INHOUD
Chapter 1: introduction and overview ....................................................................................................9
1.1 brain enthusiasm: the relevance of distinguishing fact from fiction ................................................9
Box 1.1 neuroscepticism and neuroscience ................................................................................. 10
1.2 the basis of neural signals ......................................................................................................... 10
1.2.1 information transfer in neurons ........................................................................................... 10
1.2.2 signal processing ................................................................................................................ 11
1.2.3 other signals in the brain: molecular and hemodynamc signals ............................................. 13
1.2.4 maps in the brain: from the activity of single neurons to signals without single-neuron resolution
.................................................................................................................................................. 14
1.3 a short overview of methods in human neuroscience .................................................................. 16
1.3.1 techniques to measure brain structure ................................................................................ 16
1.3.2 techniques to measure hemodynamic correlates of neural activity ........................................ 17
1.3.3 techniques to measure electrophysiological activity ............................................................. 17
Part I: structural neuroimaging ............................................................................................................ 20
Chapter 2: the physics behind magnetic resonance imaging (MRI) ........................................................ 20
2.1 the effect of magnetic fiels on the human body ........................................................................... 20
2.2 from resonance to imaging ........................................................................................................ 23
box 2.1 Fourier analysis of MRI signals and the concept of k-space ................................................ 26
2.3 how do these physical principles give rise to an image with anatomical structure? ....................... 28
2.4 the hardware of a scanner ......................................................................................................... 30
2.5 parameters that are chosen by the user...................................................................................... 31
Chapter 3: structural imaging methods ............................................................................................... 33
3.1 Structural T1-weighted MRI........................................................................................................ 33
3.1.1 quality check ...................................................................................................................... 33
3.1.2 finding structure in anatomical images and normalization ..................................................... 34
volume-based normalization.................................................................................................... 34
template reference spaces for normalization ............................................................................ 34
segmentation and segmentation-based normalization .............................................................. 35
surface extraction and surface-based normalization ................................................................. 36
3.1.3 approaches to investigate brain morphometry...................................................................... 37
Box 3.1 quantitative imaging ........................................................................................................ 38
3.1.4 statistical analysis and interpretation .................................................................................. 38
3.1.5 voxel-based lesion behaviour mapping ................................................................................ 39
3.1.6 the relevance of brain structure for behaviour and mind ........................................................ 39
3.2 diffusion-weighted imaging (DWI)............................................................................................... 41
1
, 3.2.1 data acquisition and preprocessing ..................................................................................... 41
3.2.2 diffusion tensor imaging (DTI) .............................................................................................. 42
rugby balls in the brain ............................................................................................................. 42
tensor estimation .................................................................................................................... 43
tractography ........................................................................................................................... 44
statistics ................................................................................................................................. 45
interpretation .......................................................................................................................... 45
3.2.3 advanced approaches to capture heterogeneity of diffusion in voxels .................................... 46
high angular resolution diffusion imaging (HARDI) ..................................................................... 47
multi-shell diffusion ................................................................................................................ 47
3.2.4 the relevance of anatomical connectivity for behaviour and mind .......................................... 48
3.3 magnetic resonance spectroscopy (MRS) ................................................................................... 49
3.3.1 data acquisition .................................................................................................................. 49
from biological structure to a frequency spectrum .................................................................... 49
single-voxel MRS and MRS imaging ........................................................................................... 50
water suppression and editing .................................................................................................. 51
3.3.2 data analysis ...................................................................................................................... 52
3.3.3 the relevance of molecular indices for behaviour and mind ................................................... 53
Part II: hemodynamic neuroimaging .................................................................................................... 55
Chapter 4: hemodynamic imaging methods ........................................................................................ 55
Box 4.1 why neuroscientists and behavioural scientists measure blood ......................................... 55
4.1 hemodynamics and its relationship to neural activity .................................................................. 55
4.1.1 the hemodynamic response function ................................................................................... 55
4.1.2 the relationship between the HRF and different aspects of neural activity .............................. 57
4.2 functional magnetic resonance imaging (fMRI)............................................................................ 60
4.2.1 blood-oxygenation-level dependent fMRI ............................................................................. 60
blood oxygenation and the physics of fMRI ................................................................................ 60
measuring the BOLD contrast .................................................................................................. 61
4.2.2 arterial spin labeling (ASL) fMRI ........................................................................................... 62
4.2.3 the relevance of fMRI for behaviour ...................................................................................... 62
4.3 positron emission tomography (PET) .......................................................................................... 62
4.3.1 the physics of PET ............................................................................................................... 62
4.3.2 using PET for measuring neural activity ................................................................................ 63
4.3.3 unique contributions of PET ................................................................................................. 64
4.4 functional near-infrared spectroscopy (fNIRS) ............................................................................ 65
4.5 a comparison of research with fMRI, PET, and fNIRS ................................................................... 66
Chapter 5: designing a hemodynamic imaging experiment ................................................................... 68
2
, 5.1 think befor you start an experiment ............................................................................................ 68
5.2 which conditions to include: the subtraction method .................................................................. 68
5.2.1 the subtraction method ...................................................................................................... 68
5.2.2 considerations about the subtraction method ...................................................................... 69
5.3 how to present the conditions: the block design ......................................................................... 70
5.3.1 the block design and the hemodynamic response function ................................................... 70
5.3.2 the block design in practice in fMRI and fNIRS ...................................................................... 72
5.3.3 a few examples of classical studies using a block design ...................................................... 73
5.4 the event-related design ............................................................................................................ 74
5.4.1 more advanced designs and analysis ................................................................................... 75
5.5 the baseline or rest condition .................................................................................................... 75
5.5.1 the role of a baseline in task-based fMRI .............................................................................. 75
5.5.2 regions activated during a resting baseline ........................................................................... 76
5.6 task and stimuli in the scanner .................................................................................................. 77
Box 5.1 from the design to scanning................................................................................................. 78
Chapter 6: image processing .............................................................................................................. 79
6.1 software packages .................................................................................................................... 79
Box 6.1 preprocessing step 0: quality control ................................................................................... 80
Box 6.2 external quality control through transparency and reproducibility .......................................... 80
6.2 properties of the images ............................................................................................................ 81
6.3 preprocessing step 1: slice timing .............................................................................................. 83
6.4 preprocessing step 2: motion correction .................................................................................... 84
6.5 preprocessing step 3: coregistration .......................................................................................... 86
6.6 preprocessing step 4: normalization .......................................................................................... 87
6.7 preprocessing step 5: spatial smoothing .................................................................................... 87
Chapter 7: basic statistical analyses ................................................................................................... 89
7.1 statistical analyses: the general linear model ............................................................................. 89
7.1.1 simple linear regression ...................................................................................................... 89
7.1.2 multiple linear regression .................................................................................................... 90
7.1.3 the general linear model applied to fMRI data ....................................................................... 90
7.1.4 data cleaning prior to applying the GLM................................................................................ 91
7.1.5 the efficiency of a design and correlation between predictors ............................................... 92
7.2 determining significance and interpreting it ................................................................................ 94
7.2.1 calculating a simple test statistic: a t-contrast ..................................................................... 94
7.2.2 correction for multiple comparisons, or how to avoid brain activity in a dead salmon ............. 95
7.2.3 combining data across participants: second-level whole-brain analysis ................................ 97
7.2.4 region-of-interest analyses .................................................................................................. 97
3
, 7.2.5 another statistical caveat: double dipping and circular analyses ........................................... 98
7.2.6 statistical inference ............................................................................................................ 98
Chapter 8: advanced statistical analyses .......................................................................................... 100
8.1 functional connectivity: designs and analyses .......................................................................... 100
8.1.1 correlations in brain activity .............................................................................................. 100
8.1.2 interpretation of correlations in brain activity ..................................................................... 101
8.1.3 modeling directional functional connectivity ...................................................................... 103
8.1.4 task-related modulations of connectivity ........................................................................... 104
8.1.5 resting-state fMRI (RS fMRI) ............................................................................................... 105
The implementation and analysis of RS fMRI ........................................................................... 105
Brain networks and RS fMRI ................................................................................................... 105
8.2 multi-voxel pattern analyses .................................................................................................... 107
8.2.1 a schematic tutorial of MVPA ............................................................................................. 107
8.2.2 a specific example of MVPA ............................................................................................... 108
8.2.3 the potential of MVPA to move beyond neophrenology ........................................................ 110
8.2.4 what do we measure with MVPA? ...................................................................................... 111
Box 8.1 from group studies to individual diagnostics using advanced methods ................................ 113
8.3 functional MRI adaptation ....................................................................................................... 113
Part III: electrophysiological neuroimaging ........................................................................................ 115
Chapter 9: electromagnetic field of the brain ..................................................................................... 115
9.1 electrophysiological activity of the brain ................................................................................... 115
9.1.1 from neurons to electric field............................................................................................. 115
9.1.2 magnetic field of the neural activity.................................................................................... 116
9.1.3 from field to sensors ......................................................................................................... 117
9.2 electromagnetic field signals ................................................................................................... 118
9.2.1 properties of the field signal .............................................................................................. 118
9.2.2 dimensions and resolution of the field signal ...................................................................... 120
Box 9.1 From the field to neurons .................................................................................................. 121
Box 9.2 FAQ: negative amplitude in evoked potentials .................................................................... 121
9.3 brain dynamics vs. mind dynamics .......................................................................................... 121
Chapter 10: electroencephalography and magnetoencephalography.................................................. 123
10.1 electroencephalography (EEG)............................................................................................... 123
10.1.1 EEG electrodes ............................................................................................................... 124
Box 10.1 The international 10-20 system in 5 steps .................................................................. 126
Reference and ground electrodes ........................................................................................... 127
EOG electrodes ..................................................................................................................... 128
Active electrodes................................................................................................................... 129
4
, Box 10.2 Dry electrodes ......................................................................................................... 129
Overview ............................................................................................................................... 129
10.2.2 EEG amplifier ................................................................................................................. 130
10.1.3 procedure for EEG data acquisition .................................................................................. 131
10.2 magnetoencephalography (MEG) ........................................................................................... 132
10.2.1 MEG sensors .................................................................................................................. 132
10.2.2 magnetically shielded room ............................................................................................ 134
10.2.3 procedure for MEG data acquisition ................................................................................. 134
Box 10.3 magnetoencephalography with optically pumped magnetometers .................................... 135
10.3 comparison between EEG and MEG ....................................................................................... 136
Chapter 11: basic analysis of electrophysiological signals.................................................................. 138
11.1 noises .................................................................................................................................. 139
11.1.1 biological noises ............................................................................................................. 139
11.1.2 artifactual and environmental noises ............................................................................... 141
11.1.3 visual inspection ............................................................................................................. 141
11.2 data format and analysis software ......................................................................................... 141
11.2.1 data format .................................................................................................................... 141
11.2.2 analysis software ............................................................................................................ 142
11.3 preprocessing ....................................................................................................................... 143
11.3.1 referencing ..................................................................................................................... 143
11.3.2 segmentation and channel rejection ................................................................................ 144
11.3.3 independent component analysis for preprocessing ......................................................... 144
11.3.4 filtering for preprocessing ................................................................................................ 146
11.3.5 resampling ..................................................................................................................... 146
11.3.6 more about preprocessing .............................................................................................. 147
11.4 spectral analysis ................................................................................................................... 147
11.4.1 workflow of spectral analysis........................................................................................... 148
11.4.2 more about FFT............................................................................................................... 149
11.4.3 spectral plots ................................................................................................................. 149
frequency resolution and Welch’s method .............................................................................. 151
11.4.4 frequency bands of M/EEG signal ..................................................................................... 152
11.4.5 statistical analysis .......................................................................................................... 153
11.4.6 pros and cons ................................................................................................................. 154
Box 11.1 ANOVA and power spectrum ........................................................................................ 154
11.5 event-related potential and event-related field analysis........................................................... 155
11.5.1 more about trial averaging ............................................................................................... 155
11.5.2 workflow of ERR analysis ................................................................................................. 156
5
, 11.5.3 time- and surface plot of ERR .......................................................................................... 157
11.5.4 statistical analysis .......................................................................................................... 158
11.5.5 the naming of ERR ........................................................................................................... 159
11.5.6 pros and cons ................................................................................................................. 161
11.6 steady-state evoked response ............................................................................................... 162
11.6.1 more about ssER ............................................................................................................ 163
11.6.2 statistical analysis .......................................................................................................... 164
11.6.3 pros and cons ................................................................................................................. 164
Chapter 12: advanced data analysis ................................................................................................. 165
12.1 time-frequency analysis ........................................................................................................ 165
12.1.1 short time Fourier transform ............................................................................................ 165
12.1.2 Wavelet transform .......................................................................................................... 167
12.1.3 STFT vs. wavelet ............................................................................................................. 170
12.1.4 analysis of time-frequency data ....................................................................................... 171
12.2 phase analysis ...................................................................................................................... 172
12.2.1 computation of the phase ............................................................................................... 173
12.2.2 circular statistics ............................................................................................................ 177
12.2.3 phase synchrony ............................................................................................................ 178
12.2.4 inter-trial phase coherence ............................................................................................. 180
12.2.5 trial averaging revisited ................................................................................................... 183
Box 12.1 mathematical expressions for oscillation ......................................................................... 185
Box 12.2 network analysis ............................................................................................................. 186
12.3 autoregression and Granger causality .................................................................................... 187
12.3.1 autoregression ............................................................................................................... 188
12.3.2 Granger causality ............................................................................................................ 189
Part IV: complementary methods ...................................................................................................... 191
Chapter 13: multi-modal imaging ...................................................................................................... 192
13.1 the spatial and temporal unfolding of neural representations .................................................. 193
Box 13.1 from biological to artificial brains ..................................................................................... 195
13.2 simultaneous application of EEG and fMRI ............................................................................. 196
13.3 M/EEG source localization ..................................................................................................... 198
13.4 differentiating between representational and acces theories of disorders ................................ 201
13.5 clinical diagnostics with multi-modal imaging ......................................................................... 203
Chapter 14: causal methods to modulate brain activity ...................................................................... 206
Box 14.1 ethical concerns related to neuromodulation ................................................................... 207
14.1 microstimulation and deep brain stimulation .......................................................................... 208
14.2 focused ultrasound stimulation ............................................................................................. 210
6
, 14.3 transcranial magnetic stimulation (TMS) ................................................................................. 211
14.4 transcranial current stimulation (TCS) .................................................................................... 214
Chapter 15: computational neuroimaging ......................................................................................... 218
15.1 computational models .......................................................................................................... 218
15.2 computational models of behaviour and cognition .................................................................. 220
15.2.1 effects of social networks on brain function ..................................................................... 220
15.2.2 prediction error and reinforcement learning ..................................................................... 221
15.2.3 drift diffusion and evidence accumulation ........................................................................ 222
15.3 computational models of neural processing ........................................................................... 224
15.3.1 population receptive fields .............................................................................................. 224
15.3.2 encoding models ............................................................................................................ 226
Chapter 16: conclusion .................................................................................................................... 229
16.1 why we are all so excited about human neuroimaging ............................................................. 229
16.1.1 an explosion of knowledge about the human brain ............................................................ 229
16.1.2 explaining the human mind ............................................................................................. 230
16.2 important limitations and challenges ..................................................................................... 231
16.2.1 limited predictive power in real-life situations with N = 1 ................................................... 231
16.2.2 from neuroscience to behaviour ...................................................................................... 232
16.2.3 what do we measure? ..................................................................................................... 234
16.3 a look into the future: improving science ................................................................................ 234
16.3.1 technical improvements and what (not) to expect ............................................................. 234
16.3.2 progress in open science ................................................................................................. 235
16.3.3 united we stand, divided we fall ....................................................................................... 237
16.4 wrap-up: towards a mic drop at the coffee bar ........................................................................ 238
Lecture 12: application of imaging .................................................................................................... 239
The lesion method in neuropsychology .......................................................................................... 239
Cerebrovascular accident (CVA) ................................................................................................ 239
The lesion method in neuropsychology....................................................................................... 240
Clinical presentation of spatial neglect .......................................................................................... 241
Changes in brain structure associated with spatial neglect ............................................................. 241
Conclusion ............................................................................................................................... 245
Changes in brain function associated with spatial neglect .............................................................. 245
Lesion neuroanatomy of spatial attention................................................................................... 246
Brain lesions change activity levels of intact regions ................................................................... 248
Brain lesions change dynamic brain states ................................................................................. 249
Neural mechanisms of spatial neglect ....................................................................................... 250
The “lesion” method in neuropsychology anno 2026....................................................................... 250
7
,Restoring brain function in spatial neglect ..................................................................................... 250
Take home message ..................................................................................................................... 252
8
,HUMAN BRAIN IMAGING
CHAPTER 1: INTRODUCTION AND OVERVIEW
Learning objectives:
• Read and understand human neuroscience and neuropsychology papers
• Include human brain imaging into your own thinking in a wide variety of domains of interest,
theoretical as well as clinical
• Develop a critical mindset when reading about and applying human brain imaging for research as
well as clinical purposes
History:
• Mid-19th century: post-mortem brain tissue analysis
o E.g. Paul Broca: impairment of speech correlated with a specific damaged part of the
brain
o E.g. Phineas Gage: changes in behaviour correlated with frontal lobe damage
• 1930: electroencephalography
• 1970: radiographic methods
• 1980-1990: positron emission tomography, functional magnetic resonance
Decade of the brain
Increase in frequency of application of brain imaging methods across all scientific disciplines
1.1 BRAIN ENTHUSIASM: THE RELEVANCE OF DISTINGUISHING FACT FROM FICTION
Examples of science fiction
• Willem Verbeke: people applying for jobs would undergo brain scans as supplement to traditional
job interviews and behavioural testing
o Brain scans can tell us whether a person is a good fit for a job
• Cout of law
o Lie detection
o fMRI to justify claims about personality
o Degree of which they can be expected to have control over their actions
Brain scans often lack validity and reliability to justify strong claims at level of individual
subjects
• Locked-in syndrome
o Brain imaging can be used to test state of consciousness even though they lack ability to
communicate
o Typical experiment:
▪ Ask patient yes/no answers by imaging two very different events which are so
different they can be distinguished based on elicited brain activity
• Answer yes by imaging playing tennis and no by imaging navigating
through a house
• Artificial intelligence
o Train an AI model to learn the association between brain activity and images people see
(plane, dining room, …)
o Ask AI what image was shown to participants by only giving their brain activity → AI can
predict this image (only for one specific person!)
9
, • Brain imaging as essential tool for objective diagnosis of diseases
o Great progress on neurological diseases (example: mild cognitive impairment)
o Less progress in psychiatric and mental syndromes
▪ Results are not consistent enough → media often doesn’t recognize this nuance
Commonalities in examples:
• Media coverage is based on scientific investigations that appeared in peer-reviewed journals
• Science is primarily valid and important, peer-reviewed studies advance knowledge
• BUT: information and claims that make it into the media often stretch far beyond original scope
BOX 1.1 NEUROSCEPTICISM AND NEUROSCIENCE
Due to science fiction about neuroscience there has been a counter-action: neuroscepticism
• Brain imaging as neolocalizationism and neophrenology
o Phrenology in 19th century: features of the skull were related to mental functions →
never empirically proven
o Brain-behavior correlations in neuroscience are empirically proven
• Why is the localization of brain functions relevant?
o Need to know where a mental function resides in the brain before we can study it
neuroscientifically
o Brains scans help investigate how the mental function is implemented through neural
networks and circuits
• ‘brain’-hype
o Using the word brain or neuro is considered a good way to sell a story or
program
o Evolution:
▪ Best-sellers about the brain have decreased
▪ Scientific papers on the topic brain are still increasing
1.2 THE BASIS OF NEURAL SIGNALS
1.2.1 INFORMATION TRANSFER IN NEURONS
Neuron structure: Action potential
travels along the
axon to all
• Dendritic tree terminals.
• Soma (cell body)
• Axon
Post-synaptic potential is
determined by integrating input of
many synapses at the dendrites. It
can hyper- and depolarize.
Brain organisation:
• Cell bodies = grey matter
o Cerebral cortex mainly consists of grey matter
o Grey matter beneath the cortex (subcortical) = nuclei
• Axons = white matter
o Large volume underneath the cortex
o Peripheral nervous system → axons form nerve bundles and tracts
10
Chapter 1: introduction and overview ....................................................................................................9
1.1 brain enthusiasm: the relevance of distinguishing fact from fiction ................................................9
Box 1.1 neuroscepticism and neuroscience ................................................................................. 10
1.2 the basis of neural signals ......................................................................................................... 10
1.2.1 information transfer in neurons ........................................................................................... 10
1.2.2 signal processing ................................................................................................................ 11
1.2.3 other signals in the brain: molecular and hemodynamc signals ............................................. 13
1.2.4 maps in the brain: from the activity of single neurons to signals without single-neuron resolution
.................................................................................................................................................. 14
1.3 a short overview of methods in human neuroscience .................................................................. 16
1.3.1 techniques to measure brain structure ................................................................................ 16
1.3.2 techniques to measure hemodynamic correlates of neural activity ........................................ 17
1.3.3 techniques to measure electrophysiological activity ............................................................. 17
Part I: structural neuroimaging ............................................................................................................ 20
Chapter 2: the physics behind magnetic resonance imaging (MRI) ........................................................ 20
2.1 the effect of magnetic fiels on the human body ........................................................................... 20
2.2 from resonance to imaging ........................................................................................................ 23
box 2.1 Fourier analysis of MRI signals and the concept of k-space ................................................ 26
2.3 how do these physical principles give rise to an image with anatomical structure? ....................... 28
2.4 the hardware of a scanner ......................................................................................................... 30
2.5 parameters that are chosen by the user...................................................................................... 31
Chapter 3: structural imaging methods ............................................................................................... 33
3.1 Structural T1-weighted MRI........................................................................................................ 33
3.1.1 quality check ...................................................................................................................... 33
3.1.2 finding structure in anatomical images and normalization ..................................................... 34
volume-based normalization.................................................................................................... 34
template reference spaces for normalization ............................................................................ 34
segmentation and segmentation-based normalization .............................................................. 35
surface extraction and surface-based normalization ................................................................. 36
3.1.3 approaches to investigate brain morphometry...................................................................... 37
Box 3.1 quantitative imaging ........................................................................................................ 38
3.1.4 statistical analysis and interpretation .................................................................................. 38
3.1.5 voxel-based lesion behaviour mapping ................................................................................ 39
3.1.6 the relevance of brain structure for behaviour and mind ........................................................ 39
3.2 diffusion-weighted imaging (DWI)............................................................................................... 41
1
, 3.2.1 data acquisition and preprocessing ..................................................................................... 41
3.2.2 diffusion tensor imaging (DTI) .............................................................................................. 42
rugby balls in the brain ............................................................................................................. 42
tensor estimation .................................................................................................................... 43
tractography ........................................................................................................................... 44
statistics ................................................................................................................................. 45
interpretation .......................................................................................................................... 45
3.2.3 advanced approaches to capture heterogeneity of diffusion in voxels .................................... 46
high angular resolution diffusion imaging (HARDI) ..................................................................... 47
multi-shell diffusion ................................................................................................................ 47
3.2.4 the relevance of anatomical connectivity for behaviour and mind .......................................... 48
3.3 magnetic resonance spectroscopy (MRS) ................................................................................... 49
3.3.1 data acquisition .................................................................................................................. 49
from biological structure to a frequency spectrum .................................................................... 49
single-voxel MRS and MRS imaging ........................................................................................... 50
water suppression and editing .................................................................................................. 51
3.3.2 data analysis ...................................................................................................................... 52
3.3.3 the relevance of molecular indices for behaviour and mind ................................................... 53
Part II: hemodynamic neuroimaging .................................................................................................... 55
Chapter 4: hemodynamic imaging methods ........................................................................................ 55
Box 4.1 why neuroscientists and behavioural scientists measure blood ......................................... 55
4.1 hemodynamics and its relationship to neural activity .................................................................. 55
4.1.1 the hemodynamic response function ................................................................................... 55
4.1.2 the relationship between the HRF and different aspects of neural activity .............................. 57
4.2 functional magnetic resonance imaging (fMRI)............................................................................ 60
4.2.1 blood-oxygenation-level dependent fMRI ............................................................................. 60
blood oxygenation and the physics of fMRI ................................................................................ 60
measuring the BOLD contrast .................................................................................................. 61
4.2.2 arterial spin labeling (ASL) fMRI ........................................................................................... 62
4.2.3 the relevance of fMRI for behaviour ...................................................................................... 62
4.3 positron emission tomography (PET) .......................................................................................... 62
4.3.1 the physics of PET ............................................................................................................... 62
4.3.2 using PET for measuring neural activity ................................................................................ 63
4.3.3 unique contributions of PET ................................................................................................. 64
4.4 functional near-infrared spectroscopy (fNIRS) ............................................................................ 65
4.5 a comparison of research with fMRI, PET, and fNIRS ................................................................... 66
Chapter 5: designing a hemodynamic imaging experiment ................................................................... 68
2
, 5.1 think befor you start an experiment ............................................................................................ 68
5.2 which conditions to include: the subtraction method .................................................................. 68
5.2.1 the subtraction method ...................................................................................................... 68
5.2.2 considerations about the subtraction method ...................................................................... 69
5.3 how to present the conditions: the block design ......................................................................... 70
5.3.1 the block design and the hemodynamic response function ................................................... 70
5.3.2 the block design in practice in fMRI and fNIRS ...................................................................... 72
5.3.3 a few examples of classical studies using a block design ...................................................... 73
5.4 the event-related design ............................................................................................................ 74
5.4.1 more advanced designs and analysis ................................................................................... 75
5.5 the baseline or rest condition .................................................................................................... 75
5.5.1 the role of a baseline in task-based fMRI .............................................................................. 75
5.5.2 regions activated during a resting baseline ........................................................................... 76
5.6 task and stimuli in the scanner .................................................................................................. 77
Box 5.1 from the design to scanning................................................................................................. 78
Chapter 6: image processing .............................................................................................................. 79
6.1 software packages .................................................................................................................... 79
Box 6.1 preprocessing step 0: quality control ................................................................................... 80
Box 6.2 external quality control through transparency and reproducibility .......................................... 80
6.2 properties of the images ............................................................................................................ 81
6.3 preprocessing step 1: slice timing .............................................................................................. 83
6.4 preprocessing step 2: motion correction .................................................................................... 84
6.5 preprocessing step 3: coregistration .......................................................................................... 86
6.6 preprocessing step 4: normalization .......................................................................................... 87
6.7 preprocessing step 5: spatial smoothing .................................................................................... 87
Chapter 7: basic statistical analyses ................................................................................................... 89
7.1 statistical analyses: the general linear model ............................................................................. 89
7.1.1 simple linear regression ...................................................................................................... 89
7.1.2 multiple linear regression .................................................................................................... 90
7.1.3 the general linear model applied to fMRI data ....................................................................... 90
7.1.4 data cleaning prior to applying the GLM................................................................................ 91
7.1.5 the efficiency of a design and correlation between predictors ............................................... 92
7.2 determining significance and interpreting it ................................................................................ 94
7.2.1 calculating a simple test statistic: a t-contrast ..................................................................... 94
7.2.2 correction for multiple comparisons, or how to avoid brain activity in a dead salmon ............. 95
7.2.3 combining data across participants: second-level whole-brain analysis ................................ 97
7.2.4 region-of-interest analyses .................................................................................................. 97
3
, 7.2.5 another statistical caveat: double dipping and circular analyses ........................................... 98
7.2.6 statistical inference ............................................................................................................ 98
Chapter 8: advanced statistical analyses .......................................................................................... 100
8.1 functional connectivity: designs and analyses .......................................................................... 100
8.1.1 correlations in brain activity .............................................................................................. 100
8.1.2 interpretation of correlations in brain activity ..................................................................... 101
8.1.3 modeling directional functional connectivity ...................................................................... 103
8.1.4 task-related modulations of connectivity ........................................................................... 104
8.1.5 resting-state fMRI (RS fMRI) ............................................................................................... 105
The implementation and analysis of RS fMRI ........................................................................... 105
Brain networks and RS fMRI ................................................................................................... 105
8.2 multi-voxel pattern analyses .................................................................................................... 107
8.2.1 a schematic tutorial of MVPA ............................................................................................. 107
8.2.2 a specific example of MVPA ............................................................................................... 108
8.2.3 the potential of MVPA to move beyond neophrenology ........................................................ 110
8.2.4 what do we measure with MVPA? ...................................................................................... 111
Box 8.1 from group studies to individual diagnostics using advanced methods ................................ 113
8.3 functional MRI adaptation ....................................................................................................... 113
Part III: electrophysiological neuroimaging ........................................................................................ 115
Chapter 9: electromagnetic field of the brain ..................................................................................... 115
9.1 electrophysiological activity of the brain ................................................................................... 115
9.1.1 from neurons to electric field............................................................................................. 115
9.1.2 magnetic field of the neural activity.................................................................................... 116
9.1.3 from field to sensors ......................................................................................................... 117
9.2 electromagnetic field signals ................................................................................................... 118
9.2.1 properties of the field signal .............................................................................................. 118
9.2.2 dimensions and resolution of the field signal ...................................................................... 120
Box 9.1 From the field to neurons .................................................................................................. 121
Box 9.2 FAQ: negative amplitude in evoked potentials .................................................................... 121
9.3 brain dynamics vs. mind dynamics .......................................................................................... 121
Chapter 10: electroencephalography and magnetoencephalography.................................................. 123
10.1 electroencephalography (EEG)............................................................................................... 123
10.1.1 EEG electrodes ............................................................................................................... 124
Box 10.1 The international 10-20 system in 5 steps .................................................................. 126
Reference and ground electrodes ........................................................................................... 127
EOG electrodes ..................................................................................................................... 128
Active electrodes................................................................................................................... 129
4
, Box 10.2 Dry electrodes ......................................................................................................... 129
Overview ............................................................................................................................... 129
10.2.2 EEG amplifier ................................................................................................................. 130
10.1.3 procedure for EEG data acquisition .................................................................................. 131
10.2 magnetoencephalography (MEG) ........................................................................................... 132
10.2.1 MEG sensors .................................................................................................................. 132
10.2.2 magnetically shielded room ............................................................................................ 134
10.2.3 procedure for MEG data acquisition ................................................................................. 134
Box 10.3 magnetoencephalography with optically pumped magnetometers .................................... 135
10.3 comparison between EEG and MEG ....................................................................................... 136
Chapter 11: basic analysis of electrophysiological signals.................................................................. 138
11.1 noises .................................................................................................................................. 139
11.1.1 biological noises ............................................................................................................. 139
11.1.2 artifactual and environmental noises ............................................................................... 141
11.1.3 visual inspection ............................................................................................................. 141
11.2 data format and analysis software ......................................................................................... 141
11.2.1 data format .................................................................................................................... 141
11.2.2 analysis software ............................................................................................................ 142
11.3 preprocessing ....................................................................................................................... 143
11.3.1 referencing ..................................................................................................................... 143
11.3.2 segmentation and channel rejection ................................................................................ 144
11.3.3 independent component analysis for preprocessing ......................................................... 144
11.3.4 filtering for preprocessing ................................................................................................ 146
11.3.5 resampling ..................................................................................................................... 146
11.3.6 more about preprocessing .............................................................................................. 147
11.4 spectral analysis ................................................................................................................... 147
11.4.1 workflow of spectral analysis........................................................................................... 148
11.4.2 more about FFT............................................................................................................... 149
11.4.3 spectral plots ................................................................................................................. 149
frequency resolution and Welch’s method .............................................................................. 151
11.4.4 frequency bands of M/EEG signal ..................................................................................... 152
11.4.5 statistical analysis .......................................................................................................... 153
11.4.6 pros and cons ................................................................................................................. 154
Box 11.1 ANOVA and power spectrum ........................................................................................ 154
11.5 event-related potential and event-related field analysis........................................................... 155
11.5.1 more about trial averaging ............................................................................................... 155
11.5.2 workflow of ERR analysis ................................................................................................. 156
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, 11.5.3 time- and surface plot of ERR .......................................................................................... 157
11.5.4 statistical analysis .......................................................................................................... 158
11.5.5 the naming of ERR ........................................................................................................... 159
11.5.6 pros and cons ................................................................................................................. 161
11.6 steady-state evoked response ............................................................................................... 162
11.6.1 more about ssER ............................................................................................................ 163
11.6.2 statistical analysis .......................................................................................................... 164
11.6.3 pros and cons ................................................................................................................. 164
Chapter 12: advanced data analysis ................................................................................................. 165
12.1 time-frequency analysis ........................................................................................................ 165
12.1.1 short time Fourier transform ............................................................................................ 165
12.1.2 Wavelet transform .......................................................................................................... 167
12.1.3 STFT vs. wavelet ............................................................................................................. 170
12.1.4 analysis of time-frequency data ....................................................................................... 171
12.2 phase analysis ...................................................................................................................... 172
12.2.1 computation of the phase ............................................................................................... 173
12.2.2 circular statistics ............................................................................................................ 177
12.2.3 phase synchrony ............................................................................................................ 178
12.2.4 inter-trial phase coherence ............................................................................................. 180
12.2.5 trial averaging revisited ................................................................................................... 183
Box 12.1 mathematical expressions for oscillation ......................................................................... 185
Box 12.2 network analysis ............................................................................................................. 186
12.3 autoregression and Granger causality .................................................................................... 187
12.3.1 autoregression ............................................................................................................... 188
12.3.2 Granger causality ............................................................................................................ 189
Part IV: complementary methods ...................................................................................................... 191
Chapter 13: multi-modal imaging ...................................................................................................... 192
13.1 the spatial and temporal unfolding of neural representations .................................................. 193
Box 13.1 from biological to artificial brains ..................................................................................... 195
13.2 simultaneous application of EEG and fMRI ............................................................................. 196
13.3 M/EEG source localization ..................................................................................................... 198
13.4 differentiating between representational and acces theories of disorders ................................ 201
13.5 clinical diagnostics with multi-modal imaging ......................................................................... 203
Chapter 14: causal methods to modulate brain activity ...................................................................... 206
Box 14.1 ethical concerns related to neuromodulation ................................................................... 207
14.1 microstimulation and deep brain stimulation .......................................................................... 208
14.2 focused ultrasound stimulation ............................................................................................. 210
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, 14.3 transcranial magnetic stimulation (TMS) ................................................................................. 211
14.4 transcranial current stimulation (TCS) .................................................................................... 214
Chapter 15: computational neuroimaging ......................................................................................... 218
15.1 computational models .......................................................................................................... 218
15.2 computational models of behaviour and cognition .................................................................. 220
15.2.1 effects of social networks on brain function ..................................................................... 220
15.2.2 prediction error and reinforcement learning ..................................................................... 221
15.2.3 drift diffusion and evidence accumulation ........................................................................ 222
15.3 computational models of neural processing ........................................................................... 224
15.3.1 population receptive fields .............................................................................................. 224
15.3.2 encoding models ............................................................................................................ 226
Chapter 16: conclusion .................................................................................................................... 229
16.1 why we are all so excited about human neuroimaging ............................................................. 229
16.1.1 an explosion of knowledge about the human brain ............................................................ 229
16.1.2 explaining the human mind ............................................................................................. 230
16.2 important limitations and challenges ..................................................................................... 231
16.2.1 limited predictive power in real-life situations with N = 1 ................................................... 231
16.2.2 from neuroscience to behaviour ...................................................................................... 232
16.2.3 what do we measure? ..................................................................................................... 234
16.3 a look into the future: improving science ................................................................................ 234
16.3.1 technical improvements and what (not) to expect ............................................................. 234
16.3.2 progress in open science ................................................................................................. 235
16.3.3 united we stand, divided we fall ....................................................................................... 237
16.4 wrap-up: towards a mic drop at the coffee bar ........................................................................ 238
Lecture 12: application of imaging .................................................................................................... 239
The lesion method in neuropsychology .......................................................................................... 239
Cerebrovascular accident (CVA) ................................................................................................ 239
The lesion method in neuropsychology....................................................................................... 240
Clinical presentation of spatial neglect .......................................................................................... 241
Changes in brain structure associated with spatial neglect ............................................................. 241
Conclusion ............................................................................................................................... 245
Changes in brain function associated with spatial neglect .............................................................. 245
Lesion neuroanatomy of spatial attention................................................................................... 246
Brain lesions change activity levels of intact regions ................................................................... 248
Brain lesions change dynamic brain states ................................................................................. 249
Neural mechanisms of spatial neglect ....................................................................................... 250
The “lesion” method in neuropsychology anno 2026....................................................................... 250
7
,Restoring brain function in spatial neglect ..................................................................................... 250
Take home message ..................................................................................................................... 252
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,HUMAN BRAIN IMAGING
CHAPTER 1: INTRODUCTION AND OVERVIEW
Learning objectives:
• Read and understand human neuroscience and neuropsychology papers
• Include human brain imaging into your own thinking in a wide variety of domains of interest,
theoretical as well as clinical
• Develop a critical mindset when reading about and applying human brain imaging for research as
well as clinical purposes
History:
• Mid-19th century: post-mortem brain tissue analysis
o E.g. Paul Broca: impairment of speech correlated with a specific damaged part of the
brain
o E.g. Phineas Gage: changes in behaviour correlated with frontal lobe damage
• 1930: electroencephalography
• 1970: radiographic methods
• 1980-1990: positron emission tomography, functional magnetic resonance
Decade of the brain
Increase in frequency of application of brain imaging methods across all scientific disciplines
1.1 BRAIN ENTHUSIASM: THE RELEVANCE OF DISTINGUISHING FACT FROM FICTION
Examples of science fiction
• Willem Verbeke: people applying for jobs would undergo brain scans as supplement to traditional
job interviews and behavioural testing
o Brain scans can tell us whether a person is a good fit for a job
• Cout of law
o Lie detection
o fMRI to justify claims about personality
o Degree of which they can be expected to have control over their actions
Brain scans often lack validity and reliability to justify strong claims at level of individual
subjects
• Locked-in syndrome
o Brain imaging can be used to test state of consciousness even though they lack ability to
communicate
o Typical experiment:
▪ Ask patient yes/no answers by imaging two very different events which are so
different they can be distinguished based on elicited brain activity
• Answer yes by imaging playing tennis and no by imaging navigating
through a house
• Artificial intelligence
o Train an AI model to learn the association between brain activity and images people see
(plane, dining room, …)
o Ask AI what image was shown to participants by only giving their brain activity → AI can
predict this image (only for one specific person!)
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, • Brain imaging as essential tool for objective diagnosis of diseases
o Great progress on neurological diseases (example: mild cognitive impairment)
o Less progress in psychiatric and mental syndromes
▪ Results are not consistent enough → media often doesn’t recognize this nuance
Commonalities in examples:
• Media coverage is based on scientific investigations that appeared in peer-reviewed journals
• Science is primarily valid and important, peer-reviewed studies advance knowledge
• BUT: information and claims that make it into the media often stretch far beyond original scope
BOX 1.1 NEUROSCEPTICISM AND NEUROSCIENCE
Due to science fiction about neuroscience there has been a counter-action: neuroscepticism
• Brain imaging as neolocalizationism and neophrenology
o Phrenology in 19th century: features of the skull were related to mental functions →
never empirically proven
o Brain-behavior correlations in neuroscience are empirically proven
• Why is the localization of brain functions relevant?
o Need to know where a mental function resides in the brain before we can study it
neuroscientifically
o Brains scans help investigate how the mental function is implemented through neural
networks and circuits
• ‘brain’-hype
o Using the word brain or neuro is considered a good way to sell a story or
program
o Evolution:
▪ Best-sellers about the brain have decreased
▪ Scientific papers on the topic brain are still increasing
1.2 THE BASIS OF NEURAL SIGNALS
1.2.1 INFORMATION TRANSFER IN NEURONS
Neuron structure: Action potential
travels along the
axon to all
• Dendritic tree terminals.
• Soma (cell body)
• Axon
Post-synaptic potential is
determined by integrating input of
many synapses at the dendrites. It
can hyper- and depolarize.
Brain organisation:
• Cell bodies = grey matter
o Cerebral cortex mainly consists of grey matter
o Grey matter beneath the cortex (subcortical) = nuclei
• Axons = white matter
o Large volume underneath the cortex
o Peripheral nervous system → axons form nerve bundles and tracts
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