Acute neuroimmune stimulation impairs verbal memory in adults: A PET brain imaging study.

Psychiatric and neurologic disorders are often characterized by both neuroinflammation and cognitive dysfunction. To date, however, the relationship between neuroinflammation and cognitive dysfunction remains understudied in humans. Preclinical research indicates that experimental induction of neuroinflammation reliably impairs memory processes. In this paradigm development study, we translated those robust preclinical findings to humans using positron emission tomography (PET) imaging with [11C]PBR28, a marker of microglia, and lipopolysaccharide (LPS), a potent neuroimmune stimulus. In a sample of 18 healthy adults, we extended our previous findings that LPS administration increased whole-brain [11C]PBR28 availability by 31-50%, demonstrating a robust neuroimmune response (Cohen's ds > 1.6). We now show that LPS specifically impaired verbal learning and recall, hippocampal memory processes, by 11% and 22%, respectively (Cohen's ds > 0.9), but did not alter attention, motor, or executive processes. The LPS-induced increase in [11C]PBR28 binding was correlated with significantly greater decrements in verbal learning performance in the hippocampus (r = -0.52, p = .028), putamen (r = -0.50, p = .04), and thalamus (r = -0.55, p = .02). This experimental paradigm may be useful in investigating mechanistic relationships between neuroinflammatory signaling and cognitive dysfunction in psychiatric and neurologic disorders. It may also provide a direct approach to evaluate medications designed to rescue cognitive deficits associated with neuroinflammatory dysfunction.

N-acetylcysteine reduces cocaine-seeking behavior and anterior cingulate glutamate/glutamine levels among cocaine-dependent individuals.

N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm3 ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.

A neurobiological correlate of stress-induced nicotine-seeking behavior among cigarette smokers.

Stress is known to influence smoking relapse. Experimental studies indicate that acute stress increases nicotine-seeking behavior, yet neurobiological mechanisms remain poorly understood. Herein, we investigated disrupted excitatory neural activity in the dorsolateral prefrontal cortex (dlPFC) as a mechanism of stress-induced nicotine-seeking behavior. Non-treatment-seeking cigarette smokers were screened for psychiatric, medical, and neuroimaging contraindications. Using a double-blind, placebo-controlled, randomized crossover design, participants (N = 21) completed two oral-dosing sessions: stress (yohimbine 54 mg + hydrocortisone 10 mg) vs placebo (lactose 54 mg + lactose 10 mg). During each experimental session, working memory proficiency, dlPFC excitatory neural activity, nicotine-seeking behavior, and subjective effects were measured. dlPFC excitatory neural activity was quantified via glutamate modulation during working memory performance using functional proton magnetic resonance spectroscopy. Nicotine-seeking behavior was assayed using a cigarette puffs vs money choice progressive ratio task. Results indicated that yohimbine + hydrocortisone evoked a sustained physiological stress response (elevated heart rate, blood pressure, saliva cortisol, and saliva α-amylase levels; ps < .05). Relative to placebo levels, acute stress increased nicotine-seeking behavior (ps < .05), disrupted dlPFC glutamate modulation (p = .025), and impaired dlPFC function (working memory proficiency; ps < .05). The stress-induced increase in nicotine-seeking behavior was linearly related to the stress-induced disruption of dlPFC glutamate modulation (R2  = 0.24-0.37; ps < .05). These findings suggest that disrupted dlPFC excitatory neural activity is a neurobiological correlate of acute stress-induced nicotine-seeking behavior. These findings further emphasize the central role of the dlPFC in regulating drug-seeking behavior. Future studies are needed to evaluate interventions to improve dlPFC resilience to acute stress effects, including neurostimulation, working memory training, and "anti-stress" medications.

Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation.

Working memory processes are associated with the dorsolateral prefrontal cortex (dlPFC). Prior research using proton functional magnetic resonance spectroscopy (1H fMRS) observed significant dlPFC glutamate modulation during letter 2-back performance, indicative of working memory-driven increase in excitatory neural activity. Acute stress has been shown to impair working memory performance. Herein, we quantified dlPFC glutamate modulation during working memory under placebo (oral lactose) and acute stress conditions (oral yohimbine 54 mg + hydrocortisone 10 mg). Using a double-blind, randomized crossover design, participants (N = 19) completed a letter 2-back task during left dlPFC 1H fMRS acquisition (Brodmann areas 45/46; 4.5 cm3). An automated fitting procedure integrated with LCModel was used to quantify glutamate levels. Working memory-induced glutamate modulation was calculated as percentage change in glutamate levels from passive visual fixation to 2-back levels. Results indicated acute stress significantly attenuated working memory-induced glutamate modulation and impaired 2-back response accuracy, relative to placebo levels. Follow-up analyses indicated 2-back performance significantly modulated glutamate levels relative to passive visual fixation during placebo but not acute stress. Biomarkers, including blood pressure and saliva cortisol, confirmed that yohimbine + hydrocortisone dosing elicited a significant physiological stress response. These findings support a priori hypotheses and demonstrate that acute stress impairs dlPFC function and excitatory activity. This study highlights a neurobiological mechanism through which acute stress may contribute to psychiatric dysfunction and derail treatment progress. Future research is needed to isolate noradrenaline vs. cortisol effects and evaluate anti-stress medications and/or behavioral interventions.

Differences in steady-state glutamate levels and variability between 'non-task-active' conditions: Evidence from 1H fMRS of the prefrontal cortex.

Proton functional magnetic resonance spectroscopy (1H fMRS) is a noninvasive neuroimaging technique capable of detecting dynamic changes in glutamate related to task-related demands at a temporal resolution under 1 min. Several recent 1H fMRS studies demonstrated elevated steady-state levels of glutamate of 2% or greater during different 'task-active' conditions, relative to a 'non-task-active' control condition. However, the 'control' condition from these studies does vary with respect to the degree of constraining behavior, which may lead to different glutamate levels or variability between 'control' conditions. The purpose of this 1H fMRS study was to compare the steady-state levels and variability of glutamate in the left dorsolateral prefrontal cortex (dlPFC) of 16 healthy adults across four different putative 'non-task-active' conditions: relaxed with eyes closed, passive visual fixation crosshair, visual flashing checkerboard, and finger tapping. Results showed significantly lower glutamate levels during the passive visual fixation crosshair than the visual flashing checkerboard and the finger tapping conditions. Moreover, glutamate was significantly less variable during the passive visual fixation crosshair and the visual flashing checkerboard than the relaxed eyes closed condition. Of the four conditions, the passive visual fixation crosshair condition demonstrated the lowest and least variable glutamate levels potentially reflecting the least dlPFC engagement, but greatest behavioral constraint. These results emphasize the importance of selecting a proper 'control' condition to reflect accurately a 'non-task-active' steady-state level of glutamate with minimal variability during 1H MRS investigations.

Mediational Pathways Among Trait Impulsivity, Heroin-use Consequences, and Current Mood State.

BACKGROUND: This study examined whether lifetime heroin-use consequences mediate the relationship between trait impulsivity and three current mood outcomes: depression symptoms, stress levels, and perception of life events. METHOD: Regular heroin users (N = 163) were assessed using the Barratt Impulsiveness Scale (BIS-11) to measure trait impulsivity; a standardized Drug History and Use Questionnaire to measure lifetime adverse consequences of heroin use; Beck Depression Inventory II to measure current depression symptoms; Stress subscale of the Depression Anxiety Stress scale; and Hassles and Uplifts scale to measure perception of life events. RESULTS: BIS-11 Attentional and Motor impulsivity were positively related to number of adverse heroin-use consequences, depression symptoms, and stress level, and negatively associated with positive perception of events. A greater number of heroin-use consequences was related to more depression symptoms, higher stress, more negative perception of events, injection heroin use, and earlier ages of first and regular heroin use. In six mediation models, lifetime heroin-use consequences partially mediated relationships between two trait impulsivity domains (Attentional, Motor) and current mood measures (depression symptoms, stress, perception of events). CONCLUSIONS: The present findings suggest that current negative mood can be a response to the accumulated burden of heroin-use consequences, particularly in the presence of high trait impulsivity.

Functional mu opioid receptor polymorphism (OPRM1 A(118) G) associated with heroin use outcomes in Caucasian males: A pilot study.

BACKGROUND: Heroin's analgesic, euphoric and dependence-producing effects are primarily mediated by the mu opioid receptor (MOR). A single gene, OPRM1, encodes the MOR. The functional polymorphism A(118)G, located in exon 1 of the OPRM1 gene, results in anatomically-specific reductions in MOR expression, which may alter an individual's response to heroin. In prior studies 118G (rare allele) carriers demonstrated significantly greater opioid tolerance, overdose vulnerability, and pain sensitivity than 118AA homozygotes. Those findings suggest OPRM1 genotype may impact characteristics of heroin use. METHODS: The present pilot study characterized the impact of OPRM1 genotype (rs1799971, 118G allele carriers vs. 118AA homozygotes) on heroin-use phenotypes associated with heroin dependence severity in a sample of male, Caucasian chronic heroin users (n = 86). RESULTS: Results indicate that 118G allele carriers reported significantly more heroin use-related consequences and heroin-quit attempts, and were more likely to have sought treatment for their heroin use than 118AA homozygotes. CONCLUSIONS: These preliminary findings, consistent with extant data, illustrate a role for OPRM1 allelic variation on heroin use characteristics, and provide support for considering genotype in heroin treatment and relapse prevention.

Disseminating behavioural activation for depression via online training: preliminary steps.

BACKGROUND: Despite the availability of evidence-based treatments for depression, large gaps exist between empirical research and clinical practice. AIMS: To make preliminary steps toward the dissemination of Behavioural Activation (BA) via online training by examining clinicians' interest in learning BA via online training and the effects of a preliminary version of BA online training. METHOD: In study 1, practising clinicians (n = 540) completed a survey that assessed attitudes towards learning BA using an online training format. In study 2, we conducted a small, pilot randomized controlled trial (n = 46) to examine preliminary efficacy of teaching BA principles and treatment strategies with a precursor version of BA online training. RESULTS: Study findings suggest that clinicians have interest in learning about BA via online training and that clinicians participating in BA online training evidence high satisfaction and significant gains in self-efficacy using BA and knowledge of BA terms and concepts. CONCLUSIONS: These results support the importance of efforts to disseminate BA and the viability of online training as an easily accessible and affordable training option.

Automated radiosynthesis of [11C]CPPC for in-human PET imaging applications.

The macrophage colony-stimulating factor 1 receptor (CSF1R) is almost exclusively expressed in microglia, representing a biomarker target for imaging of microglia availability. [11C]CPPC has specific binding affinity to CSF1R and suitable kinetic properties for in vivo PET imaging of microglia. However, previous studies reported a low radiochemical yield, motivating additional research to optimize [11C]CPPC radiochemistry. In this work, we report an automated radiosynthesis of [11C]CPPC on a Synthra MeIPlus module with improved radiochemical yield. The final [11C]CPPC product was obtained with excellent chemical/radiochemical purities and molecular activity, facilitating high-quality in-human PET imaging applications.

Mediational pathways among drug use initiation, use-related consequences, and quit attempts.

Background: Factors that predict attempts to discontinue drug use are clinically relevant and may inform treatment. This study investigated drug use-related consequences as a predictor of drug quit attempts and treatment seeking among two cohorts of persons who use drugs. Methods: Drug use and clinical characteristics were assessed among persons who use cocaine (N=176; urine-verified; 'Cocaine Cohort') and among those who use heroin (N=166; urine-verified; 'Heroin Cohort'). Mediation analyses assessed relationships among age at initial drug use, adverse drug-specific use-related consequences, and drug-specific quit attempts, separately for each cohort. Forward conditional logistic regression models evaluated drug use and clinical symptom scores as predictors of drug-specific treatment seeking. Results: Controlling for age, mediation models showed that drug use consequences fully mediated the relationship between age at initial drug use and number of drug-specific quit attempts for the 'Cocaine Cohort' and 'Heroin Cohort' (R2=0.30, p<.001; R2=0.17, p<.001; respectively). Reporting more consequences predicted more quit attempts in each cohort, accounting for duration of use (ps<.001). Reporting more consequences also predicted greater likelihood of seeking drug use treatment (ps<.001) and was associated with more severe clinical symptoms in each cohort (ps<.05). Conclusions: Using a parallel analysis design, we showed that reporting more drug-specific use-related consequences predicted more drug-specific quit attempts and greater likelihood to seek treatment in two cohorts: persons who use cocaine and those who use heroin. Our findings suggest that experiencing more drug use consequences predicts more attempts to seek drug abstinence and that assessment of consequences may be informative for treatment.

HIV chronicity as a predictor of hippocampal memory deficits in daily cannabis users living with HIV.

Background: Antiretroviral medications have increased the lifespan of persons living with HIV (PLWH) thereby unmasking memory decline that may be attributed to chronological age, HIV symptomatology, HIV disease chronicity, and/or substance use (especially cannabis use which is common among PLWH). To date, few studies have attempted to disentangle these effects. In a sample of daily cannabis-using PLWH, we investigated whether hippocampal memory function, assessed via an object-location associative learning task, was associated with age, HIV chronicity and symptom severity, or substance use. Methods: 48 PLWH (12.9 ± 9.6 years since HIV diagnosis), who were 44 years old on average (range: 24-64 years; 58 % male) and reported daily cannabis use (recent use confirmed by urinalysis) completed the study. We assessed each participant's demographics, substance use, medical history, current HIV symptoms, and hippocampal memory function via a well-validated object-location associative learning task. Results: Multiple regression analyses found that living more years since HIV+ diagnosis predicted significantly worse associative learning total score (r=-0.40) and learning rate (r=-0.34) whereas chronological age, cannabis-use characteristics, and recent HIV symptom severity were not significantly related to hippocampal memory function. Conclusions: In daily cannabis-using PLWH, HIV chronicity was related to worse hippocampal memory function independent from cannabis use, age, and HIV symptomatology. Object-location associative learning performance could serve as an 'early-warning' metric of cognitive decline among PLWH. Future research should examine longitudinal changes in associative learning proficiency and evaluate interventions to prevent hippocampal memory decline among PLWH. ClinicalTrials.gov: NCT01536899.

Is the Neuroimmune System a Therapeutic Target for Opioid Use Disorder? A Systematic Review.

Opioid use disorder (OUD) is an epidemic in the United States. In the past 12 months alone, there have been 75,000+ deaths attributed to opioid overdose: more than any other year in American history. Current pharmacotherapies for the treatment of OUD effectively suppress opioid withdrawal symptoms, but long-term relapse rates remain unacceptably high. Novel treatments for OUD are desperately needed to curb this epidemic. One target that has received considerable recent interest is the neuroimmune system. The neuroimmune system is anchored by glial cells, i.e., microglia and astrocytes, but neuroimmune signaling is known to influence neurons, including altering neurotransmission, synapse formation, and ultimately, brain function. Preclinical studies have shown that experimental attenuation of pro-inflammatory neuroimmune signaling modulates opioid addiction processes, including opioid reward, tolerance, and withdrawal symptoms, which suggests potential therapeutic benefit in patients. Whereas the peripheral immune system in OUD patients has been studied for decades and is well-understood, little is known about the neuroimmune system in OUD patients or its viability as a treatment target. Herein, we review the literature describing relationships between opioid administration and the neuroimmune system, the influence of neuroimmune signaling on opioid addiction processes, and the therapeutic potential for targeting the neuroimmune system in OUD subjects using glial modulator medications.

Sex and the dopaminergic system: Insights from addiction studies.

Sex differences are present in psychiatric disorders associated with disrupted dopamine function, and thus, sex differences in dopamine neurobiology may underlie these clinical disparities. In this chapter, we review sex differences in the dopaminergic system with a focus on substance use disorders, especially tobacco smoking, as our exemplar disorder. This chapter is organized into five sections describing sex differences in the dopaminergic system: (1) neurobiology, (2) role of sex hormones, (3) genetic underpinnings, (4) cognitive function, and (5) influence on addiction. In each section, we provide an overview of the topic area, summarize sex differences identified to date, highlight addiction research, especially clinical neuroimaging studies, and suggest avenues for future research.

Quantification of [11C]PBR28 data after systemic lipopolysaccharide challenge.

BACKGROUND: Lipopolysaccharide (LPS) is a classic immune stimulus. LPS combined with positron emission tomography (PET) 18 kDa translocator protein (TSPO) brain imaging provides a robust human laboratory model to study neuroimmune signaling. To evaluate optimal analysis of these data, this work compared the sensitivity of six quantification approaches. METHODS: [11C]PBR28 data from healthy volunteers (N = 8) were collected before and 3 h after LPS challenge (1.0 ng/kg IV). Quantification approaches included total volume of distribution estimated with two tissue, and two tissue plus irreversible uptake in whole blood, compartment models (2TCM and 2TCM-1k, respectively) and multilinear analysis-1 (MA-1); binding potential estimated with simultaneous estimation (SIME); standardized uptake values (SUV); and SUV ratio (SUVR). RESULTS: The 2TCM, 2TCM-1k, MA-1, and SIME approaches each yielded substantive effect sizes for LPS effects (partial η2 = 0.56-0.89, ps <. 05), whereas SUV and SUVR did not. CONCLUSION: These findings highlight the importance of incorporating AIF measurements to quantify LPS-TSPO studies.

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review.

There is tremendous interest in the role of the neuroimmune system and inflammatory processes in substance use disorders (SUDs). Imaging biomarkers of the neuroimmune system in vivo provide a vital translational bridge between preclinical and clinical research. Herein, we examine two imaging techniques that measure putative indices of the neuroimmune system and review their application among SUDs. Positron emission tomography (PET) imaging of 18 kDa translocator protein availability is a marker associated with microglia. Proton magnetic resonance spectroscopy quantification of myo-inositol levels is a putative glial marker found in astrocytes. Neuroinflammatory responses are initiated and maintained by microglia and astrocytes, and thus represent important imaging markers. The goal of this review is to summarize neuroimaging findings from the substance use literature that report data using these markers and discuss possible mechanisms of action. The extant literature indicates abused substances exert diverse and complex neuroimmune effects. Moreover, drug effects may change across addiction stages, i.e. the neuroimmune effects of acute drug administration may differ from chronic use. This burgeoning field has considerable potential to improve our understanding and treatment of SUDs. Future research is needed to determine how targeting the neuroimmune system may improve treatment outcomes.

Working Memory Modulates Glutamate Levels in the Dorsolateral Prefrontal Cortex during 1H fMRS.

Glutamate is involved in excitatory neurotransmission and metabolic processes related to brain function. Previous studies using proton functional magnetic resonance spectroscopy (1H fMRS) have demonstrated elevated cortical glutamate levels by 2-4% during visual and motor stimulation, relative to periods of no stimulation. Here, we extended this approach to working memory cognitive task performance, which has been consistently associated with dorsolateral prefrontal cortex (dlPFC) activation. Sixteen healthy adult volunteers completed a continuous visual fixation "rest" task followed by a letter 2-back working memory task during 1H fMRS acquisition of the left dlPFC, which encompassed Brodmann areas 45 and 46 over a 4.5-cm3 volume. Using a 100% automated fitting procedure integrated with LCModel, raw spectra were eddy current-, phase-, and shift-corrected prior to quantification resulting in a 32s temporal resolution or 8 averages per spectra. Task compliance was high (95 ± 11% correct) and the mean Cramer-Rao Lower Bound of glutamate was 6.9 ± 0.9%. Relative to continuous passive visual fixation, left dlPFC glutamate levels were significantly higher by 2.7% (0.32 mmol/kg wet weight) during letter 2-back performance. Elevated dlPFC glutamate levels reflect increased metabolic activity and excitatory neurotransmission driven by working memory-related cognitive demands. These results provide the first in vivo demonstration of elevated dlPFC glutamate levels during working memory.

Automated Voxel Placement: A Linux-based Suite of Tools for Accurate and Reliable Single Voxel Coregistration.

BACKGROUND: Single-voxel proton magnetic resonance spectroscopy (1H MRS) is a powerful technique for studying in vivo neurochemistry, but has an often-overlooked source of error variance: inconsistent voxel placement between scans. We developed and evaluated an Automated Voxel Placement (AVP) procedure for accurate and reliable 1H MRS voxel prescription. AVP is a suite of Linux-based programs that facilitate automated template-driven single-voxel coregistration. METHODS: Three studies were conducted to evaluate AVP for prescription of one voxel: left dorsolateral prefrontal cortex. First, we evaluated how robust AVP was to 'extreme' subject head positions/angulations within the scanner head coil. Second, subjects (N = 13) were recruited and underwent MR scans. Manual voxel prescription (n = 5) was contrasted with AVP (n = 8). A subset of AVP subjects (n = 4) completed a second scan. Third, ongoing data collection (n = 16; recruited for a separate study) helped evaluate AVP. Voxel placement accuracy was quantified as 3D geometric voxel overlap percentage between each subject's voxel and the template voxel. Reliability was quantified as 3D geometric voxel overlap percentage across subjects at each time point and within subjects who completed two scans. RESULTS: Results demonstrated that AVP was robust to 'extreme' head positions (97.5% - 97.9% overlap with the template voxel). AVP was significantly more accurate (baseline and follow-up: 96.2% ± 3.0% and 97.6% ± 1.4% overlap) than manual voxel placement (67.7% ± 22.8% overlap; ps<.05). AVP was reliable within- (97.9%) and between-subjects (94.2% and 97.2% overlap; baseline and follow-up; respectively). Finally, ongoing data collection indicates AVP is accurate (96.0%). CONCLUSION: These pilot studies demonstrated that AVP was feasible, accurate, and reliable method for automated single voxel coregistration.

Developing a scale of domains of negative consequences of chronic heroin use.

BACKGROUND: Chronic use of heroin typically leads to numerous negative life consequences and serious clinical impairment. Increased negative consequences can result in poor treatment outcomes as well as adverse health effects and impaired social functioning. Certain risk factors, including early substance use initiation, concurrent use of other illicit substances, and injection drug use are associated with an increase in negative consequences. This study examined whether there are unique domains of heroin consequences and, if so, whether these domains are related to specific substance use characteristics. METHODS: Data regarding substance use characteristics were collected from 370 non-treatment seeking, heroin-using, 18 to 55year-old participants from the Detroit metropolitan area. Principal component analysis (PCA) was used to analyze the factor structure of 21 negative heroin consequence items. RESULTS: PCA demonstrated that heroin consequences could be divided into 5 unique domains. These unique domains were related to specific substance use characteristics and heroin consequence domains. Injection heroin use was significantly associated with increased Factor 1 consequences (primarily acute medical problems) but not with consequences in other domains. Certain substance use characteristics, such as injection status and earlier onset of marijuana use, were associated with increased consequences in specific domains. CONCLUSIONS: These findings support the existence of unique domains of negative consequences, and indicate that some risk factors (e.g. injection use) may be specific to these domains. Potential tailored-treatment strategies aimed at improving treatment engagement and reducing harm for heroin use based on person-specific risks and negative consequences are discussed.

Network Profiles of the Dorsal Anterior Cingulate and Dorsal Prefrontal Cortex in Schizophrenia During Hippocampal-Based Associative Memory.

Schizophrenia is a disorder characterized by brain network dysfunction, particularly during behavioral tasks that depend on frontal and hippocampal mechanisms. Here, we investigated network profiles of the regions of the frontal cortex during memory encoding and retrieval, phases of processing essential to associative memory. Schizophrenia patients (n = 12) and healthy control (HC) subjects (n = 10) participated in an established object-location associative memory paradigm that drives frontal-hippocampal interactions. Network profiles were modeled of both the dorsal prefrontal (dPFC) and the dorsal anterior cingulate cortex (dACC) as seeds using psychophysiological interaction analyses, a robust framework for investigating seed-based connectivity in specific task contexts. The choice of seeds was motivated by previous evidence of involvement of these regions during associative memory. Differences between patients and controls were evaluated using second-level analyses of variance (ANOVA) with seed (dPFC vs. dACC), group (patients vs. controls), and memory process (encoding and retrieval) as factors. Patients showed a pattern of exaggerated modulation by each of the dACC and the dPFC during memory encoding and retrieval. Furthermore, group by memory process interactions were observed within regions of the hippocampus. In schizophrenia patients, relatively diminished modulation during encoding was associated with increased modulation during retrieval. These results suggest a pattern of complex dysfunctional network signatures of critical forebrain regions in schizophrenia. Evidence of dysfunctional frontal-medial temporal lobe network signatures in schizophrenia is consistent with the illness' characterization as a disconnection syndrome.

The dorsal prefrontal and dorsal anterior cingulate cortices exert complementary network signatures during encoding and retrieval in associative memory.

Cognitive control includes processes that facilitate execution of effortful cognitive tasks, including associative memory. Regions implicated in cognitive control during associative memory include the dorsal prefrontal (dPFC) and dorsal anterior cingulate cortex (dACC). Here we investigated the relative degrees of network-related interactions originating in the dPFC and dACC during oscillating phases of associative memory: encoding and cued retrieval. Volunteers completed an established object-location associative memory paradigm during fMRI. Psychophysiological interactions modeled modulatory network interactions from the dPFC and dACC during memory encoding and retrieval. Results were evaluated in second level analyses of variance with seed region and memory process as factors. Each seed exerted differentiable modulatory effects during encoding and retrieval. The dACC exhibited greater modulation (than the dPFC) on the fusiform and parahippocampal gyrus during encoding, while the dPFC exhibited greater modulation (than the dACC) on the fusiform, hippocampus, dPFC and basal ganglia. During retrieval, the dPFC exhibited greater modulation (than the dACC) on the parahippocampal gyrus, hippocampus, superior parietal lobule, and dPFC. The most notable finding was a seed by process interaction indicating that the dACC and the dPFC exerted complementary modulatory control on the hippocampus during each of the associative memory processes. These results provide evidence for differentiable, yet complementary, control-related modulation by the dACC and dPFC, while establishing the primacy of dPFC in exerting network control during both associative memory phases. Our approach and findings are relevant for understanding basic processes in human memory and psychiatric disorders that impact associative memory-related networks.