Insight into brain sex differences of typically developed infants and brain pathologies: A systematic review.

The continually advancing landscape of neuroscientific and imaging research has broadened our comprehension of sex differences encoded in the human brain, expanding from the hypothalamus and sexual behaviour to encompass the entire brain, including its diverse lobes, structures, and functions. However, less is known about sex differences in the brains of neonates and infants, despite their relevance to various sex-linked diseases that develop early in life. In this review, we provide a synopsis of the literature evidence on sex differences in the brains of neonates and infants at the morphological, structural and network levels. We also briefly overview the present evidence on the sex bias in some brain disorders affecting infants and neonates.

Early assessment of lateralization and sex influences on the microstructure of the white matter corticospinal tract in healthy term neonates.

We assessed the sex and the lateralization differences in the corticospinal tract (CST) during the early postnatal period. Twenty-five healthy term neonates (13 girls, aged 39.2 ± 1.2 weeks, and 12 boys aged 38.6 ± 3.0 weeks) underwent Diffusion Tensor Imaging (DTI). Fiber tracking was performed to extract bilaterally the CST pathways and to quantify the parallel (E1 ) and perpendicular (E23 ) diffusions, the apparent diffusion coefficient (ADC), and fractional anisotropy (FA). The measurements were performed on the entire CST fibers and on four segments: base of the pons (CST-Po), cerebral peduncles (CST-CP), posterior limb of the internal capsule (CST-PLIC), and corona-radiata (CST-CR). Significantly higher E1 , lower E23, and higher FA in the right compared to the left were noted in the CST-PLIC of the girls. Significantly lower E23 and lower ADC with higher FA in the right compared to left were observed in the CST-CP of the boys. Moreover, the CST-PLIC of the boys had significantly higher E1 in the right compared to the left. There was a significant increase in left CST E1 of boys when compared with girls. Girls had a significantly lower E1 , lower E23 and, lower ADC in the left CST-CP compared with boys. In addition, girls had a significantly lower E23 and higher FA in the right CST-PLIC compared with boys. Sex differences and lateralization in structure-based segments of the CST were found in healthy term infants during early postnatal period. These findings are vital to understanding motor development of healthy term born neonates to better interpret newborn infants with abnormal neurodevelopment.

Total cerebrovascular blood flow and whole brain perfusion in children sedated using propofol with or without ketamine at induction: An investigation with 2D-Cine PC and ASL.

BACKGROUND: Multiple sedation regimes may be used to facilitate pediatric MRI scans. These regimes might affect cerebral blood flow and hemodynamics to varying degrees, particularly in children who may be vulnerable to anesthetic side effects. PURPOSE: To compare the effects of propofol monosedation solely (Pm group) vs. a combination of propofol and ketamine (KP group) on brain hemodynamics and perfusion. STUDY TYPE: Prospective double-blind randomized trial. FIELD STRENGTH/SEQUENCES: 1.5T and 3T. 2D-Cine phase contrast (2D-Cine PC) and pseudocontinuous arterial spin labeling (ASL). POPULATION: Children aged from 3 months to 10 years referred for MRI with deep sedation were randomized into either the KP or the Pm group. Perfusion images were acquired with ASL followed by single-slice 2D-Cine PC acquired between the cervical vertebra C2 and C3. ASSESSMENT: Average whole-brain perfusion (WBP ml.min-1 .100 ml-1 ) was extracted from the ASL perfusion maps and total cerebrovascular blood flow (CVF) was quantified by bilaterally summing the flow in the vertebral and the internal carotid arteries. The CVF values were converted to units of ml.min-1 .100 g-1 to calculate the tissue CVF100g (ml.min-1 .100 g-1 ). Images were assessed by a neuroradiologist and data from n = 81 (ASL) and n = 55 (PC) cases with no apparent pathology were entered into the analysis. STATISTICAL TESTS: Multivariate analysis of covariance was performed to compare drug sedation effects on WBP, CVF, and CVF100g . RESULTS: No significant difference in arterial flow was observed (P = 0.57), but the KP group showed significantly higher WBP than the Pm group, covarying for scanner and age (P = 0.003). A correlation analysis showed a significant positive correlation between mean WBP (ml.min-1 .100 g-1 ) and mean CVF100g . DATA CONCLUSION: The KP group showed higher perfusion but no significant difference in vascular flow compared with the Pm group. WBP and CVF100g correlated significantly, but ASL appeared to have more susceptibility to perfusion differences arising from the different sedation regimes. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;50:1433-1440.

Regional differences in interhemispheric structural fibers in healthy, term infants.

Using fiber tracking we investigated the early interhemispheric to cortical development by segmenting the corpus callosum (CC) in five substructures, genu, rostrum, body, isthmus, and splenium, and to examine gender differences in healthy, term neonates. Twenty neonates (11 boys aged 39 ± 2 days, nine girls aged 39 ± 1 days) were scanned in natural sleep with diffusion tensor imging and 35 gradient directions. Fiber tracking was performed using the FACT algorithm. The CC was segments in five substructures on midsagittal imaging. The fiber axial and radial diffusion were measured along with apparent diffusion coefficient and fractional anisotropy. Volume measures were performed for each of these substructures using high-resolution isotropic 3D T1-weighted images. Radial and mean diffusivity in all measured interhemispheric connections were significantly higher in male newborn infants than in female. Second, a gender-dependent regional difference of the measured interhemispheric connections exists. There was no volume difference between boys and girls in any of the five studied sudsubstructures. In addition there was no association between macrostructural and microstructural differences either in boys or girls. The cytoarchitecture and the integrity of the interhemispheric fibers is more developed in female infants in all subdivisions of the CC, except for the isthmus. This might result from a larger axonal diameter, highly packed fibers, or more well-developed myelin sheath. © 2016 Wiley Periodicals, Inc.

Diffusion tensor imaging of patients with proteolipid protein 1 gene mutations.

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder of the central nervous system (CNS) caused by a wide variety of mutations affecting proteolipid protein 1 (PLP1). We assessed the effects of PLP1 mutations on water diffusion in CNS white matter by using diffusion tensor imaging. Twelve patients with different PLP1 point mutations encompassing a range of clinical phenotypes were analyzed, and the results were compared with a group of 12 age-matched controls. The parallel (λ// ), perpendicular (λ⊥ ), and apparent diffusion coefficients (ADC) and fractional anisotropy were measured in both limbs of the internal capsule, the genu and splenium of corpus callosum, the base of the pons, and the cerebral peduncles. The mean ADC and λ⊥ in the PMD patient group were both significantly increased in all selected structures, except for the base of the pons, compared with controls. PMD patients with the most severe disease, however, had a significant increase of both λ// and λ⊥ . In contrast, more mildly affected patients had much smaller changes in λ// and λ⊥ . These data suggest that myelin, the structure responsible in part for the λ⊥ barrier, is the major site of disease pathogenesis in this heterogeneous group of patients. Axons, in contrast, the structures mainly responsible for λ// , are much less affected, except within the subgroup of patients with the most severe disease. Clinical disability in patients with PLP1 point mutation is thus likely determined by the extent of pathological involvement of both myelin and axons, with alterations of both structures causing the most severe disease. © 2014 Wiley Periodicals, Inc.

Altered water diffusivity in cortical association tracts in children with early deprivation identified with Tract-Based Spatial Statistics (TBSS).

Institutional rearing is associated with neurocognitive and behavioral difficulties. Although such difficulties are thought to reflect abnormal neurologic development resulting from early social deprivation (ED) and there is evidence for functional abnormality in children with histories of ED, the impact of early deprivation on brain anatomy has received little study in humans. The present study utilized an objective and sensitive neuroimaging analysis technique (Tract-Based Spatial Statistics) to evaluate white matter fractional anisotropy (FA) and diffusivity in a group of right-handed children with histories of ED (n = 17; mean age = 10.9 + 2.6 years) as compared with age-matched healthy controls (n = 15; mean age = 11.7 + or - 2.8 years). Participants underwent magnetic resonance imaging diffusion tensor imaging sequences and comprehensive neuropsychological evaluations. Results revealed reduced FA in frontal, temporal, and parietal white matter including components of uncinate and superior longitudinal fasciculi, in children with histories of ED, providing further support for limbic and paralimbic abnormalities in children with such histories. Furthermore, white matter abnormalities were associated with duration of time in the orphanage and with inattention and hyperactivity scores. It is suspected that the observed white matter abnormalities are associated with multiple depriving factors (e.g., poor prenatal care, postnatal stress) associated with institutional caregiving.

Alterations in frontal lobe tracts and corpus callosum in young children with autism spectrum disorder.

Major frontal lobe tracts and corpus callosum (CC) were investigated in 32 children with autism spectrum disorder (ASD, mean age: 5 years), 12 nonautistic developmentally impaired children (DI, mean age: 4.6 years), and 16 typically developing children (TD, mean age: 5.5 years) using diffusion tensor imaging tractography and tract-based spatial statistics. Various diffusion and geometric properties were calculated for uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFO), arcuate fasciculus (AF), cingulum (Cg), CC, and corticospinal tract. Fractional anisotropy was lower in the right UF, right Cg and CC in ASD and DI children; in right AF in ASD children; and in bilateral IFO in DI children, compared with TD children. Apparent diffusion coefficient was increased in right AF in both ASD and DI children. The ASD group showed shorter length of left UF and increased length, volume, and density of right UF; increased length and density of CC; and higher density of left Cg, compared with the TD group. Compared with DI group, ASD group had increased length, volume, and density of right UF; higher volume of left UF; and increased length of right AF and CC. Volume of bilateral UF and right AF and fiber density of left UF were positively associated with autistic features.

Abnormal water diffusivity in corticostriatal projections in children with Tourette syndrome.

The fronto-striato-thalamic circuit has been implicated in the pathomechanism of Tourette Syndrome (TS). To study white and gray matter comprehensively, we used a novel technique called Tract-Based Spatial Statistics (TBSS) combined with voxel-based analysis (VBA) of diffusion tensor MR images in children with TS as compared to typically developing controls. These automated and unbiased methods allow analysis of cerebral white matter and gray matter regions. We compared 15 right-handed children with TS (mean age: 11.6 ± 2.5 years, 12 males) to 14 age-matched right-handed healthy controls (NC; mean age: 12.29 ± 3.2 years, 6 males). Tic severity and neurobehavioral scores were correlated with FA and ADC values in regions found abnormal by these methods. For white matter, TBSS analysis showed regions of increased ADC in the corticostriatal projection pathways including left external capsule and left and right subcallosal fasciculus pathway in TS group compared to NC group. Within the TS group, ADC for the left external capsule was negatively associated with tic severity (r= -0.586, P = 0.02). For gray matter, VBA revealed increased ADC for bilateral orbitofrontal cortex, left putamen, and left insular cortex. ADC for the right and left orbitofrontal cortex was highly correlated with internalizing problems (r = 0.665; P = 0.009, r = 0.545; P = 0.04, respectively). Altogether, this analysis revealed focal diffusion abnormalities in the corticostriatal pathway and in gray matter structures involved in the fronto-striatal circuit in TS. These diffusion abnormalities could serve as a neuroimaging marker related to tic severity and neurobehavioral abnormalities in TS subjects.

Fold-Over Oversampling Effects in the Measurements of Cerebral Cerebrospinal Fluid and Blood Flows with 2D Cine Phase-Contrast MRI.

This prospective study investigated the effects of fold-over oversampling on phase-offset background errors with 2D-Cine phase contrast (Cine-PC) magnetic resonance imaging (MRI). It was performed on brain MRI and compared to conventional Full-field of view FOV coverage and it was tested with two different velocity encoding (Venc) values. We chose Venc = 100 mm/s to encode cerebrospinal fluid (CSF) flows in the aqueduct and 600 mm/s to encode blood flow in the carotid artery. Cine-PC was carried out on 10 healthy adult volunteers followed simultaneously by an acquisition on static agar-gel phantom to measure the phase-offset background errors. Pixel-wise correction of both the CSF and the blood flows was calculated through 32 points of the cardiac-cycle. We compared the velocity-to-noise ratio, the section area, the absolute and the corrected velocity (peak; mean and minimum), the net flow, and the stroke volume before and after correction. We performed the statistical T-test to compare Full-FOV and fold-over and Bland-Altman plots to analyze their differences. Our results showed that following phase-offset error correction, the blood stroke-volume was significantly higher with Full-FOV compared to fold-over. We observed a significantly higher CSF mean velocity and net flow values in the fold-over option. Compared to Full-FOV, fold-over provides a significantly larger section area and significantly lower peak velocity-offset in the aqueduct. No significant difference between the two coverages was reported before and after phase-offset in blood flow measurements. In conclusion, fold-over oversampling can be chosen as an alternative to increase spatial resolution and accurate cerebral flow quantification in Cine-PC.

Diffusion tensor imaging of frontal lobe in autism spectrum disorder.

To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 +/- 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 +/- 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.

Absence of arcuate fasciculus in children with global developmental delay of unknown etiology: a diffusion tensor imaging study.

OBJECTIVE: To investigate cortical association tracts using diffusion tensor imaging (DTI) in children with global developmental delay of unknown etiology. STUDY DESIGN: We performed DTI in 20 patients (age range: 18-83 months, mean: 45 +/- 16 months, 12 males) with a history of global developmental delay and 10 typically developing children (age range: 26-99 months, mean: 54 +/- 24 months, 5 males). DTI tractography was performed to isolate major cortical association tracts. RESULTS: In 9 out of 20 patients, arcuate fasciculus (AF) was absent bilaterally and in another 2 patients, it was absent in left hemisphere. In contrast, AF was present bilaterally in all typically developing children. Fractional Anisotropy (FA) of inferior longitudinal fasciculus (ILF) was asymmetric in the control group but not in the developmental delay group (P = .04). FA was significantly reduced in right ILF in developmentally delayed children compared with controls (P = .03). FA of other association tracts was not different between patients and controls (P = NS). The apparent diffusion coefficient (ADC) showed no asymmetry for these tracts in controls or developmentally delayed children (P = NS). CONCLUSIONS: DTI can be used to identify absence of AF and inadequate maturation of ILF in children with global developmental delay of unknown etiology.

Microstructural abnormalities of striatum and thalamus in children with Tourette syndrome.

We applied diffusion-tensor MRI (DT-MRI) to investigate directly the water diffusivity within subcortical gray matter structures comprising the fronto-striato-thalamic (FST) circuit, which is implicated in the pathophysiology of Tourette syndrome (TS). We investigated the structural integrity of basal ganglia and thalamus in 23 children with TS and 35 age-matched healthy controls (NC), and examined the association of DT-MRI measures to tic severity and comorbid symptoms. We measured parallel (lambda(1)) and perpendicular (lambda(23)) diffusivity, mean diffusivity (MD), and fractional anisotropy (FA) in both hemispheres. Compared with NC, the TS group showed a significant increase in lambda(1) (P = 0.003) and MD (P = 0.027) in the bilateral putamen, an increase in lambda(23) in right thalamus (P = 0.008), and a reversed asymmetry of FA (P = 0.03) in the thalamus. There was a significant positive correlation between lambda(23) in right thalamus and tic severity. TS patients showed significantly lower left caudate volume (P = 0.011) and bilateral thalamic volumes (left, P = 0.035, right P = 0.006) compared with NC. These findings support the notion that microstructural dysfunction measured by DT-MRI in component regions of the FST circuit contribute to the pathophysiology in TS.

Diffusion tensor analysis of temporal and extra-temporal lobe tracts in temporal lobe epilepsy.

OBJECTIVE: To determine whether the major temporal lobe white matter tracts in patients with temporal lobe epilepsy manifest abnormal water diffusion properties. METHODS: Diffusion tensor MRI measurements were obtained from tractography for uncinate, arcuate, inferior longitudinal fasciculi and corticospinal tract in 13 children with left temporal lobe epilepsy and normal conventional MRI, and the data were compared to measurements in 12 age-matched normal volunteers. The relationship between tensor parameters and duration of epilepsy was also determined. RESULTS: All four tracts in the affected left hemisphere showed lower mean anisotropy, planar and linear indices, but higher spherical index in patients versus controls. Diffusion changes in the left uncinate and arcuate fasciculus correlated significantly with duration of epilepsy. Arcuate fasciculus showed a reversal of the normal left-right asymmetry. Various diffusion abnormalities were also seen in the four tracts studied in the right hemisphere. CONCLUSION: Our findings indicate abnormal water diffusion in temporal lobe and extra-temporal lobe tracts with robust changes in the direction perpendicular to the axons. Diffusion abnormalities associated with duration of epilepsy suggest progressive changes in ipsilateral uncinate and arcuate fasciculus due to chronic seizure activity. Finally, our results in arcuate fasciculus are consistent with language reorganization to the contralateral right hemisphere.

Diffusion tensor imaging of brain plasticity after occipital lobectomy.

Reorganization involving residual visual pathways with unilateral damage to the primary visual cortex was previously described. Using diffusion tensor imaging, we measured water diffusion-related changes in the optic radiation contralateral to occipital lobe ablation in children with intractable epilepsy. We studied 10 children who had undergone a resection of the unilateral occipital cortex and 13 control subjects. Diffusion tensor imaging was acquired using a 1.5 Tesla magnetic resonance scanner. Fiber bundles representing optic radiation were tracked. Diffusion parameters included mean fractional anisotropy, apparent diffusion coefficient, and diffusion parallel and perpendicular to the fiber tract. In the surgical group, fractional anisotropy values of optic radiation contralateral to the side of resection exhibited a significant positive partial correlation (r = 0.752, P = 0.019) with duration of time between surgery and diffusion tensor imaging acquisition, after controlling for age. The apparent diffusion coefficient and parallel diffusivity were higher in the surgical versus the control group, but did not differ among patients. After unilateral resection of the occipital lobe, the contralateral optic radiation undergoes significant changes in anisotropy. Such structural white-matter changes may represent an adaptive response because of unilateral occipital ablation, and may account for plasticity changes observed in functional magnetic resonance imaging.

An innovative approach to investigate the dynamics of the cerebrospinal fluid in the prepontine cistern: A feasibility study using spatial saturation-prepared cine PC-MRI.

PURPOSES: Accurate measurements of the cerebrospinal fluid that flows through the prepontine cistern (PPC) are challenging due to artefacts originating from basilar artery blood flow. We aim to accurately quantify cerebrospinal fluid (CSF) flow and stroke volume in the PPC, which is essential before endoscopic third ventriculostomy. MATERIALS AND METHODS: We developed a new PC-MRI sequence prepared with Hadamard saturation bands to accurately quantify CSF flow in the PPC by suppressing the blood signal in the surrounding vessels. In total, 28 adult hydrocephalic patients (age 59 ± 20 years) were scanned using conventional PC-MRI and our developed sequence. CSF was separately extracted from the PPC and the foramen of Magendie, and flow (min and max) and stroke volume were quantified. RESULTS: Our modifications result in a complete deletion of signal from flowing blood, resulting in significantly reduced CSF stroke volume (Conv = 446 ± 113 mm(3), Dev = 390 ± 119 mm(3), p = 0.006) and flow, both minimum (Conv = -1630 ± 486 mm(3)/s, Dev = -1430 ± 406 mm(3)/s, p = 0.005) and maximum (Conv = 2384 ± 657 mm(3)/s, Dev = 1971 ± 62 mm(3)/s, p = 0.002) compared with the conventional sequence, whereas no change in the area of interest was noted (Conv = 236 ± 65 mm(2), Dev = 249 ± 75 mm(2), p = 0.21). CONCLUSIONS: Accurate and reproducible CSF flow and stroke volume measurements in the PPC can be achieved with sat-band prepared cine PC-MRI.

The role of the thalamus in neuro-cognitive dysfunction in early unilateral hemispheric injury: a multimodality imaging study of children with Sturge-Weber syndrome.

BACKGROUND: Sturge-Weber syndrome (SWS) with unilateral hemispheric involvement is a clinical model of early onset, chronic, often progressive hemispheric injury, resulting in variable neuro-cognitive impairment. AIMS: To evaluate if abnormal diffusion and metabolism of the thalamus, a central relay station with extensive cortical connections, may serve as a simple imaging marker of neuro-cognitive dysfunction in SWS. METHODS: We obtained both diffusion tensor imaging and FDG PET in 20 children (11 girls; age range: 3-12.4 years) with unilateral SWS. Diffusion parameters as well as FDG uptake were measured in thalami, compared to normal control values, and correlated with the extent of cortical hypometabolism, deep venous abnormalities and cognitive (IQ) as well as fine motor functions. RESULTS: Children with SWS had significantly higher thalamic glucose metabolic asymmetry than controls (p=0.001). Thalamic metabolic asymmetries correlated positively with the asymmetry of thalamic diffusivity (p=0.001) and also with the extent of cortical hypometabolism (p<0.001). Severe thalamic asymmetries of glucose metabolism and diffusion were strong predictors of low IQ (metabolism: p=0.002; diffusivity: p=0.01), even after controlling for age and extent of cortical glucose hypometabolism in children with left hemispheric involvement. Ipsilateral thalamic glucose hypometabolism was also associated with impairment of fine motor functions (p=0.002). CONCLUSIONS: Both diffusion and glucose metabolic abnormalities of the thalamus are closely related to cognitive functions, independent of age and cortical metabolic abnormalities, in children with unilateral SWS. Thalamic metabolic asymmetry is a robust but simple imaging marker of neuro-cognitive outcome in children with early unilateral hemispheric injury caused by Sturge-Weber syndrome.

Multimodality neuroimaging in Tourette syndrome: alpha-[11C] methyl-L-tryptophan positron emission tomography and diffusion tensor imaging studies.

Previous studies in Tourette syndrome have reported lateralized abnormalities of neurotransmitters and microstructure of the cortico-striato-thalamo-cortical circuit. The authors analyzed the relationship between serotonin synthesis and microstructural changes in the subcortical structures (caudate nucleus, lentiform nucleus, and thalamus) related to this circuit, using alpha-[(11)C]methyl-L-tryptophan positron emission tomography (PET) and diffusion tensor imaging, respectively, in 16 children with Tourette syndrome. Correlations between diffusion tensor imaging and alpha-[(11)C]methyl-L-tryptophan PET asymmetry values were found in the caudate nucleus. The findings suggested higher serotonin synthesis on the side of more abnormal diffusion, characterized by lower fractional anisotropy and parallel diffusivity but higher perpendicular diffusivity. Altogether, these imaging abnormalities suggest asymmetric immature microstructure in the caudate nucleus associated with abnormally increased serotonin synthesis in Tourette syndrome. The observed diffusion tensor imaging changes are likely related to abnormal connectivity in the cortico-striato-thalamo-cortical circuit, which may result in cortical disinhibition and increased serotonin synthesis; this could provide a new therapeutic target.

Altered fronto-striato-thalamic connectivity in children with Tourette syndrome assessed with diffusion tensor MRI and probabilistic fiber tracking.

The aim of the study was to determine whether abnormal connectivity of the fronto-striato-thalamic circuit underlies the morphological changes in subcortical structures of patients with Tourette syndrome and to correlate these changes with neurobehavioral measures. A total of 18 children with Tourette syndrome and 12 age-matched healthy controls underwent diffusion tensor magnetic resonance imaging. Tractography of the fronto-striato-thalamic circuit was achieved using probability distribution function of individual voxels. The Tourette syndrome group had significantly lower probability of connection between caudate nucleus and anterior-dorsolateral-frontal cortex on the left (P = .038). Obsessive-compulsive behavior was negatively associated with connectivity score of the left caudate and anterior dorsolateral frontal cortex (P = .01) and was positively associated with connectivity score for the subcallosal gyrus (P = .009) and for the lentiform nucleus (P = .008). The abnormal connectivity among components of the fronto-striato-thalamic circuit bilaterally (ie, seeds on the caudate and thalamus) in patients with Tourette syndrome provides direct evidence for the involvement of these circuits in the pathophysiology.