Increased fronto-temporal perfusion in bipolar disorder

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Journal of Affective Disorders 110 (2008) 106 – 114

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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,⁎ b c

a Department of Medical and Morphological Researches, Section of Radiology, University of Udine, Udine, Italy Verona-Udine Brain Imaging and Neuropsychology Program, Inter-University Center for Behavioural Neurosciences, University of Udine, Italy 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, Italy e 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, Italy g 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 2008 Available online 21 February 2008

Abstract Objectives: Previous imaging reports showed over-activation of fronto-limbic structures in bipolar patients, particularly in response to emotional stimuli. In this study, for the first time, we used perfusion weighted imaging (PWI) to analyze lobar cerebral blood volume (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 normal controls (mean age ± SD = 45.07 ± 10.30 years; 13 males, 16 females) were studied. PWI images were obtained following intravenous injection of paramagnetic contrast agent (Gadolinium-DTPA), with a 1.5 T Siemens magnet using an echo-planar sequence. The contrast of enhancement (CE), was calculated pixel by pixel as the ratio of the maximum signal intensity drop during 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 correlations between CE measure and age or clinical variables were found (p N 0.05). Conclusion: This study found increased left frontal and temporal CBV in bipolar disorder. Fronto-temporal hyper-perfusion may sustain 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 Medicina Clinica e Sperimentale, Cattedra di Psichiatria, Policlinico Universitario, Via Colugna 50, 33100 Udine, Italy. Tel.: +39 0432 55 9494; fax: +39 0432 54 5526. E-mail address: [email protected] (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 disabling psychiatric illness characterized by depressive, manic, and euthymic phases along with cognitive disturbances

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(Brambilla et al., 2007a; Salvatore et al., 2007). An altered anterior-limbic network including dorsolateral prefrontal cortex, anterior cingulate and amygdala has been suggested to be involved in the pathophysiology of the disease (Brambilla et al., 2005). Indeed, functional and biochemical abnormalities and over-activation of prefrontal areas and limbic structures during emotional tasks have consistently been reported in patients suffering from bipolar illness (Yildiz-Yesiloglu and Ankerst, 2006; Yurgelun-Todd and Ross, 2006). Furthermore, increased prefronto-limbic metabolism and perfusion have been shown in some positron emission tomography (PET) and single photon emission computed tomography (SPECT) reports in bipolar disorder, specifically in the left hemisphere, suggesting potential vascular abnormalities (Drevets 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 and Drevets, 2002; Kruger et al., 2003). In this regard, increased white matter hyperintensities, which are considered to be related to vascular pathology, have often been observed in bipolar illness (Altshuler et al., 1995; Breeze et al., 2003; Silverstone et al., 2003; Pillai et al., 2002). Perfusion weighted imaging (PWI) is a relatively recent non-invasive technique capable of exploring the cerebral vascular organization by means of dynamic acquisitions of a contrast medium. PWI is sensitive to local changes in regional cerebral perfusion during the first-passage of the paramagnetic contrast bolus through the brain capillaries, which leads to a transient loss in signal. As compared to SPECT, PWI provides information on cerebral blood volume (CBV) and brain vasculature without exposure to ionizing radiations, with elevated spatial resolution and reduced cost, with the advantage that this information can be obtained during an ordinary clinical MRI session (Edelman et al., 1990; Rosen et al., 1990). Therefore, PWI is a useful complementary technique to conventional MRI to investigate brain micro-hemodynamic abnormalities in bipolar disorder, which may play a key role, along with structural and functional components, to further understand the pathophysiology of the disease. Indeed, blood supply is crucial in sustaining neural integrity, energy and activation (Hanson and Gottesman, 2005). Thus, cerebral hemodynamic alterations may in part sustain fine cytoarchitectural and cellular abnormalities, ultimately representing the vascular basis potentially accompanying structural and biochemical abnormalities in bipolar disorder. In this study, for the first time, we investigated cerebral lobe perfusion with PWI in bipolar disorder in order to further explore the vascular component to the pathophy-


siology of the illness. We expected, based on previously published findings, increased cerebral perfusion in bipolar patients, particularly in frontal and temporal lobes, which would 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, and seven euthymic; 10 bipolar type I, 4 bipolar type II) and 29 normal controls (mean age ± SD = 45.07 ± 10.30 years; 13 males, 16 females; all Caucasians) were studied (Table 1). Patients were recruited from the South-Verona Psychiatric Care Register (PCR) (Amaddeo et al., 1997; Tansella and Burti, 2003), a community-based mental health register. The clinical diagnosis of bipolar disorder was confirmed using the IGC-SCAN Item Group Checklist of the Schedule for Clinical Assessment in Neuropsychiatry (IGC-SCAN) (World Health Organization, 1992). The IGC is a semi-structured standardized checklist of the SCAN encompassing 41 psychopathological item groups (World Health Organization, 1992; Wing et al., 1990), each of them including several symptoms. Trained research clinical psychologists, with extensive experience in doing SCAN, had to be fully reliable with a senior investigator, achieving similar diagnoses for at least 8 out of 10 IGC-SCAN. Moreover, the psychopathological item groups completed by the raters were compared in Table 1 Demographic and clinical variables for bipolar and normal subjects

Age (years) Males/females Race Age at onset (years) Length of illness (years) Number of hospitalizations Lifetime psychotropic treatment (years) HDRS BRMRS

Normal controls (N = 29)

Bipolar disorder Statistics p patients (N = 14)

45.31 ± 10.35 13/16 Caucasian –

49.00 ± 12.30 6/8 Caucasian 33.69 ± 14.64

14.15 ± 12.88

3.53 ± 3.41

14.22 ± 11.68

– –

6.89 ± 5.82 1.00 ± 1.76

t = 1.03 0.31 χ2 = 0.01 0.91

HDRS = Hamilton Depression Rating Scale; BRMRS = Bech–Rafaelsen Mania Rating Scale.


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order to discuss any major symptom discrepancies. Also, we regularly assured reliability of the IGC-SCAN diagnoses by holding consensus meeting with treating psychiatrists and a senior investigator. The Italian version of the SCAN was edited by our group (Tansella and Nardini, 1996) and our investigators attended specific training courses held by official trainers in order to learn how to administer the IGC-SCAN. Subsequently, diagnoses for bipolar disorder were also double-checked with the clinical consensus of two staff psychiatrists, according to the DSM IV criteria. Patients with other Axis I disorders, alcohol or substance abuse, history of traumatic head injury with loss of consciousness, epilepsy or other neurological or medical diseases, including hypertension and diabetes, were excluded from the study. All patients, except one, were receiving psychotropic medications and none of them was on any cardiovascular drug at the time of imaging, including β-blockers or nitrates. Specifically, they were taking one or more of the following medications: lithium (n = 6), antipsychotics (n = 7), valproic acid (n = 1), SSRIs (n = 3), or benzodiazapines (n = 7). Female patients were not taking contraceptives. Patients' clinical information was retrieved from psychiatric interviews, the attending psychiatrist, and medical charts. Clinical symptoms were characterized using the Hamilton Depression Rating Scale (HDRS) and the Bech–Rafaelsen Mania Rating Scale (BRMRS). Symptom rating reliability was established and monitored utilizing similar procedures as to the IGC-SCAN. Control individuals had no DSM-IV axis I disorders, as determined by a brief interview modified from the SCID-IV non-patient version (SCID-NP), no history of psychiatric disorders among first-degree relatives, no history of alcohol or substance abuse, no history of head injury, and no current neurological or medical illness, including hypertension and diabetes. They were subjects undergoing MR scanning for dizziness without evidence of central nervous system abnormalities on the serial conventional MR images and on the pre- and post-contrast MR acquisitions, as reviewed by the neuroradiologist (R.C.). Dizziness was of peripheral origin due to benign paroxysmal positional vertigo or to non-toxic labyrinthitis. All control individuals completely recovered at the time of MR scanning and were considered for the purposes of this study only after a full medical history and general neurologic, otoscopic, and physical examination. Also, none of them was on medication at the time of participation in the study, including drugs for nausea or vertigo or contraceptives. This research study was approved by the biomedical Ethics Committee of the Azienda Ospedaliera di Verona.

All subjects provided signed informed consent, after having understood all issues involved in study participation. 2.2. MRI procedure MRI scans were acquired with a 1.5 T Siemens Magnetom Symphony Maestro Class, Syngo MR 2002B. A standard head coil was used for RF transmission and reception of the MR signal and restraining foam pads were utilized for minimizing head motion. T1-weighted images were first obtained to verify subject's head position and image quality (TR = 450 ms, TE = 14 ms, flip angle = 90°, FOV = 230×230, slice thickness = 5 mm, matrix size = 384×512, NEX = 2). PD/T2-weighted images were then acquired (TR = 2500 ms, TE = 24/121 ms, flip angle = 180°, FOV = 230×230, slice thickness = 5 mm, matrix size= 410×512, NEX = 2), according to an axial plane parallel to the anterior–posterior commissure (AC– PC), for clinical neurodiagnostic evaluations (exclusion of focal lesions). Perfusion-weighted acquisitions, consisting of echo-planar imaging of T2-weighted sequence, were acquired 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) immediately before, during, and after injection of a bolus of Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA), a paramagnetic agent with intravascular space distribution. Contrast material (0.1 mmol/kg) administration was started after 4 s by power injector (Medrad Spectris MR injector) through an 18 or 20-gauge angiocatheter through the right antecubital vein at a rate of 2.5 mL/s, followed immediately by 25 mL of continuous saline flush. The same neuroradiologist (R.C.) controlled timing and accuracy of gadolinium administration for all patients and controls. Finally, a post-contrast sequence was also collected in the axial plane in order to exclude for possible focal lesions (spin echo T1-weighted images, TR = 448 ms, TE = 14 ms, slice thickness = 5 mm, matrix size = 384×512). Normal controls and patients with bipolar disorder completed the MRI session without any apparent hyperventilation due to anxiety reaction. Indeed, in order to minimize any possible anxiety symptoms, fellows from our research group carefully provided full information on MRI and personally accompanied subjects at the MR center, waiting for them until the end of the session. 2.3. Post-processing and image analysis Raw echo-planar data of the images were first transferred to a commercial workstation and semi-

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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 software written 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) for defined regions of interest (ROI) was calculated pixel per pixel as the maximum signal drop of the SI/time curve (Fig. 1). Motion correction was not incorporated in the processing algorithm, however image distortions due to motion effects were not detected in our dataset. Specifically, CE quantitatively describes the peak contrast enhancement and qualitatively provides an inverse estimation of CBV. CE was calculated as the ratio between the minimum signal value (i.e. the maximum signal intensity, SI, drop) during the first passage of contrast bolus (Sm) and the baseline prebolus 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 and viceversa. The peak height of contrast enhancement has previously been used as a reliable measure of CBV in various brain lesions, such as cerebral tumours or stroke (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 on two axial perfusion-weighted image (Fig. 1). All measurements were obtained manually by a trained evaluator, who was blind to the diagnosis of bipolar disorder and to subjects' identity. The intra-class correlation coefficients (ICCs), which were calculated by having two independent raters trace 10 scans, were higher than 0.90 for all CE values. The temporal and the occipital lobes were traced in the first slice where the preoccipital scissura was visible and in the following one. The frontal cortex was traced in the two slices where the superior frontal sulcus was clearly visible; the

parietal lobe was detected in the last slice where corpus callosum and lateral ventricles were visible and in the next one, the postcentral sulcus was used as a landmark. The CE for each lobe was obtained as the mean value of the corresponding right and left side from the two selected slices and the laterality index was calculated according to the following formula: (right-left CE)/ (right+left CE)×100. 2.4. Statistical analyses All analyses were conducted using the SPSS for Windows software, version 11.0 (SPSS Inc., Chicago), and the 2-tailed statistical significance level was set at p b 0.05. Multivariate ANCOVA was performed to compare CE measures between patients with bipolar disorder and normal controls. Pearson's and Spearman's correlations were used to examine the effects of age and clinical variables on CE values, respectively. 3. Results None of the subjects reported any adverse reaction to rapid power injection of the contrast material and susceptibility artifacts inherent in echo-planar imaging did not interfere with imaging or post-processing. Compared to normal controls, patients with bipolar disorder had significantly lower CE values for left frontal and temporal lobes (F = 7.22, df = 1/38, p = 0.01; F = 4.97, df = 1/38, p = 0.03, respectively; multivariate ANCOVA, age, gender and mean total brain CE as covariates) (Table 2, Fig. 2). CE inversely estimates the cerebral blood volume (CBV), being high when the CBV is low and viceversa; therefore patients with bipolar disorder had significantly higher left frontotemporal CBV in comparison to controls. The laterality index was significantly inverse in patients with bipolar

Table 2 Lobar percentage of contrast enhancement in normal subjects and bipolar patients Contrast enhancement (%)

Normal subjects (N = 29)

Bipolar disorder patients (N = 14)

Statistics (df = 1/38)


Right frontal cortex Left frontal cortex Right temporal cortex Left temporal cortex Right parietal cortex Left parietal cortex Right occipital cortex Left occipital cortex

70.25 ± 5.13 70.76 ± 5.30 67.74 ± 4.77 69.17 ± 4.64 71.55 ± 4.33 71.66 ± 4.38 71.50 ± 4.85 72.29 ± 4.07

67.79 ± 6.33 66.68 ± 7.34 64.36 ± 5.88 65.26 ± 5.76 69.73 ± 4.98 69.28 ± 5.29 68.83 ± 6.50 68.77 ± 6.69

F = 0.74 F = 7.22 F = 3.16 F = 4.97 F = 0.05 F = 0.35 F = 0.29 F = 2.52

0.40 0.01 0.08 0.03 0.82 0.56 0.59 0.12

ANCOVA analyses were performed for right and left hemisphere contrast enhancement, using age, gender, and mean total brain contrast enhancement (CE) as covariates.

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Fig. 2. Contrast of enhancement for left frontal and temporal lobes in normal subjects and bipolar disorder patients. A) Left frontal cortex B) Left temporal 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).

disorder (right greater than left) compared to normal individuals (left greater than right) for frontal cortex (F = 6.12, df = 1/38, p = 0.017, respectively), but not for other lobes (multivariate ANCOVA with age and gender as covariates, p N 0.05). CE values did not significantly associate with age in both groups (Pearson's correlations, p N 0.05) and with clinical variables in patients with bipolar illness (i.e. age at onset, length of illness, number of prior hospitalizations, psychotropic lifetime treatment, lithium dosages, HDRS and BRMRS scores) (Spearman's correlations, p N 0.05) (Table 3). Also, no differences were found for any CE values amongst euthymic, depressed or hypomanic patients or between smoker (N = 7) and nonsmoker bipolar subjects (N = 7) (multivariate ANCOVA, age, gender and mean total brain CE as covariates, p N 0.05).

4. Discussion This study showed regional hyper-perfusion in left frontal and temporal lobes in patients with bipolar disorder. To our best knowledge, this is the first time that cerebral blood volumes are investigated with non-invasive magnetic resonance technique in bipolar illness. Our findings are consistent with previous SPECT and PET studies reporting increased metabolism and perfusion in prefrontal cortex and temporal structures, specifically in the left hemisphere of bipolar patients (Blumberg et al., 2000; Drevets et al., 2002; O'Connell et al., 1995; Ketter et al., 2001; Ketter and Drevets, 2002). Also, the findings of inverse frontal asymmetry index in bipolar patients support the hypothesis that impaired cerebral asymmetry may in part sustain the pathophysiology of the disease (Brambilla et al., 2003; Klar, 1999; Reite et al., 1999). Interestingly, a recent

Table 3 Correlations between clinical variables and CE values in patients with bipolar disorder Contrast enhancement (%)

Age at onset

Length of illness

Prior hospitalizations

Psychotropic lifetime



Right frontal cortex Left frontal cortex Right temporal cortex Left temporal cortex Right parietal cortex Left parietal cortex Right occipital cortex Left occipital cortex

0.18 (0.53) 0.32 (0.28) 0.07 (0.81) −0.02 (0.93) − 0.11 (0.71) −0.14 (0.64) −0.05 (0.85) −0.09 (0.76)

0.14 (0.64) 0.11 (0.69) 0.21 (0.47) −0.05 (0.85) 0.32 (0.28) 0.19 (0.51) −0.09 (0.74) 0.10 (0.73)

− 0.41 (0.15) − 0.47 (0.10) − 0.32 (0.27) − 0.36 (0.21) − 0.16 (0.58) − 0.15 (0.62) − 0.32 (0.27) − 0.30 (0.31)

0.03 (0.93) 0.07 (0.84) 0.23 (0.54) − 0.27 (0.47) 0.37 (0.31) 0.07 (0.84) − 0.47 (0.19) − 0.08 (0.83)

− 0.46 (0.29) − 0.42 (0.33) − 0.42 (0.33) − 0.17 (0.70) − 0.10 (0.81) − 0.14 (0.75) − 0.14 (0.75) − 0.17 (0.70)

0.20 (0.57) 0.32 (0.36) 0.007 (0.98) − 0.27 (0.44) − 0.08 (0.82) − 0.30 (0.39) − 0.32 (0.36) − 0.20 (0.57)

HDRS = Hamilton depression rating scale; BRMRS = Bech–Rafaelsen mania rating scale. Spearman's correlation analyses were performed, correlation coefficients and significance values (in the brackets) are reported.


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SPECT study found hyper-perfusion in left orbitofrontal cortex and superior temporal gyrus in a subject suffering from major depression, who developed manic symptoms after a right hemispheric stroke (Mimura et al., 2005). Finally, a SPECT study found a direct relationship between the degree of severity in executive (prefrontal) functions and greater perfusion of temporal (and frontal) lobes in individuals with bipolar disorder (Benabarre et al., 2005). Recently, several fMRI experiments have shown overactivation of prefrontal cortex and temporal structures in bipolar patients in response to emotional stimuli (Chang et al., 2004; Elliott et al., 2004; Lawrence et al., 2004; Malhi et al., 2004a,b). Therefore, prefrontal and temporal areas may be hyper-perfused at rest and over-activated during emotion modulation in bipolar disorder. In contrast, hypoperfusion of frontal and temporal lobes have consistently been reported in schizophrenia (Blackwood et al., 1999; Li et al., 2005; Medved et al., 2001; Novak et al., 2005; Suzuki et al., 2005; Vaiva et al., 2002). Potentially, micro-vascular impairments of prefrontotemporal connections in the left hemisphere may sustain such altered neuronal metabolism. Indeed, in humans, under normal conditions, an increase in regional cerebral blood flow is sustained by increased neural activity, providing adequate supply of nutrients to meet increased metabolic demands (Villringer and Dirnagl, 1995). This blood flow augmentation is regulated by dilatory metabolites and other vasoactive substances released by activated neurons and by astrocytes, causing local metabolically driven vasodilation and "hyperemia" (Abott, 2002; Paulson, 2002; Harder et al., 2002). In case of prolonged neuronal activation, sustained production of vasoactive substances may promote neoangiogenesis, potentially leading to increased capillary density (Harder et al., 2002). Hypothetically, chronic fronto-temporal hyper-activation in bipolar disorder may lead to hyper-perfusion, being potentially sustained by neo-angiogenesis. However, these observations remain mainly speculative and further investigations are needed to explore whether micro-vascular changes may play a role for the neurobiology of bipolar illness. There are few caveats which may confound our findings. First, the two groups were not a priori matched for age and gender. Therefore, although these variables were taken into consideration in the statistical analyses, our findings warrant replication in well-matched groups. Second, the recruitment of controls may represent a methodological limitation, since they were selected from individuals undergoing MR scanning for dizziness. However, they were fully recovered at time of imaging and had no evidences of central nervous system abnormalities. Furthermore, control individuals were not

experiencing a neurological illness, since dizziness was due to benign paroxysmal positional vertigo or to nontoxic labyrinthitis, having no direct influences on brain perfusion or intracranial vasculature organization (Swartz and Longwell, 2005; Bruzzone et al., 2004). Third, our patients were being treated with psychotropic drugs at the time of the scanning and were experiencing different mood episodes. Nonetheless, no significant effects of medication lifetime treatment or of mood states were shown on CE measures. Similarly, episode type and cigarette smoking did not significantly affect cerebral blood volumes in bipolar disorder patients. Finally, possible influences of blood CO2 levels, due to hyperventilation, on CE values cannot completely be excluded. Anyway, the potential vasodilatory effect of increased CO2 blood levels would have occurred in both patients and controls, eventually without any confounding effects. A few considerations must be made with regard to the PWI technique. It seems to be promising in the study of brain perfusion because it can be conveniently inserted in a routine MR session without the use of ionizing radiations. This latter observation is important as PWI can be repeated in post treatment follow-ups. With respect to SPECT, the costs of MR are relatively low. While the PWI is still less widely available as a neurodiagnostic tool, the rapid diffusion of high magnetic field scanners in hospitals and major innovations in advanced MR technique could make PWI in the future a routine tool to study cerebral perfusion. In conclusion, increased left fronto-temporal perfusion was found in bipolar disorder in this study. Longitudinal imaging studies in juvenile and first-episode patients are expected to further explore brain micro-hemodynamics in patients with bipolar illness. The understanding of the role of the vascular component of bipolar disorder would provide a more comprehensive synthesis of the underlying pathophysiology of the illness. Role of the funding sources This work was partly supported by a grant from the American Psychiatric Institute for Research and Education (APIRE); a grant from the Italian Ministry for University and Research (PRIN n. 2005068874); by StartCup Veneto 2007 and by a grant from the Veneto Region, Italy, (159/03, DGRV n. 4087). None of these funding agencies had any further role in study design; in the collection, analysis and interpretation of data; in the writing of the report, and in the decision to submit the paper for publication. Conflict of Interest No authors of this manuscript has fees and grants from, employment by, consultancy for, shared ownership in, or any close relationship with, an organisation whose interests, financial or otherwise, may by affected by the publication of the paper.

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