Alterations in self-reported sensory gating and interoception in individuals frequently using cannabis.

Background: Cannabis use is associated with altered processing of external (exteroceptive) and internal (interoceptive) sensory stimuli. However, little research exists on whether subjective experiences of these processes are altered in people who frequently use cannabis. Altered exteroception may influence externally oriented attention, whereas interoceptive differences have implications for intoxication, craving, and withdrawal states.Objectives: The goal of the current study was to investigate subjective experiences of exteroceptive sensory gating and interoception in people frequently using cannabis. We hypothesized subjective impairments in sensory gating and elevations in affect-related interoceptive awareness; furthermore, such deviations would relate to cannabis use patterns.Methods: This cross-sectional study of community adults 18-40 years old included 72 individuals (50% female) who used cannabis at least twice a week (not intoxicated during study) and 78 individuals who did not use cannabis (60% female). Participants completed the Sensory Gating Inventory and the Multidimensional Assessment of Interoceptive Awareness-2 surveys. People using cannabis completed surveys on cannabis use patterns. Analyses tested group differences and associations with cannabis use.Results: People using cannabis reported impaired sensory gating (d = 0.37-0.44; all p values < 0.05) and elevations of interoceptive awareness related to detection and affect (d = 0.21-0.61; all p values < 0.05). Problematic cannabis use was associated with increased sensory gating impairments (r = 0.37, p < .05). Interoceptive awareness was unrelated to cannabis use variables.Conclusion: These findings extend literature on subjective experiences of sensory processing in people using cannabis. Findings may inform inclusion of external attentional tendencies and internal bodily awareness in assessments of risk and novel treatment approaches.

Impaired Sleep Mediates the Relationship Between Interpersonal Trauma and Subtypes of Delusional Ideation.

BACKGROUND AND HYPOTHESIS: Trauma is a robust risk factor for delusional ideation. However, the specificity and processes underlying this relationship are unclear. Qualitatively, interpersonal traumas (i.e., trauma caused by another person) appear to have a specific relationship with delusional ideation, particularly paranoia, given the commonality of social threat. However, this has not been empirically tested and the processes by which interpersonal trauma contributes to delusional ideation remain poorly understood. Given the role of impaired sleep in both trauma and delusional ideation, it may be a critical mediator between these variables. We hypothesized that interpersonal trauma, but not non-interpersonal trauma, would be positively related to subtypes of delusional ideation, especially paranoia, and that impaired sleep would mediate these relationships. STUDY DESIGN: In a large, transdiagnostic community sample (N = 478), an exploratory factor analysis of the Peter's Delusion Inventory identified three subtypes of delusional ideation, namely magical thinking, grandiosity, and paranoia. Three path models, one for each subtype of delusional ideation, tested whether interpersonal trauma and non-interpersonal trauma were related to subtypes of delusional ideation, and impaired sleep as a mediating variable of interpersonal trauma. STUDY RESULTS: Paranoia and grandiosity were positively related to interpersonal trauma and unrelated to non-interpersonal trauma. Furthermore, these relationships were significantly mediated by impaired sleep, which appeared strongest for paranoia. In contrast, magical thinking was unrelated to traumatic experiences. CONCLUSIONS: These findings support a specific relationship between interpersonal trauma and paranoia as well as grandiosity, with impaired sleep appearing as an important process by which interpersonal trauma contributes to both.

Sex differences in neuroendocrine, sympathetic nervous system, and affect responses to acute stress in cannabis users.

RATIONALE: Cannabis is the most widely used illicit substance in the USA and is often reportedly used for stress reduction. Indeed, cannabinoids modulate signaling of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. However, the role of biological sex in this interaction between cannabis use and stress is poorly understood, despite sex differences in neurobiological stress responsivity, endocannabinoid signaling, and clinical correlates of cannabis use. OBJECTIVE: The study aims to examine the role of biological sex in multisystem stress responsivity in cannabis users. METHODS: Frequent cannabis users (> 3 times/week, n = 48, 52% male) and non-users (n = 41, 49% male) participated in an acute psychosocial stress paradigm. Saliva was collected at eight timepoints and analyzed for hypothalamic-pituitary-adrenal (cortisol) and sympathetic (alpha-amylase) indices of stress responsivity, and basal estradiol. Subjective ratings of negative affect, including distress, were collected at three timepoints. RESULTS: Cannabis users showed blunted pre-to-post-stress cortisol reactivity. Female cannabis users demonstrated greater blunted cortisol reactivity than their male counterparts. Sex moderated the effect of cannabis use on alpha-amylase responsivity over time, wherein female cannabis users showed flattened alpha-amylase responses across the stressor compared to male cannabis users and both non-user groups. Qualitatively, female cannabis users demonstrated the greatest pre-to-post-stress change in subjective distress. Differences in stress responding were not explained by estradiol or distress intolerance. CONCLUSIONS: Biological sex impacts multisystem stress responding in cannabis users. Paradoxically, female cannabis users showed the least physiological, but greatest subjective, responses to the stressor. Further research into sex differences in the effects of cannabis use is warranted to better understand mechanisms and clinical implications.

Insular and Striatal Correlates of Uncertain Risky Reward Pursuit in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Risk-taking in specific contexts can be beneficial, leading to rewarding outcomes. Schizophrenia is associated with disadvantageous decision-making, as subjects pursue uncertain risky rewards less than controls. However, it is unclear whether this behavior is associated with more risk sensitivity or less reward incentivization. Matching on demographics and intelligence quotient (IQ), we determined whether risk-taking was more associated with brain activation in regions affiliated with risk evaluation or reward processing. STUDY DESIGN: Subjects (30 schizophrenia/schizoaffective disorder, 30 controls) completed a modified, fMRI Balloon Analogue Risk Task. Brain activation was modeled during decisions to pursue risky rewards and parametrically modeled according to risk level. STUDY RESULTS: The schizophrenia group exhibited less risky-reward pursuit despite previous adverse outcomes (Average Explosions; F(1,59) = 4.06, P = .048) but the comparable point at which risk-taking was volitionally discontinued (Adjusted Pumps; F(1,59) = 2.65, P = .11). Less activation was found in schizophrenia via whole brain and region of interest (ROI) analyses in the right (F(1,59) = 14.91, P < 0.001) and left (F(1,59) = 16.34, P < 0.001) nucleus accumbens (NAcc) during decisions to pursue rewards relative to riskiness. Risk-taking correlated with IQ in schizophrenia, but not controls. Path analyses of average ROI activation revealed less statistically determined influence of anterior insula upon dorsal anterior cingulate bilaterally (left: χ2 = 12.73, P < .001; right: χ2 = 9.54, P = .002) during risky reward pursuit in schizophrenia. CONCLUSIONS: NAcc activation in schizophrenia varied less according to the relative riskiness of uncertain rewards compared to controls, suggesting aberrations in reward processing. The lack of activation differences in other regions suggests similar risk evaluation. Less insular influence on the anterior cingulate may relate to attenuated salience attribution or inability for risk-related brain region collaboration to sufficiently perceive situational risk.

Evidence of familial confounding of the association between cannabis use and cerebellar-cortical functional connectivity using a twin study.

Cerebellar-cortical resting-state functional connectivity (rsFC) has been reported to be altered in cannabis users. However, this association may be due to genetic and environmental confounding rather than a causal relationship between cannabis use and changes in rsFC. In this co-twin control study, linear mixed models were used to assess relationships between the number of lifetime cannabis uses (NLCU) and age of cannabis onset (ACO) with cerebellar-cortical rsFC. The rsFC with seven functional networks was evaluated in 147 monozygotic and 82 dizygotic twin pairs. Importantly, the use of genetically informed models in this twin sample facilitated examining whether shared genetic or environmental effects underlie crude associations between cannabis measures and connectivity. Individual-level phenotypic analyses (i.e., accounting for twin-pair non-independence) showed that individuals in the full sample with earlier ACO and higher NLCU had lower cerebellar rsFC within the VA, DA, and FP networks. Yet, there were no significant differences in cerebellar-cortical rsFC between monozygotic twins who were discordant for cannabis measures. These findings suggest shared genetic or environmental confounds contribute to associations between cannabis use and altered cerebellar-cortical rsFC, rather than unique causal impacts of cannabis use on cerebellar-cortical rsFC.

Emotion regulation and delusion-proneness relate to empathetic tendencies in a transdiagnostic sample.

Empathetic tendencies (i.e., perspective taking and empathic concern) are a key factor in interpersonal relationships, which may be impacted by emotion regulation (i.e., reappraisal and suppression) and mental health symptoms, such as psychotic-like experiences. However, it is unclear if certain psychotic-like experiences, such as delusion-proneness, are still associated with reduced empathetic tendencies after accounting for emotion regulation style and dimensions of psychopathology that are often comorbid. In the current study, linear models tested these associations in a transdiagnostic community sample (N = 128), using the Interpersonal Reactivity Index (IRI), Emotion Regulation Questionnaire, and the Peter's Delusion Inventory. Results indicated that perspective taking was positively associated with reappraisal and negatively associated with delusion-proneness, after controlling for age, sex, race, intelligence, and symptoms of anxiety and depression. A significant change in R 2 supported the addition of delusion-proneness in this model. Specificity analyses demonstrated perspective taking was also negatively associated with suppression, but this relationship did not remain after accounting for the effects of reappraisal and delusion-proneness. Additional specificity analyses found no association between empathic concern and reappraisal or delusion-proneness but replicated previous findings that empathic concern was negatively associated with suppression. Taken together, delusion-proneness accounts for unique variance in perspective taking, which can inform future experimental research and may have important implications for psychosocial interventions.

A review of risky decision-making in psychosis-spectrum disorders.

The investigation of risky decision-making has a prominent place in clinical science, with sundry behavioral tasks aimed at empirically quantifying the psychological construct of risk-taking. However, use of differing behavioral tasks has resulted in lack of agreement on risky decision-making within psychosis-spectrum disorders, as findings fail to converge upon the typical, binary conceptualization of increased risk-seeking or risk-aversion. The current review synthesizes the behavioral, risky decision-making literature to elucidate how specific task parameters may contribute to differences in task performance, and their associations with psychosis symptomatology and cognitive functioning. A paring of the literature suggests that: 1) Explicit risk-taking may be characterized by risk imperception, evidenced by less discrimination between choices of varying degrees of risk, potentially secondary to cognitive deficits. 2) Ambiguous risk-taking findings are inconclusive with few published studies. 3) Uncertain risk-taking findings, consistently interpreted as more risk-averse, have not parsed risk attitudes from confounding processes that may impact decision-making (e.g. risk imperception, reward processing, motivation). Thus, overgeneralized interpretations of task-specific risk-seeking/aversion should be curtailed, as they may fail to appropriately characterize decision-making phenomena. Future research in psychosis-spectrum disorders would benefit from empirically isolating contributions of specific processes during risky decision-making, including the newly hypothesized risk imperception.

Task-related neural mechanisms of persecutory ideation in schizophrenia and community monozygotic twin-pairs.

Perceptions of spiteful behavior are common, distinct from rational fear, and may undergird persecutory ideation. To test this hypothesis and investigate neural mechanisms of persecutory ideation, we employed a novel economic social decision-making task, the Minnesota Trust Game (MTG), during neuroimaging in patients with schizophrenia (n = 30) and community monozygotic (MZ) twins (n = 38; 19 pairs). We examined distinct forms of mistrust, task-related brain activation and connectivity, and investigated relationships with persecutory ideation. We tested whether co-twin discordance on these measurements was correlated to reflect a common source of underlying variance. Across samples persecutory ideation was associated with reduced trust only during the suspiciousness condition, which assessed spite sensitivity given partners had no monetary incentive to betray. Task-based activation contrasts for specific forms of mistrust were limited and unrelated to persecutory ideation. However, task-based connectivity contrasts revealed a dorsal cingulate anterior insula network sensitive to suspicious mistrust, a left frontal-parietal (lF-P) network sensitive to rational mistrust, and a ventral medial/orbital prefrontal (vmPFC/OFC) network that was sensitive to the difference between these forms of mistrust (all p < .005). Higher persecutory ideation was predicted only by reduced connectivity between the vmPFC/OFC and lF-P networks (p = .005), which was only observed when the intentions of the other player were relevant. Moreover, co-twin differences in persecutory ideation predicted co-twin differences in both spite sensitivity and in vmPFC/OFC-lF-P connectivity. This work found that interconnectivity may be particularly important to the complex neurobiology underlying persecutory ideation, and that unique environmental variance causally linked persecutory ideation, decision-making, and brain connectivity.

Feature selection framework for functional connectome fingerprinting.

The ability to uniquely characterize individual subjects based on their functional connectome (FC) is a key requirement for progress toward precision psychiatry. FC fingerprinting is increasingly studied in the neuroimaging community for this purpose, where a variety of approaches have been developed for effective FC fingerprinting. Recent independent studies showed that fingerprinting accuracy suffers at large sample sizes and when coarser parcellations are used for computing the FC. Quantifying this problem and understanding the reasons these factors impact fingerprinting accuracy is crucial to develop more accurate fingerprinting methods for large sample sizes. Part of the challenge in fingerprinting is that FC captures both generic and subject-specific information. A systematic approach for identifying subject-specific FC information is crucial for making progress in addressing the fingerprinting problem. In this study, we addressed three gaps in our understanding of the FC fingerprinting problem. First, we studied the joint effect of sample size and parcellation granularity. Second, we explained the reason for reduced fingerprinting accuracy with increased sample size and reduced parcellation granularity. To this end, we used a clustering quality metric from the data mining community. Third, we developed a general feature selection framework for systematically identifying resting-state functional connectivity (RSFC) elements that capture information to uniquely identify subjects. In sum, we evaluated six different approaches from this framework by quantifying both subject-specific fingerprinting accuracy and the decrease in accuracy with an increase in sample size to identify which approach improved quality metrics the most.

The Role of Hippocampal Functional Connectivity on Multisystem Subclinical Abnormalities in Schizophrenia.

OBJECTIVE: Schizophrenia is associated with excess medical mortality: patients have an average life expectancy one to two decades shorter than the general population. This study investigates the relationship between aberrant hippocampal resting-state functional connectivity in schizophrenia and cumulative subclinical effects of chronic stress on metabolic, cardiovascular, and immune function using the allostatic load index. METHODS: Cumulative stress was estimated using allostatic load total score (range, 0-13) in 46 patients with schizophrenia and 31 controls matched for age and sex (patients: age = 36.1 [13.7] years, sex = 32/14 male/female; controls: age = 35.5 [14.1], sex = 21/10 male/female). Hippocampal functional connectivity was assessed using resting-state functional magnetic resonance imaging; hippocampal structural connectivity was assessed using fornix fractional anisotropy. Linear regression analysis was used a) to test the hypothesis that aberrant hippocampal resting-state functional connectivity in schizophrenia (identified in analysis of schizophrenia - control differences) is associated with elevated allostatic load scores in patients and b) to determine the association between fornix fractional anisotropy with allostatic load. RESULTS: In patients, higher allostatic load was significantly associated with reduced resting functional connectivity between the left hippocampus and right cingulate cortex and left precentral gyrus, but higher connectivity between the right hippocampus and left cerebellum lobe VI (corrected p values <. 05). In controls, reductions in both hippocampal structural connectivity and hippocampal-cingulate functional connectivity were associated with higher allostatic load scores. CONCLUSIONS: These findings support basic neuroscience evidence that cumulative stress and hippocampal function are closely connected and suggest that abnormal hippocampal functional communication in schizophrenia may be related to elevated multisystem subclinical medical issues in patients as indexed by allostatic load.

Cingulum and abnormal psychological stress response in schizophrenia.

Stress is implicated in many aspects of schizophrenia, including heightened distress intolerance. We examined how affect and microstructure of major brain tracts involved in regulating affect may contribute to distress intolerance in schizophrenia. Patients with schizophrenia spectrum disorders (n = 78) and community controls (n = 95) completed diffusion weighted imaging and performed psychological stress tasks. Subjective affect was collected pre and post stressors. Individuals who did not persist during one or both stress tasks were considered distress intolerant (DI), and otherwise distress tolerant (DT). Fractional anisotropy (FA) of the dorsal cingulum showed a significant diagnosis x DT/DI phenotype interaction (p = 0.003). Post-hoc tests showed dorsal cingulum FA was significantly lower in DI patients compared with DI controls (p < 0.001), but not different between DT groups (p = 0.27). Regarding affect responses to stress, irritability showed the largest stress-related change (p < 0.001), but irritability changes were significantly reduced in DI patients compared to DI controls (p = 0.006). The relationship between irritability change and performance errors also differed among patients (ρ = -0.29, p = 0.011) and controls (ρ = 0.21, p = 0.042). Further modeling highlighted the explanatory power of dorsal cingulum for predicting DI even after performance and irritability were taken into account. Distress intolerance during psychological stress exposure is related to microstructural properties of the dorsal cingulum, a key structure for cognitive control and emotion regulation. In schizophrenia, the affective response to psychological stressors is abnormal, and distress intolerant patients had significantly reduced dorsal cingulum FA compared to distress intolerant controls. The findings provide new insight regarding distress intolerance in schizophrenia.

Clinical and genetic validity of quantitative bipolarity.

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h2 = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h2 = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.

Aberrant Middle Prefrontal-Motor Cortex Connectivity Mediates Motor Inhibitory Biomarker in Schizophrenia.

BACKGROUND: Inhibitory deficits in motor cortex in schizophrenia have been well demonstrated using short-interval intracortical inhibition (SICI) by transcranial magnetic stimulation. However, it remains unknown whether these deficits originate from dysfunction of motor cortex itself or reflect abnormal modulations of motor cortex by other schizophrenia-related brain areas. METHODS: The study was completed by 24 patients with schizophrenia spectrum disorders and 30 healthy control subjects. SICI was obtained by delivering transcranial magnetic stimulation over the left motor cortex. Resting-state functional magnetic resonance imaging and diffusion tensor imaging fractional anisotropy were used to measure functional connectivity (FC) and white matter microstructures, respectively. Stimulation sites for SICI at motor cortex were used as the seeds to obtain whole-brain FC maps. Clinical symptoms were assessed with the Brief Psychiatric Rating Scale. RESULTS: In schizophrenia, left prefrontal cortex-motor cortex FC was inversely associated with SICI but positively associated with the underlying white matter microstructure at the left corona radiata and also associated with overall symptoms (all corrected p < .05). Mediation analysis showed that the prefrontal-motor cortex FC significantly mediated the corona radiata white matter effects on SICI (p = .007). CONCLUSIONS: Higher resting-state left prefrontal-motor cortex FC, accompanied by a higher fractional anisotropy of left corona radiata, predicted fewer inhibitory deficits, suggesting that the inhibitory deficits in motor cortex in schizophrenia may in part be mediated by a top-down prefrontal influence. SICI may serve as a robust biomarker indexing inhibitory dysfunction at anatomic as well as circuitry levels in schizophrenia.

Aberrant Frontostriatal Connectivity in Negative Symptoms of Schizophrenia.

Negative symptoms represent a distinct component of psychopathology in schizophrenia (SCZ) and are a stable construct over time. Although impaired frontostriatal connectivity has been frequently described in SCZ, its link with negative symptoms has not been carefully studied. We tested the hypothesis that frontostriatal connectivity at rest may be associated with the severity of negative symptoms in SCZ. Resting state functional connectivity (rsFC) data from 95 mostly medicated patients with SCZ and 139 healthy controls (HCs) were acquired. Negative symptoms were assessed using the Brief Negative Symptom Scale. The study analyzed voxel-wise rsFC between 9 frontal "seed regions" and the entire striatum, with the intention to reduce potential biases introduced by predefining any single frontal or striatal region. SCZ showed significantly reduced rsFC between the striatum and the right medial and lateral orbitofrontal cortex (OFC), lateral prefrontal cortex, and rostral anterior cingulate cortex compared with HCs. Further, rsFC between the striatum and the right medial OFC was significantly associated with negative symptom severity. The involved striatal regions were primarily at the ventral putamen. Our results support reduced frontostriatal functional connectivity in SCZ and implicate striatal connectivity with the right medial OFC in negative symptoms. This task-independent resting functional magnetic resonance imaging study showed that medial OFC-striatum functional connectivity is reduced in SCZ and associated with severity of negative symptoms. This finding supports a significant association between frontostriatal connectivity and negative symptoms and thus may provide a potential circuitry-level biomarker to study the neurobiological mechanisms of negative symptoms.

Elevated allostatic load early in the course of schizophrenia.

Stress plays a significant role in schizophrenia from disease onset to exacerbation of psychotic symptoms. Allostatic load (AL) is a measure of cumulative stress to the organism. This study is an extension of our previous work on AL and its relationship to brain structures. Here, we further determined whether elevated AL is a function of illness chronicity, or if it is already present early in the course of schizophrenia. AL was compared in schizophrenia patients early in the illness (within 5 years of disease onset), patients with chronic schizophrenia (more than 5 years of illness), and two groups of healthy controls that were age-and sex-matched to the two patient groups. This work is presented with an expanded sample and includes about two-thirds of the participants who were previously reported. We found that patients with early psychosis had significantly elevated AL score compared with their age-matched controls (p = 0.005). Chronic course patients also had elevated AL compared with age-matched controls (p = 0.003). Immune and stress hormone AL subcomponents were nominally higher in early-stage patients compared with controls (p = 0.005 and 0.04, respectively). Greater AL was also associated with more severe positive psychotic symptoms in early-stage patients (r = 0.54, p = 0.01). Elevated levels of allostatic load are already present in the early years of the schizophrenia illness, particularly in patients with more severe psychotic symptoms. AL may be a useful evaluation for the need of early intervention on psychosomatic comorbidity.

Cerebellar-Stimulation Evoked Prefrontal Electrical Synchrony Is Modulated by GABA.

Cerebellar-prefrontal connectivity has been recognized as important for behaviors ranging from motor coordination to cognition. Many of these behaviors are known to involve excitatory or inhibitory modulations from the prefrontal cortex. We used cerebellar transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) to probe cerebellar-evoked electrical activity in prefrontal cortical areas and used magnetic resonance spectroscopy (MRS) measures of prefrontal GABA and glutamate levels to determine if they are correlated with those potentials. Cerebellar-evoked bilateral prefrontal synchrony in the theta to gamma frequency range showed patterns that reflect strong GABAergic inhibitory function (r = - 0.66, p = 0.002). Stimulation of prefrontal areas evoked bilateral prefrontal synchrony in the theta to low beta frequency range that reflected, conversely, glutamatergic excitatory function (r = 0.66, p = 0.002) and GABAergic inhibitory function (r = - 0.65, p = 0.002). Cerebellar-evoked prefrontal synchronization had opposite associations with cognition and motor coordination: it was positively associated with working memory performance (r = 0.57, p = 0.008) but negatively associated with coordinated motor function as measured by rapid finger tapping (r = - 0.59, p = 0.006). The results suggest a relationship between regional GABA levels and interregional effects on synchrony. Stronger cerebellar-evoked prefrontal synchrony was associated with better working memory but surprisingly worse motor coordination, which suggests competing effects for motor activity and cognition. The data supports the use of a TMS-EEG-MRS approach to study the neurochemical basis of large-scale oscillations modulated by the cerebellar-prefrontal connectivity.

Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia.

Frontal glutamatergic synapses are thought to be critical for adaptive, long-term stress responses. Prefrontal cortices, including the anterior cingulate cortex (ACC) contribute to stress perception and regulation, and are involved in top-down regulation of peripheral glucocorticoid and inflammatory responses to stress. Levels of kynurenic acid (KYNA) in saliva increase in response to psychological stress, and this stress-induced effect may be abnormal in people with schizophrenia. Here we test the hypothesis that ACC glutamatergic functioning may contribute to the stress-induced salivary KYNA response in schizophrenia. In 56 patients with schizophrenia and 58 healthy controls, our results confirm that levels of KYNA in saliva increase following psychological stress. The magnitude of the effect correlated negatively with proton magnetic resonance spectroscopy (MRS) glutamate + glutamine (r = -.31, p = .017) and glutamate (r = -0.27, p = .047) levels in the ACC in patients but not in the controls (all p ≥ .45). Although, a causal relationship cannot be ascertained in this cross-sectional study, these findings suggest a potentially meaningful link between central glutamate levels and kynurenine pathway response to stress in individuals with schizophrenia.

TMS evoked N100 reflects local GABA and glutamate balance.

BACKGROUND: Animal studies suggest that synchronized electrical activities in the brain are regulated by the primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate, respectively. Identifying direct evidence that this same basic chemical-electrical neuroscience principle operates in the human brains is critical for translation of neuroscience to pathological research. OBJECTIVE/HYPOTHESIS: We hypothesize that the background neurochemical concentrations may affect the cortical excitability probed by transcranial magnetic stimulation (TMS). METHODS: We used TMS with simultaneous evoked potential recording to probe the cortical excitability and determined how background frontal cortical GABA and glutamate levels measured using magnetic resonance spectroscopy (MRS) modulate frontal electrical activities. RESULTS: We found that TMS-evoked N100 reflects a balance between GABA-inhibitory and glutamate-excitatory levels. About 46% of individual variances in frontal N100 can be explained by their glutamate/GABA ratio (r = -0.68, p = 0.001). Both glutamate (r = -0.51, p = 0.019) and GABA (r = 0.55, p = 0.01) significantly contributed to this relationship but in opposite directions. CONCLUSION: The current finding encourages additional mechanistic studies to develop TMS evoked N100 as a potential electrophysiological biomarker for translating the known inhibitory GABAergic vs. excitatory glutamatergic chemical-electrical principle from animal brain studies to human brain studies.

Glutamatergic Response to Heat Pain Stress in Schizophrenia.

Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system. As schizophrenia is associated with glutamatergic abnormalities, we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex (dACC), a key region involved in perception of and reaction to stress. To test this, we developed a somatic stress paradigm involving pseudorandom application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC. This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia. Across groups, glutamate levels significantly decreased following exposure to thermal pain, while ratio of glutamine to glutamate significantly increased. However, schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls, after controlling for heat pain tolerance. Furthermore, in patients, the acute glutamate response was positively correlated with childhood trauma (r = .41, P = .050) and inversely correlated with working memory (r = -.49, P = .023). These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients, which may point toward novel approaches to understanding how stress contributes to the illness.

Fornix Structural Connectivity and Allostatic Load: Empirical Evidence From Schizophrenia Patients and Healthy Controls.

OBJECTIVE: The fornix is a white matter tract carrying the fibers connecting the hippocampus and the hypothalamus, two essential stress-regulatory structures of the brain. We tested the hypothesis that allostatic load (AL), derived from a battery of peripheral biomarkers indexing the cumulative effects of stress, is associated with abnormalities in brain white matter microstructure, especially the fornix, and that higher AL may help explain the white matter abnormalities in schizophrenia. METHODS: Using 13 predefined biomarkers, we tested AL in 44 schizophrenic patients and 33 healthy controls. Diffusion tensor imaging was used to obtain fractional anisotropy (FA) values of the fornix and other white matter tracts. RESULTS: AL scores were significantly elevated in patients compared with controls (F(3,77) = 7.87, p = .006). AL was significantly and inversely correlated with FA of fornix in both controls (r = -.58, p = .001) and patients (r = -.36, p = .023). Several nominally significant (p < .05 but did not survive Bonferroni correction for multiple comparison) correlations were also observed between AL and FA of other white matter tracts in schizophrenic patients. However, the fornix was the only tract exhibiting a correlation with AL in both groups. CONCLUSIONS: These results provide initial evidence that allostatic processes are linked to fornix microstructure in clinical participants.