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Using MRI and MRS to investigate gray matter deficits in schizophrenia
AbstrJcts
ments, and is not observl!d after adminisll'lition of nonantidcprclisant psyc:holropic drugs, demonslrating thc phannacological specificity for antidepressants. ThIs and related work is conslslent with Ihe possibilily Ihal CREB meditnes the induction of BDNF. Up-regulation of BDNF in response to antidepressant treatments is most prominent in the dent:ltc gyrus granule cell layer. and CA I and CA3 pyramidal cell layers of hippocampus. Neurons in these cell layt:rs are known to be vulnel'llble to the dnmaging effecL<; of slress. as weH as olher types of ncuronal insult. In addition, stress is reported to decrease IC\lcls of BDNF in these cell layers. Thus. alrophy or death of these neurons :1.<; a result of prior neuronal insult or genctie vulnerability ~ould contribute to the pathophysiology of depression, and could explain why stress leads to depression only in certain individuals. We have found that antidepressant treatments abo blocks the down·regulation of BDNF in response to stress. Thus, up· regulation of BDNF by chronic untideprcssant treatments could serve to protect and/or promote the repair of vulncr.lble neurons in the hippocampus.
205. RESONANCE AND POSITRON EMISSION TOMOGRAPHY
DlOL PSYCIiIATRY 1996:39:500·(lI'i6
559
the pathophysiology of schizophrcnill has led 10 the inlcrpretntion of imaging resuhs in the conte;o;t of inter-related systems of bruin function. rather than isolated focal brain llbnom1alities. Furthermore. an important goal of imaging studies is to dcscrlbe unusual Ceatures of schizophrenic brains that represent abnonnalilies central to the development of the tfisordcr. inrluding abn0ffi111lities lhat may represent \'ulnernbilit1es or risk factors. as wellns those that are direcily related to psychopathology. Identifying bmin pathology that distinguishes schizophrenics bruins has proven difficult because it involves detecting mthcr subtle changes against a background of extensive nomtal varintion. Application of powerful new MR techniques conlinues to increase our understanding of these subtle chnnges. The importan~e of magnetic resonance spectroscopy (MRS) is derived from the infonnation it pro\'ides regarding thc chemiCllI content of the tissue being studied. Funclional MRI (fMRI) provides a method for the assessment of functional archileclllre by measurin~ changes in oxidation ami regional blood flow in discrete regions of the bmin in response to challenge paradigms, These technologies promise to facilitate both the detection of cortical anonml ies as well as provide the melhods necessary for the systematic exploration of cortical :structure and function nceded to examine bl"'Jin dysfunction from n network perspective.
N.C. Andreasen, V. Swayze, D.S, O'Leary, P. Nopoulos, T. Cizudlo, G. Harris, S. Arndt, &
M. Flaum Mentnl Health Clinical Research Center, University of Iowa Hosptinls & Clinics. 200 Hawkins Drive, Iowa City,IA 52242-1057 The syndrome of schizophrenia presents wilh u complex UITay of symptoms that am diflicult to explain at the neuml level. Data collected using Magnetic Resonance (MR) ami Positron Emission Tomogrophy (PET) suggest that this complex arr.lY could occur liS a consequeilce of misconncctions lind mismatches ill midline circuitry thai is reticularthalamic.cingulate·cortJcal. MR sludies have shown a variety of abnormalities, including callosal agenesis, cnvum septi pellucidi, decrclIsed thalamic sh~e, decreased (rontlll size, llnd changes in signal intensity in white mattcr tracts between !he thalamu~ and the rronta! cortex. PET studies using II dicholic listening parndigm suggestthm patients suffering Crom schizophrenia ha\lc n brain blood now abnormality consistent with a difficulty in focusing or shifling :llleniion, which may n:nect the functional substrate of the anmomical abnommlilies.
206. MAGNETIC RESONANCE IMAGING IN SCHIZOPHRENIA D.A. Yurgelun.Todd l •2 , A.R. Sherwood 1, D. Kinneyl, & P.F, Renshaw l •2 IConsolic.lated Department of Psychiatry. Harvard Medical School, Doston, MA: :!Bruin 'muging Cenler, McLean Hospital, Belmont. MA In ",;vo magnetic resonance Imaging of schizophrenic patients permits the direct and noninvasi\lc study of brain biochemislry. structure, IIlld function. Over thc last dccade, a number of morpholosicallibnonnalitic!' have been found in schizophrenic brains on the basis oC qualitative and quantitntl\le assessment of MR images. Changes in ventrlcular volume, cortical volume, temporal lobll structures nnd subcortical resions have been reportcd. The sClirch Cor a precise nnd specific location underlying
207. USING MRI AND MRS TO INVESTIGATE ORAY MATIER DEFICITS IN SCHIZOPHRENIA K.O. Lim Stanford University and Veternl1S Affairs Pulo Alto Health Cure System Cross scctiollal struclural MRI .~tudie.<; of schizophrenia have demonstrated widl!spread cortical gray malter dendt which exists early in the course of the disease nnd does not incrt:ase with length of illness in some populations. Gray maller volumes as measured with MRI include bolh neuronal and glial cells. Proton MRS enables Ihe identification oC a number of different metabolites in the proton spectrum in tnrget tissue. A prominent peak is N-acclylaspanic acid (NAA), an amino acid thought to be present almost cxclusively in neuronal cells. but not in mature glial cclls. nnd higher in gmy mailer than while mailer. Proton spectroscopic studies in schizophrenia havc sencmlly found 11 decre:lse in NAA levels in schi7.0phrcnic patil!nts compared with cOfllrols. The functional significance of this is unclear because large spectroscopic voxels contain unknown mixtures of gray matter, white mailer or CSF. While il is not currently feu.<;ible to collect .'ipectro~copie infonnation from homogenous vo:
ments, and is not observl!d after adminisll'lition of nonantidcprclisant psyc:holropic drugs, demonslrating thc phannacological specificity for antidepressants. ThIs and related work is conslslent with Ihe possibilily Ihal CREB meditnes the induction of BDNF. Up-regulation of BDNF in response to antidepressant treatments is most prominent in the dent:ltc gyrus granule cell layer. and CA I and CA3 pyramidal cell layers of hippocampus. Neurons in these cell layt:rs are known to be vulnel'llble to the dnmaging effecL<; of slress. as weH as olher types of ncuronal insult. In addition, stress is reported to decrease IC\lcls of BDNF in these cell layers. Thus. alrophy or death of these neurons :1.<; a result of prior neuronal insult or genctie vulnerability ~ould contribute to the pathophysiology of depression, and could explain why stress leads to depression only in certain individuals. We have found that antidepressant treatments abo blocks the down·regulation of BDNF in response to stress. Thus, up· regulation of BDNF by chronic untideprcssant treatments could serve to protect and/or promote the repair of vulncr.lble neurons in the hippocampus.
205. RESONANCE AND POSITRON EMISSION TOMOGRAPHY
DlOL PSYCIiIATRY 1996:39:500·(lI'i6
559
the pathophysiology of schizophrcnill has led 10 the inlcrpretntion of imaging resuhs in the conte;o;t of inter-related systems of bruin function. rather than isolated focal brain llbnom1alities. Furthermore. an important goal of imaging studies is to dcscrlbe unusual Ceatures of schizophrenic brains that represent abnonnalilies central to the development of the tfisordcr. inrluding abn0ffi111lities lhat may represent \'ulnernbilit1es or risk factors. as wellns those that are direcily related to psychopathology. Identifying bmin pathology that distinguishes schizophrenics bruins has proven difficult because it involves detecting mthcr subtle changes against a background of extensive nomtal varintion. Application of powerful new MR techniques conlinues to increase our understanding of these subtle chnnges. The importan~e of magnetic resonance spectroscopy (MRS) is derived from the infonnation it pro\'ides regarding thc chemiCllI content of the tissue being studied. Funclional MRI (fMRI) provides a method for the assessment of functional archileclllre by measurin~ changes in oxidation ami regional blood flow in discrete regions of the bmin in response to challenge paradigms, These technologies promise to facilitate both the detection of cortical anonml ies as well as provide the melhods necessary for the systematic exploration of cortical :structure and function nceded to examine bl"'Jin dysfunction from n network perspective.
N.C. Andreasen, V. Swayze, D.S, O'Leary, P. Nopoulos, T. Cizudlo, G. Harris, S. Arndt, &
M. Flaum Mentnl Health Clinical Research Center, University of Iowa Hosptinls & Clinics. 200 Hawkins Drive, Iowa City,IA 52242-1057 The syndrome of schizophrenia presents wilh u complex UITay of symptoms that am diflicult to explain at the neuml level. Data collected using Magnetic Resonance (MR) ami Positron Emission Tomogrophy (PET) suggest that this complex arr.lY could occur liS a consequeilce of misconncctions lind mismatches ill midline circuitry thai is reticularthalamic.cingulate·cortJcal. MR sludies have shown a variety of abnormalities, including callosal agenesis, cnvum septi pellucidi, decrclIsed thalamic sh~e, decreased (rontlll size, llnd changes in signal intensity in white mattcr tracts between !he thalamu~ and the rronta! cortex. PET studies using II dicholic listening parndigm suggestthm patients suffering Crom schizophrenia ha\lc n brain blood now abnormality consistent with a difficulty in focusing or shifling :llleniion, which may n:nect the functional substrate of the anmomical abnommlilies.
206. MAGNETIC RESONANCE IMAGING IN SCHIZOPHRENIA D.A. Yurgelun.Todd l •2 , A.R. Sherwood 1, D. Kinneyl, & P.F, Renshaw l •2 IConsolic.lated Department of Psychiatry. Harvard Medical School, Doston, MA: :!Bruin 'muging Cenler, McLean Hospital, Belmont. MA In ",;vo magnetic resonance Imaging of schizophrenic patients permits the direct and noninvasi\lc study of brain biochemislry. structure, IIlld function. Over thc last dccade, a number of morpholosicallibnonnalitic!' have been found in schizophrenic brains on the basis oC qualitative and quantitntl\le assessment of MR images. Changes in ventrlcular volume, cortical volume, temporal lobll structures nnd subcortical resions have been reportcd. The sClirch Cor a precise nnd specific location underlying
207. USING MRI AND MRS TO INVESTIGATE ORAY MATIER DEFICITS IN SCHIZOPHRENIA K.O. Lim Stanford University and Veternl1S Affairs Pulo Alto Health Cure System Cross scctiollal struclural MRI .~tudie.<; of schizophrenia have demonstrated widl!spread cortical gray malter dendt which exists early in the course of the disease nnd does not incrt:ase with length of illness in some populations. Gray maller volumes as measured with MRI include bolh neuronal and glial cells. Proton MRS enables Ihe identification oC a number of different metabolites in the proton spectrum in tnrget tissue. A prominent peak is N-acclylaspanic acid (NAA), an amino acid thought to be present almost cxclusively in neuronal cells. but not in mature glial cclls. nnd higher in gmy mailer than while mailer. Proton spectroscopic studies in schizophrenia havc sencmlly found 11 decre:lse in NAA levels in schi7.0phrcnic patil!nts compared with cOfllrols. The functional significance of this is unclear because large spectroscopic voxels contain unknown mixtures of gray matter, white mailer or CSF. While il is not currently feu.<;ible to collect .'ipectro~copie infonnation from homogenous vo: