From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

BACKGROUND: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. OBJECTIVE: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS. METHODS: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. RESULTS: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. CONCLUSIONS: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society.

Oxidative phosphorylation in creatine transporter deficiency.

X-linked creatine transporter deficiency (CTD) is one of the three types of cerebral creatine deficiency disorders. CTD arises from pathogenic variants in the X-linked gene SLC6A8. We report the first phosphorus (31 P) MRS study of patients with CTD, where both phosphocreatine and total creatine concentrations were found to be markedly reduced. Despite the diminished role of creatine and phosphocreatine in oxidative phosphorylation in CTD, we found no elevation of lactate or lowered pH, indicating that the brain energy supply still largely relied on oxidative metabolism. Our results suggest that mitochondrial function is a potential therapeutic target for CTD.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Elevated lactate as an early marker of brain injury in inflicted traumatic brain injury.

BACKGROUND: Traumatic brain injury is a major cause of disability and death in the pediatric population. The metabolic and neurochemical abnormalities that underlie traumatic brain injury remain poorly understood, but hypoxia-ischemic injury might play an important role. OBJECTIVE: This study evaluated children with inflicted traumatic brain injury using magnetic resonance spectroscopy (MRS). We postulated that children with hypoxic-ischemic injury indicated by elevated lactate in the acute phase of injury will have worse early neurological status and short-term clinical outcomes than those without lactate upon MRS. MATERIALS AND METHODS: This prospective study employed proton MRS to sample bilaterally the frontal lobes and the parasagittal cortex within the parietal and occipital lobes of 11 patients with inflicted traumatic brain injury who were undergoing a clinical MRI examination. Patients' measured clinical course while hospitalized included initial neurological evaluation, presence of seizure activity, need for admission to the pediatric intensive care unit (PICU), number of days hospitalized, presence of retinal hemorrhages and presence of bone fractures. Measurement of outcome was determined using the Pediatric Overall Performance Category Scale (POPCS; 1=good performance; 6=death). RESULTS: Four children demonstrated elevated lactate and diminished N-acetyl aspartate (a neuronal marker) within several regions, indicating global ischemic injury (lactate-positive global group). These four children all had seizure activity and abnormal initial neurological examinations and required admission to the PICU. The mean POPCS for this group was 3.25. In four other children, lactate was detected within at least one region, indicating a focal ischemic injury (lactate-positive focal group); two of these children had seizure activity, and two had an abnormal initial neurological examination. The mean POPCS score was 1.5 for this group. The remaining three children had no evidence of lactate upon MRS (lactate-negative group). These children did not have seizure activity, did not require admission to the PICU, nor did they have initial abnormal neurological examinations. The mean POPCS score was 1.3 for this group. SUMMARY: Patients with inflicted traumatic brain injury and evidence of hypoxic-ischemic injury as indicated by elevated lactate on MRS tend to have worse early neurological status and early outcome scores. Lactate levels as sampled by MRS might predict early clinical outcome in inflicted traumatic brain injury.

Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders.

OBJECTIVE: Few studies have examined the neurochemical abnormalities that might be associated with pediatric bipolar disorder. The aim of this study was to use magnetic resonance spectroscopy to evaluate several brain regions implicated in bipolar disorder in children with a mood disorder and a familial risk for bipolar disorder. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. Specifically, decreased N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr) of the prefrontal cortex and cerebellar vermis would reflect impairments in neuronal function and cellular metabolism, and elevated myo-inositol (mI) would reflect impaired phosphoinositide metabolism, potentially representing early markers of neurophysiologic changes that might underlie the development of bipolar disorder. METHODS: Children with a mood disorder and at least one parent with bipolar disorder (n = 9) and healthy children (n = 10) group matched for age (8-12 years), race, sex, education, and Tanner stage were evaluated using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. Proton magnetic resonance spectroscopy was acquired using 8-cc volumes within the frontal cortex, frontal white matter, and the cerebellar vermis. Metabolite ratios (NAA/Cr, cholines (Cho)/Cr, mI/Cr, NAA/Cho, NAA/mI, and Cho/mI) and concentrations (NAA, Cr, Cho, and mI) were calculated and compared between groups. RESULTS: The trend in concentration levels of NAA and Cr was approximately 8% lower for children with a mood disorder than healthy children within the cerebellar vermis. The frontal cortex in children with a mood disorder revealed elevated mI concentration levels, approximately 16% increased, compared with healthy children. CONCLUSIONS: Similar to findings in adults with bipolar disorders, neurochemical abnormalities within the frontal cortex and the cerebellar vermis were present in this preliminary comparison of children with a mood disorder and a familial risk for bipolar disorder. Larger sample sizes are needed to replicate these findings.

Methylsulfonylmethane observed by in vivo proton magnetic resonance spectroscopy in a 5-year-old child with developmental disorder: effects of dietary supplementation.

Proton magnetic resonance spectroscopy (MRS) revealed a distinct resonance at 3.15 ppm in the brain of a 5-year-old male diagnosed with autism. The resonance assignment is attributable to ingestion of methylsulfonylmethane (MSM) as a dietary supplement. Glucosamine with MSM is marketed as a source of dietary sulfur and treatment of joint pain. Recognition of this chemical on brain proton MRS as an exogenous compound is necessary to avoid confusion as a pathologic metabolite of pediatric metabolic disease.

Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy.

OBJECTIVES: Proton magnetic resonance spectroscopy (MRS) provides insight into neurochemical processes. Imaging and postmortem studies have implicated abnormalities of structure and function within the frontal lobe. Patients with bipolar disorder having a manic or mixed episode were hypothesized to demonstrate metabolic abnormalities within the frontal lobe. METHODS: Seventeen patients with bipolar disorder type I (ages 16-35 years, mean 22 +/- 7.3 years) hospitalized for a manic (n = 9) or mixed (n = 8) episode and 21 healthy subjects (ages 16-35 years, mean 21.7 +/- 5.2 years) were evaluated with proton MRS. The gray matter medially and white matter laterally within the frontal lobe were sampled. Metabolite concentrations were calculated for each voxel, corrected for cerebral spinal fluid (CSF) contributions to the voxel, and compared between study populations. RESULTS: Patients demonstrated with multivariate analyses of variance (MANOVA) a significant overall difference in gray matter metabolite concentrations compared with healthy subjects. The largest effect sizes for group differences were found with reductions of N-acetyl aspartate (NAA) and Choline (Cho) concentrations (f = 0.41 and 0.37, respectively). A significant group difference with MANOVA in white matter metabolite concentrations was also observed with the largest effect size at f = 0.44 for elevation of the composite amino acid (AA) concentration. CONCLUSIONS: A reduction of NAA within the gray matter of patients suggests neuronal dysfunction. Altered phospholipid metabolism suggestive of a trend toward decreased volume is implicated with a reduction of Cho concentrations. Within white matter, composite concentrations of AAs were elevated in patients indicating altered neurotransmission.