The Brain’s Functional Connectivity Profile in Bipolar Disorder

What’s the science?

Differences in the brain’s connectivity or wiring are thought to underlie different psychiatric disorders. One functionally connected network in the brain is the reward network, which includes the nucleus accumbens. One role of this network is to seek out stimuli that are positive or pleasurable. In individuals with bipolar disorder, a connection between the nucleus accumbens and the ventromedial prefrontal cortex has been found to be abnormal during anticipation of reward. However, whether this altered connectivity is present in individuals with bipolar disorder while they are not experiencing symptoms is not known. This week in Biological Psychiatry, Whittaker and colleagues used functional magnetic resonance imaging (fMRI) to understand how connectivity of the brain’s reward network is altered in bipolar disorder.

How did they do it?

88 participants (35 with bipolar disorder, 30 unaffected siblings of those with bipolar disorder, and 23 healthy controls) aged 35-60 were included in the final analyses for the study. Individuals with bipolar disorder participated when they were in a euthymic state (a calm, normal mood) and had had no major mood or psychotic episodes for a month before scanning. IQ was measured in all participants using the National Adult Reading Test. fMRI data were collected while the participants were at rest (‘resting state’; not performing any task). The blood oxygen dependent level (BOLD) signal was recorded, which is a measure of fluctuations in the blood oxygen levels in the brain, (an indirect measure of brain activity). In each participant, the nucleus accumbens was identified, and the correlation between the activity of the nucleus accumbens and all other brain regions was measured (this correlation of activity between two brain regions is referred to as ‘functional connectivity’). The group of individuals with bipolar disorder was compared with the group of unaffected siblings as well as healthy controls, and the unaffected siblings were also compared with the healthy control group.

What did they find?

Across all participants, activity at rest in the nucleus accumbens was strongly positively correlated with activity in subcortical structures of the brain such as the hippocampus and amygdala, and cortical regions such as the ventromedial prefrontal cortex, anterior cingulate, and postcentral gyrus. There was a stronger functional connection between the nucleus accumbens and the ventromedial prefrontal cortex in the bipolar disorder group versus in healthy controls. The strength of this connection in the bipolar disorder group was not predicted by use of mood stabilizers (e.g. lithium). When the ventromedial prefrontal cortex was selected as a region of interest and group comparisons were performed, siblings exhibited connectivity midway between connectivity levels of the bipolar group (stronger connectivity) and the healthy control group (weaker connectivity). When depression and mania scores were included as covariates in the group comparison analyses, group differences remained. Depression and mania scores were not related to individual differences in functional connectivity amongst individuals with bipolar disorder.

                                       Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What’s the impact?

This study is the first to examine functional connectivity of a key region of the reward network (the nucleus accumbens) in individuals with bipolar disorder and unaffected siblings. Strong functional connectivity (i.e. correlated brain activity) between the nucleus accumbens and ventromedial prefrontal cortex may be a biomarker for bipolar disorder. The study has important implications for understanding the role of the reward network in bipolar disorder.

Whittaker et al., The functional connectivity between nucleus accumbens and the ventromedial prefrontal cortex as an endophenotype for bipolar disorder. Biological Psychiatry (2018). Access the original scientific publication here.

The Association Between Blood Pressure, Brain Infarcts and Alzheimer’s Disease

What's the science?

Hypertension is known to be associated with stroke, however, it’s still unclear how blood pressure is related to stroke and brain infarcts (tissue injury occurring as a result of stroke). Brain infarcts are common in aging and often go undetected. Evidence for the association between blood pressure and infarcts is mixed, and further, no one has investigated whether blood pressure in late life is associated with neurodegenerative diseases like Alzheimer’s disease. Recently in Neurology, Arvanitakis and colleagues test whether blood pressure in late life is associated with brain infarcts and Alzheimer’s disease.

How did they do it?

1288 elderly adults completed a longitudinal study of aging (8-year follow-up). Systolic and diastolic blood pressure were recorded at baseline and annually throughout the study. The authors measured the mean blood pressure as well as the rate of change in blood pressure over time. History of medications and diseases were collected. Brains were assessed for neuropathology post-mortem (after autopsy). This assessment identified cerebrovascular disease (infarcts) using gross examination, microinfarcts with staining, atherosclerosis with vessel examination and arteriosclerosis with tissue staining. They also examined neurodegenerative pathology, including amyloid-beta plaques and neurofibrillary tangles.

What did they find?

Risk of having one or more brain infarcts was higher in individuals with a higher systolic blood pressure (46% increased risk of one or more infarcts on average for an individual who was 1 standard deviation above the mean systolic blood pressure). Higher mean systolic blood pressure was associated with a greater risk of gross infarcts and micro-infarcts. The more rapid the decline in blood pressure over time, the greater the risk of developing one or more infarcts was. Individuals with a higher mean systolic blood pressure also had higher degrees severity of atherosclerosis and arteriosclerosis. Mean diastolic blood pressure was associated with brain infarcts, however the rate of decline was not. Using a linear regression model, they found that higher systolic blood pressure was associated with a higher number of neurofibrillary tangles (Alzheimer’s disease pathology), but was not associated with changes in amyloid plaque pathology. There was no relationship between rate on decline in systolic blood pressure and Alzheimer’s disease pathology. 

What's the impact?

Higher systolic blood pressure in late life is associated with a greater number of brain infarcts. Higher blood pressure in late life may be associated with Alzheimer’s disease pathology (neurofibrillary tangles). Very little research exists on the link between blood pressure and Alzheimer’s disease pathology. We now know that blood pressure in late life is associated with brain infarcts and potentially the development of Alzheimer’s disease pathology.

Arvanitakis et al., Late-life blood pressure association with cerebrovascular and Alzheimer’s disease pathology. Neurology (2018). Access the original scientific publication here.

Smoking Tobacco is Associated with Reduced CB1R Density in the Brain

Post by Shireen Parimoo

What’s the science?

The cannabinoid type 1 receptor (CB1R) is a presynaptic receptor that’s present throughout the brain. It’s highly concentrated in areas involved in reward and addiction, like the basal ganglia, and it modulates GABA and glutamate (neurotransmitter) release in response to substances such as cannabinoids, alcohol, and nicotine. CB1R density is reduced in the brains of people with alcohol dependence and in chronic cannabis users. As CB1Rs are activated by nicotine, would CB1R density also be lower in smokers? In previous studies, participants who smoked tobacco also had alcohol and cannabis use disorder, making it difficult to find a direct link between nicotine use and CB1R density. This week in Biological Psychiatry, Hirvonen and colleagues systematically examined CB1R density in the brains of participants with nicotine dependence (and no other substance use disorder).

How did they do it?

Forty-six healthy men participated in the study; 18 had mild-to-moderate tobacco use disorder (smokers) and 28 were non-smokers (healthy controls). None of the participants had alcohol or cannabis use disorder. All participants underwent a two hour positron emission tomography (PET) scan, before which they were injected with [18F]FMPEP-d2, a radioligand that binds to CB1 receptors in the brain. This technique allows us to infer the density of CB1Rs by estimating the ratio of the concentration of ligand in the brain to plasma (VT). The authors also obtained genotype data from 43 participants, as carriers of the C allele of a single nucleotide polymorphism (SNP), rs2023239, in the gene CNR1 (encoding the CB1R receptor) tend to have higher levels of [18F]FMPEP-d2 binding. Participants’ smoking habits, like the age at which they started smoking and their frequency of smoking, were collected. Finally, the authors combined data from previous studies that used PET imaging in participants with alcohol and cannabis use disorder in order to examine the effect of smoking, substance use disorder, genotype, and body-mass index (BMI) on CB1R density in the brain.

What did they find?

Smokers had reduced CB1R density across several brain regions versus non-smokers. CB1R density was not reduced uniformly across the brain; it ranged from a 17% decrease in the prefrontal cortex to a 28% decrease in the midbrain. Even after ruling out the effect of BMI and genotype, the difference in CB1R density in the brains of smokers and non-smokers remained significant. Interestingly, CB1R density was not related to the age at which participants started smoking, how often they smoked, or to their level of nicotine dependence. After combining data across multiple studies, the authors also found an effect of smoking, other substance use disorders, and BMI on CB1R density. However, these effects diminished when the authors accounted for the effect of genotype. Finally, participants with a substance use disorder who also smoked did not exhibit additional CB1R down-regulation compared to those who only smoked (although CB1R density in both groups was still lower than in healthy controls).

What’s the impact?

This is the first study to report reduced CB1R density across various brain regions of male smokers compared to healthy controls, without the confounding effect of other substance use disorders. Importantly, the authors also demonstrated that consumption of multiple substances – such as alcohol and tobacco – does not have an additive effect on CB1R density above and beyond dependence on one substance. These results provide further insight into the effects of nicotine dependence, though more research is needed to determine whether these findings will generalize to females and to other substance use disorders.

Hirvonen et al., Decreased Cannabinoid CB1 Receptors in Male Tobacco Smokers Examined with Positron Emission Tomography. Biological Psychiatry (2018). Access the original scientific publication here.