The Link Between Inflammation and Cognitive Impairment in Severe Mental Illness

 Post by Lani Cupo

The takeaway

A large, multivariate investigation of inflammation and cognition in severe mental illness reveals patterns of immune activation associated with poor verbal learning and processing speed in individuals across diagnoses.

What's the science?

The link between inflammation and mental illness has been investigated, however, the associations between immune activation and cognitive ability in severe mental illnesses, like schizophrenia and bipolar disorder, have often glossed over individual differences in both domains. To help clarify the relationship, variability amongst both healthy individuals and those with severe mental illness must be examined. This week in Molecular Psychiatry, Saether and colleagues attempt to capture individual variance between cognitive ability and inflammation in health and severe mental illness with a multivariate analysis technique, canonical correlation analysis (CCA).

How did they do it?

The authors had access to a large pool of participants (770 healthy controls [HC], 343 with schizophrenia, and 289 with bipolar disorder). Diagnoses were determined by clinical assessments conducted by trained psychologists and medical doctors. Clinical psychologists and trained researchers administered cognitive assessments, recording variables including fine-motor speed, psychomotor processing speed, mental processing speed, verbal learning, attention, verbal memory, semantic fluency, working memory, and cognitive control. To quantify inflammation, the authors included 22 markers of neuroinflamation from a blood sample. CCA is a technique that relates two independent set of variables (each called a variate) to one another, generating new linear combinations of variables (canonical variate pairs) reflecting patterns of covariation between variates. The significance of each resulting variate pair is assessed with permutation testing, allowing the authors to determine whether each pattern of covariance is likely to arise due to chance. The participant demographics can be mapped onto the correlations to examine subgroups within the patterns. The authors organized these “loading scores” (how individual participant scores mapped onto the canonical variates) into clusters using a clustering procedure (hierarchical clustering) to establish subgroups. They confirmed the stability of the identified clusters with a resampling technique.

What did they find?

From the CCA, the authors derived two significant canonical variate pairs representing relationships of covariance among the variables. Of these, the first canonical variate pair was determined to be more reproducible in a set of un-tested samples and, therefore, further examined. This canonical variate pair captured a correlation between poor verbal learning and psychomotor processing speed with an increased presence of 4 markers of innate immune activation. Mapping diagnoses onto the correlation revealed the potential for subgroups.

The clustering analysis revealed two subgroups; Cluster 1 included worse scores on cognitive domains and increased inflammatory markers, compared to Cluster 2. The majority of HCs were in Cluster 2, while the majority of participants with severe mental illness were in Cluster 1. Of the participants with severe mental illness, those in Cluster 1 exhibited worse functioning and symptomatology and higher pharmaceutical usage than those in Cluster 2. Overall, Cluster 1 represented a group that captured most of the participants with severe mental illness and exhibited decreased cognitive ability and increased inflammation. However, group assignments did transcend diagnosis.

What's the impact?

This study is one of the first to show how the relationship between cognitive dysfunction and inflammation transcends diagnosis. Regardless of diagnosis or impairment, there is a relationship between increased innate inflammation and cognitive dysfunction, emphasizing the importance of examining heterogeneity between individuals. In a subset of individuals with severe mental illness, this may provide an important link for future investigation and treatment approaches.

Access the original scientific publication here

A New and Effective Tool for Improving Memory in Older Adults

Post by Megan McCullough

The takeaway

A smartphone application called HippoCamera was shown to be an effective tool for improving the recall of episodic memories and increasing different memory representations in the hippocampus in older adults. 

What's the science?

There is a relationship between age and the ability to re-experience the past and recall specific memories about life events. Previous research has shown that as humans get older, there is a decline in memory recollection that may correlate with a decrease in the differentiation of hippocampal activity. Despite numerous studies that have confirmed these findings, there are limited behavioral interventions that have been shown to successfully target episodic memories. This week in PNAS,  Martin and colleagues aimed to test the effectiveness of a smartphone application on the ability of older adults to improve episodic memory recall.

How did they do it?

The authors tested their self-developed smartphone app on older adults, as age has been correlated with a decrease in the ability to recall details about specific everday life events that they wish to remember. HippoCamera allows users to create memory cues of specific events that they personally value and hope to remember. These cues consist of a short verbal description created by the user as well as a short video recording of the event. The users then can rate the significance of the event in the app. Cues were randomly assigned to either a replay condition, where the user could view it multiple times, or a control condition, where the cue was never replayed. This study consisted of two experiments, either a 2-week intervention, or a 10-week one. In both experiments, the authors conducted two memory tests to test the effectiveness of the smartphone app on memory recall. The authors also performed functional magnetic resonance imaging scans (fMRI) one weeks after the end of the intervention (both experiments) to measure brain activity related to memory of events evaluated in the memory tests.

What did they find?

The authors found that HippoCamera was an effective and user-friendly memory aid intervention for older adults. The authors conducted memory tests of personal life events that the participants recorded with the app both one week after the end of HippoCamera intervention and around 3 months after the use of the HippoCamera. The data support the conclusion that the use of HippoCamera enhances the recall of personal, episodic memories. After the 10-week intervention, participants were able to recall even more details about the event versus after the 2-week intervention. As for the results of the fMRI scans, they showed that use of HippoCamera altered how episodic information was represented in the hippocampus. The app promoted differentiation of memory-related activity patterns in the brain which correlated with the increase in recollection of event details.

What's the impact?

This study tested a non-invasive, user-friendly memory intervention that can be utilized to improve memory for life events in older adults. HippoCamera was shown to improve episodic recollection and increase differentiated activity in the hippocampus. Effective and safe tools such as HippoCamera can potentially improve memory for meaningful life events and therefore the quality of life of individuals of aging adults.

Access the original scientific publication here

The Impact of Decreased Dopamine on Compulsive Alcohol Use

Post by Leanna Kalinowski

The takeaway

Researchers have uncovered a critical role of decreased dopamine in the nigrostriatal pathway in compulsive alcohol use behaviors.

What's the science?

Compulsive alcohol use – defined as the continued seeking and drinking of alcohol despite it having significant negative consequences – is a hallmark symptom of alcohol use disorder (AUD) that impacts millions of people across the globe. Previous research has heavily implicated the mesolimbic dopamine pathway in the etiology of AUD. Specifically, initial alcohol consumption is associated with an increase of dopamine in this pathway, while extended alcohol consumption subsequently leads to a significant decrease of dopamine in this pathway.

More recently, the neighboring nigrostriatal dopamine pathway has also been implicated in AUD. However, due to previous beliefs that this pathway was solely responsible for motor functions, the role of the nigrostriatal pathway in compulsive alcohol use has been significantly understudied. This week in Molecular Psychiatry, Goutaudier and colleagues investigated the role of decreased dopamine in the nigrostriatal pathway on compulsive alcohol use.

How did they do it?

In the first experiment, rats were first trained to press a lever for alcohol in an operant self-administration chamber. Following consistent alcohol self-administration and consumption for 38 sessions, the researchers then identified rats with compulsive-like alcohol use by pairing the alcohol lever with a mild foot shock for 6 sessions, thereby imposing negative consequences for continued alcohol use. Following this procedure, rats were divided into two groups: “foot shock-sensitive” if their lever presses for alcohol decreased following the introduction of foot shocks, or “foot shock resistant” if their lever presses for alcohol increased following the introduction of foot shocks. Ten days after the last alcohol self-administration session, dopamine levels in the brain were analyzed using enzyme-linked immunosorbent assay (ELISA).

In the second experiment, the researchers used chemogenetics to selectively turn off dopamine signaling in the nigrostriatal pathway. To do this, they first started with rats that were bred to conditionally inhibit the th gene; this gene provides instructions for making tyrosine hydroxylase, which is an enzyme that is required for the synthesis of dopamine. Half of these rats then received an injection of a virus, which expresses hM4Di, into the substantia nigra (i.e., the beginning of the nigrostriatal dopamine pathway). hM4Di can then be activated by injecting the rats with C21 (an hM4Di agonist), which then selectively and temporarily inhibits the th gene and blocks dopamine synthesis in the substantia nigra. The other half of the rats received an injection of mCherry into the substantia nigra, which acts as a control that does not inhibit the th gene following C21 exposure.

Both groups of rats then underwent the same alcohol self-administration procedure as described in experiment 1. Following the identification of compulsive-like alcohol use after the initial foot shock sessions, the rats were then injected with C21 to block dopamine signaling in the hM4Di rats, after which their foot shock sensitivity was once again tested for 6 sessions.

What did they find?

First, the researchers found that foot shock-resistant rats (i.e., those with compulsive-like alcohol use) had lower dopamine levels in the anterior dorsolateral striatum – the main output structure of the nigrostriatal pathway – compared to foot shock-sensitive rats. This suggests that this neural pathway is at least somewhat responsible for compulsive-like alcohol use. Second, the researchers found that inhibition of nigrostriatal dopamine signaling causes rats that were previously foot shock-sensitive to persist through the foot shocks and continue to self-administer alcohol. This behavior was not observed in mCherry/control rats, suggesting that blocking dopamine activity in the nigrostriatal pathway is sufficient to induce compulsive alcohol-seeking behaviors in animals that previously did not exhibit these behaviors.

What's the impact?

Taken together, results from this study uncover a critical role of the nigrostriatal pathway – particularly low dopamine levels – in compulsive alcohol use. These results may pave the way for potential new treatment strategies for individuals with an alcohol use disorder. Future studies should determine whether these neural mechanisms are specific to compulsive alcohol use, or if they are also present with compulsive use of other drugs.

Access the original scientific publication here.