Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Fluency-dependent cortical activation associated with speech production and comprehension in second language learners.

This functional magnetic resonance imaging (fMRI) study investigated the brain regions underlying language task performance in adult second language (L2) learners. Specifically, we identified brain regions where the level of activation was associated with L2 fluency levels. Thirty Japanese-speaking adults participated in the study. All participants were L2 learners of English and had achieved varying levels of fluency, as determined by a standardized L2 English proficiency test, the Versant English Test (Pearson Education Inc., 2011). When participants performed the oral sentence building task from the production tasks administered, the dorsal part of the left inferior frontal gyrus (dIFG) showed activation patterns that differed depending on the L2 fluency levels: The more fluent the participants were, the more dIFG activation decreased. This decreased activation of the dIFG might reflect the increased automaticity of a syntactic building process. In contrast, when participants performed an oral story comprehension task, the left posterior superior temporal gyrus (pSTG) showed increased activation with higher fluency levels. This suggests that the learners with higher L2 fluency were actively engaged in post-syntactic integration processing supported by the left pSTG. These data imply that L2 fluency predicts neural resource allocation during language comprehension tasks as well as in production tasks. This study sheds light on the neural underpinnings of L2 learning by identifying the brain regions recruited during different language tasks across different modalities (production vs. comprehension).

Spatio-temporal correlations from fMRI time series based on the NN-ARx model.

For the purpose of statistical characterization of the spatio-temporal correlation structure of brain functioning from high-dimensional fMRI time series, we introduce an innovation approach. This is based on whitening the data by the Nearest-Neighbors AutoRegressive model with external inputs (NN-ARx). Correlations between the resulting innovations are an extension of the usual correlations, in which mean-correction is carried out by the dynamic NN-ARx model instead of the static, standard linear model for fMRI time series. Measures of dependencies between regions are defined by summarizing correlations among innovations at several time lags over pairs of voxels. Such summarization does not involve averaging the data over each region, which prevents loss of information in case of non-homogeneous regions. Statistical tests based on these measures are elaborated, which allow for assessing the correlation structure in search of connectivity. Results of application of the NN-ARx approach to fMRI data recorded in visual stimuli experiments are shown. Finally, a number of issues related with its potential and limitations are commented.

Neural representation of animacy in the early visual areas: a functional MRI study.

Animacy helps to identify objects as living entities. To test the hypothesis that the perception of animacy via visual motion cues is represented in the same ventral visual pathways associated with living object identification through static visual information processing, 28 normal volunteers underwent functional MRI whilst tracking the movements of a self-propelling object. The target movement was held constant between conditions, whilst the animacy was externally manipulated by the presence of "chasers", from which the target was perceived to be escaping, and by "obstacles", which were static geometric objects with which the target avoided collision. The perception of target animacy was most powerfully induced by chasers, and a proximity effect was more prominently produced by obstacles. Animacy as induced by a chaser was associated with effects in the bilateral occipital poles (OPs) and the left inferior temporal gyrus to the lateral occipital complex (LOC). The LOC showed a stronger animacy effect, relative to the proximity effect, than the OPs. The effective connectivity between the LOC and the OPs was bi-directionally enhanced by the chasers. These findings suggest that both the LOC and the OPs play important roles in the identification of animated entities through the integration of information about the relationships between objects encoded in retinotopic coordinates.

Ventrolateral prefrontal cortex activity associated with individual differences in arbitrary delayed paired-association learning performance: a functional magnetic resonance imaging study.

To describe the neural substrates of successful episodic long-term memory encoding, we collected functional magnetic-resonance imaging data as participants completed an arbitrary delayed auditory paired-association learning task. During the task, subjects learned predefined but hidden stimulus pairs by trial and error based on visual feedback. Delay period activity represents the retrieval of the relationship between the cue item and its candidate for associates, that is, working memory. Our hypothesis was that the neural substrates of working memory would be related to long-term memory encoding in a performance-dependent manner. Thus, inter-individual variance in performance following a fixed learning set would be associated with differing neural activations during the delay period. The number of learning trials was adjusted such that performance following completion of the learning set varied across subjects. Each trial consisted of the successive presentation of two stimuli (first stimulus and second stimulus [S2]) with a fixed delay interval, allowing extraction of sustained activity during the delay period. Sustained activities during the delay period were found in the bilateral dorsolateral prefrontal cortex, intraparietal sulcus, and left ventrolateral prefrontal cortex, as well as the premotor and pre-supplementary motor areas. The activities did not change in strength across learning, suggesting that these effects represent working memory components. The sustained activity in the ventrolateral prefrontal region was correlated with task performance. Task performance was also positively correlated with the decrement in S2/feedback-related activity during learning in the superior temporal sulcus, a region previously shown to be involved in association learning. These findings are consistent with lesion and neuroimaging studies showing that the ventrolateral prefrontal cortex plays an important role in long-term memory encoding, and raise the possibility that working memory processes interact with long-term memory formation as represented by the covariation of activity in the superior temporal sulcus and the ventrolateral prefrontal cortex.

Neural substrates of intermanual transfer of a newly acquired motor skill.

In healthy humans, the two cerebral hemispheres show functional specialization to a degree unmatched in other animals, and such strong hemispheric specialization contributes to unimanual skill acquisition [1, 2]. When most humans learn a new motor skill with one hand, this process results in performance improvements in the opposite hand as well [3-6]. Despite the obvious adaptive advantage of such intermanual transfer, there is no direct evidence identifying the neural substrates of this form of skill acquisition [7-9]. Here, we used functional magnetic resonance imaging (fMRI) to study brain regions activated during intermanual transfer of a learned sequence of finger movements. First, we found that the supplementary motor area (SMA) has more activity when a skill has transferred well than when it has transferred poorly. Second, we found that fMRI activity in the ventrolateral posterior thalamic nucleus correlated with successful future intermanual transfer, whereas activity in the ventrolateral anterior thalamic nucleus correlated with past intermanual transfer. Third, we found that repetitive transcranial magnetic stimulation applied over the SMA blocked intermanual transfer without affecting skill acquisition. These findings provide direct evidence for an SMA-based mechanism that supports intermanual transfer of motor-skill learning.

Suppression of the non-dominant motor cortex during bimanual symmetric finger movement: a functional magnetic resonance imaging study.

Patterns of bimanual coordination in which homologous muscles are simultaneously active are more stable than those in which homologous muscles are engaged in an alternating fashion. This may be attributable to the stronger involvement of the dominant motor cortex in ipsilateral hand movements via interaction with the non-dominant motor system, known as neural crosstalk. We used functional magnetic resonance imaging to investigate the neural representation of the interhemispheric interaction during bimanual mirror movements. Thirteen right-handed subjects completed four conditions: sequential finger tapping using the right and left index and middle fingers, bimanual mirror and parallel finger tapping. Auditory cues (3 Hz) were used to keep the tapping frequency constant. Task-related activation in the right primary motor cortex was significantly less prominent during mirror than unimanual left-handed movements. This was mirror- and non-dominant side-specific; parallel movements did not cause such a reduction, and the left primary motor cortex showed no such differential activation across the unimanual right, bimanual mirror, and bimanual parallel conditions. Reducing the contralateral innervation of the left hand may increase the fraction of the force command to the left hand coming from the left primary motor cortex, enhancing the neural crosstalk.

fMRI activation maps based on the NN-ARx model.

The most significant progresses in the understanding of human brain functions have been possible due to the use of functional magnetic resonance imaging (fMRI), which when used in combination with other standard neuroimaging techniques (i.e., EEG) provides researchers with a potential tool to elucidate many biophysical principles, established previously by animal comparative studies. However, to date, most of the methods proposed in the literature seeking fMRI signs have been limited to the use of a top-down data analysis approach, thus ignoring a pool of physiological facts. In spite of the important contributions achieved by applying these methods to actual data, there is a disproportionate gap between theoretical models and data-analysis strategies while trying to focus on several new prospects, like for example fMRI/EEG data fusion, causality/connectivity patterns, and nonlinear BOLD signal dynamics. In this paper, we propose a new approach which will allow many of the abovementioned hot topics to be addressed in the near future with an underlying interpretability based on bottom-up modeling. In particular, the theta-MAP presented in the paper to test brain activation corresponds very well with the standardized t test of the SPM99 toolbox. Additionally, a new Impulse Response Function (IRF) has been formulated, directly related to the well-established concept of the hemodynamics response function (HRF). The model uses not only the information contained in the signal but also that in the structure of the background noise to simultaneously estimate the IRF and the autocorrelation function (ACF) by using an autoregressive (AR) model with a filtered Poisson process driving the dynamics. The short-range contributions of voxels within the near-neighborhood are also included, and the potential drift was characterized by a polynomial series. Since our model originated from an immediate extension of the hemodynamics approach [Friston, K.J., Mechelli, A., Turner, R., Price C.J. (2000a). Nonlinear responses in fMRI: the balloon model, volterra kernels, and other hemodynamics. NeuroImage 12, 466-477.], a natural interpretability of the results is feasible.

Neural substrates participating in acquisition of facial familiarity: an fMRI study.

The amygdala is related to recognition of faces and emotions, and functional magnetic resonance imaging (fMRI) studies have reported that the amygdala is habituated over time with repetition of facial stimuli. When subjects are presented repeatedly with unfamiliar faces, they come to gradually recognize the unfamiliar faces as familiar. To investigate the brain areas participating in the acquisition of familiarity to repeatedly presented unfamiliar faces, we conducted an fMRI study in 16 healthy subjects. During the task periods, the subjects were instructed to see presented unfamiliar faces repeatedly and to judge whether the face was male or female or whether the face had emotional valences. The experiment consisted of nine sessions. To clarify the brain areas that showed increasing or decreasing activation as the experimental session proceeded, we analyzed the fMRI data using specified linear covariates in the face recognition task from the first session to the ninth session. Imaging data were investigated on a voxel-by-voxel basis for single-group analysis according to the random effect model using Statistical Parametric Mapping. The bilateral posterior cingulate cortices showed significant increases in activity as the experimental sessions proceeded, while the activation in the right amygdala and the left medial fusiform gyrus decreased. Thus, the posterior cingulate cortex may play an important role in the acquisition of facial familiarity.

Functional magnetic resonance imaging evidence for a representation of the ear in human primary somatosensory cortex: comparison with magnetoencephalography study.

Our previous study (T. Nihashi et al., 2001, Neuro- Image 13: 295-304), using magnetoencephalography (MEG), revealed somatotopy of the ear in the human primary somatosensory cortex (SI); that is, the signals following stimulation of the ear reach both the neck and face areas of the SI. However, since this was the first report on somatotopy of the ear in humans, we performed an fMRI activation study to confirm the somatotopic representation, and compared the electrical activity by MEG and the cerebral blood flow change by fMRI. We studied eight healthy subjects using 3-T MRI. We stimulated three parts of the left ear: the helix, the lobulus, and the tragus. First, we identified the location of the ear area in the SI based on our previous MEG study, in which equivalent current dipoles (ECDs) were located in the neck and/or face areas of the SI. Then, we determined the search volume as a sphere with a 15-mm radius, which was placed in the neck and/or face area. We analyzed whether or not fMRI activation occurred inside such spheres. Stimulation of the helix activated the neck area of the SI in four of eight subjects, and both the neck and face areas in two. No activation was observed in two subjects. Stimulation of the lobulus activated the neck area in one subject, the face area in two, both in four, and neither in one. Stimulation of the tragus activated the face in four, both in three, and neither in one. These fMRI findings confirm the result of MEG that the representation of the ear in the SI is separated into neck and face areas.

Differential amygdala response during facial recognition in patients with schizophrenia: an fMRI study.

Human lesion or neuroimaging studies suggest that amygdala is involved in facial emotion recognition. Although impairments in recognition of facial and/or emotional expression have been reported in schizophrenia, there are few neuroimaging studies that have examined differential brain activation during facial recognition between patients with schizophrenia and normal controls. To investigate amygdala responses during facial recognition in schizophrenia, we conducted a functional magnetic resonance imaging (fMRI) study with 12 right-handed medicated patients with schizophrenia and 12 age- and sex-matched healthy controls. The experiment task was a type of emotional intensity judgment task. During the task period, subjects were asked to view happy (or angry/disgusting/sad) and neutral faces simultaneously presented every 3 s and to judge which face was more emotional (positive or negative face discrimination). Imaging data were investigated in voxel-by-voxel basis for single-group analysis and for between-group analysis according to the random effect model using Statistical Parametric Mapping (SPM). No significant difference in task accuracy was found between the schizophrenic and control groups. Positive face discrimination activated the bilateral amygdalae of both controls and schizophrenics, with more prominent activation of the right amygdala shown in the schizophrenic group. Negative face discrimination activated the bilateral amygdalae in the schizophrenic group whereas the right amygdala alone in the control group, although no significant group difference was found. Exaggerated amygdala activation during emotional intensity judgment found in the schizophrenic patients may reflect impaired gating of sensory input containing emotion.

Blood volume of gliomas determined by double-echo dynamic perfusion-weighted MR imaging: a preliminary study.

BACKGROUND AND PURPOSE: After bolus injection, gadopentetate dimeglumine causes a T2* rate change in permeable tissue that is contaminated by the T1 shortening effect due to the leakage of contrast agent. Therefore, tumor vascularity as reported in previous single-echo perfusion-weighted MR imaging studies has been underestimated. Our aim was to quantitatively and qualitatively evaluate the degree of blood volume of glioblastoma multiformes (GBMs) underestimated by this T1 shortening effect. METHODS: We used double-echo dynamic MR imaging after a bolus injection of gadopentetate dimeglumine (double-echo perfusion-weighted MR imaging) to simultaneously determine tumor blood volume without (V(T1U)) and with (V(T1C)) T1 shortening correction. MR imaging was performed in five consecutive patients with GBMs. The ratios of V(T1U) and V(T1C) were calculated and compared by means of quantitative analysis. The degree of tumor blood volume as determined by V(T1U) and V(T1C) maps were qualitatively compared using a three-point scale. RESULTS: All GBMs showed contrast enhancement on postcontrast T1-weighted images. In all subjects, the values of V(T1U) were significantly lower than those of V(T1C) (mean +/- SD, 2.05 +/- 1.01 vs. 3.62 +/- 1.40, respectively [P <.05]), indicating that tumor blood volume obtained by double-echo perfusion-weighted MR imaging was significantly higher than that by single-echo imaging. In the qualitative analysis, tumor blood volume on the V(T1U) map was less conspicuous than that on the V(T1C) map. CONCLUSION: Careful attention should be paid to the underestimation of tumor blood volume resulting from T1 shortening effects when using single-echo perfusion-weighted MR imaging. Double-echo imaging may be more suitable for the analysis of blood volume in GBMs.

Attention to emotion modulates fMRI activity in human right superior temporal sulcus.

A parallel neural network has been proposed for processing various types of information conveyed by faces including emotion. Using functional magnetic resonance imaging (fMRI), we tested the effect of the explicit attention to the emotional expression of the faces on the neuronal activity of the face-responsive regions. Delayed match to sample procedure was adopted. Subjects were required to match the visually presented pictures with regard to the contour of the face pictures, facial identity, and emotional expressions by valence (happy and fearful expressions) and arousal (fearful and sad expressions). Contour matching of the non-face scrambled pictures was used as a control condition. The face-responsive regions that responded more to faces than to non-face stimuli were the bilateral lateral fusiform gyrus (LFG), the right superior temporal sulcus (STS), and the bilateral intraparietal sulcus (IPS). In these regions, general attention to the face enhanced the activities of the bilateral LFG, the right STS, and the left IPS compared with attention to the contour of the facial image. Selective attention to facial emotion specifically enhanced the activity of the right STS compared with attention to the face per se. The results suggest that the right STS region plays a special role in facial emotion recognition within distributed face-processing systems. This finding may support the notion that the STS is involved in social perception.

Copper-62 ATSM as a hypoxic tissue tracer in myocardial ischemia.

Copper-62 labeled diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) has been proposed as a generator produced positron-emitting tracer for hypoxic tissue imaging. To clarify the usefulness of 62Cu-ATSM for myocardial ischemia, 62Cu-ATSM PET was performed in 7 patients with coronary artery disease. Increased myocardial uptake of 62Cu-ATSM was observed (myocardium/blood ratio: 3.09) in one patient with unstable angina, who had increased 18F-fluorodeoxyglucose (18F-FDG) uptake under the fasting condition. The other 6 patients, who were clinically stable, did not have increased 62Cu-ATSM uptake, although abnormal 18F-FDG uptake was seen in 4 patients. This preliminary study suggests that 62Cu-ATSM is a promising PET tracer for hypoxic imaging in acute ischemia.

FDG PET for evaluating the change of glucose metabolism in prostate cancer after androgen ablation.

In the clinical study of prostate cancer, the effect of androgen ablation on glucose metabolism in cancer tissue has not been elucidated. The purpose of this study was to investigate the change in glucose utilization due to endocrine therapy for prostate adenocarcinoma. Ten patients with histologically proven prostate cancer were prospectively investigated with (18)F-fluorodeoxyglucose and positron emission tomography (FDG PET) prior to and after the initiation of endocrine therapy. FDG uptake was calculated to measure glucose utilization in cancer tissue. The change in FDG accumulation was compared with changes in serum prostate specific antigen (PSA) level and prostate size. FDG accumulation in the prostate decreased in all patients 1-5 months after the initiation of hormone therapy. The serum PSA level and prostate size measured on computerized tomography (CT) also decreased in these periods. A decrease in FDG accumulation was also demonstrated in metastatic sites. In this study, there appeared to be a decrease in FDG uptake in prostate cancer after endocrine therapy not only in primary prostate cancer lesions but also at metastatic sites, suggesting that the glucose utilization by tumours was suppressed by androgen ablation.

Functional mapping of human medial frontal motor areas. The combined use of functional magnetic resonance imaging and cortical stimulation.

Two functional brain-mapping techniques, functional magnetic resonance imaging (fMRI) and cortical stimulation by chronically implanted subdural electrodes, were used in combination for presurgical evaluation of three patients with intractable, partial motor seizures. Brain mapping was focused on characterizing motor-related areas in the medial frontal cortex, where all patients had organic lesions. Behavioral tasks for fMRI involved simple finger and foot movements in all patients and mental calculations in one of them. These tasks allowed us to discriminate several medial frontal motor areas: the presupplementary motor areas (pre-SMA), the somatotopically organized SMA proper, and the foot representation of the primary motor cortex. All patients subsequently underwent cortical stimulation through subdural electrodes placed onto the medial hemispheric wall. In each patient, the cortical stimulation map was mostly consistent with that patient's brain map by fMRI. By integrating different lines of information, the combined fMRI and cortical stimulation map will contribute not only to safe and effective surgery but also to further understanding of human functional neuroanatomy.

Characterization of acetate metabolism in tumor cells in relation to cell proliferation: acetate metabolism in tumor cells.

To reveal the metabolic fate of acetate in neoplasms that may characterize the accumulation patterns of [1-(11)C]acetate in tumors depicted by positron emission tomography. Four tumor cell lines (LS174T, RPMI2650, A2780, and A375) and fibroblasts in growing and resting states were used. In uptake experiments, cells were incubated with[1-(14)C]acetate for 40 min. [(14)C]CO(2) was measured in the tight-air chamber, and the metabolites in cells were identified by thin layer chromatography and paper chromatography. The glucose metabolic rate of each cell line was measured with [2,6-(3)H]2-deoxy-glucose (DG), and the growth activity of each cell line was estimated by measuring the incorporation of [(3)H]methyl thymidine into DNA. Compared with resting fibroblasts, all four tumor cell lines showed higher accumulation of (14)C activity from [1-(14)C]acetate. These tumor-to-normal ratios of [1-(14)C]acetate were larger than those of DG. Tumor cells incorporated (14)C activity into the lipid-soluble fraction, mostly of phosphatidylcholine and neutral lipids, more prominently than did fibroblasts. The lipid-soluble fraction of (14)C accumulation in cells showed a positive correlation with growth activity, whereas the water-soluble and CO(2) fractions did not. These findings suggest that the high tumor-to-normal ratio of [1-(14)C]acetate is mainly due to the enhanced lipid synthesis, which reflects the high growth activity of neoplasms. This in vitro study suggests that [1-(11)C]acetate is appropriate for estimating the growth activity of tumor cells.

Ultrasound activates the auditory cortex of profoundly deaf subjects.

Using three-dimensional PET, the cortical areas activated by bone-conducted ultrasound were measured from five profoundly deaf subjects and compared with the cortical areas of normal-hearing subjects activated by stimuli through bone-conducted ultrasonic, air-conducted, bone-conducted, and vibro-tactile hearing aids. All of the hearing aids, including the ultrasonic hearing aid, consistently activated the medial portion of the primary auditory cortex of the normal volunteers. The same cortical area was also significantly activated in the profoundly deaf subjects although the percentage increase in regional cerebral blood flow (rCBF) was smaller than in normal subjects. These results suggest that extra-cochlear routes convey information to the primary auditory cortex and can therefore produce detectable sound sensation even in the profoundly deaf subjects, who reported a sensation themselves.

An fMRI study of the functional neuroanatomy of picture encoding in younger and older adults.

Age-related changes in the neural mechanisms of picture encoding were investigated using functional magnetic resonance imaging (fMRI). Seven younger and seven older adults were studied while they were encoding pairs of concrete-related, concrete-unrelated, and abstract pictures. Functional (T2*-weighted) and anatomical (T1-weighted) images of the brain were obtained using a 1.5 T MRI scanner. The results in the younger adults showed that the left dorsal prefrontal cortex (PFC) was activated during associative learning of the concrete-unrelated or abstract pictures. The results also suggest that both ventral and dorsal visual pathways are involved in the encoding of abstract pictures, and that the right superior parietal lobule likely mediates spatial information of the abstract pictures. The older adults showed significant activation in the left dorsal PFC under concrete-unrelated and abstract conditions. However, the older adults failed to activate either the left ventral and right dorsal PFC under the concrete-unrelated condition, or the parietal areas under abstract condition. A direct comparison between the two age groups demonstrates that the older adults had a reduced activation in the bilateral parieto-temporo-occipital areas under abstract condition, and in the right temporo-occipital area extending to the fusiform gyrus under the concrete-unrelated condition. Finally, age difference was found in correlation between memory performance and amplitude of signal change in the parahippocampal gyrus and fusiform gyrus under the concrete-unrelated and abstract conditions. These changes in neural response likely underlie the age-related memory decline in relation to pictorial information.