What we can do and what we cannot do with fMRI

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What we can do and what we cannot do with fMRI

• nIKOS K. Logothetis

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Goals of Article

• Provide an overview of fMRI in its current state
• Examine relationship between haemodynamic
  signals and neurons
• Explain how constraints on neuroimaging data
  interpretation

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fMRI Research

• Since first publication in 1991, over 19,000
  papers have been published referencing fMRI
• Since 2007 approximately eight fMRI related
  papers are published a day
• 43 - cognitive anatomy associated with task or
  stimulus
• 22 - ROI studies examing physiological
  properties
• 8 - Neuropsychology
• 5 - Properties of fMRI
• Remainder Plasticity, drug action,
  experimental designs and analysis methods

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Advantages of fMRI

• Noninvasive procedure
• Ever-increasing availability
• Relatively high spatiotemporal resolution
• Provides data for entire brain while subject
  carries out a task

CREDIT LOTFI B. MERABET/MASSACHUSETTS EYE AND
EAR INFIRMARY
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Shortcomings

• Haemodynamic-based (surrogate signal)
• Spatial specificity and temporal response are
  subject to physical and biological constraints
• Reflects neuronal mass activity

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A Brief Overview of fMRI

• Measures tissue perfusion, blood-volume changes,
  or changes in concentration of O2
• Blood-oxygen-level-dependent (BOLD) is most
  common in human neuroimaging
• Spatial specificity increases with magnetic
  field strength
• 87 of studies use conventional gradient-echo
  echoplanar imaging (GE-EPI). Others use variants
  of spin-echo echoplanar imaging (SE-EPI)

• B0 Main static field
• B1 Field generated by excitation pulses
• Use subtraction methods to analyze data
• Studies look at activity of functional subunits
  and instances of joint or conditional activation
• Use voxel-based analysis (MVPA on rise)

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Neurons and Voxels

• Approximately 90,000-100,000 neurons under 1
  square mm of cortical surface
• Primary visual cortex has twice amount
• fMRI resolution
• 9-16 square mm
• 5-7 mm slice thickness
• Average voxel size 55 cubic mm
• Each voxel contains approximately 5.5 million
  neurons
• With 100 billion neurons in the brain, thats
  approximately 18,000 voxels (130,000?)

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Contents of a Single Voxel
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Differences in gradient and spin techniques
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What do Activation Maps Represent?

• Does activation of an area mean it is involved
  in the task at hand?
• Input-Local Processing-Output Model and brain
  connectivity is mostly bidirectional
• Excitation-Inhibition Networks (EIN)
• Can be thought of as microcircuits
• Final response determined by the sum of all
  components
• Net excitation or inhibition might occur when
  afferents drive overall E-I in opposite
  directions
• Responses to large sustained input may vary

• Microcircuits act as drivers, transmitting
  stimulus info, or modulators, adjusting
  sensitivity/specificity
• Cognitive capacities are more likely to induce
  large changes in the fMRI signal than the sensory
  signals
• Changes in E-I balance affect metabolic demand
  and subsequently increase local cerebral blood
  flow, however this does not necessarily mean
  excitatory activity

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Excitation-Inhibition and fMRI Data
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Does Inhibition cause a metabolic increase?

• fMRI studies using dichotomous systems and
  electrophysiological evidence
• Inhibitory neuron density is 10-15 times lower
  than excitatory and ATP is not directly expended
  in the uptake of Cl2
• Modeling inhibition is unlikely straightforward
  and subject to ROI

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Blood Oxygen Level Dependent (BOLD)

• Most common technique for human neuroimaging
• Sense differences in magnetic sensitivity of
  Oxyhemoglobin and Deoxyhemoglobin
• Types of EIN activity
• Single-unit (isolated neurons near electrode tip)
• Multiple-unit (small neuron populations 100-300mm
  radius)
• Perisynaptic (within 0.5-3mm radius of electrode
  tip)
• Multiple unit and local field potentials (LFP)
  separation by frequency band
• LFP shortcoming is its ambiguity

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Conclusion

• fMRI signals cannot easily differentiate between
  function-specific processing and neuromodulation,
  bottom-up and top-down signals, and may potential
  confuse excitation and inhibition
• Despite its shortcomings, fMRI is still one of
  the best tools for relevant research
• Suggested Multimodual approach is necessary to
  properly study function and dysfunction

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The neural Signature of satiation is associated
with ghrelin response and triglyceride metabolism

• Xue Sun, Maria Veldhuizen, Amanda Wray, Ivan de
  Araujo, Robert Sherwin, Rajita Sinha, Dana Small

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Purpose of Study

• Use fMRI to measure brain response to palatable
  food under different caloric intake conditions
• Look for internal indicators of metabolic state
• Look at differences between perception of food
  availability

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Experimental Design
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Measurements from Blood Samples
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Example Data Collected
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Conclusion

• Satiation-induced brain response to palatable
  and energy dense food are influenced by
  circulating ghrelin and triglycerides
• Fixed portions and volitional meal termination
  may influence the brains response
• Suggested examine relationship between control
  over meal termination and self-control in making
  food-related decisions

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Why BOLD-fMRI????

• Magnetic Resonance Imaging (MRI) clearly
  identify the olfactory bulb (OB) layers.
• Functional MRI (fMRI) map the activity patterns
  evoked by odorants.
• Blood oxygenation level dependent- fMRI
  (BOLD-fMRI)reveal dynamics of neuronal responses
  and properties of adaptation.

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Materials Methods

• Animals
• 18 Adult Sprague Dawley rats (250-230g)
• Tecniques
• BOLD-fMRI
• Local field potential (LFP)
• Odorants used
• Iso-amyl acetate (IAA) Octanal (OCT)

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RESULTS (Fig.1)OB layers reordered simultaneously
LFP recordings
Transient sharp potential
gt300 Hz
Recording sites
GLGlomerular layer MCL Mitral cell layer GCL
Glomerular cell layer
High signals in the mitral cell layer (MCL)
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RESULTS (Fig.2)Activity maps induced by odorants
stimulation
plt0.01
Different activated patterns are evoked by
different odorants.
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RESULTS (Fig.3)Layer-depend BOLD responses in
the OB
Global activity maps
Intensity of signal
n8
n9
n9
Absolute intensity of the signals in a given
layer was affected significantly by odor type and
concentration.
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RESULTS (Fig.4)Local Field signals after IAA
exposure
Traces
Normalized time-frequence graphs
All neural activity is high in GCL after odor
stimulation.
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RESULTS (Fig.4)LFP signals after multiple
odorants perception
Neuronal oscillations
Frequency bands
plt0.01
Confirmation of the strongest responses GCL level.
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RESULTS (Fig. 5)Relationship of temporal
response profiles of BOLD and LFP signals in the
OB
Correlation analysis Software R
plt0.01
Similar responses from BOLD and LFP analysis.
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RESULTS (Fig. 6)Temporal features through LFP
and BOLD tecniques
BOLD vs LFP bands
LFP signals
Worst correlation
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CONCLUSIONS

• BOLD signals (Indirect measure)
• local neuronal activity
• Well correlated with

Effected by
Hemodynamics Metabolism Neuroanatomy
LFPsignals (direct measure)
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Aim of the study

• Observation of different areas of the brain
  involved in odor perception using fMRI with BOLD
  effect on awake animals.

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Materials Methods (1)
- Animals Adult  ? Sprague Dawley
rats n 58
- Nose poke assay
Behavioral motivation to odors
Pour odorants (1ml of 1 of solution
(odorant/water) Benzbenzaldehyde (almond
odor), Iso-amyl acetate (banana odor) Methyl
benzoate (rosy odor) Limonene (citrus odor)
Elevated circular wooden platform
Adapted from http//www.med-associates.com/
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Materials Methods (2)
- Imaging on awake animals
Blood oxygenation level dependent functional
magnetic resonace imaging (BOLD-fMRI)
Pour odorants Benzbenzaldehyde (almond
odor) Iso-amyl acetate (banana odor) Methyl
benzoate (rosy odor) Limonene (citrus
odor) Commercial odorants Penaut oil Standard
rat chow
Adapted from Ferris et al., Front.Neuro. 2014
http//www.youtube.com/watch?vW5Jup13isqw
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RESULTS(Fig. 1)BOLD activation pattern for the
entire brain
Benzhaldehyde and penaut oil increases change in
BOLD signal.
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RESULTSNeuronal activation described by 3D
volume renderings (BOLD-fMRI) in

• Primary olfactory system (POS)
• Involved in taste and smell.
• Associate disorders i.e. Parkinson's disease and
  Alzheimer's disease.
• Cortical circuit of Papez
• Involved in emotional reactions and in part
  releated to memory.
• Associate disorders i.e. Alzehimers desease and
  Parkinsons desease.
• Hippocampus
• Involved in short-term and long-term memory,
  spatial navigation.
• Associate disorders i.e. Alzehimers disease and
  Temporal lobe epilepsys desease.
• Amygdaloid system
• Involved in  processing of memory, decision-making
  and emotional reactions.
• Associate disorders i.e. autism and epilepsys
  desease.

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RESULTS (Fig. 2)Odorants produce activation in
the POS
n9/odorant
banana odor
almond odor
rosy odor
citrus odor
Benzaldheyde increases significantly neuronal
activity.
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RESULTS (Fig. 2)BOLD signals intensity in the POS
Positive BOLD response
Neurons start working and using up blood
For each odrant gradual increase of BOLD signals
intensity.
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RESULTS (Fig.3)Odorants produce activation in
cortical circuit of Papez (1)
almond odor
citrus odor
banana odor
rosy odor
Roubustly activation to the smell of almond
(Benzaldehyde).
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RESULTS (Fig. 3)Odorants produce activation in
cortical circuit of Papez (2)
The activation is significantly increases by the
smell of almond.
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RESULTS (Fig. 4)Odorants produce activation in
the Hippocampus
banana odor
rosy odor
almond odor
citrus odor
CA1, CA3, DG and subiculum are significatly
activated by almond smell.
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RESULTS (Fig. 5)Odorants produce activation in
amygdala
Anterior, lateral and posterior nuclei are
partially activated by odorants.
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RESULTS (Fig. 6)Nose poke assay Odor preference
Rats prefer the odorant benzaldheyde (almond).
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DISCUSSION

• Benzaldehyde (almond) smell extends beyond the
  olfactory bulb
• Activation of the anterior nuclei of the Thalamus
• ?cornerstone of the neural circuitry of emotion
• Rats have genes that code for odorants receptors
  in the olfactory bulb
• M71 is a benzaldehyde-sensitive odorant receptor

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CONCLUSION

• BOLD-fMRI can be used
• On awake animals (avoiding in this way anesthesia
  artifacts)
• To idenfy neural circuits that have an innate
  preference for food odorants
• Activation of lymbic pathways, hippocampus and
  regions of the cortical Papez circuit in response
  to the odorants associated with high
  calorie/protein sources