[11C]PBR28 MR-PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder.

Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance-positron emission tomography (MR-PET) scanner with the second-generation TSPO radiotracer [11C]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age- and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR-PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.

Cyclic Vomiting Syndrome is characterized by altered functional brain connectivity of the insular cortex: A cross-comparison with migraine and healthy adults.

Cyclic Vomiting Syndrome (CVS) has been linked to episodic migraine, yet little is known about the precise brain-based mechanisms underpinning CVS, and whether these associated conditions share similar pathophysiology. We investigated the functional integrity of salience (SLN) and sensorimotor (SMN) intrinsic connectivity networks in CVS, migraine and healthy controls using brain functional Magnetic Resonance Imaging. CVS, relative to both migraine and controls, showed increased SLN connectivity to middle/posterior insula, a key brain region for nausea and viscerosensory processing. In contrast, this same region showed diminished SMN connectivity in both CVS and migraine. These results highlight both unique and potentially shared pathophysiology between these conditions, and suggest a potential target for therapeutics in future studies.

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity.

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.

Emotional contagion for pain is intact in autism spectrum disorders.

Perceiving others in pain generally leads to empathic concern, consisting of both emotional and cognitive processes. Empathy deficits have been considered as an element contributing to social difficulties in individuals with autism spectrum disorders (ASD). Here, we used functional magnetic resonance imaging and short video clips of facial expressions of people experiencing pain to examine the neural substrates underlying the spontaneous empathic response to pain in autism. Thirty-eight adolescents and adults of normal intelligence diagnosed with ASD and 35 matched controls participated in the study. In contrast to general assumptions, we found no significant differences in brain activation between ASD individuals and controls during the perception of pain experienced by others. Both groups showed similar levels of activation in areas associated with pain sharing, evidencing the presence of emotional empathy and emotional contagion in participants with autism as well as in controls. Differences between groups could be observed at a more liberal statistical threshold, and revealed increased activations in areas involved in cognitive reappraisal in ASD participants compared with controls. Scores of emotional empathy were positively correlated with brain activation in areas involved in embodiment of pain in ASD group only. Our findings show that simulation mechanisms involved in emotional empathy are preserved in high-functioning individuals with autism, and suggest that increased reappraisal may have a role in their apparent lack of caring behavior.

Migraineurs without aura show microstructural abnormalities in the cerebellum and frontal lobe.

The involvement of the cerebellum in migraine pathophysiology is not well understood. We used a biparametric approach at high-field MRI (3 T) to assess the structural integrity of the cerebellum in 15 migraineurs with aura (MWA), 23 migraineurs without aura (MWoA), and 20 healthy controls (HC). High-resolution T1 relaxation maps were acquired together with magnetization transfer images in order to probe microstructural and myelin integrity. Clusterwise analysis was performed on T1 and magnetization transfer ratio (MTR) maps of the cerebellum of MWA, MWoA, and HC using an ANOVA and a non-parametric clusterwise permutation F test, with age and gender as covariates and correction for familywise error rate. In addition, mean MTR and T1 in frontal regions known to be highly connected to the cerebellum were computed. Clusterwise comparison among groups showed a cluster of lower MTR in the right Crus I of MWoA patients vs. HC and MWA subjects (p = 0.04). Univariate and bivariate analysis on T1 and MTR contrasts showed that MWoA patients had longer T1 and lower MTR in the right and left pars orbitalis compared to MWA (p < 0.01 and 0.05, respectively), but no differences were found with HC. Lower MTR and longer T1 point at a loss of macromolecules and/or micro-edema in Crus I and pars orbitalis in MWoA patients vs. HC and vs. MWA. The pathophysiological implications of these findings are discussed in light of recent literature.

A randomised controlled trial of bumetanide in the treatment of autism in children.

Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study,(1) we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition. Sixty children with autism or Asperger syndrome (3-11 years old) received for 3 months placebo or bumetanide (1 mg daily), followed by 1-month wash out. Determination of the severity of autism was made with video films at day 0 (D0) and D90 by blind, independent evaluators. Bumetanide reduced significantly the Childhood Autism Rating Scale (CARS) (D90-D0; P<0.004 treated vs placebo), Clinical Global Impressions (P<0.017 treated vs placebo) and Autism Diagnostic Observation Schedule values when the most severe cases (CARS values above the mean ± s.d.; n=9) were removed (Wilcoxon test: P-value=0.031; Student's t-test: P-value=0.017). Side effects were restricted to an occasional mild hypokalaemia (3.0-3.5 mM l(-1) K(+)) that was treated with supplemental potassium. In a companion study, chronic bumetanide treatment significantly improved accuracy in facial emotional labelling, and increased brain activation in areas involved in social and emotional perception (Hadjikhani et al., submitted). Therefore, bumetanide is a promising novel therapeutic agent to treat autism. Larger trials are warranted to better determine the population best suited for this treatment.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Migraine aura and related phenomena: beyond scotomata and scintillations.

Migraine affects the cortical physiology and may induce dysfunction both ictally and interictally. Although visual symptoms predominate during aura, other contiguous cortical areas related to less impressive symptoms are also impaired in migraine. Answers from 72.2% migraine with aura and 48.6% of migraine without aura patients on human faces and objects recognition, colour perception, proper names recalling and memory in general showed dysfunctions suggestive of prosopagnosia, dyschromatopsia, ideational apraxia, alien hand syndrome, proper name anomia or aphasia, varying in duration and severity. Symptoms frequently occurred in a successively building-up pattern fitting with the geographical distribution of the various cortical functions. When specifically inquired, migraineurs reveal less evident symptoms that are not usually considered during routine examination. Spreading depression most likely underlies the aura symptoms progression. Interictal involvement indicates that MWA and MWoA are not completely silent outside attacks, and that both subforms of migraine may share common mechanisms.

Influence of EEG electrodes on the BOLD fMRI signal.

Measurement of the EEG during fMRI scanning can give rise to image distortions due to magnetic susceptibility, eddy currents or chemical shift artifacts caused by certain types of EEG electrodes, cream, leads, or amplifiers. Two different creams were tested using MRS and T2* measurements, and we found that the one with higher water content was superior. This study introduces an index that quantifies the influence of EEG equipment on the BOLD fMRI signal. This index can also be used more generally to measure the changes in the fMRI signal due to the presence of any type of device inside (or outside) of the field of view (e.g., with fMRI and diffuse optical tomography, infrared imaging, transcranial magnetic stimulation, ultrasound imaging, etc.). Quantitative noise measurements are hampered by the normal variability of functional activation within the same subject and by the different slice profiles obtained when inserting a subject multiple times inside a MR imaging system. Our measurements account for these problems by using a matched filtering of cortical surface maps of functional activations. The results demonstrate that the BOLD signal is not influenced by the presence of EEG electrodes when using a properly constructed MRI compatible recording cap.

Mechanisms of migraine aura revealed by functional MRI in human visual cortex.

Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 +/- 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.

Mapping visual cortex in monkeys and humans using surface-based atlases.

We have used surface-based atlases of the cerebral cortex to analyze the functional organization of visual cortex in humans and macaque monkeys. The macaque atlas contains multiple partitioning schemes for visual cortex, including a probabilistic atlas of visual areas derived from a recent architectonic study, plus summary schemes that reflect a combination of physiological and anatomical evidence. The human atlas includes a probabilistic map of eight topographically organized visual areas recently mapped using functional MRI. To facilitate comparisons between species, we used surface-based warping to bring functional and geographic landmarks on the macaque map into register with corresponding landmarks on the human map. The results suggest that extrastriate visual cortex outside the known topographically organized areas is dramatically expanded in human compared to macaque cortex, particularly in the parietal lobe.

Where is 'dorsal V4' in human visual cortex? Retinotopic, topographic and functional evidence.

In flattened human visual cortex, we defined the topographic homologue of macaque dorsal V4 (the 'V4d topologue'), based on neighborhood relations among visual areas (i.e. anterior to V3A, posterior to MT+, and superior to ventral V4). Retinotopic functional magnetic resonance imaging (fMRI) data suggest that two visual areas ('LOC' and 'LOP') are included within this V4d topologue. Except for an overall bias for either central or peripheral stimuli (respectively), the retinotopy within LOC and LOP was crude or nonexistent. Thus the retinotopy in the human V4d topologue differed from previous reports in macaque V4d. Unlike some previous reports in macaque V4d, the human V4d topologue was not significantly color-selective. However, the V4d topologue did respond selectively to kinetic motion boundaries, consistent with previous human fMRI reports. Because striking differences were found between the retinotopy and functional properties of the human topologues of 'V4v' and 'V4d', it is unlikely that these two cortical regions are subdivisions of a singular human area 'V4'.

Local and global attention are mapped retinotopically in human occipital cortex.

Clinical evidence suggests that control mechanisms for local and global attention are lateralized in the temporal-parietal cortex. However, in the human occipital (visual) cortex, the evidence for lateralized local/global attention is controversial. To clarify this matter, we used functional MRI to map activity in the human occipital cortex, during local and global attention, with sustained visual fixation. Data were analyzed in a flattened cortical format, relative to maps of retinotopy and spatial frequency peak tuning. Neither local nor global attention was lateralized in the occipital cortex. Instead, local attention and global attention appear to be special cases of visual spatial attention, which are mapped consistently with the maps of retinotopy and spatial frequency tuning, in multiple visual cortical areas.

Projection of rods and cones within human visual cortex.

There are two basic types of photoreceptors in the retina: rods and cones. Using a single stimulus viewed at two different light levels, we tested whether input from rods and input from cones are topographically segregated at subsequent levels of human visual cortex. Here we show that rod-mediated visual input produces robust activation in area MT+, and in the peripheral representations of multiple retinotopic areas. However, such activation was selectively absent in: (1) a cortical area selectively activated by colored stimuli (V8) and (2) the foveal representations of lower tier retinotopic areas. These cortical differences reflect corresponding differences in perception between scotopic and photopic conditions.

Functional analysis of primary visual cortex (V1) in humans.

Human area V1 offers an excellent opportunity to study, using functional MRI, a range of properties in a specific cortical visual area, whose borders are defined objectively and convergently by retinotopic criteria. The retinotopy in V1 (also known as primary visual cortex, striate cortex, or Brodmann's area 17) was defined in each subject by using both stationary and phase-encoded polar coordinate stimuli. Data from V1 and neighboring retinotopic areas were displayed on flattened cortical maps. In additional tests we revealed the paired cortical representations of the monocular "blind spot." We also activated area V1 preferentially (relative to other extrastriate areas) by presenting radial gratings alternating between 6% and 100% contrast. Finally, we showed evidence for orientation selectivity in V1 by measuring transient functional MRI increases produced at the change in response to gratings of differing orientations. By systematically varying the orientations presented, we were able to measure the bandwidth of the orientation "transients" (45 degrees).

The representation of the ipsilateral visual field in human cerebral cortex.

Previous studies of cortical retinotopy focused on influences from the contralateral visual field, because ascending inputs to cortex are known to be crossed. Here, functional magnetic resonance imaging was used to demonstrate and analyze an ipsilateral representation in human visual cortex. Moving stimuli, in a range of ipsilateral visual field locations, revealed activity: (i) along the vertical meridian in retinotopic (presumably lower-tier) areas; and (ii) in two large branches anterior to that, in presumptive higher-tier areas. One branch shares the anterior vertical meridian representation in human V3A, extending superiorly toward parietal cortex. The second branch runs antero-posteriorly along lateral visual cortex, overlying motion-selective area MT. Ipsilateral stimuli sparing the region around the vertical meridian representation also produced signal reductions (perhaps reflecting neural inhibition) in areas showing contralaterally driven retinotopy. Systematic sampling across a range of ipsilateral visual field extents revealed significant increases in ipsilateral activation in V3A and V4v, compared with immediately posterior areas V3 and VP. Finally, comparisons between ipsilateral stimuli of different types but equal retinotopic extent showed clear stimulus specificity, consistent with earlier suggestions of a functional segregation of motion vs. form processing in parietal vs. temporal cortex, respectively.

Cross-modal transfer of information between the tactile and the visual representations in the human brain: A positron emission tomographic study.

Positron emission tomography in three-dimensional acquisition mode was used to identify the neural populations involved in tactile-visual cross-modal transfer of shape. Eight young male volunteers went through three runs of three different matching conditions: tactile-tactile (TT), tactile-visual (TV), and visual-visual (VV), and a motor control condition. Fifteen spherical ellipsoids were used as stimuli. By subtracting the different matching conditions and calculating the intersections of statistically significant activations, we could identify cortical functional fields involved in the formation of visual and tactile representation of the objects alone and those involved in cross-modal transfer of the shapes of the objects. Fields engaged in representation of visual shape, revealed in VV-control, TV-control and TV-TT, were found bilaterally in the lingual, fusiform, and middle occipital gyri and the cuneus. Fields engaged in the formation of the tactile representation of shape, appearing in TT-control, TV-control and TV-VV, were found in the left postcentral gyrus, left superior parietal lobule, and right cerebellum. Finally, fields active in both TV-VV and TV-TT were considered as those involved in cross-modal transfer of information. One field was found, situated in the right insula-claustrum. This region has been shown to be activated in other studies involving cross-modal transfer of information. The claustrum may play an important role in cross-modal matching, because it receives and gives rise to multimodal cortical projections. We propose here that modality-specific areas can communicate, exchange information, and interact via the claustrum.