- Email: [email protected]
Phosphorous-31 magnetic resonance spectroscopy of the basal ganglia in depressed subjects
Abstmcis
four IS mm slicl:s with :.l nominal voxel volume of 0.84 mL. We previously found reduced NAA in the hippocampal area (HIPPO) and in the dorsolateral prefrontal corteX (DLPFC) of patients with schizophrcnia. TIlc purpose of this study was to assess the reproducibility of lH-MRSI in severol brain regions (especially HIPPO and DLPFC) both in patient'i with schizophrenia and normal controls. We studied len patients (on a stnble dose of neuroleptics) and tcn age anr.! sex matched controls. E:lch subject underwent two studies with a mcan lime interval of 3 months, Regions of interest (ROIs) were drawn in HIPPO. DLPFC and several other brain regions in cortex. white matter and basal ganglia. Metabolite signal intensities were sludied as ratios of the area under each peak (NAAlCRE, NAAICHO and CHO/CRE). Stlllislical analysis (ANOVA. Bonferroni corrected) revealed: I) patients consistently show significantly reduced NANCRE and NANCHO. but not CHO/CRE, only in HIPPO and DLPFC; 2) no interaction between diagnosis and day of the study for any ROJ. The variability of ROls was also described by use of the coefficient of variation (CV=standard deviation/mean). HIPPO and DLPFC showed fairI)' low variability especially for NAN CRE and CHO/eRE both in patients and nanno11 controls. The NAA reduction in HIPPO and DLPFC is stable over this relatively short time interval.
462. PROTON MAGNETIC RESONANCE STUDY OF THE HIPPOCAMPUS IN SCHIZOPHRENIA
OlOL PSYCHIATRY 1996:39:500-666
635
463. PROTON MAGNETIC RESONANCE SPECTROSCOPIC IMAGING IN A MONKEY MODEL OF SCHIZOPHRENIA: PRELIMINARY RESULTS A. Bertolino, R.C. Saunders, J.A Frankl & n.R. Weinberger Clinical Brain Disorders Branch, NIMH. NIH, 9000 RQl;kvillc Pike, Bethesda, MD 20892 Proton magnetic resonance spectroscopic imaging (IH-MRS!) permits acquisition and imaging of sign:lls from metab-olites such as N-Acetyl· aspartate (NAA. a marker of neuronal density), choline-contllining compounds (CHO. a marker of cell membrane phospholipids turnover), creatine/phosphocreatine (CRE. used il'i an internal standard) and lact3te from four 15 mm sliccs with a nominal voxcl volume of 0,&4 mL. A miscommunication of mesial tcmporolimbic structures and prefrontal cortex (PFC) has been implicated in the physiopathology of schizophre· nia. We have studied 6 rhesus monkeys: two were nonnal controls four had had surgic:lI ablation of mesial temporolimbie structures (two within 3 weeks of binh and two at live years of age). Monkeys with lesions were allowed at le:lst threc years of recovery from surgery. All monkeys were anaesthetized before IH·MRSI with ketamine Hel and xylazine (2:3) Regions of interest (ROI) were drawn blindly on coplanar MRls bilalcrlllly for PFC, :'lCllsory/molor conex (SMC) and subcortical white mailer (WM). Metabolite signal intensities were studied as ratios of the area under the peaks: NANCRE and CHO/CRE. Monkeys with limbic lesions showed: I) reduced NANCRE only in PFC (23% for perinatal. 5% for :ldult); 2) increased CHO/CRE in :Ill ROIs (19% for perinmal and of 15% for lldult on average). TIlesc preliminary results suggest that following lcmporolimbic damage. monkeys show evidence of neuronal pathology (as assessed by reduced NAA) selectively in PFC llnd also or a regionally non-specific cell membrane phospholipids disorder (as assessed b y increased CHO).
L.S. Kegeles l , C.A. Kaufmann l, S. Chan 2 , J. Gormant, J.1. Manni. & D. Malaspina l IN.Y. State Psychiatric Institute ami Columbia Presbyterian Hospital Department of Psychiatry: ::!Columoia Presbyterian Hospital Depanment of Radiology. New York. NY 10032 Asymmetry of hippocampal volume in schizophrenia has been dcmonstrated in both po~tmortem and if! V;I'(} imaging studies and has led to hypotheses concerning the role of this finding in the pllthophysiology of the illness. Another avenue of investigation has studied the possible role of glulamate neurotrnnsmission in schizophrenia and its relation 10 the widely accepted hypothesis of dopaminergic neurotransmission derangement. While II possible glutamate/dopamine interaction remains controversial, the evidence that glutamate transmission is also deranged in the illness is considerable. This sluJ)' aims to forge a pretlminary link between the hippocampal structural and glutamatergic neumlrnnsmission lines of evidencl:l by combining the structurul imllging (MRl) lind functional spectroscopic (MRS) cllpabilities of ;/1 vivo magnellc re~o nanee using C cl'lnventional-strcngth 1.5 Tesla clinielll mngnet. In the second phase of the study it is planned lo use the newly inslaller.! Columbia high.field 5 Tesla magnet. offering among the highest field strengths for human npplication. 10 resolve the spectral peaks of glutamate. glutamine lind GABA (currenli)' poorly resolvable with conventional technology), renning and removing a limitation of the initial phase. Preliminary results of the initial phase arc presenled and discussed here. including a suggestion of the hypothesized asymmetry of volume and glutamate concentration.
464. PHOSPHOROUS·31 MAGNETIC RESONANCE SPECTROSCOPY OF THE BASAL GANGLIA IN DEPRESSED SUBJECTS
C.M. Moore!'3, J.D. Christensen t ,3. B. Lafer'·3. M. Fava2 •3 • & P.F. Renshaw l ,3 lBrain Imaging Center, McLean Hospital. Belmont. MA 02178: 2Clinical Psychophannacology Unit. Massachusells General Hospital, Boston, MA 02144; JConsolidated Dcpanment of Psychiatry. Harvartl Medical School. Boston. MA Positron emission lomography and single pholen emission tomography studies have shown decreases in nuortxleoxyglucose metabolism and blood flow. respectively. in the basal gnnglia of patients with unipolar depression relative to comparison subjects. These ahernllons might be associated wilh a decrease in high energy phosphale metabolism. Phosphorous (lIp) mllgnelic resonance spectroscopy (MRS) provides a
636
BIOl PSYCHIATRY
Abstracts
1996;39:500 - 666
means to noninvasivcly detemlinll brain Icvels of a number of metabolites including the high enerf!Y phosphates phosphocreatine (PCr) and a. ~ and 'Y- nucleoside triphosphate (NTP). and inorganic phosphlllC (Pi). This study used in vivo .lIp MRS to 31:quire metabolic information from a 45 cm' region surrounding the ba.~nl ganglin of 36 unmedicated subjects wilh major depression and 17 matched comparison subjects. The I3-NTP resonance, which primarily arises from adenosine triphosphate (ATP), wa.'i reduced by 17% (p<0.02~ F=5.96: df;.;52) in the subjects with major depression: no other resonances v3ricd significantly. This decrease in p.NTP in the depressed subjects, in the presencc of a constant PCr to Pi ratio, is consistent with the presence of metabolic abnomlalities wilhin neurons and/or glial cells. This profile of metabolite change is unusual. since NTP concentration is usually maintained at the expense of Per. owing to the higher phosphate group tl'l1nsfer potential of Per. Since the creatine kinase reaction is ncar equilibrium in human brain. decrea.~es in ATP are most likely associated with dccreases in adcnosine diphosplHlte (ADP). thus maintaining a constant ratio of ATP/ADP, as well as with decreases in the total adenosine pool.
465. DEVELOPMENT OF AUDITORY CONTINUOUS PERFORMANCE TASKS FOR FUNCTIONAL MRI LJ. Seidman 1.2, H. Brciter l ,\ J.M. Goldstein 1.2, J.M. Good man l. 2 , P. Woodruff3 , K. O'Craven 3 , R. Savoy3, D.N. Kennedy3.1. Baker. K. Kwong 3 • M.T. Tsuang l •2 , & B. Rosen 3
466. 3-D fMRI OF WORKING MEMORY IN SCHIZOPHRENIA J.H. Callicott l • K. Tallent I , A. Bertolino l • N. Ramsey I. A. Santha'. M. Knable I, R. Cop~oIa 1• T. GOldbe~l. V. Mattayl. P. van Gelderen , J.A. Frank. C.T.W. Moonen 2 , & D.R.Weinberger' IClinical Brain Disorders BrJnch. IRP, NIMH, Washington, D.C. 20032; 21n_ Vivo NMR Cemer. NtH, Bethesda. MD; .lLaboratory of Diilgnostic Radiology Research, NIH. Bethesda. MD In prior functional neuroimaging studies, putients with schizophrenia (SCZ) have shown quantitative and qualitlltive differences in conical activation during working memory tasks - particularly in the prefrontal cortex (PFC). Functional magnetic resonance imaging (fMRI) utilizcs changes in blood oxygenation to map cortical activation. Using the 3-D fMRl pulse sequence PRESTO, we exnmined a cohort of 10 SCZ and 10 age-matched Ilonnal controls (NC) perfonning a variation of the "2 Back" working memory ta.~k. An esscnti31 feature of this vaIiation is that it requires a continuous motor rcsponse throughout the task. Subjccts respond by pushing a bunon box evel}' lo8 sec thus generating a sensory-motor cortical (SM) signal which cnn be used to validate activation in other conical rcgions. such as PFC. Difference images between "on" and "ofr' states were analyzed on a voxel-by-voxcl basis u~ing a Z statistic adjusted by Bonferroni correction for the total number of voxels. Z scores above a critical threshold ("activated" vOKels) were displayed on co-regi~tercd anntomic images for region of intcrest (ROl) analy~is. NC and SCZ showed similnr activation (as mea.~urcd by mean number of activated voxcls) in SM but not PFC. Group differences in perfomlance. subject movemenl. and measures of voxel variance will be discussed us possible explanations for thcse findings. Howevcr. these duta seem consistent with prior findings in SCZ using PET and SPECT.
IDept. of Psychialry. Harvard Medical School; ~Harvard Institute of Psychiatric Epidemiology nnd Genetics: ;!MGH-NMR Cenler The goal of this study was to develop allentioo tasks specifically designed for MRI imaging of normal subjects (NS), schizophrenic patients (SCZ) amI thcir first degree relatives (REL). and olher groups with allcntional disorders. We designed five different vcrsions of the auditory CPT which demand varied deBrees of working memory and interference control, thus the tasks were graded on level of effortful processing. Tasks and analyses were designcd to uneonfound the effects of working mcmory and interferencc suppression on performancc during sustained attentional processing. For each task, target blocks alternate with control blocks in an A-B-A·B design. While Icvcl of diffiCUlty for the target blocks increnses across lasks, the control block task remains the 5ame. Preliminary cognitive data from 17 NS and 18 REL suggests that REL nre selectively impaired on tll~ks which require both working memory and interferencc supprc5sion. but not on tasks which require working memory alone or simple vigilance. Overall perfonnance on the control blocks remained eon5tant for bolh groups. indicnting that performance on target blocks wa~ not due to II generol fatigue effect. Repeateu performance on the interference lind working mcmory task of NS vs REL wns compared over 4 blocks. A longitudinal random effects model wa.'i used to estimate differential change in pcrfomlnnce over time between the groups. Nonnals showed 11 significant increase in pcrronnance over time, while relativcs pcrfonnance did not improve over time suggesting a learning effect in nonnuls that WllS not present in relatives.
467. FUNCTIONAL MRI OF EFFORTFUL ATTENTION IN HUMANS H.C. Breiter. LJ. Seidman. J.M. Goodman. J.M. Goldstein, K.M. O'Craven, R.M. Weisskoff, P.W.R. Woodruff. R. Savoy, A. Jiang. D. Kennedy. W. Kennedy. M.T. Tsuang. & B.R. Rosen Harvard Medical School and MGH-NMR Center, Charlestown. MA 02129 Using functional MRI (fMRI), we investigaled whether an auditory effortful attention task would activllte networks reported for visual selective attention. Seven normal men participated. Fifteen contiguous 7mm axial images covedns ponllto pllrietal cortcx were acquired with an asymmetric spin-ccho instllsean sequence. The paradigm employed nn A-B-A-S design. In A, subjects fCsponded to the leiter "a" when immediately preceded by a "q" (QA). In condition B subjects responded 10 the leiter "ll" preceded by 11 "q" four lellers previously (Q3A), while isnoring embedded false cues nnd targets. Subjects were scanned three times. FMRI time scries data was lransfomlcd into Talair..lch space and
four IS mm slicl:s with :.l nominal voxel volume of 0.84 mL. We previously found reduced NAA in the hippocampal area (HIPPO) and in the dorsolateral prefrontal corteX (DLPFC) of patients with schizophrcnia. TIlc purpose of this study was to assess the reproducibility of lH-MRSI in severol brain regions (especially HIPPO and DLPFC) both in patient'i with schizophrenia and normal controls. We studied len patients (on a stnble dose of neuroleptics) and tcn age anr.! sex matched controls. E:lch subject underwent two studies with a mcan lime interval of 3 months, Regions of interest (ROIs) were drawn in HIPPO. DLPFC and several other brain regions in cortex. white matter and basal ganglia. Metabolite signal intensities were sludied as ratios of the area under each peak (NAAlCRE, NAAICHO and CHO/CRE). Stlllislical analysis (ANOVA. Bonferroni corrected) revealed: I) patients consistently show significantly reduced NANCRE and NANCHO. but not CHO/CRE, only in HIPPO and DLPFC; 2) no interaction between diagnosis and day of the study for any ROJ. The variability of ROls was also described by use of the coefficient of variation (CV=standard deviation/mean). HIPPO and DLPFC showed fairI)' low variability especially for NAN CRE and CHO/eRE both in patients and nanno11 controls. The NAA reduction in HIPPO and DLPFC is stable over this relatively short time interval.
462. PROTON MAGNETIC RESONANCE STUDY OF THE HIPPOCAMPUS IN SCHIZOPHRENIA
OlOL PSYCHIATRY 1996:39:500-666
635
463. PROTON MAGNETIC RESONANCE SPECTROSCOPIC IMAGING IN A MONKEY MODEL OF SCHIZOPHRENIA: PRELIMINARY RESULTS A. Bertolino, R.C. Saunders, J.A Frankl & n.R. Weinberger Clinical Brain Disorders Branch, NIMH. NIH, 9000 RQl;kvillc Pike, Bethesda, MD 20892 Proton magnetic resonance spectroscopic imaging (IH-MRS!) permits acquisition and imaging of sign:lls from metab-olites such as N-Acetyl· aspartate (NAA. a marker of neuronal density), choline-contllining compounds (CHO. a marker of cell membrane phospholipids turnover), creatine/phosphocreatine (CRE. used il'i an internal standard) and lact3te from four 15 mm sliccs with a nominal voxcl volume of 0,&4 mL. A miscommunication of mesial tcmporolimbic structures and prefrontal cortex (PFC) has been implicated in the physiopathology of schizophre· nia. We have studied 6 rhesus monkeys: two were nonnal controls four had had surgic:lI ablation of mesial temporolimbie structures (two within 3 weeks of binh and two at live years of age). Monkeys with lesions were allowed at le:lst threc years of recovery from surgery. All monkeys were anaesthetized before IH·MRSI with ketamine Hel and xylazine (2:3) Regions of interest (ROI) were drawn blindly on coplanar MRls bilalcrlllly for PFC, :'lCllsory/molor conex (SMC) and subcortical white mailer (WM). Metabolite signal intensities were studied as ratios of the area under the peaks: NANCRE and CHO/CRE. Monkeys with limbic lesions showed: I) reduced NANCRE only in PFC (23% for perinatal. 5% for :ldult); 2) increased CHO/CRE in :Ill ROIs (19% for perinmal and of 15% for lldult on average). TIlesc preliminary results suggest that following lcmporolimbic damage. monkeys show evidence of neuronal pathology (as assessed by reduced NAA) selectively in PFC llnd also or a regionally non-specific cell membrane phospholipids disorder (as assessed b y increased CHO).
L.S. Kegeles l , C.A. Kaufmann l, S. Chan 2 , J. Gormant, J.1. Manni. & D. Malaspina l IN.Y. State Psychiatric Institute ami Columbia Presbyterian Hospital Department of Psychiatry: ::!Columoia Presbyterian Hospital Depanment of Radiology. New York. NY 10032 Asymmetry of hippocampal volume in schizophrenia has been dcmonstrated in both po~tmortem and if! V;I'(} imaging studies and has led to hypotheses concerning the role of this finding in the pllthophysiology of the illness. Another avenue of investigation has studied the possible role of glulamate neurotrnnsmission in schizophrenia and its relation 10 the widely accepted hypothesis of dopaminergic neurotransmission derangement. While II possible glutamate/dopamine interaction remains controversial, the evidence that glutamate transmission is also deranged in the illness is considerable. This sluJ)' aims to forge a pretlminary link between the hippocampal structural and glutamatergic neumlrnnsmission lines of evidencl:l by combining the structurul imllging (MRl) lind functional spectroscopic (MRS) cllpabilities of ;/1 vivo magnellc re~o nanee using C cl'lnventional-strcngth 1.5 Tesla clinielll mngnet. In the second phase of the study it is planned lo use the newly inslaller.! Columbia high.field 5 Tesla magnet. offering among the highest field strengths for human npplication. 10 resolve the spectral peaks of glutamate. glutamine lind GABA (currenli)' poorly resolvable with conventional technology), renning and removing a limitation of the initial phase. Preliminary results of the initial phase arc presenled and discussed here. including a suggestion of the hypothesized asymmetry of volume and glutamate concentration.
464. PHOSPHOROUS·31 MAGNETIC RESONANCE SPECTROSCOPY OF THE BASAL GANGLIA IN DEPRESSED SUBJECTS
C.M. Moore!'3, J.D. Christensen t ,3. B. Lafer'·3. M. Fava2 •3 • & P.F. Renshaw l ,3 lBrain Imaging Center, McLean Hospital. Belmont. MA 02178: 2Clinical Psychophannacology Unit. Massachusells General Hospital, Boston, MA 02144; JConsolidated Dcpanment of Psychiatry. Harvartl Medical School. Boston. MA Positron emission lomography and single pholen emission tomography studies have shown decreases in nuortxleoxyglucose metabolism and blood flow. respectively. in the basal gnnglia of patients with unipolar depression relative to comparison subjects. These ahernllons might be associated wilh a decrease in high energy phosphale metabolism. Phosphorous (lIp) mllgnelic resonance spectroscopy (MRS) provides a
636
BIOl PSYCHIATRY
Abstracts
1996;39:500 - 666
means to noninvasivcly detemlinll brain Icvels of a number of metabolites including the high enerf!Y phosphates phosphocreatine (PCr) and a. ~ and 'Y- nucleoside triphosphate (NTP). and inorganic phosphlllC (Pi). This study used in vivo .lIp MRS to 31:quire metabolic information from a 45 cm' region surrounding the ba.~nl ganglin of 36 unmedicated subjects wilh major depression and 17 matched comparison subjects. The I3-NTP resonance, which primarily arises from adenosine triphosphate (ATP), wa.'i reduced by 17% (p<0.02~ F=5.96: df;.;52) in the subjects with major depression: no other resonances v3ricd significantly. This decrease in p.NTP in the depressed subjects, in the presencc of a constant PCr to Pi ratio, is consistent with the presence of metabolic abnomlalities wilhin neurons and/or glial cells. This profile of metabolite change is unusual. since NTP concentration is usually maintained at the expense of Per. owing to the higher phosphate group tl'l1nsfer potential of Per. Since the creatine kinase reaction is ncar equilibrium in human brain. decrea.~es in ATP are most likely associated with dccreases in adcnosine diphosplHlte (ADP). thus maintaining a constant ratio of ATP/ADP, as well as with decreases in the total adenosine pool.
465. DEVELOPMENT OF AUDITORY CONTINUOUS PERFORMANCE TASKS FOR FUNCTIONAL MRI LJ. Seidman 1.2, H. Brciter l ,\ J.M. Goldstein 1.2, J.M. Good man l. 2 , P. Woodruff3 , K. O'Craven 3 , R. Savoy3, D.N. Kennedy3.1. Baker. K. Kwong 3 • M.T. Tsuang l •2 , & B. Rosen 3
466. 3-D fMRI OF WORKING MEMORY IN SCHIZOPHRENIA J.H. Callicott l • K. Tallent I , A. Bertolino l • N. Ramsey I. A. Santha'. M. Knable I, R. Cop~oIa 1• T. GOldbe~l. V. Mattayl. P. van Gelderen , J.A. Frank. C.T.W. Moonen 2 , & D.R.Weinberger' IClinical Brain Disorders BrJnch. IRP, NIMH, Washington, D.C. 20032; 21n_ Vivo NMR Cemer. NtH, Bethesda. MD; .lLaboratory of Diilgnostic Radiology Research, NIH. Bethesda. MD In prior functional neuroimaging studies, putients with schizophrenia (SCZ) have shown quantitative and qualitlltive differences in conical activation during working memory tasks - particularly in the prefrontal cortex (PFC). Functional magnetic resonance imaging (fMRI) utilizcs changes in blood oxygenation to map cortical activation. Using the 3-D fMRl pulse sequence PRESTO, we exnmined a cohort of 10 SCZ and 10 age-matched Ilonnal controls (NC) perfonning a variation of the "2 Back" working memory ta.~k. An esscnti31 feature of this vaIiation is that it requires a continuous motor rcsponse throughout the task. Subjccts respond by pushing a bunon box evel}' lo8 sec thus generating a sensory-motor cortical (SM) signal which cnn be used to validate activation in other conical rcgions. such as PFC. Difference images between "on" and "ofr' states were analyzed on a voxel-by-voxcl basis u~ing a Z statistic adjusted by Bonferroni correction for the total number of voxels. Z scores above a critical threshold ("activated" vOKels) were displayed on co-regi~tercd anntomic images for region of intcrest (ROl) analy~is. NC and SCZ showed similnr activation (as mea.~urcd by mean number of activated voxcls) in SM but not PFC. Group differences in perfomlance. subject movemenl. and measures of voxel variance will be discussed us possible explanations for thcse findings. Howevcr. these duta seem consistent with prior findings in SCZ using PET and SPECT.
IDept. of Psychialry. Harvard Medical School; ~Harvard Institute of Psychiatric Epidemiology nnd Genetics: ;!MGH-NMR Cenler The goal of this study was to develop allentioo tasks specifically designed for MRI imaging of normal subjects (NS), schizophrenic patients (SCZ) amI thcir first degree relatives (REL). and olher groups with allcntional disorders. We designed five different vcrsions of the auditory CPT which demand varied deBrees of working memory and interference control, thus the tasks were graded on level of effortful processing. Tasks and analyses were designcd to uneonfound the effects of working mcmory and interferencc suppression on performancc during sustained attentional processing. For each task, target blocks alternate with control blocks in an A-B-A·B design. While Icvcl of diffiCUlty for the target blocks increnses across lasks, the control block task remains the 5ame. Preliminary cognitive data from 17 NS and 18 REL suggests that REL nre selectively impaired on tll~ks which require both working memory and interferencc supprc5sion. but not on tasks which require working memory alone or simple vigilance. Overall perfonnance on the control blocks remained eon5tant for bolh groups. indicnting that performance on target blocks wa~ not due to II generol fatigue effect. Repeateu performance on the interference lind working mcmory task of NS vs REL wns compared over 4 blocks. A longitudinal random effects model wa.'i used to estimate differential change in pcrfomlnnce over time between the groups. Nonnals showed 11 significant increase in pcrronnance over time, while relativcs pcrfonnance did not improve over time suggesting a learning effect in nonnuls that WllS not present in relatives.
467. FUNCTIONAL MRI OF EFFORTFUL ATTENTION IN HUMANS H.C. Breiter. LJ. Seidman. J.M. Goodman. J.M. Goldstein, K.M. O'Craven, R.M. Weisskoff, P.W.R. Woodruff. R. Savoy, A. Jiang. D. Kennedy. W. Kennedy. M.T. Tsuang. & B.R. Rosen Harvard Medical School and MGH-NMR Center, Charlestown. MA 02129 Using functional MRI (fMRI), we investigaled whether an auditory effortful attention task would activllte networks reported for visual selective attention. Seven normal men participated. Fifteen contiguous 7mm axial images covedns ponllto pllrietal cortcx were acquired with an asymmetric spin-ccho instllsean sequence. The paradigm employed nn A-B-A-S design. In A, subjects fCsponded to the leiter "a" when immediately preceded by a "q" (QA). In condition B subjects responded 10 the leiter "ll" preceded by 11 "q" four lellers previously (Q3A), while isnoring embedded false cues nnd targets. Subjects were scanned three times. FMRI time scries data was lransfomlcd into Talair..lch space and