In stabilized outpatients with schizophrenia, peripheral inflammation was associated with brain perfusion changes of frontal, temporal and parietal regions. A negative correlation was found between perfusion of the right inferior frontal gyrus and persistence of psychotic symptoms under antipsychotic treatment, more specifically of positive, negative and excitement symptoms.
Peripheral inflammation was first negatively correlated with perfusion of the right fronto-temporal and bilateral parietal areas. Brain perfusion is a biomarker of global brain functioning through global synaptic activity. Peripheral inflammation induces microglial activation in the brain (the so-called neuroinflammation) [14], which has been extensively explored in schizophrenia in the last decade. In schizophrenia patients, peripheral inflammation can alter the blood-brain barrier, increasing its permeability and the impact on brain perfusion, supporting the “mild encephalitis” hypothesis of schizophrenia [15]. Neuroinflammation has been suggested to accelerate brain neuroprogression and ageing (the so-called “inflammaging” process) [16]. This neuro-progression may induce an increase in the microglia density reported in post-mortem schizophrenia brain studies [17]. Based on our results, one could hypothesize that inflammation-associated brain perfusion changes may be the long-term consequence of the ongoing “brainflammaging” process. This assumption is consistent with a mean illness duration of 13 years in our sample, while inflammation is often identified in the early phases of these illnesses [18], suggesting that the brains of the participants were probably exposed to chronic low-grade inflammation for several years.
The right inferior frontal gyrus was the only area which perfusion was correlated to both peripheral inflammation and persistence of positive symptoms under treatment. The frontal cortex is the richest brain area in dopaminergic neurons and is responsible for language processing and speech production, which has been recently demonstrated as a reliable marker of schizophrenia[19]. The right inferior frontal gyrus is also involved in the recognition of emotions of fear, disgust and anger[20]. Emotion recognition deficits, particularly to negative emotions, has been found as a useful predictor of schizophrenia risk[21]. This lobe is connected to prefrontal cortex that is involved in social interactions, which may explain the correlation between decreased perfusion of this area and increased emotional and social withdrawal[21]. Our patients were treated by antipsychotics, which suggests that frontal perfusion changes correlated to inflammation were also correlated to persistence of psychotic symptoms under treatment. The association of inflammation with persistence of psychotic symptoms under treatment has been well-established elsewhere[22], and anti-inflammatory strategies have shown effectiveness in improving schizophrenia symptomatology[23].
In addition, we found that the higher hs-CRP levels (those ≥ 3mg/L) were associated with increased perfusion of the left amygdala. This cut-off was used as previously shown to qualify “low-grade peripheral inflammation” [13], on the complementary hypothesis of non-linear relationship between hs-CRP levels and brain perfusion. This dose effect may be the result of a synergistic reaction of glutamate and quinolinic acid, a product of neuroinflammation [24]. Amygdala is classically associated with anxiety, which is poorly investigated in the schizophrenia scales. This may explain the absence of correlation between amygdala perfusion and psychotic symptomatology in our results. However, this result is consistent with amygdala alterations consistently found in patients with schizophrenia[25]. Changes in the perfusion of amygdala have been associated with increased bone-marrow activity, arterial inflammation and risk of later cardiovascular events in middle-aged men without identified disease[26]. Future studies should determine whether perfusion changes in amygdala perfusion of patients with schizophrenia may help predicting their risk of cardiovascular events, as this is the second cause of death in this population after 35 years[27].
While peripheral inflammation has been associated with depressive symptoms in schizophrenia[28], we found no significant association between brain perfusion of our 5 areas and depressive symptomatology. This suggests that other mechanisms may mediate the association between inflammation and depression in schizophrenia, e.g. diet, physical activity, physical illness or social isolation.
Strengths. Although the role of peripheral inflammation has been extensively explored in schizophrenia in the last two decades, its correlation with brain perfusion is reported for the first time in this study. All patients were assessed using the same protocol to limit heterogeneity. They were recruited through a large regional geographical aera to limit the selection bias. Our results were adjusted for important confounding factors including age, sex, educational level, illness duration, antidepressant, chlorpromazine equivalent dose, tobacco smoking and obesity.
Limits and perspectives. Although our sample was large, enabling adjustment for multiple confounding factors, our results should be replicated in other populations including schizophrenia patients with different sociodemographic and illness characteristics. Our sample consisted of middle-aged patients with a mean illness duration that was quite long (approximately 13 years), suggesting that the brain perfusion changes in our results are probably the biomarkers of mid- to long-term inflammatory processes. Further explorations of earlier stages of the illness (such as early illness and the prodromic phase) may help understanding the illness trajectory associated with inflammatory processes in schizophrenia. It is well known that long-term inflammation is associated with cognitive impairment in schizophrenia[29], however we did not carry out a cognitive test battery in the present study to explore the associations with cognitive impairment. Mitochondrial dysfunctions and oxidative stress could also participate to the observed brain perfusion abnormalities. Inflammatory disturbances are often associated with oxidative stress, however no marker of oxidative stress and mitochondrial dysfunction was available in daily practice. The question of the definition of low-grade peripheral inflammation remains open, other pro-inflammatory markers like IL-6, TNF and IL-1 would be potentially more prone to capture low-grade inflammation. However, these markers are not available in daily clinical practice.