Changes in White Matter Microstructure Impact Cognition by Disrupting the Ability of Neural Assemblies to Synchronize.

Cognition is compromised by white matter (WM) injury but the neurophysiological alterations linking them remain unclear. We hypothesized that reduced neural synchronization caused by disruption of neural signal propagation is involved. To test this, we evaluated group differences in: diffusion tensor WM microstructure measures within the optic radiations, primary visual area (V1), and cuneus; neural phase synchrony to a visual attention cue during visual-motor task; and reaction time to a response cue during the same task between 26 pediatric patients (17/9: male/female) treated with cranial radiation treatment for a brain tumor (12.67 ± 2.76 years), and 26 healthy children (16/10: male/female; 12.01 ± 3.9 years). We corroborated our findings using a corticocortical computational model representing perturbed signal conduction from myelin. Patients show delayed reaction time, WM compromise, and reduced phase synchrony during visual attention compared with healthy children. Notably, using partial least-squares-path modeling we found that WM insult within the optic radiations, V1, and cuneus is a strong predictor of the slower reaction times via disruption of neural synchrony in visual cortex. Observed changes in synchronization were reproduced in a computational model of WM injury. These findings provide new evidence linking cognition with WM via the reliance of neural synchronization on propagation of neural signals.SIGNIFICANCE STATEMENT By comparing brain tumor patients to healthy children, we establish that changes in the microstructure of the optic radiations and neural synchrony during visual attention predict reaction time. Furthermore, by testing the directionality of these links through statistical modeling and verifying our findings with computational modeling, we infer a causal relationship, namely that changes in white matter microstructure impact cognition in part by disturbing the ability of neural assemblies to synchronize. Together, our human imaging data and computer simulations show a fundamental connection between WM microstructure and neural synchronization that is critical for cognitive processing.

Gamma deficits as a neural signature of cognitive impairment in children treated for brain tumors.

Cognitive impairment is consistently reported in children treated for brain tumors, particularly in the categories of processing speed, memory, and attention. Although tumor site, hydrocephalus, chemotherapy, and cranial radiation therapy (CRT) are all associated with poorer function, CRT predicts the greatest deficits. There is a particularly high correlation between CRT and slowed information-processing speed. Cortical gamma-band oscillations have been associated with processing behaviorally relevant information; however, their role in the maintenance of cognition in individuals with processing deficits is unclear. We examined gamma oscillations using magnetoencephalography (MEG) in children undergoing CRT to test whether gamma characteristics can be a signature of cognitive impairment in this population. We collected resting-state data as well as data from baseline and active periods during two visual-motor reaction time tasks of varying cognitive loads from 18 healthy children and 20 patients. We found that only high-gamma oscillations (60-100 Hz), and not low-gamma oscillations (30-59 Hz), showed significant group differences in absolute power levels. Overall, compared with healthy children, patients showed the following: (1) lower total high-gamma (60-100 Hz) power during the resting state, as well as during task-related baseline and performance measures; (2) no change in gamma reactivity to increases in cognitive load; and (3) slower processing speeds both inside and outside MEG. Our findings show that high-gamma oscillations are disrupted in children after treatment for a brain tumor. The temporal dynamic of the high-gamma response during information processing may index cognitive impairment in humans with neurological injury.

Relations between white matter maturation and reaction time in childhood.

White matter matures with age and is important for the efficient transmission of neuronal signals. Consequently, white matter growth may underlie the development of cognitive processes important for learning, including the speed of information processing. To dissect the relationship between white matter structure and information processing speed, we administered a reaction time task (finger abduction in response to visual cue) to 27 typically developing, right-handed children aged 4 to 13. Magnetoencephalography and Diffusion Tensor Imaging were used to delineate white matter connections implicated in visual-motor information processing. Fractional anisotropy (FA) and radial diffusivity (RD) of the optic radiation in the left hemisphere, and FA and mean diffusivity (MD) of the optic radiation in the right hemisphere changed significantly with age. MD and RD decreased with age in the right inferior fronto-occipital fasciculus, and bilaterally in the cortico-spinal tracts. No age-related changes were evident in the inferior longitudinal fasciculus. FA of the cortico-spinal tract in the left hemisphere and MD of the inferior fronto-occipital fasciculus of the right hemisphere contributed uniquely beyond the effect of age in accounting for reaction time performance of the right hand. Our findings support the role of white matter maturation in the development of information processing speed.

White matter maturation in visual and motor areas predicts the latency of visual activation in children.

In humans, white matter maturation is important for the improvement of cognitive function and performance with age. Across studies the variables of white matter maturity and age are highly correlated; however, the unique contributions of white matter to information processing speed remain relatively unknown. We investigated the relations between the speed of the visually-evoked P100m response and the biophysical properties of white matter in 11 healthy children performing a simple, visually-cued finger movement. We found that: (1) the latency of the early, visually-evoked response was related to the integrity of white matter in both visual and motor association areas and (2) white matter maturation in these areas accounted for the variations in visual processing speed, independent of age. Our study is a novel investigation of spatial-temporal dynamics in the developing brain and provides evidence that white matter maturation accounts for age-related decreases in the speed of visual response. Developmental models of cortical specialization should incorporate the unique role of white matter maturation in mediating changes in performance during tasks involving visual processing.

Neural and cognitive function in a pediatric brain injury model: The impact of task complexity.

Acquired brain injury (ABI) in childhood/adolescence results in dysfunctional neural and attentional resources during minimal and higher task load. Impact of injury on these resources during increasing load, when task design (e.g., stimuli, timing) is held constant, is not yet well understood. We examined neural communication, processing speed and controlled attention in pediatric brain tumor survivors (PBTS; Mtime since treatment = 6.78 years) and typically developing children (TDC; n = 57). Participants performed simple-go and choice reaction time (RxnT) tasks during magnetoencephalography. The weighted phase lag index estimated seed-based and whole-brain functional connectivity. Group differences were assessed using tmax and network based statistics. Mean RxnT and response accuracy measured performance. Linear models assessed group differences. Tasks were analyzed individually to account for a difference in trial numbers. During both tasks, PBTS demonstrated decreased seed-based connectivity in the high gamma frequency (60-100 Hz; p < .01) relative to TDC. During the choice task alone, PBTS also demonstrated decreased theta (4-7 Hz) and alpha (8-12 Hz) seed-based connectivity (p < .01), and increased RxnT in adolescence (p < .05). ABI in childhood/adolescence may predominantly disrupt recruitment of neural and attentional resources necessary for higher load tasks. These findings advance understanding of the impact of task load on brain function and cognition during development, and effects of injury.

Preliminary Observations of Resting-State Magnetoencephalography in Nonmedicated Children with Obsessive-Compulsive Disorder.

Background: Cortico-striato-thalamo-cortical (CSTC) network alterations are hypothesized to contribute to symptoms of obsessive-compulsive disorder (OCD). To date, very few studies have examined whether CSTC network alterations are present in children with OCD, who are medication naive. Medication-naive pediatric imaging samples may be optimal to study neural correlates of illness and identify brain-based markers, given the proximity to illness onset. Methods: Magnetoencephalography (MEG) data were analyzed at rest, in 18 medication-naive children with OCD (M = 12.1 years ±2.0 standard deviation [SD]; 10 M/8 F) and 13 typically developing children (M = 12.3 years ±2.2 SD; 6 M/7 F). Whole-brain MEG-derived resting-state functional connectivity (rs-fc), for alpha- and gamma-band frequencies were compared between OCD and typically developing (control) groups. Results: Increased MEG-derived rs-fc across alpha- and gamma-band frequencies was found in the OCD group compared to the control group. Increased MEG-derived rs-fc at alpha-band frequencies was evident across a number of regions within the CSTC circuitry and beyond, including the cerebellum and limbic regions. Increased MEG-derived rs-fc at gamma-band frequencies was restricted to the frontal and temporal cortices. Conclusions: This MEG study provides preliminary evidence of altered alpha and gamma networks, at rest, in medication-naive children with OCD. These results support prior findings pointing to the relevance of CSTC circuitry in pediatric OCD and further support accumulating evidence of altered connectivity between regions that extend beyond this network, including the cerebellum and limbic regions. Given the substantial portion of children and youth whose OCD symptoms do not respond to conventional treatments, our findings have implications for future treatment innovation research aiming to target and track whether brain patterns associated with having OCD may change with treatment and/or predict treatment response.

Visuomotor Activation of Inhibition-Processing in Pediatric Obsessive Compulsive Disorder: A Magnetoencephalography Study.

Background: Response inhibition engages the cortico-striato-thalamo-cortical (CSTC) circuit, which has been implicated in children, and youth with obsessive compulsive disorder (OCD). This study explored whether CSTC engagement during response inhibition, measured using magnetoencephalography (MEG), differed in a sample of medication-naïve youth with OCD, compared to typically developing controls (TDC). Methods: Data was analyzed in 17 medication-naïve children and youth with OCD (11.7 ± 2.2 SD years) and 13 TDC (12.6 ± 2.2 SD years). MEG was used to localize and characterize neural activity during a Go/No-Go task. Task performance on Go/No-Go conditions and regional differences in amplitude of activity during Go and No-Go condition between OCD vs. TDC were examined using two-sample t-tests. Post-hoc analysis with Bayesian t-tests was used to estimate the certainty of outcomes. Results: No differences in Go/No-Go performance were found between OCD and TDC groups. In response to the visual cue presented during the Go condition, participants with OCD showed significantly increased amplitude of activity in the primary motor (MI) cortex compared to TDC. In addition, significantly reduced amplitude of PCu was found following successful stopping to No-Go cues in OCD vs. TDC during No-Go task performance. Bayesian t-tests indicated high probability and large effect sizes for the differences in MI and PCu amplitude found between groups. Conclusion: Our preliminary study in a small medication-naïve sample extends previous work indicating intact response inhibition in pediatric OCD. While altered neural response in the current study was found during response inhibition performance in OCD, differences localized to regions outside of the CSTC. Our findings suggest that additional imaging research in medication-naïve samples is needed to clarify regional differences associated with OCD vs. influenced by medication effects, and suggest that MEG may be sensitive to detecting such differences.

Mapping of the cortical spinal tracts using magnetoencephalography and diffusion tensor tractography in pediatric brain tumor patients.

Prior to resection of a cerebral brain tumor, mapping of the functional and structural anatomy of the adjacent tissue is essential to reduce the risk of damage to descending and ascending pathways. We investigated the effectiveness of concurrent magnetoencephalography (MEG) and diffusion tensor imaging (DTI) tractography to delineate the motor cortex and associated corticospinal tract (CST) in a case series of children with brain tumors seen for pre-surgical evaluation. Using activation points generated from MEG to launch tractography, we delineated the CST of four patients and eight control subjects. Displacement of the CST was considerably larger in children with tumors located in the center of the hemisphere than in children whose tumors were more posteriorly located. Our findings suggest that the use of concurrent MEG and DTI may be an effective tool in the pre-surgical evaluation of eloquent cortex and associated white matter tracts in pediatric brain tumor patients.

GABA(A) receptors mediate the opposing roles of dopamine and the tegmental pedunculopontine nucleus in the motivational effects of ethanol.

Recent work has demonstrated that changes in ventral tegmental area (VTA) GABA(A) receptor ion conductance properties are responsible for switching morphine's positive reinforcing properties from a dopamine-independent to a dopamine-dependent pathway when an animal transitions from a non-deprived (minimal drug exposure) to a dependent (chronic drug exposure) and withdrawn state. Here we show that a double dissociation of ethanol's positive reinforcing properties is exactly opposite to that seen with morphine. In C57BL/6 mice, ethanol-conditioned place preferences were blocked in dopamine D2 receptor knockout non-deprived mice, but not by a lesion of the tegmental pedunculopontine nucleus (TPP). On the other hand, TPP lesions, but not a D2 receptor mutation, blocked ethanol-conditioned place preferences in ethanol-dependent and withdrawn mice. The opposite effects of ethanol and opiates can be explained by their proposed actions through a common VTA GABA(A) receptor switching mechanism.

MEG event-related desynchronization and synchronization deficits during basic somatosensory processing in individuals with ADHD.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised. METHODS: We used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms. RESULTS: Healthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8-12 Hz) and beta (15-30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls. CONCLUSION: Our findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input (e.g., detection of a tactile stimulus, stimulus predictability) and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing.

Temporal information processing in ADHD: findings to date and new methods.

The ability to perceive and represent time is a fundamental but complex cognitive skill that allows us to perceive and organize sequences of events and actions, and to anticipate or predict when future events will occur. It is a multidimensional construct, and a variety of methods have been used to understand timing performance in ADHD samples, which makes it difficult to integrate findings across studies. While further replication is needed, growing evidence links ADHD to problems in several aspects of temporal information processing, including duration discrimination, duration reproduction, and finger tapping. Neuroimaging studies of ADHD have also implicated cerebellar, basal ganglia, and prefrontal regions of the brain, which are believed to subserve temporal information processing. This line of research implicates more basic cognitive mechanisms than previously linked with ADHD and challenges researchers to develop and utilize innovative, multidisciplinary, scientific methods to dissect the various components of temporal information processing. Recent advances in neuroimaging, such as magnetoencephalography in collaboration with structural magnetic resonance imaging, can discriminate temporal processing at the level of a millisecond. This approach can lay the groundwork to provide a more precise understanding of neural network activity during different aspects and stages of temporal information processing in ADHD.

Neural correlates of delayed visual-motor performance in children treated for brain tumours.

Both structural and functional neural integrity is critical for healthy cognitive function and performance. Across studies, it is evident that children who are affected by neurological insult commonly demonstrate impaired cognitive abilities. Children treated with cranial radiation for brain tumours suffer substantial structural damage and exhibit a particularly high correlation between the degree of neural injury and cognitive deficits. However the pathophysiology underlying impaired cognitive performance in this population, and many other paediatric populations affected by neurological injury or disease, is unknown. We wished to investigate the characteristics of neuronal function during visual-motor task performance in a group of children who were treated with cranial radiation for brain tumours. We used Magnetoencephalography to investigate neural function during visual-motor reaction time (RT) task performance in 15 children treated with cranial radiation for Posterior Fossa malignant brain tumours and 17 healthy controls. We found that, relative to controls, the patient group showed: 1) delayed latencies for neural activation in both visual and motor cortices; 2) muted motor responses in the alpha (8-12Hz) and beta (13-29Hz) bandwidths, and 3) potentiated visual and motor responses in the gamma (30-100Hz) bandwidth. Collectively these observations indicate impaired neural processing during visual-motor RT performance in this population and that delays in the speed of visual and motor neuronal processing both contribute to the delays in the behavioural response. As increases in gamma activity are often observed with increases in attention and effort, increased gamma activities in the patient group may reflect compensatory neural activity during task performance. This is the first study to investigate neural function in real-time during cognitive performance in paediatric brain tumour patients.

Altered cortical morphology in sensorimotor processing regions in adolescents and adults with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is common in children and frequently persists into adulthood. While ADHD is characterized by developmentally inappropriate, persistent and impairing levels of inattention, impulsiveness and hyperactivity, it is also associated with sensorimotor deficits and altered neural processing of somatosensory stimuli, as well as with executive function deficits. The latter are associated with thinning of frontal lobe structures in ADHD; however, few structural neuroimaging studies have focused on changes in brain morphology in sensorimotor regions in this population. Moreover, little is known about morphological changes that occur in these regions throughout the developmental trajectory into adulthood. In this preliminary cross-sectional study, we examined cortical thickness with a focus on brain regions involved in sensorimotor processing in adolescents and adults with ADHD compared to neurotypical cohorts. Compared to controls, adolescents with ADHD showed significant increased cortical thickness in the pre-supplementary motor area (SMA) and adults with ADHD showed increased thickness in the primary somatosensory cortex (SI). Based on these differences, we collated the data from the adolescents and adults and examined possible age×group interaction effects on cortical thickness. A significant interaction effect was found in SI where healthy participants showed decreased thickness in this region at older ages, whereas the ADHD cohort showed little change. Results suggest that sensorimotor brain regions are altered in ADHD and these changes may not dissipate in adolescence, but rather persist into adulthood.

Abnormal neural reactivity to unpredictable sensory events in attention-deficit/hyperactivity disorder.

BACKGROUND: Cortical oscillations in the sensorimotor region in the 8-12-Hz range ("mu rhythms") are associated with basic somatosensory and motor processes as well as top-down processes such as learning, attention, expectancy, and inhibition. Recent studies suggest that reactivity of these rhythms to sensory input reflects a link between perception and action and that abnormalities in this reactivity might reflect impairment in perception-to-action mechanisms. Individuals with attention-deficit/hyperactivity disorder (ADHD) are impaired in tasks requiring sensorimotor function, attention, expectancy, and inhibition, yet their sensorimotor mu responses are unknown. Thus, we investigated mu reactivity in a group of adults with ADHD. METHODS: Sixteen adults with ADHD and 16 matched control subjects received median nerve stimulation in predictable patterns (trains of four stimuli followed by 4-sec gap) or unpredictable patterns (randomly presented trains of two, four, or six stimuli followed by 4-sec gap). With magnetoencephalography, we examined the effects of stimulus patterning (predictable, unpredictable) on mu reactivity to somatosensory stimuli. RESULTS: Compared with control subjects, the ADHD group showed lower mu reactivity overall and no modulation by unpredictable somatosensory input. By contrast, the control group showed robust mu reactivity to stimuli presented in unpredictable but not predictable patterns. These changes were stronger in the contralateral hemisphere compared with the ADHD group. CONCLUSIONS: Cortical mu rhythms are modulated by stimulus predictability and might be involved in attentional alerting (awareness of when an unexpected stimulus occurs). Diminished mu modulation in adult ADHD suggests a possible underlying deficit in the perception-to-action system.