Journal of Affective Disorders 110 (2008) 106–114www.elsevier.com/locate/jad

Research report

Increased fronto-temporal perfusion in bipolar disorder

N. Agarwal a,b, M. Bellani c,d, C. Perlini c,d, G. Rambaldelli c,d, M. Atzori c,d, R. Cerini e,F. Vecchiato e, R. Pozzi Mucelli e, Nicola Andreone c,d, M. Balestrieri b,f,

M. Tansella c,d, P. Brambilla b,f,g,h,⁎

a Department of Medical and Morphological Researches, Section of Radiology, University of Udine, Udine, Italyb Verona-Udine Brain Imaging and Neuropsychology Program, Inter-University Center for Behavioural Neurosciences, University of Udine, Italyc Verona-Udine Brain Imaging and Neuropsychology Program, Inter-University Center for Behavioural Neurosciences, University of Verona, Italy

d Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Verona, Italye Department of Morphological and Biomedical Sciences, Section of Radiology, University of Verona, GB Rossi Hospital, Verona, Italy

f Department of Pathology and Experimental & Clinical Medicine, Section of Psychiatry, University of Udine, Udine, Italyg Scientific Institute, IRCCS 'E. Medea', Udine, Italy

h CERT-BD, Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

Received 12 November 2007; received in revised form 11 January 2008; accepted 11 January 2008Available online 21 February 2008

Abstract

Objectives: Previous imaging reports showed over-activation of fronto-limbic structures in bipolar patients, particularly in responseto emotional stimuli. In this study, for the first time, we used perfusion weighted imaging (PWI) to analyze lobar cerebral bloodvolume (CBV) in bipolar disorder to further explore the vascular component to its pathophysiology.Methods: Fourteen patients with DSM-IV bipolar disorder (mean age±SD=49.00±12.30 years; 6 males, 8 females) and 29 normalcontrols (mean age±SD=45.07±10.30 years; 13 males, 16 females) were studied. PWI images were obtained followingintravenous injection of paramagnetic contrast agent (Gadolinium-DTPA), with a 1.5 T Siemens magnet using an echo-planarsequence. The contrast of enhancement (CE), was calculated pixel by pixel as the ratio of the maximum signal intensity dropduring the passage of contrast agent (Sm) by the baseline pre-bolus signal intensity (So) (CE=Sm/So⁎100) for frontal, temporal,parietal, and occipital lobes, bilaterally, on two axial images. Higher CE values correspond to lower CBV and viceversa.Results: Bipolar patients had significantly lower CE values in left frontal and temporal lobes (p=0.01 and p=0.03, respectively)and significantly inverse laterality index for frontal lobe (p=0.017) compared to normal controls. No significant correlationsbetween CE measure and age or clinical variables were found (pN0.05).Conclusion: This study found increased left frontal and temporal CBV in bipolar disorder. Fronto-temporal hyper-perfusion maysustain over-activation of these structures during emotion modulation, which have been observed in patients with bipolar illness.© 2008 Elsevier B.V. All rights reserved.

Keywords: Neuroimaging; NMR; Perfusion; Gadolinium; Vascular organization; Depression

⁎ Corresponding author. Dipartimento di Patologia e MedicinaClinica e Sperimentale, Cattedra di Psichiatria, Policlinico Universi-tario, Via Colugna 50, 33100 Udine, Italy. Tel.: +39 0432 55 9494; fax:+39 0432 54 5526.

E-mail address: paolo.brambilla@uniud.it (P. Brambilla).

0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved.doi:10.1016/j.jad.2008.01.013

1. Introduction

Bipolar disorder is a serious, chronic and disablingpsychiatric illness characterized by depressive, manic,and euthymic phases along with cognitive disturbances

Table 1Demographic and clinical variables for bipolar and normal subjects

Normalcontrols(N=29)

Bipolar disorderpatients (N=14)

Statistics p

Age (years) 45.31±10.35 49.00±12.30 t=1.03 0.31Males/females 13/16 6/8 χ2=0.01 0.91Race Caucasian CaucasianAge at onset

(years)– 33.69±14.64

Length of illness(years)

– 14.15±12.88

Number ofhospitalizations

– 3.53±3.41

Lifetimepsychotropictreatment(years)

– 14.22±11.68

HDRS – 6.89±5.82BRMRS – 1.00±1.76

HDRS=Hamilton Depression Rating Scale; BRMRS=Bech–Rafael-sen Mania Rating Scale.

107N. Agarwal et al. / Journal of Affective Disorders 110 (2008) 106–114

(Brambilla et al., 2007a; Salvatore et al., 2007). Analtered anterior-limbic network including dorsolateralprefrontal cortex, anterior cingulate and amygdala has beensuggested to be involved in the pathophysiology of thedisease (Brambilla et al., 2005). Indeed, functional andbiochemical abnormalities and over-activation of prefron-tal areas and limbic structures during emotional tasks haveconsistently been reported in patients suffering frombipolar illness (Yildiz-Yesiloglu and Ankerst, 2006;Yurgelun-Todd and Ross, 2006). Furthermore, increasedprefronto-limbic metabolism and perfusion have beenshown in some positron emission tomography (PET) andsingle photon emission computed tomography (SPECT)reports in bipolar disorder, specifically in the left hemi-sphere, suggesting potential vascular abnormalities (Dre-vets et al., 1997, 2002; O'Connell et al., 1995; Ketter et al.,2001; Migliorelli et al., 1993; Buchsbaum et al., 1986;Cohen et al., 1989; Delvenne et al., 1990; Ketter andDrevets, 2002; Kruger et al., 2003). In this regard,increased white matter hyperintensities, which are con-sidered to be related to vascular pathology, have often beenobserved in bipolar illness (Altshuler et al., 1995; Breeze etal., 2003; Silverstone et al., 2003; Pillai et al., 2002).

Perfusion weighted imaging (PWI) is a relativelyrecent non-invasive technique capable of exploring thecerebral vascular organization by means of dynamicacquisitions of a contrast medium. PWI is sensitive tolocal changes in regional cerebral perfusion during thefirst-passage of the paramagnetic contrast bolus throughthe brain capillaries, which leads to a transient loss insignal. As compared to SPECT, PWI provides informa-tion on cerebral blood volume (CBV) and brainvasculature without exposure to ionizing radiations,with elevated spatial resolution and reduced cost, withthe advantage that this information can be obtainedduring an ordinary clinical MRI session (Edelman et al.,1990; Rosen et al., 1990). Therefore, PWI is a usefulcomplementary technique to conventional MRI toinvestigate brain micro-hemodynamic abnormalities inbipolar disorder, which may play a key role, along withstructural and functional components, to further under-stand the pathophysiology of the disease. Indeed, bloodsupply is crucial in sustaining neural integrity, energyand activation (Hanson and Gottesman, 2005). Thus,cerebral hemodynamic alterations may in part sustainfine cytoarchitectural and cellular abnormalities, ulti-mately representing the vascular basis potentially ac-companying structural and biochemical abnormalities inbipolar disorder.

In this study, for the first time, we investigated cerebrallobe perfusion with PWI in bipolar disorder in order tofurther explore the vascular component to the pathophy-

siology of the illness. We expected, based on previouslypublished findings, increased cerebral perfusion in bipolarpatients, particularly in frontal and temporal lobes, whichwould complement previous imaging findings.

2. Methods

2.1. Participants

Fourteen patients with DSM-IV bipolar disorder(mean age±SD=49.00±12.30 years; 6 males, 8 females;all Caucasians; three depressed, four hypomanic, andseven euthymic; 10 bipolar type I, 4 bipolar type II) and 29normal controls (mean age±SD=45.07±10.30 years; 13males, 16 females; all Caucasians) were studied (Table 1).Patients were recruited from the South-Verona PsychiatricCare Register (PCR) (Amaddeo et al., 1997; Tansella andBurti, 2003), a community-based mental health register.The clinical diagnosis of bipolar disorder was confirmedusing the IGC-SCAN Item Group Checklist of theSchedule for Clinical Assessment in Neuropsychiatry(IGC-SCAN) (World Health Organization, 1992). TheIGC is a semi-structured standardized checklist of theSCAN encompassing 41 psychopathological item groups(World Health Organization, 1992; Wing et al., 1990),each of them including several symptoms. Trainedresearch clinical psychologists, with extensive experiencein doing SCAN, had to be fully reliable with a seniorinvestigator, achieving similar diagnoses for at least 8 outof 10 IGC-SCAN. Moreover, the psychopathologicalitem groups completed by the raters were compared in

108 N. Agarwal et al. / Journal of Affective Disorders 110 (2008) 106–114

order to discuss any major symptom discrepancies.Also, we regularly assured reliability of the IGC-SCANdiagnoses by holding consensus meeting with treatingpsychiatrists and a senior investigator. The Italian versionof the SCAN was edited by our group (Tansella andNardini, 1996) and our investigators attended specifictraining courses held by official trainers in order to learnhow to administer the IGC-SCAN. Subsequently, diag-noses for bipolar disorder were also double-checked withthe clinical consensus of two staff psychiatrists, accordingto the DSM IV criteria. Patients with other Axis Idisorders, alcohol or substance abuse, history of traumatichead injury with loss of consciousness, epilepsy or otherneurological or medical diseases, including hypertensionand diabetes, were excluded from the study. All patients,except one, were receiving psychotropic medications andnone of them was on any cardiovascular drug at the timeof imaging, including β-blockers or nitrates. Specifically,they were taking one or more of the following medica-tions: lithium (n=6), antipsychotics (n=7), valproic acid(n=1), SSRIs (n=3), or benzodiazapines (n=7). Femalepatients were not taking contraceptives. Patients' clinicalinformationwas retrieved frompsychiatric interviews, theattending psychiatrist, and medical charts. Clinicalsymptomswere characterized using theHamiltonDepres-sion Rating Scale (HDRS) and the Bech–RafaelsenMania Rating Scale (BRMRS). Symptom rating relia-bility was established and monitored utilizing similarprocedures as to the IGC-SCAN.

Control individuals had no DSM-IV axis I disorders,as determined by a brief interview modified from theSCID-IV non-patient version (SCID-NP), no history ofpsychiatric disorders among first-degree relatives, nohistory of alcohol or substance abuse, no history ofhead injury, and no current neurological or medicalillness, including hypertension and diabetes. They weresubjects undergoing MR scanning for dizziness withoutevidence of central nervous system abnormalities onthe serial conventional MR images and on the pre- andpost-contrast MR acquisitions, as reviewed by theneuroradiologist (R.C.). Dizziness was of peripheralorigin due to benign paroxysmal positional vertigoor to non-toxic labyrinthitis. All control individualscompletely recovered at the time of MR scanning andwere considered for the purposes of this study onlyafter a full medical history and general neurologic,otoscopic, and physical examination. Also, none ofthem was on medication at the time of participationin the study, including drugs for nausea or vertigo orcontraceptives.

This research study was approved by the biomedicalEthics Committee of the Azienda Ospedaliera di Verona.

All subjects provided signed informed consent, afterhaving understood all issues involved in studyparticipation.

2.2. MRI procedure

MRI scans were acquired with a 1.5 T SiemensMagnetom Symphony Maestro Class, Syngo MR 2002B.A standard head coil was used for RF transmission andreception of theMR signal and restraining foam pads wereutilized for minimizing head motion. T1-weighted imageswere first obtained to verify subject's head position andimage quality (TR=450 ms, TE=14 ms, flip angle=90°,FOV= 230×230, slice thickness = 5 mm, matrixsize=384×512, NEX=2). PD/T2-weighted images werethen acquired (TR=2500 ms, TE=24/121 ms, flipangle=180°, FOV=230×230, slice thickness=5 mm,matrix size=410×512, NEX=2), according to an axialplane parallel to the anterior–posterior commissure (AC–PC), for clinical neurodiagnostic evaluations (exclusion offocal lesions). Perfusion-weighted acquisitions, consistingof echo-planar imaging of T2-weighted sequence, wereacquired in the axial plane parallel to the AC–PC line(20 sequential images for 60 repetitions, TR=2160 ms,TE=47 ms, FOV=230×230, slice thickness=5 mm,matrix size=256×256, NEX=1, EPI factor=128) imme-diately before, during, and after injection of a bolus ofGadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), a paramagnetic agent with intravascular spacedistribution. Contrast material (0.1 mmol/kg) administra-tion was started after 4 s by power injector (MedradSpectris MR injector) through an 18 or 20-gaugeangiocatheter through the right antecubital vein at a rateof 2.5mL/s, followed immediately by 25mLof continuoussaline flush. The same neuroradiologist (R.C.) controlledtiming and accuracy of gadolinium administration for allpatients and controls. Finally, a post-contrast sequence wasalso collected in the axial plane in order to exclude forpossible focal lesions (spin echo T1-weighted images,TR=448 ms, TE=14 ms, slice thickness=5 mm, matrixsize=384×512). Normal controls and patients with bipolardisorder completed the MRI session without any apparenthyperventilation due to anxiety reaction. Indeed, in order tominimize any possible anxiety symptoms, fellows fromour research group carefully provided full information onMRI and personally accompanied subjects at the MRcenter, waiting for them until the end of the session.

2.3. Post-processing and image analysis

Raw echo-planar data of the images were firsttransferred to a commercial workstation and semi-

Fig. 1. Regions of interest placed in cortical lobes with respective contrast enhancement. A) Frontal lobe, B) Temporal lobe, C) Parietal lobe, D) Occipital lobe.

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automatically processed by using in-house softwarewritten in MATLab (version 7; The Mathworks Inc.,Natick, MA), as per a method previously described(Brambilla et al., 2007b). From the signal of intensity(SI)/time data, the contrast enhancement (CE) fordefined regions of interest (ROI) was calculated pixelper pixel as the maximum signal drop of the SI/timecurve (Fig. 1). Motion correction was not incorporatedin the processing algorithm, however image distortionsdue to motion effects were not detected in our dataset.Specifically, CE quantitatively describes the peakcontrast enhancement and qualitatively provides aninverse estimation of CBV. CE was calculated as theratio between the minimum signal value (i.e. themaximum signal intensity, SI, drop) during the firstpassage of contrast bolus (Sm) and the baseline pre-bolus signal value of the SI/time curve (So) (CE=Sm/So×100, given as a percentage) for bilateral frontal,temporal, parietal, occipital lobes on two axial images.Lower CE values correspond to higher CBV andviceversa. The peak height of contrast enhancementhas previously been used as a reliable measure of CBVin various brain lesions, such as cerebral tumours orstroke (Berchtenbreiter et al., 1999; Cha et al., 2000;Derex et al., 2004).

ROI corresponded to right and left frontal, temporal,parietal and occipital cortex and were hand-drawn ontwo axial perfusion-weighted image (Fig. 1). Allmeasurements were obtained manually by a trainedevaluator, who was blind to the diagnosis of bipolardisorder and to subjects' identity. The intra-classcorrelation coefficients (ICCs), which were calculatedby having two independent raters trace 10 scans, werehigher than 0.90 for all CE values. The temporal and theoccipital lobes were traced in the first slice where thepreoccipital scissura was visible and in the followingone. The frontal cortex was traced in the two sliceswhere the superior frontal sulcus was clearly visible; the

Table 2Lobar percentage of contrast enhancement in normal subjects and bipolar pa

Contrast enhancement (%) Normal subjects (N=29) Bipola

Right frontal cortex 70.25±5.13 67.79Left frontal cortex 70.76±5.30 66.68Right temporal cortex 67.74±4.77 64.36Left temporal cortex 69.17±4.64 65.26Right parietal cortex 71.55±4.33 69.73Left parietal cortex 71.66±4.38 69.28Right occipital cortex 71.50±4.85 68.83Left occipital cortex 72.29±4.07 68.77

ANCOVA analyses were performed for right and left hemisphere contrast enha(CE) as covariates.

parietal lobe was detected in the last slice where corpuscallosum and lateral ventricles were visible and in thenext one, the postcentral sulcus was used as a landmark.The CE for each lobe was obtained as the mean value ofthe corresponding right and left side from the twoselected slices and the laterality index was calculatedaccording to the following formula: (right-left CE)/(right+left CE)×100.

2.4. Statistical analyses

All analyses were conducted using the SPSSfor Windows software, version 11.0 (SPSS Inc.,Chicago), and the 2-tailed statistical significance levelwas set at pb0.05. Multivariate ANCOVA wasperformed to compare CE measures between patientswith bipolar disorder and normal controls. Pearson'sand Spearman's correlations were used to examine theeffects of age and clinical variables on CE values,respectively.

3. Results

None of the subjects reported any adverse reaction torapid power injection of the contrast material andsusceptibility artifacts inherent in echo-planar imagingdid not interfere with imaging or post-processing.Compared to normal controls, patients with bipolardisorder had significantly lower CE values for leftfrontal and temporal lobes (F=7.22, df=1/38, p=0.01;F=4.97, df=1/38, p=0.03, respectively; multivariateANCOVA, age, gender and mean total brain CE ascovariates) (Table 2, Fig. 2). CE inversely estimates thecerebral blood volume (CBV), being high when theCBV is low and viceversa; therefore patients withbipolar disorder had significantly higher left fronto-temporal CBV in comparison to controls. The lateralityindex was significantly inverse in patients with bipolar

tients

r disorder patients (N=14) Statistics (df=1/38) p

±6.33 F=0.74 0.40±7.34 F=7.22 0.01±5.88 F=3.16 0.08±5.76 F=4.97 0.03±4.98 F=0.05 0.82±5.29 F=0.35 0.56±6.50 F=0.29 0.59±6.69 F=2.52 0.12

ncement, using age, gender, and mean total brain contrast enhancement

Fig. 2. Contrast of enhancement for left frontal and temporal lobes in normal subjects and bipolar disorder patients. A) Left frontal cortex B) Lefttemporal cortex. CE values for left frontal and temporal lobes were significantly lower in patients with bipolar disorder compared to normal controls(F=7.22, p=0.01; F=4.97, p=0.03, respectively; ANCOVA, age, gender and mean total brain CE as covariates).

111N. Agarwal et al. / Journal of Affective Disorders 110 (2008) 106–114

disorder (right greater than left) compared to normalindividuals (left greater than right) for frontal cortex(F=6.12, df=1/38, p=0.017, respectively), but not forother lobes (multivariate ANCOVAwith age and genderas covariates, pN0.05).

CE values did not significantly associate with age inboth groups (Pearson's correlations, pN0.05) and withclinical variables in patients with bipolar illness (i.e. ageat onset, length of illness, number of prior hospitaliza-tions, psychotropic lifetime treatment, lithium dosages,HDRS and BRMRS scores) (Spearman's correlations,pN0.05) (Table 3). Also, no differences were foundfor any CE values amongst euthymic, depressed orhypomanic patients or between smoker (N=7) and non-smoker bipolar subjects (N=7) (multivariate ANCOVA,age, gender and mean total brain CE as covariates,pN0.05).

Table 3Correlations between clinical variables and CE values in patients with bipol

Contrast enhancement (%) Age at onset Length of illness Prior hos

Right frontal cortex 0.18 (0.53) 0.14 (0.64) −0.41 (0Left frontal cortex 0.32 (0.28) 0.11 (0.69) −0.47 (0Right temporal cortex 0.07 (0.81) 0.21 (0.47) −0.32 (0Left temporal cortex −0.02 (0.93) −0.05 (0.85) −0.36 (0Right parietal cortex −0.11 (0.71) 0.32 (0.28) −0.16 (0Left parietal cortex −0.14 (0.64) 0.19 (0.51) −0.15 (0Right occipital cortex −0.05 (0.85) −0.09 (0.74) −0.32 (0Left occipital cortex −0.09 (0.76) 0.10 (0.73) −0.30 (0

HDRS=Hamilton depression rating scale; BRMRS=Bech–Rafaelsen macorrelation coefficients and significance values (in the brackets) are reported

4. Discussion

This study showed regional hyper-perfusion in leftfrontal and temporal lobes in patients with bipolar disorder.To our best knowledge, this is the first time that cerebralblood volumes are investigatedwith non-invasivemagneticresonance technique in bipolar illness. Our findings areconsistent with previous SPECTand PETstudies reportingincreased metabolism and perfusion in prefrontal cortexand temporal structures, specifically in the left hemisphereof bipolar patients (Blumberg et al., 2000; Drevets et al.,2002; O'Connell et al., 1995; Ketter et al., 2001; Ketter andDrevets, 2002). Also, the findings of inverse frontalasymmetry index in bipolar patients support the hypothesisthat impaired cerebral asymmetry may in part sustain thepathophysiology of the disease (Brambilla et al., 2003;Klar, 1999; Reite et al., 1999). Interestingly, a recent

ar disorder

pitalizations Psychotropic lifetime HDRS BRMRS

.15) 0.03 (0.93) −0.46 (0.29) 0.20 (0.57)

.10) 0.07 (0.84) −0.42 (0.33) 0.32 (0.36)

.27) 0.23 (0.54) −0.42 (0.33) 0.007 (0.98)

.21) −0.27 (0.47) −0.17 (0.70) −0.27 (0.44)

.58) 0.37 (0.31) −0.10 (0.81) −0.08 (0.82)

.62) 0.07 (0.84) −0.14 (0.75) −0.30 (0.39)

.27) −0.47 (0.19) −0.14 (0.75) −0.32 (0.36)

.31) −0.08 (0.83) −0.17 (0.70) −0.20 (0.57)

nia rating scale. Spearman's correlation analyses were performed,.

112 N. Agarwal et al. / Journal of Affective Disorders 110 (2008) 106–114

SPECT study found hyper-perfusion in left orbitofrontalcortex and superior temporal gyrus in a subject sufferingfrom major depression, who developed manic symptomsafter a right hemispheric stroke (Mimura et al., 2005).Finally, a SPECTstudy found a direct relationship betweenthe degree of severity in executive (prefrontal) functionsand greater perfusion of temporal (and frontal) lobes inindividuals with bipolar disorder (Benabarre et al., 2005).Recently, several fMRI experiments have shown over-activation of prefrontal cortex and temporal structures inbipolar patients in response to emotional stimuli (Changet al., 2004; Elliott et al., 2004; Lawrence et al., 2004;Malhiet al., 2004a,b). Therefore, prefrontal and temporal areasmay be hyper-perfused at rest and over-activated duringemotion modulation in bipolar disorder. In contrast, hypo-perfusion of frontal and temporal lobes have consistentlybeen reported in schizophrenia (Blackwood et al., 1999; Liet al., 2005;Medved et al., 2001;Novak et al., 2005; Suzukiet al., 2005; Vaiva et al., 2002).

Potentially, micro-vascular impairments of prefronto-temporal connections in the left hemisphere may sustainsuch altered neuronal metabolism. Indeed, in humans,under normal conditions, an increase in regionalcerebral blood flow is sustained by increased neuralactivity, providing adequate supply of nutrients to meetincreased metabolic demands (Villringer and Dirnagl,1995). This blood flow augmentation is regulated bydilatory metabolites and other vasoactive substancesreleased by activated neurons and by astrocytes, causinglocal metabolically driven vasodilation and "hyperemia"(Abott, 2002; Paulson, 2002; Harder et al., 2002). Incase of prolonged neuronal activation, sustained pro-duction of vasoactive substances may promote neo-angiogenesis, potentially leading to increased capillarydensity (Harder et al., 2002). Hypothetically, chronicfronto-temporal hyper-activation in bipolar disordermay lead to hyper-perfusion, being potentially sustainedby neo-angiogenesis. However, these observationsremain mainly speculative and further investigationsare needed to explore whether micro-vascular changesmay play a role for the neurobiology of bipolar illness.

There are few caveats which may confound ourfindings. First, the two groups were not a priori matchedfor age and gender. Therefore, although these variableswere taken into consideration in the statistical analyses, ourfindings warrant replication in well-matched groups.Second, the recruitment of controls may represent amethodological limitation, since they were selected fromindividuals undergoing MR scanning for dizziness.However, they were fully recovered at time of imagingand had no evidences of central nervous systemabnormalities. Furthermore, control individuals were not

experiencing a neurological illness, since dizziness wasdue to benign paroxysmal positional vertigo or to non-toxic labyrinthitis, having no direct influences on brainperfusion or intracranial vasculature organization (Swartzand Longwell, 2005; Bruzzone et al., 2004). Third, ourpatients were being treated with psychotropic drugs at thetime of the scanning andwere experiencing different moodepisodes. Nonetheless, no significant effects of medicationlifetime treatment or of mood states were shown on CEmeasures. Similarly, episode type and cigarette smokingdid not significantly affect cerebral blood volumes inbipolar disorder patients. Finally, possible influences ofblood CO2 levels, due to hyperventilation, on CE valuescannot completely be excluded. Anyway, the potentialvasodilatory effect of increased CO2 blood levels wouldhave occurred in both patients and controls, eventuallywithout any confounding effects.

A few considerations must be made with regard tothe PWI technique. It seems to be promising in the studyof brain perfusion because it can be convenientlyinserted in a routine MR session without the use ofionizing radiations. This latter observation is importantas PWI can be repeated in post treatment follow-ups.With respect to SPECT, the costs of MR are relativelylow. While the PWI is still less widely available as aneurodiagnostic tool, the rapid diffusion of highmagnetic field scanners in hospitals and major innova-tions in advanced MR technique could make PWI in thefuture a routine tool to study cerebral perfusion.

In conclusion, increased left fronto-temporal perfusionwas found in bipolar disorder in this study. Longitudinalimaging studies in juvenile and first-episode patients areexpected to further explore brain micro-hemodynamics inpatients with bipolar illness. The understanding of the roleof the vascular component of bipolar disorder wouldprovide a more comprehensive synthesis of the under-lying pathophysiology of the illness.

Role of the funding sourcesThis work was partly supported by a grant from the American

Psychiatric Institute for Research and Education (APIRE); a grant fromthe Italian Ministry for University and Research (PRIN n.2005068874); by StartCup Veneto 2007 and by a grant from theVeneto Region, Italy, (159/03, DGRV n. 4087).

None of these funding agencies had any further role in studydesign; in the collection, analysis and interpretation of data; in thewriting of the report, and in the decision to submit the paper forpublication.

Conflict of InterestNo authors of this manuscript has fees and grants from,

employment by, consultancy for, shared ownership in, or any closerelationship with, an organisation whose interests, financial orotherwise, may by affected by the publication of the paper.

113N. Agarwal et al. / Journal of Affective Disorders 110 (2008) 106–114

Acknowledgements

Part of this work was presented at the StanleyMeeting,Barcelona, Spain, October 2006. This work was partlysupported by grants from the American PsychiatricInstitute for Research and Education, the Italian Ministryfor Education, University and Research (PRIN n.2005068874), StartCup Veneto 2007, and the VenetoRegion, Italy, (159/03, DGRV n. 4087) to Dr. Brambilla.

References

Abott, N., 2002. Astrocyte-endothelial interactions and blood-brainpermeability. J. Anat. 200, 629–638.

Altshuler, L.L., Curran, J.G., Hauser, P., Mintz, J., Denicoff, K., Post,R., 1995. T2 hyperintensities in bipolar disorder: magneticresonance imaging comparison and literature meta-analysis. Am.J. Psychiatry 152, 1139–1144.

Amaddeo, F., Beecham, J., Bonizzato, P., Fenyo, A., Knapp, M.,Tansella, M., 1997. The use of a case register to evaluate the costsof psychiatric care. Acta Psychiatr. Scand. 95, 189–198.

Benabarre, A., Vieta, E., Martínez-Arán, A., Garcia-Garcia, M.,Martín, F., Lomeña, F., Torrent, C., Sánchez-Moreno, J., Colom,F., Reinares, M., Brugue, E., Valdés, M., 2005. Neuropsycholo-gical disturbances and cerebral blood flow in bipolar disorder.Aust. N. Z. J. Psychiatry 39, 227–234.

Berchtenbreiter, C., Bruening, R., Wu, R.H., Penzkofer, H., Weber, J.,Reiser, M., 1999. Comparison of the diagnostic information inrelative cerebral blood volume, maximum concentration, andsubtraction signal intensity maps based on magnetic resonanceimaging of gliomas. Invest. Radiol. 34, 75–81.

Blackwood, D.H., Glabus,M.F., Dunan, J., O'Carroll, R.E.,Muir,W.J.,Ebmeier, K.P., 1999. Altered cerebral perfusion measured bySPECT in relatives of patients with schizophrenia. Correlationswith memory and P300. Br. J. Psychiatry 175, 357–366.

Blumberg, H.P., Stern, E., Martinez, D., Ricketts, S., de Asis, J.,White, T., Epstein, J., McBride, P.A., Eidelberg, D., Kocsis, J.H.,Silbersweig, D.A., 2000. Increased anterior cingulate and caudateactivity in bipolar mania. Biol. Psychiatry 48, 1045–1052.

Brambilla, P., Harenski, K., Nicoletti, M., Mallinger, M.A., Frank, E.,Kupfer, D.J., Keshavan, M.S., Soares, J.C., 2003. MRI study ofcorpus callosum abnormalities in bipolar patients. Biol. Psychiatry54, 1294–1297.

Brambilla, P., Glahn, D.C., Balestrieri, M., Soares, J.C., 2005.Magnetic resonance findings in bipolar disorder. Psychiatr. Clin.North Am. 28, 443–467.

Brambilla, P., Cerini, R., Fabene, P.F., Andreone, N., Rambaldelli, G.,Farace, P., Versace, A., Perlini, C., Pelizza, L., Gasparini, A., Gatti,R., Bellini, M., Dusi, N., Barbui, C., Nosè, M., Tournikioti, K.,Sbarbati, A., Tansella, M., 2007b. Assessment of cerebral bloodvolume in schizophrenia: a magnetic resonance imaging study.J. Psychiatr. Res. 41, 502–510.

Brambilla, P., MacDonald III, A.W., Sassi, R.B., Johnson, M.K.,Mallinger, A.G., Carter, Soares, J.C., 2007a. Context processingperformance in bipolar disorder patients. Bipolar Disord. 9, 230–237.

Breeze, J.L., Hesdorffer, D.C., Hong, X., Frazier, J.A., Renshaw, P.F.,2003. Clinical significance of brain white matter hyperintensitiesin young adults with psychiatric illness. Harv. Rev. Psychiatr. 11,269–283.

Bruzzone, M.G., Grisoli, M., De Simone, T., Regna-Gladin, C.,2004. Neuroradiological features of vertigo. Neurol. Sci. 24,S20–S23.

Buchsbaum, M.S., Wu, J., DeLisi, L.E., Holcomb, H., Kessler, R.,Johnson, J., King, A.C., Hazlett, E., Langston, K., Post, R.M.,1986. Frontal cortex and basal ganglia metabolic rates assessed bypositron emission tomography with [18F]2-deoxyglucose inaffective illness. J. Affect. Disord. 10, 137–152.

Cha, S., Lu, S., Johnson, G., Knopp, E.A., 2000. Dynamicsusceptibility contrast MR imaging: correlation of signal intensitychanges with cerebral blood volume measurements. J. Magn.Reson. Imaging. 11, 114–119.

Chang, K., Adleman, N.E., Dienes, K., Simeonova, D.I., Menon, V.,Reiss, A., 2004. Anomalous prefrontal-subcortical activation infamilial pediatric bipolar disorder: a functional magnetic resonanceimaging investigation. Arch. Gen. Psychiatry 61, 781–792.

Cohen, R.M., Semple, W.E., Gross, M., Nordahl, T.E., King, A.C.,Pickar, D., Post, R.M., 1989. Evidence for common alterations incerebral glucose metabolism in major affective disorders andschizophrenia. Neuropsychopharmacology 2, 241–254.

Delvenne, V., Delecluse, F., Hubain, P.P., Schoutens, A., De Maertelaer,V., Mendlewicz, J., 1990. Regional cerebral blood flow in patientswith affective disorders. Br. J. Psychiatry 157, 359–365.

Derex, L., Hermier, M., Adeleine, P., Pialat, J.B., Wiart, M.,Berthezene, Y., Froment, J.C., Trouillas, P., Nighoghossian, N.,2004. Influence of the site of arterial occlusion on multiple baselinehemodynamic MRI parameters and post-thrombolytic recanaliza-tion in acute stroke. Neuroradiology 46, 883–887.

Drevets, W.C., Price, J.L., Bardgett, M.E., Reich, T., Todd, R.D.,Raichle, M.E., 2002. Glucose metabolism in the amygdala indepression: relationship to diagnostic subtype and plasma cortisollevels. Pharmacol. Biochem. Behav. 71, 431–447.

Drevets, W.C., Price, J.L., Simpson, J.R., Todd, R.D., Reich, T.,Vannier, M., Raichle, M.E., 1997. Subgenual prefrontal cortexabnormalities in mood disorders. Nature 386, 824–827.

Edelman, R.R., Mattle, H.P., Atkinson, D.J., Hill, T., Finn, J.P.,Mayman, C., Ronthal, M., Hoogewoud, H.M., Kleefield, J., 1990.Cerebral blood flow: assessment with dynamic contrast-enhancedT2⁎-weighted MR imaging at 1.5 T. Radiology 176, 211–220.

Elliott, R., Ogilvie, A., Rubinsztein, J.S., Calderon, G., Dolan, R.J.,Sahakian, B.J., 2004. Abnormal ventral frontal response duringperformance of an affective go/no go task in patients with mania.Biol. Psychiatry 55, 1163–1170.

Hanson, D.R., Gottesman, I.I., 2005. Theories of schizophrenia: agenetic-inflammatory-vascular synthesis. BMCmed. genet. 11, 7–24.

Harder, D.R., Zhang, C., Gebremedhin, D., 2002. Astrocytes functionin matching blood flow to metabolic activity. News Physiol. Sci.16, 27–31.

Ketter, T.A., Drevets, W.C., 2002. Neuroimaging studies of bipolardepression: functional neuropathology, treatment effects, andpredictors of clinical response. Clin. Neurosci. Res. 2, 182–192.

Ketter, T.A., Kimbrell, T.A., George, M.S., Dunn, R.T., Speer, A.M.,Benson, B.E., Willis, M.W., Danielson, A., Frye, M.A., Herscov-itch, P., Post, R.M., 2001. Effects of mood and subtype on cerebralglucose metabolism in treatment refractory bipolar disorders. Biol.Psychiatry 49, 97–109.

Klar, A.J., 1999. Genetic models for handedness, brain lateralization,schizophrenia, and manic-depression. Schizophr. Res. 39, 207–218.

Kruger, S., Seminowicz, D., Goldapple, K., Kennedy, S.H., Mayberg,H.S., 2003. State and trait influences on mood regulation in bipolardisorder: blood flow differences with an acute mood challenge.Biol. Psychiatry 54, 1274–1283.

114 N. Agarwal et al. / Journal of Affective Disorders 110 (2008) 106–114

Lawrence, N.S., Williams, A.M., Surguladze, S., Giampietro, V.,Brammer, M.J., Andrew, C., Frangou, S., Ecker, C., Phillips, M.L.,2004. Subcortical and ventral prefrontal cortical neural responsesto facial expressions distinguish patients with bipolar disorder andmajor depression. Biol. Psychiatry 55, 578–587.

Li, X., Tang, J., Wu, Z., Zhao, G., Liu, C., George, M.S., 2005. SPECTstudy of Chinese schizophrenic patients suggests that cerebralhypoperfusion and laterality exist in different ethnic groups. WorldJ. Biol. Psychiatry 6, 98–106.

Malhi, G.S., Lagopoulos, J., Sachdev, P., Mitchell, P.B., Ivanovski, B.,Parker, G.B., 2004a. Cognitive generation of affect in hypomania:an fMRI study. Bipolar Disord. 6, 271–285.

Malhi, G.S., Lagopoulos, J., Ward, P.B., Kumari, V., Mitchell, P.B.,Parker, G.B., Ivanovski, B., Sachdev, P., 2004b. Cognitivegeneration of affect in bipolar depression: an fMRI study. Eur. J.Neurosci. 19, 741–754.

Medved, V., Petrovic, R., Isgum, V., Szirovicza, L., Hotujac, L., 2001.Similarities in the pattern of regional brain dysfunction in negativeschizophrenia and unipolar depression: a single photon emission-computed tomography and auditory evoked potentials study. Prog.Neuropsychopharmacol. Biol. Psychiatry 25, 993–1009.

Migliorelli, R., Starkstein, S.E., Tesón, A., de Quirós, G., Vázquez, S.,Leiguarda, R., Robinson, R.G., 1993. SPECT findings in patientswith primary mania. J. Neuropsychiatry Clin. Neurosci. 5,379–383.

Mimura, M., Nakagome, K., Hirashima, N., Ishiwata, H., Kamijima,K., Shinozuka, A., Matsuda, H., 2005. Left frontotemporalhyperperfusion in a patient with post-stroke mania. PsychiatryRes. 139, 263–267.

Novak, B., Milcinski, M., Grmek, M., Kocmur, M., 2005. Early effectsof treatment on regional cerebral blood flow in first episodeschizophrenia patients evaluated with 99Tc-ECD-SPECT. NeuroEndocrinol. Lett. 26, 685–689.

O'Connell, R.A., Van Heertum, R.L., Luck, D., Yudd, A.P., Cueva, J.E.,Billick, S.B., Cordon, D.J., Gersh, R.J., Masdeu, J.C., 1995. Single-photon emission computed tomography of the brain in acute maniaand schizophrenia. J. Neuroimaging 5, 101–104.

Paulson, O., 2002. Blood brain barrier, brain metabolism and cerebralblood flow. Eur. Neuropsychopharmacol. 12, 465–501.

Pillai, J.J., Friedman, L., Stuve, T.A., Trinidad, S., Jesberger, J.A.,Lewin, J.S., Findling, R.L., Swales, T.P., Schulz, S.C., 2002.Increased presence of white matter hyperintensities in adolescentpatients with bipolar disorder. Psychiatry Res. 114, 51–56.

Reite, M., Teale, P., Rojas, D.C., Arciniegas, D., Sheeder, J., 1999.Bipolar disorder: anomalous brain asymmetry associated withpsychosis. Am. J. Psychiatry 156, 1159–1163.

Rosen, B.R., Belliveau, J.W., Vevea, J.M., Brady, T.J., 1990. Perfusionimaging with NMR contrast agents. Magn. Reson. Med. 14,249–265.

Salvatore, P., Tohen, M., Khalsa, H.M., Baethge, C., Tondo, L.,Baldessarini, R.J., 2007. Longitudinal research on bipolardisorders. Epidemiol. Psichiatr. Soc. 16, 109–117.

Silverstone, T., McPherson, H., Li, Q., Doyle, T., 2003. Deep whitematter hyperintensities in patients with bipolar depression,unipolar depression and age-matched control subjects. BipolarDisord. 5, 53–57.

Suzuki, M., Nohara, S., Hagino, H., Takahashi, T., Kawasaki, Y.,Yamashita, I., Watanabe, N., Seto, H., Kurachi, M., 2005.Prefrontal abnormalities in patients with simple schizophrenia:structural and functional brain-imaging studies in five cases.Psychiatry Res. 140, 157–171.

Swartz, R., Longwell, P., 2005. Treatment of vertigo. Am. Fam. Phys.71, 1115–1122.

Vaiva, G., Cottencin, O., Llorca, P.M., Devos, P., Dupont, S., Mazas,O., Rascle, C., Thomas, P., Steinling, M., Goudemand, M., 2002.Regional cerebral blood flow in deficit/nondeficit types ofschizophrenia according to SDS criteria. Prog. Neuropsychophar-macol. Biol. Psychiatry 26, 481–485.

Tansella, M., Burti, L., 2003. Integrating evaluative research andcommunity-based mental health care in Verona, Italy. Br. J.Psychiatry 183, 167–169.

Tansella, M., Nardini, M., 1996. World Health Organization. Schede divalutazione clinica in neuropsichiatria. SCAN 2.1. Il PensieroScientifico Editore, Roma, Italy.

Villringer, A., Dirnagl, U., 1995. Coupling of brain activity andcerebral blood flow: basis of functional neuroimaging. Cerebro-vasc. Brain Metab. Rev. 7, 240–276.

Wing, J.K., Babor, T., Brugha, T., Burke, J., Cooper, J.E., Giel, R.,Jablenski, A., Regier, D., Sartorius, N., 1990. SCAN. Schedulesfor Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry.47, 589–593.

Yildiz-Yesiloglu, A., Ankerst, D.P., 2006. Neurochemical alterationsof the brain in bipolar disorder and their implications forpathophysiology: a systematic review of the in vivo protonmagnetic resonance spectroscopy findings. Prog. Neuropsycho-pharmacol. Biol. Psychiatry. 30, 969–995.

Yurgelun-Todd, D.A., Ross, A.J., 2006. Functional magnetic reso-nance imaging studies in bipolar disorder. CNS Spectr. 11,287–297.