Nico Bunzeck

Absolute Coding of Stimulus Novelty in the Human Substantia Nigra/VTA

Novelty exploration can enhance hippocampal plasticity in animals through dopaminergic neuromodulation arising in the substantia nigra/ventral tegmental area (SN/VTA). This enhancement can outlast the exploration phase by several minutes. Currently, little is known about dopaminergic novelty processing and its relationship to hippocampal function in humans. In two functional magnetic resonance imaging (fMRI) studies, SN/VTA activations in humans were indeed driven by stimulus novelty rather than other forms of stimulus salience such as rareness, negative emotional valence, or targetness of familiar stimuli, whereas hippocampal responses were less selective. SN/VTA novelty responses were scaled according to absolute rather than relative novelty in a given context, unlike adaptive SN/VTA responses recently reported for reward outcome in animal studies. Finally, novelty enhanced learning and perirhinal/parahippocampal processing of familiar items presented in the same context. Thus, the human SN/VTA can code absolute stimulus novelty and might contribute to enhancing learning in the context of novelty.

The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance.

Functional imaging of the human dopaminergic midbrain

Invasive recording of dopamine neurons in the substantia nigra and ventral tegmental area (SN/VTA) of behaving animals suggests a role for these neurons in reward learning and novelty processing. In humans, functional magnetic resonance imaging (fMRI) is currently the only non-invasive event-related method to measure SN/VTA activity, but it is debated to what extent fMRI enables inference about dopaminergic responses within the SN/VTA. We consider the anatomical and functional parcellation of the primate SN/VTA and find that its homogeneity suggests little variation in the regional specificity of fMRI signals for reward-related dopaminergic responses. Hence, these responses seem to be well captured by the compound fMRI signal from the SN/VTA, which seems quantitatively related to dopamine release in positron emission tomography (PET). We outline how systematic investigation of the functional parcellation of the SN/VTA in animals, new developments in fMRI analysis and combined PET-fMRI studies can narrow the gap between fMRI and dopaminergic neurotransmission.

Anticipation of novelty recruits reward system and hippocampus while promoting recollection

The dopaminergic midbrain, which comprises the substantia nigra and ventral tegmental area (SN/VTA), plays a central role in reward processing. This region is also activated by novel stimuli, raising the possibility that novelty and reward have shared functional properties. It is currently unclear whether functional aspects of reward processing in the SN/VTA, namely, activation by unexpected rewards and cues that predict reward, also characterize novelty processing. To address this question, we conducted an fMRI experiment during which subjects viewed symbolic cues that predicted either novel or familiar images of scenes with 75% validity. We show that SN/VTA was activated by cues predicting novel images as well as by unexpected novel images that followed familiarity-predictive cues, an ‘unexpected novelty’ response. The hippocampus, a region implicated in detecting and encoding novel stimuli, showed an anticipatory novelty response but differed from the response profile of SN/VTA in responding at outcome to expected and ‘unexpected’ novelty. In a behavioral extension of the experiment, recollection increased relative to familiarity when comparing delayed recognition memory for anticipated novel stimuli with unexpected novel stimuli. These data reveal commonalities in SN/VTA responses to anticipating reward and anticipating novel stimuli. We suggest that this anticipatory response codes a motivational exploratory novelty signal that, together with anticipatory activation of the hippocampus, leads to enhanced encoding of novel events. In more general terms, the data suggest that dopaminergic processing of novelty might be important in driving exploration of new environments.

Theta-Coupled Periodic Replay in Working Memory

Summary Working memory allows information from transient events to persist as active neural representations [1] that can be used for goal-directed behaviors such as decision making and learning [2, 3]. Computational modeling based on neuronal firing patterns in animals suggests that one putative mechanism enabling working memory is periodic reactivation (henceforth termed “replay”) of the maintained information coordinated by neural oscillations at theta (4–8 Hz) and gamma (30–80 Hz) frequency [4–6]. To investigate this possibility, we trained multivariate pattern classifier decoding algorithms on oscillatory brain responses to images depicting natural scenes, recorded with high temporal resolution via magnetoencephalography. These classifiers were applied to brain activity recorded during the subsequent five second maintenance of the scenes. This decoding revealed replay during the entire maintenance interval. Replay was specific to whether an indoor or an outdoor scene was maintained and whether maintenance centered on configural associations of scene elements or just single scene elements. Replay was coordinated by the phase of theta and the amount of theta coordination was correlated with working memory performance. By confirming the predictions of a mechanistic model and linking these to behavioral performance in humans, these findings identify theta-coupled replay as a mechanism of working memory maintenance.

Dopamine Modulates Episodic Memory Persistence in Old Age

Activation of the hippocampus is required to encode memories for new events (or episodes). Observations from animal studies suggest that, for these memories to persist beyond 4–6 h, a release of dopamine generated by strong hippocampal activation is needed. This predicts that dopaminergic enhancement should improve human episodic memory persistence also for events encoded with weak hippocampal activation. Here, using pharmacological functional MRI (fMRI) in an elderly population in which there is a loss of dopamine neurons as part of normal aging, we show this very effect. The dopamine precursor levodopa led to a dose-dependent (inverted U-shape) persistent episodic memory benefit for images of scenes when tested after 6 h, independent of whether encoding-related hippocampal fMRI activity was weak or strong (U-shaped dose–response relationship). This lasting improvement even for weakly encoded events supports a role for dopamine in human episodic memory consolidation, albeit operating within a narrow dose range.

Contextual Novelty Changes Reward Representations in the Striatum

Reward representation in ventral striatum is boosted by perceptual novelty, although the mechanism of this effect remains elusive. Animal studies indicate a functional loop (Lisman and Grace, 2005) that includes hippocampus, ventral striatum, and midbrain as being important in regulating salience attribution within the context of novel stimuli. According to this model, reward responses in ventral striatum or midbrain should be enhanced in the context of novelty even if reward and novelty constitute unrelated, independent events. Using fMRI, we show that trials with reward-predictive cues and subsequent outcomes elicit higher responses in the striatum if preceded by an unrelated novel picture, indicating that reward representation is enhanced in the context of novelty. Notably, this effect was observed solely when reward occurrence, and hence reward-related salience, was low. These findings support a view that contextual novelty enhances neural responses underlying reward representation in the striatum and concur with the effects of novelty processing as predicted by the model of Lisman and Grace (2005).

A Common Mechanism for Adaptive Scaling of Reward and Novelty

Declarative memory is remarkably adaptive in the way it maintains sensitivity to relative novelty in both unknown and highly familiar environments. However, the neural mechanisms underlying this contextual adaptation are poorly understood. On the basis of emerging links between novelty processing and reinforcement learning mechanisms, we hypothesized that responses to novelty will be adaptively scaled according to expected contextual probabilities of new and familiar events, in the same way that responses to prediction errors for rewards are scaled according to their expected range. Using functional magnetic resonance imaging in humans, we show that the influence of novelty and reward on memory formation in an incidental memory task is adaptively scaled and furthermore that the BOLD signal in orbital prefrontal and medial temporal cortices exhibits concomitant scaled adaptive coding. These findings demonstrate a new mechanism for adjusting gain and sensitivity in declarative memory in accordance with contextual probabilities and expectancies of future events. Hum Brain Mapp, 2010.

Contextual interaction between novelty and reward processing within the mesolimbic system

Medial temporal lobe (MTL) dependent long‐term memory for novel events is modulated by a circuitry that also responds to reward and includes the ventral striatum, dopaminergic midbrain, and medial orbitofrontal cortex (mOFC). This common neural network may reflect a functional link between novelty and reward whereby novelty motivates exploration in the search for rewards; a link also termed novelty “exploration bonus.” We used fMRI in a scene encoding paradigm to investigate the interaction between novelty and reward with a focus on neural signals akin to an exploration bonus. As expected, reward related long‐term memory for the scenes (after 24 hours) strongly correlated with activity of MTL, ventral striatum, and substantia nigra/ventral tegmental area (SN/VTA). Furthermore, the hippocampus showed a main effect of novelty, the striatum showed a main effect of reward, and the mOFC signalled both novelty and reward. An interaction between novelty and reward akin to an exploration bonus was found in the hippocampus. These data suggest that MTL novelty signals are interpreted in terms of their reward‐predicting properties in the mOFC, which biases striatal reward responses. The striatum together with the SN/VTA then regulates MTL‐dependent long‐term memory formation and contextual exploration bonus signals in the hippocampus. Hum Brain Mapp, 2011.

Reward Motivation Accelerates the Onset of Neural Novelty Signals in Humans to 85 Milliseconds

Summary The neural responses that distinguish novel from familiar items in recognition memory tasks are remarkably fast in both humans and nonhuman primates. In humans, the earliest onsets of neural novelty effects emerge at about ∼150–200 ms after stimulus onset [1–5]. However, in recognition memory studies with nonhuman primates, novelty effects can arise at as early as 70–80 ms [6, 7]. Here, we address the possibility that this large species difference in onset latencies is caused experimentally by the necessity of using reward reinforcement to motivate the detection of novel or familiar items in nonhuman primates but not in humans. Via magnetoencephalography in humans, we show in two experiments that the onset of neural novelty signals is accelerated from ∼200 ms to ∼85 ms if correct recognition memory for either novel or familiar items is rewarded. Importantly, this acceleration is independent of whether the detection of the novel or the familiar scenes is rewarded. Furthermore, this early novelty effect contributed to memory retrieval because neural reward responses, which were contingent upon novelty detection, followed ∼100 ms later. Thus, under the contextual influence of reward motivation, behaviorally relevant novelty signals emerge much faster than previously held possible in humans.