Frontiers in Human Neuroscience

Published by Frontiers
Online ISSN: 1662-5161
Publications
Article
The 1000 Functional Connectomes Project is a collection of resting-state fMRI datasets from more than 1000 subjects acquired in more than 30 independent studies from around the globe. This large, heterogeneous sample of resting-state data offers the unique opportunity to study the consistencies of resting-state networks at both subject and study level. In extension to the seminal paper by Biswal et al. (2010), where a repeated temporal concatenation group independent component analysis (ICA) approach on reduced subsets (using 20 as a pre-specified number of components) was used due to computational resource limitations, we herein apply Fully Exploratory Network ICA (FENICA) to 1000 single-subject independent component analyses. This, along with the possibility of using datasets of different lengths without truncation, enabled us to benefit from the full dataset available, thereby obtaining 16 networks consistent over the whole group of 1000 subjects. Furthermore, we demonstrated that the most consistent among these networks at both subject and study level matched networks most often reported in the literature, and found additional components emerging in prefrontal and parietal areas. Finally, we identified the influence of scan duration on the number of components as a source of heterogeneity between studies.
 
Color choices in the first presentation of digits (0–9) in Sessions 1–3 for synesthete JC (i.e., over 4 years) and those from an aged matched control SB (over 10 s; in Session 1).
Percentage of consistent colors selected by the three participant groups (see legend) in their immediate consistency of 36 graphemes within Sessions 1, 2 and 3 (ages 6/7, 7/8, 10/11 respectively). Intervening years have no data because no testing took place at these ages.
Number of consistent colors selected within Sessions 1, 2 and 3 (ages 6/7, 7/8, 10/11 respectively) for letter-color synesthetes (out of 26; left panel) and digit-color synesthetes (out of 10; right panel). Black lines indicate Session 3 and 2 synesthetes; gray lines indicate Session 3 (only) synesthetes; dotted lines indicate Session 2 (only) synesthetes; dash/dotted lines with diamond data-markers indicate the means of average memory controls.
Session 3 synesthetes and “near-misses,” indicated by checks and question marks respectively.
Article
Grapheme-color synesthesia is a condition characterized by enduring and consistent associations between letter/digits and colors. This study is the continuation of longitudinal research begun by Simner et al. (2009) which aimed to explore the development of this condition in real time within a childhood population. In that earlier study we randomly sampled over 600 children and tested them aged 6/7 and 7/8 years. We identified the child synesthetes within that cohort and measured their development over 1 year, in comparison to a group of non-synesthetic children with both average and superior memories. We were able to show the beginnings of a developmental progression in which synesthetic associations (e.g., A = red) mature over time from relatively chaotic pairings into a system of fixed consistent associations. In the current study we return to this same population three years later when participants are now 10/11 years. We used the same paired-association memory task to determine the synesthetic status of our participants and to also establish synesthetes' inventories of grapheme-color associations. We compared their inventories to those from age 6/7 and 7/8 years to examine how synesthesia matures over time. Together with earlier findings, our study shows that grapheme-color synesthesia emerges with a protracted trajectory, with 34% of letters/digits fixed at age 6/7 years, 48% fixed at 7/8 years and 71% fixed at 10/11 years. We also show several cases where synesthesia is not developing in the same time-frame as peers, either because it has died out at an older age, or because it was slower to develop than other cases. Our study paints the first picture of the emergence of synesthesia in real-time over four years within a randomly sampled population of child synesthetes.
 
Article
Background: A major motivation in designing the new infant and child magnetoencephalography (MEG) system described in this manuscript is the premise that electrophysiological signatures (resting activity and evoked responses) may serve as biomarkers of neurodevelopmental disorders, with neuronal abnormalities in conditions such as autism spectrum disorder (ASD) potentially detectable early in development. Whole-head MEG systems are generally optimized/sized for adults. Since magnetic field produced by neuronal currents decreases as a function of distance(2) and infants and young children have smaller head sizes (and thus increased brain-to-sensor distance), whole-head adult MEG systems do not provide optimal signal-to-noise in younger individuals. This spurred development of a whole-head infant and young child MEG system - Artemis 123. Methods: In addition to describing the design of the Artemis 123, the focus of this manuscript is the use of Artemis 123 to obtain auditory evoked neuromagnetic recordings and resting-state data in young children. Data were collected from a 14-month-old female, an 18-month-old female, and a 48-month-old male. Phantom data are also provided to show localization accuracy. Results: Examination of Artemis 123 auditory data showed generalizability and reproducibility, with auditory responses observed in all participants. The auditory MEG measures were also found to be manipulable, exhibiting sensitivity to tone frequency. Furthermore, there appeared to be a predictable sensitivity of evoked components to development, with latencies decreasing with age. Examination of resting-state data showed characteristic oscillatory activity. Finally, phantom data showed that dipole sources could be localized with an error less than 0.5 cm. Conclusions: Artemis 123 allows efficient recording of high-quality whole-head MEG in infants four years and younger. Future work will involve examining the feasibility of obtaining somatosensory and visual recordings in similar-age children as well as obtaining recordings from younger infants. Thus, the Artemis 123 offers the promise of detecting earlier diagnostic signatures in such neurodevelopmental disorders.
 
Summary of metabolic abnormalities in the patients evaluated in this study. Abbreviations: IEM, inborn errors of metabolism; 3-OH-IVA, 3 hydroxyisovaleric acid; GLT, glucose loading test; b-OH-b, β-hydroxybutyrate; MC, methylcitrate.
Article
We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.
 
FMT uptake values in normal humans and monkeys.
Time-activity curves.
Human PET-FMT image.
Monkey PET-FMT images.
Article
Although positron emission tomography (PET) and the aromatic L-amino acid decarboxylase (AADC) tracer 6-[(18)F]fluoro-L-m-tyrosine (FMT) has been used to assess the integrity of the presynaptic dopamine system in the brain, relatively little has been published in terms of brain FMT uptake values especially for normal human subjects. Twelve normal volunteer subjects were scanned using PET and FMT to determine the range of normal striatal uptake values using Patlak graphical analysis. For comparison, seven adult rhesus monkeys were studied and the data analyzed in the same way. A subset of monkeys that were treated with a unilateral intracarotid artery infusion of the dopamine neurotoxin MPTP showed an 87% decrease in striatal FMT uptake. These findings support the use of PET and FMT to image AADC distribution in both normal and diseased brains using Patlak graphical analysis and tissue input functions.
 
| Demarcation of the corpus callosum regions of interest (ROIs): genu (red) and splenium (blue). The ROIs are displayed on a fractional anisotropy map.  
| Sample demographic information by BDNF genotype and total sample: mean ± SD.
| The effects of BDNF 66met allele on age-related differences in fractional anisotropy of genu (upper panel) and splenium (lower panel) of the corpus callosum. Black solid line and circles correspond to val homozygotes; red broken line and triangles correspond to val/met heterozygotes.
Article
Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and promotes axonal growth, but its secretion, regulated by a BDNF gene, declines with age. The low-activity (met) allele of common polymorphism BDNF val66met is associated with reduced production of BDNF. We examined whether age-related reduction in the integrity of cerebral white matter (WM) depends on the BDNF val66met genotype. Forty-one middle-aged and older adults participated in the study. Regional WM integrity was assessed by fractional anisotropy (FA) computed from manually drawn regions of interest in the genu and splenium of the corpus callosum on diffusion tensor imaging scans. After controlling for effects of sex and hypertension, we found that only the BDNF 66met carriers displayed age-related declines in the splenium FA, whereas no age-related declines were shown by BDNF val homozygotes. No genotype-related differences were observed in the genu of the corpus callosum. This finding is consistent with a view that genetic risk for reduced BDNF affects posterior regions that otherwise are considered relatively insensitive to normal aging. Those individuals with a genetic predisposition for decreased BDNF expression may not be able to fully benefit from BDNF-based plasticity and repair mechanisms.
 
| PEDro scores of included studies.
| PA intervention on neglect.
Overview of the search and selection process.
Rehabilitation interventions versus any control, outcome: immediate effects.
Rehabilitation interventions versus any control, outcome: long-lasting effects.
Article
A systematic review of the effectiveness of rehabilitation for persons with unilateral neglect (UN) after stroke was conducted by searching the computerized databases from 1997 through 2012. Randomized controlled trials (RCTs) of neglect treatment strategies for stroke patients which used the Behavioral Inattention Test (BIT) as the primary outcome measure were eligible for inclusion. Out of 201 studies initially identified, 12 RCTs covering 277 participants were selected for analysis. All had the same weakness of low power with smaller samples and limitation in the blinding of the design. Prism Adaptation (PA) was the most commonly used intervention while continuous Theta-burst stimulation (cTBS) appeared to be a new approach. Meta-analysis showed that for immediate effects, the BIT conventional subscore had a significant and large mean effect size (ES = 0.76; 95% CI 0.28-1.23; p = 0.002) whereas the BIT total score showed a modestly significant mean ES (ES = 0.55; 95% CI 0.16-0.94; p = 0.006). No significant mean ES in sensitivity analysis was found for long-lasting effects across all BIT outcomes. PA appeared to be the most effective intervention based on the results of pooled analysis. More rigorous studies should be done on repetitive transcranial magnetic stimulation (rTMS) before it can be concluded that it is a promising treatment for UN.
 
Article
There is converging evidence that electrophysiological responses over posterior cortical regions in the 200-300 ms range distinguish between physically identical stimuli that reach consciousness or remain unseen. Here, we attempt at determining the sources of this awareness-related activity using magneto-encephalographic (MEG). Fourteen subjects were presented with faint colored gratings at threshold for contrast and reported on each trial whether the grating was seen or unseen. Subjects were primed with a color cue that could be congruent or incongruent with the color of the grating, to probe to what extent two co-localized features (color and orientation) would be bound in consciousness. The contrast between neural responses to seen and unseen physically identical gratings revealed a sustained posterior difference between 190 and 350 ms, thereby replicating prior studies. We further show that the main sources of the awareness-related activity were localized bilaterally on the lateral convexity of the occipito-temporal region, in the Lateral Occipital (LO) complex, as well as in the right posterior infero-temporal region. No activity differentiating seen and unseen trials could be observed in frontal or parietal regions in this latency range, even at lower threshold. Color congruency did not improve grating's detection, and the awareness-related activity was independent from color congruency. However, at the neural level, color congruency was processed differently in grating-present and grating-absent trials. The pattern of results suggests the existence of a neural process of color congruency engaging left parietal regions that is affected by the mere presence of another feature, whether this feature reaches consciousness or not. Altogether, our results reveal an occipital source of visual awareness insensitive to color congruency, and a simultaneous parietal source not engaged in visual awareness, but sensitive to the manipulation of co-localized features.
 
Schematic representation of the Two-Stage Framework linking the cognitive and cerebral levels in expertise acquisition, through two examples. The “Examples” section shows the evolution of the effect of knowledge on how items to-be-remembered are processed: at first, items are processed almost separately, later, items are regrouped in chunks, and finally in knowledge structures, which can be viewed as super-chunks that regroup multiple chunks into a high-level pattern. In the “Cerebral Level” section, the representation of brain activity is at an ordinal scale. SST stands for statistical significance threshold; if brain activity is beneath this threshold, it goes undetected. PFC stands for prefrontal cortex, PL for parietal lobe, and MTL for medial temporal lobe. The first MTL activity on the left is almost at the same level than the statistical significance threshold in order to indicate that for novices, brain activity is sometimes detected (see section “Concluding Remarks”). For novices, detection seems to vary according to the kind of experimental paradigm, the parameters and maybe the participants of the experiments. If one considers that the MTL activity is above the statistical significance threshold for novices then functional cerebral reorganization is better suited to describe expertise acquisition; if it is beneath, then functional cerebral redistribution is better suited.
Article
In 2012, Guida, Gobet, Tardieu and Nicolas proposed a two-stage framework to explain how cognitive changes due to practice could shape experts' brain physiologically and thus explain neuroimaging data of expertise acquisition. In this paper, after presenting the motivations for such a framework and the framework itself, we examine the idea that functional cerebral reorganization (FCR) could be used as a signature for expertise.
 
Article
The timing of motor imagery has recently received attention from a number of researchers, culminating in a comprehensive review by Guillot and colleagues. This paper aims to further explore this issue, building upon the said review to suggest a number of other important timing-related issues. Specifically, we consider the possible role of bio-informational theory (Lang, 1979, 1985) and the recent proposal of "behavioral matching" in conjunction with the PETTLEP model (Holmes and Collins, 2001) of motor imagery. Furthermore, we explore the possibility that timing has important implications for motivational aspects of imagery. We then discuss the potential role of rhythm, an important but often overlooked aspect of skilled motor performance, and its links to the timing issue. Finally, we conclude by offering suggestions for future imagery timing research to examine this relatively under-researched area of imagery.
 
Article
In 2008, Lesley University Professors Geoffrey Koetsch and Ellen Schön conducted an informal survey of New England artists to ascertain the degree to which recent work in neuroscience had impacted the visual arts. The two curators mounted an exhibition (MINDmatters May-June, 2008) at the Laconia Gallery in Boston in which they showcased the work of artists who had chosen mental processes as their primary subject. These artists were reacting to the new vision of the mind revealed by science; their inquiry was subjective, sensory, and existential, not empirical. They approached consciousness from several vantage points. Some of the artists had had personal experience with pathologies of the brain such as dementia or cancer and were puzzling out the phenomenon consuming the mind of a loved one. They looked to neuroscience for clarity and understanding. Some artists were personally involved with new techniques of cognitive psychotherapy. Others were inspired by the sheer physical beauty of the brain as revealed by new imaging technologies. Two of the artists explored the links between meditation, mindfulness practice and neuroscience. Issues such as the "boundary" and "binding" problems were approached, as well as the challenge of creating visual metaphors for neural processes. One artist visualized the increasing transparency of the body as researchers introduce more and more invasive technologies.
 
Among the Desikan parcellation scheme, the regions elected as similar to Allen's model areas are the represented in full color and the remainder parcels are in faded color. On the lateral view: the superior temporal is cyan, the rostral middle frontal is purple, the lateral orbitofrontal is dark green, the pars orbitalis is khaki, the pars triangularis is dark orange, and the pars opercularis is beige. On the medial view, the medial orbitofrontal is fuchsia, the rostral anterior cingulate is dark purple, and the caudal cingulate is parme.
Final ranking of the 82 gray matter regions in the healthy controls' brain. The 17 nodes with the highest rank highlighted in yellow, are considered as the connector hubs of the network. In blue is represented the repartition of the final ranking for the control and in red for the 22q11.2DS.
Graph representation of the mean brain network for patients and controls using Gephi (http://gephi.org/) to produce optimal visualization of all the nodes and connections embedded in the networks. The circled nodes are the hubs of the network. The red circles are altered hubs and the black circles are preserved hubs. Every nodes contained in the same lobe or cerebral structure has the same color, blue for the node of the frontal lobe, magenta for the cingulate areas, green for the parietal lobe, yellow for the occipital lobe, brown for the temporal lobe and gray for the subcortical areas. The size of the nodes indicates their degree level.
Correlations between the BPRS hallucination subscale and the network efficiency in individuals with 22q11.2DS after age and gender correction. On the left hemisphere, the red regions (pars triangularis and transverse temporal) represent a negative correlation and the blue region (rostral middle frontal) represents a positive correlation.
Article
Schizophrenia is postulated to be the prototypical dysconnection disorder, in which hallucinations are the core symptom. Due to high heterogeneity in methodology across studies and the clinical phenotype, it remains unclear whether the structural brain dysconnection is global or focal and if clinical symptoms result from this dysconnection. In the present work, we attempt to clarify this issue by studying a population considered as a homogeneous genetic sub-type of schizophrenia, namely the 22q11.2 deletion syndrome (22q11.2DS). Cerebral MRIs were acquired for 46 patients and 48 age and gender matched controls (aged 6-26, respectively mean age = 15.20 ± 4.53 and 15.28 ± 4.35 years old). Using the Connectome mapper pipeline (connectomics.org) that combines structural and diffusion MRI, we created a whole brain network for each individual. Graph theory was used to quantify the global and local properties of the brain network organization for each participant. A global degree loss of 6% was found in patients' networks along with an increased Characteristic Path Length. After identifying and comparing hubs, a significant loss of degree in patients' hubs was found in 58% of the hubs. Based on Allen's brain network model for hallucinations, we explored the association between local efficiency and symptom severity. Negative correlations were found in the Broca's area (p < 0.004), the Wernicke area (p < 0.023) and a positive correlation was found in the dorsolateral prefrontal cortex (DLPFC) (p < 0.014). In line with the dysconnection findings in schizophrenia, our results provide preliminary evidence for a targeted alteration in the brain network hubs' organization in individuals with a genetic risk for schizophrenia. The study of specific disorganization in language, speech and thought regulation networks sharing similar network properties may help to understand their role in the hallucination mechanism.
 
Article
Neural plasticity in the amygdala is necessary for the acquisition and storage of memory in Pavlovian fear conditioning, but most neuroimaging studies have focused only on stimulus-evoked responses during the conditioning session. This study examined changes in the resting-state functional connectivity (RSFC) of the amygdala before and after Pavlovian fear conditioning, an emotional learning task. Behavioral results from the conditioning session revealed that participants learned normally and fMRI data recorded during learning identified a number of stimulus-evoked changes that were consistent with previous work. A direct comparison between the pre- and post-conditioning amygdala connectivity revealed a region of dorsal prefrontal cortex (PFC) in the superior frontal gyrus that showed a significant increase in connectivity following the conditioning session. A behavioral measure of explicit memory performance was positively correlated with the change in amygdala connectivity within a neighboring region in the superior frontal gyrus. Additionally, an implicit autonomic measure of conditioning was positively correlated with the change in connectivity between the amygdala and the anterior cingulate cortex (ACC). The resting-state data show that amygdala connectivity is altered following Pavlovian fear conditioning and that these changes are also related to behavioral outcomes. These alterations may reflect the operation of a consolidation process that strengthens neural connections to support memory after the learning event.
 
Article
Our current understanding of neuroanatomical abnormalities in neuropsychiatric diseases is based largely on magnetic resonance imaging (MRI) and post mortem histological analyses of the brain. Further advances in elucidating altered brain structure in these human conditions might emerge from combining MRI and histological methods. We propose a multistage method for registering 3D volumes reconstructed from histological sections to corresponding in vivo MRI volumes from the same subjects: (1) manual segmentation of white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) compartments in histological sections, (2) alignment of consecutive histological sections using 2D rigid transformation to construct a 3D histological image volume from the aligned sections, (3) registration of reconstructed 3D histological volumes to the corresponding 3D MRI volumes using 3D affine transformation, (4) intensity normalization of images via histogram matching, and (5) registration of the volumes via intensity based large deformation diffeomorphic metric (LDDMM) image matching algorithm. Here we demonstrate the utility of our method in the transfer of cytoarchitectonic information from histological sections to identify regions of interest in MRI scans of nine adult macaque brains for morphometric analyses. LDDMM improved the accuracy of the registration via decreased distances between GM/CSF surfaces after LDDMM (0.39 +/- 0.13 mm) compared to distances after affine registration (0.76 +/- 0.41 mm). Similarly, WM/GM distances decreased to 0.28 +/- 0.16 mm after LDDMM compared to 0.54 +/- 0.39 mm after affine registration. The multistage registration method may find broad application for mapping histologically based information, for example, receptor distributions, gene expression, onto MRI volumes.
 
Article
Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25-150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60-120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = -0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder.
 
| Correlations with CAPS total symptoms.
Fear conditioning and extinction procedures. Fear conditioning contingencies were established during acquisition, followed by extinction of the CS+ (to form CS+E).
During context presentation in the early extinction phase, CAPS avoidance symptoms were associated with increased activation in (A) left insula (y
= 2) and (B) right amygdala (y
= 7). During context presentation, CAPS total symptoms were associated with increased activation in (C) right hippocampus (x = 15), (D) left hippocampus (x = -22), and (E) left amygdala (y = -1). Activations presented at p < 0.00005. CAPS, clinician-administered PTSD scale.
During CS+
presentation in the early extinction phase, CAPS avoidance symptoms were associated with increased activation in (A) left insula (y = -18), (B) right amygdala (y = 5), (C) vmPFC (x = 3), (D) dmPFC (x = -8), and (E) left hippocampus (x = -24). Activations presented at p < 0.00005. vmPFC, ventromedial prefrontal cortex; dmPFC, dorsomedial prefrontal cortex.
During fixation after CS+ in the early extinction phase, CAPS avoidance symptoms were associated with increased activation in (A) left insula (y = -15), (B) right amygdala (y = 3), and (C) vmPFC (x = -6). During fixation after CS+, CAPS total symptoms were associated with increased activation in (D) right hippocampus (x = 36), (E) right insula and right amygdala (y = 0). Activations presented at p < 0.00005.
Article
Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapies.
 
| Experimental conditions for lesion and electrical stimulation studies.
Full contrast conditioning schedule.
(A–D) represent the effects of fr lesions on conditioned approach to each CS (A) and to the US (C) during the CS+ and CS- presentation. (B,D) represent the difference scores (CS+ minus CS-) derived from values represented in (A,C). n = 10 and 8 for the Sham and Lesion groups, respectively. Error bars represent S.E.M. *p < 0.01.
Representative photomicrograph of an fr lesion. Photomicrograph of section stained with cresyl violet. Electrolytic fr lesions were made consecutively on each side of the brain. Orange shaded region on the right highlights fr location and the arrows on outline the perimeter of the electrolytic region. Sham control animals underwent an identical surgical procedure with the exception that no current was passed through the stimulating electrode. Coronal section from Paxinos and Watson (2007).
Partial contrast conditioning schedule: (A,B) represent the effects of fr lesion on conditioned approach to each CS (A) and to the US (B) during the presentation of a 100% CS+ and 33% CS- presentation.
(C,D) represents the difference score (CS+ minus CS33) derived from values represented in (A,B). n = 6, 7 for the Sham and Lesion groups, respectively. Error bars represent S.E.M.
Electrical stimulation of the fr during CS+ or US presentation.
(A) represents the effects of fr stimulation during CS+ presentation on conditioned approach to the CS+ vs. the CS- as described by the Difference Score (same dependent variable as seen in Figures 1 and 2). (B) represents the effects of fr stimulation during US presentation. n = 8, 7, 8 for the Sham, CS+ Stim and US Stim groups. Error bars represent S.E.M. Difference between experimental groups: ***p < 0.001, **p < 0.01, *p < 0.05.
Article
The attribution of incentive salience to reward associated cues is critical for motivation and the pursuit of rewards. Disruptions in the integrity of the neural systems controlling these processes can lead to avolition and anhedonia, symptoms that cross the diagnostic boundaries of many neuropsychiatric illnesses. Here, we consider whether the habenula (Hb), a region recently demonstrated to encode negatively valenced events, also modulates the attribution of incentive salience to a neutral cue predicting a food reward. The Pavlovian autoshaping paradigm was used in the rat as an investigative tool to dissociate Pavlovian learning processes imparting strictly predictive value from learning that attributes incentive motivational value. Electrolytic lesions of the fasciculus retroflexus (fr), the sole pathway through which descending Hb efferents are conveyed, significantly increased incentive salience as measured by conditioned approaches to a cue light predictive of reward. Conversely, generation of a fictive Hb signal via fr stimulation during CS+ presentation significantly decreased the incentive salience of the predictive cue. Neither manipulation altered the reward predictive value of the cue as measured by conditioned approach to the food. Our results provide new evidence supporting a significant role for the Hb in governing the attribution of incentive motivational salience to reward predictive cues and further imply that pathological changes in Hb activity could contribute to the aberrant pursuit of debilitating goals or avolition and depression-like symptoms.
 
Creativity scores on the AUT and Torrance tasks separated to fluency (A), flexibility (B) and originality (C). Means were transformed into Z scores.
Article
Creativity can be defined as the ability to produce responses that are both novel and appropriate. One way to assess creativity is to measure divergent thinking (DT) abilities that involve generating multiple novel and meaningful responses to open-ended questions. DT abilities have been shown to be associated with dopaminergic (DA) activity, and impaired DT has been reported in populations with DA dysfunctions. Given the strong association between DT and the DA system, the current study examined a group of healthy individuals (N = 185) to determine the role of repeat polymorphism in exon3 of the DRD4 gene in creativity. The results show that individuals carrying the DRD4-7R allele scored significantly lower on tests of DT, particularly on the flexibility dimension of DT, compared to non-carriers. The current findings link creative cognition to the DA system and suggest that DA dysfunctions in neurological and psychiatric disorders may account for impaired creativity and cognitive flexibility in these individuals.
 
Article
The habenula is a small but important nucleus located next to the third ventricle in front of the pineal body. It helps to control the human reward system and is considered to play a key role in emotion, showing increased activation in major depressive disorders. Its dysfunction may underlie several neurological and psychiatric disorders. It is now possible to visualize the habenula and its anatomical subdivisions-medial habenula (MHB) and lateral habenula (LHB)-using MR techniques. The aim of this study was to further differentiate substructures within human lateral habenula (LHB) using ex vivo ultra-high field MR structural imaging, distinguishing between a medial part (m-LHB) and a lateral part (l-LHB). High resolution T1w images with 0.3-mm isotropic resolution and T2(*)w images with 60-micrometer isotropic resolution were acquired on a 7T MR scanner and quantitative maps of T1 and T2(*) were calculated. Cluster analysis of image intensity was performed using the Fuzzy and Noise Tolerant Adaptive Segmentation Method (FANTASM) tool. Ultra-high resolution structural MRI of ex vivo brain tissue at 7T provided sufficient SNR and contrast to discriminate the medial and lateral habenular nuclei. Heterogeneity was observed in the lateral habenula (LHB) nuclei, with clear distinctions between lateral and medial parts (m-LHB, l-LHB) and with the neighboring medial habenula (MHB). Clustering analysis based on the T1 and T2(*) maps strongly showed 4-6 clusters as subcomponents of lateral and medial habenula.
 
The result of between-group VBM comparison in the left FG. Decreased gray matter volume was detected in the abacus-trained group relative to the controls (p < 0.01, FDR corrected). The bar to the right indicates the t score level. L, left.
Group probabilistic tractography pathways connecting left FG for each group. (A) Average fiber tracts connecting the left FG in abacus-trained group (red) and control group (blue). The probability maps overlapped onto a T1-weighted image (axial, coronal, and sagittal). The green areas indicate the overlap fiber tracts pathways of both groups. L, left. (B) White matter structures showed significant enhancement of FA in the abacus-trained group using TBSS method (Hu et al., 2011). The statistical map was overlapped onto the mean FA skeleton (green) and MNI152 template (gray-scale). The FA in left occipitotemporal conjunction area, right premotor projection and corpus callosum were enhanced significantly. The location of left occipitotemporal conjunction area was marked by blue circle. L, left.
(A) A new tract projection pathway, such as left forceps major pathway, was formed from left FG to other brain regions in the abacus-trained group. This tract pathway was extracted as white matter mask. (B) Mean fractional anisotropy within this white matter mask was significantly increased in children with abacus training. SD, standard deviation.
The correlation between the mean FA value of left forceps major tracts and the GM volume in left FG. Mean FA values extracted from the tracts showing group difference of connectivity distribution and plotted against the GM volume in left FG showing group difference of structure. Negative correlation was found in the abacus-trained group (red, r = −0.64, p = 0.006) but positive correlation was found in the controls (blue, r = 0.53, p = 0.019).
Article
Evidence supports the notion that the fusiform gyrus (FG), as an integral part of the ventral occipitotemporal junction, is involved widely in cognitive processes as perceiving faces, objects, places or words, and this region also might represent the visual form of an abacus in the abacus-based mental calculation process. The current study uses a combined voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis to test whether long-term abacus training could induce structural changes in the left FG and in the white matter (WM) tracts distribution connecting with this region in school children. We found that, abacus-trained children exhibited significant smaller gray matter (GM) volume than controls in the left FG. And the connectivity mapping identified left forceps major as a key pathway connecting left FG with other brain areas in the trained group, but not in the controls. Furthermore, mean fractional anisotropy (FA) values within left forceps major were significantly increased in the trained group. Interestingly, a significant negative correlation was found in the trained group between the GM volume in left FG and the mean FA value in left forceps major, suggesting an inverse effect of the reported GM and WM structural changes. In the control group, a positive correlation between left FG GM volume and tract FA was found as well. This analysis visualized the group level differences in GM volume, FA and fiber tract between the abacus-trained children and the controls, and provided the first evidence that GM volume change in the left FG is intimately linked with the micro-structural properties of the left forceps major tracts. The present results demonstrate the structural changes in the left FG from the intracortical GM to the subcortical WM regions and provide insights into the neural mechanism of structural plasticity induced by abacus training.
 
Article
Major depressive disorder (MDD) is characterized by altered intrinsic functional connectivity within (intra-iFC) intrinsic connectivity networks (ICNs), such as the Default Mode- (DMN), Salience- (SN) and Central Executive Network (CEN). It has been proposed that aberrant switching between DMN-mediated self-referential and CEN-mediated goal-directed cognitive processes might contribute to MDD, possibly explaining patients' difficulties to disengage the processing of self-focused, often negatively biased thoughts. Recently, it has been shown that the right anterior insula (rAI) within the SN is modulating DMN/CEN interactions. Since structural and functional alterations within the AI have been frequently reported in MDD, we hypothesized that aberrant intra-iFC in the SN's rAI is associated with both aberrant iFC between DMN and CEN (inter-iFC) and severity of symptoms in MDD. Twenty-five patients with MDD and 25 healthy controls were assessed using resting-state fMRI (rs-fMRI) and psychometric examination. High-model-order independent component analysis (ICA) of rs-fMRI data was performed to identify ICNs including DMN, SN, and CEN. Intra-iFC within and inter-iFC between distinct subsystems of the DMN, SN, and CEN were calculated, compared between groups and correlated with the severity of symptoms. Patients with MDD showed (1) decreased intra-iFC within the SN's rAI, (2) decreased inter-iFC between the DMN and CEN, and (3) increased inter-iFC between the SN and DMN. Moreover, decreased intra-iFC in the SN's rAI was associated with severity of symptoms and aberrant DMN/CEN interactions, with the latter losing significance after correction for multiple comparisons. Our results provide evidence for a relationship between aberrant intra-iFC in the salience network's rAI, aberrant DMN/CEN interactions and severity of symptoms, suggesting a link between aberrant salience mapping, abnormal coordination of DMN/CEN based cognitive processes and psychopathology in MDD.
 
| Demographic and clinical data.
Regional hippocampus (HP) and amygdala (AY) volumes. Seeds for the iFC analysis were positioned in the basolateral AY (yellow) and the body of HP (green). Regional voxel-based morphometry (VBM) volumes from the basolateral AY and body of HP were averaged across hemispheres and compared between patients with major depressive disorder (MDD) and healthy controls (Con) using two-sample t-tests (p < 0.05). HP (p = 0.011) and AY (p = 0.019) volumes were reduced in MDD patients.
Intrinsic functional connectivity (iFC) patterns of hippocampus (HP) and amygdala (AY) in patients and healthy controls. Individual spatial ß-maps representing BOLD correlations of ongoing left and right HP and AY activity of patients with major depressive disorder (MDD) and healthy controls (Con), were analyzed using two ANOVA models with factors for group and hemisphere for the HP and AY, respectively. Yellow and green maps, which were superimposed on a single-subject high resolution T1 image, represent results of corresponding post hoc t-tests that reflect positive and negative FC (Pos-FC and Neg-FC, respectively) for each group and seed region (p < 0.05, FDR corrected; bars represent range of t-values).
Overlapping differences in the intrinsic functional connectivity (iFC) of the hippocampus (HP) and amygdala (AY) between patients with major depressive disorder (MDD) and healthy controls (Con). Individual spatial ß-maps, which represent BOLD correlations of ongoing left and right HP and AY BOLD activity of patients with major depressive disorder (MDD) and healthy controls (Con), were analyzed using two ANOVA models with factors for group and hemisphere for AY as well as HP. Yellow and green maps of (A,B) were superimposed on a single-subject’s high resolution T1 image, and represent the main effect of group on the FC of the AY and HP, respectively (p < 0.05, FDR corrected; bars represent range of t-values). Bar graphs on the right side reflect averaged iFC of AY and HP for MDD patients and healthy controls, respectively (two-sample t-tests, p < 0.05). In (C), regions of overlapping reduced FC of AY (A) and HP (B) are shown in red. The HP and AY have reduced FC in the dorsomedial-prefrontal cortex and fronto-insular operculum in patients.
Article
Neuroimaging studies of major depressive disorder (MDD) have consistently observed functional and structural changes of the hippocampus (HP) and amygdale (AY). Thus, these brain regions appear to be critical elements of the pathophysiology of MDD. The HP and AY directly interact and show broad and overlapping intrinsic functional connectivity (iFC) to other brain regions. Therefore, we hypothesized the HP and AY would show a corresponding pattern of aberrant intrinsic connectivity in MDD. Resting-state functional MRI was acquired from 21 patients with MDD and 20 healthy controls. ß-Maps of region-of-interest-based FC for bilateral body of the HP and basolateral AY were used as surrogates for iFC of the HP and AY. Analysis of variance was used to compare ß-maps between MDD and healthy control groups, and included covariates for age and gender as well as gray matter volume of the HP and AY. The HP and AY of MDD patient's showed an overlapping pattern of reduced FC to the dorsomedial-prefrontal cortex and fronto-insular operculum. Both of these regions are known to regulate the interactions among intrinsic networks (i.e., default mode, central executive, and salience networks) that are disrupted in MDD. These results provide the first evidence of overlapping aberrant HP and AY intrinsic connectivity in MDD. Our findings suggest that aberrant HP and AY connectivity may interact with dysfunctional intrinsic network activity in MDD.
 
| Participant characteristics. 
| The cerebral cortex network seeds and their cerebellar representations. The figures of the left and right 17-network parcellation of the human cerebral cortex are adapted with permission from Yeo et al. (2011), p. 1139, Figure 13. The network names and the cerebral cortical regions that compose the 17 networks are from the supplementary video in Baker et al. (2014). The number of voxels in each of the eroded cerebral cortical seeds was determined after the (Yeo et al., 2011) 17-network cortical parcellation  
| Differences between schizophrenia and healthy controls in cerebro-cerebellar network connectivity. 
| Decreased cerebro-cerebellar functional connectivity in higher-level association networks in schizophrenia. Regions in the posterior lobe of the cerebellum, especially Crus I and Crus II, are preferentially affected. These images were generated using a  
Article
Schizophrenia is a devastating illness characterized by disturbances in multiple domains. The cerebellum is involved in both motor and non-motor functions, and the "cognitive dysmetria" and "dysmetria of thought" models propose that abnormalities of the cerebellum may contribute to schizophrenia signs and symptoms. The cerebellum and cerebral cortex are reciprocally connected via a modular, closed-loop network architecture, but few schizophrenia neuroimaging studies have taken into account the topographical and functional heterogeneity of the cerebellum. In this study, using a previously defined 17-network cerebral cortical parcellation system as the basis for our functional connectivity seeds, we systematically investigated connectivity abnormalities within the cerebellum of 44 schizophrenia patients and 28 healthy control participants. We found selective alterations in cerebro-cerebellar functional connectivity. Specifically, schizophrenia patients showed decreased cerebro-cerebellar functional connectivity in higher level association networks (ventral attention, salience, control, and default mode networks) relative to healthy control participants. Schizophrenia patients also showed increased cerebro-cerebellar connectivity in somatomotor and default mode networks, with the latter showing no overlap with the regions found to be hypoconnected within the same default mode network. Finally, we found evidence to suggest that somatomotor and default mode networks may be inappropriately linked in schizophrenia. The relationship of these dysconnectivities to schizophrenia symptoms, such as neurological soft signs and altered sense of agency, is discussed. We conclude that the cerebellum ought to be considered for analysis in all future studies of network abnormalities in SZ, and further suggest the cerebellum as a potential target for further elucidation, and possibly treatment, of the underlying mechanisms and network abnormalities producing symptoms of schizophrenia.
 
Percent of trials exhibiting an increase in GSR values from baseline following CS+ and CS− cues.
Mean-centered PLS results. This graph represents the task-dependent contrast for the first LV (57.41% crossblock covariance; p < 0.012, CS+ vs. CS−) from the PLS analysis for the healthy controls and patients along with its spatiotemporal distribution in the brain. (A) Brain scores illustrate the weighted average of activation patterns across all voxels and participants for the entire length of the experimental tasks pertaining to LV1. The bars represent 95% confidence intervals around the mean. Bootstrap estimation is used to derive confidence intervals around the subjects’ brain scores for each condition, in each group. (B) The regions that showed increased activity in response to the CS+ are superimposed over standard MRI template.
Magnitude HRF for the striatum from group task PLS analysis (LV 1). (A) right VS [MNI coordinates (x, y, z): 12, 10, 12]; (B) right caudate (MNI: 8, 7, 10); and (C) left putamen (MNI: 24, 8, 8) showed increased activity to the CS compared to the CS in the control group, and increased activity to the CS compared to the CS in the patient group.
Magnitude HRF for the hippocampus, cingulate, and prefrontal regions from task PLS analysis (LV 1). The brain regions which showed increased activity in response to the CS+ compared to the CS− in the control group, and the opposite pattern in the patient group also included: (A) the right hippocampus [MNI coordinates (x, y, z): 24, 16, −28]; (B) right orbitofrontal cortex (BA 11; MNI: 20, 20, −24); (C) left medial frontal gyrus (BA 10; MNI: −12, 56, 8); (D) right anterior cingulate cortex (BA 32; MNI: 8, −20, 44).
Schematic of effective connectivity network associated with the control and the schizophrenia patient group in the CS⩲ condition (A,B) and in the CS− condition (C,D). The regions illustrated in this diagram include: the ventral striatum (VS), putamen and caudate (dorsal striatum or DS), hippocampus (HPC), superior medial frontal gyrus (MFG; BA 10), and orbitofrontal cortex (OFC; BA 11).
Article
It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS- conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS- condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS- compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS- in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia.
 
Article
Background: Systematic differences in functional connectivity MRI metrics have been consistently observed in autism, with predominantly decreased cortico-cortical connectivity. Previous attempts at single subject classification in high-functioning autism using whole brain point-to-point functional connectivity have yielded about 80% accurate classification of autism vs. control subjects across a wide age range. We attempted to replicate the method and results using the Autism Brain Imaging Data Exchange (ABIDE) including resting state fMRI data obtained from 964 subjects and 16 separate international sites. Methods: For each of 964 subjects, we obtained pairwise functional connectivity measurements from a lattice of 7266 regions of interest covering the gray matter (26.4 million "connections") after preprocessing that included motion and slice timing correction, coregistration to an anatomic image, normalization to standard space, and voxelwise removal by regression of motion parameters, soft tissue, CSF, and white matter signals. Connections were grouped into multiple bins, and a leave-one-out classifier was evaluated on connections comprising each set of bins. Age, age-squared, gender, handedness, and site were included as covariates for the classifier. Results: Classification accuracy significantly outperformed chance but was much lower for multisite prediction than for previous single site results. As high as 60% accuracy was obtained for whole brain classification, with the best accuracy from connections involving regions of the default mode network, parahippocampaland fusiform gyri, insula, Wernicke Area, and intraparietal sulcus. The classifier score was related to symptom severity, social function, daily living skills, and verbal IQ. Classification accuracy was significantly higher for sites with longer BOLD imaging times. Conclusions: Multisite functional connectivity classification of autism outperformed chance using a simple leave-one-out classifier, but exhibited poorer accuracy than for single site results. Attempts to use multisite classifiers will likely require improved classification algorithms, longer BOLD imaging times, and standardized acquisition parameters for possible future clinical utility.
 
Oscillatory slowing in very preterm children. Peak oscillatory frequency in each of the 72 analyzed brain regions for the full-term control and very preterm groups, as well as statistically significant regional slowing in children born very preterm. The 7- to 10-Hz scale bar corresponds to the peak oscillatory frequency for each analyzed region for the very preterm and typically developing groups. The 0.4- to 1.8-Hz scale bar indicates the difference in peak oscillatory frequency between the very preterm and typically developing groups for regions where statistically significant differences were observed (regions for which no significant group differences were observed are presented in dark blue).
| Each source location used in the analysis of spontaneous MEG activity, together with associated Brodmann area and Talairach coordinates.
Article
Children born very preterm (≤32 weeks gestational age) without major intellectual or neurological impairments often express selective deficits in visual-perceptual abilities. The alterations in neurophysiological development underlying these problems, however, remain poorly understood. Recent research has indicated that spontaneous alpha oscillations are slowed in children born very preterm, and that atypical alpha-mediated functional network connectivity may underlie selective developmental difficulties in visual-perceptual ability in this group. The present study provides the first source-resolved analysis of slowing of spontaneous alpha oscillations in very preterm children, indicating alterations in a distributed set of brain regions concentrated in areas of posterior parietal and inferior temporal regions associated with visual perception, as well as prefrontal cortical regions and thalamus. We also uniquely demonstrate that slowing of alpha oscillations is associated with selective difficulties in visual-perceptual ability in very preterm children. These results indicate that region-specific slowing of alpha oscillations contribute to selective developmental difficulties prevalent in this population.
 
| General epilepsy history and summary of diagnosis.
Pre- and post-surgical MRI study. (A) Pre-surgical MRI; IR coronal image shows reduction of left hippocampal size, with hypointensity, and loss of internal differentiation (white arrow). (B) Pre-surgical MRI; Flair coronal image reveals hyperintensity and decreased hippocampal size (white arrow). (C) Post-surgical MRI; T1 coronal image shows the absence of the hippocampal gyrus, the subiculum, and the parahippocampal gyrus, medial to collateral sulcus (white arrow). (D) Post-surgical MRI; Flair coronal image hyperintensity is observed, surrounding the surgical cavity, secondary to gliosis (white arrow).
Score-reading task. (A) Musical score excerpt presented during encoding condition (left hemisphere inactivated). (B) Musical scores excerpts presented during retrieval condition (in order to assess left hemisphere functions).
EEG activity recorded from 6 s. after propofol injection in the left hemisphere (A) and from 5 s. in the right hemisphere (B). Both EEG recordings show bilateral theta-delta slowing and theta band activity peaks post injection, which gradually decrease. No significant inter-hemisphere asymmetry is revealed. EEG activity returns to pre-injection baseline status approximately 10 min. after propofol injection. Abbreviations: LH, left hemisphere; RH, right hemisphere.
Article
The use of intracarotid propofol procedure (IPP) when assessing musical lateralization has not been reported in literature up to now. This procedure (similar to Wada Test) has provided the opportunity to investigate not only lateralization of language and memory functions on epileptic patients but also offers a functional mapping approach with superior spatial and temporal resolution to analyze the lateralization of musical abilities. Findings in literature suggest that musical training modifies functional and structural brain organization. We studied hemispheric lateralization in a professional musician, a 33 years old woman with refractory left medial temporal lobe (MTL) epilepsy (TLE). A longitudinal neuropsychological study was performed over a period of 21 months. Before epilepsy surgery, musical abilities, language and memory were tested during IPP by means of a novel and exhaustive neuropsychological battery focusing on the processing of music. We used a selection of stimuli to analyze listening, score reading, and tempo discrimination. Our results suggested that IPP is an excellent method to determine not only language, semantic, and episodic memory, but also musical dominance in a professional musician who may be candidate for epilepsy surgery. Neuropsychological testing revealed that right hemisphere's patient is involved in semantic and episodic musical memory processes, whereas her score reading and tempo processing require contribution from both hemispheres. At one-year follow-up, outcome was excellent with respect to seizures and professional skills, meanwhile cognitive abilities improved. These findings indicate that IPP helps to predict who might be at risk for postoperative musical, language, and memory deficits after epilepsy surgery. Our research suggests that musical expertise and epilepsy critically modifies long-term memory processes and induces brain structural and functional plasticity.
 
Article
There is a need for identifying biomarkers that predict chronic speech fluency/language impairment and improvement after stroke. We previously showed that the Arcuate Fasciculus lesion load (AF-LL), a combined variable of lesion site and size, predicted speech fluency in chronic aphasic patients. In the current study, we compared lesion loads of such a structural map (i.e., AF-LL) with those of a functional map (i.e., the functional grey matter lesion load (fGM-LL)) in their ability to predict speech fluency and naming performance in a large group of patients. The fGM map was constructed from functional brain images acquired during an overt speaking task in a group of healthy elderly controls. The AF map was reconstructed from high-resolution diffusion tensor images also from a group of healthy elderly controls. In addition to these two canonical maps, a combined AF-fGM was derived from summing fGM and AF maps. Each canonical map was overlaid with individual lesion masks of 50 chronic aphasic patients with varying degrees of impairment in speech production and fluency to calculate a functional and structural lesion load value for each patient, and to regress these values with measures of speech fluency and naming. We found that both AF-LL and fGM-LL independently predicted speech fluency and naming ability; however, AF lesion load explained most of the variance for both measures. The combined AF-fGM lesion load did not have a higher predictability than either AF-LL or fGM-LL alone. Clustering and classification methods confirmed that AF lesion load was best at stratifying patients into severe and non-severe outcome groups with 96% accuracy for speech fluency and 90% accuracy for naming. An AF-LL of greater than 4cc was the critical threshold that determined poor fluency and naming outcomes, and constitutes the severe outcome group. Thus, surrogate markers of impairments have the potential to predict outcomes and can be used as a stratifier in experimental studies.
 
Prosaccade latencies. The top graph (A) depicts the mean prosaccade latencies of the groups: Control, Tourette-only (TS-only), Tourette Syndrome + Attention Deficit Hyperactivity Disorder (TS+ADHD) and Tourette Syndrome + Attention Deficit Hyperactivity Disorder + Obsessive Compulsive Disorder (TS+ADHD+OCD). The bottom chart (B) shows the age-adjusted prosaccade latency of the same groups (B). The top graph (A) demonstrates the expected observation of longer saccadic latencies in a longer Gap condition (Gap800) relative an Overlap (Overlap200) condition. This pattern remains the same after each group is age-adjusted (B). Error bars indicate standard errors.
The graph depicts the mean prosaccade latencies of the groups: Control, Tourette-only (TS-only), Tourette Syndrome + Attention Deficit Hyperactivity Disorder (TS+ADHD) and Tourette Syndrome + Attention Deficit Hyperactivity Disorder + Obsessive Compulsive Disorder (TS+ADHD+OCD). It shows the expected observation of longer saccadic latencies in a long Gap condition (Gap800) relative to an Overlap (Overlap200) condition. Error bars indicate standard errors.
Antisaccade latency. The top graph (A) shows the mean antisaccade latency of each group: Control, Tourette-only (TS-only), TS + Attention Deficit Hyperactivity Disorder (TS + ADHD) and TS + ADHD+ Obsessive Compulsive Disorder (TS + ADHD + OCD) in each fixation offset condition. The expected longer saccade latency in the Gap800 condition relative to Gap200 and Overlap200 is not observed here. This pattern remains the same following Age-adjustments of each group in the bottom graph (B). The shorter saccadic latency of the TS + ADHD + OCD group relative to the other groups is still present following Age-adjustments in the Overlap200 condition (B). The error bars display standard errors.
Article
Tourette Syndrome (TS) is a childhood onset disorder of motor and vocal tics. The neural networks underlying TS overlap with those of saccade eye movements. Thus, deviations on saccadic tasks can provide important information about psychopathology of TS. Tourette syndrome often coexists with Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD). Hence, we manipulated various components of a saccade task to measure its effects on saccades of children with TS-only, TS+ADHD, TS+ADHD+OCD and healthy controls. Children looked toward (prosaccade) or in the opposite direction (antisaccade) of a peripheral target as soon as it appeared. The prosaccade and antisaccade tasks were presented in three conditions. In the Gap200 condition, the fixation dot disappeared 200 ms prior to the appearance of the peripheral target, In the Gap800 condition, the fixation dot disappeared 800 ms prior to the appearance of the peripheral target and in Overlap200 the fixation dot disappeared 200 ms after the appearance of the peripheral target. Fixation-offset manipulations had different effects on each group's antisaccades. The TS+ADHD+OCD group's antisaccade latencies and error rates remained relatively unchanged in the three conditions and displayed a pattern of eye movements that can be interpreted as enhanced. Alternatively, the TS+ADHD group displayed an overall pattern of longer saccadic latencies. Findings corroborate the hypothesis that the combination of tic disorder and ADHD results in unique behavioral profiles. It is plausible that a subgroup of children with TS develop an adaptive ability to control their tics which generalizes to enhanced volitional control of saccadic behavior as well. Supporting evidence and other findings are discussed.
 
Article
The ability to entrain movements to music is arguably universal, but it is unclear how specialized training may influence this. Previous research suggests that percussionists have superior temporal precision in perception and production tasks. Such superiority may be limited to temporal sequences that resemble real music or, alternatively, may generalize to musically implausible sequences. To test this, percussionists and nonpercussionists completed two tasks that used rhythmic sequences varying in musical plausibility. In the beat tapping task, participants tapped with the beat of a rhythmic sequence over 3 stages: finding the beat (as an initial sequence played), continuation of the beat (as a second sequence was introduced and played simultaneously), and switching to a second beat (the initial sequence finished, leaving only the second). The meters of the two sequences were either congruent or incongruent, as were their tempi (minimum inter-onset intervals). In the rhythm reproduction task, participants reproduced rhythms of four types, ranging from high to low musical plausibility: Metric simple rhythms induced a strong sense of the beat, metric complex rhythms induced a weaker sense of the beat, nonmetric rhythms had no beat, and jittered nonmetric rhythms also had no beat as well as low temporal predictability. For both tasks, percussionists performed more accurately than nonpercussionists. In addition, both groups were better with musically plausible than implausible conditions. Overall, the percussionists' superior abilities to entrain to, and reproduce, rhythms generalized to musically implausible sequences.
 
| Sample characteristics for experimental group. N and percent within grade 
| Mean Fact Recall. The figure on the left represents the mean baseline fact learning ability for seventh and eighth grade students living above and below poverty. The middle figure represents the mean change in  
| Sample characteristics for comparison group. N and Percent within cohort
| PC loadings to derive adjustment variables in GLM. 
| Percent of students commended on the Texas Assessment of Knowledge and Skills from one low SES Dallas area campus; the " No Training " group represents the eighth grade students from the same school who served as a quasi-control group.  
Article
The ability to extrapolate essential gist through the analysis and synthesis of information, prediction of potential outcomes, abstraction of ideas, and integration of relationships with world knowledge is critical for higher-order learning. The present study investigated the efficacy of cognitive training to elicit improvements in gist reasoning and fact recall ability in 556 public middle school students (grades seven and eight), vs. a sample of 357 middle school students who served as a comparison group, to determine if changes in gist reasoning and fact recall were demonstrated without cognitive training. The results showed that, in general, cognitive training increased gist reasoning and fact recall abilities in students from families in poverty as well as students from families living above poverty. However, the magnitude of gains in gist reasoning varied as a function of gender and grade level. Our primary findings were that seventh and eighth grade girls and eighth grade boys showed significant increases in gist reasoning after training regardless of socioeconomic status (SES). There were no significant increases in gist reasoning or fact recall ability for the 357 middle school students who served as a comparison group. We postulate that cognitive training in middle school is efficacious for improving gist reasoning ability and fact recall in students from all socioeconomic levels.
 
| Demographic and clinical characteristics.
| The relationship between ALFF values and tic severity in TS patients.
Brain areas with decreased ALFF in TS children compared to healthy subjects. A corrected significance level of p < 0.05 was obtained with a cluster size of 117 voxels. The left side of the image corresponds to the right side of the brain.
Brain areas with decreased/increased fALFF in TS children compared to healthy subjects. A corrected significance level of p < 0.05 was obtained with a cluster size of 117 voxels. The left side of the image corresponds to the right side of the brain.
(A) fALFF positively correlated with tic severity in the right thalamus in TS children. Significant threshold was set at p < 0.05 with a cluster size of 117 voxels. The left side of the image corresponds to the right side of the brain. (B) Scatter plots show the relationship between tic severity and average fALFF in the regions of right thalamus.
Article
Tourette syndrome (TS) is a childhood-onset chronic disorder characterized by the presence of multiple motor and vocal tics. This study investigated spontaneous low-frequency fluctuations in TS patients during resting-state functional magnetic resonance imaging (rs-fMRI) scans. We obtained rs-fMRI scans from 17 drug-naïve TS children and 15 demographically matched healthy children. We computed the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) of rs-fMRI data to measure spontaneous brain activity, and assessed the between-group differences in ALFF/fALFF and the relationship between ALFF/fALFF and tic severity scores. Our results showed that the children with TS exhibited significantly decreased ALFF in the posterior cingulate gyrus/precuneus and bilateral parietal gyrus. fALFF was decreased in TS children in the anterior cingulated cortex, bilateral middle and superior frontal cortices and superior parietal lobule, and increased in the left putamen and bilateral thalamus. Moreover, we found significantly positive correlations between fALFF and tic severity scores in the right thalamus. Our study provides empirical evidence for abnormal spontaneous neuronal activity in TS patients, which may implicate the underlying neurophysiological mechanism in TS and demonstrate the possibility of applying ALFF/fALFF for clinical TS studies.
 
Article
Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD.
 
Article
Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imaging studies have shown a significant reduction of leftward asymmetry in some key white-matter tracts in SCZ. In this paper, we review the studies that investigated both structural brain asymmetry and asymmetry of functional connectivity in healthy subjects and SCZ. From an analysis of the existing literature on this topic, we can hypothesize an overall generally attenuated asymmetry of functional connectivity in SCZ compared to healthy controls. Such attenuated asymmetry increases with the duration of the disease and correlates with psychotic symptoms. Finally, we hypothesize that structural deficits across the corpus callosum may contribute to the abnormal asymmetry of intra-hemispheric connectivity in schizophrenia.
 
The lesion (green) and the dilation of this lesion into twelve adjacent 3 mm right hemispheric perilesional regions for each patient. Additionally shown are the results of the statistical analysis highlighting the voxels showing significant task related changes (regardless of trial type) in the individual patient (blue) as well as the group of three control subjects assigned to the respective patient (red). The lesion shape, perilesional regions and the results of the statistical analyses are plotted onto the patients’ T2-FLAIR image. All images are in neurological orientation and a significance threshold of 0.05 FDR corrected for multiple comparisons was used.
The BOLD percent signal change in each 3 mm perilesional region for each of the three stroke patients (red squares) as well as the group of control subjects (black circles). The images on the left depict the data for the left hemispheric perilesional regions and the images on the right the data for the right hemispheric perilesional regions. Error bars reflect standard error of the mean.
The interhemispheric imbalance score in each 3 mm perilesional region for each of the three stroke patients (red squares) as well as the group of three control subjects assigned to the respective patient (black circles). Error bars reflect standard error of the mean.
Article
Several functional magnetic resonance imaging (fMRI) studies of acute stroke have reported that patients with behavioral deficits show abnormal signal in intact regions of the damaged hemisphere close to the lesion border relative to homologous regions of the patient's intact hemisphere (causing an interhemispheric imbalance) as well as analogous regions in healthy controls. These effects have been interpreted as demonstrating a causal relationship between the abnormal fMRI signal and the pathological behavior. Here we explore an alternative explanation: perhaps the abnormal Blood-Oxygenation Level Dependent (BOLD) fMRI signal is merely a function of distance from the acute lesion. To investigate this hypothesis, we examined three patients with an acute right hemisphere cortical stroke who did not show any overt behavioral deficits, as well as nine healthy elderly controls. We acquired fMRI data while the participants performed a simple visual orientation judgment task. In patients, we observed an abnormal interhemispheric balance consisting of lower levels of percent signal change in perilesional areas of the damaged hemisphere relative to homologous areas in neurologically healthy controls. This suggests that the physiological changes and corresponding interhemispheric imbalance detected by fMRI BOLD in acute stroke observed close to the lesion border may not necessarily reflect changes in the neural function, nor necessarily influence the individuals' (e.g., attentional) behavior.
 
Long-term average spectrum (LTAS) analysis of 1-min speech (naming) of ASD and control children. (A) Examples of normalized LTAS of five controls (C1–C5) and five ASD children (A1–A5). Note that the controls have higher and more numerous spectral peaks, whereas the ASD curves are shallower. (B) Group average of normalized LTAS for 42 controls and 41 ASD children. Error bars denote one SE of the mean. (C) Group average of the stability of the spectra across time (SD divided by the power) for each frequency. Note in (A) that the controls exhibit sharper peaks and a more periodic (harmonic) structure of the spectra. Note in (C) that the ASD spectra are in general more variable across time.
Pitch analysis of 1-min speech (naming) of ASD and control children. (A) Examples of 15-s pitch time courses for one control (top) and one autistic (bottom) children, demonstrating the difference in variability. (B) Group averages of pitch range and SD. (C) Examples of pitch occurrence histograms (across time in 10-ms windows) in five ASD children (A1–A5) and five controls (C1–C5); the same 10 children shown in Figure 1. The x-axis denotes pitch frequency (Hz) and the y-axis denotes a normalized occurrence histogram across time. (D) Group average of the pitch histograms for 41 ASD children and 42 controls. Error bars denote one SE of the mean, with points around 220 Hz showing a highly significant difference (p < 0.002). (E) A scatter plot for the pitch histogram height (log units, x-axis) and pitch SD (y-axis), with each point corresponding to one child. (F) Occurrence histogram for the data in (E) along the x-axis (pitch histogram maxima) with a Gaussian fit for each group, presented in SD units (average across groups) around the average of the means. The difference between the groups corresponds to a d′ of 1.76 and a threshold criterion allows 86% success in classification, with a sensitivity of 80%, a specificity of 90%, and a positive predictive value of 89% (four controls classified as ASD and eight ASD as controls).
Article
Children with autism spectrum disorder (ASD) who can speak often exhibit abnormal voice quality and speech prosody, but the exact nature and underlying mechanisms of these abnormalities, as well as their diagnostic power are currently unknown. Here we quantified speech abnormalities in terms of the properties of the long-term average spectrum (LTAS) and pitch variability in speech samples of 83 children (41 with ASD, 42 controls) ages 4-6.5 years, recorded while they named a sequence of daily life pictures for 60 s. We found a significant difference in the group's average spectra, with ASD spectra being shallower and exhibiting less harmonic structure. Contrary to the common impression of monotonic speech in autism, the ASD children had a significantly larger pitch range and variability across time. A measure of this variability, optimally tuned for the sample, yielded 86% success (90% specificity, 80% sensitivity) in classifying ASD in the sample. These results indicate that speech abnormalities in ASD are reflected in its spectral content and pitch variability. This variability could imply abnormal processing of auditory feedback or elevated noise and instability in the mechanisms that control pitch. The current results are a first step toward developing speech spectrum-based bio-markers for early diagnosis of ASD.
 
A good night's sleep. The normal progression of sleep stages across a night of uninterrupted sleep. REM sleep is highlighted in red.
Motor skill learning across training and test trials of the motor sequence task (MST) for healthy control participants (n = 14, open squares) and schizophrenia patients (n = 20, closed triangles) from Manoach et al. (2004). The data point for each trial represents the group average. The y-axes represent the number of correct sequences typed in each 30-s epoch. Note that the y-axes are scaled separately for controls (left) and patients (right) to better illustrate the qualitative similarity of learning curves on Day 1 and the failure of overnight improvement in the schizophrenia group only. The dashed line is positioned at the mean value of the last three training trials for both the control and patient groups. The shaded bar represents the passage of 24 h, including a night of sleep. Patients and controls did not differ in the amount of learning during training, but only controls showed significant overnight improvement.
Correlation of overnight improvement with minutes spent in slow wave sleep (SWS) and stage 2 sleep in the last quartile of the night (S2q4) in schizophrenia patients. (A) Correlation with S2q4 sleep; (B) Correlation with SWS; (C) Correlation with the product of SWS and S2q4 sleep (SWS x S2q4).
Article
Although disturbed sleep is a prominent feature of schizophrenia, its relation to the pathophysiology, signs, and symptoms of schizophrenia remains poorly understood. Sleep disturbances are well known to impair cognition in healthy individuals. Yet, in spite of its ubiquity in schizophrenia, abnormal sleep has generally been overlooked as a potential contributor to cognitive deficits. Amelioration of cognitive deficits is a current priority of the schizophrenia research community, but most efforts to define, characterize, and quantify cognitive deficits focus on cross-sectional measures. While this approach provides a valid snapshot of function, there is now overwhelming evidence that critical aspects of learning and memory consolidation happen offline, both over time and with sleep. Initial memory encoding is followed by a prolonged period of consolidation, integration, and reorganization, that continues over days or even years. Much of this evolution of memories is mediated by sleep. This article briefly reviews (i) what is known about abnormal sleep in schizophrenia, (ii) sleep-dependent memory consolidation in healthy individuals, (iii) recent findings of impaired sleep-dependent memory consolidation in schizophrenia, and (iv) implications of impaired sleep-dependent memory consolidation in schizophrenia. This literature suggests that abnormal sleep in schizophrenia disrupts attention and impairs sleep-dependent memory consolidation and task automation. We conclude that these sleep-dependent impairments may contribute substantially to generalized cognitive deficits in schizophrenia. Understanding this contribution may open new avenues to ameliorating cognitive dysfunction and thereby improve outcome in schizophrenia.
 
Article
Magnetoencephalography (MEG) provides a direct, non-invasive view of neural activity with millisecond temporal precision. Recent developments in MEG analysis allow for improved source localization and mapping of connectivity between brain regions, expanding the possibilities for using MEG as a diagnostic tool. In this paper, we first describe inverse imaging methods (e.g., minimum-norm estimation) and functional connectivity measures, and how they can provide insights into cortical processing. We then offer a perspective on how these techniques could be used to understand and evaluate auditory pathologies that often manifest during development. Here we focus specifically on how MEG inverse imaging, by providing anatomically based interpretation of neural activity, may allow us to test which aspects of cortical processing play a role in (central) auditory processing disorder [(C)APD]. Appropriately combining auditory paradigms with MEG analysis could eventually prove useful for a hypothesis-driven understanding and diagnosis of (C)APD or other disorders, as well as the evaluation of the effectiveness of intervention strategies.
 
Article
It has been proposed that synchronous and convergent afferent input arising from repetitive motor tasks may play an important role in driving the maladaptive cortical plasticity seen in focal hand dystonia (FHD). This hypothesis receives support from several sources. First, it has been reported that in subjects with FHD, paired associative stimulation produces an abnormal increase in corticospinal excitability, which was not confined to stimulated muscles. These findings provide support for the role of excessive plasticity in FHD. Second, the genetic contribution to the dystonias is increasingly recognized indicating that repetitive, stereotyped afferent inputs may lead to late-onset dystonia, such as FHD, more rapidly in genetically susceptible individuals. It can be postulated, according to the two factor hypothesis that dystonia is triggered and maintained by the concurrence of environmental factors such as repetitive training and subtle abnormal mechanisms of plasticity within somatosensory loop. In the present review, we examine the contribution of sensory-motor integration in the pathophysiology of primary dystonia. In addition, we will discuss the role of non-invasive brain stimulation as therapeutic approach in FHD.
 
Article
Schizophrenia is characterized by cortical circuit abnormalities, which might be reflected in gamma-frequency (30-100 Hz) oscillations in the electroencephalogram. Here we used a computational model of cortical circuitry to examine the effects that neural circuit abnormalities might have on gamma generation and network excitability. The model network consisted of 1000 leaky integrate-and-fire neurons with realistic connectivity patterns and proportions of neuron types [pyramidal cells (PCs), regular-spiking inhibitory interneurons, and fast-spiking interneurons (FSIs)]. The network produced a gamma oscillation when driven by noise input. We simulated reductions in: (1) recurrent excitatory inputs to PCs; (2) both excitatory and inhibitory inputs to PCs; (3) all possible connections between cells; (4) reduced inhibitory output from FSIs; and (5) reduced NMDA input to FSIs. Reducing all types of synaptic connectivity sharply reduced gamma power and phase synchrony. Network excitability was reduced when recurrent excitatory connections were deleted, but the network showed disinhibition effects when inhibitory connections were deleted. Reducing FSI output impaired gamma generation to a lesser degree than reducing synaptic connectivity, and increased network excitability. Reducing FSI NMDA input also increased network excitability, but increased gamma power. The results of this study suggest that a multimodal approach, combining non-invasive neurophysiological and structural measures, might be able to distinguish between different neural circuit abnormalities in schizophrenia patients. Computational modeling may help to bridge the gaps between post-mortem studies, animal models, and experimental data in humans, and facilitate the development of new therapies for schizophrenia and neuropsychiatric disorders in general.
 
| Significant differences in all metrics using area under the curve (AUC) for pathological gamblers (PG) and healthy controls (HCs).
| Significant differences between pathological gamblers (PG) and healthy controls (HC) in functional connectivity.
Global metrics for pathological gamblers (PG) and healthy controls (HC) in all density thresholds: (A) small worldness (σ); (B) global efficiency; (C) characteristic path length (λ); (D) averaged clustering coefficient (γ).
Mean area under the curve (AUC) values for nodal metrics in regions with statistically significant group differences (pcor < 0.05) between controls and patients with pathological gambling (PG): (A) local efficiency; (B) clustering coefficient; (C) node betweenness. Error bars reflect standard deviations; SMA: supplementary motor area.
Article
Functional neuroimaging studies of pathological gambling (PG) demonstrate alterations in frontal and subcortical regions of the mesolimbic reward system. However, most investigations were performed using tasks involving reward processing or executive functions. Little is known about brain network abnormalities during task-free resting state in PG. In the present study, graph-theoretical methods were used to investigate network properties of resting state functional magnetic resonance imaging data in PG. We compared 19 patients with PG to 19 healthy controls (HCs) using the Graph Analysis Toolbox (GAT). None of the examined global metrics differed between groups. At the nodal level, pathological gambler showed a reduced clustering coefficient in the left paracingulate cortex and the left juxtapositional lobe (supplementary motor area, SMA), reduced local efficiency in the left SMA, as well as an increased node betweenness for the left and right paracingulate cortex and the left SMA. At an uncorrected threshold level, the node betweenness in the left inferior frontal gyrus was decreased and increased in the caudate. Additionally, increased functional connectivity between fronto-striatal regions and within frontal regions has also been found for the gambling patients. These findings suggest that regions associated with the reward system demonstrate reduced segregation but enhanced integration while regions associated with executive functions demonstrate reduced integration. The present study makes evident that PG is also associated with abnormalities in the topological network structure of the brain during rest. Since alterations in PG cannot be explained by direct effects of abused substances on the brain, these findings will be of relevance for understanding functional connectivity in other addictive disorders.
 
Article
Background: Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal bone appeared to be a potential window of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF). Methods: TUS was accomplished using a linear probe (10–5 MHz). Parents volunteered ASD subjects (N = 23; males 18, females 5) for evaluations (mean = 7.46 years ± 3.97 years), and 15 neurotypical siblings were also examined (mean = 7.15 years ± 4.49 years). Childhood Autism Rating Scale (CARS2®) scores were obtained and the ASD score mean was 48.08 + 6.79 (Severe). Results: Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): (1) <0.05 cm, (2) 0.05–0.07 cm, (3) 0.08–0.10 cm, (4) >0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.41 ± 0.67. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the gray matter. For cortical dysplasia we scored: (1) none observed, (2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, (3) more common, but separated areas of cortical hypoechogenic lesions, (4) very common or confluent areas of cortical hypoechogenicity. Again all of the neurotypical siblings scored 1, while the ASD subjects’ mean score was 2.79 ± 0.93. Conclusion: TUS may be a useful screening technique for children at potential risk of ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, non-invasive qualification of EAF, and cortical lesions.
 
Gross macroscopic findings on neuropathological examination. Selected examples from each case are presented as three vertical panels with lateral views of the unsectioned brain (upper panel), coronal sections through various parts of the cerebrum (middle panel), and axial sections through the brainstem (lower panel). (A) Case 1: There is mild-to-moderate atrophy with ventricular enlargement and cavum septi pellucidi. Thinning of the corpus callosum and mild depigmentation of the substantia nigra is also evident. (B) Case 2: Unsectioned brain, ventricles, and sections of the midbrain and substantia nigra appear within normal limits with no apparent evidence of neurodegeneration. (C) Case 3: Preferential mild-to-moderate atrophy of frontal and temporal lobes with significant enlargement of ventricles seen on coronal sections. A fenestrated septum pellucidum and atrophied amygdala and hippocampus are also seen on this section. The substantia nigra of this patient shows significant loss of pigmentation. (D) Case 4: There is mild frontal and temporal lobe atrophy with enlarged ventricles and cavum septi pellucidi. Axial sections of the brainstem show normal appearing substantia nigra and a metastatic lesion in the pons. (E) Case 5: Atrophic brain is seen with moderately enlarged ventricles and a normally pigmented substantia nigra. (F) Case 6: Minimal atrophy and ventricular enlargement are seen, and there is mild loss in the substantia nigra.
Selected microscopic findings on neuropathological examination. (A) Case 1: High power view of sample of cerebral cortex stained for hyperphosphorylated-tau shows concentration of neurofibrillary tangles predominantly in the superficial layers of the gray matter and in the depths of sulci, which is characteristic of CTE. (B) Case 2: Magnified motor neuron in ventral horn of spinal cord shows a representative intracytoplasmic TDP-43 inclusion. Inset shows a hyalin inclusion. (C) Case 3: Alpha-synuclein staining showing Lewy bodies and neurites which are seen throughout the cortex, substantia nigra, and locus ceruleus. This patient also had features of CTE (not shown). Inset shows higher power view of cytoplasmic Lewy body. (D) Case 4: Immunohistochemisty showing widespread reactivity against tau-positive neurofibrillary and astrocytic tangles in multiple layers. (E) Case 5: Bielschowsky silver stain showing numerous neurofibrillary tombstones in the hippocampus. (F) Case 6: HandE/LFB and alpha-synuclein staining of representative cortical section showing diffuse Lewy bodies and Lewy neurites. Inset shows Lewy body.
Article
Background: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown. Methods: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline. Results: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Moreover, the CTE cases showed co-morbid pathology of cancer, vascular disease, and AD. Discussion: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE.
 
Article
To dissociate a choice from its antecedent neural states, motivation associated with the expected outcome must be captured in the absence of choice. Yet, the neural mechanisms that mediate behavioral idiosyncrasies in motivation, particularly with regard to complex economic preferences, are rarely examined in situations without overt decisions. We employed functional magnetic resonance imaging in a large sample of participants while they anticipated earning rewards from two different modalities: monetary and candy rewards. An index for relative motivation toward different reward types was constructed using reaction times to the target for earning rewards. Activation in the nucleus accumbens (NAcc) and anterior insula (aINS) predicted individual variation in relative motivation between our reward modalities. NAcc activation, however, mediated the effects of aINS, indicating the NAcc is the likely source of this relative weighting. These results demonstrate that neural idiosyncrasies in reward efficacy exist even in the absence of explicit choices, and extend the role of NAcc as a critical brain region for such choice-free motivation.
 
Article
The role of the motor system in the perception of visual art remains to be better understood. Earlier studies on the visual perception of abstract art (from Gestalt theory, as in Arnheim, 1954 and 1988, to balance preference studies as in Locher and Stappers, 2002, and more recent work by Locher et al., 2007; Redies, 2007, and Taylor et al., 2011), neglected the question, while the field of neuroesthetics (Ramachandran and Hirstein, 1999; Zeki, 1999) mostly concentrated on figurative works. Much recent work has demonstrated the multimodality of vision, encompassing the activation of motor, somatosensory, and viscero-motor brain regions. The present study investigated whether the observation of high-resolution digitized static images of abstract paintings by Lucio Fontana is associated with specific cortical motor activation in the beholder's brain. Mu rhythm suppression was evoked by the observation of original art works but not by control stimuli (as in the case of graphically modified versions of these works). Most interestingly, previous visual exposure to the stimuli did not affect the mu rhythm suppression induced by their observation. The present results clearly show the involvement of the cortical motor system in the viewing of static abstract art works.
 
Top-cited authors
Karl J Friston
  • University College London
Ole Jensen
  • Radboud University
Ali Mazaheri
  • Academisch Medisch Centrum Universiteit van Amsterdam
Christoph S Herrmann
  • Carl von Ossietzky Universität Oldenburg
Mel Slater
  • University of Barcelona