Lilianne R. Mujica-Parodi

Ventral striatal and medial prefrontal BOLD activation is correlated with reward-related electrocortical activity: A combined ERP and fMRI study

Functional magnetic resonance imaging (fMRI) research suggests that the ventral striatum (VS)/nucleus accumbens, medial prefrontal cortex (mPFC), and broader mesocorticolimbic dopamine system mediate aspects of reward processing from expectation of reward to pleasantness experienced upon reward attainment. In parallel, research utilizing event-related potentials (ERP) indicates that the feedback negativity (FN) is sensitive to reward vs. non-reward feedback and outcome expectation. The FN has been source localized to the mPFC and dorsal striatum, and converging evidence suggests that the FN reflects reward processing in the mesocorticolimbic system. However, the extent to which ERP and fMRI measures of reward processing are correlated has yet to be explored within the same individuals. The primary aim of the current study was to examine the convergence between fMRI (i.e., VS and mPFC) and ERP (i.e., FN) measures of reward processing in forty-two participants who completed counterbalanced fMRI and ERP sessions while performing the same monetary gambling task. For the Win>Loss comparison, fMRI activation in the mesocorticolimbic reward circuit including the VS and mPFC was positively correlated with the FN. Here, we demonstrate that monetary gains activate the VS, mPFC, caudate, amygdala, and orbital frontal cortex, enhance the FN ERP component within 300 ms post feedback, and that these measures are related. Thus, fMRI and ERP measures provide complementary information about mesocorticolimbic activity during reward processing, which may be useful in assessing pathological reward sensitivity.

Resting neural activity distinguishes subgroups of schizophrenia patients

BACKGROUND Schizophrenia is etiologically heterogeneous. It is anticipated, but unproven, that subgroups will differ in neuropathology and that neuroimaging may reveal these differences. The optimal imaging condition may be at rest, where greater variability is observed than during cognitive tasks, which more consistently reveal hypofrontality. We previously demonstrated symptom and physiologic differences between familial and sporadic schizophrenia patients and hypothesized that the groups would show different resting regional cerebral blood flow (rCBF) patterns. METHODS Ten familial and sixteen sporadic schizophrenia patients and nine comparison subjects had single photon emission computed tomography imaging during passive visual fixation. Images were spatially normalized into Talairach coordinates and analyzed for group rCBF differences using SPM with a Z value threshold of 2.80, p < .001. RESULTS The subgroups had similar age, gender, illness duration, and medication treatment. Sporadic patients had hypofrontality (anterior cingulate, paracingulate cortices, left dorsolateral and inferior-orbitofrontal), whereas familial patients had left temporoparietal hypoperfusion; all of these regions show resting activity in healthy subjects. Both groups hyperperfused the cerebellum/pons and parahippocampal gyrus; additional hyperperfusion for sporadic patients was observed in the fusiform; familial patients also hyperperfused the hippocampus, dentate, uncus, amygdala, thalamus, and putamen. CONCLUSIONS Familial and sporadic schizophrenia patients had different resting rCBF profiles, supporting the hypothesis that certain subgroups have distinct neural underpinnings. Different neuropathologic processes among subgroups of schizophrenia patients may account for the prior contradictory results of resting imaging studies.

Chemosensory Cues to Conspecific Emotional Stress Activate Amygdala in Humans

Alarm substances are airborne chemical signals, released by an individual into the environment, which communicate emotional stress between conspecifics. Here we tested whether humans, like other mammals, are able to detect emotional stress in others by chemosensory cues. Sweat samples collected from individuals undergoing an acute emotional stressor, with exercise as a control, were pooled and presented to a separate group of participants (blind to condition) during four experiments. In an fMRI experiment and its replication, we showed that scanned participants showed amygdala activation in response to samples obtained from donors undergoing an emotional, but not physical, stressor. An odor-discrimination experiment suggested the effect was primarily due to emotional, and not odor, differences between the two stimuli. A fourth experiment investigated behavioral effects, demonstrating that stress samples sharpened emotion-perception of ambiguous facial stimuli. Together, our findings suggest human chemosensory signaling of emotional stress, with neurobiological and behavioral effects.

Nonlinear complexity and spectral analyses of heart rate variability in medicated and unmedicated patients with schizophrenia.

Objective: Heart rate variability (HRV) reflects functioning of the autonomic nervous system and possibly also regulation by the neural limbic system, abnormalities of which have both figured prominently in various etiological models of schizophrenia, particularly those that address patients’ vulnerability to stress in connection to psychosis onset and exacerbation. This study provides data on cardiac functioning in a sample of schizophrenia patients that were either medication free or on atypical antipsychotics, as well as cardiac data on matched healthy controls. We included a medication-free group to investigate whether abnormalities in HRV previously reported in the literature and associated with atypical antipsychotics were solely the effect of medications or whether they might be a feature of the illness (or psychosis) itself. Method: We collected 24-hour ECGs on 19 patients and 24 controls. Of the patients, 9 were medication free and 10 were on atypical antipsychotics. All subject groups were matched for age and gender. Patient groups showed equivalent symptom severity and type, as well as duration of illness. We analyzed the data using nonlinear complexity (symbolic dynamic) HRV analyses as well as standard and relative spectral analyses. Results: For the medication-free patients as compared to the healthy controls, our data show decreased R–R intervals during sleep, and abnormal suppression of all frequency ranges, but particularly the low frequency range, which persisted even after adjusting the spectral data for the mean R–R interval. This effect was exacerbated for patients on atypical antipsychotics. Likewise, nonlinear complexity analysis showed significantly impaired HRV for medication-free patients that was exacerbated in the patients on atypical antipsychotics. Conclusions: Altogether, the data suggest a pattern of significantly decreased cardiac vagal function of patients with schizophrenia as compared to healthy controls, apart from and beyond any differences due to medication side effects. The data additionally confirm earlier reports of a deleterious effect of atypical antipsychotics on HRV, which may exacerbate an underlying vulnerability in patients. These results support previous evidence that autonomic abnormalities may be a core feature of the illness (or psychosis), and that an even more conservative approach to cardiac risk in schizophrenia than previously thought may therefore be clinically appropriate.

Limbic dysregulation is associated with lowered heart rate variability and increased trait anxiety in healthy adults

We tested whether dynamic interaction between limbic regions supports a control systems model of excitatory and inhibitory components of a negative feedback loop, and whether dysregulation of those dynamics might correlate with trait differences in anxiety and their cardiac characteristics among healthy adults.

Circuit-Wide Structural and Functional Measures Predict Ventromedial Prefrontal Cortex Fear Generalization: Implications for Generalized Anxiety Disorder

The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat–safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by ±20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.

The NIRS Analysis Package: Noise Reduction and Statistical Inference

Near infrared spectroscopy (NIRS) is a non-invasive optical imaging technique that can be used to measure cortical hemodynamic responses to specific stimuli or tasks. While analyses of NIRS data are normally adapted from established fMRI techniques, there are nevertheless substantial differences between the two modalities. Here, we investigate the impact of NIRS-specific noise; e.g., systemic (physiological), motion-related artifacts, and serial autocorrelations, upon the validity of statistical inference within the framework of the general linear model. We present a comprehensive framework for noise reduction and statistical inference, which is custom-tailored to the noise characteristics of NIRS. These methods have been implemented in a public domain Matlab toolbox, the NIRS Analysis Package (NAP). Finally, we validate NAP using both simulated and actual data, showing marked improvement in the detection power and reliability of NIRS.

Stressful Military Training : Endocrine Reactivity, Performance, and Psychological Impact

INTRODUCTION We examined the responsiveness of both cortisol and dehydroepiandrosterone sulfate (DHEAS) to the stress of survival training in military men and evaluated relationships to performance, peritraumatic dissociation, and the subsequent impact of stressful events. METHODS Baseline salivary cortisol samples were self-collected by 19 men at 0900 and 1930 in a free-living (FL) environment. DHEAS samples were also collected in a subset of this sample (N = 12). Samples were subsequently taken at similar time points during a stressful captivity (SC) phase of training. Repeated-measures analyses of variance with follow-up paired t-tests examined differences across time and conditions. RESULTS Significant increases were observed at both time points (0900 and 1930) from FL to SC in both cortisol (0900: 9.2 +/- 3.4 nmol x L(-1) vs. 18.4 +/- 10.5 nmol x L(-1); 1930: 3.5 +/- 3.0 nmol x L(-1) vs. 27.7 +/- 10.9 nmol x L(-1)) and DHEAS (0900: 1.7 +/- 1.3 ng x ml(-1) vs.6.7 +/- 3.5 ngx ml(-1); 1930: 1.5 0.84 ng x ml(-1) vs. 4.5 +/- 3.0 ng x ml(-1)). Also, overall performance during a high-intensity captivity-related challenge was inversely related to the DHEAS-cortisol ratio; conversely, overall performance during a low-intensity captivity-related challenge was positively related to DHEAS at the 0900 time point during SC. Dissociation was unrelated to endocrine indices measured during SC, while total impact of events was inversely related to percent change in DHEAS from FL to SC. CONCLUSIONS Cortisol and DHEAS increase in response to allostatic load, and may relate to human performance during SC as well as PTSD symptoms.

Ambulatory and Challenge-Associated Heart Rate Variability Measures Predict Cardiac Responses to Real-World Acute Emotional Stress

BACKGROUND Heart rate variability (HRV) measures homeostatic regulation of the autonomic nervous system in response to perturbation and has been previously shown to quantify risk for cardiac events. Despite known interactions among stress vulnerability, psychiatric illness, and cardiac health, however, this is the first study to our knowledge to compare directly the value of laboratory HRV in predicting autonomic modulation of real-world emotional stress. METHODS We recorded electrocardiograms (ECG) on 56 subjects: first, within the laboratory and then during an acute emotional stressor: a first-time skydive. Laboratory sessions included two 5-min ECG recordings separated by one ambulatory 24-hour recording. To test the efficacy of introducing a mild emotional challenge, during each of the 5-min laboratory recordings, subjects viewed either aversive or benign images. Following the laboratory session, subjects participated in the acute stressor wearing a Holter ECG. Artifact-free ECGs (n = 33) were analyzed for HRV then statistically compared across laboratory and acute stress sessions. RESULTS There were robust correlations (r = .7-.8) between the laboratory and acute stress HRV, indicating that the two most useful paradigms (long-term wake, followed by short-term challenge) were also most sensitive to distinct components of the acute stressor: the former correlated with the fine-tuned regulatory modulation occurring immediately prior and following the acute stressor, whereas the latter correlated with gross amplitude and recovery. CONCLUSIONS Our results confirmed the efficacy of laboratory-acquired HRV in predicting autonomic response to acute emotional stress and suggest that ambulatory and challenge protocols enhance predictive value.

Second-hand stress: inhalation of stress sweat enhances neural response to neutral faces

This study investigated whether human chemosensory-stress cues affect neural activity related to the evaluation of emotional stimuli. Chemosensory stimuli were obtained from the sweat of 64 male donors during both stress (first-time skydive) and control (exercise) conditions, indistinguishable by odor. We then recorded event-related potentials (ERPs) from an unrelated group of 14 participants while they viewed faces morphed with neutral-to-angry expressions and inhaled nebulized stress and exercise sweat in counter-balanced blocks, blind to condition. Results for the control condition ERPs were consistent with previous findings: the late positive potential (LPP; 400-600 ms post stimulus) in response to faces was larger for threatening than both neutral and ambiguous faces. In contrast, the stress condition was associated with a heightened LPP across all facial expressions; relative to control, the LPP was increased for both ambiguous and neutral faces in the stress condition. These results suggest that stress sweat may impact electrocortical activity associated with attention to salient environmental cues, potentially increasing attentiveness to otherwise inconspicuous stimuli.