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.

Cortical endogenous opioids and their role in facilitating repetitive behaviors in deer mice.

Deer mice provide a non-pharmacologically induced model for the study of repetitive behaviors. In captivity, these animals develop frequent jumping and rearing that resemble clinical symptoms of obsessive-compulsive behavior (OCB), autism spectrum disorder (ASD), complex motor stereotypies (CMS), and Tourette's syndrome (TS). In this study, we pursue the mechanism of repetitive behaviors by performing stereological analyses and liquid chromatography/ mass spectrometry (LC-MS/MS) measurements of glutamate (Glut), GABA, 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), leu-enkephalin (leu-enk), and dynorphin-A (dyn-A) in frontal cortex (FC), prefrontal cortex (PFC), and basal ganglia. The only significant stereological alteration was a negative correlation between repetitive behaviors and the cell count in the ventromedial striatum (VMS). Neurochemical analyses demonstrated a significant negative correlation between repetitive behaviors and endogenous opioids (leu-enk and dyn-A) in the FC - the site of origin of habitual behaviors and cortical projections to striatal MSNs participating in direct and indirect pathways. The precise neurochemical process by which endogenous opioids influence synaptic neurotransmission is unknown. One postulated cortical mechanism, supported by our findings, is an opioid effect on cortical interneuron GABA release and a consequent effect on glutamatergic cortical pyramidal cells. Anatomical changes in the VMS could have a role in repetitive behaviors, recognizing that this region influences goal-directed and habitual behaviors.

GABA and glutamate in children with Tourette syndrome: A 1H MR spectroscopy study at 7T.

Tourette syndrome (TS) is characterized by presence of chronic, fluctuating motor and phonic tics. The underlying neurobiological basis for these movements is hypothesized to involve cortical-striatal-thalamo-cortical (CSTC) pathways. Two major neurotransmitters within these circuits are γ-aminobutyric acid (GABA) and glutamate. Seventy-five participants (32 with TS, 43 controls) ages 5-12 years completed 1H MRS at 7T. GABA and glutamate were measured in dorsolateral prefrontal cortex (DLPFC), ventromedial prefrontal cortex (VMPFC), premotor cortex (PMC), and striatum, and metabolites quantified using LCModel. Participants also completed neuropsychological assessment emphasizing inhibitory control. Scans were well tolerated by participants. Across ROIs combined, glutamate was significantly higher in the TS group, compared to controls, with no significant group differences in GABA observed. ROI analyses revealed significantly increased PMC glutamate in the TS group. Among children with TS, increased PMC glutamate was associated with improved selective motor inhibition; however, no significant associations were identified between levels of glutamate or GABA and tic severity. The dopaminergic system has long been considered to have a dominant role in TS. Accumulating evidence, however, suggests involvement of other neurotransmitter systems. Data obtained using 1H MRS at 7T supports alteration of glutamate within habitual behavior-related CSTC pathways of children with TS.

Neurobiology of Tourette's syndrome: concepts of neuroanatomic localization and neurochemical abnormalities.

Despite a preponderance of evidence suggesting an organic rather than psychogenic origin for Tourette syndrome, the precise neurobiological abnormality remains speculative. Neuroanatomically, there is expanding confirmation that cortico-striato-thalamo-cortical pathways represent the site of origin for tics and accompanying neuropsychiatric problems. Pathophysiological hypothesis are generally defined based on involvement of (1) a specific anatomical site (striato-thalamic circuits, striatal compartments), (2) physiologic abnormality (excess thalamic excitation, impaired intracortical inhibition), or (3) involvement of a specific neurotransmitter or synaptic component. This review provides information essential for understanding current and future proposals pertaining to the neurobiology of this intriguing disorder.

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome.

Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). Several research groups have therefore used anatomic magnetic resonance imaging (aMRI) to obtain volumetric measurements of subregions of the frontal lobe in these disorders. Most previous studies have relied on subparcellation methods that utilize callosal landmarks to derive subregions of the frontal lobe. In contrast, we present here an investigation of frontal lobe morphometry in ADHD and TS based on a reliable frontal subparcellation protocol that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules based on prior functional studies. This highly reliable procedure subdivides the frontal lobe into five major modules: prefrontal, premotor, motor (precentral gyrus), anterior cingulate, and deep white matter. The first four modules are also segmented into gray and gyral white matter compartments. The protocol was applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD, 13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found volumetric reductions in both the gray and white matter of the prefrontal cortex. These findings, in conjunction with previous reports on basal ganglia abnormalities, suggest that prefrontal-striatal pathways may be anomalous in ADHD. In TS, we found volumetric decreases in the left deep frontal white matter. Decreases in deep white matter suggest the presence of abnormalities in long associational and projection fiber bundles in TS. The findings of this study both confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating that the reliable parcellation method presented has the potential of increasing our understanding of the role of the frontal lobe in developmental and psychiatric disorders.