See Nieuwhof and Helmich (doi:
10.1093/brain/awx267
) for a scientific commentary on this article
.
Dynamic functional connectivity may serve as a biomarker of disease state in Parkinson's disease. ...Kim
et al.
investigate the temporal properties of functional connectivity states as well as the variability of network topological organization. They reveal two discrete connectivity configurations, confirming the vulnerability of functional connectivity networks in Parkinson’s disease.
See Nieuwhof and Helmich (doi:
10.1093/brain/awx267
) for a scientific commentary on this article
.
Parkinson’s disease is a neurodegenerative disorder characterized by nigrostriatal dopamine depletion. Previous studies measuring spontaneous brain activity using resting state functional magnetic resonance imaging have reported abnormal changes in broadly distributed whole-brain networks. Although resting state functional connectivity, estimating temporal correlations between brain regions, is measured with the assumption that intrinsic fluctuations throughout the scan are stable, dynamic changes of functional connectivity have recently been suggested to reflect aspects of functional capacity of neural systems, and thus may serve as biomarkers of disease. The present work is the first study to investigate the dynamic functional connectivity in patients with Parkinson’s disease, with a focus on the temporal properties of functional connectivity states as well as the variability of network topological organization using resting state functional magnetic resonance imaging. Thirty-one Parkinson’s disease patients and 23 healthy controls were studied using group spatial independent component analysis, a sliding windows approach, and graph-theory methods. The dynamic functional connectivity analyses suggested two discrete connectivity configurations: a more frequent, sparsely connected within-network state (State I) and a less frequent, more strongly interconnected between-network state (State II). In patients with Parkinson’s disease, the occurrence of the sparsely connected State I dropped by 12.62%, while the expression of the more strongly interconnected State II increased by the same amount. This was consistent with the altered temporal properties of the dynamic functional connectivity characterized by a shortening of the dwell time of State I and by a proportional increase of the dwell time pattern in State II. These changes are suggestive of a reduction in functional segregation among networks and are correlated with the clinical severity of Parkinson’s disease symptoms. Additionally, there was a higher variability in the network global efficiency, suggesting an abnormal global integration of the brain networks. The altered functional segregation and abnormal global integration in brain networks confirmed the vulnerability of functional connectivity networks in Parkinson’s disease.
The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that ...present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation.
To determine whether TSPO VT is elevated in the prefrontal cortex, anterior cingulate cortex (ACC), and insula in patients with MDE secondary to major depressive disorder.
Case-control study in a tertiary care psychiatric hospital from May 1, 2010, through February 1, 2014. Twenty patients with MDE secondary to major depressive disorder and 20 healthy control participants underwent positron emission tomography with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide (18FFEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers.
Values of TSPO VT in the prefrontal cortex, ACC, and insula.
In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23 = 4.5 P = .001). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean SD TSPO VT, 12.5 3.6 in patients with MDE and 10.0 2.4 in controls), 32% in the ACC (mean SD TSPO VT, 12.3 3.5 in patients with MDE and 9.3 2.2 in controls), and 33% in the insula (mean SD TSPO VT, 12.9 3.7 in patients with MDE and 9.7 2.3 in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r = 0.63 P = .005).
This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT and the severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors that overlap with the symptoms of MDE.
Purpose of Review
This paper aims to provide a comprehensive discussion of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies of antisocial personality ...disorder (ASPD) and aggression.
Recent Findings
Among ASPD males with high impulsivity, the density of brainstem serotonin (5-HT) transporters shows a relationship with impulsivity, aggression, and ratings of childhood trauma. 5-HT
1B
receptor (R) binding in the striatum, anterior cingulate cortex, and orbitofrontal cortex (OFC) correlated with anger, aggression, and psychopathic traits in another study of violent offenders, most of whom were diagnosed with ASPD. Finally, the density of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that degrades 5-HT, norepinephrine, and dopamine (DA), was reported as lower in the OFC and ventral striatum of ASPD. Among non-clinical populations, 5-HT
4
R binding, as an index of low cerebral 5-HT levels, has been associated with high trait aggression, but only in males. Furthermore, evidence suggests that individuals with high-activity MAO-A genetic variants compared with low-activity MAO-A allelic variants release more DA in the ventral caudate and putamen when exposed to violent imagery.
Summary
There are very few PET or SPECT studies that exclusively sample individuals with ASPD. However, among ASPD samples, there is evidence of regional serotonergic abnormalities in the brain and alteration of neural MAO-A levels. Future studies should consider employing additional molecular probes that could target alternative neurotransmitter systems to investigate ASPD. Furthermore, examining different typologies of aggression in clinical and non-clinical populations using SPECT/PET is another important area to pursue and could shed light on the neurochemical origins of these traits in ASPD.
For a small percentage of obsessive-compulsive disorder (OCD) cases exhibiting additional neuropsychiatric symptoms, it was proposed that neuroinflammation occurs in the basal ganglia as an ...autoimmune response to infections. However, it is possible that elevated neuroinflammation, inducible by a diverse range of mechanisms, is important throughout the cortico-striato-thalamo-cortical circuit of OCD. Identifying brain inflammation is possible with the recent advance in positron emission tomography (PET) radioligands that bind to the translocator protein (TSPO). Translocator protein density increases when microglia are activated during neuroinflammation and the TSPO distribution volume (VT) is an index of TSPO density.
To determine whether TSPO VT is elevated in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex in OCD.
This case-control study was conducted at a tertiary care psychiatric hospital from May 1, 2010, to November 30, 2016. Participants with OCD (n = 20) and age-matched healthy control individuals (n = 20) underwent a fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET scan. It is a high-quality second-generation TSPO-binding PET radiotracer. All participants were drug and medication free, nonsmoking, and otherwise healthy.
The TSPO VT was measured in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex. Compulsions were assessed with the Yale-Brown Obsessive Compulsive Scale.
In the OCD and healthy groups, the mean (SD) ages were 27.4 (7.1) years and 27.6 (6.6) years, respectively, and 11 (55%) and 8 (40%) were women, respectively. In OCD, TSPO VT was significantly elevated in these brain regions (mean, 32%; range, 31%-36% except anterior cingulate cortex, 24%; analysis of variance, effect of diagnosis: P < .001 to P = .004). Slightly lower elevations in TSPO VT (22%-29%) were present in other gray matter regions. The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing compulsive behaviors significantly correlated with TSPO VT in the orbitofrontal cortex (uncorrected Pearson correlation r = 0.62; P = .005).
To our knowledge, this is the first study demonstrating inflammation within the neurocircuitry of OCD. The regional distribution of elevated TSPO VT argues that the autoimmune/neuroinflammatory theories of OCD should extend beyond the basal ganglia to include the cortico-striato-thalamo-cortical circuit. Immunomodulatory therapies should be investigated in adult OCD, rather than solely childhood OCD, particularly in cases with prominent distress when preventing compulsions.
Abstract
Evidence from several lines of research suggests decreased dopamine release in the prefrontal cortex as the neurochemical correlates of cognitive deficits in schizophrenia (SCZ). However, in ...vivo examination of cortical hypodopaminergia using positron emission tomography (PET) during cognitive task performance in SCZ remains to be investigated. We examined dopamine release in anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC), using PET while participants were performing a cognitive task. Thirteen drug-free patients with SCZ and 13 healthy volunteers (HV) matched for age and sex participated in the study. Data were acquired between 2011 and 2015. Two PET scans with 11CFLB 457 were acquired while the participants were performing the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task (SMCT). A magnetic resonance image was acquired for anatomical delineation. Differences in cortical dopamine release between SCZ and HV, indexed as percentage change in binding potential between WCST and SMCT (ΔBPND), were calculated in ACC and DLPFC. We observed significant differences in the ΔBPND in ACC (HV = 4.40 ± 6.00; SCZ = −11.48 ± 15.08; t = 3.52; P = .003) and a trend-level difference in ΔBPND in DLPFC (HV = −0.58 ± 8.45; SCZ = −7.79 ± 11.28; t = 1.84; P = .079), suggesting dopamine depletion in cortical brain regions in patients with SCZ while performing a cognitive task. These results provide the first in vivo evidence for reduced dopamine release or even dopamine depletion while performing cognitive task in ACC and DLPFC in patients with SCZ. The present results provide support for the frontal hypodopaminergia hypothesis of cognitive symptoms in SCZ.
Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson's disease (PD). Increased expression of translocator protein (TSPO) has been ...observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo.
Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand
F-FEPPA between PD patients and HC. FEPPA total distribution volume (V
) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function.
Our results revealed a significant main effect of genotype on
F-FEPPA V
in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V
between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21).
Future investigations are needed to determine the significance of
F-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.
Background A pathologic response to common life stressors, in which a hyperresponsive dopaminergic system is thought to play a key role, is a potential etiologic factor in the triggering and relapse ...of psychosis. However, there is no direct evidence that brain dopaminergic response to stress is exaggerated in psychosis. Methods Using the ability of endogenous dopamine (DA) to compete with 11 C-(+)-PHNO binding, as measured with positron emission tomography, we examined stress-induced DA release in response to a validated psychosocial stress task. We studied 12 clinical high-risk (CHR), 10 antipsychotic-naive subjects with schizophrenia (SCZ), and 12 matched healthy volunteers (HV). Stress-induced DA release was estimated as the percent change in binding potential between conditions (stress and control scan) in the striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Results We found a significant difference between groups in the AST ( F = 8.13, df = 2,31, p = .001), and at the SMST ( F = 3,64, df = 2,31, p = .03) but not in the LST ( F = .43, df = 2,31, p = .40) with CHR and SCZ having larger 11 C-(+)-PHNO displacement in response to the stress. Bonferroni-corrected comparisons confirmed that HV displacement (–2.86%) in the AST was significantly different in CHR (6.97%) and SCZ (11.44%) (with no significant difference between CHR and SCZ). Conclusions This study reveals a sensitized dopaminergic response to stress in a psychiatric condition and may have important theoretical and clinical implications regarding efforts to abort or delay relapse and/or conversion to psychosis.
Positron emission tomography (PET) imaging of monoamine oxidases (MAO-A: 11Charmine, 11Cclorgyline, and 11Cbefloxatone; MAO-B: 11Cdeprenyl-D2) has been actively pursued given clinical importance of ...MAOs in human neuropsychiatric disorders. However, it is unknown how well PET outcome measures for the different radiotracers are quantitatively related to actual MAO protein levels. We measured regional distribution (n = 38) and developmental/aging changes (21 hours to 99 years) of both MAOs by quantitative immunoblotting in autopsied normal human brain. MAO-A was more abundant than MAO-B in infants, which was reversed as MAO-B levels increased faster before 1 year and, unlike MAO-A, kept increasing steadily to senescence. In adults, regional protein levels of both MAOs were positively and proportionally correlated with literature postmortem data of MAO activities and binding densities. With the exception of 11Cbefloxatone (binding potential (BP), r = 0.61, P = 0.15), correlations between regional PET outcome measures of binding in the literature and MAO protein levels were good (P < 0.01) for 11Charmine (distribution volume, r = 0.86), 11Cclorgyline (λk3, r = 0.82), and 11Cdeprenyl-D2 (λk3 or modified Patlak slope, r = 0.78 to 0.87), supporting validity of the latter imaging measures. However, compared with in vitro data, the latter PET measures underestimated regional contrast by ~2-fold. Further studies are needed to address cause of the in vivo vs. in vitro nonproportionality.
Abstract
Stimuli previously paired with drugs of dependence can produce cravings that are associated with increased dopamine (DA) levels in limbic and striatal brain areas. Positron Emission ...Tomography (PET) imaging with
11
C-(+)-PHNO allows for a sensitive measurement of changes in DA levels. The purpose of the present study was to investigate changes in DA levels, measured with PET imaging with
11
C-(+)-PHNO, in regions of interest in smokers who had maintained abstinence for 7–10 days. Participants (N = 10) underwent two PET scans on separate days, during which they viewed either smoking-related or neutral images, in counterbalanced order. Craving was measured with the 12-item Tobacco Craving Questionnaire (TCQ) and the Questionnaire on Smoking Urges-Brief (QSU-B). Compared to neutral cues, smoking cues did not increase craving. There were no changes in
11
C-(+)-PHNO binding in the cue condition compared to the neutral condition for most regions of interest (ventral pallidum, globus pallidus, limbic striatum, associative striatum, sensorimotor striatum). However, binding potential in the substantia nigra was greater in the smoking-cue condition, indicating decreased synaptic dopamine. There is a potential change of DA level occurring in midbrain following the presentation of smoking-related cues. However, this preliminary finding would need to be validated with a larger sample.
Objective
Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine ...dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD.
Methods
We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory‐impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance.
Results
Memory‐impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex ACC and the right parahippocampal gyrus PHG) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients.
Interpretation
Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction. Ann Neurol 2015;77:269–280
PDF
