FUNDACIÓN RAMÓN ARECES  Conferencia: Esquizofrenia, cerebro y neuroimagen, lo que todavía no sabemos  Edith Pomarol-Clotet...
Esquizofrenia, cerebro yneuroimagen, lo que todavía no          sabemos        Edith Pomarol-Clotet
What has brain imagingcontributed to schizophreniaresearch?  ‘Since the advent of modern neuroimaging  techniques, the num...
Imaging approaches toschizophrenia     x   Structural brain abnormality          – CT and MRI brain imaging          – Vox...
Structural brain imaging inschizophreniaThe first generation - CT                       x    First CT study found enlarged...
Structural imaging studiesThe second generation - MRI                        Meta-analysis of 31 studies                  ...
Structural imaging studiesEmerging themes x   Progression of brain structural changes      – Is there a neurodegenerative ...
Does brain structuralabnormalityin schizophrenia progress?                 x   Meta-analysis of 27 studies,               ...
Voxel-based morphometry   Voxel-Based Morphometry (VBM) permite lacomparación,        voxel-a-voxel      (VOlumeELement),...
Meta-analysis of VBMstudies in schizophrenia                     Anterior cingulate/medial prefrontal                     ...
Diffusion tensor imaging                   x   Water molecules in white                       matter move more easily     ...
Diffusion tensor imaging                   x   Water molecules in white                       matter move more easily     ...
Multimodal structural imaging inschizophrenia                                             ‘The meta-analyses              ...
Functional imaging studiesThe first generation - hypofrontality                    x   First study documented             ...
Hypofrontality in     schizophrenia - a meta-     analysis                                                                ...
Functional imaging studiesThe second generation – hypo- andhyperfrontality                              x   ‘Although pati...
An fMRI study of workingmemory in schizoprenia                 x   32 chronic schizophrenic                     patients  ...
Tarea de N-BACKAP                1-BACK     FF          KP             P
Tarea de N-BACKAP                  2-BACK     FP          KK             UP                U
APF          FKP             P      APF         PKK                           Psychology            UU             P      ...
Dorsolateral hypo- andventromedialhyperfrontality…       Controls > Schizophrenics  -32      -26   -20   -14    -8   -2   ...
…or failure of deactivation inthe medial prefrontal cortex?Controls -32   -26   -20   -14   -8   -2   4    1016     22    ...
Functional imaging studiesEmerging themes x   Failure of de-activation/Default mode     network dysfunction x   Is there o...
The default mode network           x   A network of brain regions discovered in               2001           x   Have in c...
What does the default mode networkdo?x   The default network is active when    individuals are engaged in internally    fo...
Failure of de-activation moremarked in first-episode patientswho have, or progress to,schizophrenia
Is DMN dysfunction specific toschizophrenia?                          29 manic pts vs 46 controls                         ...
Multimodal imaging in 32schizophrenic patients and 32controls                  fMRI                  Blue – reduced activa...
DTI and tractographyfindings                        DTI                       Tractography
Functional connectivity inschizophrenia‘Neuroimaging has opened up the black boxof the brain so that mental disorders can,...
Connectivity inschizophreniax   Most studies find    evidence of reduced    connectivity in    schizophrenia        (Pette...
Conclusions  x   The anterior cingulate cortex/medial      frontal cortex is a region of topical      interest in schizoph...
Muchas graciasx   Peter J. McKennax   Raimon Salvadorx   Salvador Sarróx   Gemma Montéx   Erick J. Canalesx   Jesú Gomar  ...
Is DMN dysfunction alsofound in other psychiatricdisorders?  x   Major affective disorder       – Yes both phases of bipol...
The default mode network  x   A network of brain regions which is active      at rest but de-activates during      perform...
Andreasen’s study of    ventricular size in    schizophrenia       18                                                     ...
Functional brain imagingwith task activation                   ‘Prefrontal hypometabolism                   in schizophren...
Functional imaging:voxel-based studies x   Some studies continue to find     hypofrontality      – Most studies use task a...
Weinberger’s interpretation ofhyperfrontalityWorking harder to keep upx   ‘…the results of these studies                  ...
Other psychotic disorders: Delusional disorder    18 patients with delusional disorder vs 36 controls                     ...
Is DMN dysfunction a state ortrait marker in schizophrenia?  x   Related to chronicity?       – Present in chronic schizop...
Neurochemical imaging inschizophrenia  x   The dopamine hypothesis       – Functional excess of dopamine causes positive s...
An alternative interpretation ofhyperfrontalityFailure of de-activation       In the first instance (a), the              ...
Is there DMN dysfunction inschizophrenia? Study                      Measure        Task            DMN de-               ...
x   ‘Many illnesses previously defined as    “mental” are now recognized to have a    biological cause….schizophrenia is n...
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Edith Pomarol-Clotet - Esquizofrenia, cerebro y neuroimagen

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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

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  • Hilll et al showed that meta-manalysis supports resting hypofriontality and task related but one of thr interesting finding of this is that effect size is the ame at rest and task activating, and also the effect size of pats with less two years are effect size zero but the pts more that 2 years is neg, suggesting that hypofrontality evolves with illness coure. Nevertheless, meta-analysis supports both resting and task-related hypofrontality, with approximately equal effects for both (Hill et al, 2004).
  • This area extended over the gyrus rectus bilaterally, related fronto-medial structures, and the anterior cingulate gyrus (peak activation in BA11, Talairach [-2, 38, -2], Z-score: 5.02, p-value: 2.38*10-7). There was a second, smaller and weaker cluster of significantly greater activation relative to controls affecting parts of the right hippocampal complex and neighbouring anterior temporal regions (BA21/48, Talairach [48, -8, -14], Z-score: 3.83, p-value: .0332), an area where, once again, the controls showed significant deactivation (see Figure 1). Boxplots based on averaged levels of activation from each individual in the 2-back vs baseline contrast. Left plot: regions of interest including all voxels with significantly higher activation in controls (see upper row of figure 2) were used to extract averaged values from individual maps of coefficients (betas) for this contrast (a measure of the absolute effect of the 2-back task in the selected set of regions, comparable between subjects). Right plot: values shown are based on regions of interest extracted from all areas where patients activated more relative to controls (middle row of figure 2). While positive coefficients dominate the left plot (i.e. controls activate more than patients), the prevalence of negative coefficients in the right plot suggests a failure to deactivate in patients. fMRI findings within groups Control activations and de-activations: Comparing 2-back to baseline, the controls showed significant activation in a range of areas, many of which were contiguous. These included: left and right cerebellum, extending bilaterally to the temporal and occipital lobes; left and right superior occipital and posterior (lateral) parietal areas; basal ganglia bilaterally and both thalami; left and right insula, extending bilaterally to neighbouring areas of frontal operculum, and dorsally to the precentral gyrus; [???which blob] the previous blob areas of the left and right dorsolateral prefrontal cortex (middle and superior frontal gyrus); and the left and right supplementary motor areas. The results are shown in Figure 1. [Figure 1 about here NB ??mention thresholding] The results were similar for 1-back vs baseline, although the activation less extensive. It is also noteworthy that there was ??no ??little dorsolateral prefrontal cortex activation on the easier version of the task. The main areas of de-activation were similar in the 1-back and 2-back vs baseline comparisons. There were two large medial clusters of deactivation. One was anterior, extending from medial orbital gyrus rectus dorsally to the medial middle and dorsal frontal areas, and reaching a significant part of the anterior cingulate gyrus. The other posterior one included dorsal and medial parts of occipital lobes ??(Cunei), extending dorsally to the precuneus and anteriorly to the posterior cingulate cortex. These findings are also illustrated in Figure 2. Schizophrenic activations and de-activations: As shown in Figure 2, the pattern of activation was a broadly similar, but was overall less marked than in the controls. The areas included: left and right cerebellum, extending bilaterally to the inferior temporal (fusiform gyrus) and inferior occipital cortex; left and right insula, extending bilaterally to neighbouring areas of frontal operculum, and partially contiguously dorsally to the precentral gyrus; right dorsolateral prefrontal cortex (middle and superior frontal gyri); left and right superior occipital cortex continuous with posterior lateral parietal areas; left and right supplementary motor areas. Unlike the controls, the schizophrenic patients showed de-activation mainly in the posterior precuneus/posterior cingulate cluster, with only a small area of de-activation being evident in the medial prefrontal cortex adjacent to the anterior cingulate gyrus (see Figure 1).
  • Una manera de entender que hace el DMN es examinar que tareas hacen que se active, y estas son tareas que involucran pensamientos o reflexiones propias, dirijidos a uno mismo , o cuando recuerads memorias autobiográficas , asimismo tambien cuando piensas en el fututoo tareas de teoria de la mente pensando que piensan los otros…..hacen self directed thought , recalling autoboographical memories, thinling about the future, tom tasks. Hay gente que tb cree que el dmn está relacionado en monitorizar el medio de una forma of unexpected events reward withouthg directed counscious awareness.
  • Este es nuestro estudio de primeros episodios y aunque los estudios parecen que no tienen relacion con cuadros clínicos si que encontramos que había una relación con el diagnóstico en el sentido d que los que desarrollan la enfermedad de esquizofrenia presentaban más fallo de desactivacion que aquellos que no evolucionan a esquizofrenia.
  • Nosotros hemos hecho tres estudios en pacientes con tr bipolar…lo sorprendente es que aparece el mismo fracaso de desactivación tanto en los maniacos como en los depresicvos y incluso se ven cambios en la fase eutimica. Quizas parece que el fracaso de deactivacion no es tan grande en los eutimicos y para averiguarlo más hemos llevado a cabo otro estudio en el que hemos comparado los mismos pacientes durante el episodio de enfermedad y la remisión
  • Las conclusiones por tanto son
  • Otra pregunta importante es saber si el dmn es específico a la esquizofrenia. Aquí los hallazgos son muy coherentes, los cambios son siilares en otros trastornos mentales severos.
  • So the next imp development actually took earlier when weinberger sid that if you want to wsow hypofrontalyty it would be better to do t when the frontal are being working or execrise and this is the state of the art study in 1998. A patient doing the wsc and inhaling radioactive xenon 133 he found that there is a marginal hypofrontlaity in rest but when you are task demand then you had clear evidence, failure to activate the frontal cortex
  • One or two pet studies showing hypofront at rest? But most did fmri and they oth used fmri in WM tasks. A number of voxel-based functional imaging studies of schizophrenia, like the region of interest studies before them, have continued to find evidence of reduced prefrontal activation in schizophrenia, among other findings (refs). However, some studies – particularly those employing working memory tasks – have documented hyperfrontality. Manoach et al (1999) used a modified form of the Sternberg Item Recognition Task and found increased rather than decreased activation in the dorsolateral prefrontal cortex in schizophrenia. Callicott et al (2000), using the n-back task, found areas of both hyperfrontality and hypofrontality. In both studies the increased prefrontal activation was despite the patients’ poorer performance on the tasks. Several further studies using working memory tasks have also found hyperfrontality, or a complex pattern of increased activation and decreased activation within different subregions of the dorsolateral prefrontal cortex (themenos et al, 2005; Tan et al, 2006; Callicott et al, 2003; Hugdahl et al, 2004; Schneider et al, 2006) [check Perlstein et al, 2001],
  • Finalmente me gustaria enseñaros resultados preliminares en tr delirante donde comparamos 18 pacientes con 36 controles y otra vez encontramos fracaso de deactivacion, incremenot de la conectividad y reduccion del volmen en el medial frontal cortex. Lo interesante aquí es que los hallazgos son muy circunscrtos ya que no se observa reduccion de la activación en los pacientes con tr delirantes y la reduccion del volumen era particularmente en este sitioi.
  • Una pregunta a hacernos es es dmn disfunction related to symptoms or clinical picture or is a genenral trait factor y la respuesta parece ser que no esta particularmente relacionada con duracion de enfermedad pues tambien se encuentra en estadios tempranos de la enfermedad. No hay una cosistente asociación con síntomas. Algunos autores lo han encontrado pero no ha sido nuestro caso..un estuidio tb lo encuentra en familiares de primer grado, por lo que todos estos hallazgos nos hace pensar que es un marcador de rasgo y no de estado.
  • Estos son los estudios hasta el momento y l a mayoria de os estudios eb¡ncuentran cambios en activacion st deactivacion y tb cambios en conenctividad que ts es mayor o menor conectividad. Por otro lado no hay consistencia con los sintomas. Only one study has looked at it at cognitve function changes and there were no relation
  • Edith Pomarol-Clotet - Esquizofrenia, cerebro y neuroimagen

    1. 1. FUNDACIÓN RAMÓN ARECES Conferencia: Esquizofrenia, cerebro y neuroimagen, lo que todavía no sabemos Edith Pomarol-Clotet Madrid, 23 de marzo de 2012
    2. 2. Esquizofrenia, cerebro yneuroimagen, lo que todavía no sabemos Edith Pomarol-Clotet
    3. 3. What has brain imagingcontributed to schizophreniaresearch? ‘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. 4. Imaging approaches toschizophrenia 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. 5. Structural brain imaging inschizophreniaThe 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. 6. Structural imaging studiesThe 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. 7. Structural imaging studiesEmerging 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. 8. Does brain structuralabnormalityin 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. 9. Voxel-based morphometry Voxel-Based Morphometry (VBM) permite lacomparación, voxel-a-voxel (VOlumeELement), de la concentración de materia delos tipos de tejido entre dos grupos de sujetos.(Ahora se puede medir el volumen en vez de laconcentración) Análisis de todo el volúmen cerebral, norequiere asumir ROIs a priori. VBM permite representar sobre los mapas,zonas o clusters de deterioro o crecimiento deltejido asociado a un grupo de sujetos conrespecto al otro. Fig. 1.1- Mapa parametrico estadístico resultante en un estudio de VBM. 1
    10. 10. Meta-analysis of VBMstudies in schizophrenia Anterior cingulate/medial prefrontal cortex bilaterally Posterior cingulate gyrus Middle and inferior frontal gyri Insula/operculum bilaterally (Fornito et al, 2009)
    11. 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. 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. 13. Multimodal structural imaging inschizophrenia ‘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. 14. Functional imaging studiesThe 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. 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) dActivation 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. 16. Functional imaging studiesThe second generation – hypo- andhyperfrontality 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 studiesusing the n-back task
    17. 17. An fMRI study of workingmemory 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. 18. Tarea de N-BACKAP 1-BACK FF KP P
    19. 19. Tarea de N-BACKAP 2-BACK FP KK UP U
    20. 20. APF FKP P APF PKK Psychology UU P Physics-32 -26 -20 -14 -8 -2 4 1016 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. 21. Dorsolateral hypo- andventromedialhyperfrontality… 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. 22. …or failure of deactivation inthe medial prefrontal cortex?Controls -32 -26 -20 -14 -8 -2 4 1016 22 28 34 40 46 52 58 Schizophrenics-32 -26 -20 -14 -8 -2 4 1016 22 28 34 40 46 52 58
    23. 23. Functional imaging studiesEmerging themes x Failure of de-activation/Default mode network dysfunction x Is there overlap between structural and functional abnormality? x Altered functional connectivity
    24. 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. 25. What does the default mode networkdo?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. 26. Failure of de-activation moremarked in first-episode patientswho have, or progress to,schizophrenia
    27. 27. Is DMN dysfunction specific toschizophrenia? 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. 28. Multimodal imaging in 32schizophrenic patients and 32controls fMRI Blue – reduced activation Orange – failure of de-activation Voxel-based morphometry (Pomarol-Clotet et al, 2010)
    29. 29. DTI and tractographyfindings DTI Tractography
    30. 30. Functional connectivity inschizophrenia‘Neuroimaging has opened up the black boxof the brain so that mental disorders can, for thefirst time, be studied as abnormalities in the connectionsbetween distant areas of the brain or, in some cases, problemsin the coordination of brain areas whose activity is normallysynchronized….the latest research shows that themalfunctioning of entire circuits may underlie manymental disorders.’
    31. 31. Connectivity inschizophreniax 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. 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. 33. Muchas graciasx Peter J. McKennax Raimon Salvadorx Salvador Sarróx Gemma Montéx Erick J. Canalesx Jesú Gomar sx Maria Anguerax Amalia Guerrerox Paloma Fernandez-Corcuerax Noemi Morox Elena rodríguez-Canox Benedikt Amannx José M. Goikolea (HC)x Eduard Vieta (HC)x Bibiana Sans-Sansax Silvia Alonsox Teresa Maristany (SJD)x Ramó n Landínx Especialmente a nuestros pacientes Jordi Ortiz-Gil
    34. 34. Is DMN dysfunction alsofound in other psychiatricdisorders? 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. 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. 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 confirmedpatients 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. 37. Functional brain imagingwith 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. 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. 39. Weinberger’s interpretation ofhyperfrontalityWorking harder to keep upx ‘…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. 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. 41. Is DMN dysfunction a state ortrait 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. 42. Neurochemical imaging inschizophrenia 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. 43. An alternative interpretation ofhyperfrontalityFailure 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. 44. Is there DMN dysfunction inschizophrenia? 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. 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)

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