presented at the SBP meeting - Washington DC, May 12-16 ..

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BRAIN IMAGING - PERSPECTIVES FOR STUDIES OF
PSYCHIATRIC DISORDERS

• Jair C. Soares, M.D.
• Division of Mood and Anxiety Disorders, Dept of
  Psychiatry, University of Texas Health Sciences
  Center in San Antonio

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INTRODUCTION

• Major psychiatric disorders - causation still
  largely unknown
• Mechanisms involved currently being investigated
• Improved methodologies available
• Brain diseases?

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INTRODUCTION

• For many years - no direct access to study the
  brains of living human subjects
• Peripheral blood cell and platelet models, CSF
  studies, post-mortem samples - very considerable
  limitations
• Lack of satisfactory animal models for
  psychiatric conditions
• Methodological difficulties prevented further
  advance of this field

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BRAIN IMAGING METHODS

• Brain imaging - potential for studies of
  pathophysiology of psychiatric disorders
• Anatomical and functional investigations
• MRI
• fMRI, PET
• Methods for in vivo neurochemical brain studies
• Magnetic resonance spectroscopy (MRS)
• Radiotracer imaging - receptors, neurotransmitters

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INTRODUCTION

• Our work brain imaging investigations in mood
  disorders - focus on bipolar disorder
• Are there detectable anatomical or functional
  brain abnormalities in bipolar or unipolar
  patients?
• How do such abnormalities related to symptoms,
  illness course, or treatment response?
• Any evidence that those are brain diseases?

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Brain Circuits - Mood Regulation(Sheline, 2000)
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MRI - MORPHOMETRIC STUDIES

• Subtle anatomical abnormalities - brain regions
  involved in mood regulation
• BP disorder
• prefrontal regions - subgenual, DLPFC
• medial temporal lobe - amygdala, hippocampus
• thalamus
• striatum
• cerebellum - vermis
• enlarged lateral and 3rd ventricles, cortical
  atrophy?

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MRI - MORPHOMETRIC STUDIES
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MRI - MORPHOMETRIC STUDIES
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HYPERINTENSE LESIONS

• Non-specific abnormalities - likely to reflect
  increased water density, due to minor
  cerebrovascular damage
• Late life depression - increased rates of WMH
• may disrupt brain pathways interconnecting
  regions involved in mood regulation

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HYPERINTENSE LESION (T2-weighted MRI)
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FUNCTIONAL STUDIES

• largely PET, more recently fMRI studies
• main areas of abnormalities prefrontal cortex -
  Broadman areas 24 or 25, amygdala (Mayberg et al,
  Drevets et al)
• some conflicting findings, time-course of changes
  not well characterized

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Brain Activation in Depression(Drevets, 2000)
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Brain Activation and Fluoxetine Response(Mayberg
et al, 2000)
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IN VIVO NEUROCHEMICAL BRAIN STUDIES

• Recent advances in methods for in vivo
  neurochemical brain studies
• Magnetic resonance spectroscopy (MRS)
• SPECT AND PET receptor imaging
• PET and fMRI - pharmacological paradigms

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DLPFC 1H MRS SPECTRA AT 1.5T - 8CC VOXELS
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1H MRS STUDIES

• N-Acetyl Aspartate (NAA) - marker of neuronal
  viability/function - decreased with various
  neuronal insults
• In bipolar patients
• Reduced NAA levels in DLPC (Winsberg et al, 2000)
• Reduced levels in DLPC, and increased in thalamus
  (Deicken et al, 2000)
• No changes in lenticulate nuclei (Ohara et al,
  1998)
• No changes in anterior cingulate (Soares et al,
  1999), and R or L frontal lobe (Hamawaka et al,
  1999)

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Cortical GABA Concentrations in Healthy and
Depressed Subjects
3.0
3.0
2.5
2.5
2.0
2.0
Cortical GABA mmole sKg Brain
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0
HealthyMales
DepressedMales
HealthyFemales
DepressedFemales
Sanacora et al. Arch Gen Psychiatry.
1999561043-1047.
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RADIOTRACER RECEPTOR STUDIES

• New radiotracers for in vivo brain imaging
• SPECT 123I
• PET 18F, 11C
• Allow quantitative image studies of receptor
  systems, or studies of neurotransmitter release

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18F-DEUTEROALTANSERIN
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5HT2A STUDIES IN MOOD DISORDERS

• decreased 5HT2A receptor binding in frontal
  regions in depressed UPs - in most studies no
  abnormalities
• may go down with antidepressant treatment
• generally small samples
• BP patients not examined

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PET - 11C-raclopride(Farde et al.)
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CONCLUSIONS - MOOD DISORDERS

• Subtle anatomical, functional, and neurochemical
  abnormalities in key brain regions involved in
  mood regulation
• Degenerative changes, or developmental
  abnormalities?
• Reflection of vulnerability conferred by specific
  genes?
• How does it interact with stress and
  environmental factors?

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Structural abnormalities in schizophrenia
- Ventriculomegaly ( lateral and third
ventricles) - Diffuse gray matter loss -
Decreased Volume in frontal temporal cortex -
Possible thalamic volume reductions - Reduced
Corpus callosal size Keshavan et al.
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Dorsolateral PFC Left BA 46/9
Right BA 44
Left BA 44
Barch, Carter, MacDonald, Noll and Cohen Archives
of General Psychiatry 2000
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CONCLUSIONS

• Brain imaging likely to result in substantial
  advances to understanding of pathophysiology of
  psychiatric disorders
• Strategies that will involve longitudinal studies
  of first-episode patients and high-risk subjects
  likely to be of particular benefit

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ACKNOWLEDGEMENTS

• MH 01736, MH 29618, MH 30915 - NIMH
• Theodore and Vada Stanley Foundation
• National Alliance for Research in Schizophrenia
  and Affective Disorders (NARSAD)