A pilot study of cortical glutathione in youth with depression.

AIM: This study used proton magnetic resonance spectroscopy (1H MRS) to measure in vivo brain glutathione (GSH) in adolescents with major depressive disorder (MDD), and explored the relationship between GSH and illness severity and chronicity. Secondarily, associations between GSH and anhedonia, a key symptom of MDD in adolescents, were investigated. METHODS: Occipital cortex GSH levels were obtained in 19 psychotropic medication-free adolescents with MDD (ages 12-21) and compared to those in eight healthy control adolescents. Correlations between GSH levels and anhedonia severity were examined both in the full participant sample and within the MDD group. Within the MDD group, correlations between GSH levels and illness severity and chronicity were assessed. RESULTS: Occipital GSH levels were lower in adolescents with MDD compared to controls, but did not correlate with anhedonia (either within the MDD group or the full sample), MDD severity, or onset. There were also no group differences in levels of total choline, creatine, and N-acetylaspartate - all neurometabolites that were simultaneously detected with 1H MRS. CONCLUSIONS: Although preliminary, findings add new data to support the role of oxidative stress in MDD and suggest that lower GSH may be a potential marker of MDD early on in the course of illness.

Decreased Anterior Cingulate Cortex γ-Aminobutyric Acid in Youth With Tourette's Disorder.

BACKGROUND: γ-Aminobutyric acid has been implicated in the pathophysiology of Tourette's disorder. The present study primarily sought to examine in vivo γ-aminobutyric acid levels in the anterior cingulate cortex in psychotropic medication-free adolescents and young adults. Secondarily, we sought to determine associations between γ-aminobutyric acid in the anterior cingulate cortex and measures of tic severity, tic-related impairment, and anxiety and depression symptoms. METHODS: γ-Aminobutyric acid levels were measured using proton magnetic resonance spectroscopy. Analysis of covariance compared γ-aminobutyric acid levels in 15 youth with Tourette's disorder (mean age = 15.0, S.D. = 2.7) and 36 healthy comparison subjects (mean age = 15.9, S.D. = 2.1). Within the Tourette disorder group, we examined correlations between γ-aminobutyric acid levels and tic severity and tic-related impairment, as well as anxiety and depression severity. RESULTS: Anterior cingulate cortex γ-aminobutyric acid levels were lower in participants with Tourette's disorder compared with control subjects. Within the Tourette disorder group, γ-aminobutyric acid levels did not correlate with any clinical measures. CONCLUSIONS: Our findings support a role for γ-aminobutyric acid in Tourette's disorder. Larger prospective studies will further elucidate this role.

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.

UNLABELLED: Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing. At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation. PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

Usefulness of proton and phosphorus MR spectroscopic imaging for early diagnosis of Parkinson's disease.

BACKGROUND AND PURPOSE: Cerebral mitochondrial dysfunction has been observed in Parkinson's disease (PD). If mitochondrial dysfunction is an early event contributing to PD development, then noninvasive techniques that detect disturbed energy metabolism in vivo might be useful tools for early diagnosis and treatment monitoring. In the present study, we tested the hypothesis that proton ((1) H) and phosphorus ((31) P) magnetic resonance spectroscopy (MRS) measures of brain metabolites are able to differentiate between individuals with early PD and healthy volunteers (HVs). METHODS: During this cross-sectional study including 20 subjects with early PD and 15 age-matched HV, ventricular lactate (anaerobic glycolysis); and regional levels of N-acetylaspartate (neuronal integrity); choline (membrane turnover); creatine (energy metabolism); ATP and other phosphate-containing compounds (oxidative phosphorylation) were determined using brain (1) H and (31) P MRS. RESULTS: No metabolic abnormalities were detectable in early-stage PD patients. Metabolite concentrations were not related to age, disease duration, or Unified Parkinson's Disease Rating Scale motor scores. DISCUSSION: In early PD, neither (1) H nor (31) P MRS were able to detect metabolic abnormalities, a finding that is in contrast to published data in more advanced PD cohorts. MRS under dynamic conditions might uncover latent energy deficits in early PD, thus warranting future study.

Sex differences in cerebral energy metabolism in Parkinson's disease: a phosphorus magnetic resonance spectroscopic imaging study.

OBJECTIVE: To test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson's disease (PD). METHODS: Phosphorus magnetic resonance spectroscopy ((31)P MRS) was used to determine high-energy phosphate (phosphocreatine and ATP) and low-energy phosphate (free phosphate) levels in the striatum and temporoparietal cortical gray matter (GM) in 10 men and 10 women with PD, matched for age at onset, disease duration, and UPDRS scores. RESULTS: In the hemisphere more affected by PD, both ATP and high energy phosphate (HEP: phosphocreatine + ATP) content in striatum was 15% lower in men versus women with PD (p = .050 and p = .048, respectively). Similar decreases by 16% in ATP (p = .023) and 12% in HEP (p = .046) were observed in GM in men versus women with PD. In contrast, there were no detectable sex differences in ATP or HEP in healthy age-matched controls. CONCLUSIONS: Men with PD have lower levels of ATP and high energy phosphate than women in brain regions affected by PD. These findings suggest that there may be a greater burden of mitochondrial dysfunction in PD in men versus women with PD.

Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers.

OBJECTIVE: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ((1)H MRSI) and to assess their potential as prognostic biomarkers. METHODS: In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with (1)H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]). RESULTS: Consistent with prior studies, the patients with MELAS had higher lactate (p < 0.001) and lower NAA levels (p = 0.01) than HVs. Unexpectedly, converters showed higher NAA (p = 0.042), tCho (p = 0.004), and total creatine (p = 0.002), in addition to higher lactate levels (p = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype. CONCLUSIONS: (1)H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype.

Noninvasive brain stimulation for treatment of right- and left-handed poststroke aphasics.

BACKGROUND: Accumulating evidence from single case studies, small case series and randomized controlled trials seems to suggest that inhibitory noninvasive brain stimulation (NIBS) over the contralesional inferior frontal gyrus (IFG) of right-handers in conjunction with speech and language therapy (SLT) improves recovery from poststroke aphasia. Application of inhibitory NIBS to improve recovery in left-handed patients has not yet been reported. METHODS: A total of 29 right-handed subacute poststroke aphasics were randomized to receive either 10 sessions of SLT following 20 min of inhibitory repetitive transcranial magnetic stimulation (rTMS) over the contralesional IFG or 10 sessions of SLT following sham stimulation; 2 left-handers were treated according to the same protocol with real rTMS. Language activation patterns were assessed with positron emission tomography prior to and after the treatment; 95% confidence intervals for changes in language performance scores and the activated brain volumes in both hemispheres were derived from TMS- and sham-treated right-handed patients and compared to the same parameters in left-handers. RESULTS: Right-handed patients treated with rTMS showed better recovery of language function in global aphasia test scores (t test, p < 0.002) as well as in picture-naming performance (ANOVA, p = 0.03) than sham-treated right-handers. In treated right-handers, a shift of activation to the ipsilesional hemisphere was observed, while sham-treated patients consolidated network activity in the contralesional hemisphere (repeated-measures ANOVA, p = 0.009). Both left-handed patients also improved, with 1 patient within the confidence limits of TMS-treated right-handers (23 points, 15.9-28.9) and the other patient within the limits of sham-treated subjects (8 points, 2.8-14.5). Both patients exhibited only a very small interhemispheric shift, much less than expected in TMS-treated right-handers, and more or less consolidated initially active networks in both hemispheres. CONCLUSION: Inhibitory rTMS over the nondominant IFG appears to be a safe and effective treatment for right-handed poststroke aphasics. In the 2 cases of left-handed aphasics no deterioration of language performance was observed with this protocol. However, therapeutic efficiency is less obvious and seems to be more related to the dominance pattern prior to the stroke than to the TMS intervention.

Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia.

BACKGROUND AND PURPOSE: Modulation of activity in language networks using repetitive transcranial magnetic stimulation (rTMS) may possibly support recovery from poststroke aphasia. Case series and feasibility studies seem to indicate a therapeutic effect; however, randomized sham-controlled, proof-of-principle studies relating clinical effects to activation patterns are missing. METHODS: Twenty-four patients with subacute poststroke aphasia were randomized to a 10-day protocol of 20-minute inhibitory 1 Hz rTMS over the right triangular part of the posterior inferior frontal gyrus or sham stimulation, followed by 45 minutes of speech and language therapy. Activity in language networks was measured with O-15-water positron emission tomography during verb generation before and after treatment. Language performance was assessed using the Aachen Aphasia Test battery. RESULTS: The primary outcome measure, global Aachen Aphasia Test score change, was significantly higher in the rTMS group (t test, P=0.003). Increases were largest for subtest naming (P=0.002) and tended to be higher for comprehension, token test, and writing (P<0.1). Patients in the rTMS group activated proportionally more voxels in the left hemisphere after treatment than before (difference in activation volume index) compared with sham-treated patients (t test, P=0.002).There was a moderate but significant linear relationship between activation volume index change and global Aachen Aphasia Test score change (r2=0.25; P=0.015). CONCLUSIONS: Ten sessions of inhibitory rTMS over the right posterior inferior frontal gyrus, in combination with speech and language therapy, significantly improve language recovery in subacute ischemic stroke and favor recruitment of left-hemispheric language networks.

Prefrontal cortical blood flow predicts response of depression to rTMS.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for resistant major depressive disorder. The response rate of rTMS for depression is modest, motivating the search for biomarkers predictive of treatment response. METHODS: Thirteen patients (mean age 45 years, three males) with current major depression resistant to at least one antidepressant trial in the current episode were treated with a 25 day course of rTMS over the left dorsolateral prefrontal cortex (DLPFC). Resting state cerebral perfusion was measured prior to the first day of treatment and after the final day of treatment. Treatment response was measured using the Hamilton Depression Rating Scale-24 Item (Ham-D). Baseline cerebral perfusion was compared in responders to non-responders. In addition, post-treatment cerebral perfusion was compared to pre-treatment in responders as well as in non-responders. RESULTS: Six individuals responded to rTMS. Responders had greater resting state blood flow in the left DLPFC (the target site) at baseline compared to non-responders. Non-responders showed greater baseline activity in the left medial frontal cortex. Neither group exhibited changes during treatment, nor did the combined group. LIMITATIONS: This study suffers from low sample size and resulting small responder and non-responder subgroups. The sample was not balanced to gender. A normal control group was not included. CONCLUSIONS: We believe this is the first study to compare pre-treatment brain perfusion patterns of depressed individuals who responded to rTMS to those who did not. Our results suggest stronger left DLPFC perfusion in responders and stronger medial prefrontal perfusion in non-responders both at baseline and post-treatment. These results await confirmation in a larger, prospective, placebo-controlled study.

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.

Chronic fatigue syndrome (CFS) is a complex illness, which is often misdiagnosed as a psychiatric illness. In two previous reports, using (1)H MRSI, we found significantly higher levels of ventricular cerebrospinal fluid (CSF) lactate in patients with CFS relative to those with generalized anxiety disorder and healthy volunteers (HV), but not relative to those with major depressive disorder (MDD). In this third independent cross-sectional neuroimaging study, we investigated a pathophysiological model which postulated that elevations of CSF lactate in patients with CFS might be caused by increased oxidative stress, cerebral hypoperfusion and/or secondary mitochondrial dysfunction. Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate; (ii) single-voxel (1)H MRS to measure levels of cortical glutathione (GSH) as a marker of antioxidant capacity; (iii) arterial spin labeling (ASL) MRI to measure regional cerebral blood flow (rCBF); and (iv) (31)P MRSI to measure brain high-energy phosphates as objective indices of mitochondrial dysfunction. We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. GSH did not differ significantly between the two patient groups. In addition, we found lower rCBF in the left anterior cingulate cortex and the right lingual gyrus in patients with CFS relative to HVs, but rCBF did not differ between those with CFS and MDD. We found no differences between the three groups in terms of any high-energy phosphate metabolites. In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability. Collectively, the results of this third independent study support a pathophysiological model of CFS in which increased oxidative stress may play a key role in CFS etiopathophysiology.

Effects of repetitive transcranial magnetic stimulation in aphasic stroke: a randomized controlled pilot study.

BACKGROUND AND PURPOSE: Although functional imaging studies suggest that recruitment of contralesional areas hinders optimal functional reorganization in patients with aphasic stroke, only limited evidence is available on the efficacy of noninvasive brain stimulation such as repetitive transcranial magnetic stimulation aimed at suppression of contralateral overactivation. METHODS: In this randomized, controlled, blinded pilot study, the effect of 1-Hz repetitive transcranial magnetic stimulation over right-hemispheric Broca homolog in subjects with poststroke aphasia in the subacute stage was examined. According to their group allocation, patients received, in addition to conventional speech and language therapy, multiple sessions of repetitive transcranial magnetic stimulation either over the right-hemispheric inferior frontal gyrus (intervention group) or over the vertex (control group). The primary outcome parameter was the change in laterality indices as quantified by activation positron emission tomography before and after the 2-week intervention period. The clinical efficacy was evaluated with the Aachen Aphasia Test. RESULTS: At baseline, no group differences were discovered for age, laterality indices, or mean Aachen Aphasia Test scores. Four patients were lost to follow-up, but none due to side effects of the transcranial magnetic stimulation. Positron emission tomography revealed an activation shift toward the right hemisphere in the control group (P=0.0165), which was absent in the intervention group. Furthermore, the latter improved significantly clinically by a mean of 19.8 points in the Aachen Aphasia Test total score (P=0.002), whereas the control group did not. There was however no clear linear relationship between the extent of laterality shift and clinical improvement (r=0.193, P=nonsignificant). CONCLUSIONS: Repetitive transcranial magnetic stimulation might be an effective, safe, and feasible complementary therapy for poststroke aphasia.

Localizing Broca's area for transcranial magnetic stimulation: Comparison of surface distance measurements and stereotaxic positioning.

BACKGROUND: Precise placement of transcranial magnetic stimulation (TMS) coils over target regions is crucial for correct interpretation of TMS effects. Modern frameless stereotaxic systems yield high accuracy, but require extensive equipment and cannot be used in every setting, for example, during functional imaging sessions. OBJECTIVE: The aim of this study was the development of a method for TMS-coil placement based on individual imaging data without the need for external tracking devices. METHODS: We compared coil positioning over Broca's area using an advanced stereotaxic navigation system with placement according to the surface distance measurements (SDM) method. By using the SDM-method, 3-dimensional renderings adapted from individual T1-weighted magnetic resonance imaging (MRI) data were created to identify Broca's area and Broca's homologue, respectively, and to define anatomic landmarks on the skin's surface. Distances between these landmarks were used to localize the real target on the individual's head. RESULTS: The mean Euclidean distance between surface positions as determined with the two methods was 8.31 mm and the mean difference of estimated virtual electric field intensity at the target point was 7.37 V/m corresponding to 4.01% of maximum field strength. CONCLUSIONS: Our findings suggest that, compared with a state-of-the-art frameless stereotaxy system, the SDM-method yields a reasonable accuracy for positioning of a TMS-coil over Broca's area in terms of spatial coordinates.