Risk Factors for Aggression in Individuals with and without Mental Illness

What’s the science?

Childhood exposure to head trauma, sexual or physical abuse, or maltreatment, can have detrimental effects. These environmental risk factors as well as urban dwelling (urbanicity) and migration (moving to a new country), and secondary risk factors (alcohol and cannabis use) have previously been found to influence — when accumulated —  the onset and severity of mental illnesses, including schizophrenia. Individuals with schizophrenia who had more of these risk factors have been found to be more likely to be hospitalized in forensic units (due to criminal conduct or violence) than those who had fewer risk factors. This week in Molecular Psychiatry, Mitjans and colleagues explored whether the presence of risk factors in childhood predicted criminal conduct independent of mental illness.

How did they do it?

The authors studied childhood risk factors in four separate cohorts of individuals who had schizophrenia or were schizoaffective (schizophrenia symptoms + mood symptoms), as well as in two cohorts of healthy individuals. First, in a discovery sample of individuals with schizophrenia, they studied males who had <1 (low risk) or >3 (high risk) risk factors. The authors examined the relationship between risk factors with forensic hospitalization, as well as with a violent aggression severity score (VASS). In other schizophrenia cohorts, a VASS was not available, so a proxy for aggression (past forensic hospitalization or conviction for a violent crime) was used. Finally, they also modelled the effect of risk factors on a proxy for aggression in healthy individuals of the Spanish general population (urbanicity was not available for this population).

What did they find?

In the discovery sample as well as in a replication sample of individuals with schizophrenia, 27% of high-risk individuals were in a forensic unit, while only 6% of low-risk individuals were. The addition of each risk factor increased the risk of forensic hospitalization as well as an aggression score in a step-wise fashion (more risk factors=more risk for aggression). The same step-wise pattern was noted for other cohorts of individuals with schizophrenia, using the proxy for aggression. In the discovery sample, the authors noted that risk factors increased early aggression (before 18 years old) occurring before schizophrenia onset, suggesting aggression (due to underlying risk factors) may be independent of mental illness. The same step-wise pattern for the effect of risk factors on aggression was found in two cohorts of healthy individuals. This finding provided further evidence that the relationship between risk factors and aggression was independent of mental illness.

What’s the impact?

This study is the first to suggest that aggression in individuals with or without mental illness may be related to risk factors in childhood — and not to the presence of mental illness itself. In both individuals with and without mental illness, the effect of risk factors on aggression or violence appears to be cumulative — a greater number of risk factors leads to a greater risk for aggression or violence. This work has important social implications and underscores the importance of preventative measures for at-risk individuals.

M. Mitjans et al., Violent aggression predicted by multiple pre-adult environmental hits. Molecular Psychiatry (2018). Access the original scientific publication here.

A Pattern of Brain Activity related to Cognitive Reserve

What’s the science?

‘Cognitive reserve’ refers to an individual’s capacity to maintain good brain function despite aging or a disease affecting the brain, such as Alzheimer’s. IQ is often used as a proxy for measuring cognitive reserve, however, cognitive reserve specifically refers to the resilience of the brain. Several studies have attempted to use functional magnetic resonance imaging (fMRI) to understand how the brain’s cognitive networks might be resilient. These studies have focused on performance on (typically one) cognitive task, but cognitive reserve is likely utilized for a range of tasks. This week in NeuroImage, Stern and colleagues performed fMRI experiments to elucidate a brain network related to cognitive reserve across many tasks.

How did they do it?

The authors included healthy individuals (ages 20-80: 255 individuals in main sample, 149 in a replication sample), who completed 12 cognitive tasks as part of the Reference Ability Neural Network study, while undergoing fMRI. The 12 tasks probed cognitive abilities: vocabulary, perceptual speed, fluid reasoning, and episodic memory. An additional memory task and executive control task were used for validation of the cognitive reserve network identified during analysis. Brain structure (cortical thickness) and brain function (fMRI) data were collected. IQ was measured using the NART IQ test. The authors analyzed brain regions where activity (fMRI blood oxygen-dependent signal) covaried with IQ in a task-invariant way. Age was included as a covariate in analyses because it was correlated with IQ.

What did they find?

The authors identified a cognitive network/activity pattern of brain regions in which activity co-varied with IQ in a task-invariant way (during cognition, across all tasks). Generally, the network was located in the cerebellum, temporal and parietal lobes, the medial frontal gyrus, inferior frontal gyrus, and anterior cingulate. Brain activity in the identified cognitive reserve brain network was significantly positively or negatively related to IQ in different brain regions. After accounting for brain structure (cortical thickness), brain function in the identified cognitive reserve network explained additional variance in fluid reasoning (beyond variance in fluid reasoning explained by brain structure). Further, the authors found an interaction whereby there was a greater relationship between fluid reasoning and brain structure in individuals with a lower cognitive reserve network score (less strong expression of the pattern/network).

What’s the impact?

This is the first study to assess the concept of cognitive reserve in a wide array of tasks, using neuroimaging. A pattern of brain activity during a variety of cognitive tasks was found to be related to IQ, and is referred to as a cognitive reserve network. The study has future implications for diseases in which cognitive reserve may be critical for protection against cognitive decline, such as Alzheimer’s.

Y. Stern et al., A task-invariant cognitive reserve network. NeuroImage (2018). Access the original scientific publication here.

Activation of Astrocytes Strengthens Synapses and Enhances Memory

What's the science?

Astrocytes can do more than just surround and insulate neurons: they can actually sense and modify neuronal activity. Memory disruption is easy to produce; however, techniques that can enhance memory are rare. Previous work suggests that astrocytes are required for long-term potentiation and memory. Whether astrocytes may also be able to induce long-term potentiation on their own, however, is unclear. This week in Cell, Adamsky, Kol and colleagues test whether activation of astrocytes using chemogenetics is sufficient to induce potentiation in neurons and enhance memory.

How did they do it?

The authors used a chemogenetic (chemically engineering molecules) approach in mice: they expressed a G-protein coupled receptor specifically in astrocytes, and used this engineered receptor to activate astrocytes in the CA1 region of the hippocampus (important for memory) via increasing their intracellular calcium levels. They measured the excitatory post-synaptic currents in neurons in the hippocampus using whole-cell patch clamp and field recordings. These experiments allowed them to observe whether there was any long-term potentiation (plasticity required for memory) as a result of the astrocyte activation compared to control slices without astrocyte activation. Lastly, they tested to see whether chemogenetic astrocyte activation had any effect on spatial (a maze exploration task) and contextual memory (fear conditioning).

What did they find?

There was a 50% increase in the excitatory post-synaptic current amplitude of hippocampal neurons after astrocyte activation, demonstrating that astrocyte activation was sufficient to induce long-term potentiation. No similar potentiation was seen in control slices. This potentiation lingered long after the astrocytes were no longer activated, and was mediated by the same mechanisms of 'regular' potentiation (i.e. via the NMDA receptor). Mice treated to induce astrocyte activation 30 minutes prior to a maze task, performed significantly better than control mice. These mice also showed 40% more freezing (indicating enhanced memory of the context in which the foot shock was delivered ) than control mice. Astrocyte activation induced memory enhancement only when induced before acquisition (not before recall) showing that the astrocyte activation plays an important role during the learning process, rather than the retrieval. They then tested whether general neuronal activation (not astrocytic) has any effect on potentiation and memory to see whether these effects were specific to astrocytes and found that increasing neuronal activation did not enhance memory, but rather impaired it. They showed that this is due to the fact that astrocytic activity increases neuronal activity in a task-dependent manner - only in learning mice, but not in home-caged mice. Finally, they used optogenetics (which has better temporal resolution) to test whether astrocyte activation was enhancing memory specifically at the acquisition stage, and found it to induce an even bigger improvement in the contextual memory task.

What's the impact?

This is the first study to show that astrocyte activation is sufficient to produce long-term potentiation in hippocampal neurons and enhance memory performance. Previous research showed that astrocyte inhibition could impair memory, however, now we know that astrocytes alone can induce memory enhancement and that astrocytes may be more important for cognitive function than we once thought. Astrocyte activation could be one target for developing memory-enhancing drugs.

Adamsky, Kol et al., Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement. Cell (2018). Access the original scientific publication here.