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

INTRODUCTION

Major psychiatric disorders - causation still largely unknown

Mechanisms involved currently being investigated

Improved methodologies available Brain diseases?

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

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

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?

Brain Circuits - Mood Regulation(Sheline, 2000)

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?

MRI - MORPHOMETRIC STUDIES

MRI - MORPHOMETRIC STUDIES

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

HYPERINTENSE LESION (T2-weighted MRI)

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

Brain Activation in Depression(Drevets, 2000)

Brain Activation and Fluoxetine Response(Mayberg et al, 2000)

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

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

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)

Cortical GABA Concentrations in Healthy and Depressed Subjects

Sanacora et al. Arch Gen Psychiatry. 1999;56:1043-1047.

Cor

tical

GA

BA

mm

ole

s’K

g B

rain

1.0

2.0

3.0

0.0HealthyMales

DepressedMales

1.5

2.5

0.5

HealthyFemales

DepressedFemales

1.0

2.0

3.0

0.0

1.5

2.5

0.5

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

[18F]-DEUTEROALTANSERIN

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

PET - [11C]-raclopride(Farde et al.)

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?

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.

Healthy Controls

Schizophrenia Patients

Short Long-0.1

-0.05

0

0.05

0.1

0.15

Delay

Dorsolateral PFCLeft BA 46/9

Short Long0

0.05

0.1

0.15

0.2

Delay

Left BA 44

Short Long0

0.05

0.1

0.15

0.2

Delay

Right BA 44

Barch, Carter, MacDonald, Noll and CohenArchives of General Psychiatry 2000

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

ACKNOWLEDGEMENTS

MH 01736, MH 29618, MH 30915 - NIMH Theodore and Vada Stanley Foundation National Alliance for Research in

Schizophrenia and Affective Disorders (NARSAD)