E LECTROENCEPHALOGRAPHIC (EEG) COHERENCE STUDY OF WORKING MEMORY BRAIN OSCILLATIONS

1. ELECTROENCEPHALOGRAPHIC (EEG) COHERENCE STUDY OF WORKING MEMORY BRAIN OSCILLATIONS Dr. Simon Brežan Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia coauthors:Vita Štukovnik,Veronika Rutar,Jurij Dreo, Vito Logar, Blaž Koritnik, Grega Repovš, Blaž Konec, Janez Zidar INTERNATIONAL NEUROSCIENCE CONFERENCE, SINAPSA, LJUBLJANA 2005

2. WORKING MEMORY (WM) • memory processes: encoding, storage, recall • memory structure: sensory memory (attention)> short-term memory (rehearsal/replacement)> long-term memory • active role of short term memory – working memory- central for intelligent goal-directed behaviour, coherent thoughts, language etc. DEFINITION: complex of cognitive processes for time- and capacity- limited maintenance, manipulation and utilization of mental representations

3. MODEL OF WORKING MEMORY (BADDELEY, 2000) • central executive (CE): attentional control of subsystems, manipulation of information, planning, strategy selection, inhibition • slave subsystems: • phonological loop: 2 separated components: storage and rehearsal of verbal information • visuospatial sketchpad: separated storage and rehearsal of visual and spatial information • episodic buffer: integration of information from other subsystems and episodic long-term memory

4. NEUROPHYSIOLOGICAL AND NEUROANATOMICAL BASIS OF WORKING MEMORY NEUROPHYSIOLOGICAL VIEW • basic neurophysiological mechanism of WM: repeated reverberations of electrical impulses in reverberational (feedback) loops (Štrucl, 1999)? • repeated excitation of a synapse in excitational loop> increase of excitatory postsynaptic potential (EPSP) – postsynaptic facilitation. • postsinaptic facilitation – preservation/maintenance of specific information in WM? • role of active repeating?

5. NEUROANATOMICAL VIEW Cell electrophysiological and functional brain imaging studies (Fletcher and Henson, 2001, etc.) • various components of working memory: different anatomically separated neuronal networks • specific brain activity: • (pre)frontal (VLFC, DLFC, AFC) cortex • premotor cortex • limbic cortex and other subcortical structures • posterior association parietal areas • hypothetical lateralization of functions (Postle et al., 2000): • verbal information (phonological loop): left hemisphere • visuospatial information (visuospatial sketchpad): right hemisphere • central executive: heteromodal association cortex of (pre)frontal brain regions (Gathercole, 1999)?

6. BINDING PROBLEM • BINDING PROBLEM: The mechanisms for functional integration (‘binding’) of different brain areas, responsible for specific (WM) functions? • Paralell and distributed processing of information in the brain: • Functional integration - coupling (visual perception, complex motor patterns, visuo-motor integration, cognitive functions): key for understanding brain functioning • The code for functional coupling: synchronised oscillations of neuronal networks between anatomically separated brain areas? • Measure of synchronised brain oscillations: EEG coherence

8. ELECTROENCEPHALOGRAPHY (EEG), SIGNAL ANALYSIS: EEG COHERENCE AND POWER SPECTRA • EEG: repeated, periodic electrical activity of (pyramidal) cortical neurons • activity of many neurons (synaptic EPSPs, IPSPs) –ionic currents>field potentials, macropotential (EEG signal): • intrinsic qualities of neurons, dynamic interactions between neuronal networks- changing pattern of synchronization and desynchronization of regional brain cells- amplitude changes of specific frequencybands. • EEG - great time resolution (milisec), distinct patterns of activity • brain rhythms, frequency bands for oscillations (delta: 0,5-4 Hz, theta: 4-7 Hz, alpha: 8-13 Hz, beta: 13-30 Hz, gamma: 30-50 Hz) • specific functional, behavioral, spatial correlates- switching neural networks between different functional states- activating or inhibiting neural systems?

9. EEG COHERENCE AND POWER SPECTRA POWER SPECTRUM - degree of representation (power) of specific frequency band inthe signal; basic input data for coherence calculation > different levels of regional cortical activity or different level of regional synchronization-activation or inhibition of neural networks EEG COHERENCE – measure of degree of similarity, phase-locking (“synchronization”) of 2 distant signals for specific frequency band > different degrees of long-range synchronization of oscillations between separate cortical regions for specific frequency band measure of functional coupling – binding and communication between separated brain centers 2 different operational systems of the brain

10. Φxy(ω)- value of cross-correlation power spectrum of signals x, y Φxx(ω)- value of auto-correlation power spectrum of signal x Φyy(ω)- value of auto-correlation power spectrum of signal y Cxy(ω): coherence value between signals x and y

11. WORKING MEMORY AND SYNCHRONIZED BRAIN OSCILLATIONS – POWER SPECTRA AND EEG COHERENCE STUDIES synchronous oscillations- correlation with specific behavioural contexts and cognitive tasks – numerous studies The neurophysiological theory of (working) memory: • Brain oscillations in different frequency bands subserve specific (memory) functions and operate over different spatial scales. • Multiple superimposed synchronized (coherent) oscillations in different frequency bands with different spatial patterns and functional correlates govern specific mental functions.

12. EEG WORKING MEMORY STUDIES EEG COHERENCE changes • increases mainly in theta, alpha and gamma band(working memory processes) (Serrien et al., 2003; Sauseng et al., 2004; Sarnthein et al, 1998; Jensen et al., 2002, etc.) • changes of power spectra and coherence with different memory load(Gevins et al., 1997, Jensen, 2000, etc.) POWER SPECTRA changes • decrease in lower alpha band(non-specific effect of attention, mental effort)(Klimesch et al., 1998, etc.) • decrease in upper alpha band (correlate of semantic processing)(Basar et al., 2000, etc.) • or increase in alpha band(active inhibition of disturbing neural networks not needed for the memory task) (Klimesch et al., 1998, etc.) • increase in theta band: frontal midline theta rhythm (memory maintenance, attention, mental effort) (Klimesch et al.; Gevins et al. 1997, etc.,) • increase in gamma band (sensory, perceptional, attentional, working memory processes)(Jensen, 2000; Babiloni et al., 2004, etc.)

13. SPATIAL SCALES OF COHERENCE CHANGES IN WM TASKS • MAINLY (PRE)FRONTO- TEMPORO- PARIETAL INCREASES OF THETA, ALPHA COHERENCE • MAINLY FRONTOCENTRAL INCREASES OF THETA AND GAMMA OSCILLATIONS- POWER SPECTRUM INCREASES (FRONTAL MIDLINE THETA RHYTHM); THETA SOURCE?? • → INACCORDANCE WITH BADDELEY’S MODEL OF WM: SEPARATE SYSTEMS FOR STORAGE (POSTERIOR) AND ACTIVE MAINTENANCE, UPDATING OF INFORMATION (FRONTAL BRAIN AREAS) in modal specific subsystems • NEED FOR INFORMATION EXCHANGE, COOPERATION, FUNCTIONAL COUPLING BETWEEN ANTERIOR AND POSTERIOR BRAIN REGIONS • LONG RANGE- SLOW RHYTHMS, SHORT RANGE- FAST RHYTHMS • TOP-DOWN CONTROL- CENTRAL EXECUTIVE

14. OUR STUDY OF WORKING MEMORY AND BRAIN OSCILLATIONS AIM • To examine the neurophysiological mechanisms of working memory processes • To investigate task-related coherence (and power spectra) changes for different EEG frequencies during the processes of working memory • Search for possible differences in coherence (and power spectra) changes between maintenance and manipulation processes in working memory. HYPOTHESES • Increases in fronto-posterior coherence in working memory tasks • Increases in bilateral (pre)frontal coherence for manipulation vs. maintenance-only processes of working memory (prefrontal central executive?)

15. METHODS PARTICIPANTS • 11 healthy right-handed volunteers (4 males, 7 females); informed consent, aged between 20-35 • average number of set repetition per each task/person= 38 • 10 min training of paradigm before recording EEG RECORDING • Dark quiet room, projection of different tasks on computer screen- cca. 80 cm from the eyes • EEG cap (E1-S Electro-Cap) - 29 electrodes, standard 10-20 International electrode system with extra electrodes: Fp1, Fp2, Fz, FCz, Cz, CPz, Pz; impedance below 5kΩ • EEG aparat: Medelec (Profile Multimedia EEG System, version 2.0, Oxford Instruments Medical Systems Division, Surrey, England) • EOG measurement (6 additional eye electrodes, Croft 2000)- 20 min calibration task • Synchroniztation signal between 2 computers • Presentation software for paradigm programming

17. COGNITIVE WM PARADIGM Modified Sternberg paradigm of working memory CONTROL + 2 EXPERIMENTAL CONDITIONS: • alternating the type of task coincidentaly during recording sessions! “WAIT”: control task with ‘no’ memory demands (ignore the set, fixate the cross, relax) TASK: matching the serial position of goal stimulus with simultaneosly presented set of letters SET (M, D, O) TASK instruction (WAIT) FIXATION (5500ms) GOAL (3 D) ANSWER (NO) ANALYSIS! SET (M D O) “MEMORIZE”: rehearsal (retention) of information in WM TASK: matching the serial position of goal stimulus with rehearsed originally presented set SET (F, J, C, I, Z) TASK instruction (MEMORIZE) RETENTION (5500ms)GOAL (1 F) ANSWER (YES) ANALYSIS! “REORDER”: manipulation and rehearsal (retention) of information in WM TASK: matching the serial position of goal stimulus with alphabetical order of presented set SET (K, C, M, A) TASK instruction (REORDER) RETENTION (5500ms)GOAL (2 M) ANSWER (NO) ANALYSIS!

18. DATA ANALYSIS • Special independent computer programmes were designed for coherence and power spectra analysis: • Borland Delphi 7.0 (with EOG artefact correction- modified Croft correction procedure) and Matlab software (no EOG correction) • .edf conversion of EEG recordings • Analysis of 5500ms retention/fixation periods in all 3 types of tasks, selection of artefact-free epochs

19. Borland Delphi 7.0 data analysis • Our analytical procedure • Measuring EEG volatage and recording them in .EDF files • Correcting EEG voltages with the RAAA EOG correction method • Dividing the 5 secod retention periods for all sets of every task into five 1 second periods. • Transforming the time-domain EEG signal of all five 1 second periods into a frequency-domain signal via a Fast Fourier Transform alghoritm. • Averaging the frequency-domain EEG signals for all five 1 second periods for every set of every task to obtain the Average-frequency-domain signal for that set of that task for each person. • Calculating Power-Spectra and Coherence for every set of every task for each person. • Averaging of Power-Spectra and Coherence for every task from all the sets in that task for every person. Thus obtaining the Average-task PS and C for every person. • Averaging of Power-Spectra and Coherence for all persons for every task Thus obtaining the Average-person PS and C. • Averaging the Power-Spectra and Coherence in the desired frequency bands. Thus obtaining the Average-band PS and C that are displayed in our results. • Optionally comparing Average-band PS and C for two different tasks.

21. Statistical analysis • To calculate the border coherence-difference values that are significant at desired p-levels we created from 50.000 to 100.000 (depending on the frequency band) randomly distributed simulated EEG measurements that fit our experimental design exactly: • a total of 11 people, 4 with 56 sets per person, 7 with 28 sets of one task per person • per each set an average of five 1 second retention periods • a 1 Hz resolution in the Fourier transform • From these simulations we obtained a sampling distribution curve that fits our experiment design as accurately as possible. The border-coherence values that are significant at desired p-levels were then estimated through a two-tailed t-test by calculating the area under the sampling distribution curve that fits the desired p-level. • FB 1: Delta (1-4 Hz), Theta (4-7 Hz), Alpha 1 (7-10 Hz), Alpha 2 (10-13 Hz) • FB 2: Beta (13-30 Hz) • FB 3: Gamma (30–50 Hz)

22. RESULTS • Increases and decreases of coherence for different frequency bands with differences between 3 tasks will be showed: only for statistical significance p < 0.1 FOR ALL IMAGES • New schematic model of the head with coherence value TASK DIFFERENCES presented • Colour scale: warm colours- coherence increases between electrodes cold colours- coherence decreases between electrodes

23. COHERENCE CHANGESMEMORIZE VS. WAIT (CONTROL) TASK (P < 0.1) ALPHA 1 EXPLAINATION OF SCHEME! • (Pre)fronto-central • fronto-parietal • fronto-occipital increases • Interhemispheric bitemporal increases • Temporo- parietal increases

24. MEMORIZE VS. WAIT ALPHA 2 • Fronto-central increases • interhemispheric frontotemporal increases • fronto-parieto-occipital increases • Temporo-parietal increases

25. MEMORIZE VS. WAIT GAMMA Less intensive increases, dominant: • fronto-parietal • fronto-temporal • fronto-central increases

26. MEMORIZE VS. WAIT THETA • Fronto- central increases • Fronto- occipital increases • Interhemispheric bitemporal increases • Frontotemporo-parietooccipital increases

27. REORDER VS. WAIT ALPHA 1 • (pre)fronto-centro-parietal increases • temporo- central • interhemisheric bitemporal • parieto-occipital increases

28. REORDER VS. WAIT ALPHA 2 • Prefronto-central increases • Fronto-centro-parietal • Fronto-temporal • Centro-temporal • Interhemispheric bitemporal • Temporo-occipital

29. REORDER VS. WAIT GAMMA Less intensive but • simmilar pattern of coherence increases

30. REORDER VS. WAIT THETA • Fronto-central • Fronto-parietal • Frontotemporo-occipital increases

31. REORDER VS. MEMORIZE ALPHA 1 • Centro-temporal increase • Occipito-temporal increase • Decreases of coherence

32. REORDER VS. MEMORIZE ALPHA 2 • Fronto-central • Fronto-temporo-parietal • Parieto-occipital increases • Interhemispheric bitemporal increases • Decreases of coherence

33. REORDER VS. MEMORIZE GAMMA Less intensive increases Prefronto-centro-parieto-occipital axis increases

34. REORDER VS. MEMORIZE THETA Mainly • (Pre)fronto-parietooccipital axis increases

35. ADDITIONAL DATA ANAYLSIS AND DIFFERENT WAY OF DATA PRESENTATION //MATLAB SOFTWARE (no EOG correction) • The influence of EOG correction procedures on EEG coherence? >>SIMMILAR TRENDS IN COHERENCE VALUES Memorise vs. wait task THETA coherence changes

36. Reorder vs. wait task THETA coherence changes

37. Reorder vs. memorize task THETA coherence changes

38. SUMMARY OF RESULTS • WM TASKS: COHERENCE INCREASES MAINLY IN ALPHA 2, ALPHA 1, THETA (AND ALSO GAMMA) FREQUENCY BANDS • FOR MEMORIZE (WM MAINTENANCE) VS. WAIT (CONTROL) TASK • FOR REORDER (WM MANIPULATION) VS. WAIT (CONTROL) • SPATIAL SCALES OF INCREASES: MAINLY FRONTO-POSTERIOR, FRONTOTEMPORAL, BITEMPORAL LONG- RANGECONNECTIONS IN THE BRAIN • REORDER (WM MANIPULATION) VS. MEMORIZE (MAINTENANCE-ONLY): COHERENCE INCREASES MAINLY IN ALPHA2 AND THETA BAND • SPATIAL SCALES:ALSO ANTERIO-POSTERIOR BRAIN AXIS, BITEMPORAL INTERHEMISPHERICALLY, BUT NO (PRE)FRONTAL INTERHEMISHERIC INCREASES • DECREASES OF COHERENCE– OTHER AREAS

39. INTERPRETATION OF RESULTS • Greatest coherence (synchronization) increases -retention WM periods in ALPHA AND THETA(and gamma) frequency bands • widespread fronto-parietal association brain areas involved- in accordance with other studies and Baddeley’s model of WM!+ • temporal interhemispheric connections? • Different EEG frequencies appear to have different functional correlates? • LIJ (Lisman, Idiart, Jensen, 1998) WM MODEL!!! • The increased theta coherence-working memory processes (storage, rehearsal and scanning) • Alpha band directly involved in memory processes or reflects increased mental effort, attention? Role not known yet, results contradictive in different studies • Gamma band is believed to be correlated with sensory processing and the very content of information processing, but could also reflect increased attentiveness.

40. LATERALIZATION? Verbal memory tasks seem to activate primarly left brain hemisphere, but visuospatial memory tasks activate predominantly right brain hemisphere- we didn’t demonstrate significant lateralization patterns! possible reasons?volume conduction, low spatial resolution, visuospatial strategies The neuronal synchronization (increased coherence)– functional coupling role in interaction of posterior association cortex (where sensory information is stored), and (pre)frontal cortex, where relevant current information is held, rehearsed and updated (Baddeley’s model, phonological loop) Decreases of coherence: functional decoupling of disturbing processes, selective attention?

41. Manipulation- CE function • We found increases of coherence in fronto- parietal loops also compared to memorize only • Central executive also demands funtional integration of anterio-posterior neural circuits- brain regions and not primarily prefrontal interhemispheric communication? • Role of interhemispheric connections in temporal brain regions (alpha 2- semantic memory?)

42. LIJ NEUROPHYSIOLOGICAL MODEL OF WORKING MEMORY (Lisman, Idiart and Jensen, 1998) Figure --. Concept of LIJ working memory model. Three memory items (A, B, C) are loaded in memory buffer, the theta period increases by one gamma period with each item added. In retention interval (delay period), items are maintained by activity-dependent intrinsic properties of the neurons coding these items. After probe presentation the items can be scanned – compared with the probe as they are activated. After scanning, motor response and answer can be initiated. RT – reaction time

43. Figure --. LIJ model as a multi-item short-term memory buffer. Theta and gamma oscillations play an important role in the concept. An afterdepolarization (ADP) is triggered after a cell fires (sensory input) and it causes depolarizing ramp that serves to trigger the same cell to fire again after delay. These ramps are temporarily offset for different memories, an offset that causes different memories to fire in different gamma cycles. The key function of this buffer is to perpetuate the firing of cells in a way that retains serial order. The repeat time is determined by theta oscillations due to external input. Gamma oscillations arise from alternating global feedback inhibition and excitation (the cell with most depolarized ramp will fire again) because of separate firing of different memory codes.

44. DISCUSSION – CRITICAL APPROACH • BETTER STATISTICAL SIGNIFICANCE?- PROBLEM OF CONTROL- WAIT TASK (absolute coherence values!): spontaneous non-intentional memory set repetition?- encoding before instruction; inhibitory instruction context (WM?), ‘working space’ preparation; resting state correlated networks? • PROBLEM OF VOLUME CONDUCTION- electrical charge flow> voltage/ signal masking effect • INFLUENCE OF EOG CORRECTION PROCEDURE? • LOW SPATIAL RESOLUTION IN EEG, occipital-parietal transfer of signal, interhemispherically? NO LATERALIZATION IN VERBAL TASK? • ELECTROMAGNETIC INFLUENCES, OTHER ARTEFACTS- SIGNAL TO NOISE RATIO

45. FUTURE PERSPECTIVES • ‘LAPLACE’ CORRECTION (Nunez) FOR VOLUME CONDUCTION • ADDITION OF NEW ‘PURELY’ SENSORY-PERCEPTIVE CONTROL TASK • ELECTRODE POSITIONING DETERMINATION • HIGHER SAMPLING RATE • choosing appropriate cognitive paradigms and neuropsychological tests- possible to study physiological and patophysiological aspects of cognitive, motor and sensory brain function!!! • new future perspectives for possible search of patophysiological mechanisms and etiological factors contributing to many different neurological diseases!

46. MAIN REFERENCES Baddeley, A. (2000). The episodic buffer: a new component of working memory? Trends in cognitive science, 4(11), 417-423. Jensen O, Tesche CD (2002). Frontal theta activity in humans increases with memory load in a working memory task.. Eur J Neurosci. 2002;15(8):1395-9. Jensen, O. in Lisman, J.E. (1998). An oscillatory short-term memory buffer model can account for data on the Sternberg task. The journal of neuroscience, 18(24), 10688-10699. Babiloni, C., Carducci, F., Vecchio, F., Rossi, S., Babiloni, F., Cincotti, F., Cola, B., Miniussi, C. in Rossini, P.M. (2004). Functional frontoparietal connectivity during short-term memory as revealed by high resolution EEG coherence analysis. Behavioral neurosciencies, 118(4), 687-697. Klimesch W. Memory processes, brain oscillations and EEG synchronization. Internal journal of psychophysiology (1996); 24: 6-100. Klimesch, W., Doppelmayr, M., Schwaiger, P. Auinger in Winkler, Th. (1999). „Paradoxical“ alpha synchonisation in memory task. Cognitive brain research, 7, 493-501. Sarnthein, J., Petsche, H., Rappelsberger, P., Shaw, G.L. in von Stein, A. (1998). Synchronization between prefrontal and posterior association cortex during human working memory. Neurobiology, 95, 7092-7096. Sauseng, P., Klimesch W., Doppelmayr, M., Hanslmayr, S., Schabus, M. in Gruber, W.R. (2004). Theta coupling in the human electroencephalogram during a working memory task. Neuroscience letters, 354, 123-126. Serrien, D.J., Pogosyan A.H. in Brown, P. (2003). Influence of working memory on patterns of motor related cortico-cortical coupling. Experimental brain research. Dostopno na spletni strani Stam, C.J., van Cappellen van Walsum, A.M. in Micheloyannis, S. (2002). Variability of EEG synchronization during a working momory task in healthy subjects. International journal of psychophysiology, 46, 53-66.

47. ABSOLUTE VALUES OF THETA COHERENCE-WAIT VS. MEMORIZE TASK

48. ABSOLUTE VALUES OF THETA COHERENCE- WAIT VS. REORDER TASK