Academic Appointments

All Publications

  • Medial forebrain bundle structure is linked to human impulsivity. Science advances MacNiven, K. H., Leong, J. K., Knutson, B. 2020; 6 (38)


    Comparative research indicates that projections from midbrain dopamine nuclei [including the ventral tegmental area (VTA)] to the ventral striatum [including the nucleus accumbens (NAcc)] critically support motivated behavior. Using diffusion-weighted imaging and probabilistic tractography in humans, we characterized the trajectory and structure of two tracts connecting the VTA and NAcc, as well as others connecting the substantia nigra and dorsal striatum. Decreased structural coherence of an inferior VTA-NAcc tract was primarily and replicably associated with increased trait impulsivity and also distinguished individuals with a stimulant use disorder from healthy controls. These findings suggest that decreased coherence of the inferior VTA-NAcc tract is associated with increased impulsivity in humans and identify a previously uncharacterized structural target for diagnosing disorders marked by impulsivity.

    View details for DOI 10.1126/sciadv.aba4788

    View details for PubMedID 32938676

  • Apparent Effects of Opioid Use on Neural Responses to Reward in Chronic Pain. Scientific reports Martucci, K. T., MacNiven, K. H., Borg, N. n., Knutson, B. n., Mackey, S. C. 2019; 9 (1): 9633


    Neural responses to incentives are altered in chronic pain and by opioid use. To understand how opioid use modulates the neural response to reward/value in chronic pain, we compared brain functional magnetic resonance imaging (fMRI) responses to a monetary incentive delay (MID) task in patients with fibromyalgia taking opioids (N = 17), patients with fibromyalgia not taking opioids (N = 17), and healthy controls (N = 15). Both groups of patients with fibromyalgia taking and not taking opioids had similar levels of pain, psychological measures, and clinical symptoms. Neural responses in the nucleus accumbens to anticipated reward and non-loss outcomes did not differ from healthy controls in either fibromyalgia group. However, neural responses in the medial prefrontal cortex differed, such that patients with fibromyalgia not taking opioids demonstrated significantly altered responses to anticipated rewards and non-loss outcomes compared to healthy controls, but patients with fibromyalgia taking opioids did not. Despite limitations including the use of additional non-opioid medications by fibromyalgia patients taking opioids, these preliminary findings suggest relatively "normalized" neural responses to monetary incentives in chronic pain patients who take opioids versus those who do not.

    View details for DOI 10.1038/s41598-019-45961-y

    View details for PubMedID 31270360

  • Association of Neural Responses to Drug Cues With Subsequent Relapse to Stimulant Use. JAMA network open MacNiven, K. H., Jensen, E. L., Borg, N., Padula, C. B., Humphreys, K., Knutson, B. 2018; 1 (8): e186466


    Although chronic relapse is a characteristic of addiction to stimulants, conventional measures (eg, clinical, demographic, and self-report) do not robustly identify which individuals are most vulnerable to relapse.To test whether drug cues are associated with increased mesolimbic neural activity in patients undergoing treatment for stimulant use disorder and whether this activity is associated with risk for subsequent relapse.This prospective cohort study of 76 participants included a control group for baseline group comparisons. Veteran patients (n = 36) with stimulant use disorders were recruited from a 28-day residential treatment program at the Veterans Affairs Palo Alto Health Care System. Healthy controls (n = 40) were recruited from the surrounding community. Baseline data were collected between September 21, 2015, and January 26, 2018, from patients and healthy controls using functional magnetic resonance imaging during a performance of a reward cue task. Patients' stimulant use was subsequently assessed after treatment discharge (at approximately 1, 3, and 6 months) to assess relapse outcomes.Primary measures included neural responses to drug and food cues in estimated mesolimbic volumes of interest, including the medial prefrontal cortex, nucleus accumbens (NAcc), and ventral tegmental area. The primary outcome variable was relapse (defined as any stimulant use), assessed both dichotomously (3 months after discharge) and continuously (days to relapse). Brain activity measures were contrasted between groups to validate neural measures of drug cue reactivity, which were then used to estimate relapse outcomes of patients.Relative to controls (n = 40; 16 women and 24 men; mean [SD] age, 32.0 [11.6] years), patients (n = 36; 2 women and 34 men; mean [SD] age, 43.4 [13.3] years) showed increased mesolimbic activity in response to drug cues (medial prefrontal cortex, t74 = 2.90, P = .005, Cohen d = 0.66; NAcc, t74 = 2.39, P = .02, Cohen d = 0.54; and ventral tegmental area, t74 = 4.04, P < .001, Cohen d = 0.92). In patients, increased drug cue response in the NAcc (but not other volumes of interest) was associated with time to relapse months later (Cox proportional hazards regression hazard ratio, 2.30; 95% CI, 1.40-3.79). After controlling for age, NAcc response to drug cues classified relapsers (12 patients; 1 woman and 11 men; mean [SD] age, 49.3 [14.1] years) and abstainers (21 patients; 1 woman and 20 men; mean [SD] age, 39.3 [12.3] years) at 3 months with 75.8% classification accuracy. Model comparison further indicated that NAcc responses to drug cues were associated with relapse above and beyond estimations of relapse according to conventional measures.Responses in the NAcc to stimulant cues appear to be associated with relapse in humans. Identification of neural markers may eventually help target interventions to the most vulnerable individuals.

    View details for DOI 10.1001/jamanetworkopen.2018.6466

    View details for PubMedID 30646331

    View details for PubMedCentralID PMC6324538

  • Distinct neural circuits support incentivized inhibition. NeuroImage Leong, J. K., MacNiven, K. H., Samanez-Larkin, G. R., Knutson, B. 2018; 178: 435–44


    The ability to inhibit responses under high stakes, or "incentivized inhibition," is critical for adaptive impulse control. While previous research indicates that right ventrolateral prefrontal cortical (VLPFC) activity plays a key role in response inhibition, less research has addressed how incentives might influence this circuit. By combining a novel behavioral task, functional magnetic resonance imaging (FMRI), and diffusion-weighted imaging (DWI), we targeted and characterized specific neural circuits that support incentivized inhibition. Behaviorally, large incentives enhanced responses to obtain money, but also reduced response inhibition. Functionally, activity in both right VLPFC and right anterior insula (AIns) predicted successful inhibition for high incentives. Structurally, characterization of a novel white-matter tract connecting the right AIns and VLPFC revealed an association of tract coherence with incentivized inhibition performance. Finally, individual differences in right VLPFC activity statistically mediated the association of right AIns-VLPFC tract coherence with incentivized inhibition performance. These multimodal findings bridge brain structure, brain function, and behavior to clarify how individuals can inhibit impulses, even in the face of high stakes.

    View details for PubMedID 29803959

  • Altered prefrontal correlates of monetary anticipation and outcome in chronic pain. Pain Martucci, K. T., Borg, N., MacNiven, K. H., Knutson, B., Mackey, S. C. 2018


    Chronic pain may alter both affect- and value-related behaviors, which represents a potentially treatable aspect of chronic pain experience. Current understanding of how chronic pain influences the function of brain reward systems, however, is limited. Using a monetary incentive delay task and functional magnetic resonance imaging (fMRI), we measured neural correlates of reward anticipation and outcomes in female participants with the chronic pain condition of fibromyalgia (N = 17) and age-matched, pain-free, female controls (N = 15). We hypothesized that patients would demonstrate lower positive arousal, as well as altered reward anticipation and outcome activity within corticostriatal circuits implicated in reward processing. Patients demonstrated lower arousal ratings as compared with controls, but no group differences were observed for valence, positive arousal, or negative arousal ratings. Group fMRI analyses were conducted to determine predetermined region of interest, nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), responses to potential gains, potential losses, reward outcomes, and punishment outcomes. Compared with controls, patients demonstrated similar, although slightly reduced, NAcc activity during gain anticipation. Conversely, patients demonstrated dramatically reduced mPFC activity during gain anticipation-possibly related to lower estimated reward probabilities. Further, patients demonstrated normal mPFC activity to reward outcomes, but dramatically heightened mPFC activity to no-loss (nonpunishment) outcomes. In parallel to NAcc and mPFC responses, patients demonstrated slightly reduced activity during reward anticipation in other brain regions, which included the ventral tegmental area, anterior cingulate cortex, and anterior insular cortex. Together, these results implicate altered corticostriatal processing of monetary rewards in chronic pain.

    View details for PubMedID 29790868

  • Association of Neural Responses to Drug Cues With Subsequent Relapse to Stimulant Use JAMA Netw Open MacNiven, K. H., Jensen, E. L., Borg, N., Padula, C. B., Humphreys, K., Knutson, B. 2018
  • Mere Exposure: Preference Change for Novel Drinks Reflected in Human Ventral Tegmental Area JOURNAL OF COGNITIVE NEUROSCIENCE Ballard, I. C., Hennigan, K., McClure, S. M. 2017; 29 (5): 793–804

    View details for DOI 10.1162/jocn_a_01098

  • Distinct midbrain and habenula pathways are involved in processing aversive events in humans. journal of neuroscience Hennigan, K., D'Ardenne, K., McClure, S. M. 2015; 35 (1): 198-208


    Emerging evidence implicates the midbrain dopamine system and its interactions with the lateral habenula in processing aversive information and learning to avoid negative outcomes. We examined neural responses to unexpected, aversive events using methods specialized for imaging the midbrain and habenula in humans. Robust activation to aversive relative to neutral events was observed in the habenula and two regions within the ventral midbrain: one located within the ventral tegmental area (VTA) and the other in the substantia nigra (SN). Aversive processing increased functional connectivity between the VTA and the habenula, putamen, and medial prefrontal cortex, whereas the SN exhibited a different pattern of functional connectivity. Our findings provide evidence for a network comprising the VTA and SN, the habenula, and mesocorticolimbic structures that supports processing aversive events in humans.

    View details for DOI 10.1523/JNEUROSCI.0927-14.2015

    View details for PubMedID 25568114

    View details for PubMedCentralID PMC4287142

  • Social Cognitive Conflict Resolution: Contributions of Domain-General and Domain-Specific Neural Systems JOURNAL OF NEUROSCIENCE Zaki, J., Hennigan, K., Weber, J., Ochsner, K. N. 2010; 30 (25): 8481-8488


    Cognitive control mechanisms allow individuals to behave adaptively in the face of complex and sometimes conflicting information. Although the neural bases of these control mechanisms have been examined in many contexts, almost no attention has been paid to their role in resolving conflicts between competing social cues, which is surprising given that cognitive conflicts are part of many social interactions. Evidence about the neural processing of social information suggests that two systems--the mirror neuron system (MNS) and mental state attribution system (MSAS)--are specialized for processing nonverbal and contextual social cues, respectively. This could support a model of social cognitive conflict resolution in which competition between social cues would recruit domain-general cognitive control mechanisms, which in turn would bias processing toward the MNS or MSAS. Such biasing could also alter social behaviors, such as inferences made about the internal states of others. We tested this model by scanning participants using functional magnetic resonance imaging while they drew inferences about the social targets' emotional states based on congruent or incongruent nonverbal and contextual social cues. Conflicts between social cues recruited the anterior cingulate and lateral prefrontal cortex, brain areas associated with domain-general control processes. This activation was accompanied by biasing of neural activity toward areas in the MNS or MSAS, which tracked, respectively, with perceivers' behavioral reliance on nonverbal or contextual cues when drawing inferences about targets' emotions. Together, these data provide evidence about both domain-general and domain-specific mechanisms involved in resolving social cognitive conflicts.

    View details for DOI 10.1523/JNEUROSCI.0382-10.2010

    View details for Web of Science ID 000279076900014

    View details for PubMedID 20573895

    View details for PubMedCentralID PMC2916865

  • Predictive knowledge of stimulus relevance does not influence top-down suppression of irrelevant information in older adults CORTEX Zanto, T. P., Hennigan, K., Ostberg, M., Clapp, W. C., Gazzaley, A. 2010; 46 (4): 564–74


    Our ability to focus attention on task-relevant stimuli and ignore irrelevant distractions is reflected by differential enhancement and suppression of neural activity in sensory cortices. Previous research has shown that older adults exhibit a deficit in suppressing task-irrelevant information, the magnitude of which is associated with a decline in working memory performance. However, it remains unclear if a failure to suppress is a reflection of an inability of older adults to rapidly assess the relevance of information upon stimulus presentation when they are not aware of the relevance beforehand. To address this, we recorded the electroencephalogram (EEG) in healthy older participants (aged 60-80 years) while they performed two different versions of a selective face/scene working memory task, both with and without prior knowledge as to when relevant and irrelevant stimuli would appear. Each trial contained two faces and two scenes presented sequentially followed by a 9 sec delay and a probe stimulus. Participants were given the following instructions: remember faces (ignore scenes), remember scenes (ignore faces), remember the xth and yth stimuli (where x and y could be 1st, 2nd, 3rd or 4th), or passively view all stimuli. Working memory performance remained consistent regardless of task instructions. Enhanced neural activity was observed at posterior electrodes to attended stimuli, while neural responses that reflected the suppression of irrelevant stimuli was absent for both tasks. The lack of significant suppression at early stages of visual processing was revealed by P1 amplitude and N1 latency modulation indices. These results reveal that prior knowledge of stimulus relevance does not modify early neural processing during stimulus encoding and does not improve working memory performance in older adults. These results suggest that the inability to suppress irrelevant information early in the visual processing stream by older adults is related to mechanisms specific to top-down suppression.

    View details for DOI 10.1016/j.cortex.2009.08.003

    View details for Web of Science ID 000275800000013

    View details for PubMedID 19744649

    View details for PubMedCentralID PMC2826515