High Definition Fiber Tracking (HDFT) is new MRI based technology that can make a circuit diagram of the connections in an individual’s brain. The goal is to provide a biomarker for differentiating between the various subtypes found within Autism Spectrum Disorder (ASD) based on the brain connectivity differences. In brain connectivity images, the tracts or cables of the language portion of a child’s brain with ASD can be inspected and contrasted to those of a typical brain. Knowing what is atypical will aid in targeting treatment. We identify what links have been compromised and better consider how to most effectively use therapy to establish functional abilities which compensate for the uncharacteristic links in each child’s brain. Quantifying the extent of these connective differences will facilitate research to develop more effective future treatments.

HDFT visualizes the brain cables or tracts in exquisite detail (see Figure 1 below). For example, we can map a child’s language system to quantify the size of cables which support various language functions. The development of the X-ray scans transformed diagnostic abilities in orthopedics by providing non-invasive images of the bones. HDFT may do the same for developmental connection disorders. This technology will allow clinicians to observe and compare the integrity of 40 tracts in the brain. These tracts, much like the bones, are the support structures for brain functioning. The nerve fiber tracts that can be seen on HDFT images are the "inter-office" communication lines that enable different specialized parts of the brain to communicate with each other. They are like telephone and internet cables that enable different specialized brain departments, such as the region of the brain that hears words, to communicate with the region that produces speech. HDFT can measure the "band width" of the cable connection. Is the connection really poor like an old-fashioned "dial up" internet connection or is the connection high speed broadband internet? In the past, these tracts or brain cables could rarely be detected or seen with any clarity. Now, with HDFT, we can provide the high definition image of millions of brain connections.

With clear pictures of connection problems, we can better target specific therapies. For example, by quantifying the integrity of each link in the brain’s language network, we expect to find that some children will show missing, reduced and over connected tracts that may account for differential language ability. We hypothesize that the subtypes of ASD (e.g., preverbal - no single words, stereotyped and echolalia and difficult speech - single words/phrases) each have different patterns of reduced connections (see answer #5).

It is important to establish effective communication with children early in life to approximate a normal developmental path. Depending on which link is compromised, different modes of communication might be extremely difficult or even impossible to achieve. The parents and treatment teams must decide what priority to give in the training of communication skills. For example, whether to best prioritize goals with regard to speech production, speech comprehension or use of augmentative communication systems (e.g. use of Picture Exchange Communication System, Dynavox, IPad and other devices). Knowing how children with different connection anomalies developed the most effective communication will support better decision making, and ultimately lead to better treatment. We are currently engaged in research to collect such data (see #10).

Temple was kind to allow us to create an HDFT map of her brain and has given us permission to talk about what we found in the language parts of her brain. We are still collecting data; as we seek to understand structural differences between the brain of individuals with ASD vs. the “neurotypical” brain. We did virtual dissections of Temple’s language system (see Figure 1 below). We found key connections in Temple’s brain to be out of the typical range in the major language tract which is called the arcuate fasciculus. Interestingly, we found most links were similar to a control brain but some links were dramatically increased and some decreased in Temple’s brain relative to a control brain (e.g., the volume of the axons from the left hemisphere projecting from the area of visual object information to the frontal and motor cortex is ten times that of the control, in contrast the volume of the axons that connect between speaking what you hear and speaking what you see is one tenth that of the control). We think this pattern of increased and decreased connectivity might account for Temple’s high visual skills, combined with the difficulty of acquiring language as a child. We note these are early interpretations and much work must still be done. It could be that these differences in Temple’s brain resulted from living with autism, and finding new ways to see the world. It could also be that they were there at birth. It is encouraging to find that this new HDFT technology can visualize and quantify such differences. We believe applying this technology to more cases will lead to insights and understanding of the brain mechanisms of ASD.

Figure 3 shows the steps of an HDFT connectivity analysis applied to language mapping in ASD. Step 1 involves collecting high resolution diffusion MRI information using state of the art equipment (3T MRI scanners with 32 channel head coils, novel pulse programming). Step 2 utilizes sophisticated computational techniques to accurately map the path of axons connecting different brain areas. Step 3 involves segmenting the brain into specific tracts and areas (40 tracts and 150 areas per brain). Step 4 quantifies the left and right side differences or differences compared to normal control brains. Step 5 involves creating a person-specific circuit diagram of the connectivity. For autism, we quantify 40 major tracts but then do a detailed mapping within sub-tracts of the language network doing virtual dissection of clusters of fibers of the arcuate fasciculus (the major language tract of the brain). Step 6 involves providing an HDFT case report, which is currently implemented as an iPad application. This case report provides the clinical treatment team and the parent a detailed quantification, visualization and interpretation of any connectivity anomalies.

We have received many favorable remarks from parents who appreciate “seeing” connection disruptions. We had one case of a child with autism looking at the images of the tracts and explaining to the parent they now understood how they were different. The mother wrote me stating “As a mother of a son with Asperger's Syndrome, I thought you might be interested to know that at the age of 8 my son … was able to describe for me how his brain functions. I recently watched a 60 Minutes interview in which you demonstrated your HDFT technology with the results from Temple Grandin's brain scan. I was shocked to see that the pictures showed what my son had described to me… My son was relieved to find out that his atypical behaviors were not his fault. As I was driving down the street, he exclaimed his eureka moment from the back seat of our van. He said, "I know why it is! People who are normal have straight lines in their brains. I have autism and I have bumps in my lines ... and, on the really crazy days, my brain is ... plaid!!" One of the problems in dealing with ASD is coping with a diagnosis that tells you little specific about the brain. You naturally want to learn what makes your loved one different. We now have the technology to show key tracts and quantify differences. In the years ahead we hope to be able to explain what each of those tracts does so the child and parent can understand the differences. They can then use specific information target specific tracts to grow through training. Developing early communications is critical in dealing with life and building bonds within a family.

The HDFT scanning technology continues to advance and the scan times are reducing. HDFT requires high performance scanning on high end 3T MRI machines outfitted with specialized brain coils and using new software to collect and analyze the data. The analyst methods are currently only available at the University of Pittsburgh Medical Center. The HDFT scan time is about ten minutes but is part of a full clinical scan taking about thirty minutes. MRIs are very safe, there are no injected agents. It is important that the child can remain still during the scan. The child can watch videos during the scan.

HDFT scanning is still a research protocol. It is not covered by insurance programs. We are collecting the data that will facilitate getting approvals in the years ahead. The research must be carefully done and it is a slow process. It will likely take several years. There are some limited opportunities to sign up for research protocols.

Our HDFT work is being applied to a variety of clinical connection disorders (http://www.lrdc.pitt.edu/Schneider/2012 HDFT Neurosurgery Newsletter Winter Highlights.pdf). We are currently scanning about a hundred traumatic brain injury (TBI) and neurosurgery patients a year. Our clinical research protocols include examination of broken connections in TBI (http://www.lrdc.pitt.edu/Schneider/Shin ..Schneider Okonkwo 2012 HDFT TBI Visualizing and Interpreting Damage.pdf), connections disrupted by brain tumors, strokes, and vascular problems (http://www.lrdc.pitt.edu/Schneider/Fernandez-Miranda (in Press) High-Definition Fiber Tractography of the Human Brain Neuroanatomical Validation and Neurosurgical Applications.pdf) and neurodegenerative diseases, including Alzheimer’s and Huntington’s. We believe HDFT diagnoses methods can make a difference in all these areas. Our TBI and neurosurgery are the most advanced efforts at this point. You can view a 3 minute video on how HDFT is applied in TBI (http://hdft.lrdc.pitt.edu/content/video). We are adapting the technology we use for TBI and neurosurgical diagnosis for autism (see answer #10).

There are many good resources for general information on ASD (e.g., see http://www.autismspeaks.org/, http://www.autism-society.org/, http://www.nih.gov/, and http://www.cdc.gov/). The book by Temple & Panek The Autistic Brain: Thinking Across the Spectrum provides a readable account of the technology for the general reading. I think the best academic review of autism as a connection disorder is by Schipul, Keller, & Just: 2011 Inter-regional brain communication and its disturbance in autism that appeared in Frontiers in Systems Neuroscience (http://www.frontiersin.org/Systems_Neuroscience/10.3389/fnsys.2011.00010...). For more about HDFT see my web page (http://schneiderlab.lrdc.pitt.edu/), or see the information on our https://HDFT.info web site.

We are starting a protocol to scan 4-year-old children with ASD and with various types of language problems to determine if they show different patterns of connectivity using HDFT. We will follow the children through treatment to determine what levels of language function developed and what rehabilitation therapies were most effective. It will be several years before we have enough results to identify clear patterns.

There are many research groups using a wide range of methods to understand ASD. It is likely that both genetic and environmental factors contribute to the disrupted connectivity in ASD. An HDFT map of tract anomalies shows the combined effects. It is important to note that genetics and environment interact in complex ways. We will use HDFT data to quantify different connective states and then seek to find genetic and environmental factors that correlate with these connective subtypes.