Esquizofrenia, cerebro y neuroimagen, lo que todav

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Esquizofrenia, cerebro y neuroimagen, lo que
todavía no sabemos
Edith Pomarol-Clotet
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What has brain imaging contributed to
schizophrenia research?

• Since the advent of modern neuroimaging
  techniques, the number of studies of the
  pathophysiological changes of schizophrenia has
  dramatically increased, with more than 1000
  reports published in the past 10 years.
• Structural brain imaging studies have shown a
  subtle, almost universal, decrease in grey
  matter, enlargement of ventricles, and focal
  alteration of white matter tracts.
• fMRI studies show abnormalities in the brain
  response to cognitive tasks, with an abnormal
  network response characterised by both
  hyperactivity and hypoactivity in different brain
  regions.
• (van Os Kapur, the Lancet, 2009)

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Imaging approaches to schizophrenia

• Structural brain abnormality
• CT and MRI brain imaging
• Voxel-based morphometry (VBM)
• Diffusion tensor imaging (DTI)
• Functional brain abnormality
• Functional imaging at rest
• Functional imaging during task performance
• Connectivity analysis
• Biochemical abnormality
• Imaging of dopamine neuronal function
• Imaging of glutamate neuronal function (not yet
  performed in schizophrenia)

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Structural brain imaging in schizophreniaThe
first generation - CT

• First CT study found enlarged lateral ventricles
• But small sample of institutionalized pts
• (Johnstone et al, 1976)
• Larger study confirmed enlargement
• Small in degree
• Only detectable visually in 10 of cases
• (Weinberger et al, 1979)
• Subsequent studies
• Almost all find enlargement
• Present at onset of illness, does not progress
• ie is neurodevelopmental in nature
• (Harrison, 1999)

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Structural imaging studiesThe second generation
- MRI

• Meta-analysis of 31 studies
• Lateral ventricles
• 26 bigger (30 studies)
• Whole brain
• 2 smaller (31 studies)
• Frontal lobes
• 5 smaller (13 studies)
• Temporal lobes
• 2.5 smaller (25 studies)
• Hippocampus/amygdala
• 5-9 smaller (15 studies)
• Also
• 2 for gray matter reduction and 1 white matter
  reduction
• (Wright et al, 2000)

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Structural imaging studiesEmerging themes

• Progression of brain structural changes
• Is there a neurodegenerative process in addition
  to the neurodevelopmental ?
• Voxel based structural analysis
• Where are the grey matter changes localized?
• Diffusion tensor imaging
• Are white matter tracts affected?
• Multimodal imaging
• Do grey and white matter findings converge?

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Does brain structural abnormality in
schizophrenia progress?

• Meta-analysis of 27 studies, follow-up 1-10
  years.
• Subjects with schizophrenia showed significantly
  greater decreases over time in whole brain
  volume, whole brain gray matter, frontal gray and
  white matter, parietal white matter, and temporal
  white matter volume, as well as larger increases
  in lateral ventricular volume.
• Difference/year
• -.07 whole brain volume
• -.59 whole brain gray matter
• -.32 frontal white matter
• .35 lateral ventricles
• (Olabi et al, 2011)

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Voxel-based morphometry

• Voxel-Based Morphometry (VBM) permite la
  comparación, voxel-a-voxel (VOlume ELement), de
  la concentración de materia de los tipos de
  tejido entre dos grupos de sujetos. (Ahora se
  puede medir el volumen en vez de la
  concentración)
• Análisis de todo el volúmen cerebral, no
  requiere asumir ROIs a priori.
• VBM permite representar sobre los mapas, zonas o
  clusters de deterioro o crecimiento del tejido
  asociado a un grupo de sujetos con respecto al
  otro.

Fig. 1.1- Mapa parametrico estadístico resultante
en un estudio de VBM.
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Meta-analysis of VBM studies in schizophrenia
Anterior cingulate/medial prefrontal cortex
bilaterally
Posterior cingulate gyrus
Middle and inferior frontal gyri
Insula/operculum bilaterally
(Fornito et al, 2009)
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Diffusion tensor imaging

• Water molecules in white matter move more easily
  along the axonal bundles than perpendicular to
  them
• This anisotropy can be measured using MRI
  (fractional anisotropy, FA)
• FA is reduced in disorders affecting white matter
  integrity
• Can use tractography algorithms to delineate
  affected tracts

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Diffusion tensor imaging

• Water molecules in white matter move more easily
  along the axonal bundles than perpendicular to
  them
• This anisotropy can be measured using MRI
  (fractional anisotropy, FA)
• FA is reduced in disorders affecting white matter
  integrity
• Can use tractography algorithms to delineate
  affected tracts

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Multimodal structural imaging in schizophrenia
The meta-analyses revealed overlapping GM and
WM structural findings in schizophrenia,
characterized by bilateral anterior cortical,
limbic and subcortical GM abnormalities, and WM
changes in regions including tracts that connect
these structures... (Bora et al, 2011)
Red grey matter, Green white matter, Blue DTI
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Functional imaging studiesThe first generation -
hypofrontality

• First study documented hypofrontality
• Reduced prefrontal metabolism at rest
• (Ingvar Franzen, 1974)
• Not well-replicated subsequently
• Found in only 10/27 well-designed studies
• (Chua McKenna, 1995)
• Hypofrontality more easily demonstrated during
  performance of a frontal task
• (Weinberger et al, 1988)

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Hypofrontality in schizophrenia - a meta-analysis
(Hill et al, 2004)
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Functional imaging studiesThe second generation
hypo- and hyperfrontality

• Although patients with schizophrenia engaged the
  DLPFC less than comparison subjects, they
  overactivated a portion of the anterior
  cingulate.
• (Glahn et al, 2005)

Meta-analysis of 12 studies using the n-back task
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An fMRI study of working memory in schizoprenia

• 32 chronic schizophrenic patients
• 32 controls matched for age, sex WAT-estimated IQ
• Scanned while performing 1 and 2 back versions of
  the n-back task
• baseline task of viewing sequence of asterisks
• 1.5T scanner
• Blocked design
• (Pomarol-Clotet et al, 2008)

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Tarea de N-BACK
A
1-BACK
P
F
F
K
P
P
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Tarea de N-BACK
A
2-BACK
P
F
P
K
K
U
P
U
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Psychology
Physics
Statistics
Contrasting experimental stimuli cause changes in
local brain blood supply which are measured by
rapid, repeated measurements of MR signal, and
statistically mapped onto brain anatomy
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Dorsolateral hypo- and ventromedial
hyperfrontality
Controls gt Schizophrenics
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or failure of deactivation in the medial
prefrontal cortex?
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Functional imaging studiesEmerging themes

• Failure of de-activation/Default mode network
  dysfunction
• Is there overlap between structural and
  functional abnormality?
• Altered functional connectivity

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The default mode network

• A network of brain regions discovered in 2001
• Have in common that they are active at rest but
  de-activate during performance of most cognitive
  tasks
• Also activates during performance of a small
  number of certain tasks
• Includes as hubs two midline regions
• Anterior medial PFC/ACC
• Posterior PCC/precuneus
• (Gusnard et al, 2001 Raichle et al, 2001
  Greicius et al,2003)

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What does the default mode network do?

• The default network is active when individuals
  are engaged in internally focused tasks including
  autobiographical memory retrieval, envisioning
  the future, and conceiving the perspectives of
  others.
• May also have a role in low-level monitoring of
  the external world for unexpected events, ie an
  exploratory state or watchfulness.
• (Buckner et al, 2008)

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Failure of de-activation more marked in
first-episode patients who have, or progress to,
schizophrenia
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29 manic pts vs 46 controls(Pomarol-Clotet et
al, 2011)
Is DMN dysfunction specific to schizophrenia?
41 bipolar depressed pts vs 41 controls (Fernánde
z-Corcuera et al, in press)
44 euthymic pts vs 44 controls (Pomarol-Clotet
et al, in preparation)
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Multimodal imaging in 32 schizophrenic patients
and 32 controls
fMRI Blue reduced activation Orange failure
of de-activation
Voxel-based morphometry
(Pomarol-Clotet et al, 2010)
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DTI and tractography findings

DTI

Tractography
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Functional connectivity in schizophrenia
Neuroimaging has opened up the black box of the
brain so that mental disorders can, for the first
time, be studied as abnormalities in the
connections between distant areas of the brain
or, in some cases, problems in the coordination
of brain areas whose activity is normally
synchronized.the latest research shows that the
malfunctioning of entire circuits may underlie
many mental disorders.
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Connectivity in schizophrenia

• Most studies find evidence of reduced
  connectivity in schizophrenia
• (Petterson-Yeo, et al, 2011)
• Studies of resting state/DMN connectivity are
  divided between those finding decreased and
  increased connectivity
• Often implicate the medial frontal cortex
• (Salgado-Pineda et al, 2011)

Significantly increased connectivity in the
medial frontal cortex in 32 chronic schizophrenic
patients compared to 32 controls (Salvador et
al, 2010))
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Conclusions

• The anterior cingulate cortex/medial frontal
  cortex is a region of topical interest in
  schizophrenia
• As well as the dorsolateral prefrontal cortex
• DMN dysfunction is an increasingly
  well-established finding
• Not specific to schizophrenia, also seen in other
  major psychiatric disorders
• Emerging theme is overlap between structural and
  functional brain abnormality in schizophrenia
• And perhaps other disorders

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Muchas gracias

• Peter J. McKenna
• Raimon Salvador
• Salvador Sarró
• Gemma Monté
• Erick J. Canales
• Jesús Gomar
• Maria Anguera
• Amalia Guerrero
• Paloma Fernandez-Corcuera
• Noemi Moro
• Elena rodríguez-Cano
• Benedikt Amann
• José M. Goikolea (HC)
• Eduard Vieta (HC)
• Bibiana Sans-Sansa
• Silvia Alonso
• Teresa Maristany (SJD)
• Ramón Landín
• Jordi Ortiz-Gil

Especialmente a nuestros pacientes
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Is DMN dysfunction also found in other
psychiatric disorders?

• Major affective disorder
• Yes both phases of bipolar disorder, and euthymia
• (Pomarol-Clotet 2010), Fernández-Corcuera, under
  review)
• Yes unipolar major depression
• (Sheline et al, 2009, Rodríguez-Cano, unpub)
• Delusional disorder
• Present in similar area to schizophrenia
• (Vicens et al, submitted)

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The default mode network

• A network of brain regions which is active at
  rest but de-activates during performance of most
  cognitive tasks
• Especially two midline regions
• Anterior medial PFC/ACC
• Posterior PCC/precuneus
• Currently believed to carry out operations
  related to self
• Theory of mind, recollection of autobiographical
  memories, planning for future, stimulus-independe
  nt thought, etc
• (Gusnard et al, 2001 Greicius et al, 2003
• Gusnard, 2005)

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Andreasens study of ventricular size in
schizophrenia

• Large sample
• Well matched for age, sex, education
• Enlargement confirmed
• Small in degree
• Overlap with wide normal range

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Functional brain imaging with task activation
Prefrontal hypometabolism in schizophrenia is
most apparent during, and perhaps dependent upon,
circumstances in which there is demand for
specific prefrontal function (Weinberger, 1988)
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Functional imagingvoxel-based studies

• Some studies continue to find hypofrontality
• Most studies use task activation
• Three influential studies found hyperfrontality
• No hypofrontality (Sternberg task)
• (Manoach et al, 1999)
• Plus areas of hypofrontality (n-back task)
• (Callicott et al, 2000, 2003)
• Hyperfrontality supported by meta-analysis
• Although we find clear support for
  hypofrontality, we also document consistently
  increased activation in anterior cingulate and
  left frontal pole regions in patients with
  schizophrenia compared to that in controls.
• (Glahn et al, 2005 Minzenberg et al, 2010)

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Weinbergers interpretation of hyperfrontalityWor
king harder to keep up
Schizophrenics

• the results of these studies suggest that when
  patients are able to keep up with the processing
  demands, they tend to do so less efficiently by
  engaging greater cerebral metabolic activity or a
  less focused cortical activity state.
• at least part of the increased or intact
  activation might serve to compensate for some
  underlying neural dysfunction, even as the
  overall network architecture might be
  inefficient.
• (Tan et al, 2007)

Controls
Hyperfrontality
Hypofrontality


fMRI response
Working Memory Load
(Callicott et al, 2003)
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Other psychotic disorders Delusional disorder
18 patients with delusional disorder vs 36
controls
Failure to de-activate
Resting state connectivity
VBM
(Vicens et al, submitted)
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Is DMN dysfunction a state or trait marker in
schizophrenia?

• Related to chronicity?
• Present in chronic schizophrenia
• (eg Pomarol-Clotet el al, 2008)
• Present in early course schizophrenia
• (Whitfield-Gabrieli et al, 2009)
• Present in first-episode patients
• (Guerrero et al , 2010)
• Related to schizophrenic symptoms?
• Yes (especially positive symptoms)
• (Liang et al, 2006 Bluhm et al, 2007
• Whitfield-Gabrieli et al (2009)
• No (no association with any class of symptoms)
• Pomarol-Clotet et al (2008)
• Present in relatives of schizophrenic pts?
• Yes Whitfield-Gabrieli et al (2009)

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Neurochemical imaging in schizophrenia

• The dopamine hypothesis
• Functional excess of dopamine causes positive
  symptoms (delusions, hallucinations) of
  schizophrenia
• Strongly supported by circumstantial evidence
• Dopamine agonists (eg amphetamine) provoke
  psychosis
• All antipsychotic drugs work by blocking dopamine
  receptors
• But direct evidence of dopamine receptor
  increases in drug-naive patients negative
• The glutamate hypothesis
• Functional deficiency of glutamate causes
  positive and negative symptoms (apathy, emotional
  withdrawal)
• Equivocally supported by circumstantial evidence
• Glutamate antagonists (eg PCP) cause psychotic
  symptoms
• Glutamate agonists do not improve positive or
  negative symptoms
• Some support from PM brain studies

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An alternative interpretation of hyperfrontality
Failure of de-activation

• In the first instance (a), the task of interest
  has a greater increase above baseline than the
  control task.
• In the second instance (b), the task of interest
  has less of a decrease from the baseline.
• In both cases, the difference in activity between
  the control task and the task of interest would
  be interpreted as an increase.

(Gusnard Raichle, 2001)
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Is there DMN dysfunction in schizophrenia?
Study Measure Task DMN de-activation Connectivity Related to
Anterior Posterior
Liang et al. (2006) fMRI parcellation Resting state - - ? Positive symptoms
Bluhm et al. (2007) fMRI ROI Resting state - - ? Positive symptoms
Garrity et al. (2007) fMRI ICA Oddball ? ? - -
Zhou et al. (2007) fMRI ROI Resting state - - ? -
Harrison et al. (2007) fMRI Oddball ? ? - Emotional awareness of others
Pomarol Clotet et al. (2008) fMRI N-back ? Neither symptoms nor cognition
Kim et al. (2009) fMRI Sternberg ? ?
Whitfield-Gabrieli et al (2009) fMRI N-back ? - ? Positive and negative symptoms
Calhoun et al. (2008) fMRI Oddball N/A N/A - -
(updated from Broyd et al, 2009)
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• Many illnesses previously defined as mental
  are now recognized to have a biological
  cause.schizophrenia is now viewed and treated as
  a developmental brain disorder.
• (Insel, 2010)