Edith Pomarol-Clotet, Unidad de Psicosis e Investigación de Complejo Asistencial en Salud Mental Benito Menni. "Esquizofrenia, cerebro y neuroimagen, lo que todavía no sabemos" Evento: El papel de los investigadores ante los grandes retos de la innovación en salud. Madrid, 23 de marzo de 2012

1. FUNDACIÓN RAMÓN ARECES
Conferencia: Esquizofrenia, cerebro y neuroimagen, lo que todavía no sabemos
Edith Pomarol-Clotet
Madrid, 23 de marzo de 2012

2. Esquizofrenia, cerebro y
neuroimagen, lo que todavía no
sabemos
Edith Pomarol-Clotet

3. 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)

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

5. Structural brain imaging in
schizophrenia
The first generation - CT
x First CT study found enlarged lateral
ventricles
– But small sample of institutionalized pts
(Johnstone et al, 1976)
x Larger study confirmed enlargement
– Small in degree
– Only detectable visually in 10% of cases
(Weinberger et al, 1979)
x Subsequent studies
– Almost all find enlargement
– Present at onset of illness, does not
progress
– ie is ‘neurodevelopmental’ in nature
(Harrison, 1999)

6. Structural imaging studies
The second generation - MRI
Meta-analysis of 31 studies
x Lateral ventricles
– 26% bigger (30 studies)
x Whole brain
– 2% smaller (31 studies)
x Frontal lobes
– 5% smaller (13 studies)
x Temporal lobes
– 2.5% smaller (25 studies)
x Hippocampus/amygdala
– 5-9% smaller (15 studies)
x Also
– 2% for gray matter reduction and 1%
white matter reduction
(Wright et al, 2000)

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

8. Does brain structural
abnormality
in schizophrenia progress?
x Meta-analysis of 27 studies,
follow-up 1-10 years.
x ´ 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.’
x Difference/year
– -.07% whole brain volume
– -.59% whole brain gray matter
– -.32% frontal white matter
– +.35% lateral ventricles
(Olabi et al, 2011)

9. 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. 1

10. 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)

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

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

13. 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

14. Functional imaging studies
The first generation - hypofrontality
x First study documented
‘hypofrontality’
– Reduced prefrontal metabolism at
rest
(Ingvar & Franzen, 1974)
x Not well-replicated subsequently
– Found in only 10/27 well-designed
studies
(Chua & McKenna, 1995)
x Hypofrontality more easily
demonstrated during
performance of a ‘frontal’ task
(Weinberger et al, 1988)

15. Hypofrontality in
schizophrenia - a meta-
analysis
1.5
No. of Total N Effect size 1.0
studies (d)
Resting hypofrontality 38 1474 -0.32 0.5
(relative)
Resting hypofrontality 25 950 -0.55 0.0
(absolute) d
Activation hypofrontality 17 685 -0.37 -0.5
(relative)
Activation hypofrontality 10 347 -0.42 -1.0
(absolute)
-1.5
-2.0
Acute (N=8) Mixed (N=14) Chronic (N=20)
(Hill et al, 2004)

16. Functional imaging studies
The second generation – hypo- and
hyperfrontality
x ‘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

17. An fMRI study of working
memory in schizoprenia
x 32 chronic schizophrenic
patients
x 32 controls matched for
age, sex WAT-estimated
IQ
x 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)

18. Tarea de N-BACK
AP 1-BACK
FF
KP
P

19. Tarea de N-BACK
AP 2-BACK
FP
KK
UP
U

20. APF
FKP
P
APF
PKK Psychology
UU
P Physics
-32 -26 -20 -14 -8 -2 4 10
16 22 28 34 40 46 52 58
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

21. Dorsolateral hypo- and
ventromedial
hyperfrontality…
Controls > Schizophrenics
-32 -26 -20 -14 -8 -2 4 10
16 22 28 34 40 46 52 58
16 22 28 34 40 46 52 58
Schizophrenics > Controls
-32 -26 -20 -14 -8 -2 4 10
16 22 28 34 40 46 52 58

22. …or failure of deactivation in
the medial prefrontal cortex?
Controls
-32 -26 -20 -14 -8 -2 4 10
16 22 28 34 40 46 52 58
Schizophrenics
-32 -26 -20 -14 -8 -2 4 10
16 22 28 34 40 46 52 58

23. Functional imaging studies
Emerging themes
x Failure of de-activation/Default mode
network dysfunction
x Is there overlap between structural and
functional abnormality?
x Altered functional connectivity

24. The default mode network
x A network of brain regions discovered in
2001
x 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
x 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)

25. What does the default mode network
do?
x 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.
x 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)

26. Failure of de-activation more
marked in first-episode patients
who have, or progress to,
schizophrenia

27. Is DMN dysfunction specific to
schizophrenia?
29 manic pts vs 46 controls
(Pomarol-Clotet et al, 2011)
41 bipolar depressed pts vs 41 controls
(Fernández-Corcuera et al, in press)
44 euthymic pts vs 44 controls
(Pomarol-Clotet et al, in preparation)

28. 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)

29. DTI and tractography
findings
DTI
Tractography

30. 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.’

31. Connectivity in
schizophrenia
x Most studies find
evidence of reduced
connectivity in
schizophrenia
(Petterson-Yeo, et al,
2011)
x Studies of resting
state/DMN Significantly increased connectivity in
connectivity are the medial frontal cortex in 32 chronic
divided between schizophrenic patients compared to
those finding 32 controls
decreased and
increased (Salvador et al, 2010))
connectivity
– Often implicate the
medial frontal cortex
(Salgado-Pineda et al,
2011)

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

33. Muchas gracias
x Peter J. McKenna
x Raimon Salvador
x Salvador Sarró
x Gemma Monté
x Erick J. Canales
x Jesú Gomar
s
x Maria Anguera
x Amalia Guerrero
x Paloma Fernandez-Corcuera
x Noemi Moro
x Elena rodríguez-Cano
x Benedikt Amann
x José M. Goikolea (HC)
x Eduard Vieta (HC)
x Bibiana Sans-Sansa
x Silvia Alonso
x Teresa Maristany (SJD)
x Ramó n Landín
x
Especialmente a nuestros pacientes
Jordi Ortiz-Gil

34. Is DMN dysfunction also
found in other psychiatric
disorders?
x 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)
x Delusional disorder
– Present in similar area to schizophrenia
(Vicens et al, submitted)

35. The default mode network
x A network of brain regions which is active
at rest but de-activates during
performance of most cognitive tasks
x Especially two ‘midline’ regions
– Anterior: medial PFC/ACC
– Posterior: PCC/precuneus
x Currently believed to carry out operations
related to ‘self’
– Theory of mind, recollection of autobiographical
memories, planning for future, ‘stimulus-
independent’ thought, etc
(Gusnard et al, 2001; Greicius et al, 2003;
Gusnard, 2005)

36. Andreasen’s study of
ventricular size in
schizophrenia
18
Patients (N=101)
16
x Large sample
Controls (N=60)
14 x Well matched for age,
12 sex, education
No of 10
x Enlargement confirmed
patients
8 x Small in degree
6 x Overlap with wide normal
4 range
2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Ventricle-brain ratio

37. 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)

38. Functional imaging:
voxel-based studies
x Some studies continue to find
hypofrontality
– Most studies use task activation
x 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)
x 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.’

39. Weinberger’s interpretation of
hyperfrontality
Working harder to keep up
x ‘…the results of these studies Schizophrenics
suggest that when patients
are able to keep up with the Controls
processing demands, they
tend to do so less efficiently
by engaging greater cerebral Hyperfrontality Hypofrontality
fMRI response
metabolic activity or a less
focused cortical activity
state….
x …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.’ Working Memory Load
(Tan et al, 2007)
(Callicott et al, 2003)

40. 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)

41. Is DMN dysfunction a state or
trait marker in schizophrenia?
x 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)
x 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)
x Present in relatives of schizophrenic pts?
– Yes Whitfield-Gabrieli et al (2009)

42. Neurochemical imaging in
schizophrenia
x 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
x 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

43. An alternative interpretation of
hyperfrontality
Failure of de-activation
In the first instance (a), the
a
x +
task of interest has a
greater increase above
baseline than the control
Activation
0
task. Baseline Control task Task of interest
x In the second instance (b),
the task of interest has -
less of a decrease from b
the baseline. +
x In both cases, the
difference in activity
Activation
Baseline Control task Task of interest
0
between the control task
and the task of interest
would be interpreted as an
increase.
-
(Gusnard & Raichle, 2001)

44. Is there DMN dysfunction in
schizophrenia?
Study Measure Task DMN de- Connectivity Related to
activation
Anterior Posterior
Liang et al. fMRI Resting state - - ↓ Positive symptoms
(2006) parcellation
Bluhm et al. fMRI ROI Resting state - - ↓ Positive symptoms
(2007)
Garrity et al. fMRI ICA Oddball ↑ ↓ - -
(2007)
Zhou et al. fMRI ROI Resting state - - ↑ -
(2007)
Harrison et al. fMRI Oddball ↑ ↑ - Emotional awareness
(2007) of others
Pomarol Clotet et al. fMRI N-back ↓ Neither symptoms nor
(2008) cognition
Kim et al. fMRI Sternberg ↓ ?
(2009)
Whitfield-Gabrieli et al fMRI N-back ↓ - ↑ Positive and negative
(2009) symptoms
Calhoun et al. fMRI Oddball N/A N/A - -
(2008)
(updated from Broyd et al, 2009)

45. x ‘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)