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Almost all cortical areas are connected to the subcortical basal ganglia (BG) through parallel recurrent inhibitory and excitatory loops, exerting volitional control over automatic behavior. As this model is largely based on non-human primate research, we used high resolution functional MRI and diffusion tensor imaging (DTI) to investigate the functional and structural organization of the human (pre)frontal cortico-basal network controlling eye movements. Participants performed saccades in darkness, pro- and antisaccades and observed stimuli during fixation. We observed several bilateral functional subdivisions along the precentral sulcus around the human frontal eye fields (FEF): a medial and lateral zone activating for saccades in darkness, a more fronto-medial zone preferentially active for ipsilateral antisaccades, and a large anterior strip along the precentral sulcus activating for visual stimulus presentation during fixation. The supplementary eye fields (SEF) were identified along the medial wall containing all aforementioned functions. In the striatum, the BG area receiving almost all cortical input, all saccade related activation was observed in the putamen, previously considered a skeletomotor striatal subdivision. Activation elicited by the cue instructing pro or antisaccade trials was clearest in the medial FEF and right putamen. DTI fiber tracking revealed that the subdivisions of the human FEF complex are mainly connected to the putamen, in agreement with the fMRI findings. The present findings demonstrate that the human FEF has functional subdivisions somewhat comparable to non-human primates. However, the connections to and activation in the human striatum preferentially involve the putamen, not the caudate nucleus as is reported for monkeys. This could imply that fronto-striatal projections for the oculomotor system are fundamentally different between humans and monkeys. Alternatively, there could be a bias in published reports of monkey studies favoring the caudate nucleus over the putamen in the search for oculomotor functions.

White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ~85%), surface area (~85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = -0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization.

BACKGROUND: Functional neural networks in the human brain can be studied from correlations between activated gray matter regions measured with fMRI. However, while providing important information on gray matter activation, no information is gathered on the co-activity along white matter tracts in neural networks. METHODOLOGY/PRINCIPAL FINDINGS: We report on a functional diffusion tensor imaging (fDTI) method that measures task-related changes in fractional anisotropy (FA) along white matter tracts. We hypothesize that these fractional anisotropy changes relate to morphological changes of glial cells induced by axonal activity although the exact physiological underpinnings of the measured FA changes remain to be elucidated. As expected, these changes are very small as compared to the physiological noise and a reliable detection of the signal change would require a large number of measurements. However, a substantial increase in signal-to-noise ratio was achieved by pooling the signal over the complete fiber tract. Adopting such a tract-based statistics enabled us to measure the signal within a practically feasible time period. Activation in the sensory thalamocortical tract and optic radiation in eight healthy human subjects was found during tactile and visual stimulation, respectively. CONCLUSIONS/SIGNIFICANCE: The results of our experiments indicate that these FA changes may serve as a functional contrast mechanism for white matter. This noninvasive fDTI method may provide a new approach to study functional neural networks in the human brain.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease selectively affecting upper and lower motor neurons. Patients with ALS suffer from progressive paralysis and eventually die on average after three years. The underlying neurobiology of upper motor neuron degeneration and its effects on the complex network of the brain are, however, largely unknown. Here, we examined the effects of ALS on the structural brain network topology in 35 patients with ALS and 19 healthy controls. Using diffusion tensor imaging (DTI), the brain network was reconstructed for each individual participant. The connectivity of this reconstructed brain network was compared between patients and controls using complexity theory without--a priori selected--regions of interest. Patients with ALS showed an impaired sub-network of regions with reduced white matter connectivity (p = 0.0108, permutation testing). This impaired sub-network was strongly centered around primary motor regions (bilateral precentral gyrus and right paracentral lobule), including secondary motor regions (bilateral caudal middle frontal gyrus and pallidum) as well as high-order hub regions (right posterior cingulate and precuneus). In addition, we found a significant reduction in overall efficiency (p = 0.0095) and clustering (p = 0.0415). From our findings, we conclude that upper motor neuron degeneration in ALS affects both primary motor connections as well as secondary motor connections, together composing an impaired sub-network. The degenerative process in ALS was found to be widespread, but interlinked and targeted to the motor connectome.

Almost all cortical areas in the vertebrate brain take part in recurrent connections through the subcortical basal ganglia (BG) nuclei, through parallel inhibitory and excitatory loops. It has been suggested that these circuits can modulate our reactions to external events such that appropriate reactions are chosen from many available options, thereby imposing volitional control over behavior. The saccade system is an excellent model system to study cortico-BG interactions. In this study two possible pathways were investigated that might regulate automaticity of eye movements in the human brain; the cortico-tectal pathway, running directly between the frontal eye fields (FEF) and superior colliculus (SC) and the cortico-striatal pathway from the FEF to the SC involving the caudate nucleus (CN) in the BG. In an event-related fMRI paradigm participants made pro- and anti-saccades. A DTI scan was made for reconstruction of white matter tracts between the FEF, CN and SC. DTI fiber tracts were used to divide both the left and right FEF into two sub-areas, projecting to either ipsilateral SC or CN. For each of these FEF-zones an event-related fMRI timecourse was extracted. In general activity in the FEF was larger for anti-saccades. This increase in activity was lateralized with respect to anti-saccade direction in FEF zones connected to the SC but not for zones only connected to the CN. These findings suggest that activity along the contralateral FEF-SC projection is responsible for directly generating anti-saccades, whereas the pathway through the BG might merely have a gating function withholding or allowing a pro-saccade.

Abstract Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P

BackgroundIndividuals at ultra-high risk for psychosis (UHR) present with subtle alterations in cerebral white matter (WM), which appear to be associated with clinical and functional outcome. The effect of cognitive remediation on WM organization in UHR individuals has not been investigated previously.MethodsIn a randomized, clinical trial, UHR individuals aged 18 to 40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation for 20 weeks. Cognitive remediation comprised 20 x 2-h sessions of neurocognitive and social-cognitive training. Primary outcome was whole brain fractional anisotropy derived from diffusion weighted imaging, statistically tested as an interaction between timepoint and treatment group. Secondary outcomes were restricted to five predefined region of interest (ROI) analyses on fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. For significant timepoint and treatment group interactions within these five ROIs, we explored associations between longitudinal changes in WM and cognitive functions/clinical symptoms. Finally, we explored dose-response effects of cognitive remediation on WM.ResultsA total of 111 UHR individuals were included. Attrition-rate was 26%. The cognitive remediation group completed on average 12 h of neurocognitive training, which was considerably lower than per protocol. We found no effect of cognitive remediation on whole-brain FA when compared to treatment as usual. Secondary ROI analyses revealed a nominal significant interaction between timepoint*treatment of AD in left medial lemniscus (P=0.016) which did not survive control for multiple comparisons. The exploratory test showed that this change in AD correlated to improvements of mental flexibility in the cognitive remediation group (p=0.001). We found no dose-response effect of neurocognitive training on WM.ConclusionsCognitive remediation comprising 12 h of neurocognitive training on average did not improve global or regional WM organization in UHR individuals. Further investigations of duration and intensity of cognitive training as necessary prerequisites of neuroplasticity-based changes are warranted.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02098408.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Intelligence is a measure of general cognitive functioning capturing a wide variety of different cognitive functions. It has been hypothesized that the brain works to minimize the resources allocated toward higher cognitive functioning. Thus, for the intelligent brain, it may be that not simply more is better, but rather, more efficient is better. Energy metabolism supports both inhibitory and excitatory neurotransmission processes. Indeed, in glutamatergic and GABAergic neurons, the primary energetic costs are associated with neurotransmission. We tested the hypothesis that minimizing resources through the excitation–inhibition balance encompassing gamma-aminobutyric acid (GABA) and glutamate may be beneficial to general cognitive functioning using 7 T 1H-MRS in 23 healthy individuals (male/female = 16/7, 27.7 ± 5.3 years). We find that a higher working memory index is significantly correlated with a lower GABA to glutamate ratio in the frontal cortex and with a lower glutamate level in the occipital cortex. Thus, it seems that working memory performance is associated with the excitation–inhibition balance in the brain.

PurposeTo assess reproducibility of glutamate measurement in the human brain by two short echo time (TE) 1H-MRS sequences [stimulated echo acquisition mode (STEAM) and semi-localized by adiabatic selective refocusing (sLASER)] at 7 T. Reliable assessment of glutamate is important when studying a variety of neurological and neuropsychiatric disorders. At 7 T, the glutamate signal can be separated from the glutamine signal and hence more accurately measured as compared to lower field strengths. A sLASER sequence has been developed for 7 T, using field focusing at short TE, resulting in twice as much signal as can be obtained using STEAM and improved localization accuracy due to a decreased chemical shift artifact.Materials and methodsEight subjects were scanned twice using both STEAM and sLASER. Data were acquired from the frontal and occipital brain region. Subsequently, intraclass correlations were computed for the estimated metabolite concentrations.ResultssLASER has higher ICC’s for glutamate concentration as compared to STEAM in both the frontal and occipital VOI, which is probably due to the higher sensitivity and localization accuracy.ConclusionWe conclude that sLASER 1H-MRS at 7 T is a reliable method to obtain reproducible measures of glutamate levels in the human brain at such high accuracy that individual variability, even between age-matched subjects, is measured.

In a previous study we reported on a non-invasive functional diffusion tensor imaging (fDTI) method to measure neuronal signals directly from subtle changes in fractional anisotropy along white matter tracts. We hypothesized that these fractional anisotropy changes relate to morphological changes of glial cells induced by axonal activity. In the present study we set out to replicate the results of the previous study with an improved fDTI scan acquisition scheme. A group of twelve healthy human participants were scanned on a 3 Tesla MRI scanner. Activation was revealed in the contralateral thalamo-cortical tract and optic radiations during tactile and visual stimulation, respectively. Mean percent signal change in FA was 3.47% for the tactile task and 3.79% for the visual task, while for the MD the mean percent signal change was only -0.10% and -0.09%. The results support the notion of different response functions for tactile and visual study. With this study we successfully replicated our previous findings using the same types of stimuli but on a different group of healthy participants and at different field-strength. The successful replication of our first fDTI results suggests that the non-invasive fDTI method is robust enough to study the functional neural networks in the human brain within a practically feasible time period.