Neuroimaging techniques, such as functional MRI and Diffusion Tensor Imaging have become increasingly useful in characterizing the cognitive and neural deficits in autism. An examination of brain connectivity in autism at a network level along with adaptations for scanning children with developmental disabilities is presented.
Newly emerging theories suggest that the brain does not function as a cohesive unit in autism, and this discordance is reflected in the behavioral symptoms displayed by individuals with autism. While structural neuroimaging findings have provided some insights into brain abnormalities in autism, the consistency of such findings is questionable. Functional neuroimaging, on the other hand, has been more fruitful in this regard because autism is a disorder of dynamic processing and allows examination of communication between cortical networks, which appears to be where the underlying problem occurs in autism. Functional connectivity is defined as the temporal correlation of spatially separate neurological events1. Findings from a number of recent fMRI studies have supported the idea that there is weaker coordination between different parts of the brain that should be working together to accomplish complex social or language problems2,3,4,5,6. One of the mysteries of autism is the coexistence of deficits in several domains along with relatively intact, sometimes enhanced, abilities. Such complex manifestation of autism calls for a global and comprehensive examination of the disorder at the neural level. A compelling recent account of the brain functioning in autism, the cortical underconnectivity theory,2,7 provides an integrating framework for the neurobiological bases of autism. The cortical underconnectivity theory of autism suggests that any language, social, or psychological function that is dependent on the integration of multiple brain regions is susceptible to disruption as the processing demand increases. In autism, the underfunctioning of integrative circuitry in the brain may cause widespread underconnectivity. In other words, people with autism may interpret information in a piecemeal fashion at the expense of the whole. Since cortical underconnectivity among brain regions, especially the frontal cortex and more posterior areas 3,6, has now been relatively well established, we can begin to further understand brain connectivity as a critical component of autism symptomatology.
A logical next step in this direction is to examine the anatomical connections that may mediate the functional connections mentioned above. Diffusion Tensor Imaging (DTI) is a relatively novel neuroimaging technique that helps probe the diffusion of water in the brain to infer the integrity of white matter fibers. In this technique, water diffusion in the brain is examined in several directions using diffusion gradients. While functional connectivity provides information about the synchronization of brain activation across different brain areas during a task or during rest, DTI helps in understanding the underlying axonal organization which may facilitate the cross-talk among brain areas. This paper will describe these techniques as valuable tools in understanding the brain in autism and the challenges involved in this line of research.
1. Special Techniques for Scanning Individuals with Developmental Disabilities:
While neuroimaging itself is a complex technique, using MRI to scan the pediatric population and people with developmental disorders can be extremely challenging.The main problems are: 1) Head motion: people with disorders, especially children, may find it difficult to keep still in the fMRI scanner throughout a scanning session. This might result in head motion which in turn may affect the quality of the data; 2) Children with autism have extreme sensory sensitivities and may be bothered by factors, such as scanner noise, being in closed space, temperature and so on; and 3) Anxiety and getting adjusted to a new environment can be difficult for people with autism. A change in their routine can pose problems if not prepared well. Therefore, innovative procedures with careful preparations are needed to achieve good yield, and to improve the quality of the data collected. We incorporate valuable insights gained from theory and practice to prepare a participant for an MRI scan, to make the experiment and scanning process enjoyable for the participant, and to process the collected data, some of which are:
2. Use of Stimulus Presentation Software and Button Response Devices to Communicate with the Scanner:
3. Use of Static and Dynamic Visual Stimuli to Elicit Brain Responses in Participants with Autism:
While an excellent experimental design is critical to any scientific study, striking a chord with the participants can have a significant impact on the data acquired, especially in neuroimaging. The stimuli should be at the level of comprehension of the participant, and the experiment should be short, precise, and enjoyable. If adequate attention is not given to these elements, the quality of the data can be negatively affected. Special care is taken to try to make the experimental tasks challenging and enjoyable by creating innovative stimuli.
4. Data Acquisition, Storage, Analysis, & Quality Control:
Data Acquisition:
Data Storage and Data Analysis:
Quality Control:
5. Examining the Brain in Autism at a Network Level: fMRI-based Investigation of Functional Connectivity and DTI-based Examination of Anatomical Connectivity:
Functional Connectivity:
Functional connectivity refers to the synchronization of brain activation across different regions in the brain. The correlation of the time course of activation across brain areas is taken as evidence of the communication or connectivity between those regions. The steps involved in this analysis are as follows:
Anatomical Connectivity (DTI):
In order to examine the white matter integrity across the brain, the diffusion tensor images are analyzed using fMRIB Software Library (FSL)9. Below are the main steps involved:
6. Representative Results:
The primary results emerging from our studies pertain to weakened neural response in participants with autism (in terms of activation, change in signal intensity, and in functional connectivity) and the possible use of altered cortical route in accomplishing cognitive and social tasks. For instance, the core regions found to be mediating a function (for e.g. posterior superior temporal sulcus at the temporoparietal junction in inferring intentions of others; see Figure 2) seem to under-respond in autism, relative to typical control participants. In addition, the core region seems underconnected functionally with other nodes, especially the spatially distant ones (figure 3). With DTI, we also find some anatomical basis to these findings (see Figure 4), providing a comprehensive, network-level picture of brain organization in autism.
Figure 1. Flow-chart depicting the methods and procedures.
Figure 2: A) Increased activation in a typical language task, such as sentence comprehension (left inferior frontal gyrus, and left posterior superior temporal sulcus); B) Increased bilateral posterior superior temporal sulci activation in neurotypical participants during attribution of mental states to others (FWE corrected threshold of p< 0.05).
Figure 3. Significantly reduced functional connectivity (synchronization of brain activation) between frontal and temporal regions in a social cognition task in participants with autism (p< 0.05). LSTG: left superior temporal gyrus, RSTG: right superior temporal gyrus, RIFG: right inferior frontal gyrus, ROI: Region of Interest, FCA: functional connectivity.
Figure 4. DTI Tractography results showing a white matter fiber bundle proceeding from the temporal lobe to the temporoparietal junction. The initial starting point for tractography was an ROI identified by TBSS as having a significantly smaller FA value in young adults with autism when compared to age matched typical control participants.
The methods and procedures described in this paper are grounded in basic principles of cognitive neuroscience and neuroimaging. Taken together, these methods provide a compelling framework for assessing the brain functioning at the systems level in children, adults, and in people with disorders. Studies grounded in these methods have been especially influential in characterizing the discordant brain functioning in individuals with autism.
Although the techniques presented here are transferrable to other populations to address related theoretical questions11,12,13,14, careful attention is needed for pediatric neuroimaging, as well as for neuroimaging in people with developmental disorders: 1) Despite the number of precautionary and preparatory measures we take for scanning, head motion still poses a major concern in neuroimaging. The scanner is extremely sensitive to head motion, with a rotational movement of just 0.5 mm causing significant motion artifacts. While we presented a number of techniques to help reduce anxiety and in turn reduce movement, such as the mock scanner and decorating the scanner room, any effort in these lines may be worthwhile. Currently, we are trying to adapt a feedback paradigm using movies for training to keep the head movement to minimum; 2) Another issue pertains to the participant dropout, especially in children. Many children refuse to enter the scanner or panic after the scan is started; 3) Yet another issue is associated with the inherent heterogeneity in the manifestation of developmental disorders. Researchers of developmental disorders have to be careful in addressing the variability in their sample which otherwise might be buried under the often reported group-level inferences; and 4) Even minor equipment issues can have significant impact on the research protocol and investigator uses. For instance, the stimulus presentation program E-Prime does not have the capability to play video stimuli. Although the latest version of this software plays videos, that version is incompatible with the IFIS system. In such instance, we use Inquisit software to play our animations and videos, but with the additional step of having to manually synchronize the video with the scanner computer. Despite some of the limitations mentioned above, functional MRI has several advantages making it one of the best neuroimaging techniques to study brain function: 1) Unlike techniques like Positron Emission Tomography (PET), fMRI does not require injecting radioactive isotopes into the human body; 2) the spatial resolution of fMRI is better than techniques like Electroencephalography (EEG); and 3) the acquisition time can be short depending on the paradigm, which may be helpful in working with people with disorders like autism.
In order to characterize the neurobiology of complex, multidimensional disorders like autism, comprehensive neuroscience approaches, that encompass novel and diverse methods and techniques, are needed.Current theories of autism posit that underconnectivity of brain regions, especially between frontal cortex and more posterior areas, may be vital in explaining the key deficits in autism. The next possible logical step in this direction is to address such problems through translational approaches with a goal to improve altered connectivity in the autistic brain. A longitudinal study targeting brain plasticity to assess brain responses before and after intensive cognitive intervention could show the possible impact intervention can have on behavioral, cognitive, and neural responses in individuals with autism. By continuing to develop and fine-tune our techniques, such as functional, effective,and anatomical connectivity, we can gain a better understanding of this pervasive developmental disorder and translate the knowledge gained to intervention.
The authors have nothing to disclose.
The authors would like to thank Autumn Alexander, Jeff Killen, Charles Wells, Kathy Pearson, and Vaibhav Paneri for their help with the project at different stages. This work is supported by the UAB Department of Psychology Faculty startup funds, the McNulty-Civitan Scientist Award& the CCTS Pilot Research Grant (5UL1RR025777) to RK.