Program for Cognitive Sciences Program for Cognitive Sciences (PICS)(PICS)

Dr. Joy Hirsch, DirectorDr. Joy Hirsch, Director

Harry D. Schneider, MD.Co-Investigator

Debra SchneiderClinical Coordinator

Autism Research Program

COLUMBIA UNIVERSITY

TODAY’S CHAT…

The discovery of language-specific areas and their connections in the brains of children with low-functioning autism.

FMRI-based emerging theories leading to practical applications and treatments.

Sharing knowledge is a good thing!

• Most of what I know is from parents who keep me up to date about new biomedical interventions and behavioral treatments.

• In return, I try to teach them something about functional MRI – and linguistics.

• Let’s have a go at functional MRI first.

I. Principles of Functional Specificity in the BrainI. Principles of Functional Specificity in the Brain

• The Real Estate Principle: a

fundamental notion of brain

organization.

• It suggests the brain’s real

estate is divided into subunits

based on function.

To understand MRI we need to review the atom.

MRI is based on the spinning of protons:

• Scanner Environment [1.5] T

• Protons align along an axis

Outside Field Inside FieldProtons in Brain

(scattered)

B. Spinning protons are little magnets: B. Spinning protons are little magnets: they make electricity.they make electricity.

[3.0] T

(aligned)

Protons in Brain

MAGNETISM MAKES ELECTRICITY!

• Protons precess around the axis and create a small electrical current (MRI signal)

RFi

(precess)

(wobble)

• A radio frequency pulse (63.3 mHz on an “FM radio”) is applied to aligned protons

FINDING THE REAL ESTATEFINDING THE REAL ESTATE

These currents have different strengths depending upon local magnetic field strengths: we use them to find their location of origin in the brain

This electrical current is emitted by the protons as they relax into their aligned state.

RFo

Location of signals are recorded for structural MRI

uniform

gradieieldfield

For functional MRI: Blood Oxygen Level

Dependent Signal (BOLD SIGNAL)

Deoxy-HGB is paramagnetic and distorts the local magnetic field, causing signal loss (Pauling,1936)Result:Less distortion of the magnetic field in local MR signal increase

Neural activation is associated with an increase in blood flow and oxygen use.(Roy & Sherrington, 1890)Result:Reduction in the proportion of deoxy-HGB in the local vasculature.

PhysiologyPhysiology PhysicsPhysics

Computations to get a Functional MRI Computations to get a Functional MRI MapMap

Functional Functional Brain MapBrain Map

Reconstruction

Alignment

Voxel by voxel analysis

Graphical representation

Normal Language Areas of the Cortex

With fMRI we use Diffusion Tensor Imaging (DTI)

Wernicke

Broca

Passive listening:

Arcuate Fasciculus

Axial view of functional activity Sagittal view of DTI Connections between Broca’s and Wernicke’s Areas

DTI: Neural Connections

DTI map of a typical language system.

CLINICAL APPLICATIONS OF fMRICLINICAL APPLICATIONS OF fMRI

The science of the mind leads to the The science of the mind leads to the treatment of the mind.treatment of the mind.

Mapping for neurosurgical planning

Assessment of cognitive function in

non-responsive adults and babies

Neural reorganization in dyslexia.

Low-functioning language Autism!

Neurosurgical planning: fMRI Task BatteryNeurosurgical planning: fMRI Task Battery

(active)

PictureNaming

Listeningto Words

(passive)

Language

GTsGFiGTTGOi

VisionReversing

Checkerboard

CaS

(passive)

MotorFinger Thumb

Tapping

GPrC

(active)

SensoryTouch

GPoC

(passive)

From Hirsch, J., et al; Neurosurgery 47: 711-722, 2000

Applications of the Real Estate PrincipleApplications of the Real Estate Principle

Hirsch, J., Columbia University.

fMRI TO DIAGNOSE AND INFORM TREATMENT OF ALTERNATIVE AND ATYPICAL NEUROCIRCUITRY OF BRAIN

Shaywitz, et al. 1998

Howard & Hirsch, 2004

Dyslexia Non-impaired

Dyslexia occurs in 15% of the U.S. population

Diagnoses Based On Variations in NeurocircuitryDiagnoses Based On Variations in Neurocircuitry

Program for Imaging and Cognitive Sciences J. Hirsch, Columbia University

Anxiety Disorders,

PTSD

Neural Reorganization

Eating Disorders, AN,

Obesity

Deception

NeuroGenetics

Neural SurgicalPlanning

SeizureLocalization

AutismDisorders of

Consciousness

DecisionSciences

NeuroLaw

LanguageAcquisition

Pain

IV. FUTURE DIRECTIONS FOR BRAIN MAPPING IN CLINICAL

NEUROSCIENCE

Now on to even more boring stuff!

LINGUISTICS

HOW DID YOU LEARN YOUR (FIRST) LANGUAGE?

• No one really taught it to you!

• There were no verbs to conjugate.

• There were no behavioral interventions.

• You just looked, listened and one day you began speaking!

What about language development in a neurotypical child?

• Because languages are infinite and a childhood is only finite, children can not just memorize language, they must leap into the linguistic unknown and generalize to an infinite world of as-yet unspoken sentences. (Pinker, 1994)

• This is done by acquiring grammar. The child is a ‘naturalist’, passively observing the speech of other‘s. The child picks up grammar “implicitly” (unconsciously).

• Chomsky: “Language is innate” (we are born “hard-

wired” to learn a language.

Neurotypical grammar (cont’d):

• Although some children might say “Mommy gived the book”

• A child never learns to say:

“Mommy the gives book”

• The unconscious grammar machine does not allow for too much error!

OUR BRAINS HAVE TWO (2) memory systems

• 1) The Explicit System – also called the “declarative” system and the conscious memory systems.

Conscious vs. Unconscious!

• 2) The Implicit System – also called the “procedural” and unconscious systems”

OUR BRAINS HAVE TWO (2) memory systems

• 1) The Explicit System – also called the “declarative” system and the conscious memory systems.

• REMEMBER THE 2 MEMORY SYSTEMS!

• 2) The Implicit System – also called the “procedural” and unconscious systems”

Implicit and Explicit Memory: an important distinction!

• Implicit memory: our previous experiences aid in the performance of tasks without conscious awareness of these previous experiences (Schacter, 1987). “déjà vu”: “If you give me the first letter, I will remember the word.”

In daily life, people rely on implicit memory (procedural memory) that allows us to remember how to tie our shoes or ride a bicycle without consciously thinking about these activities

On the other hand, Explicit Memory

• Explicit memory is the conscious, intentional recollection of previous experiences and information.

• In daily life, people rely on explicit memory (declarative memory), that stores facts: memories that can be consciously discussed, textbook learning, knowledge, memories of personal events, and learning new vocabulary.

A good example: How do we drive a car?

• Implicitly ? (automatic and unconscious)

• Explicitly? (thinking about what we learned in driving school)?

• Or both ways? e.g. “Did you ever drive home…”

A BRAIN MODEL of LANGUAGE

Our mental grammar (SVO) depends on a neural system composed of a network of basal-ganglia connected to frontal, parietal and cerebellar structures: this is implicit, unconscious memory or procedural memory.

Learning words depends on a different brain system- the temporal-lobe and hippocampus: this is (conscious, explicit or) declarative memory which stores facts and events you can recall.

Normal Language Areas of the Cortex: explicit learning

The Procedural Brain (“Reptile” Brain)- for the infant’s language!

What are the parts of the Procedural Memory Machine:

• Basal Ganglia (Parkinson's disease).

• Cerebellum (balance, movement)

• Substantia Nigra (dopamine)

• Thalamus (a translator for brain)

• Superior temporal cortex (comprehension areas)

• pre-SMA : motor planning areas.

How do children “learn to speak”?

• The do not “learn” it, they “acquire” it.

• ALL CHILDREN FROM BIRTH TO ABOUT AGE TWO (2) USE THE IMPLICIT SYSTEM FOR LANGUAGE.

• IT IS AN UNCONSCIOUS PROCESS THAT DOES NOT INVOLVE TEACHING!

For the Purposes of this talk,Let’s keep it simple:

• Implicit = Unconscious = Procedural

MEMORY

• Explicit = Conscious = Declarative

Do the two systems work together?

• NO ! But, teaching explicitly face to face can “help” implicit learning indirectly:

• It can help the brain focus on relevant items, such as sounds, parts of words.

• It can make these relevant language features stand out more, such as concentrating on the ends of words or what happens between words.

Is Grammar just another skill, like driving a car?

• YES!

• It is no coincidence that the beginnings of grammar follow closely on the heels of a baby – the ability to walk and talk both appear around fifteen months! (Pinker, 1994)

THINK OF AMNESIA

• A person with amnesia (retrograde) can not remember what happened in the past – but they can remember how to drive a car! They do NOT forget implicit stuff!

• A person with anterograde amnesia can not remember what the just learned: “each day is a new day” – but they can be taught to drive! They can be taught implicit stuff!

A NEUROTYPICAL CHILD’S LANGUAGE

What about an ‘autistic’ child’s language acquisition?

Language Production• No words by 12 to 14 months.• Less than one dozen words by age 18 months.• No two-word phrases by age two years or sentences by age

three years• Inability to use language conversationally, "talking to talk" .• Inability to recount an event or tell a coherent story.

Language Comprehension:• How much do they really understand?• Have they acquired the procedural grammar “blueprint”.?• If they can understand: “ the boy hugs the girl”, can they also understand “the girl is hugged by the boy’?

Do LFA autism children use implicit or explicit processes ?

• Low-functioning children with autism (generally) have to MEMORIZE almost of the language they can produce ! This is explicit or declarative memory and it takes up a lot of space on the brain’s “hard drive”.

• This is a huge mental process, using up a lot of brain energy and by itself may not lead to full language recovery.

SYNTAX DEPENDS ON PROCEDURAL MEMORY

• Faulty procedural learning may complicate the simultaneous application of different elements of verbal communication.

• Verbal “intonation” of children with ASD is better in repetition tasks (declarative memory)

• Than in spontaneous speech (procedural memory)

Faulty procedural memory

a child with ASD will not able to memorize: • prepositions, adjectives, adverbs• pronouns: I, you, he, she, my, your, etc.),• things (this, that, these, those),• places (here, there, above, below, etc.),• times (now, tomorrow, yesterday); • ungrammatical sentences • Word meaning (frequently used words)

The Infant Needs Procedural memory

• Learning of categories requires procedural memory: difficult in ASD children

• If some categories are learned, many ASD kids might not be able to understand them within the meaning of WHOLE sentences, which the procedural system needs to reconstruct in the brain actions described by another speaker.

• The absence of imaginative activity might also occur, because of the problems surrounding the learning of concepts and categories, which also requires procedural memory.

What does the LFA brain have to do with this?

• There is often limited, implicit “innate” grammar usable in autism, because deep brain structures have been partially damaged. The language-learning template was most likely NOT blueprinted in many kids!

• The ability to speak requires being able to retrieve the grammar template from other brain areas – in ASD the connections to these areas are not intact.

• Our goal is to stimulate these brain areas to acquire the template – i.e., to give them back a basic language blueprint – and then to help them restore neural connections to retrieve it!

Autism is a “Spectrum Disorder”

• Autistic brains are different from neurotypical brains and low-functioning autistic brains are different from high-functioning autistic brains.

• There is more pathology in the grey matter, the white matter fibers, specific brain areas (e.g. the cerebellum) and the connections between these areas.

Alternative Neurocircuitry in Autism Spectrum DisorderAlternative Neurocircuitry in Autism Spectrum Disorder

Autism occurs in as many as 1 child in 150 in the U.S.

NEUROTYPICAL CHILD 7

Diffusion Tensor Imaging (DTI): LF autism

Wernicke

BrocaArcuate Fasciculus

DTI map: Wernicke’s Area does NOT reach

Broca’s Area.

AUTISTIC 6 YEAR OLD

AUTISTIC 7 YEAR OLD

Language “Real Estate”

Language Connectivity

Normal Autistic 6 yr. old Autistic 7 yr. old

TITLE

What do the activations show?

• We do not always find typical language areas, such as Broca’s and Wernicke’s areas, become activated to passive language listening.

• Broca’s area sometimes responds to music without responding to language!

• The “language activations” are often pushed towards the posterior parts of the brain (sensory integration areas).

What else do we see in the connections?

• The connections from Wernicke’s area, when present, do not make it to Broca’s area, which they should via the Arcuate Fasciculus.

• Sometimes these connections are incomplete, sometimes they are very meager in appearance, and sometimes they go the wrong way: to the back of the brain instead of the front.

• Sometimes they take a “southern route” towards the front of the brain, instead of a northern one – which they should take.

Some initial thoughts.

• DTI confirms the notion that not only abnormal areas for language are activated, but the neural circuitry that is established deviates from those seen in a neurotypical brain.

• There are other known language pathways that we have yet to confirm with DTI. These are the ones that go to the deep structures in the cortex.

• We have reason to believe, based on neuropsychological evaluations, that there may be some connectivity to these areas.

BACK TO THE FIRST SLIDE

What about practical applications and treatments?

What are some “Emerging Theories” in autism?

Novel Treatments for Autism

1. Novel language rehabilitations.

2. Application of musicology to linguistics.

3. Virtual movement: cerebellar stimulation.

4. Neuromodulation.

What’s available: excellent evidence-based communication interventions.

• ABA - from BF Skinner to (Lovaas et al, 1966): strengthening effects of reinforcement during teaching

• Stimulus-stimulus pairing: e.g. phoneme + reward.

• Milieu-based interventions: time delay, milieu teaching, natural language paradigms.

What do we have that’s novel? 1) A “Language-Template”

Rehabilitation Program.• Language is innate! (Chomsky, 1965): we

are born with a “blueprint” for grammar”.• Our brains depend on primitive brain

systems (e.g. the basal ganglia) to acquire this grammar “blueprint.

• Emerging Theory: implicit (procedural) grammar training can create a (new) language template: the brain areas for grammar-learning are ‘plastic’!

“Back to the Future”

• We need to activate the innate “brain module” in children with autism.

• Some of this IMPLCIT training involves “unconsciously, inadvertently, ‘learning’ to speak a language for the first time all over again” !

An emerging theory (cont’d)

We can modulate the successful acquisition of this grammar template: “dopamine”.

(substantia nigra, Parkinson’s D, basal ganglia) 1. with the use of “language-specific motivations”.

(integrative motivation)

2. with novel implicit training techniques geared to stimulate the basal ganglia via dopaminergic brain pathways (it is imitation, joint attention - but it’s more than that)

DOPAMINE PATHWAYS

DOPAMINERGIC PATHWAYSTOP: BASAL GANGLIA

BOTTOM: DOPAMINE, EMOTIONS

Caudate Putamen

,mygdalaA

Substantia Nigra Amygdala

PROXIMITY OF BASAL GANGLIA AND SUBSTANTIA NIGRA

.

2) What about the application of “musicology” to language

Music therapy is useful with autistic children: non threatening, socially interactive, uses musical games with eye contact (it has the “right stuff”).

Emerging Theory: the evolution of language, gesture (hand movements) and music use cerebral networks that are functionally linked.

Our neuroimaging findings indicate a strong “overlap of neural resources” involved in the processing of language and music.

MUSIC IN OUR HEADS!

. Research has found that songs get stuck in our heads because they create a "brain itch" that can only be scratched by

repeating the tune over and over.

Application of musicology to language (cont’d)

Investigations: We are still discovering which aspects of music are best suited to facilitate unconscious acquisition of the rules of grammar.

• 1. Rhythm: “It’s hard to stay still”: an evolutionary primitive response. - can produce unaware body movement resulting from processing the beat by motor areas of the brain – the same areas that process language acquisition functions.

2. Syntax: Broca’s Area has been shown to be involved in the detection of music structural irregularities (and tones) as well detecting as grammar structure irregularities. (“off key” is the same thing as “bad grammar”).

.

3)The cerebellum: Language and Body Movement

• The cerebellum plays an important role in the integration of sensory perception and motor control, providing proprioceptive (internal) feedback on the position of the body in space.

• The cerebellum works with many neural pathways receiving constant feedback on body position to fine-tune motor our body movements.

Cerebellar connections

• The cerebellum connects to frontal brain areas to help generate “inner speech” (speech motor planning”

• It also connects to primitive language areas used to acquire our first language.

• Common real estate: “Sung” (explicit) language and spoken language share many common features and overlap in the posterior cerebellum, a region known to represent the lips and tongue.

Gross (Grey’s) Anatomy 101

The cerebellum in Autism

• Cerebellar dysfunction (pathology) is high in ASD: but, we have seen activations!

• The cerebellar areas that are damaged are often areas that receive auditory and visual input: some implicit language areas may be partially spared.

• Initiation of speech may be altered or halted by cerebellar injury in autism.

4) Cerebellar “therapy” and implicit language acquisition

• Emerging Theory: stimulating the cerebellum by virtual movement (e.g. spinning) may stimulate growth of new neural connections from the cerebellum to implicit language areas (Broca’s area, basal ganglia: the “reptile brain”)

• Practical Application: Combining virtual movement technology (“Top Gun”) – or simply bouncing on a ball - with implicit language-learning techniques is being developed to modulate language acquisition in children with autism.

5) NEUROMODULATION

• Transcranial Magnetic Stimulation.

• Transcranial Direct Current Stimulation.

Transcranial Magnetic Stimulation

How do we think TMS works?

• To perform TMS experiments, a stimulator (i.e., pulse generator) is needed to which different stimulation coils can be connected to apply brief magnetic pulses. These induce flows of electrical current within brain cells.

• It has been hypothesized that these currents enhance cortical synapses and modulate important neurotransmitters.

Can TMS be used in ASD?

SO FAR THE DATA HAVE NOT BEEN VERY GOOD WITH TMS,

BUT, WE HAVE SUCCESS

WITH TDCS !!

Transcranial Direct Current Stimulation (tDCS)

tDCS is SAFE !

tDCS supplies a weak constant direct current to the scalp to depolarize neurons below.

tDCS gives between 0.5 and 4 mA of direct current delivered through two sponge electrodes soaked in saline solution.

The saline-soaked sponges keep current densities low and safe.

Anodal (+) tDCS enhances excitability, whereas cathodal (-) tDCS reduces it.

How best to use tDCS?

• Stimulate speech areas of robust activation seen on individual child’s functional MRI (e.g. Wernicke’s Area) that are not connected to other speech areas.

• Stimulate areas of no activation, but known to be important to speech: areas of speech motor planning an execution:

- Wernicke’s Area: drive it to Broca’s area - Broca’s; supplementary motor area - basal ganglia and cerebellum - frontolimbic system (motivation)

• Use tDCS with implicit learning techniques !

This is tDCS & implicit learning !

What do some “smart people” at Columbia think?

We can use functional MRI to inquire about abnormalities in brain activations and connectivity.

We can use these to guide very early interventions to improve the language outcome of children with autism.

But…..

We need your help to figure this all out !!!