Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects.

BACKGROUND: Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism. METHOD: Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed. RESULTS: A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum. CONCLUSIONS: Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

Bilateral bispectral index monitoring during and after electroconvulsive therapy compared with magnetic seizure therapy for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective and established treatment for depression. Magnetic seizure therapy (MST) has recently been developed and seems equally effective while associated with fewer side-effects. Both require general anaesthesia, which could be quantified using the bispectral index (BIS). We compared ECT and MST with respect to recovery times, left-sided BIS, and left-right differences in BIS. METHODS: In this prospective, observational study, we enrolled 10 successive patients receiving ECT and 10 patients undergoing MST. Anaesthesia was performed with propofol and monitored with a bilateral BIS sensor. The seizure was elicited when the BIS was within a range from 50 to 60. The time to eye opening was measured and bilateral BIS were recorded for 10 min after seizure induction. RESULTS: A comparable anaesthetic depth was observed in the ECT and MST groups at baseline [mean (standard deviation, sd) BIS values of 94.1 (4.1) and 95.5 (3.0), respectively] and before seizure induction [mean (sd) BIS values of 52.3 (9.6) and 55.2 (10.3), respectively]. Post-ictally, MST patients opened their eyes significantly earlier than ECT patients [3.0 (1.0) vs 6.7 (1.3) min, P<0.001]. They showed a significantly higher BIS at 2 min after seizure induction [69.2 (10.1) vs 50.9 (15.9), P=0.003], and this difference was still present at 10 min after seizure induction [BIS 81.5 (6.5) vs 68.0 (16.4), P<0.001]. Significant differences between the left and right BIS were observed in neither the ECT nor the MST group. CONCLUSIONS: At a comparable anaesthetic depth, MST is superior to ECT in terms of post-ictal recovery, which is correctly reflected by higher post-ictal BIS values. Unilateral BIS monitoring is sufficient to monitor anaesthetic depth in ECT and MST patients. TRIAL REGISTRY NUMBER: NCT 01318018.

Clinical milestones predict symptom remission over 6-month and choice of treatment of patients with major depressive disorder (MDD).

BACKGROUND: It is uncertain as to what short-term outcomes predict long-term treatment compliance and outcomes in patients with MDD. AIMS: To determine what treatment milestones predict symptom remission with long-term treatment with antidepressant medication. METHOD: Pooled analysis of four randomised, double-blind, active comparator, 6-month trials in MDD. RESULTS: Patients received double-blind treatment with escitalopram (N=699) or a comparator (citalopram, duloxetine, or paroxetine) (N=699). Onset of effect at week 2 was correlated with response at week 8, and response at week 8 with completion of 6-month treatment. Week 8 response was associated with a greater probability of achieving later remission. Week 24 remission (MADRS>or=10) was significantly (p<0.01) higher for patients treated with escitalopram (70.7%) than for the pooled comparators (64.7%). Week 24 complete remission (MADRS

Pattern of regional cerebral blood-flow changes induced by acute heroin administration--a perfusion MRI study.

PURPOSE: Although both the subjective and physiological effects of abused psychotropic substances have been characterized, less is known about their effects on brain function. We examined the actions of intravenous diacetylmorphine (heroin), the most widely abused opioid, on regional cerebral blood flow (rCBF), as assessed by perfusion-weighted MR imaging (PWI) in a double-blind and placebo-controlled setting. MATERIAL AND METHODS: Eight male subjects dependent of diacetylmorphine (mean age 36 years, range: 26 to 44 years), who had participated in a clinical diacetylmorphine maintenance program, underwent PWI with gadolinium injection. At two sessions separated by 2-7 days, the participants were examined 80 s after intravenous administration of either diacetylmorphine or saline. rCBF in four regions of interest (amygdala, vermis of the cerebellum, anterior cingulated cortex and thalamus) was compared with heroin versus placebo. RESULTS: In the cerebellum, thalamus and cingulated cortex, there were no significant differences in perfusion values between diacetylmorphine and placebo. In the amygdala, perfusion values were 0.8+/-0.4 and 0.5+/-0.2 on the left, and 0.9+/-0.4 and 0.6+/-0.3 on the right, with diacetylmorphine and with placebo, respectively (t-test results were P=0.044 and P=0.033 on the left and right sides, respectively). Other differences in perfusion values between the drug and placebo did not reach statistical significance. CONCLUSION: Perfusion MRI demonstrated differences in brain hemodynamics induced by drug intake.

PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects.

OBJECTIVE: Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge. METHOD: Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers. RESULTS: All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site. CONCLUSIONS: These results support the concept of dopamine system involvement in human cocaine abuse.

Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study.

OBJECTIVE: Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated whether prefrontal repetitive transcranial magnetic stimulation influenced obsessive-compulsive disorder symptoms. METHOD: Twelve patients with obsessive-compulsive disorder were given repetitive transcranial magnetic stimulation (80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes) to a right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days, randomized. The patients' symptoms and mood were rated for 8 hours afterward. RESULTS: Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. CONCLUSIONS: These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder.

Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects.

OBJECTIVE: Humans experience the subjective effects of mu and kappa opioid agonists differently: mu agonists produce mainly euphoria, while kappa agonists are more likely to produce dysphoria. This study tested the hypothesis that these subjective effects would be associated with anatomically distinct changes in regional cerebral blood flow (CBF) relative to baseline as assessed with single photon emission computed tomography (SPECT). METHOD: Nine nondependent opioid abusers participated in the study. In the first phase of the study, the participants were acclimated to effects of the study drugs. In the second phase they underwent repeat challenges with the study drugs followed by an assessment of CBF with use of the SPECT tracer [99mTc]HMPAO. Medications tested were the prototypic mu agonist hydromorphone, the mixed agonist/antagonist butorphanol (which has a kappa agonist component of activity), and saline placebo. RESULTS: Subjective effects of the drugs were distinctly different. Hydromorphone produced increased ratings of "good effects," while butorphanol led to more "bad effects." Hydromorphone significantly increased regional CBF in the anterior cingulate cortex, both amygdalae, and the thalamus--all structures belonging to the limbic system. Butorphanol caused a less distinct picture of regional CBF increases, mainly in the area of both temporal lobes. CONCLUSIONS: This study demonstrates that opioids with different subjective effects also produce statistically significant patterns of change in regional CBF from baseline, and the regions of statistical significance appear in different brain regions. In addition, these results demonstrate the applicability of SPECT functional neuroimaging in the study of medications with potential abuse liability.

Decreased regional cortical gray matter volume in schizophrenia.

OBJECTIVE: The authors hypothesized that cortical gray matter volume reduction in schizophrenia is greatest in the heteromodal association cortex. This area comprises a highly integrated, reciprocally interconnected system that coordinates higher order cortical functions. METHOD: Total brain and regional gray matter volumes were calculated in 46 schizophrenic patients and 60 age and sex-matched comparison subjects by using magnetic resonance images. Disease specificity was examined by assessing 27 patients with bipolar disorder. Approximations to the dorsolateral prefrontal cortex, inferior parietal lobule, and superior temporal gyrus were selected as regions of interest for the heteromodal association cortex. Occipital and sensorimotor areas were used as comparison regions to test the hypothesis for regional specificity. RESULTS: Gray matter volume was reduced in schizophrenic patients in index regions even after covariance for overall brain volume, sex, and age. Bipolar disorder patients did not exhibit heteromodal gray matter reduction. Comparison regions did not differ among the three groups. Global gray matter volume was not different among groups after covariance for global brain volume. Comprehensive individual region post hoc analysis found no additional gray matter differences. CONCLUSIONS: These findings support the theory of disproportionate reduction of gray matter volume in the heteromodal association cortex specific to schizophrenia.

Magnetic resonance imaging measurement of gray matter volume reductions in HIV dementia.

OBJECTIVE: The authors recently reported smaller basal ganglia volumes for patients with HIV-associated dementia than for HIV-infected patients without dementia and a seronegative comparison group. The purpose of the current study was to determine whether HIV dementia is associated with volume reductions in other brain regions. METHOD: The authors measured volumes of CSF and gray and white tissue on cranial magnetic resonance images from homosexual men who were 1) infected with HIV with HIV-associated dementia complex, 2) infected with HIV without dementia, and 3) HIV seronegative. RESULTS: Results suggest that loss of white matter occurs with HIV infection and is more severe in HIV-positive patients with dementia than in those without dementia. There was some generalized volume reduction in gray matter in HIV-positive demented patients, although group differences did not reach significance when adjusted for age. Volume of posterior cortex, however, was significantly smaller among HIV-positive patients with dementia than in either remaining group. There were no significant differences between HIV-positive nondemented patients and HIV-negative subjects in these regions. CONCLUSIONS: In conjunction with findings from previous research, the authors conclude that HIV dementia is associated with specific gray matter volume reduction in basal ganglia and posterior cortex, as well as with generalized volume reduction of white matter.

Exploratory factor analysis of MRI brain structure measures in schizophrenia.

Much of the literature shows various regional structural brain abnormalities in schizophrenia, but the complexity and variability of brain makes it difficult to determine how these regions are related. Statistical methods which estimate factors underlying patterns of covariance have not been widely used, but could be useful for analyzing such complex data. We applied exploratory and confirmatory factor analysis procedures to specific cortical and subcortical regional brain volume measures from MRI data in 60 normal and 44 schizophrenic subjects. Basal ganglia, heteromodal cortical gray, and medial temporal lobe factors were present in both the normal and the schizophrenia groups. The factor structure observed in the normal group showed a high degree of bilateral symmetry which is present but disrupted in the schizophrenia group. In the bilateral data, the disruption is most pronounced with medial and lateral temporal lobe structures including entorhinal cortex and anterior and posterior superior temporal gyri. There was a significant correlation between the basal ganglia factor and the heteromodal cortical gray factor in the normal group that was not present in the schizophrenia group. In the unilateral data, left posterior superior temporal gyrus did not load onto any factor in the schizophrenia group. Confirmatory factor analyses showed significant differences between the two groups in factor structure. A number of specific brain regions are affected in schizophrenia, and structural relationships between groups of regions also are abnormal. The results suggest that heteromodal dorsolateral prefrontal and superior temporal cortical gray regions are structurally related, whereas inferior parietal cortical gray is less so. These results should be viewed as preliminary as the ratio of parameters to subjects was relatively low, and replication is needed. However, the results demonstrate the potential utility of latent structure methods such as factor analysis in study of complex relationships in neuropsychiatric data.

MR volume segmentation of gray matter and white matter using manual thresholding: dependence on image brightness.

PURPOSE: To describe a quantitative MR imaging segmentation method for determination of the volume of cerebrospinal fluid, gray matter, and white matter in living human brain, and to determine the method's reliability. METHODS: We developed a computer method that allows rapid, user-friendly determination of cerebrospinal fluid, gray matter, and white matter volumes in a reliable manner, both globally and regionally. This method was applied to a large control population (N = 57). RESULTS: Initially, image brightness had a strong correlation with the gray-white ratio (r = .78). Bright images tended to overestimate, dim images to underestimate gray matter volumes. This artifact was corrected for by offsetting each image to an approximately equal brightness. After brightness correction, gray-white ratio was correlated with age (r = -.35). The age-dependent gray-white ratio was similar to that for the same age range in a prior neuropathology report. Interrater reliability was high (.93 intraclass correlation coefficient). CONCLUSIONS: The method described here for gray matter, white matter, and cerebrospinal fluid volume calculation is reliable and valid. A correction method for an artifact related to image brightness was developed.

SPECT brain blood flow changes with continuous ligand infusion during previously learned WCST performance.

Performance of the Wisconsin Card Sorting Test (WCST) and related brain-activation patterns reflect both task learning and execution. Normal subjects learned the WCST prior to performance during slow SPECT ligand infusion. Blood flow increased in bilateral inferior frontal, right middle and inferior parietal cortices. Activity decreased in hippocampi, temporal cortex, anterior cingulate and caudate.

Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers.

This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.

Structural differences in the cerebral cortex of healthy female and male subjects: a magnetic resonance imaging study.

There are both reproductive and nonreproductive behavioral differences between men and women. Brain regions involved in determining sexual behavior have been reported to differ between the sexes. Nonreproductive, cognitive functional differences between sexes might be reflected in higher-order cortical structural dimorphisms, which have not previously been studied. We hypothesized that cortical regions involved in verbal behavior (which is sexually dimorphic) would differ between sexes. Using magnetic resonance imaging, we assessed gray matter volumes in several cortical regions in 17 women and 43 men. Women had 23.2% (dorsolateral prefrontal cortex) and 12.8% (superior temporal gyrus) greater gray matter percentages (corrected for overall brain size and age) than men in a language-related cortical region, but not in a more visuospatially related cortical region. These data seem to establish sexually dimorphic structural differences in the cerebral cortex, consistent with prior cerebral blood flow reports.

Cerebral blood flow in obsessive-compulsive patients with major depression: effect of treatment with sertraline or desipramine on treatment responders and non-responders.

We examined the effects of sertraline and of desipramine on patients with OCD and comorbid major depressive episodes at study entry. Sixteen patients, 9 receiving sertraline and 7 desipramine, received HMPAO SPECT scans while free of medication and after 12 weeks of treatment. Patients on sertraline showed significantly reduced regional cerebral blood flow (rCBF) in the right prefrontal and temporal regions. Patients on desipramine showed more diffuse rCBF reductions in frontal and temporal regions, more so in the left side. In a second analysis, patients who had a symptom reduction on the Yale-Brown Obsessive Compulsive Scale (YBOCS), irrespective of the type of medication, were retrospectively classified as 'responders' to treatment. Eleven patients were 'responders' and 5 'non-responders'. Before being medicated, responders differed from non-responders through higher rCBF in prefrontal regions, mostly on the left, and higher rCBF in the cingulate and basal ganglia bilaterally. After 12 weeks of treatment, responders showed a diffuse reduction of rCBF in prefrontal regions while non-responders showed only a few scattered low-frequency responses. Thus, higher prefrontal and subcortical activity was associated with better response to drug treatment. In addition, clinical change, but not the administration of medication as such, was associated with a decrease of prefrontal rCBF.

High frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral cortex: EEG topography during waking and subsequent sleep.

Repetitive transcranial magnetic stimulation (rTMS) is a novel research tool in neurology and psychiatry. It is currently being evaluated as a conceivable alternative to electroconvulsive therapy for the treatment of mood disorders. Eight healthy young (age range 21-25 years) right-handed men without sleep complaints participated in the study. Two sessions at a 1-week interval, each consisting of an adaptation night (sham stimulation) and an experimental night (rTMS in the left dorsolateral prefrontal cortex or sham stimulation; crossover design), were scheduled. In each subject, 40 trains of 2-s duration of rTMS (inter-train interval 28 s) were applied at a frequency of 20 Hz (i.e. 1600 pulses per session) and at an intensity of 90% of the motor threshold. Stimulations were scheduled 80 min before lights off. The waking EEG was recorded for 10-min intervals approximately 30 min prior to and after the 20-min stimulations, and polysomnographic recordings were obtained during the subsequent sleep episode (23.00-07.00 h). The power spectra of two referential derivations, as well as of bipolar derivations along the antero-posterior axis over the left and right hemispheres, were analyzed. rTMS induced a small reduction of sleep stage 1 (in min and percentage of total sleep time) over the whole night and a small enhancement of sleep stage 4 during the first non-REM sleep episode. Other sleep variables were not affected. rTMS of the left dorsolateral cortex did not alter the topography of EEG power spectra in waking following stimulation, in the all-night sleep EEG, or during the first non-REM sleep episode. Our results indicate that a single session of rTMS using parameters like those used in depression treatment protocols has no detectable side effects with respect to sleep in young healthy males.

Transcranial magnetic stimulation for treating depression.

BACKGROUND: Transcranial magnetic stimulation can either excite or inhibit cortical areas of the brain, depending on whether the speed of the repetitive stimulation is applied at high or low frequencies. It has been used for physiological studies and it has also been proposed as a treatment for depression. OBJECTIVES: To assess the clinical efficacy and safety of transcranial magnetic stimulation for treating depression. SEARCH STRATEGY: An electronic search was performed including the Cochrane Collaboration Depression, Neurosis and Anxiety Review Group trials register (last searched June, 2001), the Cochrane Controlled Trials Register (Issue 2, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), PsycLIT (1980-2001), and bibliographies from reviewed articles. Unpublished data and grey literature were searched through personal communications with researchers. SELECTION CRITERIA: Randomised controlled trials assessing the therapeutic efficacy and safety of transcranial magnetic stimulation for depression. DATA COLLECTION AND ANALYSIS: All reviewers independently extracted the information and verified it by cross-checking. Disagreements were resolved through discussion. Continuous data: When similar studies were grouped, the overall standardised mean difference was calculated under a fixed effect model weighted by the inverse variance method with 95% confidence intervals. (In the presence of statistical heterogeneity, a random effects model was to be used.) MAIN RESULTS: Sixteen trials were included in the review and fourteen contained data in a suitable form for quantitative analysis. Most comparisons did not show differences between rTMS and other interventions. No difference was seen between rTMS and sham TMS using the Beck Depression Inventory or the Hamilton Depression Rating Scale, except for one time period (after two weeks of treatment) for left dorsolateral prefrontal cortex and high frequency; and also for right dorsolateral prefrontal cortex and low frequency, both in favour of rTMS and both using the Hamilton scale. Comparison of rTMS (left dorsolateral prefrontal cortex and high frequency) with electroconvulsive therapy showed no difference except for psychotic patients after two weeks treatment, using the Hamilton scale, which indicated that electroconvulsive therapy was more effective than rTMS. REVIEWER'S CONCLUSIONS: The information in this review suggests that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit.

Computerized Wisconsin Card Sorting Test: comparison with manual administration.

Computer-based testing in neuropsychology potentially offers important advantages. These include improvement in reliability and more efficient use of resources. For tests such as the Wisconsin Card Sorting Test (WCST) in which examiners must provide on-going feedback to subjects, reliability may be decreased by variability and errors in test presentation, errors in response recording and feedback, and errors in scoring. In addition, an important aspects of neuropsychological assessment is qualitative, that is, observations of the processes by which the subject responds to the test situation. The mechanics of administering the WCST hinder the examiner from allocating attention for observing these processes. Accordingly, we have automated both the administration and the scoring of the WCST. Although potential benefits of computerizing the WCST seem likely, it is possible that factors which cannot at present be duplicated by a computer may effect performance. This study compared performance between the standard manual Heaton version of the WCST and the computerized version. In a group of 33 normal and psychiatric subjects, there were significant differences in the number of Errors and the number of Correct responses, but no significant differences in performance were found for Perseverative Responses, Perseverative Errors, and Set Breaks. The mean number of Categories achieved was 2.0 for the computer administered version and 2.4 for the manual version: this difference was only marginally significant (p = 0.065). The computerized form of the WCST appears to yield similar quantitative results on scores which are most specifically affected by brain injuries in testing with the manual form. Lower variance was seen in the computer scores. This result is consistent with more reliable administration and accuracy in data acquisition and scoring in the computer version. The results overall indicate that the computer version is not a substitute for a human examiner, rather, the computer can function as a reliable partner, carrying out the mechanics of test presentation and scoring, freeing the examiner to more fully support the subject in taking the test and to observe the non-quantitative aspects of test performance.

Deep brain stimulation for major depression.

A third of patients suffering from major depression cannot be helped by conventional treatment methods. These patients face reduced quality of life, high risk of suicide, and little hope of recovery. Deep brain stimulation (DBS) is under scientific evaluation as a new treatment option for these treatment-resistant patients. First clinical studies with small samples have been stimulated at the subgenual cingulate gyrus (Cg25/24), the anterior limb of the capsula interna (ALIC), and the nucleus accumbens (NAcc). Long-term antidepressant effects, augmentation of social functioning, and normalization of brain metabolism have been shown in about 50% of patients. Cognitive safety regarding attention, learning, and memory has been reported. Adverse events were wound infection, suicide, and hypomania, amongst others. Larger studies are under way to confirm these preliminary encouraging results. New hypothesis-guided targets (e.g., medial forebrain bundle, habenula) are about to be assessed in clinical trials. The application of DBS for other psychiatric diseases (e.g., bipolar disorder, alcohol dependency, opioid addiction, schizophrenia) is debated and single case studies are under way. Standards are needed for study registration, target selection, patient inclusion and monitoring, and publication of results to guarantee safety for the patients and scientific exchange.