Harvard Medical School Beth Israel Deaconess Medical Center

Boston, MA

Robert Stickgold

Some of the work presented here was sponsored by Sepracor, Inc.

Sleep, Memory and Dreams:

Putting It All Together

OHSU Brain Institute, Portland OR April 2017

Today’s Outline

1) The physiology of sleep

2) The diversity of memory evolution

a) Stabilization and enhancement

b) Selection, gist, rules and insight

3) Sleep, memory and dreams

4) Sleep and psychiatric disorders

The Physiology and

Chemistry of the Brain

Change Across the

Night

A Good Night’s Sleep

11 PM 1 AM 3 AM 5 AM 7 AM

Wake

I/REM

II

III

IV Stage 2 NREM

SWS

REM sleep

Sleep Physiology

EEG Wake

Stage 2

Stage 4

REM 2 sec

EOG Stage 1

Stage 2

REM

EMG Wake

Stage 4

REM

Neuromodulation Varies Across

the Wake-Sleep Cycle

Active Wake

ACh

NE 5-HT

Quiet Wake

REM SWS

Ach: Atropine (belladonna) and scopolamine

NE: MAO inhibitors, cocaine

5-HT: SSRI’s, LSD

Regional Activation in REM Sleep

Sleep Balances

Emotional Memories

• Peter Hu

• Matt Walker

Emotional Words

Emotional Memory After Sleep Deprivation

Sleep

No Sleep

Neutral,

Negative,

Positive

Negative Stimuli

amygdala

mOFC

Yoo et al. (2007) Curr Biol 17, R877-878

Emotional Memory After Sleep Deprivation

No Sleep Sleep Sleep

Sleep Sleep Sleep

encoding test

M

em

ory

Recognitio

n

neutral negative positive

Deprived

Sleep

Emotional Memory After Sleep Deprivation

Sleep and

Memory Evolution

Stabilization & Enhancement

• Matthew Walker

• Tiffany Brakefield

• Alexandra Morgan

1 2 3 4

Sequence

4-1-3-2-4

Sleep Enhances

Procedural Learning

• Matthew Walker

• Tiffany Brakefield

• Alexandra Morgan

1 2 3 4

Sequence

4-1-3-2-4

Sleep Enhances

Procedural Learning

Learning Rate Saturates Rapidly

10 PM

10 AM

1

Post-training Baseline Training Trials

(lasting 12 mins)

2 3 4 5 6 7 8 9 10 11 12

12

# S

eq

uen

ces /

30 s

ec

16

20

24

Walker et al. Neuron 35, 205 (2002)

10PM

p<0.0001

SLEEP

10AM 10PM 20

22

24

26

28

# S

eq

uen

ces /

30 s

ec

10AM 20

22

24

26

28

n.s.

Walker et al. Neuron 35, 205 (2002)

Motor Sequence Learning

Sleep and

Memory Evolution

Salience, Gist, Rules, Insight (four examples)

Sleep Consolidates Emotional Memory

• Jessica Payne

• Elizabeth Kensinger

Emotional Trade-Off

30 min

100

90

80

70

60

50

Neutral Emotional

Item

s R

ecogniz

ed (

%)

30 min

Emotional Trade-off

Objects

Backgrounds

0

-4

-8

-12 Change fro

m 3

0 m

in (

%)

Neutral Scenes

Changes Over 12 Hr Wake or Sleep

Objects

Backgrounds

12 hr wake

Emotional Scenes

12 hr sleep

12 hr wake

12 hr sleep

n.s. n.s.

Sleep Consolidates Episodic

Declarative Memory

• Jessica Payne

• Ruth Propper

Word Lists Door House Ledge

Glass Open Breeze

Pane Frame Curtain

Shade View

Verbal Memory Task

nurse sick lawyer medicine health hospital dentist physician ill patient office stethoscope table doctor cotton

nurse

sick

lawyer

medicine

health

hospital

dentist

physician

ill

patient

office

stethoscope

+

D-R-M: 12-Hour Deterioration

15

0

-15

-30

-45

-60 Studied words

Gist words

*

% C

hange (

rela

tive t

o 2

0 m

in

Wake

Sleep

*

Payne et al., Neurobiol Learn Mem 92, 327 (2009)

Weather Prediction Task

• Ina Djonlagic

• Andy Rosenfeld

• Murray Barsky

Sleep Enhances Rules

?!?

Probabilistic Learning

Card 1 Card 2 Card 3 Card 4

80% 60% 40% 20%

Djonlagic et al., Learn Mem 16, 751 (2009)

Sleep Enhances Performance

0

2

4

6

8

10

12

14

p = 0.01

Observation

Impro

vem

ent

(% o

f tr

ials

)

Wake

Sleep

Djonlagic et al., Learn Mem 16, 751 (2009)

Sleep Enhances Insight

Number Reduction Task

1 1 4 4 9 4 9 4

1 4 4 1 9 9 1

• Ulrich Wagner

• Jan Born

Wagner et al. (2004) Nature 427: 352

Development of Insight

Wake/ Night

Wake/ Day

Sleep/ Night

0%

20%

40%

60% S

ub

jec

ts g

ain

ing

in

sig

ht

1 1 4 4 9 4 9 4

1 9 1 4 4 1 9 9

Sleep, Memory and

Dreams

New Experiences are Replayed

at Sleep Onset Hypnagogic dreams

• April Malia

• Denise Maguire

• David Roddenberry

• Karen Emerge

• Laura Babkes

Hypnagogic Images of Tetris

Group (n) Nights % Ss % Rpts

Novices 2 75% 10.4%

Experts 2 or 3 50% 4.7%

Reports of Tetris Imagery

“Just seeing Tetris shapes floating around in my head like

they could in the game, falling down, sort of putting them

together in my mind” (JEG - Day 2)

NOVICE

“…seeing in my mind how the game pieces kind of float

down and fit into the other pieces and am also rotating

them” (TRP - Day 2)

EXPERT

Amnesiacs 3 60% 7.4%

Hypnagogic Images of Tetris

Group (n) Nights % Ss % Rpts

Novices 2 75% 10.4%

Experts 2 or 3 50% 4.7%

Reports of Tetris Imagery

“Just seeing Tetris shapes floating around in my head like

they could in the game, falling down, sort of putting them

together in my mind” (JEG - Day 2)

NOVICE

“…seeing in my mind how the game pieces kind of float

down and fit into the other pieces and am also rotating

them” (TRP - Day 2)

EXPERT

“I see images that are turned on their side. I don’t know

what they are from, I wish I could remember, but they’re

like blocks” (JEG - Day 2)

AMNESIAC

Dream Content Predicts

Sleep-Dependent Consolidation

NREM Napping

• Erin Wamsley

• Matt Tucker

NYTime.com April 22, 2010

± NREM

Nap

12 pm 2 4 6 pm

Train Test

WAKE (n=16)

SLEEP (n=16)

-100

Impro

vem

ent

(sec)

150

100

50

0

-50

p=.01

Wamsley et al. Curr Biol 20, 850 (2010)

± NREM

Nap

12 pm 2 4 6 pm

Train Test

WAKE SLEEP

REPORTS

p=0.0003

WAKE (n=16)

SLEEP (n=16)

-100

Impro

vem

ent

(sec)

150

100

50

0

-50

p=.01

n.s.

Not maze related

Maze related

0

100

200

300

400

Impro

vem

ent

(sec)

Wamsley et al. Curr Biol 20, 850 (2010)

n.s.

SLEEP WAKE

Not maze related

Maze related

0

100

200

300

400

Impro

vem

ent

(sec)

Quiet wakefulness

“I was thinking about the game that I used to play in high school, “Counter-Strike”, because of the same layout . . . and also I was just planning, and trying to remember the maze and trying to figure out the route”

“ . . . thinking [about] what we have to do in the second maze test . . . wondered if it was going to be, like, the same . . .”

Dream reports

“I was thinking about the maze and kinda having people as check points, I guess, and then that led me to think about when I went on this trip few years ago and we went to see these bat caves, and they're kind of like, maze-like”

“Looking for something” in a maze

“Just hearing the music” from the task

Quiet wakefulness (useful?)

Dream reports (useless?) p=0.0003

Wamsley et al. Curr Biol 20, 850 (2010)

• Stabilization and enhancement

• Salience selection

• Rule and gist extraction

• Network integration

Imagined scenarios

Narrative development

Future projection

Sleep-Dependent Memory Processing:

A Whole-Brain Process

DREAMING

Hippocampus

Neocortex

Sleep & Psychiatry Schizophrenia and PTSD

Sleep-Dependent Learning

is Impaired in Schizophrenia

(Study funded by Sepracor & Co.)

• Dara Manoach

• Erin Wamsley

• Ann Shinn

• Donald Goff

Motor Skill Learning in Chronic Schizophrenia

Manoach et al. Biol Psychiatry 56, 951 (2004)

9

11

13

15

17

19

21

2 4 6 8 10 12 2 4 6 8 10 12

Trials

# S

equences / 3

0 s

ec (

contr

ols

)

4

6

8

10

12

14

16

# S

equences / 3

0 s

ec (S

Z)

Stage 2 NREM Spindles in

SZ and Controls

Controls SZ

2.0

1.5

1.0

0.5 Sp

ind

le d

en

sit

y (

min

-1)

p < .0001)

Manoach et al. Biol Psychiatry 56, 951 (2004)

Spindle Sigma Power

Wamsley et al. Sleep 36, 1369 (2013)

Impact of Eszopiclone

Over

nig

ht

Impro

vem

ent

(%)

5

0

10

15

20

25

30

*

baseline baseline placebo

*

eszopiclone

Controls Schizophrenia patients

Wamsley et al. Sleep 36, 1369 (2013)

Spindle Sigma Power

Wamsley et al. Sleep 36, 1369 (2013)

Improvement and Stage 2 NREM

0%

60%

40%

20%

-20%

20 40 60 80 100

% Stage 2 NREM sleep – 4th Quarter

% Initia

l im

pro

vem

ent

SZ pts w/ eszopiclone

Young controls

PTSD

A Disorder of Sleep-Dependent

Memory Evolution

PTSD – What is it?

Stickgold (2002) J Clin Psychol 58, 61–75

Traumatic

Event Trauma

Memory

PTSD

Stasis

Sleep!

Trauma

Resolution Processing

? (the therapist’s job!)

Trauma Resolution and

Sleep-Dependent Memory Evolution

The normal resolution of trauma requires:

• Normalizing emotional memories

• Separating emotions from their contexts

• Extracting gist representations and rules

• Integrating the trauma memory with older

memories

• Gaining insight

Stickgold (2002) J Clin Psychol 58, 61–75

This memory processing occurs preferentially in

REM sleep, which guide the evolution of

memories over time

PTSD – A Failure of Sleep-Dependent

Memory Evolution

When processes involved in the normal sleep-

dependent evolution of trauma memories fail,

PTSD may inevitably follow.

Stickgold (2002) J Clin Psychol 58, 61–75

• Sleep plays a critical role in the evolution of memories, stabilizing and strengthening them.

• But it also identifies, analyzes, and maintains our most important memories, finding patterns in them, extracting gist and facilitating insight.

• Disruption of these processes may contribute to psychiatric disorders, including SZ and PTSD.

Summary

But perhaps more importantly, these

systems carry out what may well be the

most sophisticated function that the

human brain performs – the building of

models of ourselves and our world,

providing clues to the course of our future

and creating the very meaning of our

lives.