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Background: Existing models of the pathophysiology of bipolar disorder posit disruption in neural circuits of emotion regulation and reward processing. However, few fMRI studies have compared regional brain activity and connectivity in different mood states in bipolar disorder to determine if manic symptomatology is reflected in specific circuit abnormalities. The purpose of this study was to test the hypothesis that bipolar mania is associated with altered connectivity between cortical regions thought to regulate subcortical structures such as the amygdala and striatum., Methods: 28 subjects with bipolar disorder in a manic state, 24 different bipolar subjects in a euthymic state, and 23 matched healthy comparison subjects underwent resting state fMRI scans. Several cortical and sub-cortical structures implicated in the pathogenesis of bipolar disorder were selected for study. We conducted a whole-brain analysis of functional connectivity of these regions., Results: Bipolar mania was differentiated from euthymia by decreased functional connectivity between the amygdala and anterior cingulate cortex (ACC). Mania was also characterized by increased connectivity between amygdala and dorsal frontal cortical structures that are normally anti-correlated in emotion regulation tasks., Limitations: Both groups of bipolar subjects were prescribed medications. The study was not longitudinal in design., Conclusions: Compared to bipolar subjects in a euthymic state, subjects in the manic state demonstrate disrupted functional connectivity between brain regions involved in the regulation of emotion and the amygdala. This disruption of activity in neural circuits involved in emotion may underlie the emotional dysregulation inherent to a bipolar manic episode., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities., Methods: In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1 × 3 × 3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants., Results: The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group., Conclusions: The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Schizophrenia is a heterogeneous disorder that may consist of multiple etiologies and disease processes. Auditory hallucinations (AH), which are common and often disabling, represent a narrower and more basic dimension of psychosis than schizophrenia. Previous studies suggest that abnormal primary auditory cortex activity is associated with AH pathogenesis. We thus investigated functional connectivity, using a seed in primary auditory cortex, in schizophrenia patients with and without AH and healthy controls, to examine neural circuit abnormalities associated more specifically with AH than the myriad other symptoms that comprise schizophrenia., Methods: Using resting-state fMRI (rsfMRI), we investigated functional connectivity of the primary auditory cortex, located on Heschl's gyrus, in schizophrenia spectrum patients with AH. Participants were patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder with lifetime AH (n=27); patients with the same diagnoses but no lifetime AH (n=14); and healthy controls (n=28)., Results: Patients with AH vulnerability showed increased left Heschl's gyrus functional connectivity with left frontoparietal regions and decreased functional connectivity with right hippocampal formation and mediodorsal thalamus compared to patients without lifetime AH. Furthermore, among AH patients, left Heschl's gyrus functional connectivity covaried positively with AH severity in left inferior frontal gyrus (Broca's area), left lateral STG, right pre- and postcentral gyri, cingulate cortex, and orbitofrontal cortex. There were no differences between patients with and without lifetime AH in right Heschl's gyrus seeded functional connectivity., Conclusions: Abnormal interactions between left Heschl's gyrus and regions involved in speech/language, memory, and the monitoring of self-generated events may contribute to AH vulnerability., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy.

Objective: Few magnetic resonance imaging (MRI) studies of bipolar disorder (BPD) have investigated the entire cerebral cortex. Cortical gray matter (GM) volume deficits have been reported in some studies of adults with BPD; this study assessed the presence of such deficits in children with BPD., Methods: Thirty-two youths with DSM-IV BPD (mean age 11.2 +/- 2.8 years) and 15 healthy controls (HC) (11.2 +/- 3.0 years) had structured and clinical interviews, neurological examinations, neurocognitive testing, and MRI scanning on a 1.5 T GE Scanner. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere, and these units were combined into frontal (FL), temporal (TL), parietal (PL), and occipital (OL) lobe volumes. Volumetric differences were examined using univariate linear regression models with alpha = 0.05., Results: Relative to controls, the BPD youth had significantly smaller bilateral PL, and left TL. Analysis of PL and TL gyri showed significantly smaller volume in bilateral postcentral gyrus, and in left superior temporal and fusiform gyri, while the parahippocampal gyri were bilaterally increased in the BPD group. Although the FL overall did not differ between groups, an exploratory analysis showed that the right middle frontal gyrus was also significantly smaller in the BPD group., Conclusions: Children with BPD showed deficits in PL and TL cortical GM. Further analyses of the PL and TL found differences in areas involved in attentional control, facial recognition, and verbal and declarative memory. These cortical deficits may reflect early age of illness onset.

Objective: Cleft of the secondary palate without cleft lip is difficult to visualize sonographically. This study was performed to assess the utility of sonography, standard magnetic resonance (MR) imaging, and real-time MR imaging in the diagnosis of isolated cleft palate., Methods: We prospectively assessed 5 fetuses at risk for isolated cleft palate on the basis of family history, micrognathia, or both, using sonography and standard and real-time single-shot fast spin echo MR sequences. Written informed consent was obtained under our Institutional Review Board-approved Health Insurance Portability and Accountability Act-compliant protocol. Images were assessed for confidence in a diagnosis of cleft or normal palate. Prenatal and postnatal diagnoses were compared., Results: In 3 fetuses, micrognathia was visualized by sonography and MR imaging with standard and real-time sequences. One fetus at 19 weeks had a wide cleft of the entire secondary palate, and another fetus at 33 weeks had a cleft of the soft palate; these defects were seen only with real-time MR imaging. One 35-week gestational age fetus had a cleft soft palate that was visualized on standard and real-time MR imaging. Two fetuses with no abnormalities had the normal midline secondary palate seen only on real-time MR imaging. In all fetuses, real-time images were helpful in assessing the secondary palate because the entire midline naso-oropharynx could be visualized., Conclusions: Real-time MR imaging allows for rapid assessment of the midline structures, providing accurate diagnosis of isolated cleft palate.

Background: Youths with bipolar disorder are ideal for studying illness pathophysiology given their early presentation, lack of extended treatment, and high genetic loading. Adult bipolar disorder MRI studies have focused increasingly on limbic structures and the thalamus because of their role in mood and cognition. On the basis of adult studies, the authors hypothesized a priori that youths with bipolar disorder would have amygdalar, hippocampal, and thalamic volume abnormalities., Method: Forty-three youths 6-16 years of age with DSM-IV bipolar disorder (23 male, 20 female) and 20 healthy comparison subjects (12 male, eight female) similar in age and sex underwent structured and clinical interviews, neurological examination, and cognitive testing. Differences in limbic and thalamic brain volumes, on the logarithmic scale, were tested using a two-way (diagnosis and sex) univariate analysis of variance, with total cerebral volume and age controlled., Results: The subjects with bipolar disorder had smaller hippocampal volumes. Further analysis revealed that this effect was driven predominantly by the female bipolar disorder subjects. In addition, both male and female youths with bipolar disorder had significantly smaller cerebral volumes. No significant hemispheric effects were seen., Conclusions: These findings support the hypothesis that the limbic system, in particular the hippocampus, may be involved in the pathophysiology of pediatric bipolar disorder. While this report may represent the largest MRI study of pediatric bipolar disorder to date, more work is needed to confirm these findings and to determine if they are unique to pediatric bipolar disorder.

The objective of the present study was to examine patterns of cortical activation underlying D-cycloserine's therapeutic efficacy in schizophrenic patients using functional magnetic resonance imaging (fMRI). We measured frontal and temporal lobe activation following a word fluency task in 12 subjects meeting DSM-IV criteria for schizophrenia at baseline and after 8 weeks of supervised treatment, using a double-blind, placebo-controlled design. Half of the patients received D-cycloserine (n = 6) as a supplement to their conventional neuroleptic treatment while the other half (n = 6) was augmented with placebo. Patients receiving D-cycloserine, but not placebo, demonstrated a significant increase in temporal lobe activation. This increased activation was significantly associated with a reduction in negative symptoms. These results suggest that the addition of D-cycloserine to conventional neuroleptics may improve negative symptoms through enhanced temporal lobe function.

Objective: The authors hypothesized that changes in brain membrane composition resulting from omega-3 fatty acid administration in patients with bipolar disorder would result in greater membrane fluidity, as detected by reductions in T(2) values., Method: Women with bipolar disorder (N=12) received omega-3 fatty acids for 4 weeks. A cohort of bipolar subjects (N=9) and a group without bipolar disorder (N=12) did not receive omega-3 fatty acids. T(2) values were acquired at baseline and after 4 weeks., Results: Bipolar subjects who received omega-3 fatty acids had significant decreases in T(2). There was a dose-dependent effect when the bipolar omega-3 fatty acid group was subdivided into high- and low-dose cohorts., Conclusions: Omega-3 fatty acids lowered T(2) values, consistent with the hypothesis that the fluidity of cell membranes was altered. Further studies are needed to clarify the significance of alterations in brain physiology induced by omega-3 fatty acids, as reflected in T(2) values.

Alterations in brain high-energy phosphate metabolism, determined by in vivo magnetic resonance spectroscopy (MRS), have been reported in subjects with a number of brain disorders including major depression, schizophrenia, and substance abuse. It is not clear to what extent these changes can be modified by pharmacological or nutritional means. To address this possibility, we evaluated changes in brain chemistry that were associated with oral creatine (Cr) administration. We hypothesized that oral Cr supplementation, by increasing brain creatine and high-energy phosphate stored in phosphocreatine, would result in an increase in the creatine resonance, as measured using proton 1H-MRS, and a decrease in the beta-nucleoside triphosphate (NTP) peak and an increase in the phosphocreatine (PCr) peak, as measured by phosphorus 31P-MRS, in brain of healthy human subjects. Fifteen healthy male subjects (age=22.9+/-2.2; body mass index=22.9+/-1.7), who were without any axis I disorders or physical or neurological illness, were recruited. Ten subjects took creatine-monohydrate, 0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days (creatine group). Five comparison subjects took equivalent amounts of sucrose as placebo (placebo group). Both 1H- and 31P-MRS scans were acquired at baseline, as well as at day 7 and day 14 of oral supplementation. 1H-MRS: Water suppressed localized spectra were acquired using a single-voxel (1.5 cm x 2 cm x 2 cm) proton MRS PRESS sequence in the left frontal lobe. 31P-MRS: Phosphorus spectral data were recorded from a 5-cm-thick axial brain slice using a short-TE slice selective spin-echo pulse sequence. The creatine group had significantly increased brain creatine levels (8.1% and 9.3%, in creatine/N-acetyl aspartate and creatine/choline ratios, respectively) compared to the placebo group over the 2-week period. The creatine group had significantly decreased beta-NTP levels (7.8%) and marginally increased PCr (3.4%) over the same period. In addition, the brain inorganic phosphate level increased over the same period in the creatine group (9.8%). The current study is the first multinuclear (1H and 31P) MRS study to evaluate changes in brain high-energy phosphate metabolism following oral creatine supplementation in healthy human subjects. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including major depression, schizophrenia, cocaine and opiate abuse, where alterations in brain high-energy phosphate metabolism have been reported.

Background: Cerebellar abnormalities, including decreased tissue volume, have been implicated in the pathophysiology of bipolar disorder. Relatively little research has focused on blood flow in the cerebellum of patients with bipolar disorder. Furthermore, the significance of metabolic changes in the brains of psychiatric patients may be confounded by the effects of various pharmacotherapies. Having previously found differences in cerebellar blood volume in patients with bipolar disorder compared to healthy control subjects, this study examined whether some variability in the patient population may be an effect of medication., Methods: In this study, we have examined the association between medication status and cerebellar blood volume. Thirteen healthy comparison subjects and 21 bipolar patients underwent dynamic susceptibility contrast magnetic resonance imaging. Nine cerebellar regions were identified, and the absolute cerebellar blood volume data from each was compared to medication status measures., Results: Patients on conventional antipsychotics had the lowest mean absolute blood volume measures for all cerebellar regions, whereas those on atypical antipsychotics had the highest blood volume measures. Comparison subjects had cerebellar blood volume measures in the middle, with results closer to subjects in the atypical group., Conclusions: This evidence suggests that antipsychotic treatment may influence cerebellar blood volume. This effect will be important in considering imaging studies on medicated patients with bipolar disorder and may suggest novel pathways by which these medications affect their changes.

ObjectivesThis trial examined the efficacy of a stress management program in reducing neuroimaging markers of multiple sclerosis (MS) disease activity.MethodsA total of 121 patients with relapsing forms of MS were randomized to receive stress management therapy for MS (SMT-MS) or a wait-list control condition. SMT-MS provided 16 individual treatment sessions over 24 weeks, followed by a 24-week post-treatment follow-up. The primary outcome was the cumulative number of new gadolinium-enhancing (Gd+) brain lesions on MRI at weeks 8, 16, and 24. Secondary outcomes included new or enlarging T2 MRI lesions, brain volume change, clinical exacerbation, and stress.ResultsSMT-MS resulted in a reduction in cumulative Gd+ lesions (p = 0.04) and greater numbers of participants remained free of Gd+ lesions during the treatment (76.8% vs 54.7%, p = 0.02), compared to participants receiving the control treatment. SMT-MS also resulted in significantly reduced numbers of cumulative new T2 lesions (p = 0.005) and a greater number of participants remaining free of new T2 lesions (69.5% vs 42.7%, p = 0.006). These effects were no longer detectable during the 24-week post-treatment follow-up period.ConclusionsThis trial indicates that SMT-MS may be useful in reducing the development of new MRI brain lesions while patients are in treatment.Classification of evidenceThis study provides Class I evidence that SMT-MS, a manualized stress management therapy program, reduced the number of Gd+ lesions in patients with MS during a 24-week treatment period. This benefit was not sustained beyond 24 weeks, and there were no clinical benefits.Trial registrationClinicalTrials.gov, number NCT00147446.

White matter (WM) abnormalities are among the most commonly reported neuroimaging findings in bipolar disorder. Nonetheless, the specific nature and pathophysiology of these abnormalities remain unclear. Use of a combination of magnetization transfer ratio (MTR) and diffusion tensor spectroscopy (DTS) permits examination of myelin and axon abnormalities separately. We aimed to examine myelination and axon geometry in euthymic patients with bipolar disorder with psychosis (BDP) by combining these two complementary noninvasive MRI techniques. We applied a combined MRI approach using MTR to study myelin content and DTS to study metabolite (N-acetylaspartate, NAA) diffusion within axons in patients with BDP (n=21) and healthy controls (n=24). Data were collected from a 1 × 3 × 3-cm voxel within the right prefrontal cortex WM at 4 Tesla. Clinical and cognitive data were examined in association with MTR and DTS data. MTR was significantly reduced in BDP, suggesting reduced myelin content. The apparent diffusion coefficient of NAA did not differ from healthy controls, suggesting no changes in axon geometry in patients with BDP. These findings suggest that patients with BDP exhibit reduced myelin content, but no changes in axon geometry compared with controls. These findings are in contrast with our recent findings, using the same techniques, in patients with schizophrenia (SZ), which suggest both myelination and axon abnormalities in SZ. This difference may indicate that alterations in WM in BDP may have unique causes and may be less extensive than WM abnormalities seen in SZ. [ABSTRACT FROM AUTHOR]

Bipolar disorder and schizophrenia overlap in symptoms and may share some underlying neural substrates. The medial prefrontal cortex (MPFC) may have a crucial role in the psychophysiology of both these disorders. In this study, we examined the functional connectivity between MPFC and other brain regions in bipolar disorder and schizophrenia using resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI data were collected from 14 patients with bipolar disorder, 16 patients with schizophrenia, and 15 healthy control subjects. Functional connectivity maps from the MPFC were computed for each subject and compared across the three groups. The three groups showed distinctive patterns of functional connectivity between MPFC and anterior insula, and between MPFC and ventral lateral prefrontal cortex (VLPFC). The bipolar disorder group exhibited positive correlations between MPFC and insula, and between MPFC and VLPFC, whereas the control group exhibited anticorrelations between these regions. The schizophrenia group did not exhibit any resting-state correlation or anticorrelation between the MPFC and the VLPFC or insula. In contrast, neither patient group exhibited the significant anticorrelation between dorsal lateral prefrontal cortex (DLPFC) and MPFC that was exhibited by the control group. The decoupling of DLPFC with MPFC in bipolar disorder and schizophrenia is consistent with the impaired executive functioning seen in these disorders. Functional connectivity between MPFC and insula/VLPFC distinguished bipolar disorder from schizophrenia, and may reflect differences in the affective disturbances typical of each illness. [ABSTRACT FROM AUTHOR]

Racemic fluoxetine consists of R- and S-fluoxetine, which are metabolized to R and S norfluoxetine, respectively. This study was designed to compare brain levels achieved with R-fluoxetine to those achieved with racemic fluoxetine in healthy subjects using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS). In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 μM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable. While these data support the use of MRS to aid in defining the therapeutic dose range for drug development, they also highlight the need for additional studies with concurrent animal models to establish the validity of using serum drug/metabolite ratios to interpret MRS determined brain drug levels. [ABSTRACT FROM AUTHOR]

Objective: Anecdotal reports have suggested mood improvement in patients with bipolar disorder immediately after they underwent an echo-planar magnetic resonance spectroscopic imaging (EP- MRSI) procedure that can be performed within clinical MR system limits. This study evaluated possible mood improvement associated with this procedure. Method: The mood states of subjects in an ongoing EP-MRSI study of bipolar disorder were assessed by using the Brief Affect Scale, a structured mood rating scale, immediately before and after an EP-MRSI session. Sham EP-MRSI was administered to a comparison group of subjects with bipolar disorder, and actual EP-MRSI was administered to a comparison group of healthy subjects. The characteristics of the electric fields generated by the EP-MRSI scan were analyzed. Results: Mood improvement was re- ported by 23 of 30 bipolar disorder subjects who received the actual EP-MRSI examination, by three of 10 bipolar disorder subjects who received sham EP-MRSI, and by four of 14 healthy comparison subjects who received actual EP-MRSI. Significant differences in mood improvement were found between the bipolar disorder subjects who received actual EP-MRSI and those who received sham EP-MRSI, and, among subjects who received actual EP- MRSI, between the healthy subjects and the bipolar disorder subjects and to a lesser extent between the unmedicated bipolar disorder subjects and the bipolar disorder subjects who were taking medication. The electric fields generated by the EP-MRSI scan were smaller (0.7 V/m) than fields used in repetitive transcranial magnetic stimulation (rTMS) treatment of depression (1-500 V/m) and also ex- tended uniformly throughout the head, unlike the highly nonuniform fields used in rTMS. The EP-MRSI waveform, a 1-kHz train of monophasic trapezoidal gradient pulses, differed from that used in rTMS. [ABSTRACT FROM AUTHOR]

Editorial. Comments on the applications of functional brain imaging and magnetic resonance spectroscopy in psychiatry. Historical use of x-ray in imaging brain structures; Capability to observe brain chemistry and function using magnetic resonance technology; Use of high-speed imaging coils for observing brain blood flow alterations and correlating it to local brain activity.

Context: Clinical observations and case reports suggest that there are important cerebrovascular complications of cocaine use, but no studies have documented a direct link.Objective: To determine whether low-dose cocaine administration induces cerebral vasoconstriction in healthy cocaine users.Design: Randomized controlled trial.Subjects: Twenty-four healthy and neurologically normal men (mean age, 29 years) reporting median cocaine use of 8 lifetime exposures (range, 3 to >40).Intervention: Double-blind intravenous administration of cocaine (0.4 or 0.2 mg/kg) or placebo, with cerebral magnetic resonance angiography performed at baseline and 20 minutes following infusion.Main Outcome Measure: Cocaine-induced angiographic change indicative of vasoconstriction, as independently and concordantly rated by 2 reviewers blind to treatment condition.Results: Cocaine-induced cerebral vasoconstriction in a dose-related fashion (P=.03), with angiograms indicative of vasoconstriction found in 5 of 8 and 3 of 9 subjects receiving 0.4- and 0.2-mg/kg cocaine, respectively, compared with 1 of 7 subjects administered placebo. Outcome stratification by frequency of self-reported lifetime cocaine use (3-10 times, 11-40 times, or >40 times) revealed a statistically stronger dose-related effect (P<.001), suggesting that greater lifetime cocaine use was associated with a greater likelihood of vasoconstriction.Conclusions: Cocaine administration induced dose-related cerebral vasoconstriction on magnetic resonance angiograms. These changes occurred at low cocaine doses and in the absence of other risk factors, including polydrug abuse, hypertension, or cerebrovascular disease. Outcome stratification by prior cocaine use statistically strengthened the relationship between cocaine administration and vasoconstriction, suggesting that cocaine may have a cumulative residual effect in promoting cerebrovascular dysfunction. [ABSTRACT FROM AUTHOR]

The authors compared the results of computerized tomography (CT) and magnetic resonance imaging (MRI) scans of 16 psychotic patients with various diagnoses whose neurologic examinations suggested structural brain abnormalities. Blind readings showed a high concordance of findings, including ventricle-to-brain ratios, although MRI appeared superior in visualizing midline structures and identifying atrophic changes. Because it requires no ionizing radiation, MRI allows multiple studies of the same patient, study of family members, and recruitment of unbiased samples of control subjects. Use of MRI may help address questions regarding the specificity and prevalence of brain abnormalities observed with CT in psychotic patients. [ABSTRACT FROM AUTHOR]

Assesses the effect of sex on data derived from activation studies conducted using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (MRI). Methodology used to conduct the study; Results of the study.

Summary: Background: Autologous non-myeloablative haemopoietic stem cell transplantation is a method to deliver intense immune suppression. We evaluated the safety and clinical outcome of autologous non-myeloablative haemopoietic stem cell transplantation in patients with relapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta. Methods: Eligible patients had relapsing-remitting MS, attended Northwestern Memorial Hospital, and despite treatment with interferon beta had had two corticosteroid-treated relapses within the previous 12 months, or one relapse and gadolinium-enhancing lesions seen on MRI and separate from the relapse. Peripheral blood haemopoietic stem cells were mobilised with 2 g per m2 cyclophosphamide and 10 μg per kg per day filgrastim. The conditioning regimen for the haemopoietic stem cells was 200 mg per kg cyclophosphamide and either 20 mg alemtuzumab or 6 mg per kg rabbit antithymocyte globulin. Primary outcomes were progression-free survival and reversal of neurological disability at 3 years post-transplantation. We also sought to investigate the safety and tolerability of autologous non-myeloablative haemopoietic stem cell transplantation. Findings: Between January, 2003, and February, 2005, 21 patients were treated. Engraftment of white blood cells and platelets was on median day 9 (range day 8–11) and patients were discharged from hospital on mean day 11 (range day 8–13). One patient had diarrhoea due to Clostridium difficile and two patients had dermatomal zoster. Two of the 17 patients receiving alemtuzumab developed late immune thrombocytopenic purpura that remitted with standard therapy. 17 of 21 patients (81%) improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS), and five patients (24%) relapsed but achieved remission after further immunosuppression. After a mean of 37 months (range 24–48 months), all patients were free from progression (no deterioration in EDSS score), and 16 were free of relapses. Significant improvements were noted in neurological disability, as determined by EDSS score (p<0·0001), neurological rating scale score (p=0·0001), paced auditory serial addition test (p=0·014), 25-foot walk (p<0·0001), and quality of life, as measured with the short form-36 (SF-36) questionnaire (p<0·0001). Interpretation: Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial. Funding: Division of Immunotherapy, Northwestern University. [Copyright &y& Elsevier]

Background: Cognitive deficits are well-documented in patients with bipolar disorder (BPD) and may impact the efficacy of psychotherapy. Cognitive control, a form of executive functioning, is often used therapeutically to shift patients' thoughts and behaviors from automatic, maladaptive responses to adaptive coping strategies. This study examined cognitive control processing in patients with BPD using the Multi-Source Interference Task (MSIT).Method: Twenty-nine patients diagnosed with BPD and 21 healthy control (HC) subjects completed the MSIT with concurrent functional magnetic resonance imaging (fMRI).Results: Patients with BPD generally performed worse on the MSIT relative to HC participants; the BPD group had significantly lower performance accuracy and made more omission errors. Further, fMRI analyses revealed differential patterns of activation between the groups during the MSIT. Region of interest (ROI) analyses revealed that relative to HC participants, patients with BPD activated significantly fewer voxels within the cingulate cortex (CC) and more voxels within prefrontal cortex (PFC), although the PFC findings did not survive more stringent significance thresholds.Limitations: Patients and HCs were not matched for age, sex, and premorbid verbal IQ, however, these variables were controlled for statistically. Medication usage in the BPD group may have possibly impacted the results. Given a priori hypotheses, ROI analyses were utilized.Conclusions: Decreased CC activation and increased PFC activation may be associated with impaired cognitive control, demonstrated by BPD patients when completing the MSIT. Identifying the neural mechanisms which underlie key cognitive abnormalities in BPD may aid in clarifying the pathophysiology of this disorder and inform selection of potential targets for cognition remediation in BPD. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify how the activity of large-scale brain networks differs between mood states in bipolar disorder. The authors measured spontaneous brain activity in subjects with bipolar disorder in mania and euthymia and compared these states to a healthy comparison population.Methods: 23 subjects with bipolar disorder type I in a manic episode, 24 euthymic bipolar I subjects, and 23 matched healthy comparison (HC) subjects underwent resting state fMRI scans. Using an existing parcellation of the whole brain, we measured functional connectivity between brain regions and identified significant differences between groups.Results: In unbiased whole-brain analyses, functional connectivity between parietal, occipital, and frontal nodes within the dorsal attention network (DAN) were significantly greater in mania than euthymia or HC subjects. In the default mode network (DMN), connectivity between dorsal frontal nodes and the rest of the DMN differentiated both mood state and diagnosis.Limitations: The bipolar groups were separate cohorts rather than subjects imaged longitudinally across mood states.Conclusions: Bipolar mood states are associated with highly significant alterations in connectivity in two large-scale brain networks. These same networks also differentiate bipolar mania and euthymia from a HC population. State related changes in DAN and DMN connectivity suggest a circuit based pathology underlying cognitive dysfunction as well as activity/reactivity in bipolar mania. Altered activities in neural networks may be biomarkers of bipolar disorder diagnosis and mood state that are accessible to neuromodulation and are promising novel targets for scientific investigation and possible clinical intervention. [ABSTRACT FROM AUTHOR]

Background: Existing models of the pathophysiology of bipolar disorder posit disruption in neural circuits of emotion regulation and reward processing. However, few fMRI studies have compared regional brain activity and connectivity in different mood states in bipolar disorder to determine if manic symptomatology is reflected in specific circuit abnormalities. The purpose of this study was to test the hypothesis that bipolar mania is associated with altered connectivity between cortical regions thought to regulate subcortical structures such as the amygdala and striatum.Methods: 28 subjects with bipolar disorder in a manic state, 24 different bipolar subjects in a euthymic state, and 23 matched healthy comparison subjects underwent resting state fMRI scans. Several cortical and sub-cortical structures implicated in the pathogenesis of bipolar disorder were selected for study. We conducted a whole-brain analysis of functional connectivity of these regions.Results: Bipolar mania was differentiated from euthymia by decreased functional connectivity between the amygdala and anterior cingulate cortex (ACC). Mania was also characterized by increased connectivity between amygdala and dorsal frontal cortical structures that are normally anti-correlated in emotion regulation tasks.Limitations: Both groups of bipolar subjects were prescribed medications. The study was not longitudinal in design.Conclusions: Compared to bipolar subjects in a euthymic state, subjects in the manic state demonstrate disrupted functional connectivity between brain regions involved in the regulation of emotion and the amygdala. This disruption of activity in neural circuits involved in emotion may underlie the emotional dysregulation inherent to a bipolar manic episode. [ABSTRACT FROM AUTHOR]

Background We previously reported rapid mood elevation following an experimental magnetic resonance imaging procedure in depressed patients with bipolar disorder (BPD). This prompted the design, construction, and testing of a portable electromagnetic device that reproduces only the rapidly oscillating (1 kHz, <1 V/m) electromagnetic field of the experimental procedure, called low field magnetic stimulation (LFMS). Methods We used a randomized, double blind, sham controlled treatment protocol to study the effects of LFMS in a large group of stably medicated, depressed patients with either BPD (n = 41) or major depressive disorder (n = 22). Subjects received a single, 20-minute treatment. Change in mood was assessed immediately afterward using a visual analog scale (VAS), the 17-item Hamilton Depression Rating Scale (HDRS-17), and the Positive and Negative Affect Schedule scales. Results Substantial improvement (>10% of baseline) in mood was observed following LFMS treatment relative to sham treatment for both diagnostic subgroups for our primary outcomes, the VAS and the HDRS-17. These differences were not statistically significant in primary analyses stratifying by diagnosis but were significant in secondary analyses combining data across the two diagnostic groups (p = .01 VAS, p = .02 HDRS-17). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule scales as secondary measures (positive affect scale p = .02 BPD, p = .002 combined group). A finite element method calculation indicates a broad penetration of the LFMS electric field throughout the cerebral cortex. Conclusions Low field magnetic stimulation may produce rapid changes in mood using a previously unexplored range of electromagnetic fields. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) has mood-elevating actions in humans during the depressive phases of bipolar disorder. We examined whether a low-energy component of EP-MRSI (low-field magnetic stimulation [LFMS]) has antidepressant-like, locomotor-stimulating, or amnestic effects in rats. Methods: We examined the effects of LFMS on immobility in the forced swim test (FST) and activity within an open field in separate groups of rats. After exposure to forced swimming, rats received LFMS (three 20-min sessions at 1.5 G/cm and .75 V/m) before behavioral testing. We also examined the effects of LFMS on fear conditioning (FC), a learning paradigm that also involves exposure to stressful conditions. Results: Low-field magnetic stimulation reduced immobility in the FST, an antidepressant-like effect qualitatively similar to that of standard antidepressants. Low-field magnetic stimulation did not alter locomotor activity or FC. Conclusions: Low-field magnetic stimulation has antidepressant-like effects in rats that seem unrelated to locomotor-activating or amnestic effects. These findings raise the possibility that electromagnetic fields can affect the brain biology and might have physiologic consequences that offer novel approaches to therapy for psychiatric disorders. These same consequences might render MRI-based scans more invasive than previously appreciated. [Copyright &y& Elsevier]

Abstract: Purpose: Prior proton magnetic resonance spectroscopy (MRS) studies have consistently reported decreased brain n-acetyl aspartate (NAA) levels and increased myo-inositol (mI) levels in subjects with Alzheimer''s disease (AD) relative to healthy comparison subjects. These studies have usually been conducted in small and homogeneous populations of patients with established Alzheimer''s disease. Few studies have tested the usefulness of this finding in a general population seeking evaluation for memory loss and other cognitive declines. We designed a study to evaluate the significance of single-voxel proton MRS findings in these patients with memory loss and other cognitive declines. General method: Thirty-five subjects with a primary complaint of memory loss and other cognitive declines were consecutively referred over a period of 13 months to a specialty clinic. Patients with a diagnosis of mild to moderate probable Alzheimer''s disease (N=22), non-Alzheimer''s dementia (depression, multiinfarct dementia, Parkinson''s Disease, Korsakoff''s Psychosis, and bipolar disorder; N=13), and healthy comparison subjects (N=18) were examined with respect to possible differences in metabolites using proton MRS in a 3.4-ml anterior temporal lobe voxel. Findings: The Alzheimer''s disease group had 10.7% lower NAA/creatine (Cr) ratios relative to the healthy comparison group and 9.4% lower NAA/creatine relative to the non-Alzheimer''s dementia group (15.0% lower NAA/creatine relative to the depression subgroup of the non-Alzheimer''s dementia group). There were no significant differences in choline (Cho) or myo-inositol ratios among the groups. There were significant correlations between NAA/creatine ratios and mini-mental status exam (MMSE) scores in subjects with Alzheimer''s disease (t=2.41, p=0.032) but not in subjects with non-Alzheimer''s dementia or in its depression subgroup. Conclusions: This study found a reduction in the neuronal marker NAA in the anterior temporal lobe of patients diagnosed with probable Alzheimer''s disease, using a short add-on proton MRS exam. This change was not observed in patients whose memory loss and other cognitive declines were not attributed to Alzheimer''s disease, suggesting that it may aid in the diagnosis or detection of Alzheimer''s disease. [Copyright &y& Elsevier]