Joshua M. Carlson

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.

A left amygdala mediated network for rapid orienting to masked fearful faces.

A rapid response to environmental threat is highly adaptive and fearful facial expressions serve as important threat cues. The biological significance of these threat cues is demonstrated by neuroimaging findings of amygdala responses to backward masked fearful faces. Additionally, behavioral dot-probe studies reveal that backward masked fearful faces modulate spatial attention. However, little is known about the behavioral impact of the amygdala sensitivity to masked fearful faces. Using a dot-probe task with event-related functional magnetic resonance imaging (fMRI), we provide the first evidence that the amygdala is involved in orienting to backward masked fearful faces. Furthermore, this spatial attention-related amygdala response was correlated with activity in the anterior cingulate, superior temporal sulcus, and lingual gyrus.

Masked Fearful Faces Modulate the Orienting of Covert Spatial Attention

Dot probe studies indicate that masked fearful faces modulate spatial attention. However, without a baseline to compare congruent and incongruent reaction times, it is unclear which aspect(s) of attention (orienting or disengagement) is affected. Additionally, backward masking studies commonly use a neutral face as the mask stimulus. This method results in greater perceptual inconsistencies for fearful as opposed to neutral faces. Therefore, it is currently unclear whether the effects of backward masked fearful faces are due to the fearful nature of the face or perceptual inconsistencies. Equally unclear, is whether this spatial attention effect is due to orienting or disengagement. Two modified dot probe experiments with neutral (closed mouth in Experiment 1) and smiling (open mouth in Experiment 2) masks were used to determine the role of perceptual inconsistencies in mediating the spatial attention effects elicited by masked fearful faces. The results indicate that masked fearful faces modulate the orienting of spatial attention, and it appears that this effect is due to the fearful nature of the face rather than perceptual inconsistencies between the initial faces and masks.

Reward dysfunction in major depression: Multimodal neuroimaging evidence for refining the melancholic phenotype

Reward dysfunction is thought to play a core role in the pathophysiology of major depressive disorder (MDD). Event-related potential (ERP) and functional magnetic resonance imaging (fMRI) studies have identified reward processing deficits in MDD, but these methods have yet to be applied together in a single MDD sample. We utilized multimodal neuroimaging evidence to examine reward dysfunction in MDD. Further, we explored how neurobiological reward dysfunction would map onto subtypes of MDD. The feedback negativity (FN), an ERP index of reward evaluation, was recorded in 34 unmedicated depressed individuals and 42 never-depressed controls during a laboratory gambling task. Ventral striatal (VS) activation to reward was recorded in a separate fMRI session, using an identical task, among a subgroup of 24 depressed individuals and a comparison group of 18 non-depressed controls. FN amplitude was blunted in MDD. This effect was driven by a MDD subgroup characterized by impaired mood reactivity to positive events, a core feature of melancholic MDD. A similar pattern was observed for VS activation, which was also blunted among the MDD subgroup with impaired mood reactivity. Neither FN amplitude nor VS activation was related to the full, DSM-defined melancholic or atypical MDD subtypes. Across the MDD sample, FN amplitude and VS activation were correlated, indicating convergence across methods. These results indicate that not all MDD is characterized by reward dysfunction, and that there is meaningful heterogeneity in reward processing within MDD. The current study offers neurobiological evidence that impaired mood reactivity is a key phenotypic distinction for subtyping MDD, and further suggests that the existing melancholic phenotype may require further refinement.

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.

Influence of the BDNF Genotype on Amygdalo-Prefrontal White Matter Microstructure is Linked to Nonconscious Attention Bias to Threat

Cognitive processing biases, such as increased attention to threat, are gaining recognition as causal factors in anxiety. Yet, little is known about the anatomical pathway by which threat biases cognition and how genetic factors might influence the integrity of this pathway, and thus, behavior. For 40 normative adults, we reconstructed the entire amygdalo-prefrontal white matter tract (uncinate fasciculus) using diffusion tensor weighted MRI and probabilistic tractography to test the hypothesis that greater fiber integrity correlates with greater nonconscious attention bias to threat as measured by a backward masked dot-probe task. We used path analysis to investigate the relationship between brain-derived nerve growth factor genotype, uncinate fasciculus integrity, and attention bias behavior. Greater structural integrity of the amygdalo-prefrontal tract correlates with facilitated attention bias to nonconscious threat. Genetic variability associated with brain-derived nerve growth factor appears to influence the microstructure of this pathway and, in turn, attention bias to nonconscious threat. These results suggest that the integrity of amygdalo-prefrontal projections underlie nonconscious attention bias to threat and mediate genetic influence on attention bias behavior. Prefrontal cognition and attentional processing in high bias individuals appear to be heavily influenced by nonconscious threat signals relayed via the uncinate fasciculus.

Backward Masked Snakes and Guns Modulate Spatial Attention

Fearful faces are important social cues that alert others of potential threat. Even backward masked fearful faces facilitate spatial attention. However, visual stimuli other than fearful faces can signal potential threat. Indeed, unmasked snakes and spiders modulate spatial attention. Yet, it is unclear if the rapid threat-related facilitation of spatial attention to backward masked stimuli is elicited by non-face threat cues. Evolutionary theories claim that phylogenetic threats (i.e. snakes and spiders) should preferentially elicit an automatic fear response, but it is untested as to whether this response extends to enhancements in spatial attention under restricted processing conditions. Thirty individuals completed a backward masking dot-probe task with both evolutionary relevant and irrelevant threat cues. The results suggest that backward masked visual fear stimuli modulate spatial attention. Both evolutionary relevant (snake) and irrelevant (gun) threat cues facilitated spatial attention.

Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.

The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as “overgeneralization of fear.” To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cues perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.

Midbrain volume predicts fMRI and ERP measures of reward reactivity.

Ventral striatal activation measured with functional magnetic resonance imaging (fMRI) and feedback negativity amplitude measured with event-related potentials (ERPs) are each enhanced during reward processing. Recent research has found that these two neural measures of reward processing are also related to one another, such that increases in ventral striatal activity are accompanied by increases in the amplitude of the feedback negativity. Although there is a long history of research implicating the midbrain dopamine system in reward processing, there has been little research into the possibility that structural variability in the midbrain may be linked to functional variability in reward reactivity. Here, we used structural MRI to measure midbrain volumes in addition to fMRI and ERP measures of functional neural reactivity to rewards in a simple gambling task. The results suggest that as midbrain volumes increase, fMRI reward reactivity in the ventral striatum and medial prefrontal cortex also increases. A similar relationship exists between midbrain structure and the amplitude of the feedback negativity; further, this relationship is mediated specifically by activity in the ventral striatum. These data demonstrate convergence between neuroanatomical, hemodynamic, and electrophysiological measures. Thus, structural variability in the midbrain relates to variability in fMRI and ERP measures of functional reward reactivity, which may play a critical role in reward-related psychopathologies and the treatment of these disorders.