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No conflicts of interest related to this Exploring Brain Connectivity in Autism presentation and Sensory Processing Disorders � Funding � Dr. Muhkerjee: General Electric Board Member & Research Support (mild UCSF Developmental Disabilities Conference Traumatic Brain Injury) March 5, 2015 � Wallace Foundation � Kawaja and Holcombe Family Foundation � Gates Family Foundation � UCSF Academic Funds � Simons Foundation � NIMH � Families around the world: SPD.UCSF.EDU Elysa Marco MD, UCSF Associate Professor of Neurology, Psychiatry & Pediatrics Pratik Mukherjee, MD PhD Professor of Radiology DSM 5 Autism Spectrum Disorder- The Shifting Label By the end of this talk, we hope you will: B . Restricted, repetitive patterns of behavior, interests, or � Deeply question the utility and veracity of labels as diagnoses activities, as manifested by at least two of the following: � Understand the emerging findings of altered connectivity in 1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases). children with neurodevelopmental disorders with a focus on 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid information (sensory) processing differences in “autism” and thinking patterns, greeting rituals, need to take same route or eat food every day). “SPD” 3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g, strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest). 4. Hyper- or hypo-reactivity to sensory input or unusual Anxiety interests in sensory aspects of the environment (e.g., ADHD Autism apparent indifference to pain/temperature, adverse SPD response to specific sounds or textures, excessive smelling or touching of objects, visual fascination ODD DCD with lights or movement). http://www.autismspeaks.org/what-autism/diagnosis/dsm-5-diagnostic-criteria

Genetics: Just one example 16p11.2 CNV Disorder ≠ Etiology Strive for an Etiology!! Injury Genetics Environment Autism multiplex family with 16p11.2p12.2 microduplicationsyndrome in monozygotic twins and distal 16p11.2 deletion in their brotherAnne-ClaudeTabet, MarionPilorge, RichardDelorme, FrédériqueAmsellem, Jean- MarcPinard, MarionLeboyer, AlainVerloes, BrigitteBenzackenand CatalinaBetancurBACKTO ARTICLE Genetics and Sensory Processing Why the and/or’s? (and/or Autism and/or ADHD and/or Language disorder and/or schizophrenia and/or bipolar) � Copy Number Variations: 16p11.2 Unique Website: www.rarechromo.org The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population. Hanson, E et. al Biol Psychiatry 2014

Genetics and Sensory Processing Genetics and Sensory Processing (and/or Autism) (and/or Autism) � Triplet Repeat Disorders: Fragile X � Single Point Mutations: ARGHEF9 How can genetics guide treatment and Prognosis? Brain Injury/Structural malformation � Fragile X and Sensory Processing (and/or Autism) � mGLUR5 = STX209 (Arbaclofen)? � GABA � Fetal Alcohol Syndrome (other exposures) � Specialized Clinics with screening of family members � Prematurity � Investigate for associated conditions � Arghef9 � Stroke � GABA, GABA, GABA � Infection � 16p11.2 � Agenesis of the Corpus Callosum � Focus on articulation and praxis � Focus on specific aspects of cognitive control � Migraine? � Meds? � Seizures?

What did we find? Brain Injury: Prematurity Wickremasinghe, Rogers, Johnson & Marco; PAS 2012; Former Preterm Infants Exhibit Abnormal Sensory Behavior Posterior Brain Regions: Multisensory & Interhemispheric http://bestpractice.bmj.com/best- practice/monograph/674/resources/image/bp/2.h tml Brain Malformations: Agenesis of the Brain Structure/genetics: AgCC Corpus Callosum Low Registration AgCC Score of 1-4 Score of 5 Partial 43% 57% Absent Thin Demopoulos, Arroyo, Dunn, Sherr, Marco (Neurolosychology, in revision) Individuals with agenesis of the Images courtesy of Dr. Elliott Sherr corpus callosum show sensory processing differences as measured by the Sensory Profile.

How can understanding brain injury/structural differences guide treatment: Environment (Experience over Time) � AgCC: � Sensory Deprivation v. Engagement/Experience � Focus on registration- increasing intensity and salience of � Trauma/Conflict v. Comfort sensory input � Screen Time: passive v. active, addictive v. stimulating � Focus on auditory processing � Skill practice and Success � Slow it down � Consider excitation as well as inhibition-keep one hand busy when working on the other. � Prematurity � Increase the stimulus intensity � Focus on Auditory-Visual Integration! But first, What does a child neurologist and pediatric Charting our course: neuroradiologist mean by sensory processing: � 2014 Updates on sensory processing and neuroimaging Interpretation assessment Motor Planning Planning Multimodal Integration Motor Output Output Encoding Unimodal Cognitive Perception Perception Control

How are the sensory domains organized and Connected? How do we look into our kids’ brains? � Structural � CT � MRI � DTI � Functional � MEG � fMRI With a focus on sensory processing: we recruited, evaluated, and scanned kids with SPD… Biological Basis For SPD using DTI � TBSS Data Driven Approach SPD boys 8-12y compared to � Right handed boys Controls � SPD n=16 � Controls n=25 � Age Matched � 8 to 11 years old � FSIQ matched � SPD mean 113 (100-131) � Control mean 115 (97-130)

Next, we looked for volume… Then, we looked for lesions… Group SPD Controls (n=16) (n=25) Corpus Callosum 0 0 Decreased 0 0 White matter Free p Grey Matter Injury 0 0 Surfer Posterior Fossa Cyst 0 0 Total Cortex .87 Intracranial .63 TotalWhite .49 Left White .58 Right White .42 Left Cortex .94 Right Cortex .81 Fractional Anisotropy & Radial So finally, we looked at white matter integrity Diffusivity using diffusion tensor imaging (DTI) + = Based on water movement under the influence of a gradient: FA= Degree of directionality RD= rate of movement perpendicular to the WM tract. Diffusion Tensor Imaging on Teenagers, Born at Term With Moderate Hypoxic-ischemic Encephalopathy ZoltanNagy, KatarinaLindström, HelenaWesterberg, StefanSkare, JesperAndersson, BoubouHallberg, AndersLilja, OlofFlodmark, HugoLagercrantz, TorkelKlingbergand ElisabethFernell

The differences were striking! Q: how does decreased FA relate to auditory behavior? A: better connection = more typical behavior Poster Body of the Bilateral posterior Corpus thalamic radiations Callosum Sensory Profile- Auditory http://brain.oxfordjournals.org/content/128/11/2562/F7.large.jpg Q: how does decreased FA relate to multisensory behavior? Q: And what about attention?… A: better white matter = more typical behavior A: Better attention = better left frontal white matter Sensory Profile- Attention Sensory Profile- Multisensory

So we added a group of boys with autism…and What is found in autism? Shin (like Charlie Sheen) Chang! � Right handed boys � SPD n=16 � ASD n=15 � Controls n=23 � Age Matched � Between 8 to 12 years old � PIQ matched � SPD mean 116 � ASD mean 102 � Control mean113 � WMIQ: � SPD: 104 � ASD: 100 � Control: 108 J Psychiatry Neurosci. 2011 January; 36 ; Pervasive microstructure abnormalities in autism: A DTI study 2 nd Published Report How do they compare? � Both ASD and SPD groups show decreased FA in basic � HARDI Probabilistic Streamline sensory perception and integration tracts (SPD > ASD) Tractography Hypothesis Tract Based � FF Approach � SPD boys 8-12y compared to Controls � ASD boys 8-12y compared to Controls

How are they different? � The ASD group is more affected in the face processing and auditory tracts & does this relate to the real world? & does this relate to the real world? � Tract strength is correlated with working memory � Tract strength is correlated with auditory processing performance (SPD>ASD) performance (SPD>ASD) r = 0.49, p < 0.001

& does this relate to the real world? Take home message: � Tract strength is correlated with social skills (driven by the � Children with SPD and ASD show decreased connectivity in ASD group) basic (posterior) sensory tracts r = -0.39, p = 0.004 � Children with ASD are more affected in facial recognition and language tracts � These changes in connectivity correlate with working memory and social behavior across diagnosis From structure to Function: How can you measure electrical How do neurons talk to each other? activity?

Functional imaging with magnetoencephalography Minimal group differences by clinical autism diagnosis � Milli-second & milli-meter cortical activity resolution LH RH (w/MRI co-registration) Autism Amplitude (fT) Group � Non-invasive Control � Well tolerated Group � Resting Paradigms and Activity based Paradigms Slow Deviant Fast Slow Deviant Fast Bringing the bedside to the scanner… Two groupings: Clinical Autism Diagnosis and Tactile Sensitivity Autism Tactile Sensitive Controls Tactile Typical