Functional Imaging of novelty processing in the human brain

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Functional Imaging of novelty processing in the
human brain

• - Human midbrain novelty response
• Anticipation of novelty
• Novelty seeking personality trait
• by Sarah-Hélène Müller

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Structure

• I. Does the human dopaminergic midbrain respond
  to novelty and why?
• II. What are the implications of our
  understanding of motivation and memory

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Introduction

• Novelty
• Edmund Hillary climbed Mount Everest for it, Neil
  Armstrong flew into space for it, and others died
  for it - a chance to discover something never
  before seen
• A long tradition of human explorations tetifies
  to the motivating force of novelty.
• From the view of evolution in order to flourish
  every foraging species must have a drive to
  expore the unknown.
• How such a drive manifests in the brain will show
  the following presentation.

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Part I The reward system

• The mesolimbic pathway is one of the three
  important dopaminergic pathways in the brain.
• It begins in the ventral tegmental area of the
  midbrain and connects to the limbic system via
  the nucleus accumbens, the amygdala, and the
  hippocampus.
• It is known to be involved in modulating
  behavioral responses to stimuli that activate
  feelings of reward (motivation) and reinforcement

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• SN/VTA
• Especially the substantia nigra and the ventral
  tegmental area (SN/VTA) are playing a central
  role in reward processing.
• From outside the SN and VTA are easy to miss,
  nestled deep in a bend of the brain stem
• These nuclei house most of the dopaminergic
  neurons that innervate Striatum and prefrontal
  cortex

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Novelty response

• Recent fMRI studies provide evidence that SN/VTA
  midbrain region is activated not only by reward,
  but also by novel stimuli.
• This raises the question if novelty and reward
  have shared functional propeties and if novelty
  itself might have intrinsic reward value.
• The human dopaminergic midbrain in some studies
  prefers the stimulus novelty over other forms of
  stimulus salience.
• This indicates a a special biological relevance
  for novelty as an a motivating stimulus.

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Anticipation of novelty

• Dopaminergic neurons code reward prediction when
  the connection between a predictive stimulus and
  a possible subsequent reward delivery has been
  learned
• They respond to the first reliable predictor of
  reward but no longer to the delivered reward
  itself.
• Do these neurons code absolute reward magnitude
  but adapt their response instead relative to a
  predicted magnitude in a given context?
• Thus even a positive reward value could lead to a
  suppression of dopaminergic response
  if magnitude of reward is smaller than expected!

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Conclusions

• Adaptive coding has been observed for reward
  outcome not for reward predicting conditioned
  stimuli
• if SN/VTA response to novelty is scaled in an
  adaptive manner novelty is treated like a
  reward
• if there is a coding of absolute novelty
  magnitude novelty is treated like a
  predictive cue, as a bonus to explore the
  environment in search for reward rather than
  coding it.

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Points to investigate

• Response properties of human SN/VTA-Investigati
  on of anticipatory response to novel and familiar
  stimuli in fMRI-correlation with reward
  processing-Response in the absence of apparent
  reward
• Relevance of anticipation by novelty-predicting
  cues-does SN/VTA response adapt to the relative
  magnitude of novelty in a given context

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Novelty-seeking and reward-dependence

• How personally traits are associated with
  patterns of reward and memory processing ?
• It is a long standing observation that the
  novelty-seekingpersonality trait is a predictor
  of drug use and risky behaviors. The question is
  how this personality trait modulates the
  interaction in dopaminergic midbrain?
• The so called novelty-seeking personality trait
  captures the extent to which individuals respond
  to novelty with exploratory activity and positive
  excitement
• It must be distinguished from reward-dependence,
  which means a tendency to seek and stick to
  reward

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fMRI Experiments

• MethodsFunctional magnetic resonance imaging
  hemodynamic responses from SN and VTA , the
  nucleus accumbens (NAcc), and the Hippocampus of
  29 subjects were investigated and later
  correlated with novelty-seeking scores or those
  obtained for reward-dependence.
• Subjects were familiarized wit half of the
  stimuli (indoor and outdoor scenes) before
  scanning
• As effective reward serves a monetary-incentive
  delay task to elicit robust fMRI response within
  mesolombic system

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Experiment I

• Indicating cues, 50 familiar
• Experiment I required response a
  novel-versus-familiar judgmentExperiment II
  subjects indicated whether they expect a reward
  or not
• Number comparison test, fast and accurate
  response demanded
• Feedback. 50 cent gain or 20 cent loss
  (monetary-incentive), directly handed

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Data acquisition and analysis

• Novelty-seeking and reward-dependence were
  assessed using the Temperament and Character
  Inventory (TCI)
• to find out individual differences in exploration
  excitability according our paradigm on natural
  scene encoding
• and containing an appropriate measure for
  reward-dependence
• In addition to correlation analyses linear
  regressions were formed to determine which
  personally trait accounted best for the variance
  of the SN/VTA response to the four stimulus
  types
• fMRT images were sliced to a voxel size of 333
  mm Mean signal change values were extracted in
  defined regions of interest (ROIs).

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Results

• The responses in the NCT (number-comparison test)
  were faster after reward-predicting compared with
  neutral cues and also slightly faster after
  familiar compared with novel cues in both
  experiments.- this shows that reward led to a
  significant enhancement of response speed and
  accuracy

• - but there is no evidence yet that
  novelty per se led to a similar improvement
• D main percent of signal change is based on a
  region in SN/VTA

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Results

• Relationship between the personally trait and
  BOLD signal in SN/VTA
• A Exploratory excitability correlated with
  SN/VTA response to novel neutral cues. There are
  elevated activation levels to novel stimuli in
  absence of reward
• B Reward-dependence in contrast clearly
  correlates with respond to novel-rewarded cues

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Results

• Regression analysis
• Exploratory excitability explained 28 of the
  variance in SN/VTA response to novel neutral
  stimuli, not improved by including reward
  dependence
• Reward dependence significantly contributed to
  the variance of novel rewarded and marginally to
  that of familiar rewarded.Amount of variance
  explained by it was 30, after including
  exploratory excitability into the model it was
  improved by 2
• Exploratory excitability is associated with
  elevated SN/VTA activation levels in response to
  novel stimuli.Reward dependence mainly
  correlates with novel rewarded stimuli

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Comparable studies Experiment II

• Further studies investigates the SN/VTA response
  not only by reward and reward predicting stimuli
  even in the absence of reinforcement/reward
• Methods yellow or blue squares are the cues,
  indicating with 75 accuracy whether the
  following pictures would be familiar or novel.
  Subjects have to decide whether they knew them or
  not.

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fMRI results

• Cues leading to anticipation of novel pictures in
  contrast to anticipation of familiars pictures,
  led to significantly higher activity in midbrain
  areas like SN, striatum and other parts of
  dopaminergic midbrain.
• Unexpected vs. expected novel pictures mainly
  activate right SN/VTA. This activation pattern
  resembles one seen when dopaminergic neurons
  report a predicting error in reward. Not
  accociated with familiar cues or pictures.

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Novelty anticipation response

• A right SN/VTA
• B percent signal change ( NC novelty cue, FC
  familiarity cue, EF expected familiar outcome,
  UF unexpected familiar outcome, EN expected
  novel outcome, UN unexpected novel outcome
• C cluster of activation in bilateral hippocampus

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Novel outcome response

• A Cluster of activation in left hippocampus
• B percent signal change ( NC novelty cue, FC
  familiarity cue, EF expected familiar outcome,
  UF unexpected familiar outcome, EN expected
  novel outcome, UN unexpected novel outcome

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Unexpected novelty response

• A activation in right SN/VTA
• C right hippocampus

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Correlation between SN/VTA and hippocampal
activity

• In Hippocampus novelty anticipation as well as
  novel outcomes were associated with enhanced
  bilateral activity
• In cue phase there was a significant positive
  correlation between right SN/VTA activation and
  right hippocampal activityThis data indicate a
  functinal interaction between SN/VTA and
  hippocampus in novelty processing

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Stimulus Salience

• Does dopaminergic midbrain prefers stimulus
  novelty over other dimensions of stimulus
  salience?Such as being unexpected, causing
  arousal, or requiring a behavioral
  responsePreferential response would mean special
  biological relevance for novelty as motivation an
  d reinforcement
• A number of other brain regions that also provide
  in put into dopaminergic midbrain are processing
  other forms of stimulus salience (deviance,
  rareness, negative emotional valence, targetness)
  Amygdala, Hippocampus

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Experiment III

• In total 120 stimuli 80 standards, 10 target
  oddballs, 10 neutral oddballs, 10 negative
  emotional oddballs, and 10 novel ones.In form of
  pictures of male faces or in the other half
  outdoor scenes (both biologically
  relevant)Presented while subjects lie in the
  scanner, only target stimuli required a motor
  response

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Results

• B Novel vs. neutral C negative vs. neutral
• D target vs. neutral

• Novel oddballs elicited the strongest homodynamic
  response in SN/VTA (1E), but also in hippocampus
  and parahippocampal cortex
• Negative emotional valence was associated with
  activity in a midbrain area compatible with the
  locus ceruleus (1C)
• Targetness associated with strong activation in
  left and right red nucleus (1D)

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Experiment III Second fMRI study

• Does SN/VTA in the absence of apparent reward
  code absolute magnitude of novelty or adapts its
  relative magnitude I a given context?Respond to
  novelty habituate when stimuli become familiar?
• Using pictures from the first study familiar
  oddballs were presented either in the context of
  novel or very familiar oddballs
• Results Confirming results from the first
  experiment strongest activation in all four
  regions (SN/VTA, hippocampus, perihirnal cortex
  and PPA) was by noveltyBut there was no
  difference when presented in a difference
  context.The findings show that absolute novelty
  is coded.This means that novelty is not treated
  like a reward but rather as a cue that might
  predict it.

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• A SN/VTA, B Hippocampus, C Perihirnal/parahippo
  campal region, D Region corresponding to PPA

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Part II Motivation and Memory

• Novelty exploration can enhance hippocampal
  plasticity through dopaminergic neuromudulation!
• The enhancement can outlast the exploration phase
  by several minutes
• Animal studies show that dopamin release in the
  midbrain influences synaptic plasticity in the
  hippocampus, but not only during novelty but also
  15 to 30 minutes beyond exploration.In rodents
  was found a reduced threshold for LTP (long-term
  potentiation) induction, which can be blocked in
  CA1 region with D1/D2 receptor antagonists
• Is learning of familiar information improved in
  the context of novelty?The hypothesis has to be
  proved with fMRI studies of humans

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The Hippocampus
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Models of memory

• Our memory has the capability to encode
  experiences, but also it is capable of retaining
  and reproducing them.
• We have to separate different forms of memory.
  For our investigations we only need to know about
  long-term memory
• implicit motoric patterns , habit formation,
  conditioning, unconscious
• explicit knowledge about languages and grammar,
  rules and concepts ( semantic)storing of in
  formations based on autobiographic
  experiences(episodic)

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Experiments

• The hippocampus is critical in formation of
  episodic long-term memories for novel events and
  believed to provide the major input for a novelty
  signal in SN/VTA, whereas on the other hand the
  following dopamine release has an retroacting
  effect on it!
• Dopamine stabilizing LTP and LTD in CA1
  region?Regulates the gating between MTL and
  prefrontal structures
• Role of hippocampus in contributing to
  reinforcement learning less well known.
• Potential mechanism linking novelty and long-term
  memory

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Experiment II second part

• Separated memory assessmentbehavioral follow up
  study was separated from the fMRI experiments.
  Number of stimuli was reduced to allow memory
  performance to stay above chance.120 expected
  novel pictures, 40 unexpected novel pictures, 80
  distracter pictures.
• One day laterfirst decision old/new
  judgmentsecond decision remember/know/guess
  (after an old response)
  Sure/guess (after a "new decision)

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Results

• Significantly higher differences between correct
  remember/know rates for expected than unexpected
  novel picturesProportion of guess rate did not
  differ between the categories
• Analysis of the contribution of recollection and
  familiarity.Assumption recollection represents
  a hippocampus depended threshold process
• Whereas familiarity is a signal-detection process
  that can take place in absence of intact
  hippocampus.
• fMRI novelty anticipation and novelty were
  associated with enhanced bilateral activity in
  hippocampus

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Experiment III second part

• Performed outside the scanner
• 20 minutes after the fMRI experimentremember
  /know recognition task with 200 pictures from the
  first phase (50 novel oddballs, 50 familiar
  oddballs in context with novel, 50 familiar in
  context with very familiar50 very familiar
  oddballs) together with 100 new distracters-
  old/knew decision- remember know guess or
  certain/unsure
• One day aftertesting long term memory

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Results

• Recognition memory, correct know rate and correct
  hit rate for novel oddballs and novel oddballs in
  context with familiar oddballs /very familiar
  oddballs
• correct hit rate for familiar pictures from
  novelty context compared to familiar pictures
  from the familiar context confirmed a clear
  improvement in the short delay but not 1 day
  after encoding

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Discussion

• 1. Anticipation of Novelty fMRI analysis
  revealed that that cues predicting novel images
  elicited significantly higher SN/VTA activation
  than cues predicting something familiar
• This activation pattern resembles one found in
  reward paradigms where a response is seen to the
  earliest predictor of reward
• There are functional differences between novelty
  an d reward that bear further investigation

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Discussion

• Connection with Personally traits Responses to
  novelty and reward prediction can be
  distinguishedThere are individual differences in
  the tendency to seek novelty or reward
• What might be the physiological basis?Intrinsic
  synaptic and extrinsic afferent factors that
  regulate the magnitude of the burst firing
  response?Novelty seeking might be correlated
  with increased levels of indirect hippocampal
  afferent drive, larger pools of SN/VTA neurons
  being in tonic firing mode
• We are not able to say whether novelty-seekers
  actually prefer novel stimuli as rewarding, no
  subjective measure of reward preference included
  in this study
• Novelty-seeking personality trait is a predictor
  of drug use and other risky behaviors. Greater
  reinforcing effects during novelty exposureData
  could be linked to findings about ADHD, patients
  seem to show an decreased reward anticipation
  response

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Discussion

• SalienceThe investigation found that among all
  stimuli, novel pictures most powerful activated
  the SN/VTA, as well as hippocampus and striatum.
• Other types of salience activate other regions.
• This data provide evidence for a recent model
  suggesting a functional hippocampal-SN/VTA loop
• Also the experiments have shown that response to
  stimulus novelty decreases as a function of the
  number of previous exposures.
• Interesting is that we saw a pattern of stepwise
  decrease. So even though mesolombic system seems
  to prefer stimulus novelty , it is still capable
  of making a contribution to repeated stimuli!
• Absolute coding of novelty seems to be compatible
  with models that see as a motivating bonus to
  explore the environment in search for reward
  rather than being a reward itself.

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Discussion

• Does novelty enhance memory?In factSubjects
  did not show superior memory for novel pictures,
  on the opposite, compared with novel pictures
  they remembered best the familiar ones.
• But novel pictures initiate a transient memory
  boost, detectable 20 minutes later, but not one
  day later.
• The recent studies show that cues coactivate the
  SN/VTA and the hippocampus, which enhances
  long-term memory not only for the cues but also
  for the pictures following them
• Link between motivation and memory?
• A recent theory postulates two circuits, forming
  a loop, by which novelty can promote memory
• Suggesting that reward cues activate the second
  circuit, it may be that novel stimuli themselves
  are not better remembered but put the brain in a
  receptive state to remember what is yet to come

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Questions for future investigations

• what about patients with selective hippocampal
  injury, whose extrhippocampal temporal lobe seems
  to be intact?
• Clinical studies about ADHD or SchizophreniaDo
  patients schizophrenic patients have chronic
  dopaminergic hyperactivity and nevertheless a
  reduced memory capacity?What about the memory
  skills of Parkinson patients, who seem to have a
  chronic dopaminergic hypoactivity?

• Shows areas with higher activity in healthy
• persons compared to schizophrenic

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List of references

• Krebs, R.M., Schott, B.H. Duzel, E. Personality
  traits are differentially associated with
  patterns of reward and novelty processing in the
  human substantia nigra/ventral tegmental area.
  Biol Psychiatry 65, 103-10 (2009).
• Bunzeck, N. Duzel, E. Absolute coding of
  stimulus novelty in the human substantia
  nigra/VTA. Neuron 51, 369-79 (2006).
• Knutson, B. Cooper, J.C. The lure of the
  unknown. Neuron 51, 280-2 (2006).
• Wittmann, B.C., Bunzeck, N., Dolan, R.J. Duzel,
  E. Anticipation of novelty recruits reward system
  and hippocampus while promoting recollection.
  Neuroimage 38, 194-202 (2007).
• Schünke, Schulte, Schumacher, Prometheus,
  Lernatlas der Anatomie
• www.springerlink.com (pictures)
• www.viridis.de (pictures)

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Thank you for listening