. We also found that the more people reported controlling their anger, the more their orbitofrontal region was responsive to No. More can be found here (Alia-Klein et al., 2007).

 

Recent Gene-Brain-Behavior Studies in our Laboratory

When the (monoamine-oxidase-A) MAOA gene is deleted it results in aggressive behavior. This relationship was initially found in one human family where the gene had a very rare mutation and it was later validated in mice where this gene was experimentally knocked-out (deleted). Monoamine oxidase A is important for brain chemistry because it is an enzyme that breaks-down the monoamine neurotransmitters, norepinephrine, serotonin, and dopamine. Through this mechanism, MAOA plays an important role in brain development and brain functioning. The ability to map activity of the MAOA enzyme in vivo allowed us to ask whether MAOA brain activity is related to aggression. Brain MAOA activity was measured with positron emission tomography (clorgyline labeled with carbon 11). We asked the same individuals who were scanned to also complete a personality questionnaire where some of the questions were designed to capture aggressive personality traits. Results pointed to a relationship between aggressive personality and the activity of brain MAOA. People who reported more aggression in the questionnaire also had lower levels of the MAOA enzyme throughout their brain (Alia-Klein et al., 2008).

Genetic risk carriers of the low allele (i.e., low frequency) of the MAOA genotype may have increased probability of expressing their anger, potentially through differences in brain functioning during emotional contexts. The emotional context we chose to look at in the laboratory was similar to hearing No! Emphatically expressed, the emotional word No! (see study described above, Alia-Klein et al., 2007 ) can prohibit behavior through early childhood associations of hearing No! with stopping behavior. We assessed brain activity while people heard No! among other words. Results showed that carriers of the low MAOA genotype had reduced frontal cortex brain activation to No! compared with carriers of the high variant. Furthermore, only for carriers of the low-MAOA genotype, the more brain regions such as the amygdala (associated with emotional response) and thalamus (associated with regulating arousal) activated in response to No!, the more these individuals reported that they express their anger in situations of negative evaluation and rejection (Alia-Klein et al., 2009).

Cocaine addiction is also known to be related to brain changes and difficulties with self-control. We therefore asked if there are differences in the MAOA genotype and in gray-matter volume in the brains of cocaine addicted individuals as compared to healthy controls. We found that individuals with cocaine addiction had reductions in gray-matter volume in the frontal cortex and temporal cortex and in the hippocampus as compared to controls. Reductions in the orbitofrontal cortex (a specific region in the frontal cortex involved in self-control) were found only in cocaine addicted individuals who carry the low allele of the MAOA genotype. Furthermore, gray-matter reductions were related to the number of years cocaine and alcohol were used: the more years of use, the more reductions were observed in the dorsolateral prefrontal cortex (part of the frontal cortex involved in sustaining attention) and in the hippocampus (a region important for learning and memory). For more information, see Alia-Klein et al., 2011.

 

Insight into Illness can Provide Insight into Recovery

In problem behaviors, insight or awareness of the behaviors is a very important step to changing the behaviors. Some individuals lack awareness and appreciation of the severity of their illness and its impact on their dangerous behaviors (such as taking drugs and attacking others). When insight is impaired there is less perceived need for treatment. The vast majority of people who suffer from severe illness such as schizophrenia are neither aggressive nor violent. However, violence towards others by a minority of individuals is a significant public health concern and should be monitored because it could be preventable. The severity of this violence may be influenced by the extent to which individuals with schizophrenia (and other disorders) are aware that they have a serious and chronic illness that influences their thinking and their behaviors. We wanted to find out whether poor insight in schizophrenia is related to violent behavior and to problems with medication treatment adherence. Sixty male psychotic inpatients, legally detained at a forensic unit in New York City, were assessed with interviews, supplemented with information from hospital and official records, family members and the treating clinician. Results indicated that their severity of violent behavior was related to their poor adherence to medications prescribed by their doctors and to poor insight and drug use (Alia-Klein et al., 2007). We are now carrying out similar studies on insight into severity of illness/self-awareness and association with treatment outcome in drug addicted individuals.