Short reports

Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients

Catatonia is a complex psychomotor disorder characterized by motor, affective, and behavioral symptoms. Despite being known for almost 150 years, its pathomechanisms are still largely unknown.

A systematic research on PubMed, Web of Science, and Scopus was conducted to identify neuroimaging studies conducted on group or single individuals with catatonia. Overall, 33 studies employing structural magnetic resonance imaging (sMRI, n = 11), functional magnetic resonance imaging (fMRI, n = 10), sMRI and fMRI (n = 2), functional near-infrared spectroscopy (fNIRS, n = 1), single positron emission computer tomography (SPECT, n = 4), positron emission tomography (PET, n = 4), and magnetic resonance spectroscopy (MRS, n = 1), and 171 case reports were retrieved.

Observational sMRI studies showed numerous brain changes in catatonia, including diffuse atrophy and signal hyperintensities, while case-control studies reported alterations in fronto-parietal and limbic regions, the thalamus, and the striatum. Task-based and resting-state fMRI studies found abnormalities located primarily in the orbitofrontal, medial prefrontal, motor cortices, cerebellum, and brainstem. Lastly, metabolic and perfusion changes were observed in the basal ganglia, prefrontal, and motor areas. Most of the case-report studies described widespread white matter lesions and frontal, temporal, or basal ganglia hypoperfusion.

Catatonia is characterized by structural, functional, perfusion, and metabolic cortico-subcortical abnormalities. However, the majority of studies and case reports included in this systematic review are affected by considerable heterogeneity, both in terms of populations and neuroimaging techniques, which calls for a cautious interpretation. Further elucidation, through future neuroimaging research, could have great potential to improve the description of the neural motor and psychomotor mechanisms underlying catatonia.

Disturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects.

We included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from ¹⁸F-fluorodopa (¹⁸F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion.

Individual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (K_i^4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term K_i^4p × GABA (p = .016).

Our multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between K_i^4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

Epidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.

In this unique prospective longitudinal study, we used [¹⁸F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls.

[¹⁸F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.

These findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

The presence of abnormal subjective experiences in the prodromal stages of schizophrenia as well as their contribution to delusional formation have been highlighted in psychiatric literature, but their nature and their involvement in the transition and establishment of full-blown psychosis remains elusive. In this paper, we venture to form a coherent hypothesis for the formation of primary delusions by attributing importance to the emotional and affective symptoms experienced by patients during the acute state of psychosis. We underline the presence of abnormal subjective experiences described as ‘feelings’ in patients’ narratives, their co-occurrence with discernible emotional manifestations and symptoms, and their rather simultaneous retreat from the clinical picture shortly after the effective administration of antipsychotic treatment. We further distinguish them from their enveloping thought content, on the base of their different course pattern and natural characteristics. We argue that this composite emotional picture – which we call “psychotic arousal” – though resembling the acknowledged “delusional mood”, traverses the acute state of psychosis to a greater extent and intensity, as long as we observe delusions flourishing and expanding. We specifically suggest that altered subjective experiences can be seen as emotional in nature and best described as “experiential feelings”. Consequently, we reflect upon neuroscientific theories and models supporting a layered concept for the formation of consciousness that attribute a paramount role on emotions as a representation of neural maps of the material body’s state. We explore patients’ “experiential feelings” as the morbid outcome of an otherwise normal process and we provide a theoretical solution for the psychotic transition and the formation of primary delusions. Our hypothesis, eventually, responds to long-standing questions regarding the content of the delusions, their abrupt appearance, their self-referential character, their selectivity and specificity, as well as their impact on awareness and the erroneous deployment of extended consciousness. We suggest that further enquiry of the proposed hypothesis could elucidate more deeply the phenomenology of schizophrenia and benefit both psychopathology and neuroscience of self.

Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of ¹⁸F-DOPA to ¹⁸F-dopamine (k₃) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D₂ receptor agonist (aripiprazole) on k₃ and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method.

Sixty-two individuals (31 patients and 31 control subjects) underwent ¹⁸F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale.

High baseline decarboxylation rates (k₃) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k₃ for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k₃ or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment.

Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k₃ and treatment effect potentially implicate on new treatment strategies.