דורון גוטהלף' פרופ

מנהל היחידה לפסיכיאטריה של הילד

בית החולים אדמונד ולילי ספרא

לילדים

המרכז הרפואי שיבא

בפסיכיאטריה הדמייה

של הילד

Major Divisions of the Brain

FrontalLobe

Occipital Lobe

Parietal Lobe

Temporal Lobe

Cerebellum

Gray Matter and White Matter

Gray Matter White Matter

?למה חשוב להתמצא בזה

:אמצעי ללמוד על התפתחות המוח•

בנורמלי–

במצבים פתולוגים–

בתגובה לטפולים–

ורנלים הפסיכיאטרים 'חלק נכבד מהמאמרים בג•והנוירופסיכולוגים המובילים עוסקים בהדמיות מוח

פסיכיאטריה הופכת במרכזים רבים בעולם לחלק •-Neuroscienceממחלקות ל

Much Knowledge is Required to Understand Manuscripts Published in the Leading Psychiatric Journals• American Journal of Psychiatry (August 2015)

– ABCB1 genetic effects on antidepressant outcome.

– Brain correlates of the interaction between 5-HTTLPR and psychosocial stress mediating ADHD.

– Amygdala hyperactivity at rest in paranoid schizophrenia

• Journal of the the American Academy of Child &

Adolescent Psychiatry (October, 2015)

– Normal variation in early parental sensitivity predicts child structural brain development

– A neural substrate for behavioral inhibition in the risk for MDD.

MRI in Patients with Multiple Sclerosis

Lateral Ventricles Volume in Schizophrenia

SchizophreniaHealthy

ventricular size

Neuroimaging Modalities

• Structural Imaging: seeing and measuring brain

anatomy

– Volumetric MRI

– Diffusion tensor imaging (DTI)

• Functional Imaging: seeing and measuring brain

activity

– fMRI

– Resting state fMRI

Brain Development- between Ages 5 to 20 Years

Gogtay et al PNAS 2004; 101: 8174-9

Brain development in Childhood Onset Schizophrenia

Brain development in Childhood Onset Schizophrenia

Greenstein et al J Child Psychol Psychiatry 2006; 34: 30-6

Brain development in Siblings of COS

Gogtay et al Arch Gen Psychiatry 2007; 64: 772–780

The Neural Basis of Intelligence:Does Brain Size Matter

• A significant weak positive correlation (0.33) between brain size and intelligence

• Intelligence is most consistently associated with GM volume of the frontal and temporal lobes.

The Neural Basis of Intelligence:Development of Prefrontal Cortex in

Children with High IQ

Shaw et al Nature 2006; 440:676-9

Frontal Cortex

Brain Overgrowth in Autism

Courchesne et al Neuron 2007; 56:399-411

1 4 years

Brain Overgrowth in Autism

Hazlett et al Arch Gen Psychiatry 2011

Brain Overgrowth in Autism Major Divisions of the Brain

FrontalLobe

Occipital Lobe

Parietal Lobe

Temporal Lobe

Cerebellum

Gray Matter and White Matter

Gray Matter White Matter

Automated Volumetric Measurements: 3 Steps

Separation of brain tissue from

Non-brain tissue

Segmentation

Parcellation

Structural Imaging: Measuring Volume of Specific Brain Regions of

Interest (ROIs)- The Old Way

Amygdala

Amygdala

Hippocampus

FreeSurfer Segmentation- The New Way

Caudate

Pallidum

Putamen

Amygdala

Hippocampus

Lateral Ventricle

Thalamus

White Matter Cortex

Not Shown:

Nucleus Accumbens

Cerebellum

Automatic Gyral Parcellation

Precentral GyrusPostcentral Gyrus

Superior Temporal GyrusBased on individual’s folding pattern

FreeSufer Output

R.S. Desikan et al. / NeuroImage 31 (2006) 968– 980

The Effect of Ritalin on Brain Development in Adolescents with ADHD

between Age 12 to 16 Years

Shaw et al. AJP 2009; 166:58-63

Diffusion Tensor Imaging (DTI)

• A measure of-

– Impairments in white matter

– Abnormal brain connectivity

DTI

Greater anisotropy

corresponds to a higher

fractional anisotropy (FA)

value

Abnormal Brain Connectivity in Adolescents with Prodromal

Psychotic Symptoms

• 28 adolescents 13 to 16 years

old who reported psychotic

experienced compared to 28

controls

• Abnormal WM of the inferior

fronto-occipptal tract in the

prodromal adolescents

O’Hanlon et al JAMA Psychiatry 2015

Functional Magnetic Resonance Imaging (FMRI)

Allows us to acquire images of the brain while patients are

performing cognitive tasks in the MRI scanner

Resting State Activated State

During periods of neuronal activity, local blood flow and volume increase with little or no change in oxygen consumption. As a result, the oxygen content of the local venous blood is elevated, resulting in an increase in the MR signal.

fMRI Blood Oxygenation Level Dependent (BOLD) Contrast

FMRI: How It Works

• Increase in blood oxygenation accompanies neural activity during cognitive tasks

• Changes in blood oxygenation is paramagnetic

• Increased neural activity causes slight changes in the intensity values of an image compared to resting brain

• We measure these changes in intensity values to determine

– in what regions of the brain neural activity is stimulated

– how much a task is stimulating neural activity

Predicted ResponsesPREDICTED ACTIVATION IN VISUAL AREA PREDICTED ACTIVATION IN FACE AREA

A Block Design

Adapting and Analyzing FMRI Tasks

• Experimental condition: the task is comprised of the specific cognitive variable of interest

• Control condition: the task is comprised of all features of the experimental task EXCEPT the specific cognitive variable of interest

• Subtract the magnitude of neural activation during the control task from neural activation during the experimental task

• Generate “activation maps” that are superimposed on brain images

Amygdala Activiation in Response to Fearful Faces

Genes:

Multiple

interacting

variants

Cells:

Subtle

molecular

alterations

Systems:

Disturbed interactions,

neural plasticity,

information processing

Psychiatric illness

Behavior:

Psychopathology,

Social integration,

treatment response

Temperament

Cognition

Neural mechanisms mediate between gene and behavior

Treatmentresponse

Social behavior

Imaging

Genetics

Genes - Brain Activity – Affective Disorders

• Gene: Serotonin Transporter (5-HTT)

The S allele of the serotonin

Transporter was

inconsistently associated

with affective and anxiety

disorders

The S allele of the serotonin transporter gene is associated

with greater right amygdala neuronal activity, as

assessed by BOLD functional magnetic resonance

imaging, in response to fearful stimuli, compared with

individuals the l allele

Hariri et al. Science 2002; 297, 400

Resting State

• Definition - Slow activity of the brain (frequency of <0.1 Hz) when the brain is ‘resting’- not performing any task.

• Can be identified by EEG or fMRI.

• In fMRI we search for brain regions that their resting state activity is synchronized (correlated)

• There are several systems that are ‘working’when the brain is resting:– Default Mode Network

– Alert

– Attention

– Visual

Resting states

• Acquisition - participants remain still and supine for 5 minutes, preferably with eyes open to minimize heterogeneity of arousal levels.

The Default Mode Network (DMN)

מדובר במערכת שמופעלת כשאנחנו ערים אך לא •

.ממוקדים בעולם בחוץ

מערכת זו מדוכאת כאשר אנחנו עוסקים בפעילות מכוונת •

מטרה ומגיבים לגירויים

חלימה , מבטאת למעשה פעולות כגון הרהורים DMN-ה•

.הזכרות בעבר, תכנונים לעתיד, בהקיץ

שנים לערך 10מזוהת באופן קונסיסטנטי רק החל מגיל •

:כוללת את האזורים הבאים•

Medial prefrontal cortex- for planning and ToM

Hippcampus- for memories

Posterior cingulate cortex- for integration

Percuneus, parietal areas

The DMN and Psychopathology

• In autism and in ADHD- failure to deactiviate

default network activity during cognitive tasks

• In schizophrenia- overactivity of the DMN

• In depression- hyperconnectivity of the DMN in

association to degree of rumination.

?מה הוא החזון

Eight-year-old Johnny can’t wait to climb into the scanner. His mother who has

been concerned about his poor school performance, disruptive

classroom behavior, and difficulties keeping friends tries to give him

one more kiss on the forehead, but he excitedly pulls away and hops up onto

the scanner bed. The imaging tech gives mom a reassuring smile, slides

Johnny into the large magnet, and shows Johnny how to work the video

game buttons that keep him occupied during the scan. Twenty minutes later

(all too short for Johnny), it’s time for him to come out again. His child psychiatrist

enters the adjoining consultation room and there explains to mom what the brightly-

colored blobs on the incredibly realistic, seemingly 3-dimensional images of

Johnny’s brain mean. No, there are no tumors, but compared with the International

Pediatric Brain Database, Johnny’s brain is

3.5% smaller than other boys his age, his cingulate cortex and caudate are

smaller than normal, and his cortical attention network is underactive. His diagnosis

of ADHD, combined type, is confirmed, and the child psychiatrist explains to mom

why a certain pattern of colored blobs on the scan indicates Johnny is more likely to

respond to one medication than another. Reassured, mom smiles, and they all go

back to the office to review the treatment plan.

Bush, Child Adolesc Psychiatric Clin N Am 2008; 17: 385–404

האיגוד הישראלי לפסיכיאטריה ביולוגיתבקיבוץ הגושרים, 2016, במרץ 8-10 -שיתקיים ב 20-מזמין לכנס השנתי ה

מרצים אורחים מהשורה הראשונה של הפסיכיאטריה הביולוגית ומחקר המוח בארץ ובעולם�

נוירולוגיה ומדעי המוח, וחידושים בפסיכיאטריה עידכונים�

מושבים מיוחדים אודות פיתוחים מדעיים של חברות הזנק ישראליות באבחונים ובטפולים �

משלבי טכנולוגיה

פרסים לעבודות מצטיינות במחקר קליני ובמחקר בסיסי�

פוסטרים אפשר להגיש ( 2015בנובמבר 10ולהרצאות לססיותמועד אחרון להגשת הצעות �

)גם לאחר מכן

SAVE THE DATE !

, ראובן גור' פרופ -הרצאת פתיחה•:פנסילבניה' אונראובן גור •

כיצד מדעי המוח יכולים להציל "

"רוצחים מעונש מוות

טייב נינטמופע של •

בלזיצמןומאיה

התחלת מחזור חדש של תוכנית •

צעירהמחקרית מנהיגות

ADHD-וטפול ב נוירובילוגיה•

ובמבוגרים,בית ספר , בגיל הגן

Doron Gothelf

Email: gothelf@post.tau.ac.il