Frontostriatal Tracts Research Articles

Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis

Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcomes in long-term survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy without cranial radiation. In this longitudinal analysis, we used data of children with acute lymphoblastic leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA) who had been treated between June 1, 2000, and Oct 31, 2010. Eligible patients were diagnosed with non-B-cell acute lymphoblastic leukaemia, aged at least 8 years, and survivors with at least 5 years since their initial diagnosis. Brain MRIs obtained during active therapy were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event version 4. At least 5 years after their diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioural ratings of their child (Behavior Rating Inventory of Executive Function [BRIEF]). Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy, axial diffusivity, and radial diffusivity from frontal lobes, parietal lobes, and in the frontostriatal tract. The neuroradiologist, who assessed abnormal MRIs, was masked to both group assignment of survivors and the neurobehavioural and neurocognitive outcomes. The primary outcomes were neurobehavioural function, assessed from completed BRIEF, and neurocognitive performance, measured by direct neurocognitive tests (Delis-Kaplan Executive Function System, Wechsler Intelligence Scale for Children-IV/Wechsler Adult Intelligence Scale-III, Rey-Osterrieth Complex Figure Test, and Lafayette Grooved Pegboard Test). This study had completed enrolment in October, 2014, and is registered as an observational study at ClinicalTrials.gov, number NCT01014195. Between Feb 18, 2010, and Oct 22, 2014, 210 (70%) of 301 eligible survivors participated in our study of whom 190 were evaluable, 162 had an MRI. 56 participants had quantitative brain imaging data and were included in evaluable population analyses. 51 (27%) of the 190 evaluable participants had acute leukoencephalopathy. Compared with population norms, survivors were reported to have more neurobehavioural problems with working memory, organisation, initiation, and planning (p<0·001 for all). Survivors had worse scores than the general population on direct measures of memory span, processing speed, and executive function (p<0·05 for all). Survivors with a history of acute leukoencephalopathy had more neurobehavioural problems than survivors with no history of leukoencephalopathy on organisation (adjusted T-score 56·2 [95% CI 53·3-59·1] vs 52·2 [50·4-53·9], p=0·020) and initiation (55·5 [52·7-58·3] vs 52·1 [50·4-53·8], p=0·045). Survivors with acute leukoencephalopathy also had reduced white matter integrity in the frontostriatal tract at follow-up: lower fractional anisotropy (p=0·069), higher axial diffusivity (p=0·020), and higher radial diffusivity (p=0·0077). A one-unit change in the radial diffusivity index corresponded with a 15·0 increase in raw score points on initiation, 30·3 on planning, and 28·0 on working memory (p<0·05 for all). Acute leukoencephalopathy during chemotherapy treatment, without cranial radiation, for childhood acute lymphoblastic leukaemia predicted higher risk for long-term neurobehavioural problems and reduced white matter integrity in frontal brain regions. Survivors of childhood acute lymphoblastic leukaemia might benefit from preventive cognitive or behavioural interventions, particularly those who develop acute leukoencephalopathy. National Institute of Mental Health, National Cancer Institute, American Lebanese Syrian Associated Charities.

Microsurgical and Tractographic Anatomy of the Supplementary Motor Area Complex in Humans

To evaluate the microsurgical anatomy of the fiber tract connections of the supplementary motor area (SMA) and pre-SMA, and examine its potential functional role with reference to clinical trials in the literature. Ten postmortem formalin-fixed human brains (20 sides) and 1 cadaveric head were prepared following Klingler's method. The fiber dissection was performed in a stepwise fashion, from lateral to medial and also from medial to lateral, under an operating microscope, with 3D images captured at each stage. Our findings were supported by invivo magnetic resonance imaging tractography in 2 healthy subjects. The connections of the SMA complex, composed of the pre-SMA and the SMA proper, are composed of short "U" association fibers and the superior longitudinal fasciculus I, cingulum, claustrocortical fibers, callosal fibers, corticospinal tract, frontal aslant tract, and frontostriatal tract. The claustrocortical fibers may play an important role in the integration of motor, language, and limbic functions of the SMA complex. The frontostriatal tract connects the pre-SMA to the putamen and caudate nucleus, and also forms parts of both the internal capsule and the dorsal external capsule. The SMA complex has numerous connections throughout the cerebrum. An understanding of these connections is important for presurgical planning for lesions in the frontal lobe and helps explain symptoms related to SMA injury.

Changes in White Matter Organization in Adolescent Offspring of Schizophrenia Patients.

Schizophrenia is associated with frontostriatal network impairments underlying clinical and cognitive symptoms. We previously found disruptions in anatomical pathways, including the tract connecting the left nucleus accumbens and left dorsolateral prefrontal cortex (DLPFC). Similar deficits are observed in unaffected siblings of schizophrenia patients, indicating that these deficits are linked to a genetic vulnerability for the disorder. Frontostriatal tract disruptions may arise during adolescence, preceding the clinical manifestation of the disorder. However, to date, no studies have been performed to investigate frontostriatal tract connections in adolescents who are at increased familial risk for schizophrenia. In this study, we investigate the impact of familial risk on frontostriatal tract connections using diffusion tensor imaging in 27 adolescent offspring of schizophrenia patients and 32 matched control adolescents, aged 10-18 years. Mean fractional anisotropy (FA) was calculated for the tracts connecting the striatum (caudate nucleus, putamen, nucleus accumbens) and frontal cortex regions (DLPFC, medial orbital frontal cortex, inferior frontal gyrus). As expected, based on siblings data, we found an impact of familial risk on frontostriatal development: schizophrenia offspring showed increased FA in the tracts connecting nucleus accumbens and DLPFC as compared with control adolescents. Moreover, while FA increased across age in control adolescents, it did not in schizophrenia offspring. We did not find differences in FA in other frontostriatal tracts. These results indicate altered development of white matter in subjects who are at familial risk for schizophrenia and may precede frontostriatal white matter alterations in adult schizophrenia patients and siblings.

Frontostriatal anatomical connections predict age- and difficulty-related differences in reinforcement learning

Reinforcement learning (RL) is supported by a network of striatal and frontal cortical structures that are connected through white-matter fiber bundles. With age, the integrity of these white-matter connections declines. The role of structural frontostriatal connectivity in individual and age-related differences in RL is unclear, although local white-matter density and diffusivity have been linked to individual differences in RL. Here we show that frontostriatal tract counts in young human adults (aged 18–28), as assessed noninvasively with diffusion-weighted magnetic resonance imaging and probabilistic tractography, positively predicted individual differences in RL when learning was difficult (70% valid feedback). In older adults (aged 63–87), in contrast, learning under both easy (90% valid feedback) and difficult conditions was predicted by tract counts in the same frontostriatal network. Furthermore, network-level analyses showed a double dissociation between the task-relevant networks in young and older adults, suggesting that older adults relied on different frontostriatal networks than young adults to obtain the same task performance. These results highlight the importance of successful information integration across striatal and frontal regions during RL, especially with variable outcomes.

Right Cortical and Axonal Structures Eliciting Ocular Deviation During Electrical Stimulation Mapping in Awake Patients

To investigate the neural network underpinning eye movements, a cortical and subcortical intraoperative mapping using direct electrical stimulation (DES) was achieved in six awake patients during surgery for a right frontal low-grade glioma. We assessed the relationship between the occurrence of ocular deviation during both cortical and axonal DES and the anatomic location for each response. The corresponding stimulation sites were reported on a standard brain template for visual analysis and between-subjects comparisons. Our results showed that DES of the cortical frontal eye field (FEF) elicited horizontal (anterior FEF) or upward (posterior FEF) eye movements in 3 patients, supporting the fact that FEF comprises several distinct functional subregions. In addition, subcortical stimulation of the white matter tracts underneath the FEF evoked conjugate contraversive ocular deviation in 3 other patients. Interestingly, this region seems to be a crossroad between the fronto-striatal tract, the frontal aslant tract, the inferior fronto-occipital fascicle and the superior longitudinal fascicle. No deficits in eye movements were observed following surgery. To our knowledge, this is the first study reporting ocular deviation during axonal electrostimulation mapping of the white matter fibers in awake patients. Therefore, our original data issued from DES give new insights into the cortical and subcortical structures involved in the control of eye movements and their strong relationships with other functional pathways.

Different neural substrates for executive functions in youths with ADHD: a diffusion spectrum imaging tractography study.

The relationship between white-matter tracts and executive functions (EF) in attention deficit hyperactivity disorder (ADHD) has not been well studied and previous studies mainly focused on frontostriatal (FS) tracts. The authors explored the microstructural property of several fibre tracts hypothesized to be involved in EF, to correlate their microstructural property with EF, and to explore whether such associations differ between ADHD and typically developing (TD) youths. We assessed 45 youths with ADHD and 45 individually matched TD youths with a computerized test battery for multiple dimensions of EF. From magnetic resonance imaging, FS tract, superior longitudinal fasciculus (SLF), arcuate fasciculus (AF) and cingulum bundle (CB) were reconstructed by diffusion spectrum imaging tractography. The generalized fractional anisotropy (GFA) values of white-matter tracts were computed to present microstructural property of each tract. We found lower GFA in the left FS tract, left SLF, left AF and right CB, and poorer performance in set-shifting, sustained attention, cognitive inhibition and visuospatial planning in ADHD than TD. The ADHD and TD groups demonstrated different association patterns between EF and fibre tract microstructural property. Most of the EF were associated with microstructural integrity of the FS tract and CB in TD youths, while with that of the FS tract, SLF and AF in youths with ADHD. Our findings support that the SLF, AF and CB also involve in a wide range of EF and that the main fibre tracts involved in EF are different in youths with ADHD.

Abnormal frontostriatal connectivity in adolescent-onset schizophrenia and its relationship to cognitive functioning

BackgroundAdolescent-onset schizophrenia (AOS) is associated with cognitive impairment and poor clinical outcome. Cognitive dysfunction is hypothesised, in part, to reflect functional dysconnectivity between the frontal cortex and the striatum, although structural abnormalities consistent with this hypothesis have not yet been demonstrated in adolescence. ObjectiveTo characterise frontostriatal white matter (WM) tracts in relation to cognition in AOS. DesignA MRI volumetric and diffusion tensor imaging study. ParticipantsThirty-seven AOS subjects and 24 age and sex-matched healthy subjects. Outcome measuresUsing probabilistic tractography, cortical regions with the highest connection probability for each striatal voxel were determined, and correlated with IQ and specific cognitive functions after co-varying for age and sex. Fractional anisotropy (FA) from individual tracts was a secondary measure. ResultsBayesian Structural Equation modeling of FA from 12 frontostriatal tracts showed processing speed to be an intermediary variable for cognition. AOS patients demonstrated generalised cognitive impairment with specific deficits in verbal learning and memory and in processing speed after correction for IQ. Dorsolateral prefrontal cortex connectivity with the striatum correlated positively with these measures and with IQ. DTI voxel-wise comparisons showed lower connectivity between striatum and the motor and lateral orbitofrontal cortices bilaterally, the left amygdalohippocampal complex, right anterior cingulate cortex, left medial orbitofrontal cortex and right dorsolateral prefrontal cortex. ConclusionsFrontostriatal dysconnectivity in large WM tracts that can explain core cognitive deficits are evident during adolescence. Processing speed, which is affected by alterations in WM connectivity, appears an intermediary variable in the cognitive deficits seen in schizophrenia.

Association Between Acute Leukoencephalopathy and Long-Term Neurobehavioral and Brain Imaging Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated with Chemotherapy Only

▪Introduction: Leukoencephalopathy is observed in a subset of children undergoing chemotherapy for acute lymphoblastic leukemia (ALL), though the impact of these white matter abnormalities on long-term behavior and brain integrity are unknown. This study examines associations between acute (on-therapy) leukoencephalopathy and neurobehavioral ratings and white matter integrity in long-term survivors of ALL treated with chemotherapy only.Methods: 408 patients with newly diagnosed ALL were treated on St. Jude Total XV protocol which omitted cranial irradiation in all patients. Of the 369 patients who had prospective MRI scan of brain during active therapy, 294 were eligible for long-term follow-up and 189 (64%) participated in neurobehavioral assessment and brain imaging when ≥5 years post-diagnosis. Brain MRI's during therapy and at follow-up were systematically coded by a Board Certified Neuroradiologist (blinded to the neurobehavioral outcomes) using the Common Terminology Criteria for Adverse Events (CTCAE) 4.03. At follow-up, survivors' parents completed the Behavior Rating Inventory of Executive Function (BRIEF) to assess survivors' neurobehavioral problems. Diffusion tensor imaging (DTI) was conducted to assess white matter integrity. Fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were extracted from DTI voxels within the frontostriatal tract, given its association with executive function. Generalized linear models were used to examine associations among leukoencephalopathy, long-term neurobehavioral and DTI outcomes, adjusting for current age.Results: Acute leukoencephalopathy was identified in 49 survivors (28.3%), 78% of whom continued to demonstrate leukoencephalopathy at follow-up. Compared to population norms, survivors had more severe problems with working memory (mean[SD] Z-score of 0.60 [1.27]), organization (0.31[1.05]), initiation (0.25[1.10]) and planning (0.33[1.19]), all p's<0.001. Survivors who developed acute leukoencephalopathy displayed more neurobehavioral problems at follow-up than those who did not, adjusting for age at diagnosis and parents' education (Table 1). Acute leukoencephalopathy was associated with reduced white matter integrity at follow-up: lower FA (p=0.03), higher AD (p=0.03) and higher RD (p=0.002). Lower FA at follow-up was associated with more neurobehavioral problems on initiation (Est -19.3, p=0.03), planning (Est -41.3, p=0.007), working memory (Est -40.6, p=0.002) and organization (Est -23.8, p=0.02). Leukoencephalopathy at follow-up was also associated with concurrent abnormalities in white matter integrity and more neurobehavioral problems on planning and organization.Conclusions: Even without cranial radiation, approximately a quarter of ALL patients developed leukoencephalopathy during active therapy, and are at risk for long-term neurobehavioral problems and reduced white matter integrity in frontal brain regions. Survivors who develop early leukoencephalopathy may benefit from preventative cognitive and/or behavioral interventions.Table 1Survivor characteristics:Acute LeukoencephalopathyN (%) / mean [SD]No Acute LeukoencephalopathyN (%) / mean [SD]PMale (%)27 (55)62 (50)0.55Whites (%)35 (71)89 (72)0.75High risk (%)23 (47)48 (39)0.32Current age (years)15.5 [4.8]14.0 [4.6]0.06Age at diagnosis (years)7.6 [5.0]6.4 [4.0]0.38Time since diagnosis (years)7.9 [2.0]7.7 [1.7]0.76Total IV high-dose methotrexate (g/m2)15.0 [4.4]15.6 [7.4]0.69Total no. of intrathecal injections^15.1 [4.0]14.1 [4.0]0.07Total oral dexamethasone (mg/m2)1066.3 [343.0]1108.1 [286.9]0.43BRIEF domains:Neurobehavioral problemsMean [SD]*Initiation0.46 [1.1]0.17 [1.1]0.04Organization of materials0.65 [1.0]0.18 [1.0]0.004Planning0.57 [1.1]0.24 [1.2]0.04Working memory0.74 [1.4]0.54 [1.2]0.16Emotional control0.03 [1.0]0.08 [1.1]0.68Inhibition0.06 [1.1]0.08 [1.2]0.74Shift0.16 [1.3]-0.02 [1.1]0.22Monitor0.08 [1.1]0.02 [1.1]0.33*Age- and gender- adjusted scores with population mean=0 and SD=1. A higher score is indicative of more severe neurobehavioral problems.^Inthrathecal combination of methotrexate, hydrocortisone and cytarabine DisclosuresNo relevant conflicts of interest to declare.

Abnormal asymmetry in frontostriatal white matter in children with attention deficit hyperactivity disorder.

A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD-Combined Type and 22 controls) aged 10-18years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen-VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity; however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries.

Differential age-dependent associations of gray matter volume and white matter integrity with processing speed in healthy older adults

Slower processing speed (PS), a highly robust feature of cognitive aging, is associated with white matter (WM) deterioration and gray matter volume (GMV) loss. Traditional linear regression models assume a constant relationship between brain structure and cognition over time. To probe for variation in the association between WM and GMV and PS over time, we used a novel sparse varying coefficient model on data collected from 126 relatively healthy older adults (67 females, aged 58–85years) evaluated with MRI and a standardized neuropsychological test-battery. We found that WM microstructural differences indexed by fractional anisotropy values in the fronto-striatal tracts (internal and external capsule) showed a stronger association with PS before the age of 70years. Contrastingly, GMV values of the left putamen and middle occipital gyrus were more strongly correlated with PS after 70years. Additionally, within GM and WM compartments, there was heterogeneity in the temporal sequence in which different cortical and subcortical elements were most strongly associated with PS. Together, these observations provide a more nuanced account of the relationships between different structural components of the aging brain and processing speed, a key cognitive domain affected in relatively healthy older adults.

Adolescent impatience decreases with increased frontostriatal connectivity

Adolescence is a developmental period associated with an increase in impulsivity. Impulsivity is a multidimensional construct, and in this study we focus on one of the underlying components: impatience. Impatience can result from (i) disregard of future outcomes and/or (ii) oversensitivity to immediate rewards, but it is not known which of these evaluative processes underlie developmental changes. To distinguish between these two causes, we investigated developmental changes in the structural and functional connectivity of different frontostriatal tracts. We report that adolescents were more impatient on an intertemporal choice task and reported less future orientation, but not more present hedonism, than young adults. Developmental increases in structural connectivity strength in the right dorsolateral prefrontal tract were related to increased negative functional coupling with the striatum and an age-related decrease in discount rates. Our results suggest that mainly increased control, and the integration of future-oriented thought, drives the reduction in impatience across adolescence.

Role of fronto-striatal tract and frontal aslant tract in movement and speech: an axonal mapping study.

Despite a better understanding of their anatomy, the functional role of frontal pathways, i.e., the fronto-striatal tract (FST) and frontal aslant tract (FAT), remains obscure. We studied 19 patients who underwent awake surgery for a frontal glioma (14 left, 5 right) by performing intraoperative electrical mapping of both fascicles during motor and language tasks. Furthermore, we evaluated the relationship between these tracts and the eventual onset of transient postoperative disorders. We also performed post-surgical tract-specific measurements on probabilistic tractography. All patients but one experienced intraoperative inhibition of movement and/or speech during subcortical electrostimulation. On postoperative tractography, the subcortical distribution of stimulated sites corresponded to the spatial course of the FST and/or FAT. Furthermore, we found a significant correlation between postoperative worsening and distances between these tracts and resection cavity. A resection close to the (right or left) FST was correlated with transitory motor initiation disorders (p=0.026), while a resection close to the left FAT was associated with transient speech initiation disorders (p=0.003). Moreover, the measurements of average distances between resection cavity and left FAT showed a positive correlation with verbal fluency in both semantic (p=0.019) and phonemic scores (p=0.017), while average distances between surgical cavity and left FST showed a positive correlation with verbal fluency scores in both semantic (p=0.0003) and phonemic modalities (p=0.037). We suggest that FST and FAT would cooperatively play a role in self-initiated movement and speech, as a part of "negative motor network" involving the pre-supplementary motor area, left inferior frontal gyrus and caudate nucleus.

Association between microstructural integrity of frontostriatal tracts and school functioning: ADHD symptoms and executive function as mediators.

Deficits in executive function (EF), impaired school functioning and altered white matter integrity in frontostriatal networks have been associated with attention-deficit/hyperactivity disorder (ADHD). However, relationships between impairments in these areas are unclear. Using a sample of youths with and without ADHD, this study examined the association between microstructural integrity of frontostriatal tracts and school dysfunction and the mediating roles of EF and ADHD symptoms in this association. The sample included 32 Taiwanese youths with ADHD and 32 age-, sex-, handedness- and IQ-matched typically-developing (TD) youths. Participants were assessed using psychiatric interviews, parent reports on ADHD symptoms and school functioning, and EF measures from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The frontostriatal tracts were reconstructed by diffusion spectrum imaging (DSI) tractography and were subdivided into four functionally distinct segments: caudate-dorsolateral, caudate-medial prefrontal, caudate-orbitofrontal and caudate-ventrolateral tracts. Youths with ADHD, relative to TD youths, showed altered white matter integrity in all four bilateral pairs of frontostriatal tracts (decreased general fractional anisotropy, GFA), had poor attention, vigilance and response inhibition, and showed impaired school functioning. Altered microstructural integrity in frontostriatal tracts was significantly associated with school dysfunction, which was mediated by EF measures of attention/vigilance and response inhibition in addition to inattention and hyperactivity symptoms. Our findings demonstrate an association between white matter integrity in the frontostriatal networks and school functioning and suggest that EF deficits and ADHD symptoms may be the mediating mechanisms for this association. Future research is needed to test the directionality and specificity of this finding.

Assessment of whole brain white matter integrity in youths and young adults with a family history of substance-use disorders.

Individuals with a family history of substance use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH-) and this vulnerability is proportional to the number of affected relatives (FH density). The risk for developing substance use disorders peaks during adolescence to early adulthood in the general population, and that is thought to be related to delayed maturation of frontocortical and frontostriatal functional circuits. We hypothesized that FH+ youth and young adults have impaired myelination of frontocortical and frontostriatal white matter tracts. We examined fractional anisotropy (FA) data in 80 FH+ and 34 FH- youths (12.9 ± 1.0 years) and in 25 FH+ and 30 FH- young adults (24.3 ± 3.4 years). FH+ youths had lower FA values in both frontocortical and frontostriatal tracts as well as parietocortical tracts including the anterior, superior and posterior corona radiata and the superior frontal-occipital fasciculus. Moreover, FA values in these tracts were negatively correlated with FH density. FH+ adults had lower FA values in two frontocortical tracts: the genu of the corpus callosum and anterior corona radiata and also significant negative correlations between FA and FH density in these same tracts. In both groups, lower FA values corresponded to higher radial diffusivity suggesting reduced axonal myelination. We interpreted our findings as evidence for impaired myelination of frontal white matter that was proportional to FH density. Our data suggest that deficits may partially resolve with age, paralleling an age-related decline in risk for developing substance use disorders.

The Role of Fronto-Parietal and Fronto-Striatal Networks in the Development of Working Memory: A Longitudinal Study

The increase in working memory (WM) capacity is an important part of cognitive development during childhood and adolescence. Cross-sectional analyses have associated this development with higher activity, thinner cortex, and white matter maturation in fronto-parietal networks. However, there is still a lack of longitudinal data showing the dynamics of this development and the role of subcortical structures. We included 89 individuals, aged 6-25 years, who were scanned 1-3 times at 2-year intervals. Functional magnetic resonance imaging (fMRI) was used to identify activated areas in superior frontal, intraparietal cortices, and caudate nucleus during performance on a visuo-spatial WM task. Probabilistic tractography determined the anatomical pathways between these regions. In the cross-sectional analysis, WM capacity correlated with activity in frontal and parietal regions, cortical thickness in parietal cortex, and white matter structure [both fractional anisotropy (FA) and white matter volume] of fronto-parietal and fronto-striatal tracts. However, in the longitudinal analysis, FA in white matter tracts and activity in caudate predicted future WM capacity. The results show a dynamic of neural networks underlying WM development in which cortical activity and structure relate to current capacity, while white matter tracts and caudate activity predict future WM capacity.

Neural substrates of behavioral variability in attention deficit hyperactivity disorder: based on ex-Gaussian reaction time distribution and diffusion spectrum imaging tractography

Increased intra-individual variability (IIV) in reaction time (RT) across various tasks is one ubiquitous neuropsychological finding in attention deficit hyperactivity disorder (ADHD). However, neurobiological underpinnings of IIV in individuals with ADHD have not yet been fully delineated. The ex-Gaussian distribution has been proved to capture IIV in RT. The authors explored the three parameters [μ (mu), σ (sigma), τ (tau)] of an ex-Gaussian RT distribution derived from the Conners' continuous performance test (CCPT) and their correlations with the microstructural integrity of the frontostriatal-caudate tracts and the cingulum bundles. We assessed 28 youths with ADHD (8-17 years; 25 males) and 28 age-, sex-, IQ- and handedness-matched typically developing (TD) youths using the CCPT, Wechsler Intelligence Scale for Children, 3rd edition and magnetic resonance imaging (MRI). Microstructural integrity, indexed by generalized fractional anisotropy (GFA), was measured by diffusion spectrum imaging tractrography on a 3-T MRI system. Youths with ADHD had larger σ (s.d. of Gaussian distribution) and τ (mean of exponential distribution) and reduced GFA in four bilateral frontostriatal tracts. With increased inter-stimulus intervals of CCPT, the magnitude of greater τ in ADHD than TD increased. In ADHD youths, the cingulum bundles and frontostriatal integrity were associated with three ex-Gaussian parameters and with μ (mean of Gaussian distribution) and τ, respectively; while only frontostriatal GFA was associated with μ and τ in TD youths. Our findings suggest the crucial role of the integrity of the cingulum bundles in accounting for IIV in ADHD. Involvement of different brain systems in mediating IIV may relate to a distinctive pathophysiological processing and/or adaptive compensatory mechanism.

White matter tract integrity of frontostriatal circuit in attention deficit hyperactivity disorder: association with attention performance and symptoms.

The frontostriatal circuit has been postulated to account for the core symptoms such as inattention in attention deficit/hyperactivity disorder (ADHD). This study investigated the white matter integrity of frontostriatal fiber tracts using diffusion spectrum imaging (DSI) tractography and its correlations with measures of multi-dimensional aspects of inattention based on psychiatric interview and attention tasks in 25 children with ADHD and 25 matched typically developing (TD) children. All the subjects were assessed with comprehensive psychiatric interviews and the Conner's Continuous Performance Test (CCPT). DSI data were acquired on a 3-Tesla MRI system. The frontostriatal fiber pathways were reconstructed by deterministic tractography, and generalized fractional anisotropy values were measured along individual targeted tracts to investigate alterations in microstructure integrity. Children with ADHD performed worse than TD children in the dimensions of focused attention, sustained attention, impulsivity, and vigilance of the CCPT, and showed impaired integrity in four bilateral frontostriatal tracts, namely the dorsolateral-caudate, medial prefrontal-caudate, orbitofrontal-caudate, and ventrolateral-caudate tracts, and in global white matter as well. The integrity of the left orbitofronto-caudate tract was associated with the symptom of inattention in children with ADHD, compatible with the attention deficit and motivational dysfunction theories in ADHD. The integrity of the frontostriatal tracts was associated with the attention performance only in TD children, suggestive of possible recruitment of tracts other than the frontostriatal tracts implicated in attention deficits in children with ADHD. In conclusion, our results demonstrate the functional involvement of the frontostriatal circuit with respect to clinical symptoms and attention performance.

Disturbed microstructural integrity of the frontostriatal fiber pathways and executive dysfunction in children with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is recognized as an early-onset neuropsychiatric disorder with executive dysfunctions and neurobiological deficits. The authors compared executive functions and microstructural integrity of the frontostriatal circuit in children with ADHD and typically developing children. Method We assessed 25 children with ADHD and 25 age-, sex-, handedness- and intelligence-matched typically developing children by using psychiatric interviews, the Wechsler Intelligence Scale for Children - third edition, and the tasks involving executive functions in the Cambridge Neuropsychological Test Automated Battery. The frontostriatal tracts were reconstructed by diffusion spectrum imaging tractography and were subdivided into four functionally distinct segments, including dorsolateral, medial prefrontal, orbitofrontal and ventrolateral tracts. Tract-specific and matched case-control analyses were used and generalized fractional anisotropy values were computed. Children with ADHD had lower generalized fractional anisotropy of all the bilateral frontostriatal fiber tracts and poorer performance in verbal and spatial working memory, set-shifting, sustained attention, cognitive inhibition and visuospatial planning. The symptom severity of ADHD and the executive functioning performance significantly correlated with integrity of the frontostriatal tracts, particularly the left orbitofrontal and ventrolateral tracts. Children with ADHD also demonstrated loss of the leftward asymmetry in the dorsolateral and medial prefrontal tracts that was present in typically developing children. Our findings demonstrate disturbed structural connectivity of the frontostriatal circuitry in children with ADHD and add new evidence of associations between integrity of the frontostriatal tracts and measures of core symptoms of ADHD and a wide range of executive dysfunctions in both groups.

Delay Discounting and Frontostriatal Fiber Tracts: A Combined DTI and MTR Study on Impulsive Choices in Healthy Young Adults

Delay discounting, a measure of impulsive choice, has been associated with decreased control of the prefrontal cortex over striatum responses. The anatomical connectivity between both brain regions in delaying gratification remains unknown. Here, we investigate whether the quality of frontostriatal (FS) white matter tracts can predict individual differences in delay-discounting behavior. We use tract-based diffusion tensor imaging and magnetization transfer imaging to measure the microstructural properties of FS fiber tracts in 40 healthy young adults (from 18 to 25 years). We additionally explored whether internal sex hormone levels affect the integrity of FS tracts, based on the hypothesis that sex hormones modulate axonal density within prefrontal dopaminergic circuits. We calculated fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity, radial diffusivity (RD), and magnetization transfer ratio (MTR), a putative measure of myelination, for the FS tract. Results showed that lower integrity within the FS tract (higher MD and RD and lower FA), predicts faster discounting in both sexes. MTR was unrelated to delay-discounting performance. In addition, testosterone levels in males were associated with a lower integrity (higher RD) within the FS tract. Our study provides support for the hypothesis that enhanced structural integrity of white matter fiber bundles between prefrontal and striatal brain areas is associated with better impulse control.

Fronto-striatal circuitry and inhibitory control in autism: Findings from diffusion tensor imaging tractography

IntroductionRepetitive behaviour and inhibitory control deficits are core features of autism; and it has been suggested that they result from differences in the anatomy of striatum; and/or the ‘connectivity’ of subcortical regions to frontal cortex. There are few studies, however, that have measured the micro-structural organisation of white matter tracts connecting striatum and frontal cortex. AimsTo investigate differences in bulk volume of striatum and micro-structural organisation of fronto-striatal white matter in people with autism; and their association with repetitive behaviour and inhibitory control. MethodsWe compared the bulk volume of striatum (caudate nucleus, putamen and nucleus accumbens) and white matter organisation of fronto-striatal tracts using (respectively) structural magnetic resonance imaging (sMRI) and tract specific diffusion tensor imaging (DTI) measures in 21 adults with autism and 22 controls. We also assessed performance on a cognitive inhibition (go/nogo) task. ResultsBulk volume of striatal structures did not differ between groups. However, adults with autism had a significantly smaller total brain white matter volume, lower fractional anisotropy of white matter tracts connecting putamen to frontal cortical areas, higher mean diffusivity of white matter tracts connecting accumbens to frontal cortex and worse performance on the go/nogo task. Also, performance on the go/nogo task was significantly related to anatomical variation when both groups were combined; but not within the autism group alone. ConclusionsThese data suggest that autism may be associated with differences in the anatomy of fronto-striatal white matter tracts.