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The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer’s disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [(18)F]MK6240 and [(18)F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [(18)F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t(186) = −4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = −0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder.

Background: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a validated measure of neuromelanin concentration in the substantia nigra–ventral tegmental area (SN–VTA) complex and is a proxy measure of dopaminergic function with potential as a noninvasive biomarker. The development of generalizable biomarkers requires large-scale samples necessitating harmonization approaches to combine data collected across sites. Purpose: To develop a method to harmonize NM-MRI across scanners and sites. Study Type: Prospective. Population: A total of 128 healthy subjects (18–73 years old; 45% female) from three sites and five MRI scanners. Field Strength/Sequence: 3.0 T; NM-MRI two-dimensional gradient-recalled echo with magnetization-transfer pulse and three-dimensional T1-weighted images. Assessment: NM-MRI contrast (contrast-to-noise ratio [CNR]) maps were calculated and CNR values within the SN–VTA (defined previously by manual tracing on a standardized NM-MRI template) were determined before harmonization (raw CNR) and after ComBat harmonization (harmonized CNR). Scanner differences were assessed by calculating the classification accuracy of a support vector machine (SVM). To assess the effect of harmonization on biological variability, support vector regression (SVR) was used to predict age and the difference in goodness-of-fit (Δr) was calculated as the correlation (between actual and predicted ages) for the harmonized CNR minus the correlation for the raw CNR. Statistical Tests: Permutation tests were used to determine if SVM classification accuracy was above chance level and if SVR Δr was significant. A P-value

The integrity and function of catecholamine neurotransmitter systems can be assessed using neuromelanin-sensitive MRI (NM-MRI). The relevance of this method to neurodegenerative and psychiatric disorders is becoming increasingly evident, and it has potential as a clinical biomarker.To support future application of NM-MRI as a clinical biomarker by defining the normative range of NM-MRI signal and volume metrics in cognitively normal older adults.Prospective.A total of 152 cognitively normal older adults aged 53-86 years old, including 41 participants who had follow-up NM-MRI data collected 9-16 months later.A 3.0 T; NM-MRI turbo spin echo and T1-weighted magnetization-prepared rapid acquisition with gradient echo sequences.NM-MRI images were processed to yield summary measures of volume and signal (contrast-to-noise ratio, CNR) for the substantia nigra (SN) and locus coeruleus (LC) using a recently developed software employing a fully automated algorithm. Change in these metrics over time was also assessed.Mean and standard deviation of NM-MRI metrics were calculated; change over time was tested for significance using 1-sample t-tests. P values 0.05 were considered statistically significant.At baseline SN signal (CNR) was 10.02% (left) and 10.28% (right) and LC signal was 24.71% (left) and 20.42% (right). Baseline SN volume was 576 mmWe report normative values for NM-MRI signal and volume in the SN and LC of cognitively normal older adults and explore their change over time. These values may help future efforts to use NM-MRI as a clinical biomarker by facilitating identification of patients with extreme NM-MRI values.1.

BACKGROUND: Neuromelanin-sensitive MRI (NM-MRI) of the substantia nigra provides a noninvasive way to acquire an indirect measure of dopamine functioning. Despite the potential of NM-MRI as a candidate biomarker for dopaminergic pathology, studies about its reproducibility are sparse.PURPOSE: To assess the test-retest reproducibility of three commonly used NM-MRI sequences and evaluate three analysis methods.STUDY TYPE: Prospective study.POPULATION: A total of 11 healthy participants age between 20-27 years.FIELD STRENGTH/SEQUENCE: 3.0T; NM-MRI gradient recalled echo (GRE) with magnetization transfer (MT) pulse; NM-MRI turbo spin echo (TSE) with MT pulse; NM-MRI TSE without MT pulse.ASSESSMENT: Participants were scanned twice with a 3-week interval. Manual analysis, threshold analysis, and voxelwise analysis were performed for volume and contrast ratio (CR) measurements.STATISTICAL TESTS: Intraclass correlation coefficients (ICCs) were calculated for test-retest and inter- and intrarater variability.RESULTS: The GRE sequence achieved the highest contrast and lowest variability (4.9-5.7%) and showed substantial to almost perfect test-retest ICC (0.72-0.90) for CR measurements. For volume measurements, the manual analysis showed a higher variability (10.7-17.9%) and scored lower test-retest ICCs (-0.13-0.73) than the other analysis methods. The threshold analysis showed higher test-retest ICC (0.77) than the manual analysis for the volume measurements.DATA CONCLUSION: NM-MRI is a highly reproducible measure, especially when using the GRE sequence and CR measurements. Volume measurements appear to be more sensitive to inter/intrarater variability and variability in placement and orientation of the NM-MRI slab. The threshold analysis appears to be the best alternative for volume analysis.LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.

Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [11C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. Moreover, load-dependent changes in connectivity between left and right frontoparietal networks (Δ connectivity lFPN-rFPN) predicted interindividual differences in task performance more accurately than other fMRI and PET imaging measures. Δ Connectivity lFPN-rFPN was not related to cortical dopamine release capacity. A second study in unmedicated patients with schizophrenia showed no abnormalities in load-dependent connectivity but showed a weaker relationship between Δ connectivity lFPN-rFPN and working memory performance in patients compared with matched healthy individuals. Poor working memory performance in patients was, in contrast, related to deficient cortical dopamine release. Our findings indicate that interactions between brain networks dynamically adapt to fluctuating environmental demands. These dynamic adaptations underlie successful working memory performance in healthy individuals and are not well predicted by amphetamine-induced dopamine release capacity.SIGNIFICANCE STATEMENTIt is unclear how communication between brain networks responds to changing environmental demands during complex cognitive processes. Also, unknown in regard to these network dynamics is the role of neuromodulators, such as dopamine, and whether their dysregulation could underlie cognitive deficits in neuropsychiatric illness. We found that connectivity between brain networks changes with working-memory load and greater increases predict better working memory performance; however, it was not related to capacity for dopamine release in the cortex. Patients with schizophrenia did show dynamic internetwork connectivity; however, this was more weakly associated with successful performance in patients compared with healthy individuals. Our findings indicate that dynamic interactions between brain networks may support the type of flexible adaptations essential to goal-directed behavior.

BACKGROUND The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation. METHODS We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter. RESULTS In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d' = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate-corrected. Risk-allele carriers did not show any regions of reduced white matter volume. LIMITATIONS The sample size is modest given that a low-frequency variant was being examined. CONCLUSION The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP.

OBJECTIVE The objective of this study was to evaluate the association between adherence to antipsychotic medication and working alliance (WA) ratings as reported separately by case manager (CM) and patient in first-episode psychosis (FEP) and to identify whether other factors previously related to adherence influence this relationship. METHODS Adherence was evaluated every month in 81 participants who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychotic disorder (affective or nonaffective) and were treated in a specialized early intervention program. Adherence was measured, taking into account information from patient and clinician reports and pill counting. The WA, as assessed by both CM and patient, was assessed using the Working Alliance Inventory. RESULTS The WA was stable during the course of the study as rated by both patient and CM. The "task" domain of WA was the subdomain most significantly correlated to adherence in cross-sectional analysis. The WA as measured by CM at study baseline was a significant predictor of the number of subsequent months with "good" adherence independently of other variables, including adherence at treatment onset (β = 0.011; P = 0.020; 95% confidence interval, 0.002-0.020). However, the WA as measured by patients was not similarly predictive of subsequent adherence (β = 0.003; P = 0.31; 95% confidence interval, -0.003 to 0.010). CONCLUSIONS The CM-rated WA is a significant predictor of future medication adherence in FEP, suggesting that good alliance can improve adherence in this population.

Background A history of childhood symptoms of inattention–hyperactivity is often reported in first episode psychosis (FEP) as is cannabis use. In the general population childhood ADHD predicts future cannabis use but the relationship has not been tested in FEP. Method Parents of patients with a first episode of psychosis (n = 75) retrospectively assessed their affected child for symptoms of early-life disorders, namely, attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) using the Child Behaviour Checklist (CBCL). Assessments were made prospectively of cannabis use over two years following a FEP and of SCID diagnosis of cannabis-use disorder. Results Childhood hyperactivity–inattention symptoms predicted inability to maintain abstinence from cannabis following treatment (Wald = 8.4, p = .004) and lifetime cannabis-use diagnosis (Wald = 5.3, p = .022) in a logistic regression controlling for relevant covariates including symptoms of CD and ODD from ages 12 to 18. When the symptom of inattention was considered in place of the hyperactivity–inattention syndrome it predicted cannabis-use diagnosis (Wald = 6.4, p = .011) and persistent abstinence from cannabis (Wald = 5.3, p = .021). Symptoms of CD and ODD did not predict cannabis use when hyperactivity–inattention symptoms were controlled for. Conclusions Symptoms of childhood inattention–hyperactivity predict subsequent cannabis use in FEP.

This study evaluates how much agreement there is between subjective reports of adherence to antipsychotic medication and objective or derived measures of adherence in first-episode psychosis (FEP) and asks if any adherence measure could approximate a gold standard based on correlation to symptom improvement in the early phase of treatment. Adherence was assessed in 81 FEP subjects on a monthly basis by reports from patients, clinicians, family, and pill counting. A consensus measure of adherence was derived from all available sources of adherence data. Symptoms were measured using the Positive and Negative Syndrome Scale at study entry and 3 months subsequently. Adherence as measured by patient report, pill count, and clinician report were in good agreement with each other (intraclass correlation coefficient = 0.84), and all of these measures were highly correlated to consensus adherence (r values between 0.86 and 0.98). Mean adherence was slightly higher as rated by patients (83% full doses taken per month) and family members (91%) than by clinicians (76%), pill counting (73%), or consensus value (74%). Early in treatment, each measure of adherence (except family report) was significantly associated with positive symptom reduction, although the order of magnitude of this correlation was greater for pill count and consensus adherence (P < 0.01) compared with patient- or clinician-reported adherence (P < 0.05). Patient or clinician reports provide a reasonable estimate of medication adherence in FEP, but introducing pill counting or a derived measure of adherence may allow more accurate measurement.

Objective: To assess whether an Early Case Identification Program (ECIP) for first-episode psychosis (FEP), which showed no significant short-term effects, has a delayed impact on duration of untreated psychosis (DUP). Method: Using a historical control design, FEP patients were assessed on clinical variables over three consecutive phases, 2 years prior, 2 years during and 3 years after implementation of the ECIP. Additional analyses were conducted on non-affective and schizophrenia spectrum psychoses cases only. Results: There was no overall significant difference in DUP across the three phases. For cases treated within the first year of illness a nonsignificant reduction in DUP to less than 2 months observed during the active phase was sustained post-ECIP. Conclusion: In some jurisdictions community-wide early case detection may fail to have an immediate or delayed effect on DUP, especially for cases who normally present for treatment with DUP >1 year.

Although the etiology of neurodevelopmental mental disorders remains obscure, converging lines of evidence using animal modeling suggest a critical role for activity-dependent neurodevelopmental processes during neonatal life. Here, we report the behavioral effects of a novel technique designed to induce targeted, transient disruption of activity-dependent processes in early development via reduction of calcium-mediated neurotransmitter release. We examined the post-pubertal behavioral effects of neonatal (postnatal day 7) medial prefrontal cortex infusion of either vehicle or N-type and P/Q-type presynaptic voltage-dependent calcium channel blockers (omega-conotoxins MVIIA and MVIIC respectively; 6.8 and 45 pmol infused respectively) in rat pups. In a test of amphetamine-induced behavioral sensitization, neonatal omega-conotoxin MVIIA treatment significantly increased locomotion following repeated amphetamine injections (1.5 mg/kg i.p.) and significantly decreased locomotion following repeated saline injections relative to animals treated neonatally with vehicle. However, there was no effect of conotoxin treatment on the long-term expression of amphetamine sensitization. Neonatal treatment with omega-conotoxins had no effect on the other behaviors assayed, namely, acoustic startle response, prepulse inhibition of startle, novelty- and amphetamine-induced (1.5 mg/kg i.p.) locomotion, and anxiety-like behavior in the elevated plus-maze. These data confirm that transient, region-specific disruption of synaptic transmission during early development can have long-term effects on behaviors relevant to neurodevelopmental mental disorders.