Functional Brain Networks in Schizophrenia

119 Pages·2016·8.17 MB·English

Graduate
 School
 for
 Health
 Sciences

University
 of
 Bern

FROM
 REST
 TO
 TASK:

 Functional
 Brain
 Networks
 in
 Schizophrenia

PhD
 Thesis
 submitted
 by

Anja
 Katharina
 Bänninger

from
 Embrach
 ZH

for
 the
 degree
 of

PhD
 in
 Health
 Sciences
 (Neurosciences)

Thesis
 advisor

Prof.
 Dr.
 Thomas
 Koenig

University
 Hospital
 of
 Psychiatry
 and
 Psychotherapy

Faculty
 of
 Medicine
 of
 the
 University
 of
 Bern

Thesis
 co-­‐advisor

Prof.
 Dr.
 med.
 Roland
 Wiest

Institute
 for
 Diagnostic
 and
 Interventional
 Neuroradiology

 University
 Hospital
 of
 Bern

Faculty
 of
 Medicine
 of
 the
 University
 of
 Bern

Accepted
 by
 the
 Faculty
 of
 Medicine
 and
 the
 Faculty
 of
 Human
 Sciences
 of
 the

University
 of
 Bern

Bern,

  Dean
 of
 the
 Faculty
 of
 Medicine

Bern,

  Dean
 of
 the
 Faculty
 of
 Human
 Sciences
TABLE
 OF
 CONTENTS

LIST
 OF
 ABBREVIATIONS
 ...........................................................................................
 8

SUMMARY
 ........................................................................................................................
 9

1.
  INTRODUCTION
 ...................................................................................................
 11

1.1
  SCHIZOPHRENIA
 ..........................................................................................................................
 12

1.1.1
  Epidemiology
 and
 phenomenology
 .......................................................................................
 12

1.1.2
  From
 the
 perspective
 of
 biological
 psychiatry
 .................................................................
 13

1.2
  CEREBRAL
 NETWORKS
 ................................................................................................................
 14

1.2.1
  Electroencephalography
 (EEG)
 ...............................................................................................
 15

1.2.1.1
  Synchronization
 as
 binding
 mechanism
 .....................................................................
 17

1.2.2
  Functional
 Magnetic
 Resonance
 Imaging
 (fMRI)
 ............................................................
 19

1.2.2.1
  Resting
 state
 networks
 (RSNs)
 .......................................................................................
 20

1.2.3
  Multimodal
 neuroimaging
 .........................................................................................................
 22

1.2.3.1
  Combined
 EEG-­‐fMRI
 ............................................................................................................
 23

1.3
  SCHIZOPHRENIA
 AS
 DISCONNECTION
 SYNDROME
 .......................................................................
 25

1.4
  STATE
 DEPENDENT
 INFORMATION
 PROCESSING
 .........................................................................
 26

1.5
  OBJECTIVES
 .................................................................................................................................
 28

2.
  EMPIRICAL
 CONTRIBUTION
 ............................................................................
 30

2.1
  PAPER
 1:
 PRE-­‐STIMULUS
 BOLD-­‐NETWORK
 ACTIVATION
 MODULATES
 EEG
 SPECTRAL
 ACTIVITY

DURING
 WORKING
 MEMORY
 RETENTION
 ....................................................................................
 31

2.1.1
  Supplemental
 material
 of
 Paper
 1
 .........................................................................................
 43

2.2
  PAPER
 2:
 INEFFICIENT
 PREPARATORY
 FMRI-­‐BOLD
 NETWORK
 ACTIVATIONS
 PREDICT

WORKING
 MEMORY
 DYSFUNCTIONS
 IN
 PATIENTS
 WITH
 SCHIZOPHRENIA
 ...............................
 47

2.2.1
  Supplemental
 material
 of
 Paper
 2
 .........................................................................................
 63

2.3
  PAPER
 3:
 DELTA
 EEG
 SYNCHRONIZATION
 LINKED
 TO
 DMN
 ACTIVITY
 IN
 SCHIZOPHRENIA
 .....
 69

2.3.1
  Supplemental
 material
 of
 Paper
 3
 .........................................................................................
 88

3.
  GENERAL
 DISCUSSION
 .......................................................................................
 93

3.1
  THE
 DEFAULT
 MODE
 NETWORK
 (DMN)
 FROM
 REST
 TO
 TASK-­‐RELATED
 STATES
 .....................
 93

3.2
  INTERPLAY
 OF
 NETWORKS
 AND
 MODULATION
 OF
 EEG
 FREQUENCIES
 .......................................
 96

3.3
  REMAINING
 QUESTIONS
 AND
 LIMITATIONS
 ................................................................................
 97

3.4
  CONCLUDING
 REMARKS
 ..............................................................................................................
 98
4.
  PERSPECTIVES
 .....................................................................................................
 99

4.1
  THE
 SEARCH
 FOR
 VALID
 BIOMARKERS
 ........................................................................................
 99

4.2
  LINKING
 STRUCTURE
 AND
 FUNCTION
 OF
 THE
 BRAIN
 ................................................................
 100

4.3
  POSSIBLE
 THERAPEUTIC
 INTERVENTIONS
 ................................................................................
 101

REFERENCES
 ..............................................................................................................
 103

ACKNOWLEDGMENTS
 ............................................................................................
 114

CURRICULUM
 VITAE
 ...............................................................................................
 116

LIST
 OF
 PUBLICATIONS
 .........................................................................................
 119

DECLARATION
 OF
 ORIGINALITY
 ........................................................................
 120
“A
 science
 of
 the
 mind
 must
 reduce
 …
 complexities
 (of
 behavior)
 to
 their
 elements.
 A
 science
 of
 the

brain
 must
 point
 out
 the
 functions
 of
 its
 elements.
 A
 science
 of
 the
 relations
 of
 mind
 and
 brain
 must

show
 how
 the
 elementary
 ingredients
 of
 the
 former
 correspond
 to
 the
 elementary
 functions
 of
 the

latter.”

William
 James
 (1890)
LIST
 OF
 ABBREVIATIONS

ACC

  Anterior
 cingulate
 cortex

BOLD

  Blood
 oxygen
 level-­‐dependent

dAN

  Dorsal
 attention
 network

DMN

  Default
 mode
 network

DTI

  Diffusion
 tensor
 imaging

EEG

  Electroencephalography

EC

  Eyes
 closed

EO

  Eyes
 open

ERP

  Event-­‐related
 potential

FM

  Frontal-­‐midline

fMRI

  Functional
 magnetic
 resonance
 imaging

GFS

  Global
 field
 synchronization

Hz

  Hertz

ICA

  Independent
 component
 analysis

IPL

  Inferior
 parietal
 lobule

LFP

  Local
 field
 potential

lWMN

  Left
 working
 memory
 network

MEG

  Magnetoencephalography

mPFC

  Medial
 prefrontal
 cortex

MRI

  Magnetic
 resonance
 imaging

PCC

  Posterior
 cingulate
 cortex

PET

  Positron
 emission
 tomography

PrC

  Precuneus

rWMN

  Right
 working
 memory
 network

ROI

  Region
 of
 interest

RSN

  Resting
 state
 network

tDCS

  Transcranial
 direct
 current
 stimulation

TCN

  Temporally
 coherent
 network

TMS

  Transcranial
 magnetic
 stimulation

WM

  Working
 memory

8
SUMMARY

A
  primary
  goal
  of
  neuroscience
  research
  on
  psychiatric
  disorders
  such
  as

schizophrenia
  is
  to
  enhance
  the
  current
  understanding
  of
  underlying
  biological

mechanisms
 in
 order
 to
 develop
 novel
 interventions.

  Human
  brain
  functions
  are
  maintained
  through
  activity
  of
  large-­‐scale
  brain

networks.
 Accordingly,
 deficient
 perceptual
 and
 cognitive
 processing
 can
 be
 caused
 by

failures
 of
 functional
 integration
 within
 networks,
 as
 reflected
 by
 the
 disconnection

hypothesis
 of
 schizophrenia.
 Various
 neuroimaging
 techniques
 can
 be
 applied
 to
 study

functional
  brain
  networks,
  each
  having
  different
  strengths.
  Frequently
  used

complementary
  methods
  are
  the
  electroencephalography
  (EEG)
  and
  functional

magnetic
 resonance
 imaging
 (fMRI),
 which
 were
 shown
 to
 have
 a
 common
 basis.
 Given

the
 feasibility
 of
 combined
 EEG
 and
 fMRI
 measurement,
 EEG
 signatures
 of
 functional

networks
  have
  been
  described,
  providing
  complimentary
  information
  about
  the

functional
  state
  of
  networks.
  Both
  at
  rest
  and
  during
  task
  completion,
  many

independent
  EEG
  and
  fMRI
  studies
  confirmed
  deficient
  network
  connectivity
  in

schizophrenia.
 However,
 a
 rather
 diffuse
 picture
 with
 hyper-­‐
 and
 hypo-­‐
 activations

within
 and
 between
 specific
 networks
 was
 reported.
 Furthermore,
 the
 theory
 of
 state

dependent
  information
  processing
  argues
  that
  spontaneous
  and
  prestimulus
  brain

activity
  interacts
  with
  upcoming
  task-­‐related
  processes.
  Consequently,
  observed

network
 deficits
 that
 vary
 according
 to
 task
 conditions
 could
 be
 caused
 by
 differences

in
 resting
 or
 prestimulus
 state
 in
 schizophrenia.

  Based
  on
  that
  background,
  the
  present
  thesis
  aimed
  to
  increase
  the

understanding
 of
 aberrant
 functional
 networks
 in
 schizophrenia
 by
 using
 simultaneous

EEG-­‐fMRI
 under
 different
 conditions.
 One
 study
 investigated
 integrative
 mechanisms

of
  networks
  during
  eyes-­‐open
  (EO)
  resting
  state
  using
  a
  common-­‐phase

synchronization
 measure
 in
 an
 EEG-­‐informed
 fMRI
 analysis
 (study
 3).
 The
 other
 two

studies
 (studies
 1&2)
 used
 an
 fMRI-­‐informed
 EEG
 analysis:
 The
 second
 study
 was
 an

extension
 of
 the
 first,
 which
 was
 performed
 in
 healthy
 subjects
 only.
 Hence,
 the
 same

methodologies
 and
 analyses
 were
 applied
 in
 both
 studies,
 but
 in
 the
 second
 study

schizophrenia
 patients
 were
 compared
 to
 healthy
 controls.
 The
 associations
 between

four
 temporally
 coherent
 networks
 (TCNs)
 –
 the
 default
 mode
 network
 (DMN),
 the

dorsal
 attention
 network
 (dAN),
 left
 and
 right
 working
 memory
 networks
 (WMNs)
 –

and
 power
 of
 three
 EEG
 frequency
 bands
 (theta,
 alpha,
 and
 beta
 band)
 during
 a
 verbal

working
 memory
 (WM)
 task
 were
 investigated.

9
Both
 resting
 state
 and
 task-­‐related
 studies
 performed
 in
 schizophrenia
 patients

(studies
 2&3)
 revealed
 altered
 activation
 strength,
 functional
 states
 and
 interaction
 of

TCNs,
 especially
 of
 the
 DMN.
 During
 rest
 (study
 3),
 the
 DMN
 was
 differently
 integrated

through
 common-­‐phase
 synchronization
 in
 the
 delta
 (0.5
 –
 3.5Hz)
 and
 beta
 (13
 –

30Hz)
 band.
 At
 prestimulus
 states
 of
 a
 verbal
 WM
 task,
 however,
 study
 2
 did
 not
 reveal

differences
 in
 the
 activation
 level
 of
 the
 DMN
 between
 groups.
 Furthermore,
 from
 pre-­‐
to-­‐post
 stimulus,
 the
 association
 of
 the
 DMN
 with
 frontal-­‐midline
 (FM)
 theta
 (3
 –
 7Hz)

band
 was
 altered,
 and
 a
 reduced
 suppression
 of
 the
 DMN
 during
 WM
 retention
 was

detected.
 Schizophrenia
 patients
 also
 demonstrated
 abnormal
 interactions
 between

networks:
  the
  DMN
  and
  dAN
  showed
  a
  reduced
  anti-­‐correlation
  and
  the
  WMNs

demonstrated
 an
 absent
 lateralization
 effect
 (study
 2).

  The
 view
 that
 schizophrenia
 patients
 display
 TCN
 deficiencies
 is
 supported
 by

the
 results
 of
 the
 present
 thesis.
 Especially
 the
 DMN
 and
 its
 interaction
 to
 the
 task-­‐
positive
  dAN
  showed
  specific
  alterations
  at
  different
  mental
  states
  and
  their

interaction
 (during
 rest
 and
 from
 pre-­‐to-­‐post
 stimulus).
 Those
 alterations
 might
 at

least
 partly
 explain
 observed
 symptomatology
 as
 attentional
 orientation
 deficits
 in

patients.
 To
 conclude,
 functional
 networks
 as
 the
 DMN
 might
 represent
 promising

targets
  for
  novel
  treatment
  options
  such
  as
  neurofeedback
  or
  transcranial
  direct

current
 stimulation
 (tDCS).

10
1. INTRODUCTION

Human
 brain
 functions
 and
 cognition
 rely
 on
 activity
 within
 large-­‐scale
 and
 distributed

brain
 networks
 (McIntosh
 1999,
 McIntosh
 2000).
 A
 network
 consists
 of
 integrated

distributed
 regions
 that
 facilitate
 specific
 perceptual
 or
 cognitive
 operations.
 Hence,

the
 resulting
 mental
 operation
 underlying
 a
 network
 reflects
 an
 integration
 of
 all
 those

single
 operations
 from
 included
 regions.
 Aberrant
 perceptual
 and
 cognitive
 states
 can

thus
 be
 attributed
 to
 functional
 integration
 failures
 within
 brain
 networks.
 This
 idea

was
 translated
 to
 psychiatry
 with
 the
 description
 of
 schizophrenia
 as
 a
 disconnection

syndrome
 (Friston
 and
 Frith
 1995).
 When
 complementary
 neuroimaging
 techniques

such
 as
 functional
 magnetic
 resonance
 imaging
 (fMRI)
 and
 electroencephalography

(EEG)
  are
  independently
  used,
  different
  network
  properties
  are
  revealed
  without

knowing
 whether
 they
 both
 originate
 from
 the
 same
 network:
 Using
 fMRI,
 functionally

co-­‐activated
 regions
 can
 be
 identified
 with
 high
 spatial
 resolution,
 whereas
 the
 high

temporal
  resolution
  of
  the
  EEG
  can
  provide
  information
  regarding
  frequency,

amplitude
 and
 phase
 synchronization
 of
 oscillating
 neuronal
 populations
 measured
 on

the
  scalp.
  Examining
  the
  brain’s
  intrinsic
  functional
  activity
  provides
  additional

information
 to
 the
 study
 of
 task-­‐related
 activity
 to
 characterize
 human
 brain
 functions

and
 to
 detect
 biological
 markers
 of
 neurological
 and
 psychiatric
 diseases
 (Fox
 and

Raichle
  2007).
  Additionally,
  according
  to
  the
  framework
  of
  state
  dependent

information
 processing,
 the
 brains
 intrinsic
 state
 interacts
 with
 the
 typical
 response

patterns
 elicited
 by
 internal
 (e.g.
 memories,
 thoughts,
 and
 emotions)
 or
 external
 (e.g.

sensory
 information,
 task
 performance)
 stimuli.
 Consequently,
 inter-­‐trial
 variability
 in

healthy
 subjects,
 as
 well
 as
 altered
 activation
 patterns
 found
 in
 patients,
 is
 potentially

explainable
 by
 differences
 in
 the
 brain’s
 prestimulus
 or
 resting
 state.

  The
  present
  thesis
  aimed
  to
  elucidate
  functional
  large-­‐scale
  networks
  in

schizophrenia
 patients
 from
 different
 angles:
 during
 rest
 and
 within
 task-­‐related
 states

from
 pre-­‐to-­‐post
 stimulus,
 as
 well
 using
 the
 combined
 measurement
 of
 EEG
 and
 fMRI.

The
 thesis
 is
 structured
 into
 four
 chapters.
 The
 first
 chapter
 covers
 the
 theoretical

background
 including
 schizophrenia,
 cerebral
 networks,
 the
 disconnection
 hypothesis

of
  schizophrenia,
  as
  well
  as
  the
  hallmark
  theory
  of
  state
  dependent
  information

processing.
 The
 second
 chapter,
 Empirical
 contribution,
 contains
 the
 results
 of
 the

three
  studies
  conducted
  within
  this
  project:
  The
  first
  study
  “Pre-­‐stimulus
  BOLD-­‐
network
 activation
 modulates
 EEG
 spectral
 activity
 during
 working
 memory
 retention”,

the
  second
  study
  “Inefficient
  Preparatory
  fMRI-­‐BOLD
  Network
  Activations
  Predict

11