Yu Chun Lo

The loss of asymmetry and reduced interhemispheric connectivity in adolescents with autism: A study using diffusion spectrum imaging tractography

Evidence from neuroimaging and neurobiological studies suggests that abnormalities in cortical-cortical connectivity involving both local and long-distance scales may be related to autism. The present study analyzed the microstructural integrity of the long-range connectivity related to social cognition and language processing with diffusion tractography among adolescents with autism compared with neurotypical adolescents. Tract-specific analyses were used to study the long-range connectivity responsible for integrating social cognition and language processing. Specifically, three pairs of association fibers and three portions of callosal fiber tracts were analyzed. Generalized fractional anisotropy (GFA) values were measured along individual targeted fiber tracts to investigate alterations in microstructure integrity. The asymmetry patterns were also assessed in three pairs of association fibers. In neurotypical participants, we found a consistent leftward asymmetry in three pairs of association fibers. However, adolescents with autism did not demonstrate such asymmetry. Moreover, adolescents with autism had significantly lower mean GFA in three callosal fiber tracts than neurotypical participants. The loss of leftward asymmetry and reduction of interhemispheric connection in adolescents with autism suggest alterations of the long-range connectivity involved in social cognition and language processing. Our results warrant further investigation by combining developmental and neurocognitive data.

Imaging brain hemodynamic changes during rat forepaw electrical stimulation using functional photoacoustic microscopy

The present study reported the development of a novel functional photoacoustic microscopy (fPAM) system for investigating hemodynamic changes in rat cortical vessels associated with electrical forepaw stimulation. Imaging of blood optical absorption by fPAM at multiple appropriately-selected and distinct wavelengths can be used to probe changes in total hemoglobin concentration (HbT, i.e., cerebral blood volume [CBV]) and hemoglobin oxygen saturation (SO(2)). Changes in CBV were measured by images acquired at a wavelength of 570nm (lambda(570)), an isosbestic point of the molar extinction spectra of oxy- and deoxy-hemoglobin, whereas SO(2) changes were sensed by pixel-wise normalization of images acquired at lambda(560) or lambda(600) to those at lambda(570). We demonstrated the capacity of the fPAM system to image and quantify significant contralateral changes in both SO(2) and CBV driven by electrical forepaw stimulation. The fPAM system complements existing imaging techniques, with the potential to serve as a favorable tool for explicitly studying brain hemodynamics in animal models.

White matter tract integrity of frontostriatal circuit in attention deficit hyperactivity disorder: Association with attention performance and symptoms

The frontostriatal circuit has been postulated to account for the core symptoms such as inattention in attention deficit/hyperactivity disorder (ADHD). This study investigated the white matter integrity of frontostriatal fiber tracts using diffusion spectrum imaging (DSI) tractography and its correlations with measures of multi‐dimensional aspects of inattention based on psychiatric interview and attention tasks in 25 children with ADHD and 25 matched typically developing (TD) children. All the subjects were assessed with comprehensive psychiatric interviews and the Conners Continuous Performance Test (CCPT). DSI data were acquired on a 3‐Tesla MRI system. The frontostriatal fiber pathways were reconstructed by deterministic tractography, and generalized fractional anisotropy values were measured along individual targeted tracts to investigate alterations in microstructure integrity. Children with ADHD performed worse than TD children in the dimensions of focused attention, sustained attention, impulsivity, and vigilance of the CCPT, and showed impaired integrity in four bilateral frontostriatal tracts, namely the dorsolateral‐caudate, medial prefrontal‐caudate, orbitofrontal‐caudate, and ventrolateral‐caudate tracts, and in global white matter as well. The integrity of the left orbitofronto‐caudate tract was associated with the symptom of inattention in children with ADHD, compatible with the attention deficit and motivational dysfunction theories in ADHD. The integrity of the frontostriatal tracts was associated with the attention performance only in TD children, suggestive of possible recruitment of tracts other than the frontostriatal tracts implicated in attention deficits in children with ADHD. In conclusion, our results demonstrate the functional involvement of the frontostriatal circuit with respect to clinical symptoms and attention performance. Hum Brain Mapp 35:199–212, 2014.

The microstructural integrity of the corpus callosum and associated impulsivity in alcohol dependence: A tractography-based segmentation study using diffusion spectrum imaging

Previous post-mortem and structural magnetic resonance imaging (MRI) studies in patients with alcohol dependence have demonstrated abnormalities of brain white matter. The present study investigated the microstructural integrity in the corpus callosum and the associations of this integrity with neurobehavioral assessments. Twenty-five male cases fulfilling the DSM-IV diagnosis of alcohol dependence and 15 male control subjects were scanned using a 3T MRI system. Callosal fiber tracts were reconstructed by diffusion spectrum imaging tractography and were subdivided into seven functionally distinct segments. The microstructural integrity was quantified in terms of generalized fractional anisotropy (GFA). Compared with normal subjects, men with alcohol dependence showed lower GFA values on all segments of the corpus callosum. The segment interconnecting the bilateral orbitofrontal cortices was the most affected. The score on the Barratt Impulsivity Scale showed an inverse relationship with GFA on the callosal fiber tracts connecting the bilateral orbitofrontal cortices. Furthermore, the duration of regular use was negatively associated with GFA on the callosal fiber tracts connecting the bilateral temporal and parietal cortices. Our findings suggest that a high self-rated impulsivity level was associated with low anisotropy in white matter of corpus callosum sectors extending to the orbitofrontal cortex.

MicroPET imaging of noxious thermal stimuli in the conscious rat brain

Small animal positron emission tomography (microPET) has been utilized in the investigation of nociception. However, a possible drawback from previous studies is the reduced activation pattern due to the application of anesthesia. The purpose of the present study was to demonstrate a potential means of avoiding anesthesia during stimulation, as well as minimizing the confounding anesthetic effect. Sodium pentobarbital and ketamine were first evaluated to determine their effect on microPET images in the current study. [18F]-Fluorodeoxyglucose (18F-FDG) was an appropriate radiotracer to reveal activated regions in rat brains. Pentobarbital anesthesia significantly reduced 18F-FDG uptake in neural tissues, blurrier to lower contrast; therefore, ketamine was used to anesthetize animals during microPET. After the rats were anesthetized and secured in a laboratory-made stereotaxic frame, a simple, noninvasive stereotaxic technique was used to position their heads in the microPET scanner and to roughly conform the images in the stereotaxic atlas. For functional imaging, conscious rats were restrained in cages with minimal ambient noise; short repetitive thermal stimuli were applied to each rats tail subsequently. The rats were adequately anesthetized with ketamine following 30 min of scanning without stimulation. An activation index (AI) was calculated from microPET data to quantify the local metabolic activity changes according to the normalized 18F-FDG dosage. The average AI indicated a side-to-side difference for all innocuous stimulations in the thalamus. However, such side-to-side difference was only observed for noxious heat and cold stimulations in primary somatosensory cortex (SI), secondary somatosensory cortex (SII), and agranular insular cortex (AIC). The present study demonstrated the feasibility of the microPET technique to image metabolic functions of the conscious rat brain, offering better rationale and protocol designs for future pain studies.

Association between microstructural integrity of frontostriatal tracts and school functioning: ADHD symptoms and executive function as mediators

BACKGROUND Deficits in executive function (EF), impaired school functioning and altered white matter integrity in frontostriatal networks have been associated with attention-deficit/hyperactivity disorder (ADHD). However, relationships between impairments in these areas are unclear. Using a sample of youths with and without ADHD, this study examined the association between microstructural integrity of frontostriatal tracts and school dysfunction and the mediating roles of EF and ADHD symptoms in this association. METHOD The sample included 32 Taiwanese youths with ADHD and 32 age-, sex-, handedness- and IQ-matched typically-developing (TD) youths. Participants were assessed using psychiatric interviews, parent reports on ADHD symptoms and school functioning, and EF measures from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The frontostriatal tracts were reconstructed by diffusion spectrum imaging (DSI) tractography and were subdivided into four functionally distinct segments: caudate-dorsolateral, caudate-medial prefrontal, caudate-orbitofrontal and caudate-ventrolateral tracts. RESULTS Youths with ADHD, relative to TD youths, showed altered white matter integrity in all four bilateral pairs of frontostriatal tracts (decreased general fractional anisotropy, GFA), had poor attention, vigilance and response inhibition, and showed impaired school functioning. Altered microstructural integrity in frontostriatal tracts was significantly associated with school dysfunction, which was mediated by EF measures of attention/vigilance and response inhibition in addition to inattention and hyperactivity symptoms. CONCLUSIONS Our findings demonstrate an association between white matter integrity in the frontostriatal networks and school functioning and suggest that EF deficits and ADHD symptoms may be the mediating mechanisms for this association. Future research is needed to test the directionality and specificity of this finding.

Automatic Whole Brain Tract-Based Analysis Using Predefined Tracts in a Diffusion Spectrum Imaging Template and an Accurate Registration Strategy

Automated tract‐based analysis of diffusion MRI is an important tool for investigating tract integrity of the cerebral white matter. Current template‐based automatic analyses still lack a comprehensive list of tract atlas and an accurate registration method. In this study, tract‐based automatic analysis (TBAA) was developed to meet the demands. Seventy‐six major white matter tracts were reconstructed on a high‐quality diffusion spectrum imaging (DSI) template, and an advanced two‐step registration strategy was proposed by incorporating anatomical information of the gray matter from T1‐weighted images in addition to microstructural information of the white matter from diffusion‐weighted images. The automatic analysis was achieved by establishing a transformation between the DSI template and DSI dataset of the subject derived from the registration strategy. The tract coordinates in the template were transformed to native space in the individuals DSI dataset, and the microstructural properties of major tract bundles were sampled stepwise along the tract coordinates of the subjects DSI dataset. In a validation study of eight well‐known tracts, our results showed that TBAA had high geometric agreement with manual tracts in both deep and superficial parts but significantly smaller measurement variability than manual method in functional difference. Additionally, the feasibility of the method was demonstrated by showing tracts with altered microstructural properties in patients with schizophrenia. Fifteen major tract bundles were found to have significant differences after controlling the family‐wise error rate. In conclusion, the proposed TBAA method is potentially useful in brain‐wise investigations of white matter tracts, particularly for a large cohort study. Hum Brain Mapp 36:3441–3458, 2015.

NTU-DSI-122: A diffusion spectrum imaging template with high anatomical matching to the ICBM-152 space

A diffusion‐weighted (DW) template in a standard coordinate system is often necessary for the analysis of white matter (WM) structures using DW images. Although several DW templates have been constructed in the ICBM‐152 space, a template for diffusion spectrum imaging (DSI) is still lacking. In this study, we developed a DSI template in the ICBM‐152 space from 122 healthy adults. This high quality template, NTU‐DSI‐122, was built through incorporating the macroscopic anatomical information using high‐resolution T1‐weighted images and the microscopic structural information obtained from DSI datasets. Two evaluations were conducted to examine the quality of NTU‐DSI‐122. The first evaluation examined the anatomical consistency of NTU‐DSI‐122 in matching to the ICBM‐152 coordinate system. The results showed that this template matched to the ICBM‐152 templates very well across the whole brain, not only in the deep white matter regions as other DW templates but also in the superficial white matter regions. In the second evaluation, a large number of independent diffusion tensor imaging (DTI) datasets were registered to the DTI template derived from NTU‐DSI‐122. The examination was performed by quantifying the anatomical consistency among the registered DTI datasets. The results showed that using NTU‐DSI‐122 as the registration template the registered DTI datasets can achieve high anatomical alignment. Both evaluations demonstrate that NTU‐DSI‐122 is a useful high quality DW template. Therefore, NTU‐DSI‐122 can serve as a representative DSI dataset for a healthy adult population, and will be of potential value for brain research and clinical applications. The NTU‐DSI‐122 template is available at http://www.nitrc.org/projects/ntu‐dsi‐122/. Hum Brain Mapp 36:3528–3541, 2015.

Altered integrity of the right arcuate fasciculus as a trait marker of schizophrenia: a sibling study using tractography-based analysis of the whole brain.

Trait markers of schizophrenia aid the dissection of the heterogeneous phenotypes into distinct subtypes and facilitate the genetic underpinning of the disease. The microstructural integrity of the white matter tracts could serve as a trait marker of schizophrenia, and tractography‐based analysis (TBA) is the current method of choice. Manual tractography is time‐consuming and limits the analysis to preselected fiber tracts. Here, we sought to identify a trait marker of schizophrenia from among 74 fiber tracts across the whole brain using a novel automatic TBA method. Thirty‐one patients with schizophrenia, 31 unaffected siblings and 31 healthy controls were recruited to undergo diffusion spectrum magnetic resonance imaging at 3T. Generalized fractional anisotropy (GFA), an index reflecting tract integrity, was computed for each tract and compared among the three groups. Ten tracts were found to exhibit significant differences between the groups with a linear, stepwise order from controls to siblings to patients; they included the right arcuate fasciculus, bilateral fornices, bilateral auditory tracts, left optic radiation, the genu of the corpus callosum, and the corpus callosum to the bilateral dorsolateral prefrontal cortices, bilateral temporal poles, and bilateral hippocampi. Posthoc between‐group analyses revealed that the GFA of the right arcuate fasciculus was significantly decreased in both the patients and unaffected siblings compared to the controls. Furthermore, the GFA of the right arcuate fasciculus exhibited a trend toward positive symptom scores. In conclusion, the right arcuate fasciculus may be a candidate trait marker and deserves further study to verify any genetic association. Hum Brain Mapp 36:1065–1076, 2015.

Automatic spike sorting for extracellular electrophysiological recording using unsupervised single linkage clustering based on grey relational analysis

Automatic spike sorting is a prerequisite for neuroscience research on multichannel extracellular recordings of neuronal activity. A novel spike sorting framework, combining efficient feature extraction and an unsupervised clustering method, is described here. Wavelet transform (WT) is adopted to extract features from each detected spike, and the Kolmogorov-Smirnov test (KS test) is utilized to select discriminative wavelet coefficients from the extracted features. Next, an unsupervised single linkage clustering method based on grey relational analysis (GSLC) is applied for spike clustering. The GSLC uses the grey relational grade as the similarity measure, instead of the Euclidean distance for distance calculation; the number of clusters is automatically determined by the elbow criterion in the threshold-cumulative distribution. Four simulated data sets with four noise levels and electrophysiological data recorded from the subthalamic nucleus of eight patients with Parkinsons disease during deep brain stimulation surgery are used to evaluate the performance of GSLC. Feature extraction results from the use of WT with the KS test indicate a reduced number of feature coefficients, as well as good noise rejection, despite similar spike waveforms. Accordingly, the use of GSLC for spike sorting achieves high classification accuracy in all simulated data sets. Moreover, J-measure results in the electrophysiological data indicating that the quality of spike sorting is adequate with the use of GSLC.